Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5 Άγιος Νικόλαος
Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com

Αρχειοθήκη ιστολογίου

! # Ola via Alexandros G.Sfakianakis on Inoreader

Η λίστα ιστολογίων μου

Τρίτη 29 Αυγούστου 2017

How Short is Short, and Why? A Probable Case of Proportionate Dwarfism from Egypt's 3rd Intermediate Period in the Dakhleh Oasis, Egypt

Abstract

This study describes a probable proportionate dwarf from a Third Intermediate Period cemetery at Ain Tirghi in the Dakhleh Oasis, Egypt. The skeleton (Burial 22 or B22) is an adult female estimated to be in her mid to late thirties. Most medical literature defines an adult stature of 2 standard deviations below the population mean as an indicator for clinically short stature, with some bioarchaeologists and clinicians identifying severe short stature at 3 standard deviations below the population mean. B22 satisfies either criteria when compared with the Ain Tirghi adult female population mean for measurements of the radii and femora, as well as the summed measurements of the femora and tibiae. Her limb proportions were normal and this, with a lack of morphological abnormalities, eliminated several possible causes of small stature (e.g. achondroplasia). The differential diagnosis for an individual with short stature and normal proportions indicates that she represents a probable case of pituitary dwarfism, or hypopituitarism. B22 was buried in the same fashion as adjacent burials in a family group burial and showed no differential indication of physiological stress or illness. Contextualized with the Egyptological and archaeological evidence of dwarfism in Egypt, this case study considers the social perceptions of dwarfism in ancient Egypt and suggests that pituitary dwarfs, like disproportionate dwarfs, likely led normal, if not privileged lives. Therefore, according to the social theory of disability, B22 was not necessarily disabled despite her impairment.



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Erratum to: The Future of Periodontal-Systemic Associations: Raising the Standards



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Authors' Reply: "Organ Transplantation in Australia: Inequities in Access and Outcome for Indigenous Australians".

No abstract available

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Organ Transplantation in Australia: Inequities in Access and Outcome for Indigenous Australians.

No abstract available

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Lung Retransplantation: Practical and Ethical Considerations Raised by the Hannover Protocol.

No abstract available

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The Organization of Working Memory Networks is Shaped by Early Sensory Experience

Abstract
Early deafness results in crossmodal reorganization of the superior temporal cortex (STC). Here, we investigated the effect of deafness on cognitive processing. Specifically, we studied the reorganization, due to deafness and sign language (SL) knowledge, of linguistic and nonlinguistic visual working memory (WM). We conducted an fMRI experiment in groups that differed in their hearing status and SL knowledge: deaf native signers, and hearing native signers, hearing nonsigners. Participants performed a 2-back WM task and a control task. Stimuli were signs from British Sign Language (BSL) or moving nonsense objects in the form of point-light displays. We found characteristic WM activations in fronto-parietal regions in all groups. However, deaf participants also recruited bilateral posterior STC during the WM task, independently of the linguistic content of the stimuli, and showed less activation in fronto-parietal regions. Resting-state connectivity analysis showed increased connectivity between frontal regions and STC in deaf compared to hearing individuals. WM for signs did not elicit differential activations, suggesting that SL WM does not rely on modality-specific linguistic processing. These findings suggest that WM networks are reorganized due to early deafness, and that the organization of cognitive networks is shaped by the nature of the sensory inputs available during development.

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Denser Growing Fiber Connections Induce 3-hinge Gyral Folding

Abstract
Recent studies have shown that quantitative description of gyral shape patterns offers a novel window to examine the relationship between brain structure and function. Along this research line, this paper examines a unique and interesting type of cortical gyral region where 3 different gyral crests meet, termed 3-hinge gyral region. We extracted 3-hinge gyral regions in macaque/chimpanzee/human brains, quantified and compared the relevant DTI-derived fiber densities in 3-hinge and 2-hinge gyral regions. Our observations consistently showed that DTI-derived fiber densities in 3-hinge regions are much higher than those in 2-hinge regions. Therefore, we hypothesize that besides the cortical expansion, denser fiber connections can induce the formation of 3-hinge gyri. To examine the biomechanical basis of this hypothesis, we constructed a series of 3-dimensional finite element soft tissue models based on continuum growth theory to investigate fundamental biomechanical mechanisms of consistent 3-hinge gyri formation. Our computational simulation results consistently showed that during gyrification gyral regions with higher concentrations of growing axonal fibers tend to form 3-hinge gyri. Our integrative approach combining neuroimaging data analysis and computational modeling appears effective in probing a plausible theory of 3-hinge gyri formation and providing new insights into structural and functional cortical architectures and their relationship.

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Structural Connections of Functionally Defined Human Insular Subdivisions

Abstract
The organization of the human insular cortex has traditionally been considered as an anterior–posterior dichotomy, where anterior and posterior subdivisions have unique structural and functional connections. However, recent functional neuroimaging research proposes a tripartite organization where insular subdivisions have both unique and overlapping functional profiles. Studies examining unique profiles show that the dorsal anterior insula (dAI) has connections with frontal areas supporting higher-level cognitive processes, the ventral anterior insula (vAI) has connections with limbic areas supporting affective processes, and the posterior insula (PI) has connections with sensorimotor areas supporting interoceptive processes. Studies examining overlapping profiles demonstrate that all 3 subdivisions can also have similar functional profiles. The structural organization supporting a functional tripartite insula organization presenting with overlapping and unique connections is currently unknown. We used a large HARDI diffusion magnetic resonance imaging (MRI) dataset (n = 199) to demonstrate novel visualizations of insula white matter tracts supporting a tripartite structure–function insula organization. Overlapping connections of all 3 insula subdivisions consisted of association pathways (inferior fronto-occipital fasciculus, uncinate fasciculus, arcuate fasciculus) while unique connections included the corona radiata, subcortical-cortical tracts, and horizontal and u-shaped tracts. These results generally support a tripartite structure–function organization of the insular cortex, with subdivisions that exhibit both overlapping and unique connectivity profiles.

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Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura

Publication date: Available online 30 August 2017
Source:Developmental Cell
Author(s): Max A. Tischfield, Caroline D. Robson, Nicole M. Gilette, Shek Man Chim, Folasade A. Sofela, Michelle M. DeLisle, Alon Gelber, Brenda J. Barry, Sarah MacKinnon, Linda R. Dagi, Jeremy Nathans, Elizabeth C. Engle
Dural cerebral veins (CV) are required for cerebrospinal fluid reabsorption and brain homeostasis, but mechanisms that regulate their growth and remodeling are unknown. We report molecular and cellular processes that regulate dural CV development in mammals and describe venous malformations in humans with craniosynostosis and TWIST1 mutations that are recapitulated in mouse models. Surprisingly, Twist1 is dispensable in endothelial cells but required for specification of osteoprogenitor cells that differentiate into preosteoblasts that produce bone morphogenetic proteins (BMPs). Inactivation of Bmp2 and Bmp4 in preosteoblasts and periosteal dura causes skull and CV malformations, similar to humans harboring TWIST1 mutations. Notably, arterial development appears normal, suggesting that morphogens from the skull and dura establish optimal venous networks independent from arterial influences. Collectively, our work establishes a paradigm whereby CV malformations result from primary or secondary loss of paracrine BMP signaling from preosteoblasts and dura, highlighting unique cellular interactions that influence tissue-specific angiogenesis in mammals.

Graphical abstract

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Teaser

By characterizing dural cerebral vein malformations in TWIST1 mutation-positive humans and mouse models with craniosynostosis, Tischfield et al. report that cerebral vein angiogenesis requires paracrine BMP signaling from skull preosteoblasts and periosteal dura. The effects are independent from arterial influences and highlight unique cellular interactions that pattern tissue-specific vascular networks.


