bluuebunny/crossref_metadata_2025 huggingface dataset:
Chinese Education in Malaysia
Authors: Ang Ming Chee
Published: November 2018

Despite the fact that Mandarin is not accorded official language status in Malaysia, and that ethnic Chinese communities accounted for less than 30% of the country’s overall population, Malaysia is the only country outside China and Taiwan with a comprehensive and complete Chinese education system. It is also the only country in Southeast Asia that has perpetuated the Chinese education system established during the colonial era.

The prolonged endurance of the Chinese education system in Malaysia is the result of many factors: heavy brokerage and lobbying efforts by ethnic Chinese political leaders; incorporation of vernacular schools into the Malay-dominated national education system in the backdrop of the Malayan nation formation stage; social mobilization of the Chinese education movement in Malaysia; and the increasing significance of Mandarin proficiency in the world.

In particular, the assimilation policies for nation building by the Malay-dominated regime have threatened the cultural distinctiveness of the Chinese-speaking communities. Resistance from the Chinese speaking minorities is manifested through their support of the Chinese schools. Moreover, the elimination of English schools during the 1970s has unintentionally favored the Chinese primary schools. Despite their standing at that time as the “second-best” option after the English school, Chinese schools that offered the benefit of trilingual education, stricter discipline, and more competitive academic performance enjoyed an accelerated boost in student enrollments. More importantly, many parents who do not speak Chinese began to appreciate the quality of Chinese schools, and the enrollment of non-ethnic Chinese students has continued to rise ever since.

Above all, China’s rapid economic ascendancy and growing political influence since the 1990s has enhanced the importance of Mandarin as a global language. This has added value to the importance of Chinese schools as language and cultural learning institutions for Malaysian. Such opportunity has enabled the Chinese school model to become one of the most successful and inclusive educational institutions for multicultural Malaysians.
Postcolonial States and Societies in West Africa
Authors: Obadare Ebenezer
Published: November 2018

Postcolonial West African history can be understood in terms of transitions across three successive eras: a post-independence era of high nationalism; the military era, characterized by profound political and socio-economic instability; and, finally, since the early 1990s, a democratization era, marked by continued swings between fevered hopes and anguished realities. These temporalities arguably converge on a singular leitmotif, namely, the attempt by state power to preserve its privileges and the struggle by social forces to resist the state and draw effective boundaries between the private and public domains. Gloomy for most of the “lost decade” of the 1980s, the prospect for such a project appears brighter today, especially in the aftermath of pivotal shifts in the global and regional political landscapes.
Computer Simulations in the Classroom
Authors: Blum Andrew
Published: November 2018

Computer simulations can be defined in three categories: computational modeling simulations, human-computer simulations, and computer-mediated simulations. These categories of simulations are defined primarily by the role computers take and by the role humans take in the implementation of the simulation. The literature on the use of simulations in the international studies classroom considers under what circumstances and in what ways the use of simulations creates pedagogical benefits when compared with other teaching methods. But another issue to consider is under what circumstances and in what ways the use of computers can add (or subtract) pedagogical value when compared to other methods for implementing simulations. There are six alleged benefits of using simulation: encouraging cognitive and affective learning, enhancing student motivation, creating opportunities for longer-term learning, increasing personal efficiency, and promoting student-teacher relations. Moreover, in regard to the use of computer simulations, there are a set of good practices to consider. The first good practice emerges out of a realization of the unequal level of access to technology. The second good practice emerges from a clear understanding of the strengths and weaknesses of a computer-assisted simulation. The final and perhaps most fundamental good practice emerges from the idea that computers and technology more generally are not ends in themselves, but a means to help instructors reach a set of pedagogical goals.
Historical Sociology and International Relations: Interdisciplinary Approaches to Large-Scale Historical Change and Global Order
Authors: Pula Besnik , Stivachtis Yannis A.
Published: November 2018

Historical Sociology (HS) is a subfield of sociology studying the structures and processes that have shaped important features of the modern world, including the development of the rational bureaucratic state, the emergence of capitalism, international institutions and trade, transnational forces, revolutions, and warfare. HS differs from other approaches in sociology given its distinction between routine social activities and transformative moments that fundamentally reshape social structures and institutions. Within international relations, the relevance of history in the field’s study has been highly disputed. In fact, mainstream international relations (IR)—Neorealism and Liberalism—has downplayed the importance of history. Nevertheless, World History (WH) and HS have exercised a significant degree of influence over certain theoretical approaches to the study of international relations. The history of HS can be traced back to the Enlightenment period and the belief that it was possible to improve the human condition by unmaking and remaking human institutions. HS was then taken up by a second wave of historical sociologists who were asking questions about political power and the state, paving the way for greater engagement between IR and sociology. Third wave HS, meanwhile, emerged from a questioning of received theoretical paradigms, and was thus characterized by theoretical and methodological revisions, but only minor and incremental changes to the research agenda of second wave Historical Sociology.
International Regulation of Ocean Pollution and Ocean Fisheries
Authors: Jacques Peter
Published: November 2018

