bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Versus Double Anastomosis Duodenal Switch in the Management of Obesity: A Meta-analysis and Systematic Review
Authors: Nakanishi Hayato , Matar Reem H. , Vahibe Ahmet , Abu Dayyeh Barham K. , Galvani Carlos , Pullatt Rana , Davis Steven Scott , Clapp Benjamin , Ghanem Omar M.
Published: September 2022

Background:

Biliopancreatic diversion with duodenal switch (BPD-DS) is an effective yet technically challenging bariatric surgery with many complications. Alternatively, single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) was recently introduced as a simplified bariatric procedure. This meta-analysis aimed to assess the safety and efficacy of SADI-S compared with BPD-DS in the management of patients with obesity.

Methods:

Cochrane, Embase, PubMed, Scopus, and Web of Science were searched for articles from their inception to May 2022 by 2 independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis system. The review was registered prospectively with PROSPERO (CRD42022333521).

Results:

From 123 studies screened, 6 studies met the eligibility criteria, with a total of 1847 patients with obesity undergoing either SADI-S (n=818) or BPD-DS (n=1029). Preoperative body mass index was similar between the 2 groups, and the BPD-DS group had a greater % excess body mass index loss (EBMIL) (MD=−10.16%, 95% confidence interval: −11.80, −8.51, I2=0%) at 2 years compared with the SADI-S group. There was no difference observed in preoperative comorbidities and remission, including diabetes, hypertension, and dyslipidemia between SADI-S and BPD-DS cohorts. Compared with BPD-DS, SADI-S had shorter hospital stays (MD=−1.36 d, 95% CI: −2.39, −0.33, I2=86%), and fewer long-term (>30 d) complications (OR=0.56, 95% CI: 0.42, 0.74, I2=20%). Conversely, among nutritional deficiency outcomes, the SADI-S group had few patients with abnormal vitamin D (OR=0.51, 95% CI: 0.36, 0.72, I2=0%) values than the BPD-DS group.

Conclusions:

SADI-S has shown to be a possible alternative treatment option to BPD-DS in managing patients with obesity. Despite the promising results, further randomized controlled studies with more extended follow-up periods are necessary to ascertain the safety and efficacy of the treatment.
The Account of the Effect of Switch Probability on Switch and Mixing Costs: An ERP Study in a Cued Task-switching Paradigm
Authors: Wenwen Cheng , Yang Yan , Cui Liyan , Chen Ying , Zhang Weiguo , Zhang Xiong , Zhou Shu
Published: September 2022

Background:

Whether the effect of switch probability on switch and mixing costs is explained by an activation or preparation account is unclear.

Objective:

To investigate the account of the effect of switch probability on switch and mixing costs.

Method:

We used a cued task-switching paradigm with three switch probabilities (high, 75%; medium, 50%; and low, 25%) with 19 healthy young adults and recorded the cue- and target-locked event-related potentials (ERPs) and behavioral performance. The task included switch and stay trials under high, medium, and low switch conditions, as well as pure trials.

Results:

There was no significant difference in reaction time (RT) in switch and mixing costs between the high and medium switch conditions. The RT in switch and mixing costs in the high and medium switch conditions was significantly less and more than in the low switch condition, respectively. The cue-locked ERPs revealed significant effects on mixing costs (stay − pure) that were cue early frontal positivity (260–300 ms) in the high and medium switch conditions, and on switch costs (switch − stay) that were cue early central positivity (240–260 ms) in the low switch condition. Moreover, the target-locked ERPs of the mixing costs revealed significant effects on mixing costs that were target P3b (440–540 ms) in all three switch conditions, and on switch costs that were target P3b in the medium and low switch conditions.

Conclusion:

The effect of switch probability on switch and mixing costs is explained by the activation account.
Dentists’ attitudes and practices toward evidence-based dentistry: a systematic review
Authors: Feres Murilo Fernando Neuppmann , Ruiz-Rodrigues Larissa , Prado Viviane de Oliveira , Vicioni-Marques Fernanda , Feres Magda , Nelson-Filho Paulo , Flores-Mir Carlos
Published: September 2022

Introduction and aims:

Considering that attitudes toward evidence-based dentistry (EBD) may predict implementation behaviors, the objective of this systematic review was to synthesize and evaluate the existing evidence related to dentists’ attitudes and practices toward EBD.