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Chromosome biology: Different turfs for cohesin and condensin

Nature Reviews Genetics. doi:10.1038/nrg.2017.71

Author: Eytan Zlotorynski



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Model organisms: New tools, new insights — probing social behaviour in ants

Nature Reviews Genetics. doi:10.1038/nrg.2017.70

Author: Dorothy Clyde



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Genetic engineering: Pigs without PERVs

Nature Reviews Genetics. doi:10.1038/nrg.2017.73

Author: Linda Koch



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Beyond editing to writing large genomes

Nature Reviews Genetics. doi:10.1038/nrg.2017.59

Authors: Raj Chari & George M. Church



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Treatment of cutaneous iatrogenic Kaposi sarcoma with topical timolol



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Issue Information - JEB



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Neutrophilic dermatosis of hands preceding extensive small cell lung cancer



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Issue Information - TOC



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Treatment of cutaneous iatrogenic Kaposi sarcoma with topical timolol



http://ift.tt/2vIkfGe

Issue Information - JEB



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Neutrophilic dermatosis of hands preceding extensive small cell lung cancer



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Issue Information - TOC



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Range expansion potential of two co-occurring invasive vines to marginal habitats in Turkey

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Publication date: October 2017
Source:Acta Oecologica, Volume 84
Author(s): Shahid Farooq, Sonnur Tad, Huseyin Onen, Hikmet Gunal, Ugur Caldiran, Cumali Ozaslan
Niche distribution models accurately predict the potential distribution range of invasive plants into new habitats based on their climatic requirements in the native regions. However, these models usually ignore the marginal habitats which can limit the distribution of exotic plants. We therefore tested the seedling survival, growth and nutrient acquisition capabilities of two co-occurring invasive vines [Persicaria perfoliata (L.) H. Gross and Sicyos angulatus L.] in three different manipulative greenhouse experiments to infer their range expansion potential to marginal habitats in Turkey. First experiment included five different moisture availability regimes (100, 75, 50, 25 and 12.5% available water), second experiment consisted of four different salinity levels (0, 3, 6 and 12 dSm−1 soil salinity) and third experiment had four different soil textures (clay-1, clay-2, sandy loam and silt-clay-loam). Seedling mortality was only observed under extreme moisture deficiency in both plant species, while most of the transplanted seedlings of both species did not survive under 6 and 12 dSm−1 salinity levels. Soil textures had no effect on seedling survival. POLPE better tolerated low moisture availability and high salinity compared to SIYAN. Biomass production in both plant species was linearly reduced with increasing salinity and moisture deficiency. SIYAN invested more resources towards shoot, accumulated higher K and P, whereas POLPE maintained higher root-to-shoot ratio under all experimental conditions. Both plant species employed different strategies to cope with adverse environmental conditions, but failed to persist under high soil salinity and moisture deficiency. Our study suggest that both plant species have limited potential of range expansion to marginal habitats and will be limited to moist and humid areas only. Therefore, further research activities should be concentrated in these regions to develop effective management strategies against both species.



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Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research

Publication date: February 2018
Source:Current Opinion in Neurobiology, Volume 48
Author(s): J Elliott Robinson, Viviana Gradinaru
Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits.

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Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

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Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Claire Jacob
Gene regulation is essential for cellular differentiation and plasticity. Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), develop from neural crest cells to mature myelinating SCs and can at early developmental stage differentiate into various cell types. After a PNS lesion, SCs can also convert into repair cells that guide and stimulate axonal regrowth, and remyelinate regenerated axons. What controls their development and versatile nature? Several recent studies highlight the key roles of chromatin modifiers in these processes, allowing SCs to regulate their gene expression profile and thereby acquire or change their identity and quickly react to their environment.



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Mechanisms of Müller glial cell morphogenesis

Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Ryan B MacDonald, Mark Charlton-Perkins, William A Harris
Müller Glia (MG), the radial glia cells of the retina, have spectacular morphologies subserving their enormous functional complexity. As early as 1892, the great neuroanatomist Santiago Ramon y Cajal studied the morphological development of MG, defining several steps in their morphogenesis [1,2]. However, the molecular cues controlling these developmental steps remain poorly understood. As MG have roles to play in every cellular and plexiform layer, this review discusses our current understanding on how MG morphology may be linked to their function, including the developmental mechanisms involved in MG patterning and morphogenesis. Uncovering the mechanisms governing glial morphogenesis, using transcriptomics and imaging, may provide shed new light on the pathophysiology and treatment of human neurological disorders.

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Quantifying behavior to solve sensorimotor transformations: advances from worms and flies

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Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Adam J Calhoun, Mala Murthy
The development of new computational tools has recently opened up the study of natural behaviors at a precision that was previously unachievable. These tools permit a highly quantitative analysis of behavioral dynamics at timescales that are well matched to the timescales of neural activity. Here we examine how combining these methods with established techniques for estimating an animal's sensory experience presents exciting new opportunities for dissecting the sensorimotor transformations performed by the nervous system. We focus this review primarily on examples from Caenorhabditis elegans and Drosophila melanogaster—for these model systems, computational approaches to characterize behavior, in combination with unparalleled genetic tools for neural activation, silencing, and recording, have already proven instrumental for illuminating underlying neural mechanisms.



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From the statistics of connectivity to the statistics of spike times in neuronal networks

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Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Gabriel Koch Ocker, Yu Hu, Michael A Buice, Brent Doiron, Krešimir Josić, Robert Rosenbaum, Eric Shea-Brown
An essential step toward understanding neural circuits is linking their structure and their dynamics. In general, this relationship can be almost arbitrarily complex. Recent theoretical work has, however, begun to identify some broad principles underlying collective spiking activity in neural circuits. The first is that local features of network connectivity can be surprisingly effective in predicting global statistics of activity across a network. The second is that, for the important case of large networks with excitatory-inhibitory balance, correlated spiking persists or vanishes depending on the spatial scales of recurrent and feedforward connectivity. We close by showing how these ideas, together with plasticity rules, can help to close the loop between network structure and activity statistics.



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Digit ratio 2D:4D is a possible indicator for androgenetic alopecia in males

Summary

Background

Androgenetic alopecia (AGA) is the most common hair loss. The 2D:4D digit ratio refers to the ratio of the length of the second finger to that of the fourth finger and is thought as a marker of prenatal androgen exposure.

Objectives

There are many studies which have examined the relationship between 2D:4D ratio and some other diseases. In this study, we evaluated the relationship between digit ratio 2D:4D and AGA.

Methods

The study group was composed of a male with AGA and healthy controls. The lengths of patients' second and fourth fingers were measured using a digital caliper with a resolution of 0.01 mm. Finger length was measured on the palmar side of the hand from the basal metacarpophalangeal crease. The 2D:4D ratio was obtained by dividing the length of the second finger by the length of the fourth finger.

Results

A total of 99 males who have androgenetic alopecia with a score of grade III or more and 90 controls were included. The mean age of AGA group was 29.72 ± 5.53, and the mean age of control group was 19.63 ± 5.05. The left-hand 2D:4D ratios of AGA group (0.893 ± 0.267) were significantly lower than healthy controls (0.971 ± 0.028). No significant relationships were found between AGA severity, age of onset,and digit ratios.

Conclusions

The left-hand digit ratio 2D:4D is lower in AGA patients, and therefore, left-hand digit ratio 2D:4D can be used as an estimation tool for AGA development in future. There is not any correlation between digit ratio and age of onset. Also, there is no correlation between digit ratio 2D:4D and AGA severity.



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Digit ratio 2D:4D is a possible indicator for androgenetic alopecia in males

Summary

Background

Androgenetic alopecia (AGA) is the most common hair loss. The 2D:4D digit ratio refers to the ratio of the length of the second finger to that of the fourth finger and is thought as a marker of prenatal androgen exposure.

Objectives

There are many studies which have examined the relationship between 2D:4D ratio and some other diseases. In this study, we evaluated the relationship between digit ratio 2D:4D and AGA.

Methods

The study group was composed of a male with AGA and healthy controls. The lengths of patients' second and fourth fingers were measured using a digital caliper with a resolution of 0.01 mm. Finger length was measured on the palmar side of the hand from the basal metacarpophalangeal crease. The 2D:4D ratio was obtained by dividing the length of the second finger by the length of the fourth finger.

Results

A total of 99 males who have androgenetic alopecia with a score of grade III or more and 90 controls were included. The mean age of AGA group was 29.72 ± 5.53, and the mean age of control group was 19.63 ± 5.05. The left-hand 2D:4D ratios of AGA group (0.893 ± 0.267) were significantly lower than healthy controls (0.971 ± 0.028). No significant relationships were found between AGA severity, age of onset,and digit ratios.

Conclusions

The left-hand digit ratio 2D:4D is lower in AGA patients, and therefore, left-hand digit ratio 2D:4D can be used as an estimation tool for AGA development in future. There is not any correlation between digit ratio and age of onset. Also, there is no correlation between digit ratio 2D:4D and AGA severity.



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ClinVar Is a Critical Resource to Advance Variant Interpretation



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In Reply



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Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents

AbstractTumor lysis syndrome (TLS) is an uncommon but potentially life‐threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B‐cell lymphoma‐2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control.Implications for Practice.Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described.

