bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Healthcare Utilization for Medical Comorbidities Prior to Surgery Improves Postoperative Outcomes
Authors: Leeds Ira L. , Canner Joseph K. , Gani Faiz , Meyers Patrick M. , Haut Elliott R. , Efron Jonathan E. , Johnston Fabian M.
Published: June 2018

Objective:

The purpose of this study was to evaluate the impact of optimization of preoperative comorbidities by nonsurgical clinicians on short-term postoperative outcomes.

Summary background data:

Preoperative comorbidities can have substantial effects on operative risk and outcomes. The modifiability of these comorbidity-associated surgical risks remains poorly understood.

Methods:

We identified patients with a major comorbidity (eg, diabetes, heart failure) undergoing an elective colectomy in a multipayer national administrative database (2010–2014). Patients were included if they could be matched to a preoperative surgical clinic visit within 90 days of an operative intervention by the same surgeon. The explanatory variable of interest (“preoperative optimization”) was defined by whether the patient was seen by an appropriate nonsurgical clinician between surgical consultation and subsequent surgery. We assessed the impact of an optimization visit on postoperative complications with use of propensity score matching and multilevel, multivariable logistic regression.

Results:

We identified 4531 colectomy patients with a major potentially modifiable comorbidity (propensity weighted and matched effective sample size: 6037). After matching, the group without an optimization visit had a higher rate of complications (34.6% versus 29.7%, P = 0.001). An optimization visit conferred a 31% reduction in the odds of a complication (P < 0.001) in an adjusted analysis. Median preoperative costs increased by $684 (P < 0.001) in the optimized group, and a complication increased total costs of care by $14,724 (P < 0.001).

Conclusions and relevance:

We demonstrated an association between use of nonsurgical clinician visits by comorbid patients prior to surgery and a significantly lower rate of complications. These findings support the prospective study of preoperative optimization as a potential mechanism for improving postoperative outcomes.
Feeding decisions under contamination risk in bonobos
Authors: Sarabian Cecile , Belais Raphael , MacIntosh Andrew J. J.
Published: June 2018

Threats from parasites and pathogens are ubiquitous, and many use pathways that exploit host trophic interactions for their transmission. As such, host organisms have evolved a behavioural immune system to facilitate contamination-risk assessment and avoidance of potential contaminants in various contexts, including feeding. Detecting pathogen threats can rely on different sensory modalities allowing animals to screen for a wide array of contaminants. Here, we present a series of experiments in which bonobos showed clear avoidance of contaminated food items, and were sensitive to risk along a contamination probability gradient. Across experiments, bonobos appeared to use multisensorial cues to inform their feeding decisions. In addition, bonobos showed reduced tactile, gustatory and tool use activities when in the presence of contaminant versus control odours in a challenging foraging context. Our experiments build on previous work conducted in Japanese macaques and chimpanzees aiming at a better understanding of the ways in which the behavioural immune system operates in primates.

This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours’.
Anti-parasite behaviour of birds
Authors: Bush Sarah E. , Clayton Dale H.
Published: June 2018

Birds have many kinds of internal and external parasites, including viruses, bacteria and fungi, as well as protozoa, helminths and arthropods. Because parasites have negative effects on host fitness, selection favours the evolution of anti-parasite defences, many of which involve behaviour. We provide a brief review of anti-parasite behaviours in birds, divided into five major categories: (i) body maintenance, (ii) nest maintenance, (iii) avoidance of parasitized prey, (iv) migration and (v) tolerance. We evaluate the adaptive significance of the different behaviours and note cases in which additional research is particularly needed. We briefly consider the interaction of different behaviours, such as sunning and preening, and how behavioural defences may interact with other forms of defence, such as immune responses. We conclude by suggesting some general questions that need to be addressed concerning the nature of anti-parasite behaviour in birds.

This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours’.
Why do people vary in disgust?
Authors: Tybur Joshua M. , Çınar Çağla , Karinen Annika K. , Perone Paola
Published: June 2018

People vary in the degree to which they experience disgust toward—and, consequently, avoid—cues to pathogens. Prodigious work has measured this variation and observed that it relates to, among other things, personality, psychopathological tendencies, and moral and political sentiments. Less work has sought to generate hypotheses aimed at explaining why this variation exists in the first place, and even less work has evaluated how well data support these hypotheses. In this paper, we present and review the evidence supporting three such proposals. First, researchers have suggested that variability reflects a general tendency to experience anxiety or emotional distress. Second, researchers have suggested that variability arises from parental modelling, with offspring calibrating their pathogen avoidance based on their parents' reactions to pathogen cues. Third, researchers have suggested that individuals calibrate their disgust sensitivity to the parasite stress of the ecology in which they develop. We conclude that none of these hypotheses is supported by existing data, and we propose directions for future research aimed at better understanding this variation.

