bluuebunny/crossref_metadata_2025 huggingface dataset:
XB130 deficiency enhances carcinogen-induced skin tumorigenesis
Authors: Cho Hae-Ra , Wang Yingchun , Bai Xiaohui , Xiang Yun-Yan , Lu Christina , Post Alexander , Al Habeeb Ayman , Liu Mingyao
Published: February 2019

XB130 is an adaptor protein that functions as a mediator of multiple tyrosine kinases important for regulating cell proliferation, survival, migration and invasion. Formerly predicted as an oncogene, alterations of its expression are documented in various human cancers. However, the exact role of XB130 in tumorigenesis is unknown. To address its function in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on XB130 knockout (KO), heterozygous (HZ) and wild-type (WT) littermate mice. DMBA/TPA-treated XB130 KO and HZ males developed a significantly higher number of epidermal tumors that were notably larger in size than did WT mice. Interestingly, DMBA/TPA-treated female mice did not show any difference in tumor multiplicity regardless of the genotypes. The skin tumor lesions of XB130 KO males were more progressed with an increased frequency of keratoacanthoma. Deficiency of XB130 dramatically increased epidermal tumor cell proliferation. The responses to DMBA and TPA stimuli were also individually investigated to elucidate the mechanistic role of XB130 at different stages of tumorigenesis. DMBA-treated male XB130 KO mice showed compensatory p53-mediated stress response. TPA-treated XB130 KO males demonstrated more skin ulceration with more severe edema, enhanced cell proliferation, accumulation of infiltrating neutrophils and increased production of pro-inflammatory cytokine genes compared with WT mice. Enhanced activities of nuclear factor-kappa B pathway, increased protein expression of metalloproteinase-9 and ERK1/2 phosphorylation were found in these KO mice. These findings demonstrate that XB130 acts as a tumor suppressor in carcinogen-induced skin tumorigenesis that may be mediated through inhibiting inflammation.
Association Between Antibiotic Use and Hospital-onset Clostridioides difficile Infection in US Acute Care Hospitals, 2006–2012: An Ecologic Analysis
Authors: Kazakova Sophia V , Baggs James , McDonald L Clifford , Yi Sarah H , Hatfield Kelly M , Guh Alice , Reddy Sujan C , Jernigan John A
Published: February 2019

Background

Unnecessary antibiotic use (AU) contributes to increased rates of Clostridioides difficile infection (CDI). The impact of antibiotic restriction on hospital-onset CDI (HO-CDI) has not been assessed in a large group of US acute care hospitals (ACHs).

Methods

We examined cross-sectional and temporal associations between rates of hospital-level AU and HO-CDI using data from 549 ACHs. HO-CDI was defined as a discharge with a secondary International Classification of Diseases, Ninth Revision, Clinical Modification code for CDI (008.45), and treatment with metronidazole or oral vancomycin > 3 days after admission. Analyses were performed using multivariable generalized estimating equation models adjusting for patient and hospital characteristics.

Results

During 2006–2012, the unadjusted annual rates of HO-CDI and total AU were 7.3 per 10 000 patient-days (PD) (95% confidence interval [CI], 7.1–7.5) and 811 days of therapy (DOT)/1000 PD (95% CI, 803–820), respectively. In the cross-sectional analysis, for every 50 DOT/1000 PD increase in total AU, there was a 4.4% increase in HO-CDI. For every 10 DOT/1000 PD increase in use of third- and fourth-generation cephalosporins or carbapenems, there was a 2.1% and 2.9% increase in HO-CDI, respectively. In the time-series analysis, the 6 ACHs with a ≥30% decrease in total AU had a 33% decrease in HO-CDI (rate ratio, 0.67 [95% CI, .47–.96]); ACHs with a ≥20% decrease in fluoroquinolone or third- and fourth-generation cephalosporin use had a corresponding decrease in HO-CDI of 8% and 13%, respectively.

Conclusions

At an ecologic level, reductions in total AU, use of fluoroquinolones, and use of third- and fourth-generation cephalosporins were each associated with decreased HO-CDI rates.
The multiplex structure of the mental lexicon influences picture naming in people with aphasia
Authors: Castro Nichol , Stella Massimo
Published: February 2019

An emerging area of research in cognitive science is the utilization of networks to model the structure and processes of the mental lexicon in healthy and clinical populations, like aphasia. Previous research has focused on only one type of word similarity at a time (e.g., semantic relationships), even though words are multi-faceted. Here, we investigate lexical retrieval in a picture naming task from people with Broca’s and Wernicke’s aphasia and healthy controls by utilizing a multiplex network structure that accounts for the interplay between multiple semantic and phonological relationships among words in the mental lexicon. Extending upon previous work, we focused on the global network measure of closeness centrality which is known to capture spreading activation, an important process supporting lexical retrieval. We conducted a series of logistic regression models predicting the probability of correct picture naming. We tested whether multiplex closeness centrality was a better predictor of picture naming performance than single-layer closeness centralities, other network measures assessing local and meso-scale structure, psycholinguistic variables and group differences. We also examined production gaps, or the difference between the likelihood of producing a word with the lowest and highest closeness centralities. Our results indicated that multiplex closeness centrality was a significant predictor of picture naming performance, where words with high closeness centrality were more likely to be produced than words with low closeness centrality. Additionally, multiplex closeness centrality outperformed single-layer closeness centralities and other multiplex network measures, and remained a significant predictor after controlling for psycholinguistic variables and group differences. Furthermore, we found that the facilitative effect of closeness centrality was similar for both types of aphasia. Our results underline the importance of integrating multiple measures of word similarities in cognitive language networks for better understanding lexical retrieval in aphasia, with an eye towards future clinical applications.
Long-term survival and frequency of reinterventions after proximal aortic surgery: a retrospective study†
Authors: Vikholm Per , Astudillo Rafael , Thelin Stefan
Published: February 2019