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Finding Hope in Uncertain Times



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Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism

Circadian disruption is associated with metabolic disturbances such as hepatic-steatosis (HS), obesity and type-2 diabetes. We hypothesized that HS, resulting from constant-light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine driven suprachiasmatic nucleus (SCN) outputs. Indeed exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with development of HS. We investigated whether providing temporal signals such as 12-hour food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5µg/Kg) and melatonin (2.5 mg/Kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.



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The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system

Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1's effects on feeding and numerous other physiological functions.

With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha in iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.



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PCAF/GCN5-Mediated Acetylation of RPA1 Promotes Nucleotide Excision Repair

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Meimei Zhao, Rui Geng, Xiang Guo, Ruoshi Yuan, Xiao Zhou, Yanyan Zhong, Yanfei Huo, Mei Zhou, Qinjian Shen, Yinglu Li, Weiguo Zhu, Jiadong Wang
The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway. DNA-PK phosphorylates and activates PCAF upon UV damage and consequently promotes the acetylation of RPA1. Moreover, the acetylation of RPA1 is tightly regulated by HDAC6 and SIRT1. Together, our results demonstrate that the K163 acetylation of RPA1 plays a key role in the repair of UV-induced DNA damage and reveal how the specific RPA1 modification modulates the choice of distinct DNA repair pathways.

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Teaser

RPA complex is a central player in multiple DNA repair pathways. Zhao et al. show that PCAF/GCN5-mediated acetylation of RPA1 is crucial for NER repair by promoting stable RPA1/XPA complex.


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UV-Induced RPA1 Acetylation Promotes Nucleotide Excision Repair

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Hanqing He, Jiajia Wang, Ting Liu
Replication protein A (RPA) is a multifunctional, single-stranded DNA-binding protein complex and plays a critical role in DNA replication and damage response. Herein, we show that the 70-kDa subunit of RPA (RPA1) is acetylated on lysine 163 by the acetyltransferases GCN5 and PCAF and that such acetylation is reversed principally via the action of the deacetylase HDAC6. UV irradiation promotes cytoplasmic translocation of HDAC6, thereby disrupting the interaction of HDAC6 with RPA1 and increasing RPA1 acetylation. Mutation of the acetylation site of RPA1 specifically impairs the ability of the protein to interact with the key nucleotide excision repair (NER) protein XPA, reduces XPA retention at sites of DNA damage caused by UV, compromises NER, and renders the cell hypersensitive to UV irradiation. Our data suggest that the acetylation status of RPA1 played a crucial role in repair of DNA damage via NER.

Graphical abstract

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Teaser

He et al. find that the RPA1 protein becomes acetylated at lysine 163 in response to UV irradiation. Such acetylation specifically enhances interaction between RPA1 and the key NER protein XPA and promotes XPA retention at DNA damage sites. These findings suggest that RPA1 acetylation is a unique NER-related event.


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Multilayered Reprogramming in Response to Persistent DNA Damage in C. elegans

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Diletta Edifizi, Hendrik Nolte, Vipin Babu, Laia Castells-Roca, Michael M. Mueller, Susanne Brodesser, Marcus Krüger, Björn Schumacher
DNA damage causally contributes to aging and age-related diseases. Mutations in nucleotide excision repair (NER) genes cause highly complex congenital syndromes characterized by growth retardation, cancer susceptibility, and accelerated aging in humans. Orthologous mutations in Caenorhabditis elegans lead to growth delay, genome instability, and accelerated functional decline, thus allowing investigation of the consequences of persistent DNA damage during development and aging in a simple metazoan model. Here, we conducted proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment to gain comprehensive insights into the full range of physiological adaptations to unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated proteostatic response. We assign central roles for the insulin-, EGF-, and AMPK-like signaling pathways in orchestrating the adaptive response to DNA damage. Our results provide insights into the DNA damage responses in the organismal context.

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Teaser

Edifizi et al. provide a comprehensive proteomics, phosphoproteomics, and lipidomics analysis of the response to persistent DNA damage in a metazoan organism. Proteostasis shifts toward autophagy, fatty acid metabolism is attenuated, and the insulin-, EGF-, and AMPK-like signaling pathways form the center of the response network.


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NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jia Zhou, Jany Chan, Marie Lambelé, Timur Yusufzai, Jason Stumpff, Patricia L. Opresko, Markus Thali, Susan S. Wallace
Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1) and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.

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Teaser

NEIL3 DNA glycosylase activity is critical in highly proliferating cells including cancer cells. Zhou et al. show that NEIL3 is specifically active at telomeres during S/G2, and that depletion of NEIL3 causes telomere dysfunction and thus mitotic defects, revealing its involvement in telomere repair, which prevents genome instability.


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SMC Progressively Aligns Chromosomal Arms in Caulobacter crescentus but Is Antagonized by Convergent Transcription

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Ngat T. Tran, Michael T. Laub, Tung B.K. Le
The structural maintenance of chromosomes (SMC) complex plays an important role in chromosome organization and segregation in most living organisms. In Caulobacter crescentus, SMC is required to align the left and the right arms of the chromosome that run in parallel down the long axis of the cell. However, the mechanism of SMC-mediated alignment of chromosomal arms remains elusive. Here, using genome-wide methods and microscopy of single cells, we show that Caulobacter SMC is recruited to the centromeric parS site and that SMC-mediated arm alignment depends on the chromosome-partitioning protein ParB. We provide evidence that SMC likely tethers the parS-proximal regions of the chromosomal arms together, promoting arm alignment. Furthermore, we show that highly transcribed genes near parS that are oriented against SMC translocation disrupt arm alignment, suggesting that head-on transcription interferes with SMC translocation. Our results demonstrate a tight interdependence of bacterial chromosome organization and global patterns of transcription.

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Teaser

Tran et al. investigate the mechanism and function of SMC in the global organization of the Caulobacter chromosome. The findings suggest that SMC functions as a tether to actively cohese the chromosomal arms together and show that head-on transcription profoundly interferes with SMC translocation from the centromeric parS site.


http://ift.tt/2xwgru4

Feeling Stressed under the Sun? RPA1 Acetylation to the Rescue

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Debabrata Chakravarti, Tapas K. Hazra
Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.

Teaser

Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.


http://ift.tt/2xwaw8a

Lysophosphatidic Acid Receptor 4 Activation Augments Drug Delivery in Tumors by Tightening Endothelial Cell-Cell Contact

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Kazuhiro Takara, Daisuke Eino, Koji Ando, Daisuke Yasuda, Hisamichi Naito, Yohei Tsukada, Tomohiro Iba, Taku Wakabayashi, Fumitaka Muramatsu, Hiroyasu Kidoya, Shigetomo Fukuhara, Naoki Mochizuki, Satoshi Ishii, Haruhiko Kishima, Nobuyuki Takakura
Vascular normalization in tumors may improve drug delivery and anti-tumor immunity. Angiogenesis inhibitors induce hypoxia, which may facilitate malignant progression; therefore, we investigated other methods to promote vascular maturation. Here, we show that lysophosphatidic acid (LPA) enhances blood flow by promoting fine vascular networks, thereby improving vascular permeability and suppressing tumor growth when combined with anti-cancer drug treatment. Six different G protein-coupled receptors have been identified as LPA receptors (LPA1–6). In studies using mutant mice, we found that LPA4 is involved in vascular network formation. LPA4 activation induces circumferential actin bundling beneath the cell membrane and enhances linear adherens junction formation by VE-cadherin in endothelial cells. Therefore, we conclude that activation of LPA4 is a promising approach for vascular regulation.

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Teaser

Takara et al. find that lysophosphatidic acid (LPA) promotes fine capillary network formation and improves drug delivery in tumors. LPA controls localization of VE-cadherin in endothelial cells through LPA receptor 4 (LPA4) signaling.


http://ift.tt/2wghsaL

Spatiotemporal Control of Lipid Conversion, Actin-Based Mechanical Forces, and Curvature Sensors during Clathrin/AP-1-Coated Vesicle Biogenesis

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Mihaela Anitei, Christoph Stange, Cornelia Czupalla, Christian Niehage, Kai Schuhmann, Pia Sala, Aleksander Czogalla, Theresia Pursche, Ünal Coskun, Andrej Shevchenko, Bernard Hoflack
Clathrin/adaptor protein-1-coated carriers connect the secretory and the endocytic pathways. Carrier biogenesis relies on distinct protein networks changing membrane shape at the trans-Golgi network, each regulating coat assembly, F-actin-based mechanical forces, or the biophysical properties of lipid bilayers. How these different hubs are spatiotemporally coordinated remains largely unknown. Using in vitro reconstitution systems, quantitative proteomics, and lipidomics, as well as in vivo cell-based assays, we characterize the protein networks controlling membrane lipid composition, membrane shape, and carrier scission. These include PIP5K1A and phospholipase C-beta 3 controlling the conversion of PI[4]P into diacylglycerol. PIP5K1A binding to RAC1 provides a link to F-actin-based mechanical forces needed to tubulate membranes. Tubular membranes then recruit the BAR-domain-containing arfaptin-1/2 guiding carrier scission. These findings provide a framework for synchronizing the chemical/biophysical properties of lipid bilayers, F-actin-based mechanical forces, and the activity of proteins sensing membrane shape during clathrin/adaptor protein-1-coated carrier biogenesis.