This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours’.
The role of social cognition in parasite and pathogen avoidance
Authors: Kavaliers Martin , Choleris Elena
Published: June 2018

The acquisition and use of social information are integral to social behaviour and parasite/pathogen avoidance. This involves social cognition which encompasses mechanisms for acquiring, processing, retaining and acting on social information. Social cognition entails the acquisition of social information about others (i.e. social recognition) and from others (i.e. social learning). Social cognition involves assessing other individuals and their infection status and the pathogen and parasite threat they pose and deciding about when and how to interact with them. Social cognition provides a framework for examining pathogen and parasite avoidance behaviours and their associated neurobiological mechanisms. Here, we briefly consider the relationships between social cognition and olfactory-mediated pathogen and parasite avoidance behaviours. We briefly discuss aspects of (i) social recognition of actual and potentially infected individuals and the impact of parasite/pathogen threat on mate and social partner choice; (ii) the roles of ‘out-groups’ (strangers, unfamiliar individuals) and ‘in-groups’ (familiar individuals) in the expression of parasite/pathogen avoidance behaviours; (iii) individual and social learning, i.e. the utilization of the pathogen recognition and avoidance responses of others; and (iv) the neurobiological mechanisms, in particular the roles of the nonapeptide, oxytocin and steroid hormones (oestrogens) associated with social cognition and parasite/pathogen avoidance.

This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours'.
The structure and function of pathogen disgust
Authors: Curtis Val , de Barra Mícheál
Published: June 2018

Researchers have long noted that many of the multiple elicitors of disgust have some relation to infectious disease. There is an emerging consensus that disgust evolved in Animalia to direct the behaviours that reduce risk of infection, so-called ‘parasite avoidance theory’. If this is correct, then the disgust motive should be structured in a manner that reflects the ways in which infectious disease can be avoided. In this study, we generated a set of items based on the epidemiology of disease transmission. These were then rated for their capacity to elicit disgust by a large, predominantly North American/UK sample and subjected to factor analysis to identify latent variables. While a number of plausible factor solutions emerged, Velicer's MAP (minimum average partial) test suggested six domains: atypical appearance, lesions, sex, hygiene, food and animals. This structure did not exactly mirror the transmission routes of infections, as we initially predicted, but it may rather reflect distinct kinds of behavioural tasks involved in avoiding disease. This finding makes sense from the perspective of a cognitive system that evolved under selection for a behavioural response to threats from the social and biological environment. We suggest that regularly occurring types of infectious disease problems have produced regularities in the domain structure ofpathogen disgustand discuss the implications of these results for understanding the structure, function and measurement of motives such as disgust in humans and other animals.

This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours’.
Neuronal and non-neuronal signals regulate
Caernorhabditis elegans
avoidance of contaminated food
Authors: Anderson Alexandra , McMullan Rachel
Published: June 2018

One way in which animals minimize the risk of infection is to reduce their contact with contaminated food. Here, we establish a model of pathogen-contaminated food avoidance using the nematode worm
Caernorhabditis elegans
. We find that avoidance of pathogen-contaminated food protects
C. elegans
from the deleterious effects of infection and, using genetic approaches, demonstrate that multiple sensory neurons are required for this avoidance behaviour. In addition, our results reveal that the avoidance of contaminated food requires bacterial adherence to non-neuronal cells in the tail of
C. elegans
that are also required for the cellular immune response. Previous studies in
C. elegans
have contributed significantly to our understanding of molecular and cellular basis of host–pathogen interactions and our model provides a unique opportunity to gain basic insights into how animals avoid contaminated food.

This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours’.
“Antibiotic inhibition of bacteria growth in droplets reveals heteroresistance pattern at the single cell level”
Authors: Scheler Ott , Makuch Karol , Debski Pawel R. , Horka Michal , Ruszczak Artur , Pacocha Natalia , Sozański Krzysztof , Smolander Olli-Pekka , Postek Witold , Garstecki Piotr
Published: June 2018

Heteroresistance is a phenomenon where isogenic bacteria population exhibits a diverse antibiotic resistance pattern at sub-population or single cell level. The sub-populations with higher resistance can remain undetected with conventional diagnostics which makes them subsequently harder to treat. Such surviving phenotypically heterogeneous sub-populations are also a potential hotbed for novel mutations, thus increasing the resistance permanently in bacteria. Droplet microfluidics gives tools for high-throughput analysis of bacteria and their response to antibiotics at single cell level, which is difficult to obtain with traditional agar plate technologies. In here we show for the first time the precise digital quantification of drug resistance profile in isogenic population at single cell level. We also see that the inhibiting amount of drug per bacteria remains quite stable regardless of bacteria density. Interestingly, the bacteria clump together preferably near these sub-inhibitory conditions. The technology and findings we describe here provide novel quantitative insight into the heteroresistance which is a key step in understanding the pathways leading to drug resistance. This knowledge is crucial in the context of global drug resistance threat as it can help us to find tools to prevent further escalation of drug resistance.
Chromomycin A2potently inhibits glucose-stimulated insulin secretion from pancreatic β cells
Authors: Kalwat Michael A , Hwang In Hyun , Macho Jocelyn , Grzemska Magdalena G , Yang Jonathan Z , McGlynn Kathleen , MacMillan John B , Cobb Melanie H
Published: June 2018