OBJECTIVES:

We sought to analyse perioperative outcome, long-term mortality, frequency and causes of reintervention, and survival benefit in a contemporary cohort of patients undergoing proximal thoracic aortic surgery.

METHODS:

Participants comprised all patients undergoing open surgery for proximal thoracic aortic aneurysm (TAA) (n = 319) and thoracic aortic dissection type A (TAD) (n = 229) during 2005–2014 at the Department of Thoracic Surgery, Uppsala University Hospital. Long-term survival was compared to age- and sex-matched controls. Perioperative mortality and morbidity, event-free survival and causes of reoperation were also analysed.

RESULTS:

Long-term mortality was normalized in patients with TAA, and a survival benefit was seen as early as 20 months when corrected for time lost due to perioperative mortality. Long-term survivors undergoing surgery for TAD, on the other hand, had a 10-year mortality of 130% [95% confidence interval (95% CI) 120–140%] compared to age- and sex-matched controls. Moreover, their event-free survival was half that of patients with TAA (hazard ratio 2.3; 95% CI 1.7–3.2). Reintervention (i.e. reoperation or thoracic endovascular aortic repair) was also twice as common in the TAD patients (odds ratio 2.0; 95% CI 1.1–3.5). The dominant causes for reoperation among TAD patients were aortic insufficiency, aortic arch aneurysm and infection.

CONCLUSIONS:

Surgery for TAA is relatively safe, normalizes long-term mortality and confers an early survival benefit. However, TAD surgery carries a high risk of perioperative mortality and morbidity, as well as increased long-term mortality and risk of reintervention.
Adverse childhood experiences, childhood relationships and associated substance use and mental health in young Europeans
Authors: Hughes Karen , Bellis Mark A , Sethi Dinesh , Andrew Rachel , Yon Yongjie , Wood Sara , Ford Kat , Baban Adriana , Boderscova Larisa , Kachaeva Margarita , Makaruk Katarzyna , Markovic Marija , Povilaitis Robertas , Raleva Marija , Terzic Natasa , Veleminsky Milos , Włodarczyk Joanna , Zakhozha Victoria
Published: February 2019

Background

Adverse childhood experiences (ACEs) can increase risks of health-harming behaviours and poor health throughout life. While increases in risk may be affected by resilience resources such as supportive childhood relationships, to date few studies have explored these effects.

Methods

We combined data from cross-sectional ACE studies among young adults (n = 14 661) in educational institutions in 10 European countries. Nine ACE types, childhood relationships and six health outcomes (early alcohol initiation, problem alcohol use, smoking, drug use, therapy, suicide attempt) were explored. Multivariate modelling estimated relationships between ACE counts, supportive childhood relationships and health outcomes.

Results

Almost half (46.2%) of participants reported ≥1 ACE and 5.6% reported ≥4 ACEs. Risks of all outcomes increased with ACE count. In individuals with ≥4 ACEs (vs. 0 ACEs), adjusted odds ratios ranged from 2.01 (95% CIs: 1.70–2.38) for smoking to 17.68 (95% CIs: 12.93–24.17) for suicide attempt. Supportive childhood relationships were independently associated with moderating risks of smoking, problem alcohol use, therapy and suicide attempt. In those with ≥4 ACEs, adjusted proportions reporting suicide attempt reduced from 23% with low supportive childhood relationships to 13% with higher support. Equivalent reductions were 25% to 20% for therapy, 23% to 17% for problem drinking and 34% to 32% for smoking.

Conclusions

ACEs are strongly associated with substance use and mental illness. Harmful relationships are moderated by resilience factors such as supportive childhood relationships. Whilst ACEs continue to affect many children, better prevention measures and interventions that enhance resilience to the life-long impacts of toxic childhood stress are required.
Practical mixed methods strategies used to integrate qualitative and quantitative methods in community-based primary health care research
Authors: Kaur Navdeep , Vedel Isabelle , El Sherif Reem , Pluye Pierre
Published: February 2019

Background

Mixed methods (MM) are common in community-based primary health care (CBPHC) research studies. Several strategies have been proposed to integrate qualitative and quantitative components in MM, but they are seldom well conceptualized and described. The purpose of the present review was to identify and describe practical MM strategies and combinations of strategies used to integrate qualitative and quantitative methods in CBPHC research.