Graphical abstract

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Teaser

Clathrin/adaptor protein-1 (AP-1) coats control the transport of specific cargoes between the biosynthetic and endocytic pathways. Anitei et al. illustrate the coordination of protein networks controlling the biophysical properties of lipid bilayers, actin-based mechanical forces, and membrane curvature during clathrin/AP-1-coated carrier biogenesis.


http://ift.tt/2wgWwk7

Aberrant Compartment Formation by HSPB2 Mislocalizes Lamin A and Compromises Nuclear Integrity and Function

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Federica F. Morelli, Dineke S. Verbeek, Jessika Bertacchini, Jonathan Vinet, Laura Mediani, Sandra Marmiroli, Giovanna Cenacchi, Milena Nasi, Sara De Biasi, Jeanette F. Brunsting, Jan Lammerding, Elena Pegoraro, Corrado Angelini, Rossella Tupler, Simon Alberti, Serena Carra
Small heat shock proteins (HSPBs) contain intrinsically disordered regions (IDRs), but the functions of these IDRs are still unknown. Here, we report that, in mammalian cells, HSPB2 phase separates to form nuclear compartments with liquid-like properties. We show that phase separation requires the disordered C-terminal domain of HSPB2. We further demonstrate that, in differentiating myoblasts, nuclear HSPB2 compartments sequester lamin A. Increasing the nuclear concentration of HSPB2 causes the formation of aberrant nuclear compartments that mislocalize lamin A and chromatin, with detrimental consequences for nuclear function and integrity. Importantly, phase separation of HSPB2 is regulated by HSPB3, but this ability is lost in two identified HSPB3 mutants that are associated with myopathy. Our results suggest that HSPB2 phase separation is involved in reorganizing the nucleoplasm during myoblast differentiation. Furthermore, these findings support the idea that aberrant HSPB2 phase separation, due to HSPB3 loss-of-function mutations, contributes to myopathy.

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Teaser

Morelli et al. show that, in mammalian cells, HSPB2 forms liquid-like nuclear compartments that affect lamin A localization and mobility, with detrimental consequences for chromatin organization and nuclear integrity. Aberrant compartment formation by HSPB2 is regulated by HSPB3, but not by two identified HSPB3 mutants linked to myopathy.


http://ift.tt/2wgeROc

Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Laina Freyer, Chih-Wei Hsu, Sonja Nowotschin, Andrea Pauli, Junji Ishida, Keiji Kuba, Akiyoshi Fukamizu, Alexander F. Schier, Pamela A. Hoodless, Mary E. Dickinson, Anna-Katerina Hadjantonakis
Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.

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Teaser

Apela (a.k.a. Elabela, Ende, and Toddler) is a key signaling peptide that activates APLNR in mouse development. Freyer et al. show that lethal developmental defects in Apela mutants may rely on sufficient blood circulation. They suggest that extraembryonic mesoderm derivatives, including endothelial and hematopoietic progenitors, may be the first cell populations impacted by the loss of Apela.


http://ift.tt/2wgIyig

Folding of the Cerebral Cortex Requires Cdk5 in Upper-Layer Neurons in Gyrencephalic Mammals

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Yohei Shinmyo, Yukari Terashita, Tung Anh Dinh Duong, Toshihide Horiike, Muneo Kawasumi, Kazuyoshi Hosomichi, Atsushi Tajima, Hiroshi Kawasaki
Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown, mainly because genetic manipulations for the gyrencephalic brain have been unavailable. By combining in utero electroporation and the CRISPR/Cas9 system, we succeeded in efficient gene knockout of Cdk5, which is mutated in some patients with classical lissencephaly, in the gyrencephalic brains of ferrets. We show that Cdk5 knockout in the ferret cerebral cortex markedly impaired cortical folding. Furthermore, the results obtained from the introduction of dominant-negative Cdk5 into specific cortical layers suggest that Cdk5 function in upper-layer neurons is more important for cortical folding than that in lower-layer neurons. Cdk5 inhibition induced severe migration defects in cortical neurons. Taken together, our findings suggest that the appropriate positioning of upper-layer neurons is critical for cortical folding.

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Teaser

Shinmyo et al. describe a highly efficient gene knockout method for the folded cerebral cortex of ferrets using the CRISPR/Cas9 system. Loss-of-function studies of the Cdk5 gene suggest that appropriate positioning of upper-layer neurons is crucial for cortical folding.


http://ift.tt/2wgPUSO

A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Marlen Knobloch, Gregor-Alexander Pilz, Bart Ghesquière, Werner J. Kovacs, Thomas Wegleiter, Darcie L. Moore, Martina Hruzova, Nicola Zamboni, Peter Carmeliet, Sebastian Jessberger
Hippocampal neurogenesis is important for certain forms of cognition, and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. Here, we show that the rate of fatty acid oxidation (FAO) regulates the activity of NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.

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Teaser

Controlled balance between proliferation and quiescence of neural stem/progenitor cells (NSPCs) is required for lifelong neurogenesis. Knobloch et al. identify a metabolic shift in fatty acid oxidation (FAO) that governs the proliferation of NSPCs. Further, their data suggest an instructive role for FAO in regulating NSPC activity. Thus, Knobloch et al. identify FAO as a key metabolic pathway to regulate NSPC activity.


http://ift.tt/2wgz06N

Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Megan S. Wyeth, Kenneth A. Pelkey, Xiaoqing Yuan, Geoffrey Vargish, April D. Johnston, Steven Hunt, Calvin Fang, Daniel Abebe, Vivek Mahadevan, André Fisahn, Michael W. Salter, Roderick R. McInnes, Ramesh Chittajallu, Chris J. McBain
Although Netos are considered auxiliary subunits critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM)-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1)-, and parvalbumin (PV)-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

Graphical abstract

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Teaser

Netos are considered critical kainate receptor (KAR) auxiliary subunits in glutamatergic principal cells, but their roles in GABAergic interneurons remain unexplored. Wyeth et al. find that somatodendritic KARs within diverse interneurons require Neto1, whereas both Neto1 and Neto2 regulate presynaptic KAR-mediated suppression of inhibitory transmission.


http://ift.tt/2wgD5b3

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jui-Heng Tseng, Ling Xie, Sheng Song, Youmei Xie, Lauren Allen, Deepa Ajit, Jau-Shyong Hong, Xian Chen, Rick B. Meeker, Todd J. Cohen
The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.

Graphical abstract

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Teaser

Tau mislocalization and aggregation are implicated in the pathogenesis of Alzheimer's disease. Tseng et al. report that endogenous neuronal tau re-localizes to distinct neuritic foci, which are active sites of calcium deregulation, leading to aberrant tau accumulation. These findings provide insights into the early-stage tau dysfunction that occurs in vulnerable neurons.


http://ift.tt/2wgIzCQ

Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Xiaowan Wang, Qiao Zhang, Ruisi Bao, Nannan Zhang, Yingzhen Wang, Luis Polo-Parada, Andrew Tarim, Aidan Alemifar, Xianlin Han, Heather M. Wilkins, Russell H. Swerdlow, Xinglong Wang, Shinghua Ding
Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD+ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD+ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.

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Teaser

Wang et al. find that projection neuron NAMPT is essential for mitochondrial bioenergetics, motor function, and survival of adult mice and that iNAMPT is reduced in ALS patients. NMN improves health and extends the lifespan of Nampt knockout mice. Their findings suggest therapeutic avenues for motor neuron degenerative diseases.


http://ift.tt/2wgz1rn

Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Theodoros I. Roumeliotis, Steven P. Williams, Emanuel Gonçalves, Clara Alsinet, Martin Del Castillo Velasco-Herrera, Nanne Aben, Fatemeh Zamanzad Ghavidel, Magali Michaut, Michael Schubert, Stacey Price, James C. Wright, Lu Yu, Mi Yang, Rodrigo Dienstmann, Justin Guinney, Pedro Beltrao, Alvis Brazma, Mercedes Pardo, Oliver Stegle, David J. Adams, Lodewyk Wessels, Julio Saez-Rodriguez, Ultan McDermott, Jyoti S. Choudhary
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.