Enhancers or inhibitors of insulin secretion could become therapeutics as well as lead to the identification of requisite β-cell regulatory pathways and increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is co-secreted with insulin in MIN6 β-cells to perform a high-throughput natural product screen for chronic effects on glucose-stimulated insulin secretion. Using multiple phenotypic analyses, we identified that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion through at least three mechanisms: disruption of Wnt signaling, interfering with β-cell gene expression, and suppression of triggering calcium (Ca2+) influx. Chronic treatment with CMA2 largely ablated glucose-stimulated insulin secretion even post-washout, but did not inhibit glucose-stimulated generation of ATP or Ca2+influx. However, by using the KATPchannel-opener diazoxide, we uncovered defects in depolarization-induced Ca2+influx which may contribute to the suppressed secretory response. Glucose-responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. The FUSION bioinformatic database indicated that the phenotypic effects of CMA2 clustered with a number of Wnt/GSK3 pathway-related genes. Consistently, CMA2 decreased GSK3 phosphorylation and suppressed activation of a β-catenin activity reporter. CMA2 and a related compound mithramycin are described to have DNA-interaction properties, possibly abrogating transcription factor binding to critical β-cell gene promoters. We observed that CMA2, but not mithramycin, suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2-induced insulin secretion defects may involve components both proximal and distal to Ca2+influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt β-cell function through both non-cytotoxic and cytotoxic mechanisms. Future applications of CMA2 and similar aureolic acid analogs for disease therapies should consider the potential impacts on pancreatic islet function.
Microbiome interaction networks and community structure from lab-reared and field-collected Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus mosquito vectors
Authors: Hegde Shivanand , Khanipov Kamil , Albayrak Levent , Golovko George , Pimenova Maria , Saldaña Miguel A. , Rojas Mark M , Hornett Emily A. , Motl Greg C. , Fredregill Chris L. , Dennett James A. , Debboun Mustapha , Fofanov Yuriy , Hughes Grant L.
Published: June 2018

Microbial interactions are an underappreciated force in shaping insect microbiome communities. Although pairwise patterns of symbiont interactions have been identified, we have a poor understanding regarding the scale and the nature of co-occurrence and co-exclusion interactions within the microbiome. To characterize these patterns in mosquitoes, we sequenced the bacterial microbiome of Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus caught in the field or reared in the laboratory and used these data to generate interaction networks. For collections, we used traps that attracted host-seeking or ovipositing female mosquitoes to determine how physiological state affects the microbiome under field conditions. Interestingly, we saw few differences in species richness or microbiome community structure in mosquitoes caught in either trap. Co-occurrence and co-exclusion analysis identified 116 pairwise interactions substantially increasing the list of bacterial interactions observed in mosquitoes. Networks generated from the microbiome of Ae. aegypti often included highly interconnected hub bacteria. There were several instances where co-occurring bacteria co-excluded a third taxa, suggesting the existence of tripartite relationships. Several associations were observed in multiple species or in field and laboratory-reared mosquitoes indicating these associations are robust and not influenced by environmental or host factors. To demonstrate that microbial interactions can influence colonization of the host, we administered symbionts to Ae. aegypti larvae that either possessed or lacked their resident microbiota. We found that the presence of resident microbiota can inhibit colonization of particular bacterial taxa. Our results highlight that microbial interactions in mosquitoes are complex and influence microbiome composition.
Modified protocol for quick and large-scale transformation ofPichia pastoris
Authors: Kumar Ravinder
Published: June 2018