Methods

A methodological review with qualitative synthesis (grouping) was performed. Records published in English in 2015 were retrieved from the Scopus bibliographic database. Eligibility criteria were: CBPHC empirical study, MM research with detailed description of qualitative and quantitative methods and their integration. Data were extracted from included studies and grouped using a conceptual framework comprised of three theoretical types of MM integration, the seven combinations of these types and nine practical strategies (three per type of integration) and multiple combinations of strategies.

Results

Among the 151 articles reporting CBPHC and MM studies retrieved, 54 (35.7%) met the inclusion criteria for this review. The included studies provided examples of the three theoretical types of MM integration, the seven combinations of these types as well as the nine practical strategies. Overall, 15 combinations of these strategies were observed. No emerging strategy was observed that was not predicted by the conceptual framework.

Conclusions

This review can provide guidance to CBPHC researchers for planning, conducting and reporting practical strategies and combinations of strategies used for integrating qualitative and quantitative methods in MM research.
How emerging data technologies can increase trust and transparency in fisheries
Authors: Probst Wolfgang Nikolaus
Published: February 2019

The ubiquitous spread of digital networks has created techniques which can organize, store, and analyse large data volumes in an automized and self-administered manner in real time. These technologies will have profound impacts on policy, administration, economy, trade, society, and science. This article sketches how three digital data technologies, namely the blockchain, data mining, and artificial intelligence could impact commercial fisheries including producers, wholesalers, retailers, consumers, management authorities, and scientist. Each of these three technologies is currently experiencing an enormous boost in technological development and real-world implementation and is predicted to increasingly affect many aspects of fisheries and seafood trade. As any economic sector acting on global scales, fishing and seafood production are often challenged with a lack of trust along various steps of the production process and supply chain. Consumers are often not well informed on the origin and production methods of their product, management authorities can only partly control fishing and trading activities and producers can be challenged by low market prices and competition with peers. The emerging data technologies can improve the trust among agents within the fisheries sector by increasing transparency and availability of information from net to plate.
How urban characteristics affect vulnerability to heat and cold: a multi-country analysis
Authors: Sera Francesco , Armstrong Ben , Tobias Aurelio , Vicedo-Cabrera Ana Maria , Åström Christofer , Bell Michelle L , Chen Bing-Yu , de Sousa Zanotti Stagliorio Coelho Micheline , Matus Correa Patricia , Cruz Julio Cesar , Dang Tran Ngoc , Hurtado-Diaz Magali , Do Van Dung , Forsberg Bertil , Guo Yue Leon , Guo Yuming , Hashizume Masahiro , Honda Yasushi , Iñiguez Carmen , Jaakkola Jouni J K , Kan Haidong , Kim Ho , Lavigne Eric , Michelozzi Paola , Ortega Nicolas Valdes , Osorio Samuel , Pascal Mathilde , Ragettli Martina S , Ryti Niilo R I , Saldiva Paulo Hilario Nascimento , Schwartz Joel , Scortichini Matteo , Seposo Xerxes , Tong Shilu , Zanobetti Antonella , Gasparrini Antonio
Published: February 2019

Background

The health burden associated with temperature is expected to increase due to a warming climate. Populations living in cities are likely to be particularly at risk, but the role of urban characteristics in modifying the direct effects of temperature on health is still unclear. In this contribution, we used a multi-country dataset to study effect modification of temperature–mortality relationships by a range of city-specific indicators.

Methods

We collected ambient temperature and mortality daily time-series data for 340 cities in 22 countries, in periods between 1985 and 2014. Standardized measures of demographic, socio-economic, infrastructural and environmental indicators were derived from the Organisation for Economic Co-operation and Development (OECD) Regional and Metropolitan Database. We used distributed lag non-linear and multivariate meta-regression models to estimate fractions of mortality attributable to heat and cold (AF%) in each city, and to evaluate the effect modification of each indicator across cities.

Results

Heat- and cold-related deaths amounted to 0.54% (95% confidence interval: 0.49 to 0.58%) and 6.05% (5.59 to 6.36%) of total deaths, respectively. Several city indicators modify the effect of heat, with a higher mortality impact associated with increases in population density, fine particles (PM2.5), gross domestic product (GDP) and Gini index (a measure of income inequality), whereas higher levels of green spaces were linked with a decreased effect of heat.