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Teaser

Roumeliotis et al. use in-depth proteomics to assess the impact of genomic alterations on protein networks in colorectal cancer cell lines. Cell-line-specific network signatures are inferred de novo by protein quantification profiles and ultimately expose the collateral and transcript-independent effects of detrimental mutations on protein complexes.


http://ift.tt/2whrU1X

The Functional Impact of Alternative Splicing in Cancer

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Héctor Climente-González, Eduard Porta-Pardo, Adam Godzik, Eduardo Eyras
Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers).

Graphical abstract

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Teaser

Climente-González et al. show that alternative splicing (AS) changes in tumors are linked to a significant loss of functional domain families that are also frequently mutated in cancer. These domain losses happen independently of somatic mutations and lead to the remodeling of complexes and protein-protein interactions in cancer.


http://ift.tt/2wgTgoL

Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Zheng-Quan He, Bao-Long Xia, Yu-Kai Wang, Jing Li, Gui-Hai Feng, Lin-Lin Zhang, Yu-Huan Li, Hai-Feng Wan, Tian-Da Li, Kai Xu, Xue-Wei Yuan, Yu-Fei Li, Xin-Xin Zhang, Ying Zhang, Liu Wang, Wei Li, Qi Zhou
The recent success of derivation of mammalian haploid embryonic stem cells (haESCs) has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.

Graphical abstract

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Teaser

He et al. show that CDK1 and ROCK inhibition can suppress the spontaneous diploidization of haploid embryonic stem cells (haESCs) and generate haploid somatic cells of all three germ layers for genome-wide genetic screening.


http://ift.tt/2wgeNxW

Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Tadepally Lakshmikanth, Axel Olin, Yang Chen, Jaromir Mikes, Erik Fredlund, Mats Remberger, Brigitta Omazic, Petter Brodin
Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.

Graphical abstract

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Teaser

Lakshmikanth et al. conduct a systems analysis of immune reconstitution after stem cell transplantation. Using topological data analysis, combinations of cells and proteins associated with CMV and graft-versus-host disease were revealed and illustrate the potential of systems immunomonitoring to improve the development and evaluation of cancer immunotherapies.


http://ift.tt/2wgTeNF

Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Anne Rechtien, Laura Richert, Hadrien Lorenzo, Gloria Martrus, Boris Hejblum, Christine Dahlke, Rahel Kasonta, Madeleine Zinser, Hans Stubbe, Urte Matschl, Ansgar Lohse, Verena Krähling, Markus Eickmann, Stephan Becker, Rodolphe Thiébaut, Marcus Altfeld, Marylyn Addo
Predicting vaccine efficacy remains a challenge. We used a systems vaccinology approach to identify early innate immune correlates of antibody induction in humans receiving the Ebola vaccine rVSV-ZEBOV. Blood samples from days 0, 1, 3, 7, and 14 were analyzed for changes in cytokine levels, innate immune cell subsets, and gene expression. Integrative statistical analyses with cross-validation identified a signature of 5 early innate markers correlating with antibody titers on day 28 and beyond. Among those, IP-10 on day 3 and MFI of CXCR6 on NK cells on day 1 were independent correlates. Consistently, we found an early gene expression signature linked to IP-10. This comprehensive characterization of early innate immune responses to the rVSV-ZEBOV vaccine in humans revealed immune signatures linked to IP-10. These results suggest correlates of vaccine-induced antibody induction and provide a rationale to explore strategies for augmenting the effectiveness of vaccines through manipulation of IP-10.

Graphical abstract

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Teaser

Rechtien et al. apply a systems vaccinology approach to examine the early innate immune responses elicited by the Ebola vaccine rVSV-ZEBOV. They find that early innate immune responses, with IP-10 as an independent soluble marker, correlate with EBOV-GP-specific antibody induction.


http://ift.tt/2gopo4v

Immune development and environment: lessons from Amish and Hutterite children



http://ift.tt/2xvUxqB

Notch signaling patterns neurogenic ectoderm and regulates the asymmetric division of neural progenitors in sea urchin embryos [RESEARCH ARTICLE]

Dan O. Mellott, Jordan Thisdelle, and Robert D. Burke

We have examined regulation of neurogenesis by Delta/Notch signaling in sea urchin embryos. At gastrulation neural progenitors enter S-phase coincident with expression of Sp-SoxC. We used a BAC (bacterial artificial chromosome) containing GFP knocked into the Sp-SoxC locus to label neural progenitors. Live imaging and immunolocalizations indicate that Sp-SoxC-expressing cells divide producing pairs of adjacent cells expressing GFP. Over an interval of about 6 h, one cell fragments, undergoes apoptosis, and expresses high levels of activated Caspase3. A Notch reporter indicates that Notch signaling is activated in cells adjacent to cells expressing Sp-SoxC. Inhibition of -secretase, injection of Sp-Delta morpholinos, or CRISPR/Cas9-induced mutation of Sp-Delta results in supernumerary neural progenitors and neurons. Interfering with Notch signaling increases neural progenitor recruitment and pairs of neural progenitors. Thus, Notch signaling restricts the number of neural progenitors recruited and regulates the fate of progeny of the asymmetric division. We propose a model in which localized signaling converts ectodermal and ciliary band cells to neural progenitors that divide asymmetrically to produce a neural precursor and an apoptotic cell.



http://ift.tt/2vIpu8O

Perturbing phosphoinositide homeostasis oppositely affects vascular differentiation in Arabidopsis thaliana roots [RESEARCH ARTICLE]

Bojan Gujas, Tiago M. D. Cruz, Elizabeth Kastanaki, Joop E. M. Vermeer, Teun Munnik, and Antia Rodriguez-Villalon

The plant vascular network consists of specialized phloem and xylem elements that undergo two distinct morphogenetic developmental programs to become transport-functional units. While vacuolar rupture is a determinant step in protoxylem differentiation, protophloem elements never form a big central vacuole. Here we show that a genetic disturbance of phosphatidylinositol 4,5-bis-phosphate [PtdIns(4,5)P2] homeostasis rewires cell trafficking towards the vacuole in Arabidopsis thaliana roots. Consequently, an enhanced phosphoinositide-mediated vacuolar biogenesis correlate with premature programmed cell death (PCD) and secondary cell wall elaboration in xylem cells. By contrast, vacuolar fusion events in protophloem cells trigger the abnormal formation of big vacuoles, preventing cell clearance and tissue functionality. Removal of the inositol 5' phosphatase COTYLEDON VASCULAR PATTERN2 from the plasma membrane (PM) by brefeldin A (BFA) treatment increases PtdIns(4,5)P2 content at the PM and disrupts protophloem continuity. Conversely, BFA application abolishes vacuolar fusion events in xylem tissue without preventing PCD, suggesting the existence of additional PtdIns(4,5)P2–dependent cell death mechanisms. Overall, our data indicate that a tight PM phosphoinositide homeostasis is required to modulate intracellular trafficking contributing to oppositely regulate vascular differentiation.



http://ift.tt/2vqme6O

miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage [RESEARCH ARTICLE]

Björn Bluhm, Harald W. A. Ehlen, Tatjana Holzer, Veronika S. Georgieva, Juliane Heilig, Lena Pitzler, Julia Etich, Toman Bortecen, Christian Frie, Kristina Probst, Anja Niehoff, Daniele Belluoccio, Jocelyn Van den Bergen, and Bent Brachvogel

Cartilage originates from mesenchymal cell condensations that differentiate into chondrocytes of transient growth plate cartilage or permanent cartilage of the articular joint surface and trachea. MicroRNAs fine-tune the activation of entire signaling networks and thereby modulate complex cellular responses, but so far only limited data are available on miRNAs that regulate cartilage development.

Here we characterize a miRNA which promotes the biosynthesis of a key component in the RAF/MEK/ERK pathway in cartilage. Specifically, by transcriptome profiling we identified miR-322 to be upregulated during chondrocyte differentiation. Among the various miR-322 target genes in the RAF/MEK/ERK pathway only Mek1 was identified as a regulated target in chondrocytes. Surprisingly, an increased concentration of miR-322 stabilizes Mek1-mRNA to rise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation in mice linked the loss of miR-322 to decreased MEK1 levels and increased RAF/MEK/ERK pathway activation. Such mice died perinatally due to tracheal growth restriction and respiratory failure.

