bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of the National Health Service Corps Clinicians in Enhancing Staffing and Patient Care Capacity in Community Health Centers
Authors: Han Xinxin , Pittman Patricia , Erikson Clese , Mullan Fitzhugh , Ku Leighton
Published: September 2019

Objective:

The National Health Service Corps (NHSC) is a federal program to increase the supply of health professionals in underserved communities, but its role in enhancing the capacity of community health centers (CHCs) has not been investigated. This study examined the role of NHSC clinicians in improving staffing and patient care capacity in primary, dental, and mental health care in CHCs.

Methods:

Using 2013–2016 administrative data from CHCs and the NHSC, we used a generalized estimating equation approach to examine whether NHSC clinicians [staff full-time equivalents (FTEs)] complement non-NHSC clinicians in CHCs and whether their productivity (patient visits per staff FTE) was greater than that of non-NHSC clinicians in primary, dental, and mental health care.

Results:

Each additional NHSC clinician FTE was associated with a significant gain of 0.72 non-NHSC clinician FTEs in mental health care in CHCs and an increase of 0.04 non-NHSC FTEs in primary care in CHCs with more severe staffing shortages. On average, every additional NHSC clinician was associated with an increase of 2216 primary care visits, 2802 dental care visits, and 1296 mental health care visits per center-year. The adjusted visits per additional staff for NHSC clinicians were significantly greater in dental (difference=992) and mental health (difference=423) care, compared with non-NHSC clinicians.

Conclusions:

The NHSC clinicians complement non-NHSC clinicians in primary care and mental health care. They help enhance the provision of patient care in CHCs, particularly in dental and mental health services, the 2 major areas of service gaps.
Predictive Factors and Risk Model for Positive Circumferential Resection Margin Rate After Transanal Total Mesorectal Excision in 2653 Patients With Rectal Cancer
Authors: Roodbeen Sapho X. , de Lacy F. B. , van Dieren Susan , Penna Marta , Ris Frédéric , Moran Brendan , Tekkis Paris , Bemelman Willem A. , Hompes Roel
Published: September 2019

Objective:

The aim of this study was to determine the incidence of, and preoperative risk factors for, positive circumferential resection margin (CRM) after transanal total mesorectal excision (TaTME).

Background:

TaTME has the potential to further reduce the rate of positive CRM for patients with low rectal cancer, thereby improving oncological outcome.

Methods:

A prospective registry-based study including all cases recorded on the international TaTME registry between July 2014 and January 2018 was performed. Endpoints were the incidence of, and predictive factors for, positive CRM. Univariate and multivariate logistic regressions were performed, and factors for positive CRM were then assessed by formulating a predictive model.

Results:

In total, 2653 patients undergoing TaTME for rectal cancer were included. The incidence of positive CRM was 107 (4.0%). In multivariate logistic regression analysis, a positive CRM after TaTME was significantly associated with tumors located up to 1 cm from the anorectal junction, anterior tumors, cT4 tumors, extra-mural venous invasion (EMVI), and threatened or involved CRM on baseline MRI (odds ratios 2.09, 1.66, 1.93, 1.94, and 1.72, respectively). The predictive model showed adequate discrimination (area under the receiver-operating characteristic curve >0.70), and predicted a 28% risk of positive CRM if all risk factors were present.

Conclusion:

Five preoperative tumor-related characteristics had an adverse effect on CRM involvement after TaTME. The predicted risk of positive CRM after TaTME for a specific patient can be calculated preoperatively with the proposed model and may help guide patient selection for optimal treatment and enhance a tailored treatment approach to further optimize oncological outcomes.
Effects of ketamine on voltage-gated sodium channels in the barrel cortex and the ventral posteromedial nucleus slices of rats
Authors: Yin Jianyin , Fu Bao , Wang Yuan , Yu Tian
Published: September 2019

Ketamine is commonly used as a dissociative anesthetic with unique actions in the central nervous system. Previous studies have found that the thalamocortical systems play an important role in general anesthetics induced unconsciousness. Whether the voltage-gated sodium channels in the thalamocortical systems are the target of ketamine remain unclear. The present study used a whole-cell patch-clamp technique to observe the effects of ketamine on voltage-gated Na+ channels in thalamocortical pyramidal neurons. We found that IC50 of ketamine on Na+ currents in the primary somatosensory barrel cortex pyramidal neurons and the thalamus ventral posteromedial nucleus pyramidal neurons was 686.72 ± 39.92 and 842.65 ± 87.28 μM, respectively. Ketamine accelerated the Na+ channels inactivation and slowed inactivation of Na+ channels after recovery but did not affect the activation. We demonstrated the detailed suppression process of neural voltage-gated Na+ channels by ketamine on thalamocortical slice. This may provide a new insight into the mechanical explanation for the ketamine anesthesia.
RETRACTED: HOXD-AS1 confers cisplatin resistance in gastric cancer through epigenetically silencing PDCD4 via recruiting EZH2
Authors: Ye Yafei , Yang Shengnan , Han Yanping , Sun Jingjing , Xv Lijuan , Wu Lina , Ming Liang
Published: September 2019

