Environmental Science and Pollution Research

Regulating nitrate excess in lettuce-planted greenhouse soil with available carbon addition through irrigation Abstract Nitrate excess is common in greenhouse soils, imposing environmental risks and degrading vegetable quality. In this study, the effectiveness of adding sucrose as available carbon through irrigation to cut nitrate excess in lettuce-planted soil was investigated under impacts of soil texture and irrigation type. In the pot experiment using two loam soils of same origin with different clay to sand ratios (50.2% and 39.8%) and nitrate excess (116.1 and 417.7 mg/kg N), three-time sucrose addition through flood irrigation was more effective in lowering net formation of nitrate-based inorganic N and increasing lettuce yield in the soil with the higher clay to sand ratio, and sucrose addition at 150–450 mg/kg reduced nitrate accumulation and leaching, and nitrate content of lettuce at harvest by 62.5–89.6%, 19.3–36.1%, and 11.4–76.0%, respectively. In the micro-plot field experiment with two-time sucrose addition at 0.6–1.2 g/L through furrow irrigation (42 mm) into two other soils of same origin with different clay to sand ratios (56.9%, 48.4%), nitrate accumulation at 0–30-cm depth at the prone-leaching furrow location at harvest decreased by 30.9–36.0% under the higher clay to sand ratio but increased by about 35% under the lower clay to sand ratio. The nitrate content and yield of ridge-planted lettuce was less affected in either soil. Hence, carbon addition rate, irrigation type, and clay to sand ratio all affected the effect of available carbon addition on nitrate accumulation in vegetable-planted soil, and their joint impacts need better quantification for cutting nitrate excess in soil and improving vegetable quality and even yield.

Exogenous application of ascorbic acid mitigates cadmium toxicity and uptake in Maize ( Zea mays L.) Abstract Cadmium (Cd) contamination in agricultural soils is a prevalent environmental issue and poses potential threats to food security. Foliar ascorbic acid might prove a potent tool to alleviate toxicity of Cd toxicity in maize. An experiment was conducted with objectives to study exogenous ascorbic acid–modulated improvements in physiochemical attributes of maize under Cd toxicity. The experiment was conducted under completely randomized design. Treatments were comprised of varying concentrations of foliar ascorbic acid viz. 0.0, 0.1, 0.3, and 0.5 mM of AsA. Toxicity of Cd decreased the maize growth, increased lipid peroxidation, disturbed protein metabolism, and reduced the antioxidant defense capabilities compared with the control. However, foliar AsA significantly improved maize growth and development, photosynthetic capabilities, and protein concentrations in Cd-stressed maize plants. Meanwhile, the malondialdehyde contents and hydrogen peroxide accumulation levels in Cd-stressed maize plants decreased remarkably with increasing AsA concentrations. Furthermore, the combined treatments conspicuously boosted activities of superoxide dismutase, peroxidase, catalase, and glutathione reductase under the Cd stress alone. In addition, the application of AsA reduced the Cd uptake by 10.3–12.3% in grains. Conclusively, foliar ascorbic acid alleviated the negative effects of Cd stress in maize and improved photosynthetic processes, osmolytes, and antioxidant defense systems.

Body size variation of the ant Lasius niger along a metal pollution gradient Abstract The phenotypic diversity of ant workers plays a fundamental role in their biology. In this study, we asked if the body size variation of monomorphic workers of the ant Lasius niger (Formicidae) responds adaptively to metal pollution in a post-mining metal-polluted area. Nest samples of workers were collected along a pollution gradient to calculate the within-colony variance in body size (expressed as maximum head width, HW). The results showed that the body size variation of L. niger was unrelated to the pollution index but demonstrated considerable variation between colonies even within the same study site. We suggest that the differences in morphological diversity between the colonies of L. niger could be shaped by colony personality traits, i.e., by colony-specific foraging and/or the feeding efficiency of nursing workers. The study supports previous findings, showing that morphological traits in Lasius ants are weakly related to environmental metal pollution.

Impact of affluence and fossil energy on China carbon emissions using STIRPAT model Abstract Using the extended STIRPAT model, this research examines the influence of various factors on China carbon emission from 1971 to 2014, including total nuclear and alternative energy, total fossil energy, GDP per capita, total population, total urban population, merchandise trade of GDP, and services value added of GDP. Ridge regression was employed to perform the study. The research results show the positivity and significance of all factors on carbon emission. The estimated elastic coefficients reveal the most important factor influencing carbon emission is GDP per capita. Total fossil energy, total urban population, and nuclear energy of total energy use are also prominent influencing factors, while other factors such as value-added services of GDP and merchandise trade of GDP have less significant impacts on carbon emission in China. These findings of the research will be of great significance for China to control its carbon emission in the future and to mitigate global warming to some extent.

The evaluation of resistance to Co 2+ of lawn plant at seedling stage and its concentration property at adult stage Abstract In order to evaluate the resistance of lawn plant to Co2+ at germination stage and discuss its concentration property at adult stage, four kinds of lawn plant which have some growth advantages in Co2+ polluted environment were selected as experimental materials in this research. They are tall fescue, timothy grass, inflorescences, and annual ryegrass. The results show that the evaluation of resistance to Co2+ of tall fescue's seed is the highest; the evaluation of resistance to Co2+ of annual ryegrass seed is the lowest. The low consistence Co2+ could improve the seed germination. With Co2+ concentration increase, the accumulation coefficient of four plants increased at first and decreased later; the accumulation coefficient of underground portion is higher than the accumulation coefficient of aboveground; with Co2+ concentration increase, the transfer coefficient of four plants have a remarkable decline. In these plants, the accumulation coefficient of tall fescue and annual ryegrass is bigger than other two plants. As the concentration of Co2+ treatment increased to 100 mg/kg, the aboveground enrichment of Co2+ in F. elata reached 75 mg/kg, followed by L. multiflorum (68.9 mg/kg), P. pratense (48.8 mg/kg), and D. glomerata (27.2 mg/kg).The highest underground enrichment of Co2+ in F. elatareached 836.46 mg/kg, in contrast to the lowest underground enrichment in D. glomerata, 264.67 mg/kg. It shows that fescue and annual ryegrass have a better enrichment property to Co2+ and have a better prospect for the treatment of cobalt-contaminated soil. This research could provide some scientific basis and main technical approach for the soil contaminated by Co2+.

Optimization of process parameters for the synthesis of silver nanoparticles from Piper betle leaf aqueous extract, and evaluation of their antiphytofungal activity Abstract Biological methods offer eco-friendly and cost-effective alternatives for the synthesis of silver nanoparticles (AgNPs). The present study highlights a green process where AgNPs were synthesized and optimized by using silver nitrate (AgNO3) and the aqueous extract of Piper betle (Pbet) leaf as the reducing and capping agent. The stable and optimized process for the synthesis of Pbet-AgNPs was exposure of reaction mixture into the sunlight for 40 min, pH 9.0, and 2 mM AgNO3 using 1:4 diluted Pbet leaf aqueous extract. The optimized Pbet-AgNPs were characterized by UV–visible spectroscopy, high-resolution field emission scanning electron microscopy (FE-SEM), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The prepared Pbet-AgNPs were spherical in shape with size in the range of 6–14 nm. These nanoparticles were stable for 6 months in aqueous solution at room temperature under dark conditions. The biogenic synthesized Pbet-AgNPs are found to have significant antifungal activity against plant pathogenic fungi, Alternaria brassicaeand Fusarium solani. Synthesized Pbet-AgNPs potentially reduced the fungal growth in a dose-dependent manner. Microscopic observation of treated mycelium showed that Pbet-AgNPs could disrupt the mycelium cell wall and induce cellular permeability. Protein leakage assay supports these findings. Overall, this study revealed the efficacy of green synthesized AgNPs to control the plant fungal pathogens. Pbet leaves are a rich source of phenolic biomolecule(s). It was hypothesized that these biomolecule(s) mediated metal reduction reactions. In this context, the present work investigates the phytobiomolecule(s) of the aqueous extract of Pbet leaves using high-resolution liquid chromatography–mass spectroscopy (HR-LCMS) method. The analysis revealed that eugenol, chavicol, and hydroxychavicol were present in the Pbet aqueous extract.