Conclusions

This represents the largest study to date assessing the effect modification of temperature–mortality relationships. Evidence from this study can inform public-health interventions and urban planning under various climate-change and urban-development scenarios.
Randomized controlled trial of telephone-based cognitive-behavioral therapy on parenting self-efficacy and satisfaction
Authors: Ngai Fei-Wan , Wong Paul Wai-Ching , Chung Ka-Fai , Leung Kwok-Yin , Tarrant Marie
Published: February 2019

Postpartum women who participated in a telephone-based cognitive-behavioral therapy had higher parenting self-efficacy and satisfaction.
Evolutionary and developmental mismatches are consequences of adaptive developmental plasticity in humans and have implications for later disease risk
Authors: Gluckman Peter D. , Hanson Mark A. , Low Felicia M.
Published: February 2019

A discrepancy between the phenotype of an individual and that which would confer optimal responses in terms of fitness in an environment is termed ‘mismatch’. Phenotype results from developmental plasticity, conditioned partly by evolutionary history of the species and partly by aspects of the developmental environment. We discuss two categories of such mismatch with reference primarily to nutrition and in the context of evolutionary medicine. The categories operate over very different timescales. A developmental mismatch occurs when the phenotype induced during development encounters a different environment post-development. This may be the result of wider environmental changes, such as nutritional transition between generations, or because maternal malnutrition or placental dysfunction give inaccurate information about the organism's likely future environment. An evolutionary mismatch occurs when there is an evolutionarily novel environment. Developmental plasticity may involve immediate adaptive responses (IARs) to preserve survival if an environmental challenge is severe, and/or predictive adaptive responses (PARs) if the challenge does not threaten survival, but there is a fitness advantage in developing a phenotype that will be better adapted later. PARs can have long-term adverse health consequences if there is a developmental mismatch. For contemporary humans, maternal constraint of fetal growth makes PARs likely even if there is no obvious IAR, and this, coupled with the pervasive nutritionally dense modern environment, can explain the widespread observations of developmental mismatch, particularly in populations undergoing nutritional transition. Both developmental and evolutionary mismatch have important public health consequences and implications for where policy interventions may be most effective.

This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine'.
Early life programming in mice by maternal overnutrition: mechanistic insights and interventional approaches
Authors: Nicholas Lisa M. , Ozanne Susan E.
Published: February 2019

Animal models have been indispensable in elucidating the potential causative mechanisms underlying the effects of maternal diet on offspring health. Of these, the mouse has been widely used to model maternal overnutrition and/or maternal obesity and to study its effects across one or more generations. This review discusses recent findings from mouse models, which resemble the human situation, i.e. overnutrition/obesity across pregnancy and lactation. It also highlights the importance of embryo transfer models in identifying critical developmental period(s) during which specific metabolic changes are programmed in the offspring. The mouse is also an excellent tool for maternal intervention studies aimed at elucidating the longer-term effects on the offspring and for defining possible maternal factors underling the programming of metabolic adversity in offspring. While knowledge of the mouse genome and the molecular tools available have allowed great progress to be made in the field, it is clear that we need to define if the effects on the offspring are mediated by maternal obesity
per se
or if specific components of the maternal metabolic environment are more important. We can then begin to identify at-risk offspring and to design more effective interventions for the mother and/or her child.

This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
The development of individual differences in cooperative behaviour: maternal glucocorticoid hormones alter helping behaviour of offspring in wild meerkats
Authors: Dantzer Ben , Dubuc Constance , Goncalves Ines Braga , Cram Dominic L. , Bennett Nigel C. , Ganswindt Andre , Heistermann Michael , Duncan Chris , Gaynor David , Clutton-Brock Tim H.
Published: February 2019

The phenotype of parents can have long-lasting effects on the development of offspring as well as on their behaviour, physiology and morphology as adults. In some cases, these changes may increase offspring fitness but, in others, they can elevate parental fitness at a cost to the fitness of their offspring. We show that in Kalahari meerkats (Suricata suricatta), the circulating glucocorticoid (GC) hormones of pregnant females affect the growth and cooperative behaviour of their offspring. We performed a 3-year experiment in wild meerkats to test the hypothesis that GC-mediated maternal effects reduce the potential for offspring to reproduce directly and therefore cause them to exhibit more cooperative behaviour. Daughters (but not sons) born to mothers treated with cortisol during pregnancy grew more slowly early in life and exhibited significantly more of two types of cooperative behaviour (pup rearing and feeding) once they were adults compared to offspring from control mothers. They also had lower measures of GCs as they aged, which could explain the observed increases in cooperative behaviour. Because early life growth is a crucial determinant of fitness in female meerkats, our results indicate that GC-mediated maternal effects may reduce the fitness of offspring, but may elevate parental fitness as a consequence of increasing the cooperative behaviour of their daughters.

This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
Non-genetic inheritance via the male germline in mammals
Authors: Baxter Faye A. , Drake Amanda J.
Published: February 2019

Numerous studies in humans and in animal models have demonstrated that exposure to adverse environmental conditions in early life results in long-term structural and functional changes in an organism, increasing the risk of cardiometabolic, neurobehavioural and reproductive disorders in later life. Such effects are not limited to the first generation offspring but may be transmitted to a second or a number of subsequent generations, through non-genomic mechanisms. While the transmission of ‘programmed’ effects through the maternal line could occur as a consequence of multiple influences, for example, altered maternal physiology, the inheritance of effects through the male line is more difficult to explain and there is much interest in a potential role for transgenerational epigenetic inheritance. In this review, we will discuss the mechanisms by which induced effects may be transmitted through the paternal lineage, with a particular focus on the role of epigenetic inheritance.