The World Ocean, the interconnected system of oceans and major seas on Earth, faces a major governance failure that has produced a series of catastrophic systemic changes to the marine food web and the water column across all scales. As each era passes, ocean sustainability has become less of a priority compared to economic extraction, though there were many institutions forged in the post-War period, and these are explained, concluding with the development of a purposefully weak effort to protect biodiversity in Areas Beyond National Jurisdictions. Fisheries are systematically mismanaged, and there are now serious concerns for large-scale, even global, fishery collapses. Longstanding pollution issues like oil pollution have improved, but a new class of “invisibles”—carbon dioxide, heat, nitrogen, and plastics—offer growing threats. The solution to these problems must be integrated, comprehensive, and ambitious—something the Areas Beyond National Jurisdiction language does not promise.
International Relations and the Study of History
Authors: Koliopoulos Constantinos
Published: November 2018

International relations and history are inextricably linked, and with good reason. This link is centuries old: Thucydides’ History of the Peloponnesian War, one of the very earliest and one of the very greatest historical works of all time, is widely regarded as the founding textbook of international relations. Still, those two disciplines are legitimately separate. A somewhat clear boundary between them can probably be drawn around three lines of demarcation: (1) past versus present, (2) idiographic versus nomothetic, and (3) description versus analysis.

The utility of history for the analysis of international affairs has been taken for granted since time immemorial. History is said to offer three things to international relations scholars: (1) a ready source of examples, (2) an opportunity to sharpen their theoretical insights, and (3) historical consciousness, that is, an understanding of the historical context of human existence and a corresponding ability to form intelligent judgment about human affairs. This tradition continued well after international relations firmly established itself as a recognized separate discipline some time after World War II, and would remain virtually unchallenged until the 1960s.

Since the 1960s, attitudes toward history have diverged within the international relations community. Some approaches, most notably the English school and the world system analysis, have almost by definition thriven on history. History plays a fundamental role in the critical-constructivist approach, while realist scholars continue to draw regularly on history. History is far less popular, though not absent from works belonging to the liberal-idealist approach. Postmodernism is the one approach that is almost completely antithetical to the analytical use of history. Postmodernists have characterized history as merely another form of fiction and question the existence of objective truth and transhistorical knowledge. One cannot exclude the possibility that postmodernism is correct in this respect; however, it is highly unlikely that uncountable generations of people have been victims of mass deception or mass psychosis regarding the utility of history, not least in the analysis of international relations.
Liberalism and Security
Authors: Owen IV John M.
Published: November 2018

Liberalism has always been concerned with security, albeit the security of the individual; institutions, including the state, are all established and sustained by individuals and instrumental to their desires. Indeed, liberalism cannot be understood apart from its normative commitment to individualism. The tradition insists that all persons deserve, and it evaluates institutions according to how far they help individuals achieve these goals. Nor is liberalism anti-statist. Liberal theory has paid particular attention to the state as the institution defined by its ability to make individuals secure and aid their commodious living. Although liberal security literature that only examines individual states’ foreign policies may be guilty of denouncing the role of international interaction, the general liberal claim argues that the international system, under broad conditions, permits states choices. As such, for liberalism, states can choose over time to create and sustain international conditions under which they will be more or less secure. Liberalism’s history can be traced from the proto-liberalism in the Reformation to the emergence of the social contract theory and neo-theories, as well as liberalism’s focus on increasing security. Meanwhile, current debates in liberalism include the democratic peace and its progeny, reformulations of liberal international relations (IR) theory, and meta-theory. Ultimately, liberalism’s most striking recent successes concern the democratic peace and related research on democratic advantages in international cooperation. Liberalism is a useful guide to international security insofar as individuals and the groups they organize affect or erode states.
The Idea of Black Religion
Authors: Drake Jamil W.
Published: November 2018

It is impossible to provide a conclusive definition of the idea of black religion; however, certain themes, tropes, and characteristics are typically associated with the “black” in black religion. These ideas are inseparable from the ideas of race in American history. The ideas of the religious differences (e.g., institutions, theologies, practices, or values) attributed to black people are not objective or neutral. Rather, these ideas about the differences of black religion are value-laden and shaped by larger debates about the moral and intellectual capabilities, social status, and/or political struggles of black folk in the United States. In this sense, the idea of black religion is inseparable from the larger discourse about black people and their place in the republic.