Air-water PCB fluxes from southwestern Lake Michigan revisited Abstract From simultaneous air and water polychlorinated biphenyl (PCB) measurements collected in September 2010, we re-evaluated the direction and magnitude of net air-water exchange of PCBs in southwest Lake Michigan and compared them with estimations made using similar approaches 15 years prior. Air and water samples were collected during a research expedition on Lake Michigan at 5 km off the coast of Chicago, with prevailing winds from the southwest of our location. Gas-phase ΣPCB concentrations ranged from 190 to 1100 pg m−3 with a median of 770 pg m−3, which is similar to the concentrations measured in the City of Chicago at the same time and similar to concentrations measured in this part of the lake over the last 20 years. Water dissolved-phase ΣPCB concentrations ranged from 150 to 170 pg L−1 with a median of 160 pg L−1, which is one-tenth of that measured in the 1990s. ƩPCB net fluxes showed a slightly absorptive behavior, with a median of (−) 21 ng m−2 day−1 and an interquartile range of (−) 47 to (+) 5 ng m−2 day−1, where (−) and (+) fluxes indicate absorption and volatilization, respectively. Airborne PCB concentrations were higher when the winds were coming from Chicago and drive the deposition. Our fluxes are not significantly different from estimations from 1994 and 1995 and suggest that absorption of PCBs into the waters is slightly more prevalent than 15 years ago. It was confirmed that Chicago remains an important atmospheric source of PCBs to Lake Michigan.

Comparison of metabolomic responses of earthworms to sub-lethal imidacloprid exposure in contact and soil tests Abstract Eisenia fetida earthworms were exposed to sub-lethal levels of imidacloprid for 48 h via contact filter paper tests and soil tests. After the exposure, 1H nuclear magnetic resonance (NMR) metabolomics was used to measure earthworm sub-lethal responses by analyzing the changes in the polar metabolite profile. Maltose, glucose, malate, lactate/threonine, myo-inositol, glutamate, arginine, lysine, tyrosine, leucine, and phenylalanine relative concentrations were altered with imidacloprid exposure in soil. In addition to these metabolites (excluding leucine and phenylalanine), fumarate, ATP, inosine, betaine, scyllo-inositol, glutamine, valine, tryptophan, alanine, tyrosine, and isoleucine relative concentrations shifted with imidacloprid exposure during contact tests. Metabolite changes in E. fetida earthworms exposed to imidacloprid showed a non-linear concentration response and an upregulation in gluconeogenesis. Overall, imidacloprid exposure in soil induces a less pronounced response in metabolites glucose, maltose, fumarate, adenosine-5′-triphosphate (ATP), inosine, scyllo-inositol, lactate/threonine, and tyrosine in comparison to the response observed via contact tests. Thus, our study highlights that tests in soil can result in a different metabolic response in E. fetida and demonstrates the importance of different modes of exposure and the extent of metabolic perturbation in earthworms. Our study also emphasizes the underlying metabolic disruption of earthworms after acute sub-lethal exposure to imidacloprid. These observations should be further examined in different soil types to assess the sub-lethal toxicity of imidacloprid to soil-dwelling earthworms.

Toxicological effect of Parthenium hysterophorus and milk processing industry sludge on earthworms, Eisenia fetida Abstract Production of large quantities of organic waste all over the world poses major environmental and disposal problems. The present study was conducted to explore the deleterious effects of Parthenium hysterophorus and milk processing industry sludge on the health of earthworm, Eisenia fetida. Earthworms were allowed to grow in the mixture of cow dung:Parthenium hysterophorus (75:25) and cow dung:milk processing industry sludge (60:40) for 60 days. The biochemical markers viz. superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels and histological changes in earthworm's intestine were assessed after 15, 30, 45, and 60 days of exposure. The results revealed increased MDA level, while SOD, CAT, and GPx activities showed variation in both treatments. Furthermore, histopathological changes revealed damage in the intestinal tissue in both treatments during all intervals. More severe effects were registered in P. hysterophorus treatment. Obtained results may contribute to the understanding of P. hysterophorus and milk processing industry sludge induced toxic effects on earthworms and to identify defense mechanism of Eisenia fetida.

Fish assemblage structure and spatial gradients of diversity in a large tropical reservoir, Panchet in the Ganges basin, India Abstract Fish assemblage structure in Panchet, a large tropical reservoir along river Damodar, major tributary of river Ganga in India, was studied along the spatial gradient of the impoundment. Fish samples were collected bimonthly from October 2014 to September 2016. Fish community structure in terms of species composition, relative abundance, and trophic and conservation status was recorded. Spatial fish diversity was analyzed from riverine, transitional, and lacustrine zones. Sixty-two fish species were recorded wherein the family Cyprinidae dominated in number of species (26) followed by Bagridae (5). Shannon diversity index, evenness index, and species richness did not reveal significant variation (p > 0.05) across different zones. Relative abundance of individuals and species richness were maximum in the transitional zone and minimum in the lacustrine zone. Multi-dimensional scaling of fish assemblage revealed similar pattern in the riverine and transitional zones. Trophic guild of fishes indicated dominance of carnivorous species followed by planktivores. Conservation status (IUCN 2017.3) showed 4 fish species in Near Threatened category. The study suggests conservation of fish habitats to maintain diversity and sustained production. The baseline information generated in the study will be beneficial for monitoring the alteration in fish assemblage, conservation of fish diversity, and management planning.

Medicine, Health Care ,Philosophy

Education and the soul of medicine

The psychological slippery slope from physician-assisted death to active euthanasia: a paragon of fallacious reasoning Abstract In the debate surrounding the morality and legality of the practices of physician-assisted death and euthanasia, a common logical argument regularly employed against these practices is the "slippery slope argument." One formulation of this argument claims that acceptance of physician-assisted death will eventually lead down a "slippery slope" into acceptance of active euthanasia, including its voluntary, non-voluntary, and/or involuntary forms, through psychological and social processes that warp a society's values and moral perspective of a practice over an extended period of time. This formulation is known as the psychological slippery slope argument. This paper analyzes the psychological slippery slope argument as it is applied to the practice of physician-assisted death, and utilizing recent empirical evidence from various nations around the world that practice physician-assisted death and/or euthanasia, the paper argues that (1) employing the psychological slippery slope argument against physician-assisted death is logically fallacious, (2) this kind of slippery slope is unfounded in practice, and thus (3) the psychological slippery slope argument is insufficient on its own to justify continued legal prohibition of physician-assisted death.

Research ethics aspects of experimentation with LSD on human subjects: a historical and ethical review Abstract In this paper our aim is to examine whether research conducted on human participants with LSD-25 (lysergic acid diethylamide) raises unique research ethical questions or demands particular concerns with regard to the design, conduct and follow-up of these studies, and should this be the case, explore and describe those issues. Our analysis is based on reviewing publications up to date which examine the clinical, research and other uses of LSD and those addressing ethical and methodological concerns of these applications, just as some historical examinations of this subject. The first chapters of the paper give an overview regarding the history of LSD-research with human participants, healthy volunteers and patients alike. The remaining chapters have a focus on questions regarding the potential ethical issues of such human trials in the contemporary research ethics framework. We also consider briefly political and regulatory issues regarding this substance that possibly affect its clinical and research applications.

Spirituality in medical education: a concept analysis Abstract Spirituality in medical education is an abstract multifaceted concept, related to the healthcare system. As a significant dimension of health, the importance and promotion of this concept has received considerable attention all over the world. However, it is still an abstract concept and its use in different contexts leads to different perceptions, thereby causing challenges. In this regard, the study aimed to clarify the existing ambiguities of the concept of spirituality in medical education. Walker and Avant (Strategies for theory construction in nursing, Prentice Hall, Boston, 2011) concept analysis eight-step approach was used. After an extensive review of online national and international databases from 2000 to 2015, 180 articles and 3 books in English and Persian were retrieved for the purposes of the study. Analysis revealed that the defining attributes of spirituality in medical education are: teaching with all heart and soul, Life inspiring, ontological multidimensional connectedness, religious-secular spectrum, and socio-cultural intricacies. Moreover, innate wisdom, skillful treatment, transcendent education, and environmental requirements were antecedents to this concept, with the health of body and soul, intrapersonal development and elevation, and responsive treatment and education being its consequences. The defining attributes provided in this study can assist physicians, instructors, and professors to develop and implement evidence-based, health based and comprehensive education plans according to the guidelines of professional ethics and qualification of using spirituality in practice. The clarification of the noted concept facilitates further development of medical knowledge, research, and research instruments.