This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
Metabolic programming in early life in humans
Authors: Fall Caroline H. D. , Kumaran Kalyanaraman
Published: February 2019

An association of low birth weight with an increased risk of adult cardiovascular disease and diabetes led to the developmental origins of health and disease (DOHaD) hypothesis, which proposes that undernutrition during early development permanently ‘programmes’ organ structure and metabolism, leading to vulnerability to later cardio-metabolic disease. High birth weight caused by maternal gestational diabetes is also associated with later diabetes, suggesting that fetal over-nutrition also has programming effects. Post-natal factors (excess weight gain/obesity, smoking, poor diets and physical inactivity) interact with fetal exposures to increase disease risk. Animal studies have shown permanent metabolic effects in offspring after alterations to maternal or early post-natal diets but evidence in humans is largely limited to observational and quasi-experimental situations such as maternal famine exposure. Randomized trials of maternal nutritional interventions during pregnancy have so far had limited follow-up of the offspring. Moreover, interventions usually started after the first trimester and therefore missed key peri-conceptional or early pregnancy events such as epigenetic changes, placentation and fetal organogenesis. Recent and ongoing trials intervening pre-conceptionally and powered for long-term offspring follow-up will address these issues. While current preventive strategies for cardio-metabolic disease focus on high-risk individuals in mid-life, DOHaD concepts offer a ‘primordial’ preventive strategy to reduce disease in future generations by improving fetal and infant development.

This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
Cross-cultural evidence does not support universal acceleration of puberty in father-absent households
Authors: Sear Rebecca , Sheppard Paula , Coall David A.
Published: February 2019

Father absence in early life has been shown to be associated with accelerated reproductive development in girls. Evolutionary social scientists have proposed several adaptive hypotheses for this finding. Though there is variation in the detail of these hypotheses, they all assume that family environment in early life influences the development of life-history strategy, and, broadly, that early reproductive development is an adaptive response to father absence. Empirical evidence to support these hypotheses, however, has been derived from WEIRD (Western, Educated, Industrialized, Rich and Democratic) populations. Data from a much broader range of human societies are necessary in order to properly test adaptive hypotheses. Here, we review the empirical literature on father absence and puberty in both sexes, focusing on recent studies that have tested this association beyond the WEIRD world. We find that relationships between father absence and age at puberty are more varied in contexts beyond WEIRD societies, and when relationships beyond the father–daughter dyad are considered. This has implications for our understanding of how early-life environment is linked to life-history strategies, and for our understanding of pathways to adult health outcomes, given that early reproductive development may be linked to negative health outcomes in later life

This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.
Naming classes of prokaryotes based on the rules of Latin grammar
Authors: Oren Aharon , Chuvochina Maria , Schink Bernhard , Ventura Stefano
Published: February 2019

Recently a proposal was published to unify Rules 7, 8 and 9 of the International Code of Nomenclature of Prokaryotes. Based on this proposal, all names of taxa above the rank of genus must be in the feminine gender, the plural number. For the rank of class, this proposal contravenes Principle 3 of the Code, which states that the scientific names of all taxa are treated as Latin. The –ia ending of most names of classes belongs to nominative plural nouns of the neuter gender.
Clinical, imaging genetics and deformation based morphometry study of longitudinal changes after surgery for intractable aggressive behaviour
Authors: Gouveia Flavia V. , Germann Jürgen , de Morais Rosa M. C. B. , Fonoff Erich T. , Hamani Clement , Alho Eduardo Joaquim , Brentani Helena , Martins Ana Paula , Devenyi Gabriel , Patel Raihaan , Steele Christopher J. , Gramer Robert , Chakravarty M. Mallar , Martinez Raquel C. R.
Published: February 2019

Intractable aggressive behaviour is a devastating behavioural disorder that reach 30% of psychiatric aggressive patients. Neuromodulatory surgeries may be treatment alternatives to reduce suffering. We investigated the outcomes of bilateral amygdala radiofrequency ablation in four patients with intractable aggressive behaviour (life-threatening-self-injury and social aggression) by studying whole brain magnetic resonance imaging and clinical data. Post-surgery assessments revealed decreases in aggression and agitation and improvements in quality of life. Aggressive behaviour was positively correlated with serum testosterone levels and the testosterone/cortisol ratio in males. No clinically significant side effects were observed. Imaging analyses revealed preoperative amygdala volumes within normal range and confirmed appropriate lesion locations. Reduction in aggressiveness were accompanied by volumetric reduction in brain areas associated with aggressive behaviour (express genes related to aggressive behaviour), and increases in regions related to somatosensation. These findings further elucidates the neurocircuitry of aggression and suggests novel neuromodulation targets.
Does insulin signalling decide glucose levels in the fasting steady state?
Authors: Diwekar-Joshi Manawa , Watve Milind
Published: February 2019