Methods:

We included primary studies that collected information from interviews, questionnaires, or conversation sessions with dentists. The following sources were searched: Cochrane Central Register of Controlled Trials, Embase, PubMed, Scopus, and Web of Science, in addition to gray literature. The included studies were appraised according to the assessment tools recommended by the Joanna Briggs Institute for qualitative and quantitative observational studies. Descriptive data were collected in standardized tables and descriptively synthesized.

Results:

The selection process resulted in 36 included studies. Dentists share positive opinions about EBD and predominantly report willingness to learn or adopt these practices. Despite high methodological risks and significant heterogeneity, the results collected in this review indicated that scientific journals, clinical practice guidelines, and trusted colleagues are generally perceived as influential and useful by dentists, who highly consulted these information sources.

Conclusion:

Despite supportive reported attitudes toward EBD, very low certainty exists about actual EBD-related practices.
Association between sexual violence and depression is mediated by perceived social support among female University students in the Kingdom of Eswatini
Authors: Fielding-Miller Rebecca , McDougal Lotus , Frost Elizabeth , Masuku Sakhile , Shabalala Fortunate
Published: September 2022

Background

Gender-based violence is a tool that primarily functions to maintain gendered power hierarchies. As manifestations of gender-based violence, sexual assault and street harassment have been shown to have significant effects on mental wellbeing in the global North, however there is little research centering the experiences and consequences of gendered harassment in the Africa region.

Methods

We analyzed a cross-sectional random sample of women attending a major university in Eswatini in 2017 to measure the prevalence of street harassment among female university students and assess the relationship between experiences of sexual assault, sexualized street harassment, and mental health outcomes in this population.

Results

We found that in the previous 12 months, women reported experiencing high levels of sexual assault (20%), street harassment (90%), and depression/anxiety (38%). Lifetime sexual assault, past 12 months sexual assault, and street harassment were all significantly associated with symptoms of depression. We created a structural model to test hypothesized causal pathways between street harassment, previous experiences of sexual assault, and symptoms of depression, with social support as a potential mediator. We found that a history of sexual violence significantly mediated the association between street harassment and depression, and that social support mediated a large proportion of the association between both forms of gender-based violence and depression.

Conclusion

Sexualized street harassment is associated with increased anxiety and depression for nearly all women, however the effects are especially pronounced for women who have previous experiences of sexual violence. Sexualized street harassment functions as a tool to maintain gendered power hierarchies by reminding women of ongoing threat of sexual violence even in public spaces. Social support and solidarity among women is a potentially important source of resiliency against the physical and mental harms of all forms of gender based violence.
QTL mapping of the narrow-branch “Pendula” phenotype in Norway spruce (Picea abies L. Karst.)
Authors: Gil-Muñoz Francisco , Bernhardsson Carolina , Ranade Sonali Sachin , Scofield Douglas G. , Pulkkinen Pertti O. , Ingvarsson Pär K. , García-Gil M. Rosario
Published: September 2022

Pendula-phenotyped Norway spruce has a potential forestry interest for high density plantations. This phenotype is believed to be caused by a dominant single mutation. Despite the availability of RAPD markers linked to the trait, the nature of the mutation is yet unknown. We performed a Quantitative Trait Loci (QTL) mapping based on two different progenies of F1 crosses between pendula and normal crowned trees using NGS technologies. Approximately 25 % of all gene bearing scaffolds of Picea abies genome assembly v1.0 were mapped to 12 linkage groups and a single QTL, positioned near the center of LG VI, was found in both crosses. The closest probe-markers placed on the maps were positioned 0.82 cM and 0.48 cM away from the Pendula marker in two independent pendula-crowned x normal-crowned wildtype crosses, respectively. We have identified genes close to the QTL region with differential mutations on coding regions and discussed their potential role in changing branch architecture.
Dose of approved COVID-19 vaccines is based on weak evidence: a review of early-phase, dose-finding trials
Authors: Dunn David , Gilson Richard , McCormack Sheena , McCoy Laura
Published: September 2022