Obesity, political responsibility, and the politics of needs Abstract Since overweight and obesity have been framed as one of the main contemporary health challenges in industrialized countries, it has become a matter of public health efforts. While the belief that obese individuals are personally responsible for their body weight prevails in public opinion, evidence-based health science widely acknowledges that obesity is significantly influenced by socio-economic factors and thus that prevention requires structural changes. This constellation bears the chance of politicizing an issue formerly conceived of as private which really is dependent on societal contingencies, such as the particular availability of food. Reflecting on the prevention of obesity from an ethical point of view, therefore, requires an elaborate concept of political responsibility. The core thesis of this paper is that existing approaches within the field of obesity ethics fall short in reasonably grasping the political dimensions at play, due to the prevailing individualistic understanding of responsibility. Drawing upon Iris Marion Young's concept of political responsibility, I propose an alternative approach that emphasizes the structural determinants of obesity. By arguing this way, obesity prevention comes into view as a public endeavor that involves public discourse as well as shared action. Political responsibility then cannot be discharged merely by intrusive governmental action nor by individuals on their own, but should be considered as a task all of us share. As I will sketch in the last part of the paper, this includes contesting discourses on interpretations of need. Thereby, the paper contributes to recognizing obesity as a social instead of an individual problem.

Criminalization of scientific misconduct Abstract This paper discusses the criminalization of scientific misconduct, as discussed and defended in the bioethics literature. In doing so it argues against the claim that fabrication, falsification and plagiarism (FFP) together identify the most serious forms of misconduct, which hence ought to be criminalized, whereas other forms of misconduct should not. Drawing the line strictly at FFP is problematic both in terms of what is included and what is excluded. It is also argued that the criminalization of scientific misconduct, despite its anticipated benefits, is at risk of giving the false impression that dubious practices falling outside the legal regulation "do not count". Some doubts are also raised concerning whether criminalization of the most serious forms of misconduct will lower the burdens for universities or successfully increase research integrity. Rather, with or without criminalization, other measures must be taken and are probably more important in order to foster a more healthy research environment.

Moral enhancement and the good life Abstract One approach to defining enhancement is in the form of bodily or mental changes that tend to improve a person's well-being. Such a "welfarist account", however, seems to conflict with moral enhancement: consider an intervention that improves someone's moral motives but which ultimately diminishes their well-being. According to the welfarist account, this would not be an instance of enhancement—in fact, as I argue, it would count as a disability. This seems to pose a serious limitation for the account. Here, I elaborate on this limitation and argue that, despite it, there is a crucial role for such a welfarist account to play in our practical deliberations about moral enhancement. I do this by exploring four scenarios where a person's motives are improved at the cost of their well-being. A framework emerges from these scenarios which can clarify disagreements about moral enhancement and help sharpen arguments for and against it.

Rethinking the doctor–patient relationship: toward a hermeneutically-informed epistemology of medical practice Abstract Although typically implicit, clinicians face an inherent conflict between their roles as medical healers and as providers of technical biomedicine (Scott et al. in Philos Ethics Humanit Med 4:11, 2009). This conflict arises from the tension between the physicalist model which still predominates in medical training and practice and the extra-physicalist dimensions of medical practice as epitomised in the concept of patient-centred care. More specifically, the problem is that, as grounded in a "borrowed" physicalist philosophy, the dominant "applied scientist" model exhibits a number of limitations which severely restrict its ability to underwrite the effective practice of care. Moreover, being structural in character, these problems cannot be resolved by piecemeal modifications of the existing model, nor by an appeal to evidence-based medicine (Miles in J Eval Clin Pract 15(6):887–890, 2009; Miles in Folia Med 55(1):5–24, 2013; Miles et al. in J Eval Clin Pract 14(5):621–649, 2008). Hence, the need for medical theorists to "partner with experts in the humanities to build a sui generis philosophy of medicine" (Whatley in J Eval Clin Pract 20(6):961–964, 2014, p. 961). In response, the present paper seeks to vindicate the merits of hermeneutically-informed template in providing the requisite grounding. While capable of correcting for the limitations of the applied scientist model, a hermeneutically-informed template is a "both/and" approach, which seeks to complement rather than exclude the physicalist dimension, and thereby aspires to reconcile technical mastery with patient-centred care, rather than eschew one in favour of the other. As such, it can provide a cogent philosophical template for current best practice, which does justice to the art as well as the science of medical care.

Professional ethics: the case of neonatology Abstract Neonatal professionals encounter many ethical challenges especially when it comes to interventions at the limit of viability (weeks 22–25 of gestation). At times, these challenges make the moral dilemmas in neonatology tragic and they require a particular set of intellectual and moral virtues. Intellectual virtues of episteme and phronesis, together with moral virtues of courage, compassion, keeping fidelity to trust, and integrity were highlighted as key virtues of the neonatal professional. Recognition of the role of ethics requires a recognition that answering the obvious question (what shall we do?) does not always suffice. Acknowledging the tragic question (is any of the alternatives open to us free from serious moral wrongdoing) and recognizing the ethical dilemmas, where the lines between right and wrong are blurred, leads to actions taken towards establishing ethics frameworks to support decision-making. In neonatology units, such organizational support can help in allowing the team members to recognize the ethical dilemmas, avoid moral distress, and improve team cohesion and the quality of care provided. Only when the organizational structure allows ethical dilemmas to be recognized, adequate decisions can be made.

Leaving gift-giving behind: the ethical status of the human body and transplant medicine Abstract The paper argues that the idea of gift-giving and its associated imagery, which has been founding the ethics of organ transplants since the time of the first successful transplants, should be abandoned because it cannot effectively block arguments for (regulated) markets in human body parts. The imagery suggests that human bodies or their parts are transferable objects which belong to individuals. Such imagery is, however, neither a self-evident nor anthropologically unproblematic construal of the relation between a human being and their body. The paper proposes an alternative conceptualization of that relation, the identity view according to which a human being is identical with their living body. This view, which offers a new ethical perspective on some central concepts of transplant medicine and its ethical and legal standards and institutions, supports widely shared intuitive ethical judgments. On this proposal, an act of selling a human body or one of its parts is an act of trade in human beings, not in owned objects. Transfers of human body parts for treatment purposes are to be seen as sharing in another human being's misfortune rather than as giving owned objects. From the perspective of policy-making, the proposal requires, first, that informed consent for removal of transplant material be obtained from the potential benefactor. Secondly, explicit consent by the prospective benefactor is obligatory in the case of removal of transplant material from a living benefactor. Thirdly, in the case of posthumous retrieval, informed consent by the potential benefactor during their life is not ethically indispensable. Additionally, while refusal of posthumous retrieval expressed by a potential benefactor during their life must be respected, such a refusal needs ethical justification and explanation.

Mammary Gland Biology and Neoplasia

Metformin and Breast Cancer: Molecular Targets Abstract Metformin has been the first-line drug for the treatment of type II diabetes mellitus for decades, being presently the most widely prescribed antihyperglycemic drug. Retrospective studies associate the use of metformin with a reduction in cancer incidence and cancer-related death. However, despite extensive research about the molecular effects of metformin in cancer cells, its mode of action remains controversial. The major molecular targets of metformin include complex I of the mitochondrial electron transport chain, adenosine monophosphate (AMP)-activated protein kinase (AMPK), and mechanistic target of rapamycin complex 1 (mTORC1), but AMPK-independent effects of metformin have also been described. Breast cancer is one of the leading causes of cancer-related morbidity and mortality among women worldwide. Several studies have reinforced a link between breast cancer risk and diabetes. Moreover, metformin significantly reduces breast cancer risk, compared to patients who are not using metformin and is independent of diabetes status. In this review, we summarize the current molecular evidence to elucidate metformin's mode of action against breast cancer cells.

Correction to: The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast The original version of this article unfortunately contained mistakes.

A Transgenic MMTV-Flippase Mouse Line for Molecular Engineering in Mammary Gland and Breast Cancer Mouse Models Abstract Genetically engineered mouse models have become an indispensable tool for breast cancer research. Combination of multiple site-specific recombination systems such as Cre/loxP and Flippase (Flp)/Frt allows for engineering of sophisticated, multi-layered conditional mouse models. Here, we report the generation and characterization of a novel transgenic mouse line expressing a mouse codon-optimized Flp under the control of the mouse mammary tumor virus (MMTV) promoter. These mice show robust Flp-mediated recombination in luminal mammary gland and breast cancer cells but no Flp activity in non-mammary tissues, with the exception of limited activity in salivary glands. These mice provide a unique tool for studying mammary gland biology and carcinogenesis in mice.