Arguably, black religion was not a formal object of inquiry until the late 19th century, yet it often includes statements about the paganism, idolatry, and/or fetishism used to define “religion of Africa” in the colonial period. By the antebellum period, a cadre of voluntary African associations continued the ideas of pagan Africa that posited a redemptive [African] race that simultaneously sought to purify American religion from slavery and to civilize Africa from the ideas of primitivism. Throughout the 20th century, early studies of “black religion” were associated with ideas of social and moral uplift; race heredity; economic stress; transmission of Africanisms; and protest and liberation. In the end, black religion is intrinsic to U.S. intellectual and cultural history.
Sepphoris
Authors: Weiss Zeev
Published: November 2018

In the heart of the Lower Galilee lie the remains of Sepphoris, capital of the Galilee during long periods of antiquity. Both literary sources and archaeological finds indicate that the city’s population included pagans, heretics, and Christians living alongside the Jewish population. Many sages lived in the city, which, according to rabbinic literature, boasted numerous synagogues and academies (batei midrash). When Rabbi Judah ha-Nasi (the Patriarch of Judaea) moved to Sepphoris at the beginning of the 3rd century, the Jews gained a significant presence on the city council. With the growth of the Christian community came the construction of churches and the involvement of the episcopus (head of the Christian community) in municipal affairs. Economically, Sepphoris had become a well-established city due to the fertile soil in the nearby valleys and its active trade with the immediate surroundings and distant markets.

Hellenistic Sepphoris was built on its hill and slopes. Early in the 2nd century ce, the city spread considerably eastward, boasting an impressive grid of streets with a colonnaded cardo and decumanus running through its centre. Various public buildings were built in the city, including a temple, a forum, bathhouses, a theatre, a monumental building identified as a library or archive, as well as churches, synagogues, and some other structures dating to the early Byzantine period. Most of the common people lived in simple houses, while the wealthy lived in spacious, well-planned dwellings. The architectural layout of these large structures is impressive, as are the more than sixty colourful mosaics from the 3rd to 6th centuries ce uncovered in its private and public buildings. The various depictions in the mosaics have parallels in other cities of the Roman and Byzantine East, not only enhancing the ancient ruins of Sepphoris but also providing invaluable information about the city and its population. The wealth of evidence emerging from Sepphoris offers perhaps the greatest insight into Jewish society and its changing attitudes towards the Graeco-Roman culture to which it was exposed. This new outlook did not occur overnight or in all strata of Jewish society; rather, it was an ongoing process that intensified in the Roman period and reached a peak in the 5th and 6th centuries ce.
Adjuvant Therapy and Mammographic Density Changes in Women With Breast Cancer
Authors: Eriksson Louise , He Wei , Eriksson Mikael , Humphreys Keith , Bergh Jonas , Hall Per , Czene Kamila
Published: November 2018

Background

Tamoxifen decreases mammographic density. Whether compliance affects this relationship is unclear as is the relationship between other types of adjuvant treatment and changes in mammographic density.

Methods

This prospective cohort study included 2490 women diagnosed with breast cancer during 2001–2015 in Sweden. Mammographic density was assessed within 3 months of diagnosis and 6–36 months post diagnosis. Logistic regression was performed to study the association between each respective adjuvant treatment and mammographic density reduction (annual dense area decrease >15%).

Results

Intention-to-treat analyses using treatment information from the regional cancer registries showed that tamoxifen-treated patients more frequently experienced mammographic density reductions compared with nontreated patients (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.25 to 1.99), as did chemotherapy-treated patients (OR = 1.28, 95% CI = 1.06 to 1.54). For chemotherapy, the association was mainly seen in premenopausal women. Neither aromatase inhibitors nor radiotherapy was associated with density change. Tamoxifen use based on prescription and dispensation data from the Swedish Prescribed Drug Register showed that users were more likely to have density reductions compared with nonusers (adjusted OR = 2.24, 95% CI = 1.40 to 3.59). Moreover, among tamoxifen users, tamoxifen continuers were more likely than discontinuers to experience density reductions (adjusted OR = 1.50, 95% CI = 1.04 to 2.17).

Conclusions

Our results indicate that adherence influences the association between tamoxifen and mammographic density reduction. We further found that chemotherapy was associated with density reductions and propose that this is largely secondary to chemotherapy-induced ovarian failure.
Israeli staff nurse knowledge and perception of the nurse practitioner role
Authors: Dickman Chaya , Miller Tamar , Muchow Lori , Ward-Smith Peggy
Published: November 2018

This study assessed Israeli nurses' knowledge of the emerging role of master's-prepared NPs. Based on an integrated review of the literature, a study-specific survey was developed, including dichotomous knowledge items, Likert scored perception items, and self-disclosed demographic data. Analyses of the 146 responses revealed that exposure to NPs was limited. Knowledge specific to the role or clinical competency was lacking, yet the assessment capabilities and overall perception of NPs were positive. Data demonstrate a willingness to include NPs in the care model and an awareness that doing so would positively contribute to the overall health of patients.
Computing for Medicine: Can We Prepare Medical Students for the Future?
Authors: Law Marcus , Veinot Paula , Campbell Jennifer , Craig Michelle , Mylopoulos Maria
Published: November 2018

Problem

Technology can transform health care; future physicians need to keep pace to ensure optimal patient care. Because future doctors are poorly prepared in computer literacy, the authors designed a computer programming certificate course. This Innovation Report describes the course and findings from a qualitative study to understand the ways it prepares medical students to use computing science and technology in medicine.