Over the last couple of decades, methylotrophic yeast,Pichia pastorisemerges as an important yeast species owing to its increasing application in industry and basic biological research. Transformation ofPichia pastoriscells for the introduction of the gene of interest is common practice for expression and purification of a heterologous protein(s). Presently available protocol ofPichia pastoristransformation involves preparation of competent cells and followed by their transformation. Preparation of competent cells requires growth of cells to certain cell density which requires lots of resource, space, time and efforts. This limits the number of transformations that can be performed by an individual at a time. In the present paper, I will describe a modification in the available protocol which makesP. pastoristransformation hassle free. The present procedure does not require growth of pre-culture or growth of cells to certain cell density rather cells are grown in a patch on YPD plate(s) and rest procedure is performed in small eppendrof tubes which allow a large number of transformations in quickest possible time with minimal resource and efforts. In the end, I also compare various protocols in tabular form which allows the user to choose best suitable procedure depending on the available resource, time, number of transformations, requirement, and efforts. The present modified protocol does not require big centrifuge and shaker which further makes this procedure more useful. I believe that present protocol of transformation with its many unique features will be really helpful to those working withP. pastoris.
ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins
Authors: Behesti Hourinaz , Fore Taylor , Wu Peter , Horn Zachi , Leppert Mary , Hull Court , Hatten Mary E
Published: June 2018

Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits.ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in post-migratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immuno-gold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII-domain commonly disrupted by CNVs in patients including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.
ARGs-OSP: online searching platform for antibiotic resistance genes distribution in metagenomic database and bacterial whole genome database
Authors: Zhang An Ni , Hou Chen-Ju , Li Li-Guan , Zhang Tong
Published: June 2018

Background

The antibiotic resistant genes (ARGs) have been emerging as one of the top global issue s in both medical and environmental fields. The metagenomic analysis has been widely adopted in ARG-related studies, revealing a universal presence of ARGs in diverse environments from medical settings to natural habitats, even in drinking water and ancient permafrost. With the tremendous resources of accessible metagenomic datasets, it would be feasible and beneficial to construct a global profile of antibiotic resistome as a guidance of its phylogenetic and ecological distribution. And such information should be shared by an open webpage to avoid the unnecessary repeat of data processing and the bias caused by incompatible search method.

Results

Two dataset collections, the Whole Genome Database (WGD, 54,718 complete and draft bacterial genomes) and the Metagenomic Database (MGD, 854 metagenomic datasets of 7 eco-types), were downloaded and analyzed using a standard method of ARG online analysis platform (ARGs-OAP v1.0). The representativeness of WGD and MGD was evaluated to have a comprehensive coverage of ARGs in bacterial genomes and metagenomes. Besides, an ARGs online searching platform (ARGs-OSP, http://args-osp.herokuapp.com/) was developed in this study to make the data accessible to other researchers via the search and download functionality. Finally, flexible usage of the ARGs-OAP was demonstrated by evaluating the co-occurrence of class 1 integrases and total ARGs across different environments.

Conclusions

The ARGs-OSP is presented in this study as the valuable sources and references for future studies with versatile research interests, meanwhile avoiding unnecessary re-computations and re-analysis.
What can computational modeling tell us about the diversity of odor-capture structures in the Pancrustacea?
Authors: Waldrop Lindsay D. , He Yanyan , Khatri Shilpa
Published: June 2018

A major transition in the history of the Pancrustacea was the invasion of several lineages of these animals onto land. We investigated the functional performance of odor-capture organs, antennae with olfactory sensilla arrays, through the use of a computational model of advection and diffusion of odorants to olfactory sensilla while varying three parameters thought to be important to odor capture (Reynolds number, gap-width-to-sensillum-dameter ratio, and angle of the sensilla array with respect to oncoming flow). We also performed a sensitivity analysis on these parameters using uncertainty quantification to analyze their relative contributions to odor-capture performance. The results of this analysis indicate that odor capture in water and in air are fundamentally different. Odor capture in water and leakiness of the array are highly sensitive to Reynolds number and moderately sensitive to angle, whereas odor capture in air is highly sensitive to gap widths between sensilla and moderately sensitive to angle. Leakiness is not a good predictor of odor capture in air, likely due to the relative importance of diffusion to odor transport in air compared to water. We also used the sensitivity analysis to make predictions about morphological and kinematic diversity in extant groups of aquatic and terrestrial crustaceans. Aquatic crustaceans will likely exhibit denser arrays and induce flow within the arrays, whereas terrestrial crustaceans will rely on more sparse arrays with wider gaps and little-to-no animal-induced currents.
Planktonic Protist Biodiversity and Biogeography in Lakes From Four Brazilian River-Floodplain Systems
Authors: Lentendu Guillaume , Buosi Paulo Roberto Bressan , Cabral Adalgisa Fernada , Segóvia Bianca Trevisan , de Meira Bianca Ramos , Lansac-Tôha Fernando Miranda , Velho Luiz Felipe Machado , Ritter Camila , Dunthorn Micah
Published: June 2018