Dissecting Tissue-Specific Super-Enhancers by Integrating Genome-Wide Analyses and CRISPR/Cas9 Genome Editing Abstract Recent advances in genome-wide sequencing technologies have provided researchers with unprecedented opportunities to discover the genomic structures of gene regulatory units in living organisms. In particular, the integration of ChIP-seq, RNA-seq, and DNase-seq techniques has facilitated the mapping of a new class of regulatory elements. These elements, called super-enhancers, can regulate cell-type-specific gene sets and even fine-tune gene expression regulation in response to external stimuli, and have become a hot topic in genome biology. However, there is scant genetic evidence demonstrating their unique biological relevance and the mechanisms underlying these biological functions. In this review, we describe a robust genome-wide strategy for mapping cell-type-specific enhancers or super-enhancers in the mammary genome. In this strategy, genome-wide screening of active enhancer clusters that are co-occupied by mammary-enriched transcription factors, co-factors, and active enhancer marks is used to identify bona fide mammary tissue-specific super-enhancers. The in vivo function of these super-enhancers and their associated regulatory elements may then be investigated in various ways using the advanced CRISPR/Cas9 genome-editing technology. Based on our experience targeting various mammary genomic sites using CRISPR/Cas9 in mice, we comprehensively discuss the molecular consequences of the different targeting methods, such as the number of gRNAs and the dependence on their simultaneous or sequential injections. We also mention the considerations that are essential for obtaining accurate results and shed light on recent progress that has been made in developing modified CRISPR/Cas9 genome-editing techniques. In the future, the coupling of advanced genome-wide sequencing and genome-editing technologies could provide new insights into the complex genetic regulatory networks involved in mammary-gland development.

Role of Liver X Receptor in Mastitis Therapy and Regulation of Milk Fat Synthesis Abstract Mastitis is important disease that causes huge economic losses in the dairy industry. In recent years, antibiotic therapy has become the primary treatment for mastitis, however, due to drug residue in milk and food safety factors, we lack safe and effective drugs for treating mastitis. Therefore, new targets and drugs are urgently needed to control mastitis. LXRα, one of the main members of the nuclear receptor superfamily, is reported to play important roles in metabolism, infection and immunity. Activation of LXRα could inhibit LPS-induced mastitis. Furthermore, LXRα is reported to enhance milk fat production, thus, LXRα may serve as a new target for mastitis therapy and regulation of milk fat synthesis. This review summarizes the effects of LXRα in regulating milk fat synthesis and treatment of mastitis and highlights the potential agonists involved in both issues.

Androgen Receptor Signalling Promotes a Luminal Phenotype in Mammary Epithelial Cells Abstract Androgens influence mammary gland development but the specific role of the androgen receptor (AR) in mammary function is largely unknown. We identified cell subsets that express AR in vivo and determined the effect of AR activation and transgenic AR inhibition on sub-populations of the normal mouse mammary epithelium by flow cytometry and immunohistochemistry. Immunolocalisation of AR with markers of lineage identity was also performed in human breast tissues. AR activation in vivo significantly decreased the proportion of basal cells, and caused an accumulation of cells that expressed a basal cell marker but exhibited morphological features of luminal identity. Conversely, in AR null mice the proportion of basal mammary epithelial cells was significantly increased. Inhibition of AR increased basal but not luminal progenitor cell activity in vitro. A small population of AR-positive cells in a basal-to-luminal phenotype transition was also evident in human breast lobules. Collectively, these data support a role for AR in promoting a luminal phenotype in mammary epithelial cells.

STAT5-Driven Enhancers Tightly Control Temporal Expression of Mammary-Specific Genes Abstract The de novo formation of milk-secreting mammary epithelium during pregnancy is regulated by prolactin through activation of the transcription factor STAT5, which stimulates the expression of several hundred mammary-specific genes. In addition to its key role in activating gene expression in mammary tissue, STAT5, which is ubiquitously expressed in most cell types, implements T cell-specific programs controlled by interleukins. However, the mechanisms by which STAT5 controls cell-specific genetic programs activated by distinct cytokines remain relatively unknown. Integration of data from genome-wide surveys of chromatin markers and transcription factor binding at regulatory elements may shed light on the mechanisms that drive cell-specific programs. Here, we have illustrated how STAT5 controls cell-specific gene expression through its concentration and an auto-regulatory enhancer supporting its high levels in mammary tissue. The unique genomic features of STAT5-driven enhancers or super-enhancers that regulate mammary-specific genes and their dynamic remodeling in response to pregnancy hormone levels are described. We have further provided biological evidence supporting the in vivo function of a STAT5-driven super-enhancer with the aid of CRISPR/Cas9 genome editing. Finally, we discuss how the functions of mammary-specific super-enhancers are confined by the zinc finger protein, CTCF, to allow exclusive activation of mammary-specific genes without affecting common neighboring genes. This review comprehensively summarizes the molecular pathways underlying differential control of cell-specific gene sets by STAT5 and provides novel insights into STAT5-dependent mammary physiology.

A Novel 3-Dimensional Co-culture Method Reveals a Partial Mesenchymal to Epithelial Transition in Breast Cancer Cells Induced by Adipocytes Abstract Cancer metastases are accountable for almost 90% of all human cancer related deaths including from breast cancer (BC). Adipocytes can alter the tumor microenvironment, which can promote metastasis by inducing an epithelial-to-mesenchymal transition (EMT) in BC cells. However, the role of adipocytes during the mesenchymal-to-epithelial transition (MET), that can be important in metastasis, is not clear. To understand the effect of adipocytes on the BC progression, there is a requirement for a better in vitro 3-dimensional (3D) co-culture system that mimics the breast tissue and allows for more accurate analysis of EMT and MET. We developed a co-culture system to analyze the relationship of BC cells grown in a 3D culture with adipocytes. We found that adipocytes and adipocyte-derived conditioned media, but not pre-adipocytes, caused the mesenchymal MDA-MB-231 and Hs578t cells to form significantly more epithelial-like structures when compared to the typical stellate colonies formed in control 3D cultures. SUM159 cells and MCF7 cells had a less dramatic shift as they normally have more epithelial-like structure in 3D culture. Biomarker expression analysis revealed that adipocytes only induced a partial MET with proliferation unaffected. In addition, adipocytes had reduced lipid droplet size when co-cultured with BC cells. Thus, we found that physical interaction with adipocytes and ECM changes the mesenchymal phenotype of BC cells in a manner that could promote secondary tumor formation.

Gap Junctions and Wnt Signaling in the Mammary Gland: a Cross-Talk? Abstract Connexins (Cxs), the building blocks of gap junctions (GJs), exhibit spatiotemporal patterns of expression and regulate the development and differentiation of the mammary gland, acting via channel-dependent and channel-independent mechanisms. Impaired Cx expression and localization are reported in breast cancer, suggesting a tumor suppressive role for Cxs. The signaling events that mediate the role of GJs in the development and tumorigenesis of the mammary gland remain poorly identified. The Wnt pathways, encompassing the canonical or the Wnt/β-catenin pathway and the noncanonical β-catenin-independent pathway, also play important roles in those processes. Indeed, aberrant Wnt signaling is associated with breast cancer. Despite the coincident roles of Cxs and Wnt pathways, the cross-talk in the breast tissue is poorly defined, although this is reported in a number of other tissues. Our previous studies revealed a channel-independent role for Cx43 in inducing differentiation or suppressing tumorigenesis of mammary epithelial cells by acting as a negative regulator of the Wnt/β-catenin pathway. Here, we provide a brief overview of mammary gland development, with emphasis on the role of Cxs in development and tumorigenesis of this tissue. We also discuss the role of Wnt signaling in similar contexts, and review the literature illustrating interplay between Cxs and Wnt pathways.

In Vitro Models for Studying Invasive Transitions of Ductal Carcinoma In Situ Abstract About one fourth of all newly identified cases of breast carcinoma are diagnoses of breast ductal carcinoma in situ (DCIS). Since we cannot yet distinguish DCIS cases that would remain indolent from those that may progress to life-threatening invasive ductal carcinoma (IDC), almost all women undergo aggressive treatment. In order to allow for more rational individualized treatment, we and others are developing in vitro models to identify and validate druggable pathways that mediate the transition of DCIS to IDC. These models range from conventional two-dimensional (2D) monolayer cultures on plastic to 3D cultures in natural or synthetic matrices. Some models consist solely of DCIS cells, either cell lines or primary cells. Others are co-cultures that include additional cell types present in the normal or cancerous human breast. The 3D co-culture models more accurately mimic structural and functional changes in breast architecture that accompany the transition of DCIS to IDC. Mechanistic studies of the dynamic and temporal changes associated with this transition are facilitated by adapting the in vitro models to engineered microfluidic platforms. Ultimately, the goal is to create in vitro models that can serve as a reproducible preclinical screen for testing therapeutic strategies that will reduce progression of DCIS to IDC. This review will discuss the in vitro models that are currently available, as well as the progress that has been made using them to understand DCIS pathobiology.