Although over 12 billion COVID-19 vaccine doses have been administered globally, the important issue of whether the optimal doses are being used has been relatively neglected. To address this question, we reviewed the reports of early-phase dose-finding trials of the nine COVID-19 vaccines approved by World Health Organization (and one additional vaccine which showed partial clinical efficacy), extracting information on study design and findings on reactogenicity and early humoral immune response. The number of different doses evaluated per vaccine varied widely (range 1-7), as did the number of subjects studied per dose (range 15-190). As expected, the frequency and severity of adverse reactions generally increased at higher doses, although most were clinically tolerable. Higher doses also tended to elicit better immune responses, but differences between the maximum dose and the second-highest dose evaluated were small, typically less than 1.6-fold for both binding antibody concentration and neutralising antibody titre. All of the trials had at least one important design limitation: few doses evaluated, large gaps between adjacent doses, or an inadequate sample size. In general, it is therefore uncertain whether the single dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. In particular, the recommended doses for some vaccines appear to be unnecessarily high. Although reduced dosing for booster injections is an active area of research, the priming dose is equally deserving of study. We conclude by suggesting some ways in which the design of future trials of candidate COVID-19 vaccines could be improved.
Simplified Within Host and Dose-response models of SARS-CoV-2
Authors: Xu Jingsi , Carruthers Jonathan , Finnie Thomas , Hall Ian
Published: September 2022

Understanding the mechanistic dynamics of transmission is key to designing more targeted and effective interventions to limit the spread of infectious diseases. A well-described within-host model allows explicit simulation of how infectiousness changes over time at an individual level. This can then be coupled with dose-response models to investigate the impact of timing on transmission. We collected and compared a range of within-host models used in previous studies and identified a minimally-complex model that provides suitable within-host dynamics while keeping a reduced number of parameters to allow inference and limit unidentifiability issues. Furthermore, non-dimensionalised models were developed to further overcome the uncertainty in estimates of the size of the susceptible cell population, a common problem in many of these approaches. We will discuss these models, and their fit to data from the human challenge study (see Killingley et al. (2022)) for SARS-CoV-2 and the model selection results, which has been performed using ABC-SMC. The parameter posteriors have then used to simulate viral-load based infectiousness profiles via a range of dose-response models, which illustrate the large variability of the periods of infection window observed for COVID-19.
ETV6 Deficiency and Microsatellite Enhancers Drive Transcriptional Dysregulation in B-Lymphoblastic Leukemia
Authors: Kodgule Rohan , Goldman Joshua W. , Monovich Alexander C. , Saari Travis , Hall Cody N. , Rajesh Niharika , Gupta Juhi , Aguilar Athalee , Brown Noah A. , Chiang Mark Y. , Cieslik Marcin P. , Ryan Russell J.H.
Published: September 2022

Distal enhancers play critical roles in sustaining oncogenic gene expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+ B-ALL “signature” genes, including likely oncogenic drivers. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of many repeat enhancer-activated genes. Together, our findings reveal a novel epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene expression program of ETV6-RUNX1+ B-ALL.

Significance

We show that the oncogenic gene expression program of a common pediatric leukemia relies on repetitive noncoding elements that are not conserved between humans and rodents, placing important limitations on animal models for this disease. Our findings may present new opportunities for targeting cancer-specific chromatin dysregulation in leukemia.
Odorant Mixture Separation in Drosophila Early Olfactory System
Authors: Lazar Aurel A. , Liu Tingkai , Yeh Chung-Heng , Zhou Yiyin
Published: September 2022

Natural odorant scenes are complex landscapes comprising mixtures of volatile compounds. It was previously proposed that the Antennal Lobe circuit recovers the odorant identity in a concentration-invariant manner via divisive normalization of Local Neurons. It remains unclear, however, how identities of odorant components in a mixture is represented or recovered in the fruit fly early olfactory pathway. In the current work, we take a different approach from the traditional steady-state analyses that classify odorant mixture encoding into configural vs. elemental schemes. Instead, we focus on the spatio-temporal responses of the early olfactory pathway at the levels of the Antennal Lobe and the Mushroom Body, and formulate the odorant demixing problem as a blind source separation problem - where the identities of each individual odorant component and their corresponding concentration waveforms are recovered from the spatio-temporal PSTH of Olfactory Sensory Neurons (OSNs), Projection Neurons (PNs), and Kenyon Cells (KCs) respectively. Building upon previous models of the Antenna and the Antennal Lobe, we advanced a feedback divisive normalization architecture of the Mushroom Body Calyx circuit comprised of PN, KC and the giant Anterior Paired Lateral (APL) neuron. We demonstrate that the PN-KC-APL circuit produces a high dimensional representation of odorant mixture with robust sparsity, and results in greater odorant demixing performance than the PN responses.
Reading the canid skeletal story: Coxofemoral joint pathology, and suggested implications for the phylogenetic and natural history of taxa
Authors: Lawler Dennis , Tangredi Basil , Widga Christopher , Etnier Michael , Martin Terrance , Kohn Luci
Published: September 2022