Increasing evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is implicated in chemoresistance in cancers. However, the function and molecular mechanisms of lncRNAs in gastric cancer chemoresistance are still not well understood. In this study, we aimed to investigate the functional role and the underlying molecular mechanisms of lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in cisplatin (DDP) resistance in gastric cancer. Our results revealed that HOXD-AS1 was upregulated in DDP-resistant gastric cancer tissues and cells. Patients with gastric cancer with high HOXD-AS1 expression levels had a poor prognosis. Knockdown of HOXD-AS1 facilitated the sensitivity of DDP-resistant gastric cancer cells to DDP. Additionally, HOXD-AS1 epigenetically silenced PDCD4 through binding to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) on the promoter of PDCD4, thus increasing H3K27me3. More importantly, PDCD4 silencing counteracted HOXD-AS1 knockdown-mediated enhancement of DDP sensitivity in DDP-resistant gastric cancer cells. In summary, HOXD-AS1 led to DDP resistance in gastric cancer by epigenetically suppressing PDCD4 expression, providing a novel therapeutic strategy for patients with gastric cancer with chemoresistance.
Bound to the group and blinded by the leader: ideological leader–follower dynamics in a trust economic game
Authors: Gjoneska Biljana , Liuzza Marco Tullio , Porciello Giuseppina , Caprara Gian Vittorio , Aglioti Salvatore M.
Published: September 2019

Understanding the dynamics of trustworthiness in ideological contexts could influence human societies, affect electoral campaigns and ultimately impact democracy. We tested trust behaviour towards political leaders in a sample of 121 opposing/supporting voters assigned as trustors in an iterative trust game (TG). In two experiments, a famous Italian conservative leader (i.e. Silvio Berlusconi) or a famous non-politician were used as trustees in a predefined un/trustworthy TG, while trustors believed that mathematical algorithms reproduced trustee’s real behaviour. Results revealed that depending on the group, voters either relied on the situation and adjusted to the behaviour of the out-group leader (in our case left-wing voters), or on their disposition for group-loyalty with respect for authority, thus failing to adjust to the behaviour of the in-group leader (in our case right-wing voters). Our findings suggest that: (i) complex voter–leader relations in politics are reflected in the simple trustor–trustee financial interactions from behavioural economics, and (ii) being bound to one’s group and one’s leader may affect the trust economic decisions of the followers.
Increase in metazoan ecosystem engineering prior to the Ediacaran–Cambrian boundary in the Nama Group, Namibia
Authors: Cribb Alison T. , Kenchington Charlotte G. , Koester Bryce , Gibson Brandt M. , Boag Thomas H. , Racicot Rachel A. , Mocke Helke , Laflamme Marc , Darroch Simon A. F.
Published: September 2019

The disappearance of the soft-bodied Ediacara biota at the Ediacaran–Cambrian boundary potentially represents the earliest mass extinction of complex life, although the precise driver(s) of this extinction remain unresolved. The ‘biotic replacement’ model proposes that an evolutionary radiation of metazoan ecosystem engineers in the latest Ediacaran profoundly altered marine palaeoenvironments, resulting in the extinction of Ediacara biota and setting the stage for the subsequent Cambrian Explosion. However, metazoan ecosystem engineering across the Ediacaran–Cambrian transition has yet to be quantified. Here, we test this key tenet of the biotic replacement model by characterizing the intensity of metazoan bioturbation and ecosystem engineering in trace fossil assemblages throughout the latest Ediacaran Nama Group in southern Namibia. The results illustrate a dramatic increase in both bioturbation and ecosystem engineering intensity in the latest Ediacaran, prior to the Cambrian boundary. Moreover, our analyses demonstrate that the highest-impact ecosystem engineering behaviours were present well before the onset of the Cambrian. These data provide the first support for a fundamental prediction of the biotic replacement model, and evidence for a direct link between the early evolution of ecosystem engineering and the extinction of the Ediacara biota.
Background noise disrupts host–parasitoid interactions
Authors: Phillips Jennifer N. , Ruef Sophia K. , Garvin Christopher M. , Le My-Lan T. , Francis Clinton D.
Published: September 2019