Mammalian Evolution

How Mammals Conquered the Oceans

Into Landscapes of Fear: Marsupial Predators

Running Over the Same Old Ground: Stegomastodon Never Roamed South America Abstract The diversity of South American proboscideans during the Quaternary has been a subject of discussion for decades. The presence of Cuvieronius hyodon in South America is unquestioned and unanimous; however, the taxonomy of the known second South American proboscidean is still a controversy. Some authors argue that the South American species traditionally referred to Stegomastodon should instead be referred to a distinc genus, namely Notiomastodon, endemic to South America. Others authors, however, do not accept this attribution and continue to recognize the genus Stegomastodon as present in South America. In this study, we recognize several differences in the mandible, skull, dentition, and postcranial morphology of North American species of Stegomastodon and Notiomastodon, that further support the validity of Notiomastodon as a taxon separate from Stegomastodon. Indeed, a phylogenetic hypothesis of trilophodont bunodont proboscideans supports the separation between Stegomastodon and Notiomastodon, and the diversification of the common ancestor of these proboscideans may have occurred during the middle to late Miocene. No specimen with Stegomastodon diagnostic features is recognized in South America. The Stegomastodon records are restricted to the Pliocene-middle Pleistocene of North America, while Notiomastodon records are found only from the middle Pleistocene-early Holocene of South America. In this way, we recognize that Stegomastodon records are restricted to North America and that only Cuvieronius and Notiomastodon are recorded in South America.

Growth Pattern and Functional Morphology of the Cervical Vertebrae in the Gerenuk ( Litocranius walleri ): The Evolution of Neck Elongation in Antilopini (Bovidae, Artiodactyla) Abstract Long necks have evolved independently in several different taxa, but the processes underlying the evolution of this trait are not yet fully understood. In this study, we examined the skeletal mechanism underlying the neck elongation in the tribe Antilopini (Bovidae, Artiodactyla). We calculated the growth patterns of the cervical vertebrae in the gerenuk (Litocranius walleri), which possesses the longest neck in this tribe, and compared it with those in two related species. The growth rates of the vertebrae were not significantly different between species, suggesting that the long neck of the gerenuk has resulted from the elongation of the cervical vertebrae during the fetal or juvenile stage. The morphology of the cervical vertebrae of gerenuks differed from that of the closely related, relatively long-necked dama gazelle (Nanger dama), with protrusions occurring on the dorsal surface of the ventral arch of the atlas. This implies that gerenuks possess a well-developed transverse ligament of the atlas that functions to hold the dens of the axis against the atlas. We also found that the atlas lies in close proximity to the neural spine of the axis in the gerenuk, suggesting that hyperextension of the atlantoaxial joint is osteologically limited in this species. While foraging on high foliage, gerenuks flex and extend their necks freely in a bipedal posture without moving their entire body. These morphological characteristics peculiar to the gerenuk enhance the rigidity of the atlantoaxial joint and decrease the risk of subluxation of the joint during this unique foraging behavior.

Interspecific Chromosome Painting Provides Clues to the Ancestral Karyotype of the New World Monkey Genus Aotus Abstract The Neotropical monkey genus Aotus (owl or night monkeys) are among the most karyological diverse primates of the world. Their diploid numbers range from 2n = 46 to 58, but even owl monkeys with the same diploid number may have radically different karyotypes. This karyotypic variability has provided precious information for taxonomists and has a potential for aiding phylogenetic analysis of these primates. However, up to now only three out of 11 species have been analyzed with molecular cytogenetic methods. Here, we report on a fourth species, A. infulatus. Females have a diploid number of 2n = 50 while males, due to a Y/autosome translocation, have 49 chromosomes. We provide a complete map of chromosome homology between humans and A. infulatus. Comparisons with previous reports allowed us to propose a putative ancestral karyotype of the genus (2n = 52) and to deduce the rearrangements that were involved in the origin of each species chromosome complement. Integration of chromosome painting and banding analysis suggests at least three chromosomes have evolutionary new centromeres that appeared during the divergence of these four owl monkey species.

What Can an Invasive Species Tell Us about Evolution? A Study of Dental Variation in Disjunctive Populations of Microtus rossiaemeridionalis (Arvicolinae, Rodentia) Abstract The sibling vole, Microtus rossiaemeridionalis, is a North Eurasian rodent that undergoes range expansion via casual introductions by humans. The documented cases of human-mediated spread of M. rossiaemeridionalisprovide an opportunity to explore phenotypic consequences associated with the invasion events. We present an analysis of dental variability in two recently discovered invasive populations of M. rossiaemeridionalis in northern Asia (Surgut and Khabarovsk) and summarize the data on conspecifics within and outside the core range in order to uncover common and specific patterns of dental variation in the disjunctive invasive populations, and to consider the potential evolutionary significance of the phenotypic effects from neontological and paleontological standpoints. The analysis of morphotype dental patterns and inspection for rare traits suggest that the existence of invasive populations under conditions of isolation leads to a release of hidden phenotypic variation, which could be inferred from sharp increases in frequencies of reserve morphotypes and/or rare dental traits, and also from the presence of abnormalities. An atavistic anomaly of the third upper molars revealed in one individual in a fragmented habitat in Surgut recapitulates some features of the prismatic arrangement and occlusal pattern of extinct Mimomys-like arvicolines. All variants of released phenotypic variation in the invasive populations of M. rossiaemeridionalis under conditions of isolation could be interpreted as de-specialization of dentition. Such de-specialization appears to be maladaptive for a herbivore, though it might favor a transition to a more generalized diet and enhance the success during the transport, colonization, and establishment stages of the invasion.

Impact of Orogeny and Environmental Change on Genetic Divergence and Demographic History of Dipus sagitta (Dipodoidea, Dipodinae) since the Pliocene in Inland East Asia Abstract Inland East Asia encompasses particular landscapes, including discontinuous large deserts isolated by mountains, and these landscapes have been greatly impacted by the uplift of the Qinghai-Tibetan Plateau (QTP) since the Pliocene. However, little research has been performed on the impact of desertification on the evolutionary history of animals in this area. We examined a widespread desert rodent species, Dipus sagitta, to better understand the influences of geological events on the evolutionary history and phylogeographic patterns. We sequenced two mitochondrial genes and three nuclear genes from 237 individuals collected from 43 populations across inland East Asia. Phylogenetic, network, intraspecific delimitation, and population structure analyses identified a structured pattern of geographic differentiation with six well-defined evolutionary clades. High mountains (such as the Tianshan Mountains) and important climate demarcation lines (such as the 200 mm isohyet) were inferred as genetic barriers among the six clades by BARRIER analysis. The most recent common ancestor of D. sagitta was estimated to have existed in late Miocene, and the first clade was estimated to have diverged at c. 7.57 Ma, whereas the later clade diversified rapidly at approximately 2.56–1.53 Ma during the Pleistocene. Demographic analyses suggested different demographic histories among the distinct clades, and the continuous expansion that occurred during the climate oscillation period appeared to be more closely related to the increasing aridification caused by orogeny rather than climate oscillation.

Cryptoprocta spelea (Carnivora: Eupleridae): What Did It Eat and How Do We Know? Abstract The extent to which Madagascar's Holocene extinct lemurs fell victim to nonhuman predators is poorly understood. Madagascar's Holocene predator guild included several now-extinct species, i.e., crocodiles, carnivorans, and raptors. Here we focus on mammalian carnivory, specifically the roles of Cryptoprocta spelea and its still-extant but smaller-bodied sister taxon, C. ferox, the fosa. Cryptoprocta spelea was the largest carnivoran on Madagascar during the Quaternary. We ask whether some extinct lemurs exceeded the upper prey-size limits of C. spelea. We use univariate and multivariate phylogenetic generalized least squares regression models to re-evaluate the likely body mass of C. spelea. Next, we compare characteristics of the forelimb bones of C. ferox and C. spelea to those of other stealth predators specializing on small, mixed, and large-bodied prey. Finally, we examine humeri, femora, crania, and mandibles of extinct lemurs from six sites in four ecoregions of Madagascar to identify damage likely made by predators. We test the relative prevalence of carnivory by mammals, raptors, and crocodiles at different sites and ecoregions. Our data reveal that crocodiles, raptors, and the largest of Madagascar's mammalian predators, C. spelea, all preyed on large lemurs. Cryptoprocta opportunistically consumed lemurs weighing up to ~85 kg. Its forelimb anatomy would have facilitated predation on large-bodied prey. Social hunting may have also enhanced the ability of C. spelea to capture large, arboreal primates. Cryptoprocta carnivory is well represented at cave and riverine sites and less prevalent at lake and marsh sites, where crocodylian predation dominates.