Approach

The 14-month Computing for Medicine certificate course (C4M, offered beginning in February 2016), University of Toronto, is comprised of hands-on workshops to introduce programming accompanied by homework exercises, seminars by computer science experts on the application of programming to medicine, and coding projects. Using purposive and maximal variation sampling, 17 students who completed the course were interviewed from April–May 2017. Thematic analysis was performed using an iterative constant comparison approach.

Outcomes

Participants praised the C4M as an opportunity to achieve computer literacy—including language, syntax, and fundamental computational ideas (and their application to medicine)—and acquire or strengthen algorithmic and logical thinking skills for approaching problems. They highlighted that the course illustrated linkages between computer science and medicine. Participants acknowledged a sometimes-existent chasm between producers and users of technology in medicine, recommending two-way communication between the disciplines when developing technology for use in medicine.

Next Steps

We recommend that medical schools consider computer literacy an essential skill to foster future collaborative computing partnerships for improved technology use by physicians and optimal patient care. We encourage further evaluation of future iterations of the C4M and similar courses.
An Electronic Interview Tracking Tool to Guide Medical Students Through the Match: Improvements in Advising and Match Outcomes
Authors: Frayha Neda , Raczek John , Lo Julia , Martinez Joseph , Parker Donna
Published: November 2018

Problem

Medical students are applying to increasing numbers of residency programs to increase their likelihood of success in the Match. However, they have limited data to help them understand their level of competitiveness or identify programs to which they should apply.

Approach

In 2014–2015 (Match year 2015), the University of Maryland School of Medicine’s (UMSOM’s) Office of Student Affairs (OSA) implemented an electronic interview tracking tool in which students update their residency application interview status on an ongoing basis. OSA deans can filter and sort data by student, specialty, program, academic metrics, and interview status. The deans use these data to advise students in real time, provide students with examples of programs to consider, and engage clinical faculty to support students at risk of not matching.

Outcomes

In the Match years 2015, 2016, and 2017, respectively, 86% (n = 135/157), 87% (n = 138/159), and 94% (n = 151/161) of UMSOM students participated actively in this tracking tool, adding over 3,000 data points per year. Following the tool’s launch, the average number of applications per student remained stable. The UMSOM’s Match rate and percentages of students self-reporting a match in their top three choices and rating the school’s advising as “very useful” all increased, without comparable increases in national data.

Next Steps

This tool, which provides students with data-driven examples of programs to which they should consider applying, may be beneficial to students, faculty, and program directors at other institutions—and to the residency application process, if adopted broadly.
Mesenchymal stem cells as adjuvant therapy for limb lengthening in achondroplasia
Authors: Memeo Antonio , Verdoni Fabio , Ingraffia Caterina , Rossi Laura , Pedretti Leopoldo , D’Amato Raffaele D. , Peretto Laura , Mineo Giuseppe V.
Published: November 2018

Staged leg lengthening allows achondroplastic dwarfs to reach nearly normal height, but it takes long periods of external fixation and it can be burdened by delayed unions. Between 2009 and 2013, eight achondroplastic dwarfs showed delayed unions in the callus formation during femoral lengthening stages in our institute. We performed in-situ injections of bone marrow-derived stem cell concentrates. Patients underwent monthly clinical and radiographic assessment for determination of the healing rate. All eight patients showed an improvement in the regenerated bone, with an average healing index of 23.1 days/cm (range: 18.7–23.8 days/cm). The complete recovery of the delayed consolidation took on an average of 5.2 months (range: 2–10 months). The use of cellular therapy in these patients could represent an innovative application.
The Science of Motivation Applied to Clinician Burnout: Lessons for Healthcare
Authors: Norton Jameson
Published: November 2018

The science of motivation can help explain some of the root causes driving clinician burnout, a critical vulnerability in healthcare today. Research finds autonomy, mastery, and purpose to be drivers of intrinsic motivation, and healthcare leaders can use these three principles in program design and communication strategies to make progress toward rediscovering joy and passion in the life-giving work of healthcare. Leaders can achieve a competitive advantage for their organizations by applying these inherent motivators to attract, develop, and retain engaged and purposeful caregivers and by developing participative leadership to nurture a passion for caregiving.