Recent work has suggested that altered insulin signalling may not be central and as critical to the pathophysiology of type 2 diabetes as classically believed. We critically re-examine the role of insulin in glucose homeostasis using five different approaches namely (i) systematic review and meta-analysis of tissue specific insulin receptor knock-out experiments in rodents, (ii) systematic review and meta-analysis of insulin suppression and insulin enhancement experiments in rodents and humans, (iii) differentiating steady-state and post-meal state glucose levels in streptozotocin treated rats in primary experiments (iv) mathematical and theoretical considerations and (v) glucose insulin relationship in human epidemiological data. All the approaches converge on the inference that although insulin action is needed to reach a homeostatic steady-state of glucose in fasting condition, there is no evidence that insulin action determines the steady-state level of glucose. A wider scale implication of the analysis is in emphasizing the need to differentiate steady state causality from perturbed state causality or on a broader scale driver causality from navigator causality in biology. A driver cause is a factor which is necessary to attain a destination but does not by itself decide the destination. A navigator cause, on the other hand, is one which by itself may not be sufficient to drive the system to a destination but which plays a role in deciding the destination or direction. Insulin appears to be a driver but not a navigator for glucose homeostasis. All evidence suggests that insulin action is required for reaching a homeostatic steady state, but it does not determine the steady-state level of glucose.
Holding the arm still through subcortical mathematical integration of cortical commands
Authors: Albert Scott T. , Hadjiosif Alkis M. , Jang Jihoon , Krakauer John W. , Shadmehr Reza
Published: February 2019

A period of holding still follows every movement. It has been assumed that for the arm, moving and holding are functionally independent: movement is via an adaptive, feedback-dependent controller that generates commands to transport the arm, while holding is via setting of reflexes that produce a postural field at movement endpoint. This assumption predicts that commands that move the arm should not affect the postural field at movement termination. Surprisingly, we found that as the reach commands changed, so did the ensuing postural field. The postural commands depended on mathematical integration of the reach commands. Following damage to the corticospinal tract, despite severe reach impairments, the holding system faithfully integrated the imperfect reach commands on a trial-by-trial basis. Together, these findings suggest that holding the arm still is accomplished via a separate, likely subcortical structure that acts as a mathematical integrator of the commands generated by the cortical reach controller.
Central and peripheral innervation patterns of defined axial motor units in larval zebrafish
Authors: Bello-Rojas Saul , Istrate Ana E. , Kishore Sandeep , McLean David L.
Published: February 2019

Spinal motor neurons and the peripheral muscle fibers they innervate form discrete motor units that execute movements of varying force and speed. Subsets of spinal motor neurons also exhibit axon collaterals that influence motor output centrally. Here, we have usedin vivoimaging to anatomically characterize the central and peripheral innervation patterns of axial motor units in larval zebrafish. Using early born ‘primary’ motor neurons and their division of epaxial and hypaxial muscle into four distinct quadrants as a reference, we define three distinct types of later born ‘secondary’ motor units. The largest are ‘m-type’ units, which innervate deeper fast-twitch muscle fibers via medial nerves. Next in size are ‘ms-type’ secondaries, which innervate superficial fast-twitch and slow fibers via medial and septal nerves, followed by ‘s-type’ units, which exclusively innervate superficial slow muscle fibers via septal nerves. All types of secondaries innervate up to four axial quadrants. Central axon collaterals are found in subsets of primaries based on soma position and predominantly in secondary fast-twitch units (m, ms) with increasing likelihood based on number of quadrants innervated. Collaterals are labeled by synaptophysin-tagged fluorescent proteins, but not PSD95, consistent with their output function. Also, PSD95 dendrite labeling reveals that larger motor units receive more excitatory synaptic input. Collaterals are largely restricted to the neuropil, however perisomatic connections are observed between motor units. These observations suggest that recurrent interactions are dominated by motor neurons recruited during stronger movements and set the stage for functional investigations of recurrent motor circuitry in larval zebrafish.
Drivers of individual oak tree selection by acorn dispersing animals inferred from a genotyped seedling cohort
Authors: Gerzabek Gabriel , Klein Etienne K. , Hampe Arndt
Published: February 2019

Seed-dispersing animals can strongly influence plant reproductive success and resulting population structures. Few studies have disentangled different drivers of disperser foraging behavior in natural settings and their actual relevance for plant fitness. Here we adopt a novel approach to investigate the drivers of individual trees’ dispersal success in a mixed Pedunculate oak-Pyrenean oak (Quercus robur and Q. pyrenaica) forest stand. We genotyped a seedling cohort (n = 825) upon emergence and performed Bayesian parentage analyses to infer the acorn dispersal success of each oak tree in the stand. We then modeled this estimate as a function of six tree characteristics. The absolute number of animal-dispersed seedlings was exclusively predicted by crop size and the proportion of dispersed seedlings by the number of fruiting oaks in the neighborhood. Neither the oak species nor tree height, acorn size or shape played any role. Our findings contrast with results from experimental studies and suggest that effective acorn dispersers, despite being scatter-hoarders, behaved much like avian dispersers of fleshy-fruited species when selecting trees to forage on. Their behavior should favor the dominance of large, prolific trees for the dynamics and genetic composition of naturally regenerating oak stands.
Generation of dual specific bivalent BiTEs (dbBIspecific T-cell Engaging antibodies) for cellular immunotherapy
Authors: Kujawski Maciej , Li Lin , Bhattacharya Supriyo , Wong Patty , Lee Wen-Hui , Williams Lindsay , Li Harry , Chea Junie , Poku Kofi , Bowles Nicole , Vaidehi Nagarajan , Yazaki Paul , Shively John E.
Published: February 2019