While the biodiversity and biogeography of protists inhabiting many ecosystems have been intensely studied using different sequencing approaches, tropical ecosystems are relatively under-studied. Here we sampled planktonic waters from 32 lakes associated with four different river-floodplains systems in Brazil, and sequenced the DNA using a metabarcoding approach with general eukaryotic primers. The lakes were dominated by the largely free-living Discoba (mostly the Euglenida) and Ciliophora unlike previously sampled Neotropical environments, bu the community similarities between samples were likewise low. These protists inhabiting these floodplains potentially form part of the large diversity of unknown diversity in the tropics.
O-GlcNAc Homeostasis Controls Cell Fate Decisions During Hematopoiesis
Authors: Zhang Zhen , Parker Matt P. , Graw Stefan , Novikova Lesya V. , Fedosyuk Halyna , Fontes Joseph D. , Koestler Devin C. , Peterson Kenneth R. , Slawson Chad
Published: June 2018

The addition of O-GlcNAc (a single β-D-N-acetylglucosamine sugar at serine and threonine residues) by O-GlcNAc transferase (OGT) and removal by O-GlcNAcase (OGA) maintains homeostatic levels of O-GlcNAc. We investigated the role of O-GlcNAc homeostasis in hematopoiesis utilizing G1E-ER4 cells carrying a GATA-1 transcription factor fused to the estrogen receptor (GATA-1ER) that undergo erythropoiesis following the addition of β-estradiol (E2) and myeloid leukemia cells that differentiate into neutrophils in the presence of all-trans retinoic acid. During G1E-ER4 differentiation, a decrease in overall O-GlcNAc levels and an increase in GATA-1 interactions with OGT and OGA were observed. Transcriptome analysis on G1E-ER4 cells differentiated in the presence of Thiamet-G (TMG), an OGA inhibitor, identified expression changes in 433 GATA-1 target genes. Chromatin immunoprecipitation demonstrated that the occupancy of GATA-1, OGT, and OGA atLaptm5gene GATA site was decreased with TMG. Myeloid leukemia cells showed a decline in O-GlcNAc levels during differentiation and TMG reduced the expression of genes involved in differentiation. Sustained treatment with TMG in G1E-ER4 cells prior to differentiation caused a reduction of hemoglobin positive cells during differentiation. Our results show that alterations in O-GlcNAc homeostasis disrupt transcriptional programs causing differentiation errors suggesting a vital role of O-GlcNAcylation in control of cell fate.
Practical Model Selection for Prospective Virtual Screening
Authors: Liu Shengchao , Alnammi Moayad , Ericksen Spencer S. , Voter Andrew F. , Ananiev Gene E. , Keck James L. , Hoffmann F. Michael , Wildman Scott A. , Gitter Anthony
Published: June 2018

Virtual (computational) high-throughput screening provides a strategy for prioritizing compounds for experimental screens, but the choice of virtual screening algorithm depends on the dataset and evaluation strategy. We consider a wide range of ligand-based machine learning and docking-based approaches for virtual screening on two protein-protein interactions, PriA-SSB and RMI-FANCM, and present a strategy for choosing which algorithm is best for prospective compound prioritization. Our workflow identifies a random forest as the best algorithm for these targets over more sophisticated neural network-based models. The top 250 predictions from our selected random forest recover 37 of the 54 active compounds from a library of 22,434 new molecules assayed on PriA-SSB. We show that virtual screening methods that perform well in public datasets and synthetic benchmarks, like multi-task neural networks, may not always translate to prospective screening performance on a specific assay of interest.
Habitat heterogeneity drives scale-dependent biodiversity loss in a temperate marine ecosystem
Authors: Starko Samuel , Bailey Lauren , Creviston Elandra , James Katelyn , Warren Alison , Neufeld Christopher J.
Published: June 2018

Biodiversity loss is driven by interacting factors operating at different spatial scales. Yet, there remains uncertainty as to how fine-scale environmental conditions mediate biological responses to broad-scale stressors. We surveyed mid-latitude kelp bed habitats to determine whether local habitat heterogeneity has mediated changes in community diversity after more than two decades of extreme temperature events, most notably the 2013-2016 heat wave. Local wave exposure conditions were key in determining responses, with some habitats remaining stable and others experiencing near complete diversity loss, leading to local declines without regional extinctions. Wave-sheltered shores, which saw the largest declines, are a very common habitat type in the Northeast Pacific and may be especially sensitive to climate-related losses in kelp diversity and abundance. Our findings highlight how local gradients can interact with global drivers to facilitate diversity loss and demonstrate how incorporating differences between habitat patches can be essential to capturing scale-dependent biodiversity loss across the landscape.
FADS1and the timing of human adaptation to agriculture
Authors: Mathieson Sara , Mathieson Iain
Published: June 2018