In healthcare, we enjoy the privilege of serving with intelligent and caring people who are driven to make a difference on behalf of those they serve. But we also experience the human factors, friction, and uncertainty in a highly complex delivery and reimbursement structure. Each day in our hospitals, clinicians and staff face a marathon of adrenaline, stress, physical fatigue, mental strain, and emotional heights and depths. This reality demands grit and resilience to sustain the high standards of excellence and compassion necessary for delivering personalized care.

Before healthcare organizations launch new programs to address these challenges, however, we must align our leadership and communication approaches with the fundamental drivers of motivation that brought us to healthcare in the first place—and in a way that brings out the best in our care teams and builds their creative capacity for any future challenges.
The Impact of Hematologic Cancer and Its Treatment on Physical Activity Level and Quality of Life Among Children in Mainland China
Authors: Xia Wei , Li Ho Cheung William , Lam Ka Wai Katherine , Chung Oi Kwan Joyce , Song Peige , Chiu Sau Ying , Chan Chi-Fung Godfrey , Ho Ka Yan
Published: November 2018

Background

The effects of hematologic cancer and its treatment on Chinese children’s physical activity level and quality of life (QoL) remain unclear despite numerous studies conducted in Western countries and Hong Kong.

Objective

The aim of this study was to examine the effects of hematologic cancer and its treatment on the physical activity level and QoL among Chinese children.

Methods

A cross-sectional study was conducted. One hundred twenty-five children who were admitted for treatment of hematologic cancer and 243 healthy counterparts of similar age participated in this study. All participants were asked to complete the Chinese University of Hong Kong: Physical Activity Rating for Children and Youth and Pediatric Quality of Life Inventory. The children with hematologic cancer also completed a therapy-related symptom checklist.

Results

There were statistically significant differences in the mean physical activity and QoL between children with hematologic cancer and their healthy counterparts. Multiple regression analyses showed that physical activity levels and the adverse effects of hematologic cancer treatment had statistically significant effects on the children’s QoL.

Conclusions

Physical activity level and QoL in children with hematologic cancer were both lower than those in their healthy counterparts.

Implications for Practice

This study provides further evidence that hematologic cancer and the adverse effects of its treatment have negative effects on Chinese children’s QoL. Although a lack of physical activity is deeply embedded in Chinese culture, nurses should take a proactive role in effecting change by educating parents about the benefits to their children’s physiologic and psychological well-being of physical activity during and after treatment.
Cortical network fingerprints predict deep brain stimulation outcome in dystonia
Authors: Gonzalez-Escamilla Gabriel , Muthuraman Muthuraman , Reich Martin M , Koirala Nabin , Riedel Christian , Glaser Martin , Lange Florian , Deuschl Günther , Volkmann Jens , Groppa Sergiu
Published: November 2018

Background

Deep brain stimulation (DBS) is an effective evidence-based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigate whether patients optimally responding to DBS present distinct brain network organization and structural patterns.

Methods

Based on a German multicentre cohort of eighty-two dystonia patients with segmental and generalized dystonia, who received DBS implantation in the globus pallidus internus patients were classified based on the clinical response 36 months after DBS, as superior-outcome group or moderate-outcome group, as above or below 70% motor improvement, respectively. Fifty-one patients met MRI-quality and treatment response requirements (mean age 51.3 ± 13.2 years; 25 female) and were included into further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on group network properties and individual grey matter fingerprints.

Results

The moderate-outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. From all the structural integrity of the cortical mantle explained about 45% of the stimulation amplitude. Classification analyses achieved 88% of accuracy using individual grey matter atrophy patterns to predict DBS outcome.

Conclusions

The analysis of cortical integrity and network properties could be developed into independent predictors to identify dystonia patients who benefit from DBS.
Knowledge is power: Contingency instruction promotes threat extinction in high intolerance of uncertainty individuals
Authors: Morriss Jayne , van Reekum Carien M.
Published: November 2018

Extinction-resistant threat is considered to be a central feature of pathological anxiety. Reduced threat extinction is observed in individuals with high intolerance of uncertainty (IU). Here we sought to determine whether contingency instructions could alter the course threat extinction for individuals high in IU. We tested this hypothesis in two identical experiments (Exp 1 n = 60, Exp 2 n = 82) where we recorded electrodermal activity during threat acquisition with partial reinforcement, and extinction. Participants were split into groups based on extinction instructions (instructed, uninstructed) and IU score (low, high). All groups displayed larger skin conductance responses to learned threat versus safety cues during threat acquisition, indicative of threat conditioning. In both experiments, only the uninstructed high IU groups displayed larger skin conductance responses to the learned threat versus safety cue during threat extinction. These findings suggest that uncertain threat during extinction maintains conditioned responding in individuals high in IU.
Identification of biological mechanisms underlying a multidimensional ASD phenotype using machine learning
Authors: Asif Muhammad , Martiniano Hugo F.M.C. , Marques Ana Rita , Santos João Xavier , Vilela Joana , Rasga Celia , Oliveira Guiomar , Couto Francisco M. , Vicente Astrid M.
Published: November 2018