Hence, a single miRNA can stimulate the production of an inhibitory component of a central signaling pathway to impair cartilage development.



http://ift.tt/2vHYw18

Imp and Syp RNA-binding proteins govern decommissioning of Drosophila neural stem cells [RESEARCH ARTICLE]

Ching-Po Yang, Tamsin J. Samuels, Yaling Huang, Lu Yang, David Ish-Horowicz, Ilan Davis, and Tzumin Lee

The termination of the proliferation of Drosophila neural stem cells, also known as neuroblasts (NBs), requires a "decommissioning" phase that is controlled in a lineage-specific manner. Most NBs, with the exception of those of the Mushroom body (MB), are decommissioned by the ecdysone receptor and mediator complex causing them to shrink during metamorphosis, followed by nuclear accumulation of Prospero and cell cycle exit. Here, we demonstrate that the levels of Imp and Syp RNA-binding proteins regulate NB decommissioning. Descending Imp and ascending Syp expression have been shown to regulate neuronal temporal fate. We show that Imp levels decline slower in the MB than other central brain NBs. MB NBs continue to express Imp into pupation, and the presence of Imp prevents decommissioning partly by inhibiting the mediator complex. Late-larval induction of transgenic Imp prevents many non-MB NBs from decommissioning in early pupae. Moreover, the presence of abundant Syp in aged NBs permits Prospero accumulation that, in turn, promotes cell cycle exit. Together our results reveal that progeny temporal fate and progenitor decommissioning are co-regulated in protracted neuronal lineages.



http://ift.tt/2vqe9PH

DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes [RESEARCH ARTICLE]

Simon I. R. Lane, Stephanie L. Morgan, Tianyu Wu, Josie K. Collins, Julie A. Merriman, Elias ElInati, James M. Turner, and Keith T. Jones

Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on the spindle assembly checkpoint, which results in anaphase-promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes DNA damage assembles checkpoint proteins at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min. Despite this robust response, there is no measurable loss in k-fibres, or tension across the bivalent. Through pharmacological inhibition we observed the response is dependent on Mps1 kinase, Aurora kinase, and haspin. Using oocyte specific knockouts we find the response does not require the DNA damage response kinases ATM or ATR. Furthermore, checkpoint activation does not occur in response to DNA damage in fully mature eggs during meiosis II, despite the divisions being separated by just a few hours. Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores.



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Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity [RESEARCH ARTICLE]

Yixin Wang, Yi Jin, Maarja Andaloussi Mäe, Yang Zhang, Henrik Ortsäter, Christer Betsholtz, Taija Mäkinen, and Lars Jakobsson

Tissue-fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and their role in vessel maturation are unknown. Here we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, PDGFB overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate a requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels and suggest an ECM-controlled checkpoint preventing SMC investment of capillaries, which is a common feature in lymphedematous skin.



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Distinct functions for Netrin-1 in chicken and murine semicircular canal morphogenesis [RESEARCH ARTICLE]

Allison M. Nishitani, Sho Ohta, Andrea R. Yung, Tony del Rio, Michael I. Gordon, Victoria E. Abraira, Evelyn C. Aviles, Gary C. Schoenwolf, Donna M. Fekete, and Lisa V. Goodrich

The vestibular system of the inner ear detects head position using three orthogonally oriented semicircular canals; even slight changes in their shape and orientation can cause debilitating behavioral defects. During development, the canals are sculpted from pouches that protrude from the otic vesicle, the embryonic anlage of the inner ear. In the center of each pouch, a fusion plate forms where cells lose their epithelial morphology and the basement membrane breaks down. Cells in the fusing epithelia intercalate and are removed, creating a canal. In mice, fusion depends on the secreted protein Netrin-1, which is necessary for basement membrane breakdown, although the underlying molecular mechanism is unknown. Using gain-of-function approaches, we found that overexpression of Netrin-1 in the chick otic vesicle prevented canal fusion by inhibiting apoptosis. In contrast, ectopic expression of the same chicken Netrin-1 in the mouse otic vesicle, where apoptosis is less prominent, resulted in canal truncation. These findings highlight the importance of apoptosis for tissue morphogenesis and suggest that Netrin-1 may play divergent cellular roles despite its conserved expression during canal morphogenesis in chicken and mouse.



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Psychrophilic proteases dramatically reduce single cell RNA-seq artifacts: A molecular atlas of kidney development [TECHNIQUES AND RESOURCES ARTICLE]

Mike Adam, Andrew S. Potter, and S. Steven Potter

Single cell RNA-seq is a powerful methodology. Nevertheless there are important limitations, including the technical challenges of breaking down an organ or tissue into a single cell suspension. Invariably this has required enzymatic incubation at 37°C, which can be expected to result in artifact changes in gene expression patterns. We here describe a dissociation method that uses a protease with high activity in the cold, purified from a psychrophilic microorganism. The entire procedure is carried out at 6°C or colder, where mammalian transcriptional machinery is largely inactive, thereby effectively "freezing in" the in vivo gene expression patterns. To test this method we carried out RNA-seq on 20,424 single cells from P1 mouse kidneys, comparing the results of the psychrophilic protease method with procedures using 37°C incubation. We show that the cold protease method provides a great reduction in gene expression artifacts. In addition the results produce a single cell resolution gene expression atlas of the newborn mouse kidney, an interesting time in development when mature nephrons are present yet nephrogenesis remains extremely active.



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Unmet Needs in the Pathogenesis and Treatment of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with a prevalence of approximately 1 in 1000. Over the last 30 years, advances in treatment such as use of corticosteroids and immunosuppressants have improved life expectancy and quality of life for patients with lupus and the key unmet needs have therefore changed. With the reduced mortality from disease activity, development of cardiovascular disease (CVD) has become an increasingly important cause of death in patients with SLE. The increased CVD risk in these patients is partly, but not fully explained by standard risk factors, and abnormalities in the immune response to lipids may play a role. Invariant natural killer T cells, which are triggered specifically by lipid antigens, may protect against progression of subclinical atherosclerosis. However, currently our recommendation is that clinicians should focus on optimal management of standard CVD risk factors such as smoking, blood pressure and lipid levels. Fatigue is one of the most common and most limiting symptoms suffered by patients with SLE. The cause of fatigue is multifactorial and disease activity does not explain this symptom. Consequently, therapies directed towards reducing inflammation and disease activity do not reliably reduce fatigue and new approaches are needed. Currently, we recommend asking about sleep pattern, optimising pain relief and excluding other causes of fatigue such as anaemia and metabolic disturbances. For the subgroup of patients whose disease activity is not fully controlled by standard treatment regimes, a range of different biologic agents have been proposed and subjected to clinical trials. Many of these trials have given disappointing results, though belimumab, which targets B lymphocytes, did meet its primary endpoint. New biologics targeting B cells, T cells or cytokines (especially interferon) are still going through trials raising the hope that novel therapies for patients with refractory SLE may be available soon.



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Grafting materials for alveolar cleft reconstruction: a systematic review and best-evidence synthesis

The purpose of this study was to compare the efficacy of alveolar bone reconstruction for alveolar cleft patients performed with the traditional iliac graft or alternative/supplementary bone grafting materials. Electronic databases, relevant journals, and reference lists of the included studies were searched to the end of June 2016. A best-evidence synthesis was performed to draw conclusions. A total of 38 studies were included, which provided 25 pieces of evidence: seven of moderate evidence and 18 of insufficient evidence.

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Effect of body posture on chewing behaviors in healthy volunteers

Abstract

Mastication is essential to the eating process, and forms an important part of feeding behavior. Many factors related to the food bolus, such as bolus texture and size, are known to influence mastication. The aim of the present study was to determine the effects of body posture on (1) chewing duration prior to the first swallow and (2) patterns of mastication-related EMG activity. We asked 10 healthy adults to chew 8 g of steamed rice with barium sulfate while we recorded masseter, suprahyoid, and infrahyoid muscle activity and simultaneously collected videofluorographic images. Participants chewed in either an upright or reclining position. Chewing duration, which was defined as the time from the start of mastication to the first swallow, was not different between the positions. However, the variability of chewing duration was larger in the upright vs. reclining position, and the chewing duration in the reclining position was distributed around 15 s. Masseter activity gradually decreased in a time dependent manner and was significantly larger at the early vs. late stage of mastication. Suprahyoid activity was significantly larger at the early vs. middle stage of mastication in the upright position only. Finally, masseter activity per second was negatively correlated with changes in chewing duration, i.e., the larger the increase in chewing duration in the reclining position, the more the decrease in masseter activity per second. These results suggest that position-dependent changes in chewing behaviors, as described by chewing duration and EMG activity, may vary among participants.