Variation at theFADS1/FADS2gene cluster is functionally associated with differences in lipid metabolism and is often hypothesized to reflect adaptation to an agricultural diet. Here, we test the evidence for this relationship using both modern and ancient DNA data. We show that almost all the inhabitants of Europe carried the ancestral allele until the derived allele was introduced approximately 8,500 years ago by Early Neolithic farming populations. However, we also show that it was not under strong selection in these populations. We find that this allele, and other proposed agricultural adaptations atLCT/MCM6andSLC22A4, were not strongly selected until much later, perhaps as late as the Bronze Age. Similarly, increased copy number variation at the salivary amylase geneAMY1is not linked to the development of agriculture although, in this case, the putative adaptation precedes the agricultural transition. Our analysis shows that selection at theFADSlocus was not tightly linked to the initial introduction of agriculture and the Neolithic transition. Further, it suggests that the strongest signals of recent human adaptation in Europe did not coincide with the Neolithic transition but with more recent changes in environment, diet or efficiency of selection due to increases in effective population size.
Selection for protein stability enriches for epistatic interactions
Authors: Posfai Anna , Zhou Juannan , Plotkin Joshua B. , Kinney Justin B. , McCandlish David M.
Published: June 2018

A now classical argument for the marginal thermodynamic stability of proteins explains the distribution of observed protein stabilities as a consequence of an entropic pull in protein sequence space. In particular, most sequences that are sufficiently stable to fold will have stabilities near the folding threshold. Here we extend this argument to consider its predictions for epistatic interactions for the effects of mutations on the free energy of folding. Although there is abundant evidence to indicate that the effects of mutations on the free energy of folding are nearly additive and conserved over evolutionary time, we show that these observations are compatible with the hypothesis that a non-additive contribution to the folding free energy is essential for observed proteins to maintain their native structure. In particular through both simulations and analytical results, we show that even very small departures from additivity are sufficient to drive this effect.
High-throughput mapping of meiotic crossover and chromosome mis-segregation events in interspecific hybrid mice
Authors: Yin Y. , Jiang Y. , Berletch J. B. , Disteche C. M. , Noble W. S. , Steemers F. J. , Adey A. C. , Shendure J. A.
Published: June 2018

We developed “sci-LIANTI”, a high-throughput, high-coverage single-cell DNA sequencing method that combines single-cell combinatorial indexing (“sci”) and linear amplification via transposon insertion (“LIANTI”). To characterize rare chromosome mis-segregation events in male meiosis and their relationship to the landscape of meiotic crossovers, we applied sci-LIANTI to profile the genomes of 6,928 sperm and sperm precursors from infertile, interspecific F1 male mice. From 1,663 haploid and 292 diploid cells, we mapped 24,672 crossover events and identified genomic and epigenomic contexts that influence crossover hotness. Surprisingly, we observed frequent mitotic chromosome segregation during meiosis. Moreover, segregation during meiosis in individual cells was highly biased towards either mitotic or meiotic events. We anticipate that sci-LIANTI can be applied to fully characterize various recombination landscapes, as well as to other fields requiring high-throughput, high-coverage single-cell genome sequencing.

One Sentence Summary

Single-cell genome sequencing maps crossover and non-meiotic chromosome segregation during spermatogenesis in interspecific hybrid mice.
Resource supply drives even spacing of individuals along multiple trait axes in light-limited phytoplankton populations
Authors: Fontana Simone , Thomas Mridul K. , Reyes Marta , Pomati Francesco
Published: June 2018

Individual-level variation arising from responses to environmental gradients influences population and community dynamics. How such responses empirically relate to the mechanisms that govern species coexistence is however not well understood. Previous results from lake phytoplankton communities suggested that the evenness of organisms in multidimensional trait space increases with resource limitation, possibly due to resource partitioning at the individual level. Here we experimentally tested the emergence of this pattern by growing two phytoplankton species (Pseudokirchneriella subcapitata, Microcystis aeruginosa) under a gradient of light intensity, in monoculture and jointly. Under low light (resource) conditions, the populations diversified into a wide range of phenotypes, which were evenly distributed in multidimensional trait space (defined by four pigment-related trait dimensions), confirming the observed field pattern. Our results provide prime experimental evidence that resource limitation induces even spacing of conspecific and heterospecific microbial phenotypes along trait axes, and advances our understanding of trait-based coexistence.
An Integrative Boosting Approach for Predicting Survival Time With Multiple Genomics Platforms
Authors: Wong K. Y. , Fan C. , Tanioka M. , Parker J. S. , Nobel A. B. , Zeng D. , Lin D. Y. , Perou C. M.
Published: June 2018