The complex genetic architecture of Autism Spectrum Disorder (ASD) and its heterogeneous phenotype make molecular diagnosis and patient prognosis challenging tasks. To establish more precise genotype-phenotype correlations in ASD, we developed a novel machine learning integrative approach, which seeks to delineate associations between patients’ clinical profiles and disrupted biological processes inferred from their Copy Number Variants (CNVs) that span brain genes. Clustering analysis of relevant clinical measures from 2446 ASD cases in the Autism Genome Project identified two distinct phenotypic subgroups. Patients in these clusters differed significantly in ADOS-defined severity, adaptive behaviour profiles, intellectual ability and verbal status, the latter contributing the most for cluster stability and cohesion. Functional enrichment analysis of brain genes disrupted by CNVs in these ASD cases identified 15 statistically significant biological processes, including cell adhesion, neural development, cognition and polyubiquitination, in line with previous ASD findings. A Naive Bayes classifier, generated to predict the ASD phenotypic clusters from disrupted biological processes, achieved predictions with a high Precision (0.82) but low recall (0.39), for a subset of patients with higher biological Information Content scores. This study shows that milder and more severe clinical presentations can have distinct underlying biological mechanisms. It further highlights how machine learning approaches can reduce clinical heterogeneity using multidimensional clinical measures, and establish genotype-phenotype correlations in ASD. However, predictions are strongly dependent on patient’s information content. Findings are therefore a first step towards the translation of genetic information into clinically useful applications, but emphasize the need for larger datasets with very complete clinical and biological information.
Filamentation ofVibrio choleraeis an adaptation for surface attachment and biofilm architecture
Authors: Wucher Benjamin R. , Bartlett Thomas M. , Persat Alexandre , Nadell Carey D.
Published: November 2018

Collective behavior in spatially structured groups, or biofilms, is the norm among microbes in their natural environments. Though microbial physiology and biofilm formation have been studied for decades, tracing the mechanistic and ecological links between individual cell properties and the emergent features of cell groups is still in its infancy. Here we use single-cell resolution confocal microscopy to explore biofilm properties of the human pathogenVibrio choleraein conditions closely mimicking its marine habitat. We find that some – but not all – pandemic isolates produce filamentous cells than can be over 50 μm long. This filamentous morphotype gains a profound competitive advantage in colonizing and spreading on particles of chitin, the material many marineVibriospecies depend on for growth outside of hosts. Furthermore, filamentous cells can produce biofilms that are independent of all currently known secreted components of theV. choleraebiofilm matrix; instead, filamentous biofilm architectural strength appears to derive from the entangled mesh of cells themselves. The advantage gained by filamentous cells in early chitin colonization and growth is counter-balanced in longer term competition experiments with matrix-secretingV. choleraevariants, whose densely packed biofilm structures displace competitors from surfaces. Overall our results reveal a novel mode of biofilm architecture that is dependent on filamentous cell morphology and advantageous in environments with rapid chitin particle turnover. This insight provides concrete links betweenV. choleraecell morphology, biofilm formation, marine ecology, and – potentially – the strain composition of cholera epidemics.
Reproductive capacity evolves in response to ecology through common developmental mechanisms in Hawai’ianDrosophila
Authors: Sarikaya Didem P. , Church Samuel H. , Lagomarsino Laura P. , Magnacca Karl N. , Montgomery Steven , Price Donald K. , Kaneshiro Kenneth Y. , Extavour Cassandra G.
Published: November 2018

Lifetime reproductive capacity, or the total number of offspring that an individual can give rise to in its lifetime, is a fitness component critical to the evolutionary process. In insects, female reproductive capacity is largely determined by the number of ovarioles, the egg-producing subunits of the ovary. Recent work has provided insights into the genetic and environmental control of ovariole number inDrosophila melanogaster. However, whether regulatory mechanisms discovered under laboratory conditions also explain evolutionary variation in natural populations is an outstanding question. Here we report, for the first time, insights into the mechanisms regulating ovariole number and its evolution among Hawai’ianDrosophila, a large adaptive radiation of fruit flies in which the highest and lowest ovariole numbers of the genus have evolved within 25 million years. Using phylogenetic comparative methods, we show that ovariole number variation among Hawai’ianDrosophilais best explained by adaptation to specific oviposition substrates. Further, we show that evolution of oviposition on ephemeral egg-laying substrates is linked to changes the allometric relationship between body size and ovariole number. Finally, we provide evidence that the developmental mechanism principally responsible for controlling ovariole number inD. melanogasteralso regulates ovariole number in natural populations of Hawai’ian drosophilids. By integrating ecology, organismal growth, and cell behavior during development to understand the evolution of ovariole number, this work connects the ultimate and proximate mechanisms of evolutionary change in reproductive capacity.
Quantitative systems pharmacological analysis of drugs of abuse reveals the pleiotropy of their targets and the effector role of mTORC1
Authors: Pei Fen , Li Hongchun , Liu Bing , Bahar Ivet
Published: November 2018