This article is protected by copyright. All rights reserved.



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Jaw sensorimotor control in healthy adults and effects of aging

Summary

The orofacial sensorimotor system is a unique system significantly distinguished from the spinal sensorimotor system. The jaw muscles are involved in mastication, swallowing and articulatory speech movements and their integration with respiration. These sensorimotor functions are vital for sustaining life and necessitate complex neuromuscular processing to provide for exquisite sensorimotor control of numerous orofacial muscles. The function of the jaw muscles in relation to sensorimotor control of these movements may be subject to aging-related declines. This review will focus on peripheral, brainstem and higher brain centre mechanisms involved in reflex regulation and sensorimotor coordination and control of jaw muscles in healthy adults. It will outline the limited literature bearing on age-related declines in jaw sensorimotor functions and control including reduced biting forces and increased risk of impaired chewing, speaking and swallowing. The mechanisms underlying these alterations include age-related degenerative changes within the peripheral neuromuscular system and in brain regions involved in the generation and control of jaw movements. In light of the vital role of jaw sensorimotor functions in sustaining life, normal aging involves compensatory mechanisms that utilize the neuroplastic capacity of the brain and the recruitment of additional brain regions involved in sensorimotor performance and closely associated functions (e.g., cognition and memory). However, these regions are themselves susceptible to detrimental age-related changes. Thus, better understanding of the peripheral and central mechanisms underlying age-related sensorimotor impairment is crucial for developing improved treatment approaches to prevent or cure impaired jaw sensorimotor functions and to thereby improve health and quality of life.

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Changes in psychological health, subjective food intake ability, and oral health-related quality of life during orthodontic treatment

Abstract

Background

Assessing changes in patient's psychological health and oral health-related quality of life (OHRQoL) over time during orthodontic treatment may help clinicians to treat patients more carefully.

Objectives

To evaluate changes in mental health, self-reported masticatory ability, and OHRQoL during orthodontic treatment in adults.

Methods

This prospective study included 66 adults (30 men, 36 women; mean age, 24.2 ± 5.2 years). Each patient completed the Korean versions of the State-Trait Anxiety Inventory, Zung Self-Rating Depression Scale, Rosenberg self-esteem scale, key subjective food intake ability (KFIA) test for five key foods, and Oral Health Impact Profile-14 (OHIP-14K) at baseline (T0), 12 months after treatment initiation (T1), and debonding (T2).

Results

All variables changed with time. Self-esteem and the total OHIP-14K score significantly decreased and increased, respectively, at T1, with a particular increase in the psychological and social disabilities scores. There were no significant differences in any questionnaire scores before and after treatment. The total OHIP-14K score was positively correlated with trait anxiety and depression, and negatively correlated with self-esteem and KFIA at T0, regardless of the treatment duration. Older patients showed a significant increase in the total OHIP-14K score at T1 and T2. OHRQoL worsened with an increase in the treatment duration.

Conclusions

Our results suggest that OHRQoL temporarily deteriorates, with the development of psychological and social disabilities, during orthodontic treatment. This is related to the baseline age, psychological health, and self-reported masticatory function. However, patients recover once the treatment is complete.

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Masticatory performance-related factors in preschool children: Establishing a method to assess masticatory performance in preschool children using colour-changeable chewing gum

Abstract

Background

A knowledge gap regarding masticatory performance in preschool children exists, which in turn delays intervention for preventive care; therefore, a method to easily assess performance is needed.

Objective

To investigate the feasibility of assessing masticatory performance using colour-changeable chewing gum, and to investigate masticatory performance-related factors in preschool children.

Methods

This cross-sectional survey was conducted in two childcare facilities and our laboratory. First, a one-third quantity of colour-changeable chewing gum was masticated by six adults to assess the nature and progression of colour changes in this quantity. Then, masticatory performance in 370 children 4 to 6 years of age was assessed using the same quantity of colour-changeable chewing gum (60 chew strokes). The maximum bite force, body height, weight, age, and number of healthy teeth were recorded. A t-test was performed to determine whether gum-chewing experience or lack thereof produced a significant difference in masticatory performance. The Spearman's rank correlation coefficient was then determined for masticatory performance assessment values and other factors solely for children with gum-chewing experience.

Results

Measurements from 259 children were obtained. Children with gum-chewing experience demonstrated significantly higher assessment values, and were deemed to have been correctly assessed. A very weak but significant positive correlation was observed only between masticatory performance and the number of healthy teeth.

Conclusions

The masticatory performance of preschool children was easily assessed using colour-changeable chewing gum. The assessment values demonstrated significant correlation with the number of healthy teeth, but not with maximum bite force, body height, weight, or age.

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Depressive Symptoms Account for Differences between Self-reported Versus Polysomnographic Assessment of Sleep Quality in Women with Myofascial TMD

Abstract

Background

Temporomandibular disorder (TMD) patients report poor sleep quality on the Pittsburgh Sleep Quality Index (PSQI). However, polysomnographic (PSG) studies show meager evidence of sleep disturbance on standard physiological measures.

Objective

The present aim was to analyze self-reported sleep quality in TMD as a function of myofascial pain, PSG parameters, and depressive symptomatology.

Methods

PSQI scores from 124 women with myofascial TMD and 46 matched controls were hierarchically regressed onto TMD presence, ratings of pain intensity and pain-related disability, in-lab PSG variables, and depressive symptoms (Symptoms Checklist-90).

Results

Relative to controls, TMD cases had higher PSQI scores, representing poorer subjective sleep, and more depressive symptoms (both P < 0.001). Higher PSQI scores were strongly predicted by more depressive symptoms (P < 0.001, R2 = 26%). Of 19 PSG variables, two had modest contributions to higher PSQI scores: longer REM latency in TMD cases (P = 0.01, R2 = 3%) and more awakenings in all participants (P = 0.03, R2 = 2%). After accounting for these factors, TMD presence and pain ratings were not significantly related to PSQI scores.

Conclusion

These results show that reported poor sleep quality in TMD is better explained by depressive symptoms than by PSG-assessed sleep disturbances or myofascial pain. As TMD cases lacked typical PSG features of clinical depression, the results suggest a negative cognitive bias in TMD and caution against interpreting self-report sleep measures as accurate indicators of PSG sleep disturbance. Future investigations should take account of depressive symptomatology when interpreting reports of poor sleep.

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Hemophilic pseudotumor of the mandible in a patient with hemophilia B

Abstract

Introduction

Hemophilic pseudotumor is a rare complication occurring in patients with hemophilia, frequently seen in the femur, tibia, pelvic bones, iliac bones, or rarely in the maxillofacial region.

Case report

A 7-year-old male reported with a spontaneous extra-oral swelling that was managed with pre-operative transfusion of factor IX along with curettage of the lesion. Our report presents only the fourth case in literature wherein this tumor presented in a patient with hemophilia B.

Finding

Hemophilic pseudotumor is a rare entity in the maxillofacial region. High degree of suspicion is required for diagnosis, and close coordination between the medical and surgical teams aids in management.



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Gender difference and laterality of sleep position

A higher incidence in women (approximately 7:3) and a predominant involvement of the right ear (approximately 7:5) are interesting features of BPPV (benign paroxysmal positional vertigo). It is speculated that these features are related to sleep position. The first aim of this study was to compare the frequency of position shifts during sleep between men and women. The second aim was to elucidate any differences in sleep position between men and women. The third aim was to clarify the laterality of sleep position.

http://ift.tt/2x2HDTl

Gender difference and laterality of sleep position

A higher incidence in women (approximately 7:3) and a predominant involvement of the right ear (approximately 7:5) are interesting features of BPPV (benign paroxysmal positional vertigo). It is speculated that these features are related to sleep position. The first aim of this study was to compare the frequency of position shifts during sleep between men and women. The second aim was to elucidate any differences in sleep position between men and women. The third aim was to clarify the laterality of sleep position.

http://ift.tt/2x2HDTl

Repair and sensory reconstruction of the children’s finger pulp defects with perforator pedicled propeller flap in proper digital artery

OBJECTIVE: This study was designed to investigate the clinical effects of adopting perforator pedicled propeller flap in the proper digital artery for treatment and sensory reconstruction of finger pulp defects in children.