Recent technological advances have made it possible to collect multiple types of genomics data on the same set of patients. It is of great interest to integrate multiple genomics data types together for predicting disease outcomes. We propose a variable selection method, termed Integrative Boosting (I-Boost), that makes proper use of all available clinical and genomics data in predicting individual patient survival time. Through simulation studies and applications to data sets from The Cancer Genome Atlas, we demonstrate that I-Boost provides substantially higher prediction accuracy than existing variable selection methods. Using I-Boost, we show that (1) the integration of multiple genomics platforms with clinical variables significantly improves the prediction accuracy for survival time over the use of clinical variables alone; (2) gene expression values are typically more prognostic of survival time than other genomics data types; and (3) gene modules/signatures are at least as prognostic as the collection of individual gene expression data.
Differential GAP requirement for Cdc42-GTP polarization during proliferation and sexual reproduction
Authors: Castro Daniela Gallo , Martin Sophie G
Published: June 2018

The formation of a local zone of Cdc42 GTPase activity, which governs cell polarization in many cell types, requires not only local activation but also switch-off mechanisms. Here we identify Rga3, a paralog of Rga4, as a novel Cdc42 GTPase activating protein (GAP) in the fission yeastS. pombe. Contrary to Rga4, Rga3 localizes with Cdc42-GTP to sites of polarity. Rga3 is dispensable for cell polarization during mitotic growth, but limits the lifetime of unstable Cdc42-GTP patches that underlie cell pairing during sexual reproduction, masking a partly compensatory patch wandering motion. In consequence, cells lackingrga3hyperpolarize and loose out in mating competition. Rga3 synergizes with the Cdc42 GAPs Rga4 and Rga6 to restrict Cdc42-GTP zone sizes during mitotic growth. Surprisingly, triple mutant cells, which are almost fully round, retain pheromone-dependent dynamic polarization of Cdc42-GTP, extend a polarized projection and mate. Thus, the requirement for Cdc42-GTP hydrolysis by GTPase activating proteins is distinct during polarization by intrinsic or extrinsic cues.
Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions
Authors: Cascarina Sean M. , Ross Eric D.
Published: June 2018

Proteins with low-complexity domains continue to emerge as key players in both normal and pathological cellular processes. Although low-complexity domains are often grouped into a single class, individual low-complexity domains can differ substantially with respect to amino acid composition. These differences may strongly influence the physical properties, cellular regulation, and molecular functions of low-complexity domains. Therefore, we developed a bioinformatic approach to explore relationships between amino acid composition, protein metabolism, and protein function. We find that local compositional enrichment within protein sequences affects the translation efficiency, abundance, half-life, subcellular localization, and molecular functions of proteins on a proteome-wide scale. However, these effects depend upon the type of amino acid enriched in a given sequence, highlighting the importance of distinguishing between different types of low-complexity domains. Furthermore, many of these effects are discernible at amino acid compositions below those required for classification as low-complexity or statistically-biased by traditional methods and in the absence of homopolymeric amino acid repeats, indicating that thresholds employed by classical methods may not reflect biologically relevant criteria. Application of our analyses to composition-driven processes, such as the formation of membraneless organelles, reveals distinct composition profiles even for closely related organelles. Collectively, these results provide a unique perspective and detailed insights into relationships between amino acid composition, protein metabolism, and protein functions.

Author Summary

Low-complexity domains in protein sequences are regions that are composed of only a few amino acids in the protein “alphabet”. These domains often have unique chemical properties and play important biological roles in both normal and disease-related processes.While a number of approaches have been developed to define low-complexity domains, these methods each possess conceptual limitations. Therefore, we developed a complementary approach that focuses on local amino acid composition (i.e. the amino acid composition within small regions of proteins). We find that high local composition of individual amino acids is associated with pervasive effects on protein metabolism, subcellular localization, and molecular function on a proteome-wide scale. Importantly, the nature of the effects depend on the type of amino acid enriched within the examined domains, and are observable in the absence of classically-defined low-complexity (and related) domains. Furthermore, we define the compositions of proteins involved in the formation of membraneless, protein-rich organelles such as stress granules and P-bodies. Our results provide a coherent view and unprecedented resolution of the effects of local amino acid enrichment on protein biology.
Bacillus thuringiensistargets the host intestinal epithelial junctions for successful infection ofCaenorhabditis elegans
Authors: Wan Liting , Lin Jian , Du Hongwen , Bravo Alejandra , Soberón Mario , Peng Donghai , Sun Ming
Published: June 2018

Pathogenic bacteria use different strategies to infect their hosts including the simultaneous production of pore forming toxins and several virulence factors that help to synergize their pathogenic effects. However, how the pathogenic bacteria are able to complete their life cycle and break out the host intestinal barrier is poorly understood. The infectious cycle ofBacillus thuringiensis(Bt) bacterium inCaenorhabditis elegansis a powerful model system to study the early stages of the infection process. Bt produces Cry pore-forming toxins during the sporulation phase that are key virulence factors involved in Bt pathogenesis. Here we show that during the early stages of infection, the Cry toxins disrupt the midgut epithelial tissue allowing the germination of spores. The vegetative Bt cells then trigger a quorum sensing response that is activated by PlcR regulator resulting in production of different virulence factors, such as the metalloproteinases ColB and Bmp1, that besides Cry toxins are necessary to disrupt the nematode epithelial junctions causing efficient bacterial host infection and dead of the nematode. Overall our work describes a novel mechanism for Bt infection, targeting the epithelial junctions of its host midgut cells.