Existing treatments against drug addiction are often ineffective due to the complexity of the networks of protein-drug and protein-protein interactions (PPIs) that mediate the development of drug addiction and related neurobiological disorders. There is an urgent need for understanding the molecular mechanisms that underlie drug addiction toward designing novel preventive or therapeutic strategies. The rapidly accumulating data on addictive drugs and their targets as well as advances in machine learning methods and computing technology now present an opportunity to systematically mine existing data and draw inferences on potential new strategies. To this aim, we carried out a comprehensive analysis of cellular pathways implicated in a diverse set of 50 drugs of abuse using quantitative systems pharmacology methods. The analysis of the drug/ligand-target interactions compiled in DrugBank and STITCH databases revealed 142 known and 48 newly predicted targets, which have been further analyzed to identify the KEGG pathways enriched at different stages of drug addiction cycle, as well as those implicated in cell signaling and regulation events associated with drug abuse. Apart from synaptic neurotransmission pathways detected as a common upstream signaling module that ‘senses’ the early effects of drugs of abuse, pathways involved in neuroplasticity are distinguished as determinants of neuronal morphological changes. Notably, many signaling pathways converge on important targets such as mTORC1. The latter is proposed to act as a universal effector of the persistent restructuring of neurons in response to continued use of drugs of abuse.
Ethanol Experience Enhances Glutamatergic Ventral Hippocampal Inputs to D1 Receptor-Expressing Medium Spiny Neurons in the Nucleus Accumbens Shell
Authors: Kircher Daniel M. , Aziz Heather , Mangieri Regina A. , Morrisett Richard A.
Published: November 2018

ABSTRACT

Nucleus accumbens dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) have been implicated in the formation of dependence to many drugs of abuse including alcohol. Previous studies have revealed that acute alcohol exposure suppresses glutamatergic signaling within the accumbens and repeated alcohol exposure enhances glutamatergic signaling. D1-MSNs receive glutamatergic input from several brain regions and it is not currently known how individual inputs onto D1-MSNs are altered by alcohol experience. To Address this, we used virally mediated expression of Channelrhodopsin (ChR2) in ventral hippocampal (vHipp) glutamate neurons to selectively activate vHipp to D1-MSN synapses and compared synaptic adaptations in response to low and high alcohol experiencein vitroandin vivo. Alcohol experience enhanced glutamatergic activity and abolished long-term depression (LTD) at ventral hippocampal (vHipp) to D1-MSN synapses. Following chronic alcohol experience GluA2-lacking AMPA receptors, which are Ca-permeable, were inserted into vHipp to D1-MSN synapses. These alcohol-induced adaptations of glutamatergic signaling occurred at lower levels of exposure than previously reported. The loss of LTD expression and enhancement in glutamatergic signaling from the vHipp to D1-MSNs in the nucleus accumbens may play a critical role in the formation of alcohol dependence and enhancements in ethanol consumption. Reversal of alcohol-induced insertion of Ca-permeable AMPA receptors and enhancement of glutamatergic activity at vHipp to D1-MSNs presents potential targets for intervention during early exposure to alcohol.

SIGNIFICANCE STATEMENT

The work presented here is the first to elucidate how an individual glutamatergic input onto D1-MSNs of the accumbens shell (shNAc) are altered by repeated ethanol exposure. Our findings suggest that glutamatergic input from the ventral hippocampus (vHipp) onto D1-MSNs is enhanced following drinking in a two-bottle choice (2BC) paradigm and is further enhanced by chronic intermittent ethanol (CIE) vapor exposure which escalated volitional ethanol intake. A critical finding was the insertion of Ca-permeable AMPA receptors into vHipp-shNAc D1-MSN synapses following CIE exposure, and more importantly following ethanol consumption in the absence of vapor exposure. These findings suggest that enhancements of glutamatergic input from the vHipp and insertion of Ca-permeable AMPARs play a role in the formation of ethanol dependence.
Multi-scale Loading and Damage Mechanisms of Rat Tail, Plantaris, and Achilles Tendons
Authors: Lee Andrea H. , Elliott Dawn M.
Published: November 2018