The soundscape serves as a backdrop for acoustic signals dispatched within and among species, spanning mate attraction to parasite host detection. Elevated background sound levels from human-made and natural sources may interfere with the reception of acoustic signals and alter species interactions and whole ecological communities. We investigated whether background noise influences the ability of the obligate parasitoid
Ormia ochracea
to locate its host, the variable field cricket (
Gryllus lineaticeps
). As
O. ochracea
use auditory cues to locate their hosts, we hypothesized that higher background noise levels would mask or distract flies from cricket calls and result in a decreased ability to detect and navigate to hosts. We used a field manipulation where fly traps baited with playback of male cricket advertisement calls were exposed to a gradient of experimental traffic and ocean surf noise. We found that increases in noise amplitude caused a significant decline in
O. ochracea
caught, suggesting that background noise can influence parasitoid–host interactions and potentially benefit hosts. As human-caused sensory pollution increases globally, soundscapes may influence the evolution of tightly co-evolved host–parasitoid relationships. Future work should investigate whether female cricket phonotaxis towards males is similarly affected by noise levels.
Flanking heterozygosity influences the relative probability of different base substitutions in humans
Authors: Amos William
Published: September 2019

Understanding when, where and which mutations are mostly likely to occur impacts many areas of evolutionary biology, from genetic diseases to phylogenetic reconstruction. Africans and non-African humans differ in the mutability of different triplet base combinations. Africans and non-Africans also differ in mutation rate, possibly because heterozygosity is mutagenic, such that diversity lost when humans expanded out of Africa also lowered the mutation rate. I show that these phenomena are linked: as flanking heterozygosity increases, some triplets become progressively more mutable while others become less so. Africans and non-African show near-identical patterns of dependence on heterozygosity. Thus, the striking differences in triplet mutation frequency between Africans and non-Africans, at least in part, seem to be an emergent property, driven by the way changes in heterozygosity ‘out of Africa’ have differentially impacted the mutability of different triplets. As heterozygosity decreased, the mutation spectrum outside Africa became enriched for triplet mutations that are favoured by low heterozygosity while those favoured by high heterozygosity became relatively rarer.
Social learning about dangerous people by wild jackdaws
Authors: Lee Victoria E. , Régli Noémie , McIvor Guillam E. , Thornton Alex
Published: September 2019

For animals that live alongside humans, people can present both an opportunity and a threat. Previous studies have shown that several species can learn to discriminate between individual people and assess risk based on prior experience. To avoid potentially costly encounters, it may also pay individuals to learn about dangerous people based on information from others. Social learning about anthropogenic threats is likely to be beneficial in habitats dominated by human activity, but experimental evidence is limited. Here, we tested whether wild jackdaws (
Corvus monedula
) use social learning to recognize dangerous people. Using a within-subjects design, we presented breeding jackdaws with an unfamiliar person near their nest, combined with conspecific alarm calls. Subjects that heard alarm calls showed a heightened fear response in subsequent encounters with the person compared to a control group, reducing their latency to return to the nest. This study provides important evidence that animals use social learning to assess the level of risk posed by individual humans.
Conformity bias in the cultural transmission of music sampling traditions
Authors: Youngblood Mason
Published: September 2019

One of the fundamental questions of cultural evolutionary research is how individual-level processes scale up to generate population-level patterns. Previous studies in music have revealed that frequency-based bias (e.g. conformity and novelty) drives large-scale cultural diversity in different ways across domains and levels of analysis. Music sampling is an ideal research model for this process because samples are known to be culturally transmitted between collaborating artists, and sampling events are reliably documented in online databases. The aim of the current study was to determine whether frequency-based bias has played a role in the cultural transmission of music sampling traditions, using a longitudinal dataset of sampling events across three decades. Firstly, we assessed whether turn-over rates of popular samples differ from those expected under neutral evolution. Next, we used agent-based simulations in an approximate Bayesian computation framework to infer what level of frequency-based bias likely generated the observed data. Despite anecdotal evidence of novelty bias, we found that sampling patterns at the population-level are most consistent with conformity bias. We conclude with a discussion of how counter-dominance signalling may reconcile individual cases of novelty bias with population-level conformity.
Reappraisal of the Silurian placodermSilurolepisand insights into the dermal neck joint evolution
Authors: Zhu You-an , Lu Jing , Zhu Min
Published: September 2019

