Mirror Motor Activity During Right-Hand Contractions and Its Relation to White Matter in the Posterior Midbody of the Corpus Callosum

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Cortical activity during simple unimanual actions is typically lateralized to contralateral sensorimotor areas, while a more bilateral pattern is observed with an increase in task demands. In parallel, increasing task demands are associated with subtle mirror muscle activity in the resting hand, implying a relative loss in motor selectivity. The corpus callosum (CC) is crucially involved in unimanual tasks by mediating both facilitatory and inhibitory interactions between bilateral motor cortical systems, but its association with mirror motor activity is yet unknown. Here, we used diffusion-weighted imaging and bilateral electromyographic (EMG) measurements during a unimanual task to investigate potential relationships between white matter microstructure of the CC and mirror EMG activity. Participants performed an unimanual pinch force task with both hands alternatively. Four parametrically increasing force levels were exerted while EMG activity was recorded bilaterally from first dorsal interosseus muscles. Consistent with previous findings, mirror EMG activity increased as a function of force. Additionally, there was a significant relationship between the slope of increasing mirror EMG during right-hand contractions and fractional anisotropy in transcallosal fibers connecting both M1. No significant relationships were found for fibers connecting dorsal premotor cortices or supplementary motor area, indicating the local specificity of the observed brain–physiology relationship.</span>

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Distinct Spatiotemporal Response Properties of Excitatory Versus Inhibitory Neurons in the Mouse Auditory Cortex

<span class="paragraphSection"><div class="boxTitle">Abstract</div>In the auditory system, early neural stations such as brain stem are characterized by strict tonotopy, which is used to deconstruct sounds to their basic frequencies. But higher along the auditory hierarchy, as early as primary auditory cortex (A1), tonotopy starts breaking down at local circuits. Here, we studied the response properties of both excitatory and inhibitory neurons in the auditory cortex of anesthetized mice. We used in vivo two photon-targeted cell-attached recordings from identified parvalbumin-positive neurons (PVNs) and their excitatory pyramidal neighbors (PyrNs). We show that PyrNs are locally heterogeneous as characterized by diverse best frequencies, pairwise signal correlations, and response timing. In marked contrast, neighboring PVNs exhibited homogenous response properties in pairwise signal correlations and temporal responses. The distinct physiological microarchitecture of different cell types is maintained qualitatively in response to natural sounds. Excitatory heterogeneity and inhibitory homogeneity within the same circuit suggest different roles for each population in coding natural stimuli.</span>

http://ift.tt/2foqgk2

Unstable Maternal Environment Affects Stress Response in Adult Mice in a Genotype-Dependent Manner

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Early postnatal events exert powerful effects on development, inducing persistent functional alterations in different brain network, such as the catecholamine prefrontal–accumbal system, and increasing the risk of developing psychiatric disorders later in life. However, a vast body of literature shows that the interaction between genetic factors and early environmental conditions is crucial for expression of psychopathologies in adulthood. We evaluated the long-lasting effects of a repeated cross-fostering (RCF) procedure in 2 inbred strains of mice (C57BL/6J, DBA/2), known to show a different susceptibility to the development and expression of stress-induced psychopathologies. Coping behavior (forced swimming test) and preference for a natural reinforcing stimulus (saccharine preference test) were assessed in adult female mice of both genotypes. Moreover, c-Fos stress-induced activity was assessed in different brain regions involved in stress response. In addition, we evaluated the enduring effects of RCF on catecholamine prefrontal–accumbal response to acute stress (restraint) using, for the first time, a new "dual probes" in vivo microdialysis procedure in mouse. RCF experience affects behavioral and neurochemical responses to acute stress in adulthood in opposite direction in the 2 genotypes, leading DBA mice toward an "anhedonic-like" phenotype and C57 mice toward an increased sensitivity for a natural reinforcing stimulus.</span>

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Deubiquitination and Stabilization of PD-L1 by CSN5

Publication date: Available online 17 November 2016
Source:Cancer Cell
Author(s): Seung-Oe Lim, Chia-Wei Li, Weiya Xia, Jong-Ho Cha, Li-Chuan Chan, Yun Wu, Shih-Shin Chang, Wan-Chi Lin, Jung-Mao Hsu, Yi-Hsin Hsu, Taewan Kim, Wei-Chao Chang, Jennifer L. Hsu, Hirohito Yamaguchi, Qingqing Ding, Yan Wang, Yi Yang, Chung-Hsuan Chen, Aysegul A. Sahin, Dihua Yu, Gabriel N. Hortobagyi, Mien-Chie Hung
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.

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Teaser

Lim et al. show that inflammation increases PD-L1 expression in tumors through TNF-α-mediated activation of NF-κB, leading to transactivation of CSN5. CSN5 reduces PD-L1 ubiquitination and stabilizes it. Inhibition of CSN5 cooperates with anti-CTLA4 to enhance anti-tumor T cell function and reduce tumor growth.


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Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy

Publication date: Available online 17 November 2016
Source:Cancer Cell
Author(s): Anna Rita Cantelmo, Lena-Christin Conradi, Aleksandra Brajic, Jermaine Goveia, Joanna Kalucka, Andreas Pircher, Pallavi Chaturvedi, Johanna Hol, Bernard Thienpont, Laure-Anne Teuwen, Sandra Schoors, Bram Boeckx, Joris Vriens, Anna Kuchnio, Koen Veys, Bert Cruys, Lise Finotto, Lucas Treps, Tor Espen Stav-Noraas, Francesco Bifari, Peter Stapor, Ilaria Decimo, Kim Kampen, Katrien De Bock, Guttorm Haraldsen, Luc Schoonjans, Ton Rabelink, Guy Eelen, Bart Ghesquière, Jalees Rehman, Diether Lambrechts, Asrar B. Malik, Mieke Dewerchin, Peter Carmeliet
Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as an anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyper-glycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation, and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-κB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors.

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Teaser

Cantelmo et al. show that tumor endothelial cells have hyperglycolytic metabolism. Inactivation of the glycolytic activator PFKFB3 normalizes tumor vessels and improves vessel perfusion via tightening the vascular barrier, which reduces cancer cell intravasation and metastasis and improves chemotherapy response.


http://ift.tt/2gnzeCx

Corrigendum to “Review of Amyotrophic Lateral Sclerosis, Parkinson’s and Alzheimer’s diseases helps further define proteomic events of the novel paradigm for Alzheimer’s with metals as primary disease cause” [Med. Hypotheses 85 (2015) 779–790]

Publication date: January 2017
Source:Medical Hypotheses, Volume 98
Author(s): Franco Cavaleri




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Senses make sense: An individualized multisensory stimulation for dementia

Publication date: Available online 17 November 2016
Source:Medical Hypotheses
Author(s): Yuanwu Cui, Minxue Shen, Yan Ma, Shi Wu Wen
Nonpharmacologic interventions have been recommended as first-line treatments for dementia, and multisensory stimulation environment has been used as a non-pharmacological treatment to dementia patients in the last decade. However, the clinical effect of multisensory stimulation environment remains temporary and uncertain. Individualized medicine has been suggested to hold great promise in medicine, and it should be equally important for dementia. Reminiscence integrating individual experiences into therapeutic schemes has shown potential in the field of improving cognitive functions and depressive symptoms for dementia patients, and interactive music also demonstrated a positive outcome by using individualized music for the hearing aspect. We therefore hypothesize that an individualized multisensory stimulation in a natural and realistic environment integrating personal experience may be an effective intervention for patients suffering from dementia.



http://ift.tt/2fbBlY1