New Bovid Remains from the Early Pleistocene of Umbria (Italy) and a Reappraisal of Leptobos merlai Abstract The extinct bovid Leptobos is one of the most characteristic elements of Eurasian faunal assemblages during most of the Villafranchian Land Mammal Age (i.e., from the late Pliocene to most of the early Pleistocene). Several species of this genus have been established since the end of XIX Century, but their taxonomic status and phylogenetic relationships remain unclear due to the fact that most of them are described on the basis of scanty material. European species are divided into two groups or lineages. The first includes L. stenometopon, L. merlai, and the poorly known L. furtivus, the second L. etruscus and L. vallisarni. While the last two species are well documented in the Italian early Pleistocene fossil record, very little is known on the L. stenometopon-merlai-furtivus group and especially on L. merlai, whose richest sample is from the French locality of Saint Vallier. Here, we describe new material of L. merlai from the early late Villafranchian of Umbria (central Italy), including a nearly complete female cranium and a male neurocranium with horn cores. These remains constitute the best-preserved and complete sample of L. merlai in the Italian Peninsula and bring new consistency to the fossil record of this species. In addition, they serve to confirm the extension of the spatial distribution of L. merlai to the south and of the chronological distribution of this taxon from the middle to the early late Villafranchian. Finally, we offer critical remarks on some not well defined Leptobos species.

Newly Discovered Crania of Nyanzachoerus jaegeri (Tetraconodontinae, Suidae, Mammalia) from the Woranso-Mille (Ethiopia) and Reappraisal of Its Generic Status Abstract Suids are among the most common mammalian groups in the Plio-Pleistocene vertebrate fossil record of Africa and the most studied largely due to their significance as biochronological indicators. However, despite their abundance in the fossil record, the remains are mostly isolated teeth and fragmentary crania and mandibles. As a result, disagreements have persisted in terms of their taxonomy and phylogenetic relationships. Here, we present for the first time a detailed description of the cranial anatomy of Nyanzachoerus jaegeri based on two crania recovered from middle Pliocene deposits of the Woranso-Mille paleontological study area, Afar region, Ethiopia. Understanding the cranial morphology of this species is particularly significant given the recent reclassification of Nyanzachoerus jaegeri to the genus Notochoerus based largely on the incisor and symphyseal morphology of specimens from Kanapoi, Kenya. Here, we show that the two genera are clearly distinguished from each other by distinct morphological features of the cranium such as the shape of the braincase, orientation of the zygomatic arches, and premolar/molar ratio, among others. Furthermore, we show that the mandibular and dental morphological features identified by some workers as characteristic of Notochoerus are variable among tetraconodont species and that Nyanzachoerus jaegeri best fits within the genus Nyanzachoerus.

Gastrointestinal Cancer

Radiotherapy for Gastric Bleeding from Tumor Invasion of Recurrent Colon Cancer with Liver Metastasis After Resection

Correlates, Trends, and Short-Term Outcomes of Venous Thromboembolism in Hospitalized Patients with Hepatocellular Carcinoma Abstract Background and Aim The incidence and overall mortality of hepatocellular carcinoma (HCC) in the US have been increasing over the past decade. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. This study aims at examining the epidemiology, risk factors, and short-term outcomes of VTE in hospitalized patients with HCC. Methods We utilized the National Inpatient Sample for the years 2008–2013. Using the International Classification of Diseases codes, ninth edition, we identified hospitalized adult patients with a prior diagnosis of HCC who were diagnosed with VTE. Weighted multivariate logistic regression models were used to examine the effect of patients' sociodemographic and clinical characteristics on the occurrence of VTE, and to evaluate the impact of VTE on in-hospital mortality and length of hospital stay. Results We identified a total of 54,275 hospitalized patients with a prior diagnosis of HCC. The prevalence of VTE in the study cohort was 2.8% (2.5% in 2008 to 3.0% in 2013, a statistically significant increase). Older age, African American ethnicity, history of metastasis, and higher Elixhauser comorbidity index were associated with higher odds of VTE. However, having a prior diagnosis of cirrhosis, hepatitis C, or diabetes mellitus were associated with lower odds of VTE in HCC patients. Furthermore, development of VTE was associated with longer hospital stay and increased in-hospital mortality. Conclusion Our work highlights significant age, racial, and comorbid factors in the development of VTE in hospitalized patients with HCC in the US. These findings can help in stratification of HCC patients according to their VTE risk. Patients at higher risk of VTE may benefit from more aggressive pharmacologic prophylaxis, an area for future investigation.

Hepatic Abscess with Biliary Obstruction Mimicking Cholangiocarcinoma—a Case Report

An Unusual Progression of Signet-Ring Cell Carcinoma of the Appendix in a Caucasian Woman

Neuroendocrine Carcinoma of Gallbladder: A Step Beyond Palliative Therapy, Experience of 25 Cases Abstract Purpose Published literature on gall bladder neuroendocrine tumors (GB NETs) is limited with none reporting the role of multimodal therapy. Methods Patients with histologically confirmed GB NETs treated at Tata Memorial Hospital, Mumbai, from January 2010 to June 2017 were analyzed. Staging was done by contrast-enhanced computed tomography (CECT) of abdomen and chest or a positron emission topography (PET) scan. Tumor marker (CA19-9) was measured. WHO-2017 guideline was used to classify GB NETs. GB NETs were categorized as early disease (ED) (T1, T2, N0, i.e., stages I and II); locally advanced disease (LAD) (T3, T4, or N+, i.e., stage III); and metastatic disease (MD). Response to treatment was assessed with RECIST1.1 criteria. Results Twenty-five patients of GB NETs were identified; 19 with neuroendocrine carcinomas (NECs) and 6 with mixed adenoneuroendocrine carcinomas (MANECs). Two patients (8%) presented with ED, 9 (36%) with LAD, and 14 (56%) had MD. Those with ED underwent open revision radical cholecystectomy. Both received adjuvant chemotherapy (ACT) with six cycles of carboplatin-etoposide and were disease-free at 3 months of follow-up. Of the nine patients with LAD, six received three cycles of neoadjuvant chemotherapy (NACT) (carboplatin-etoposide) and three operated upfront. All six patients showed partial response to NACT and five underwent open radical cholecystectomy with R0 resection. All patients operated after NACT received three cycles of ACT. Their median follow-up was 7 months (range 3–22 months). Three patients with LAD developed metastasis after median disease-free survival of 5 months. The median survival in patients with MD was 12 (range 6–23) months. Conclusions In carefully selected patients of GB NECs, downsizing with NACT facilitates radical resection with negative margins.

Acinar Cell Carcinoma in the Background of Chronic Calcific Pancreatitis

Disappearing Lump—an Unusual Presentation of Large Metastatic Small Bowel Malignant Melanoma

Locally Recurrent Well-Differentiated Nonfunctioning Pancreatic Neuroendocrine Tumor Requiring Re-excision Including Portal Vein Resection

Pancreatic Metastases of Rectal Cancer—Case Report and Literature Review

Uncommon Initial Presentation of Gastric Cancer with Bone Metastases: a Case Report

Minds and Machines

Reply to "Prayer-Bots and Religious Worship on Twitter: A Call for a Wider Research Agenda Islamic"

Delegating Religious Practices to Autonomous Machines, A Reply to "Prayer-Bots and Religious Worship on Twitter: A Call for a Wider Research Agenda"

Prayer-Bots and Religious Worship on Twitter: A Call for a Wider Research Agenda Abstract The automation of online social life is an urgent issue for researchers and the public alike. However, one of the most significant uses of such technologies seems to have gone largely unnoticed by the research community: religion. Focusing on Islamic Prayer Apps, which automatically post prayers from its users' accounts, we show that even one such service is already responsible for millions of tweets daily, constituting a significant portion of Arabic-language Twitter traffic. We argue that the fact that a phenomenon of these proportions has gone unnoticed by researchers reveals an opportunity to broaden the scope of the current research agenda on online automation.