Silurolepis platydorsalis, a Silurian jawed vertebrate originally identified as an antiarch, is here redescribed as a maxillate placoderm close toQilinyuand is anteroposteriorly reversed as opposed to the original description. The cuboid trunk shield possesses three longitudinal cristae, obstanic grooves on the trunk shield and three median dorsal plates, all uniquely shared withQilinyu. Further preparation reveals the morphology of the dermal neck joint, with slot-shaped articular fossae on the trunk shield similar toQilinyuand antiarchs. However, new tomographic data reveal thatQilinyuuniquely bears a dual articulation between the skull roof and trunk shield, which does not fit into the traditional ‘ginglymoid’ and ‘reverse ginglymoid’ categories. An extended comparison in early jawed vertebrates confirms that a sliding-type dermal neck joint is widely distributed and other types are elaborated in different lineages by developing various laminae. Nine new characters related to the dermal neck joint are proposed for a new phylogenetic analysis, in whichSilurolepisforms a clade withQilinyu. The current phylogenetic framework conflicts with the parsimonious evolution of dermal neck joints in suggesting that the shared trunk shield characters between antiarchs andQilinyuare independently acquired, and the sliding-type joint inEntelognathusis reversely evolved from the dual articulation inQilinyu.
Geometric fluid approximation for general continuous-time Markov chains
Authors: Michaelides Michalis , Hillston Jane , Sanguinetti Guido
Published: September 2019

Fluid approximations have seen great success in approximating the macro-scale behaviour of Markov systems with a large number of discrete states. However, these methods rely on the continuous-time Markov chain (CTMC) having a particular population structure which suggests a natural continuous state-space endowed with a dynamics for the approximating process. We construct here a general method based on spectral analysis of the transition matrix of the CTMC, without the need for a population structure. Specifically, we use the popular manifold learning method of diffusion maps to analyse the transition matrix as the operator of a hidden continuous process. An embedding of states in a continuous space is recovered, and the space is endowed with a drift vector field inferred via Gaussian process regression. In this manner, we construct an ordinary differential equation whose solution approximates the evolution of the CTMC mean, mapped onto the continuous space (known as the fluid limit).
Multifractal formalisms for multivariate analysis
Authors: Jaffard Stéphane , Seuret Stéphane , Wendt Herwig , Leonarduzzi Roberto , Abry Patrice
Published: September 2019

Multifractal analysis, that quantifies the fluctuations of regularities in time series or textures, has become a standard signal/image processing tool. It has been successfully used in a large variety of applicative contexts. Yet, successes are confined to the analysis of one signal or image at a time (univariate analysis). This is because multivariate (or joint) multifractal analysis remains so far rarely used in practice and has barely been studied theoretically. In view of the myriad of modern real-world applications that rely on the joint (multivariate) analysis of collections of signals or images, univariate analysis constitutes a major limitation. The goal of the present work is to theoretically ground multivariate multifractal analysis by studying the properties and limitations of the most natural extension of the univariate formalism to a multivariate formulation. It is notably shown that while performing well for a class of model processes, this natural extension is not valid in general. Based on the theoretical study of the mechanisms leading to failure, we propose alternative formulations and examine their mathematical properties.
Laboratory investigation of crest height statistics in intermediate water depths
Authors: Karmpadakis I. , Swan C. , Christou M.
Published: September 2019

This paper concerns the statistical distribution of the crest heights associated with surface waves in intermediate water depths. The results of a new laboratory study are presented in which data generated in different experimental facilities are used to establish departures from commonly applied statistical distributions. Specifically, the effects of varying sea-state steepness, effective water depth and directional spread are investigated. Following an extensive validation of the experimental data, including direct comparisons to available field data, it is shown that the nonlinear amplification of crest heights above second-order theory observed in steep deep water sea states is equally appropriate to intermediate water depths. These nonlinear amplifications increase with the sea-state steepness and reduce with the directional spread. While the latter effect is undoubtedly important, the present data confirm that significant amplifications above second order (5–10%) are observed for realistic directional spreads. This is consistent with available field data. With further increases in the sea-state steepness, the dissipative effects of wave breaking act to reduce these nonlinear amplifications. While the competing mechanisms of nonlinear amplification and wave breaking are relevant to a full range of water depths, the relative importance of wave breaking increases as the effective water depth reduces.
Unmanned aerial vehicles reveal the impact of a total solar eclipse on the atmospheric surface layer
Authors: Bailey Sean C. C. , Canter Caleb A. , Sama Michael P. , Houston Adam L. , Smith Suzanne Weaver
Published: September 2019

We use unmanned aerial vehicles to interrogate the surface layer processes during a solar eclipse and gain a comprehensive look at the changes made to the atmospheric surface layer as a result of the rapid change of insolation. Measurements of the atmospheric surface layer structure made by the unmanned systems are connected to surface measurements to provide a holistic view of the impact of the eclipse on the near-surface behaviour, large-scale turbulent structures and small-scale turbulent dynamics. Different regimes of atmospheric surface layer behaviour were identified, with the most significant impact including the formation of a stable layer just after totality and evidence of Kelvin–Helmholtz waves appearing at the interface between this layer and the residual layer forming above it. The decrease in surface heating caused a commensurate decrease in buoyant turbulent production, which resulted in a rapid decay of the turbulence in the atmospheric surface layer both within the stable layer and in the mixed layer forming above it. Significant changes in the wind direction were imposed by the decrease in insolation, with evidence supporting the formation of a nocturnal jet, as well as backing of the wind vector within the stable layer.
Whistling shares a common tongue with speech: bioacoustics from real-time MRI of the human vocal tract
Authors: Belyk Michel , Schultz Benjamin G. , Correia Joao , Beal Deryk S. , Kotz Sonja A.
Published: September 2019