Tendinopathy, degeneration of tendon that leads to pain and dysfunction, is common in both sports and occupational settings, but multi-scale mechanisms for tendinopathy are still unknown. We recently showed that micro-scale sliding (shear) is responsible for both load transfer and damage mechanisms in rat tail tendon; however, rat tail tendon is a specialized non-load bearing tendon, and thus the load transfer and damage mechanisms are still unknown for load-bearing tendons. The objective of this study was to investigate the load transfer and damage mechanisms of load-bearing tendons using rat plantaris and Achilles tendons. We demonstrated that the micro-scale sliding is a key component for both mechanisms in plantaris tendon, similar to tail tendon. Namely, the micro-scale sliding was correlated with applied strain, demonstrating that load was transferred via micro-scale sliding in the plantaris and tail tendons. In addition, while the micro-scale strain fully recovered, the micro-scale sliding was non-recoverable and strain-dependent, and correlated with a tissue-scale mechanical parameters. When the applied strain was normalized, the % magnitudes of non-recoverable sliding was similar between the plantaris and tail tendons. Achilles tendon demonstrated some of the mechanical responses observed in plantaris and tail tendons, yet the results were inconclusive due to its complex structure. Statement of Clinical Significance: Understanding the mechanisms responsible for the pathogenesis and progression of tendinopathy can improve prevention and rehabilitation strategies and guide therapies and design of engineered constructs.
Charting the emergent organotypic landscape of the mammalian gut endoderm at single-cell resolution
Authors: Nowotschin Sonja , Setty Manu , Kuo Ying-Yi , Lui Vincent , Garg Vidur , Sharma Roshan , Simon Claire S. , Saiz Nestor , Gardner Rui , Boutet Stéphane C. , Church Deanna M. , Hoodless Pamela A. , Hadjantonakis Anna-Katerina , Pe’er Dana
Published: November 2018

To comprehensively delineate the ontogeny of an organ system, we generated 112,217 singlecell transcriptomes representing all endoderm populations within the mouse embryo until midgestation. We employed graph-based approaches to model differentiating cells for spatio-temporal characterization of developmental trajectories. Our analysis reveals the detailed architecture of the emergence of the first (primitive or extra-embryonic) endodermal population and pluripotent epiblast. We uncover an unappreciated relationship between descendants of these lineages, before the onset of gastrulation, suggesting that mixing of extra-embryonic and embryonic endoderm cells occurs more than once during mammalian development. We map the trajectories of endoderm cells as they acquire embryonic versus extra-embryonic fates, and their spatial convergence within the gut endoderm; revealing them to be globally similar but retaining aspects of their lineage history. We observe the regionalized localization of cells along the forming gut tube, reflecting their extra-embryonic or embryonic origin, and their coordinate patterning into organ-specific territories along the anterior-posterior axis.
Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity
Authors: Jones Takako I. , Chew Guo-Liang , Barraza-Flores Pamela , Schreier Spencer , Ramirez Monique , Wuebbles Ryan D. , Burkin Dean J. , Bradley Robert K. , Jones Peter L.
Published: November 2018

Background

All types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the aberrant myogenic activation of the somatically silent DUX4 gene, which initiates a cascade of cellular events ultimately leading to FSHD pathophysiology. Therefore, FSHD is a dominant gain-of-function disease that is amenable to modeling byDUX4overexpression. However, there is large variability in the patient population. Typically, progressive skeletal muscle weakness becomes noticeable in the second or third decade of life, yet there are many genetically FSHD individuals who develop symptoms much later in life or remain relatively asymptomatic throughout their lives. Conversely, in rare cases, FSHD may present clinically prior to 5-10 yrs of age, ultimately manifesting as a very severe early onset form of the disease. Thus, there is a need to control the timing and severity of pathology in FSHD-like models.

Methods

We have recently described a line of conditionalDUX4transgenic mice,FLExDUX4, that develop a myopathy upon induction of humanDUX4-flexpression in skeletal muscle. Here, we use theFLExDUX4mouse crossed with the skeletal muscle-specific and tamoxifen inducible lineACTAl-MerCreMerto generate a highly versatile bi-transgenic mouse model with chronic, low-level DUX4-fl expression and mild pathology, that can be induced to develop more severe FSHD-like pathology in a dose-dependent response to tamoxifen. We identified conditions to reproducibly generate models exhibiting mild, moderate, or severe DUX4-dependent pathophysiology, and characterized their progression.

Results

We assayed DUX4-fl mRNA and protein levels, fitness, strength, global gene expression, histopathology, and immune response, all of which are consistent with an FSHD-like myopathic phenotype. Importantly, we identified sex-specific and muscle-specific differences that should be considered when using these models for preclinical studies.

Conclusions

TheACTA1-MCM;FLExDUX4bi-transgenic mouse model expresses a chronic low level of DUX4-fl and has mild pathology and detectable muscle weakness. The onset and progression of moderate to severe pathology can be controlled via tamoxifen injection to provide consistent and readily screenable phenotypes for assessing therapies targeting DUX4-fl mRNA and protein. Thus, these FSHD-like mouse models can be used to study a range of DUX4-fl expression and pathology dependent upon investigator need, through controlled mosaic expression ofDUX4.