Can Machines Read our Minds? Abstract We explore the question of whether machines can infer information about our psychological traits or mental states by observing samples of our behaviour gathered from our online activities. Ongoing technical advances across a range of research communities indicate that machines are now able to access this information, but the extent to which this is possible and the consequent implications have not been well explored. We begin by highlighting the urgency of asking this question, and then explore its conceptual underpinnings, in order to help emphasise the relevant issues. To answer the question, we review a large number of empirical studies, in which samples of behaviour are used to automatically infer a range of psychological constructs, including affect and emotions, aptitudes and skills, attitudes and orientations (e.g. values and sexual orientation), personality, and disorders and conditions (e.g. depression and addiction). We also present a general perspective that can bring these disparate studies together and allow us to think clearly about their philosophical and ethical implications, such as issues related to consent, privacy, and the use of persuasive technologies for controlling human behaviour.

Peeking Inside the Black Box: A New Kind of Scientific Visualization Abstract Computational systems biologists create and manipulate computational models of biological systems, but they do not always have straightforward epistemic access to the content and behavioural profile of such models because of their length, coding idiosyncrasies, and formal complexity. This creates difficulties both for modellers in their research groups and for their bioscience collaborators who rely on these models. In this paper we introduce a new kind of visualization (observed in a qualitative study of a systems biology laboratory) that was developed to address just this sort of epistemic opacity. The visualization is unusual in that it depicts the dynamics and structure of a computer model instead of that model's target system, and because it is generated algorithmically. Using considerations from epistemology and aesthetics, we explore how this new kind of visualization increases scientific understanding of the content and function of computer models in systems biology to reduce epistemic opacity.

Computer Modeling and Simulation: Increasing Reliability by Disentangling Verification and Validation Abstract Verification and validation (V&V) of computer codes and models used in simulations are two aspects of the scientific practice of high importance that recently have been discussed widely by philosophers of science. While verification is predominantly associated with the correctness of the way a model is represented by a computer code or algorithm, validation more often refers to the model's relation to the real world and its intended use. Because complex simulations are generally opaque to a practitioner, the Duhem problem can arise with verification and validation due to their entanglement; such an entanglement makes it impossible to distinguish whether a coding error or the model's general inadequacy to its target should be blamed in the case of a failure. I argue that a clear distinction between computer modeling and simulation has to be made to disentangle verification and validation. Drawing on that distinction, I suggest to associate modeling with verification and simulation, which shares common epistemic strategies with experimentation, with validation. To explain the reasons for their entanglement in practice, I propose a Weberian ideal–typical model of modeling and simulation as roles in practice. I examine an approach to mitigate the Duhem problem for verification and validation that is generally applicable in practice and is based on differences in epistemic strategies and scopes. Based on this analysis, I suggest two strategies to increase the reliability of simulation results, namely, avoiding alterations of verified models at the validation stage as well as performing simulations of the same target system using two or more different models. In response to Winsberg's claim that verification and validation are entangled I argue that deploying the methodology proposed in this work it is possible to mitigate inseparability of V&V in many if not all domains where modeling and simulation are used.

Epistemic Entitlements and the Practice of Computer Simulation Abstract What does it mean to trust the results of a computer simulation? This paper argues that trust in simulations should be grounded in empirical evidence, good engineering practice, and established theoretical principles. Without these constraints, computer simulation risks becoming little more than speculation. We argue against two prominent positions in the epistemology of computer simulation and defend a conservative view that emphasizes the difference between the norms governing scientific investigation and those governing ordinary epistemic practices.

Reproducibility and the Concept of Numerical Solution Abstract In this paper, we show that reproducibility is a severe problem that concerns simulation models. The reproducibility problem challenges the concept of numerical solution and hence the conception of what a simulation actually does. We provide an expanded picture of simulation that makes visible those steps of simulation modeling that are numerically relevant, but often escape notice in accounts of simulation. Examining these steps and analyzing a number of pertinent examples, we argue that numerical solutions are importantly different from usual mathematical solutions. They are do not merely approximate the latter, but introduce new problems, including issues of artificiality, stability, and well-posedness. Consequently, simulation modelling can attain reproducibility only to a certain degree because it is working with numerical solutions (in a sense we specify in the paper).

Robotic Simulations, Simulations of Robots Abstract Simulation studies have been carried out in robotics for a variety of epistemic and practical purposes. Here it is argued that two broad classes of simulation studies can be identified in robotics research. The first one is exemplified by the use of robotic systems to acquire knowledge on living systems in so-called biorobotics, while the second class of studies is more distinctively connected to cases in which artificial systems are used to acquire knowledge about the behaviour of autonomous mobile robots. The two classes pertain to sub-areas of robotics which are apparently quite distant from one another in terms of goals, methodologies, technologies, and theoretical backgrounds. Still both are concerned with building, running, and experimenting on simulations of other systems. This paper aims to reveal and discuss some methodological commonalities between the two classes of studies. Philosophical literature on simulation methodologies has been traditionally focused on studies carried out in research fields other than robotics: this article may therefore contribute to shedding light on how the concept of simulation is used in robotics, and on the role simulation methodologies play in this research field.

The Civic Role of Online Service Providers

Digital Imaging

Evaluating Completeness of a Radiology Glossary Using Iterative Refinement Abstract A lay-language glossary of radiology, built to help patients better understand the content of their radiology reports, has been analyzed for its coverage and readability, but not for its completeness. We present an iterative method to sample radiology reports, identify "missing" terms, and measure the glossary's completeness. We hypothesized that the refinement process would reduce the number of missing terms to fewer than 1 per report. A random sample of 1000 radiology reports from a large US academic health system was divided into 10 cohorts of 100 reports each. Each cohort was reviewed in sequence by two investigators to identify terms (single words and multi-word phrases) absent from the glossary. Terms marked as new were added to the glossary and hence was shown as matched in subsequent cohorts. This HIPAA-compliant study was IRB-approved; informed consent was waived. The refinement process added a mean of 288.0 new terms per 100 reports in the first 5 cohorts vs. a mean of 66.0 new terms per 100 reports in the last 5 cohorts; the difference was statistically significant (p < .01). After reviewing 500 reports, the review process found fewer than 1 new term per report in each of 500 subsequent reports. The findings suggest that 500 to 1000 reports is adequate to test the completeness of a glossary, and that the glossary after iterative refinement achieved a high level of completeness to cover the vocabulary of radiology reports.

Improving Sensitivity on Identification and Delineation of Intracranial Hemorrhage Lesion Using Cascaded Deep Learning Models Abstract Highly accurate detection of the intracranial hemorrhage without delay is a critical clinical issue for the diagnostic decision and treatment in an emergency room. In the context of a study on diagnostic accuracy, there is a tradeoff between sensitivity and specificity. In order to improve sensitivity while preserving specificity, we propose a cascade deep learning model constructed using two convolutional neural networks (CNNs) and dual fully convolutional networks (FCNs). The cascade CNN model is built for identifying bleeding; hereafter the dual FCN is to detect five different subtypes of intracranial hemorrhage and to delineate their lesions. Using a total of 135,974 CT images including 33,391 images labeled as bleeding, each of CNN/FCN models was trained separately on image data preprocessed by two different settings of window level/width. One is a default window (50/100[level/width]) and the other is a stroke window setting (40/40). By combining them, we obtained a better outcome on both binary classification and segmentation of hemorrhagic lesions compared to a single CNN and FCN model. In determining whether it is bleeding or not, there was around 1% improvement in sensitivity (97.91% [± 0.47]) while retaining specificity (98.76% [± 0.10]). For delineation of bleeding lesions, we obtained overall segmentation performance at 80.19% in precision and 82.15% in recall which is 3.44% improvement compared to using a single FCN model.

Automatic Lumbar MRI Detection and Identification Based on Deep Learning Abstract The aim of this research is to automatically detect lumbar vertebras in MRI images with bounding boxes and their classes, which can assist clinicians with diagnoses based on large amounts of MRI slices. Vertebras are highly semblable in appearance, leading to a challenging automatic recognition. A novel detection algorithm is proposed in this paper based on deep learning. We apply a similarity function to train the convolutional network for lumbar spine detection. Instead of distinguishing vertebras using annotated lumbar images, our method compares similarities between vertebras using a beforehand lumbar image. In the convolutional neural network, a contrast object will not update during frames, which allows a fast speed and saves memory. Due to its distinctive shape, S1 is firstly detected and a rough region around it is extracted for searching for L1–L5. The results are evaluated with accuracy, precision, mean, and standard deviation (STD). Finally, our detection algorithm achieves the accuracy of 98.6% and the precision of 98.9%. Most failed results are involved with wrong S1 locations or missed L5. The study demonstrates that a lumbar detection network supported by deep learning can be trained successfully without annotated MRI images. It can be believed that our detection method will assist clinicians to raise working efficiency.