Bispecific T-cell engaging antibodies (BiTES), comprising dual anti-CD3 and anti-tumor antigen scFv fragments, are important therapeutic agents for the treatment of cancer. The dual scFv construct for BiTES requires proper protein folding while their small molecular size leads to rapid kidney clearance. Here we show that an intact (150 kDa) anti-tumor antigen antibody to CEA was joined in high yield (ca. 30%) to intact (150 kDa) anti-murine and anti-human CD3 antibodies using hinge region specific Click chemistry to form dual-specific, bivalent BiTES (db BiTES, 300 kDa). The interlocked hinge regions are compatible with a structural model that fits the electron micrographs of the 300 kDa particles. Compared to intact anti-CEA antibody, dbBiTES maintain high in vivo tumor targeting as demonstrated by PET imaging, and redirect dbBiTE coated T-cells (1 microgram/10 million cells) to kill CEA+ target cells both in vitro, and in vivo in CEA transgenic mice.
Personalized Therapy Design for Systemic Lupus Erythematosus Based on the Analysis of Protein-Protein Interaction Networks
Authors: Brant Elizabeth J. , Rietman Edward A. , Klement Giannoula Lakka , Cavaglia Marco , Tuszynski Jack A.
Published: February 2019

We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either ribosomal proteins, ubiquitination pathway proteins or heat shock proteins. We propose some of the proteins identified in this study to be considered for drug targeting.
A direct link betweenPrss53, hair curvature, and skeletal dysplasia
Authors: Deng Jichao , Song Yuning , Liu Hongmei , Sui Tingting , Chen Mao , Zhang Yuxin , Yao Bing , Xu Yuxin , Liu Zhiquan , Lai Liangxue , Li Zhanjun
Published: February 2019

In humans, protease serine S1 family member 53 (Prss53) is highly expressed in the hair follicle, especially the inner root sheath, which is associated with hair shape according to recent genome-wide association study (GWAS) data. However, no animal evidence has indicated a link betweenPrss53and hair shape to date. Here, we used CRISPR/Cas9 to generatePrss53-mutated rabbits. The homozygous (Prss53-/-) rabbits exhibited curved hair and skeletal dyskinesia with severe malformation, while the heterozygous (Prss53+/-) rabbits did not exhibit these features. The curvature features of the hair were accompanied by lesions that were generally denser and less well-defined in the cuticular septation of the hair shaft, and the compartments of the hair follicle were incomplete, as evidenced by decreased expression levels of keratinocyte differentiation genes. In addition, skeletal dysplasia, an increased lethality rate and decreased plasma calcium and serum alkaline phosphatase (ALP) levels were determined in thePrss53-/-rabbits. Furthermore, disrupted calcium metabolism, which may play a role in the hair curvature and skeletal dysplasia ofPrss53+/-rabbits, was demonstrated by using high-throughput RNA sequencing data. Thus, our study confirmed for the first time that the loss ofPrss53lead to curved hair in animals and provides new insights into the crucial role ofPrss53in calcium metabolism.

Author Summary

No animal evidence has indicated a link betweenPrss53and hair shape to date.

ThePrss53-/-rabbits exhibited curved hair and skeletal dyskinesia.

The disrupted calcium metabolism may play a role in the hair curvature and skeletal dysplasia ofPrss53+/-rabbits.
Prevalence of HIV-1 infection among foreign applicant to residency in Shanghai, China, 2005-2016
Authors: Qin Jia , Zhou Ru , Xia Jing , Wang Weixin , Pan Jun , Pan Jiahong , Zhou Xuan , Zhang Qi
Published: February 2019

Background

Shanghai is one of the biggest cities which have the highest number of entry travelers from all over the world. The HIV(human immunodeficiency virus) infection status of this population can reflect global trends of HIV prevalence to a certain extent.

Methods

A retrospective cohort study was conducted to reveal the prevalence and characteristics of HIV-1 infection among entry travelers who applied to residency in Shanghai. The HIV-1 infection rate was estimated based on the detection of HIV-1 antibody.

Results

Among 50830 entry travelers who applied to residency in Shanghai(2005-2016), 245 were determined HIV-1 positive with an infection rate of 0.48%. The detection rate of HIV was significantly higher in male (P<0.0001). Those aged 18-30 years, 31-40 years and >40years accounted for 34.3%,39.6% and 26.1% respectively of the infected population. Although there was no trend of increase in HIV-1 prevalence rates (Cochran-Armitage Z =2.543, P =0.111),proportions of individuals infected through homosexual transmission increased over the study period (Cochran-Armitage Z =5.41, P<0.001), while the proportions infected through heterosexual(Cochran-Armitage Z=3.38, P=0.001).