Author summary

The entomopathogenic bacteriaBacillus thuringiensis(Bt) are used worldwide as biopesticides due to their insecticidal properties. Crystal proteins (Cry) produced by Bt during the sporulation phase of growth are mainly responsible for their insecticidal properties. The infection process of Bt includes three successive steps, virulence, necrotrophic, and sporulation processes. During the virulence process, after ingestion by the susceptible hosts, the Cry toxins form pores in the apical membrane of intestinal cells, inducing favorable conditions for bacterial spore germination. Vegetative bacteria multiply in the host and coordinate their behavior by using the quorum sensor regulator PlcR, which leads to the production of virulence factors allowing the bacteria to kill the host. However, how the bacteria are able to disrupt the host intestinal barrier during the early stages of infection remains unknown. Here we show that Bt employs the nematicidal Cry toxins and additional virulence factors controlled by the PlcR regulon to disrupt the intestinal epithelial junctions ofC. elegansat the early stages of infection allowing that Bt bacteria complete its life cycle in the worms. Our work provides new insights into the pathogenesis of Bt, and highlights the importance of breaking down host epithelial junctions for a successful infection, a similar mechanism could be used by other pathogens-host interactions since epithelial junctions are conserved structures from insects to mammals.
ALV-J and REV synergistically activate a new oncogene of KIAA1199 via NF-κB and EGFR signaling regulated by miR-147
Authors: Zhou Defang , Xue Jingwen , Zhuang Pingping , Cui Xiyao , He Shuhai , Su Shuai , Wang Guihua , Zhang Li , Li Chengui , Huang Libo , Shang Yingli , Yao Yongxiu , Nair Venugopal , Zhang Huangge , cheng ziqiang
Published: June 2018

The tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection of avian leucosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV), as two oncogenic retroviruses, showed synergistic pathogenic effects characterized by enhanced tumor initiation and progression. The molecular mechanism underlying synergistic effects of ALV-J and REV on the neoplasia remains unclear. Here, we found co-infection of ALV-J and REV enhanced the ability of virus infection, increased viral life cycle, maintained cell survival and enhanced tumor formation. We combined the high-throughput proteomic readout with a large-scale miRNA screening to identify which molecules are involved in the synergism. Our results revealed co-infection of ALV-J and REV activated a latent oncogene of KIAA1199 and inhibited the expression of tumor suppressor miR-147. Further, enhanced KIAA1199, down-regulated miR-147, activated NF-κB and EGFR were demonstrated in co-infected tissues and tumor. Mechanistically, we showed ALV-J and REV synergistically enhanced KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. Our results contributed to the understanding of the molecular mechanisms of viral synergistic tumorgenesis, which provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes.

Author summary

The tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection with ALV-J and REV showed synergistic pathogenic effects characterized by enhanced tumor progression, however, the molecular mechanism on the neoplasia remains unclear. Our results revealed co-infection of ALV-J and REV promotes tumorigenesis by both induction of a latent oncogene of KIAA1199 and suppression of the expression of tumor suppressor miR-147. Mechanistic studies revealed that ALV-J and REV synergistically enhance KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. These results provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes, indicating the potential preventive target and predictive factor for ALV-J and REV induced tumorigenesis.
Efficient inference of single cell expression profiles with overlapping pooling and compressed sensing
Authors: Wen Xingzhao , Xu Weiqiang , Sun Xiao , Tu Jing , Lu Zuhong
Published: June 2018

Plate-based single cell RNA-Seq (scRNA-seq) methods can detect a comprehensive profile for gene expression but suffers from high library cost of each single cell. Although cost can be reduced significantly by massively parallel scRNA-seq techniques, these approaches lose sensitivity for gene detection. Inspired by group testing and compressed sensing, here, we designed a computational framework to close the gap between sensitivity and library cost. In our framework, single cells were overlapped assigned into plenty of pools. Expression profile of each pool was then obtained by using plate-based sequence approach. The expression profile of all single cells was recovered based on the pool expression and the overlapped pooling design. The inferred expression profile showed highly consistency with the original data in both accuracy and cell types identification. A parallel computing scheme was designed to boost speed when processing the enormous single cells, and elastic net regression was combined with compressed sensing to auto-adapt for both sparsely and densely expressed genes.