Towards Accurate Segmentation of Retinal Vessels and the Optic Disc in Fundoscopic Images with Generative Adversarial Networks Abstract Automatic segmentation of the retinal vasculature and the optic disc is a crucial task for accurate geometric analysis and reliable automated diagnosis. In recent years, Convolutional Neural Networks (CNN) have shown outstanding performance compared to the conventional approaches in the segmentation tasks. In this paper, we experimentally measure the performance gain for Generative Adversarial Networks (GAN) framework when applied to the segmentation tasks. We show that GAN achieves statistically significant improvement in area under the receiver operating characteristic (AU-ROC) and area under the precision and recall curve (AU-PR) on two public datasets (DRIVE, STARE) by segmenting fine vessels. Also, we found a model that surpassed the current state-of-the-art method by 0.2 − 1.0% in AU-ROC and 0.8 − 1.2% in AU-PR and 0.5 − 0.7% in dice coefficient. In contrast, significant improvements were not observed in the optic disc segmentation task on DRIONS-DB, RIM-ONE (r3) and Drishti-GS datasets in AU-ROC and AU-PR.

Integrating Wikipedia Articles and Images into an Information Resource for Radiology Patients Abstract Wikipedia—an open-access online encyclopedia—contains a large number of medically relevant articles and images that may help supplement glossaries of radiology terms. We sought to determine the extent to which concepts from a large online radiology glossary developed as part of the Patient-Oriented Radiology Reporter (PORTER) initiative could be mapped to relevant Wikipedia web pages and images using automated or semi-automated approaches. The glossary included 4090 concepts with their definitions; the concept's preferred name and lexical variants, such as plurals, adjectival forms, synonyms, and abbreviations, yielded a total of 13,030 terms. Of the 4090 concepts, 3063 (74.9%) had a corresponding English-language Wikipedia page identified by automated search with subsequent manual review. We applied the MediaWiki application programming interface (API) to generate web-service calls to identify the images from each concept's corresponding Wikipedia page; three reviewers selected relevant images to associate with the glossary's concepts. Licensing terms for the images were reviewed. For 800 randomly sampled concepts that had associated Wikipedia pages, 362 distinct images were identified from the MediaWiki library and matched to 404 concepts (51%). Three images (1%) had unspecified licensing terms; the rest were in the public domain or available via a Creative Commons license. Wikipedia and the MediaWiki library offer a large collection of medical articles and images that can be incorporated into an online lay-language glossary of radiology terms though a semi-automated approach.

A Platform Integrating Acquisition, Reconstruction, Visualization, and Manipulator Control Modules for MRI-Guided Interventions Abstract This work presents a platform that integrates a customized MRI data acquisition scheme with reconstruction and three-dimensional (3D) visualization modules along with a module for controlling an MRI-compatible robotic device to facilitate the performance of robot-assisted, MRI-guided interventional procedures. Using dynamically-acquired MRI data, the computational framework of the platform generates and updates a 3D model representing the area of the procedure (AoP). To image structures of interest in the AoP that do not reside inside the same or parallel slices, the MRI acquisition scheme was modified to collect a multi-slice set of intraoblique to each other slices; which are termed composing slices. Moreover, this approach interleaves the collection of the composing slices so the same k-space segments of all slices are collected during similar time instances. This time matching of the k-space segments results in spatial matching of the imaged objects in the individual composing slices. The composing slices were used to generate and update the 3D model of the AoP. The MRI acquisition scheme was evaluated with computer simulations and experimental studies. Computer simulations demonstrated that k-space segmentation and time-matched interleaved acquisition of these segments provide spatial matching of the structures imaged with composing slices. Experimental studies used the platform to image the maneuvering of an MRI-compatible manipulator that carried tubing filled with MRI contrast agent. In vivo experimental studies to image the abdomen and contrast enhanced heart on free-breathing subjects without cardiac triggering demonstrated spatial matching of imaged anatomies in the composing planes. The described interventional MRI framework could assist in performing real-time MRI-guided interventions.

Multi-objective Parameter Auto-tuning for Tissue Image Segmentation Workflows Abstract We propose a software platform that integrates methods and tools for multi-objective parameter auto-tuning in tissue image segmentation workflows. The goal of our work is to provide an approach for improving the accuracy of nucleus/cell segmentation pipelines by tuning their input parameters. The shape, size, and texture features of nuclei in tissue are important biomarkers for disease prognosis, and accurate computation of these features depends on accurate delineation of boundaries of nuclei. Input parameters in many nucleus segmentation workflows affect segmentation accuracy and have to be tuned for optimal performance. This is a time-consuming and computationally expensive process; automating this step facilitates more robust image segmentation workflows and enables more efficient application of image analysis in large image datasets. Our software platform adjusts the parameters of a nuclear segmentation algorithm to maximize the quality of image segmentation results while minimizing the execution time. It implements several optimization methods to search the parameter space efficiently. In addition, the methodology is developed to execute on high-performance computing systems to reduce the execution time of the parameter tuning phase. These capabilities are packaged in a Docker container for easy deployment and can be used through a friendly interface extension in 3D Slicer. Our results using three real-world image segmentation workflows demonstrate that the proposed solution is able to (1) search a small fraction (about 100 points) of the parameter space, which contains billions to trillions of points, and improve the quality of segmentation output by × 1.20, × 1.29, and × 1.29, on average; (2) decrease the execution time of a segmentation workflow by up to 11.79× while improving output quality; and (3) effectively use parallel systems to accelerate parameter tuning and segmentation phases.

The Role of the Integrated Digital Radiology System in Assessing the Impact of Patient Load on Emergency Computed Tomography (CT) Efficiency Abstract Time-critical management is of particular significance in the trauma and emergency setting, where intervals from patient arrival to diagnostic imaging and from imaging to radiology report are key determinants of outcome. This study, based in the Trauma and Emergency Unit of a large, tertiary-level African hospital with a fully digital radiology department, assessed the impact of increased workload on computerised tomography (CT) efficiency. Sequential, customised searches of the institutional radiology information system (RIS) were conducted to define two weekends in 2016 with the lowest and highest emergency CT workloads, respectively. The electronic RIS timestamps defining the intervals between key steps in the CT workflow were extracted and analysed for each weekend. With the exception of radiologist reporting time, workflow steps were significantly prolonged by increased workload. This study highlights the potential role of the integrated digital radiology system in enabling a detailed analysis of imaging workflow, thereby facilitating the identification and appropriate management of bottlenecks.

Probabilistic Modeling of Exam Durations in Radiology Procedures Abstract In this paper, we model the statistical properties of imaging exam durations using parametric probability distributions such as the Gaussian, Gamma, Weibull, lognormal, and log-logistic. We establish that in a majority of radiology procedures, the underlying distribution of exam durations is best modeled by a log-logistic distribution, while the Gaussian has the poorest fit among the candidates. Further, through illustrative examples, we show how business insights and workflow analytics can be significantly impacted by making the correct (log-logistic) versus incorrect (Gaussian) model choices.

Content-Based Image Retrieval System for Pulmonary Nodules Using Optimal Feature Sets and Class Membership-Based Retrieval Abstract Lung cancer manifests itself in the form of lung nodules, the diagnosis of which is essential to plan the treatment. Automated retrieval of nodule cases will assist the budding radiologists in self-learning and differential diagnosis. This paper presents a content-based image retrieval (CBIR) system for lung nodules using optimal feature sets and learning to enhance the performance of retrieval. The classifiers with more features suffer from the curse of dimensionality. Like classification schemes, we found that the optimal feature set selected using the minimal-redundancy-maximal-relevance (mRMR) feature selection technique improves the precision performance of simple distance-based retrieval (SDR). The performance of the classifier is always superior to SDR, which leans researchers towards conventional classifier-based retrieval (CCBR). While CCBR improves the average precision and provides 100% precision for correct classification, it fails for misclassification leading to zero retrieval precision. The class membership-based retrieval (CMR) is found to bridge this gap for texture-based retrieval. Here, CMR is proposed for nodule retrieval using shape-, margin-, and texture-based features. It is found again that optimal feature set is important for the classifier used in CMR as well as for the feature set used for retrieval, which may lead to different feature sets. The proposed system is evaluated using two independent databases from two continents: a public database LIDC/IDRI and a private database PGIMER-IITKGP, using three distance metrics, i.e., Canberra, City block, and Euclidean. The proposed CMR-based retrieval system with optimal feature sets performs better than CCBR and SDR with optimal features in terms of average precision. Apart from average precision and standard deviation of precision, the fraction of queries with zero precision retrieval is also measured.