Most human communication is carried by modulations of the voice. However, a wide range of cultures has developed alternative forms of communication that make use of a whistled sound source. For example, whistling is used as a highly salient signal for capturing attention, and can have iconic cultural meanings such as the catcall, enact a formal code as in boatswain's calls or stand as a proxy for speech in whistled languages. We used real-time magnetic resonance imaging to examine the muscular control of whistling to describe a strong association between the shape of the tongue and the whistled frequency. This bioacoustic profile parallels the use of the tongue in vowel production. This is consistent with the role of whistled languages as proxies for spoken languages, in which one of the acoustical features of speech sounds is substituted with a frequency-modulated whistle. Furthermore, previous evidence that non-human apes may be capable of learning to whistle from humans suggests that these animals may have similar sensorimotor abilities to those that are used to support speech in humans.
Plumage redness signals mitochondrial function in the house finch
Authors: Hill Geoffrey E. , Hood Wendy R. , Ge Zhiyuan , Grinter Rhys , Greening Chris , Johnson James D. , Park Noel R. , Taylor Halie A. , Andreasen Victoria A. , Powers Matthew J. , Justyn Nicholas M. , Parry Hailey A. , Kavazis Andreas N. , Zhang Yufeng
Published: September 2019

Carotenoid coloration is widely recognized as a signal of individual condition in various animals, but despite decades of study, the mechanisms that link carotenoid coloration to condition remain unresolved. Most birds with red feathers convert yellow dietary carotenoids to red carotenoids in an oxidation process requiring the gene encoding the putative cytochrome P450 enzyme CYP2J19. Here, we tested the hypothesis that the process of carotenoid oxidation and feather pigmentation is functionally linked to mitochondrial performance. Consistent with this hypothesis, we observed high levels of red ketolated carotenoids associated with the hepatic mitochondria of moulting wild house finches (Haemorhous mexicanus), and upon fractionation, we found the highest concentration of ketolated carotenoids in the inner mitochondrial membrane. We further found that the redness of growing feathers was positively related to the performance of liver mitochondria. Structural modelling of CYP2J19 supports a direct role of this protein in carotenoid ketolation that may be functionally linked to cellular respiration. These observations suggest that feather coloration serves as a signal of core functionality through inexorable links to cellular respiration in the mitochondria.
Antibiotics as chemical warfare across multiple taxonomic domains and trophic levels in brown food webs
Authors: Lucas Jane M. , Gora Evan , Salzberg Annika , Kaspari Michael
Published: September 2019

Bacteria and fungi secrete antibiotics to suppress and kill other microbes, but can these compounds be agents of competition against macroorganisms? We explore how one competitive tactic, antibiotic production, can structure the composition and function of brown food webs. This aspect of warfare between microbes and invertebrates is particularly important today as antibiotics are introduced into ecosystems via anthropogenic activities, but the ecological implications of these introductions are largely unknown. We hypothesized that antimicrobial compounds act as agents of competition against invertebrate and microbial competitors. Using field-like mesocosms, we tested how antifungal and antibacterial compounds influence microbes, invertebrates, and decomposition in the brown food web. Both antibiotics changed prokaryotic microbial community composition, but only the antibacterial changed invertebrate composition. Antibacterials reduced the abundance of invertebrate detritivores by 34%. However, the addition of antimicrobials did not ramify up the food web as predator abundances were unaffected. Decomposition rates did not change. To test the mechanisms of antibiotic effects, we provided antibiotic-laden water to individual invertebrate detritivores in separate microcosm experiments. We found that the antibiotic compounds can directly harm invertebrate taxa, probably through a disruption of endosymbionts. Combined, our results show that antibiotic compounds could be an effective weapon for microbes to compete against both microbial and invertebrate competitors. In the context of human introductions, the detrimental effects of antibiotics on invertebrate communities indicates that the scope of this anthropogenic disturbance is much greater than previously expected.
Resource distribution and internal factors interact to govern movement of a freshwater snail
Authors: Cloyed Carl S. , Dell Anthony I.
Published: September 2019