PATIENTS AND METHODS: Perforator pedicled propeller flap of proper digital arteries in thirty-one fingers from twenty-three children patients were selected for repairing the pulp defects on the 2nd to the 5th fingers. All cases were treated from September 2012 to December 2013. To properly reconstruct the pulps' feeling we needed the dorsal branch of the proper digital nerve in the flap to be consistent with the broken end of proper digital nerve in pulps' wound. A free skin graft was carried out with full-thickness skin taken from the medial thigh for flap donor area. We scheduled two post-operation return visits, one in six months and the second visit in twelve months following the operation. Parents' satisfaction with the postoperative appearance of their children's fingers was assessed based on Michigan Hand Outcome Questionnaire.

RESULTS: All operations were performed successfully and all wounds healed in the first period and all flaps survived. During the final follow-up, the shape recovery of flaps and their donor areas were examined and satisfactory results were obtained. All pulps were full and round without any obvious pigmentation or scar contracture. The sensory recovery of pulps was achieved S3+, and the two-point discrimination was 4.5 to 6.0 mm (with 5.1 mm being the average value). Parents' satisfaction with the postoperative results was very promising with twenty-one cases of very satisfied and two cases of satisfied parents.

CONCLUSIONS: The operation method used in this study demonstrated to be a safe and reliable procedure producing a very good flap blood supply as well as excellent sensory recovery and satisfactory postoperative appearance.

L'articolo Repair and sensory reconstruction of the children's finger pulp defects with perforator pedicled propeller flap in proper digital artery sembra essere il primo su European Review.



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Detection of hereditary hearing loss gene by DNA microarray

OBJECTIVE: Screening genes in patients suffering clinically sporadic deafness, using DNA microarray, and evaluating the application value of the clinical detection.

PATIENTS AND METHODS: DNA extracted from patients' venous blood was amplified by PCR, and hybridization was carried out in a myriad class clean room. Nine mutation sites of four deaf genes commonly seen in Chinese people were tested.

RESULTS: Among 24 patients, 7 cases with mutations were detected, with a positive rate of 29.17%. These include 4 cases with GJB2 gene mutation (16.67%), of which 1 case with 176 del 16 site heterozygous mutation; 1 with 235 del C site homozygous mutation; 2 with 299 del AT site heterozygous mutation; 1 with SLC26A4 gene IVS7-2A>G site heterozygous mutation (4.17%), 2 with mitochondrion 12SrRNA gene1555A>G site homogeneous mutation (8.33%). No GJB3 gene mutation was detected.

CONCLUSIONS: Gene chip technology of hereditary hearing loss can detect related mutation sites of hearing loss rapidly and with high-throughput, which meets the demands of clinical deaf gene detection.

L'articolo Detection of hereditary hearing loss gene by DNA microarray sembra essere il primo su European Review.



http://ift.tt/2vAYTLW

Effects of Aging on Vocal Fundamental Frequency and Vowel Formants in Men and Women

This study reports data on vocal fundamental frequency (fo) and the first four formant frequencies (F1, F2, F3, F4) for four vowels produced by speakers in three adult age cohorts, in a test of the null hypothesis that there are no age-related changes in these variables. Participants were 43 men and 53 women between the ages of 20 and 92 years.

http://ift.tt/2vCADZC

Detection of hereditary hearing loss gene by DNA microarray

OBJECTIVE: Screening genes in patients suffering clinically sporadic deafness, using DNA microarray, and evaluating the application value of the clinical detection.

PATIENTS AND METHODS: DNA extracted from patients' venous blood was amplified by PCR, and hybridization was carried out in a myriad class clean room. Nine mutation sites of four deaf genes commonly seen in Chinese people were tested.

RESULTS: Among 24 patients, 7 cases with mutations were detected, with a positive rate of 29.17%. These include 4 cases with GJB2 gene mutation (16.67%), of which 1 case with 176 del 16 site heterozygous mutation; 1 with 235 del C site homozygous mutation; 2 with 299 del AT site heterozygous mutation; 1 with SLC26A4 gene IVS7-2A>G site heterozygous mutation (4.17%), 2 with mitochondrion 12SrRNA gene1555A>G site homogeneous mutation (8.33%). No GJB3 gene mutation was detected.

CONCLUSIONS: Gene chip technology of hereditary hearing loss can detect related mutation sites of hearing loss rapidly and with high-throughput, which meets the demands of clinical deaf gene detection.

L'articolo Detection of hereditary hearing loss gene by DNA microarray sembra essere il primo su European Review.



http://ift.tt/2vAYTLW

Blowing the Whistle; the Ethical, Professional and Legal Implications of Raising Concerns and Self-Regulation within Dentistry

Abstract

Whistle-blowers are a necessary part of any system; dentistry is no different. The role of whistle-blowers in dentistry has been enshrined in Australian law since 2010. Raising concerns has become a legal duty as well as an ethical and professional obligation. It is important that these different aspects of raising concerns are explored as each adds another layer of consideration to the issue. The health professional's duty to whistle-blow could be viewed as problematic; the observance of this duty is associated with being trapped between a rock and a hard place where any decision to engage or not may have negative consequences. For the obligation of raising concerns to gain acceptability within the dental profession, the concept requires reframing as being necessary for the profession's continued success. The stigma of mandatory reporting needs to be removed to allow this essential process to occur. This article will discuss the ethical, professional and legal imperatives for the dental profession to engage with whistle-blowing and the likely challenges that are likely to be met in doing so.

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Prosthodontic management of maxillofacial cases: a case series

Abstract

Maxillo-facial prosthetics is an important and recognised sub-discipline of prosthodontics that forms a key component of postgraduate training programs. General dentists have a role to play in the management of maxillo-facial defect patients even though treatment usually requires a multidisciplinary approach in an institutional environment. Maxillo-facial prosthetic cases frequently present with complex histories but simple patient goals. The conservatively managed implant-retained auricular prosthesis, speech aid prosthesis and orbital prosthesis cases described in this report were completed in a postgraduate clinical residency program and highlight the intrinsic complexities, challenges and ultimately satisfaction related to cases of this nature.

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Oral health of community dwelling older Australian men: The Concord Health and Ageing in Men Project (CHAMP)

Abstract

Background

CHAMP is a cohort study of the health of a representative sample of Australian men aged 70 years and older. The aim of this report is to describe the oral health of these men.

Methods

Oral health was assessed when the men were all aged 78 years or older. Two calibrated examiners conducted a standardised intra-oral assessment. Descriptive data, with means and confidence intervals where appropriate, were analysed by statistical association tests. Participants were excluded from the collection of some periodontal assessments if they had a medical contraindication.

Results

Dental assessments of 614 participants revealed 90 (14.6%) were edentate. Men had a mean of 13.8 (CI 13.2-14.4) missing teeth and 10.3 (CI 9.8-10.8)teeth. Dentate participants had a mean of 1.1(CI 0.9-1.2) teeth with active coronal decay. Participants born in Italy had higher rates of sound teeth and lower rates of filled teeth, while those in the low income group had a higher rate of decayed teeth and lower rate of filled teeth. Thirty-four participants (5.5%) had one or more dental implants, and 66.3%relied on substitute natural teeth for functional occlusion. Of the 296 participants with full periodontal assessments, 90.9% (n=269) had one or more sites with pocket depths ≥3mm, 96.6% (n=286), had one or more sites with clinical attachment loss ≥ 5mm and 90.2% (n=267) had three or more sites with GI ≥ 2 scores.

Conclusions

There was a high prevalence of periodontal diseases and restorative burden of dentitions, which suggests that greater attention needs to be given to prevention and health maintenance in older Australian men.

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Studying the human oral microbiome: challenges and the evolution of solutions

Abstract

Since the pioneering work of van Leeuwenhoek in 1684, subsequently built upon by other renowned microbiologists Robert Koch, Willoughby Miller and G.V. Black, oral microbiology has developed innovative techniques to study the oral microflora (now termed the "oral microbiome"). The advent of molecular techniques such as DNA-DNA hybridisation, polymerase chain reaction (PCR) and DNA sequencing has created an array of opportunities to construct a comprehensive picture of the diversity and composition of the oral microbiome. Approximately 700 oral bacterial species have been identified, of which 50% have yet to be cultivated, and some of these are known only by their signature DNA sequences. The synergism of ever-evolving culture-based and state-of-the-art culture-independent molecular techniques has facilitated in-depth understanding of the dynamics, acquisition and transfer of oral bacteria, along with their role in oral and general health and disease. Further research is needed to not only analyse but also to make sense of the ever-increasing volumes of data which these molecular techniques (especially high-throughput DNA sequencing) are generating, as well as why particular bacteria are present and what they are "actually doing" there. This review presents a comprehensive literature search of oral microbiology-related methods currently used to study the oral microbiome.

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