Conclusion

The rate and characteristics of HIV-1 infection among foreign applicant to residency in Shanghai were revealed in the study. The results could provide the necessary epidemiological data for monitoring the HIV-1 epidemic among entry international travelers and to further contribute to the establishment of relevant policies and regulations for HIV control and prevention.
BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma
Authors: Herbert Katharine , Binet Romuald , Lambert Jean-Philippe , Louphrasitthiphol Pakavarin , Kalkavan Halime , Sesma-Sanz Laura , Robles-Espinoza Carla Daniela , Sarkar Sovan , Suer Eda , Andrews Sarah , Chauhan Jagat , Roberts Nicola D. , Middleton Mark R. , Gingras Anne-Claude , Masson Jean-Yves , Larue Lionel , Falletta Paola , Goding Colin R.
Published: February 2019

Whether cell types exposed to a high level of environmental insults possess cell type-specific prosurvival mechanisms or enhanced DNA damage repair capacity is not well understood. BRN2 is a tissue-restricted POU domain transcription factor implicated in neural development and several cancers. In melanoma, BRN2 plays a key role in promoting invasion and regulating proliferation. Here we found, surprisingly, that rather than interacting with transcription cofactors, BRN2 is instead associated with DNA damage response proteins and directly binds PARP1 and Ku70/Ku80. Rapid PARP1-dependent BRN2 association with sites of DNA damage facilitates recruitment of Ku80 and reprograms DNA damage repair by promoting Ku-dependent nonhomologous end-joining (NHEJ) at the expense of homologous recombination. BRN2 also suppresses an apoptosis-associated gene expression program to protect against UVB-, chemotherapy- and vemurafenib-induced apoptosis. Remarkably, BRN2 expression also correlates with a high single-nucleotide variation prevalence in human melanomas. By promoting error-prone DNA damage repair via NHEJ and suppressing apoptosis of damaged cells, our results suggest that BRN2 contributes to the generation of melanomas with a high mutation burden. Our findings highlight a novel role for a key transcription factor in reprogramming DNA damage repair and suggest that BRN2 may impact the response to DNA-damaging agents in BRN2-expressing cancers.
Contrasting perspectives – practitioner’s viewpoint on personalised marketing communication
Authors: Strycharz Joanna , van Noort Guda , Helberger Natali , Smit Edith
Published: February 2019

Purpose

The purpose of this paper is to provide insights into personalisation from a practitioner’s perspective to bridge the practitioner-academia gap and steer the research agenda. A wide scope of research has investigated personalisation from a consumer perspective. The current study aims at bridging the consumer and practitioner perspective by entering into a dialogue about the practical application of personalisation. It takes the personalisation process model by Vesanen and Raulas (2006) as the starting point.

Design/methodology/approach

Lead by the exploratory character of the study, semi-structured expert interviews were conducted with marketers, market researchers and online privacy specialists.

Findings

The results showcase how practitioners view the issues present in consumer research. First, they are overly positive about personalisation. Second, they are aware of constraining factors; findings showcase best practices to mitigate them. Finally, practitioners are aware of controversies surrounding personalisation and thus engage in ethical discussions on personalisation.

Research limitations/implications

This study shows that practitioners have somewhat different believes about the utility and appreciation of personalised marketing practices than consumers. It also shows awareness of some of the key concerns of consumers, and that such awareness translates into organisational and technological solutions that can even go beyond what is currently mandated by law. Six insights into personalised marketing as well as expectations for the future of the phenomenon are discussed to steer the research agenda.

Practical implications

Insights into the practice of personalisation contribute to a shared understanding of this phenomenon between involved actors, such as marketers, advertisers, and consumer representatives. In addition, implications for lawmakers are discussed, suggesting that the implementation of privacy laws needs more clarity and that actions aiming at improving consumer knowledge are needed.

Originality/value

The paper contributes to the literature first, by drafting a descriptive map of personalisation from a practitioners’ perspective and contrasting it with the perspective stemming from consumer research and, second, by offering insights into the current developments and direct implications for practice and future research.
Learning whilst working
Authors: D’Annunzio-Green Norma , Barron Paul
Published: February 2019

Purpose

The purpose of this paper is to examine student learner perceptions of benefits, barriers and enablers in learning whilst working, specifically focussing, on learning transfer from a university MSc in human resource management to students’ professional roles as human resource practitioners.

Design/methodology/approach

The study used in-depth semi-structured interviews with alumni of the programme who had graduated between one to three years previously.

Findings

The study found benefits (increased self-confidence, credibility and networking skills) as well as unanticipated challenges relating to individual learner characteristics, organisational culture and work-related support that hindered learning transfer.

Research limitations/implications

The study contributes to understanding the mechanisms required to support part-time learners on continuing vocational education programmes from a variety of stakeholders including students, their managers, their university and work colleagues, and academic staff. It highlights the benefits of activities designed to help students relate theory to practice and facilitate the transfer of knowledge between academic and practitioner environments.

Practical implications

The study highlights learner perspectives that are focussed on how organisational culture and line managers might play a more central role in influencing how people learn at work and facilitate the transfer of learning from formal educational interventions.

Originality/value

The study is valuable to academics and practitioners interested in improving learning transfer from formal educational to professional settings.