Movement enables mobile organisms to respond to local environmental conditions and is driven by a combination of external and internal factors operating at multiple scales. Here, we explored how resource distribution interacted with the internal state of organisms to drive patterns of movement. Specifically, we tracked snail movements on experimental landscapes where resource (algal biofilm) distribution varied from 0 to 100% coverage and quantified how that movement changed over a 24 h period. Resource distribution strongly affected snail movement. Trajectories were tortuous (i.e. Brownian-like) within resource patches but straighter (i.e. Lévy) in resource-free (bare) patches. The average snail speed was slower in resource patches, where snails spent most of their time. Different patterns of movement between resource and bare patches explained movement at larger spatial scales; movement was ballistic-like Lévy in resource-free landscapes, Lévy in landscapes with intermediate resource coverage and approximated Brownian in landscapes covered in resources. Our temporal analysis revealed that movement patterns changed predictably for snails that satiated their hunger and then performed other behaviours. These changes in movement patterns through time were similar across all treatments that contained resources. Thus, external and internal factors interacted to shape the inherently flexible movement of these snails.
Sperm cryopreservation reduces offspring growth
Authors: Nusbaumer David , Marques da Cunha Lucas , Wedekind Claus
Published: September 2019

Sperm cryopreservation is routinely used in reproductive medicine, livestock production and wildlife management. Its effect on offspring performance is often assumed to be negligible, but this still remains to be confirmed in well-controlled within-subject experiments. We use a vertebrate model that allows us to experimentally separate parental and environmental effects to test whether sperm cryopreservation influences offspring phenotype under stress and non-stress conditions, and whether such effects are male-specific. Wild brown trout (Salmo trutta) were stripped for their gametes, and a portion of each male's milt was cryopreserved. Then, 960 eggs were simultaneously fertilized with either non-cryopreserved or frozen-thawed semen and raised singly in the presence or absence of a pathogen. We found no significant effects of cryopreservation on fertilization rates, and no effects on growth, survival nor pathogen resistance during the embryo stage. However, fertilization by cryopreserved sperm led to significantly reduced larval growth after hatching. Males varied in genetic quality as determined from offspring performance, but effects of cryopreservation on larval growth were not male-specific. We conclude that cryopreservation causes a reduction in offspring growth that is easily overlooked because it only manifests itself at later developmental stages, when many other factors affect growth and survival too.
Phylogenomic analysis of gastroenteritis-associated Clostridium perfringens in England and Wales over a 7-year period indicates distribution of clonal toxigenic strains in multiple outbreaks and extensive involvement of enterotoxin-encoding (CPE) plasmids
Authors: Kiu Raymond , Caim Shabhonam , Painset Anais , Pickard Derek , Swift Craig , Dougan Gordon , Mather Alison E. , Amar Corinne , Hall Lindsay J.
Published: September 2019

Clostridium perfringensis a major enteric pathogen known to cause gastroenteritis in human adults. Although major outbreak cases are frequently reported, only limited whole-genome sequencing (WGS) based studies have been performed to understand the genomic epidemiology and virulence gene content of outbreak-associatedC. perfringensstrains. We performed phylogenomic analysis on 109C.perfringensisolates (human and food) obtained from disease cases in England and Wales between 2011 and 2017. Initial findings highlighted the enhanced discriminatory power of WGS in profiling outbreakC. perfringensstrains, when compared to the current Public Health England referencing laboratory technique of fluorescent amplified fragment length polymorphism analysis. Further analysis identified that isogenicC. perfringensstrains were associated with nine distinct care-home-associated outbreaks over the course of a 5-year interval, indicating a potential common source linked to these outbreaks or transmission over time and space. As expected, the enterotoxincpegene was encoded in all but 4 isolates (96.3 %; 105/109), with virulence plasmids encodingcpe(particularly pCPF5603 and pCPF4969 plasmids) extensively distributed (82.6 %; 90/109). Genes encoding accessory virulence factors, such as beta-2 toxin, were commonly detected (46.7 %; 51/109), and genes encoding phage proteins were also frequently identified. Overall, this large-scale genomic study of gastroenteritis-associatedC. perfringenssuggested that three majorcpe-encoding (toxinotype F) genotypes underlie these outbreaks: strains carrying (1) pCPF5603 plasmid, (2) pCPF4969 plasmid and (3) chromosomal-cpestrains. Our findings substantially expanded our knowledge on type FC. perfringensinvolved in human-associated gastroenteritis, with further studies required to fully probe the dissemination and regional reservoirs of this enteric pathogen, which may help devise effective prevention strategies to reduce the food-poisoning disease burden in vulnerable patients, such as the elderly.
Nucleus accumbens volume is related to obesity measures in an age-dependent fashion
Authors: García-García Isabel , Morys Filip , Dagher Alain
Published: September 2019

Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. While these dysregulations occur likely at the microscopic level, studies on gray matter volume reported macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta-analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether gray matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether certain variables of interest (e.g. NAcc volume) is related to another variable’s (BMI) initial values or longitudinal trajectories. Our meta-analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals such relationship is positive, while for older adults it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that higher BMI was associated with lower NAcc and thalamus volume. Overall, our study suggests that increased NAcc volume in young age might be a vulnerability factor for obesity, while in the older age decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain.
Computational Justice: Simulating Structural Bias and Interventions
Authors: Momennejad Ida , Sinclair Stacey , Cikara Mina
Published: September 2019

Gender inequality has been documented across a variety of high-prestige professions. Both structural bias (e.g., lack of proportionate representation) and interpersonal bias (e.g., sexism, discrimination) generate costs to underrepresented minorities. How can we estimate these costs and what interventions are most effective for reducing them? We used agent-based simulations, removing gender differences in interpersonal bias to isolate and quantify the impact and costs of structural bias (unequal gender ratios) on individuals and institutions. We compared the long-term impact of bias-confrontation strategies. Unequal gender ratios led to higher costs for female agents and institutions and increased sexism among male agents. Confronting interpersonal bias by targets and allies attenuated the impact of structural bias. However, bias persisted even after a structural intervention to suddenly make previously unequal institutions equal (50% women) unless the probability of interpersonal bias-confrontation was further increased among targets and allies. This computational approach allows for comparison of various policies to attenuate structural equality, and informs the design of new experiments to estimate parameters for more accurate predictions.
More affordable and effective noninvasive SNP genotyping using high-throughput amplicon sequencing
Authors: Eriksson Charlotte E. , Ruprecht Joel , Levi Taal
Published: September 2019

Non-invasive genotyping methods have become key elements of wildlife research over the last two decades, but their widespread adoption is limited by high costs, low success rates, and high error rates. The information lost when genotyping success is low may lead to decreased precision in animal population densities which could misguide conservation and management actions. Single nucleotide polymorphisms (SNPs) provide a promising alternative to traditionally used microsatellites as SNPs allow amplification of shorter DNA fragments, are less prone to genotyping errors, and produce results that are easily shared among laboratories. Here, we outline a detailed protocol for cost-effective and accurate noninvasive SNP genotyping using highly multiplexed amplicon sequencing optimized for degraded DNA. We validated this method for individual identification by genotyping 216 scats, 18 hairs and 15 tissues from coyotes (Canis latrans). Our genotyping success rate for scat samples was 93%, and 100% for hair and tissue, representing a substantial increase compared to previous microsatellite-based studies at a cost of under $5 per PCR replicate (excluding labor). The accuracy of the genotypes was further corroborated in that genotypes from scats matching known, GPS-collared coyotes were always located within the territory of the known individual. We also show that different levels of multiplexing produced similar results, but that PCR product cleanup strategies can have substantial effects on genotyping success. By making noninvasive genotyping more affordable, accurate, and efficient, this research may allow for a substantial increase in the use of noninvasive methods to monitor and conserve free-ranging wildlife populations.
Gaussian embedding-based functional brain connectomic analysis for amnestic mild cognitive impairment patients with cognitive training
Authors: Xu Mengjia , Wang Zhijiang , Zhang Haifeng , Pantazis Dimitrios , Wang Huali , Li Quanzheng
Published: September 2019

Identifying heterogeneous cognitive impairment markers at an early stage is vital for Alzheimer’s disease diagnosis. However, due to complex and uncertain brain connectivity features in the cognitive domains, it remains challenging to quantify functional brain connectomic changes during non-pharmacological interventions for amnestic mild cognitive impairment (aMCI) patients. We present a new quantitative functional brain network analysis of fMRI data based on the multi-graph unsupervised Gaussian embedding method (MG2G). This neural network-based model can effectively learn low-dimensional Gaussian distributions from the original high-dimensional sparse functional brain networks, quantify uncertainties in link prediction, and discover the intrinsic dimensionality of brain networks. Using the Wasserstein distance to measure probabilistic changes, we discovered that brain regions in the default mode network and somatosensory/somatomotor hand, fronto-parietal task control, memory retrieval, and visual and dorsal attention systems had relatively large variations during non-pharmacological training, which might provide distinct biomarkers for fine-grained monitoring of aMCI cognitive alteration.
CRISPR-Cas9 generated Pompe knock-in murine model exhibits early-onset hypertrophic cardiomyopathy and skeletal muscle weakness
Authors: Huang Jeffrey Y. , Kan Shih-Hsin , Sandfeld Emilie K. , Dalton Nancy D. , Rangel Anthony D. , Chan Yunghang , Davis-Turak Jeremy , Neumann Jon , Wang Raymond Y.
Published: September 2019

Infantile-onset Pompe Disease (IOPD), caused by mutations in lysosomal acid alpha-glucosidase (Gaa), manifests rapidly progressive fatal cardiac and skeletal myopathy incompletely attenuated by synthetic GAA intravenous infusions. The currently available murine model does not fully simulate human IOPD, displaying skeletal myopathy with late-onset hypertrophic cardiomyopathy. Bearing a Cre-LoxP induced exonic disruption of the murine Gaa gene, this model is also not amenable to genome-editing based therapeutic approaches. We report the early onset of severe hypertrophic cardiomyopathy in a novel murine IOPD model generated utilizing CRISPR-Cas9 homology-directed recombination to harbor the orthologous Gaa mutation c.1826dupA (p.Y609*), which causes human IOPD. We demonstrate the dual sgRNA approach with a single-stranded oligonucleotide donor is highly specific for the Gaac.1826 locus without genomic off-target effects or rearrangements. Cardiac and skeletal muscle were deficient in Gaa mRNA and enzymatic activity and accumulated high levels of glycogen. The mice demonstrated skeletal muscle weakness but did not experience early mortality. Altogether, these results demonstrate that the CRISPR-Cas9 generated Gaac.1826dupA murine model recapitulates hypertrophic cardiomyopathy and skeletal muscle weakness of human IOPD, indicating its utility for evaluation of novel therapeutics.
Early developmental exposure to Fluoxetine and Citalopram results in different neurodevelopmental outcomes
Authors: Liu Karine , Garcia Alfonso , Park Jenn J. , Toliver Alexis A. , Ramos Lizmaylin , Aizenman Carlos D.
Published: September 2019

Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for prenatal depression, there exists controversy over the adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated the outcomes of exposure to widely-used SSRIs fluoxetine and citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of citalopram and fluoxetine during a critical developmental period and found that the different groups of tadpoles displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, the citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for all three behaviors tested. Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function across groups; however, tectal cells from fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the citalopram group had increased K+ currents. Both the behavior and electrophysiological findings indicate that cells and circuits in the fluoxetine treated optic tecta are hyperexcitable, while the citalopram group exhibits decreased excitability. Taken all together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI used. This may explain some of the discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.
Dendritic calcium signals in rhesus macaque motor cortex drive an optical brain-computer interface
Authors: Trautmann Eric M. , O’Shea Daniel J. , Sun Xulu , Marshel James H. , Crow Ailey , Hsueh Brian , Vesuna Sam , Cofer Lucas , Bohner Gergő , Allen Will , Kauvar Isaac , Quirin Sean , MacDougall Matthew , Chen Yuzhi , Whitmire Matthew P. , Ramakrishnan Charu , Sahani Maneesh , Seidemann Eyal , Ryu Stephen I. , Deisseroth Karl , Shenoy Krishna V.
Published: September 2019

Calcium imaging has rapidly developed into a powerful tool for recording from large populations of neuronsin vivo. Imaging in rhesus macaque motor cortex can enable the discovery of new principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon (2P) imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon (2P) imaging of calcium signals from in macaques engaged in a motor task. By imaging apical dendrites, some of which originated from deep layer 5 neurons, as as well as superficial cell bodies, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement, which was stable across many weeks. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signals and successfully decoded movement direction online. By fusing 2P functional imaging with CLARITY volumetric imaging, we verify that an imaged dendrite, which contributed to oBCI decoding, originated from a putative Betz cell in motor cortical layer 5. This approach establishes new opportunities for studying motor control and designing BCIs.
A processive rotary mechanism couples substrate unfolding and proteolysis in the ClpXP degradation machinery
Authors: Ripstein Zev A. , Vahidi Siavash , Houry Walid A. , Rubinstein John L. , Kay Lewis E.
Published: September 2019

The ClpXP degradation machine consists of a hexameric AAA+ unfoldase (ClpX) and a pair of heptameric serine protease rings (ClpP) that unfold, translocate, and subsequently degrade client proteins. ClpXP is an important target for drug development against infectious diseases. Although structures are available for isolated ClpX and ClpP rings, it remains unknown how symmetry mismatched ClpX and ClpP work in tandem for processive substrate translocation into the ClpP proteolytic chamber. Here we present cryo-EM structures of the substrate-bound ClpXP complex from Neisseria meningitidis at 2.3 to 3.3 Å resolution. The structures allow development of a model in which the cyclical hydrolysis of ATP is coupled to concerted motions of ClpX loops that lead to directional substrate translocation and ClpX rotation relative to ClpP. Our data add to the growing body of evidence that AAA+ molecular machines generate translocating forces by a common mechanism.