We evaluated subtle-to-incipient pathology traits in coxofemoral joints from dry bone museum specimens of: Vulpes lagopus; Vulpes; Nyctereutes procyonoides; Urocyon cinereoargenteus; Canis lupus familiaris; and Canis latrans. Multiple intra-articular structures were evaluated on acetabula and proximal femora. Primary observations included multifocal, variable osteophytelike formations; osteophyte-like rimming of articular margins and femoral head (ligamentum teres attachment); and rough or worn bone. Within limitations on valid statistical applications, we observed little difference among the high trait frequencies across taxa, aligning with previous morphological observations.

Additionally, for this study, we evaluated the known history of the taxa, from deep time to the present, to consider our data in a phylogenetic context. Potential introgression over the evolution of Canidae, along with early history of the canid genome, likely supported broad and deep conservation of pathophysiological processes associated with observable pathology at the same intra-articular foci, across taxa. We also evaluated the “modern” natural histories of the taxa, noting that coxofemoral joint impacts of their respective life habits did not appear to influence pathology trait outcomes differentially.

We conclude that conservation of the physiology underlying subtle and incipient coxofemoral joint pathology that did not segregate among taxa. We hypothesize that the intersecting basic biology of growth-development and insult response, over long geological time, may owe in part to the evidently long histories of hybridization and generally high historical gene flow, with high levels of heterogeneity.

These data argue for new research to advance an interdisciplinary, integrated understanding of relationships among canid growth-development, incipient-to-subtle joint pathology, influences of natural histories across related taxa, and implications for genomic interrelationships.
A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion
Authors: Mann JP , Duan X , Alvarez-Guaita A , Haider A , Luijten I , Page M , Patel S , Scurria F , Protasoni M , Tábara LC , Virtue S , O’Rahilly S , Armstrong M , Prudent J , Semple RK , Savage DB
Published: September 2022

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin-2. How this selective perturbation of mitochondrial function leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation by isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation perturbs mitochondrial morphology and activates the integrated stress response selectively in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.
Is phase-dependent stability related to phase-dependent gait robustness?
Authors: Jin Jian , Kistemaker Dinant , van Dieën Jaap H. , Daffertshofer Andreas , Bruijn Sjoerd M.
Published: September 2022

I.

Predicting gait robustness is useful for targeting interventions to prevent falls. A first step towards this is to properly quantify gait robustness. However, this step already comes with challenges, as humans can withstand different magnitudes of perturbations at different phases in a gait cycle. Earlier, we showed using a simple model that phase-dependent stability measures are limited to predict gait robustness. However, phase-dependent stability measures might relate to phase-dependent gait robustness. To study this, we simulated a ‘simple’ walker model that walks stably and periodically. We applied push and pull perturbations to the stance or swing leg at each phase of the single stance phase and evaluated how phase-dependent stability measures correlate with phase-dependent gait robustness. The latter was quantified via the maximum energy deviation induced by a perturbation that the walker could withstand without falling within 50 steps. Phase-dependent stability measures were obtained, after linearizing the system in a rotating hypersurface perpendicular to the periodic trajectory, via the maximum and the sum of the eigenvalues of the reduced Jacobian matrix, i.e., the trajectory-normal divergence rate. We did not find any strong association between phase-dependent stability measures and phase-dependent robustness. Combining this with our previous assessment of gait robustness, we conclude that phase-dependent stability does not allow for predicting gait robustness, let alone predicting fall risk.
Myosin II regulatory light chain phosphorylation and formin availability modulate cytokinesis upon changes in carbohydrate metabolism
Authors: Prieto-Ruiz Francisco , Gómez-Gil Elisa , Martín-García Rebeca , Pérez-Díaz Armando Jesús , Vicente-Soler Jero , Franco Alejandro , Soto Teresa , Pérez Pilar , Madrid Marisa , Cansado José
Published: September 2022

Cytokinesis, which achieves the separation of daughter cells after mitosis completion, relies in animal cells on a contractile actomyosin ring (CAR), made of actin and class II myosins, whose activity is heavily influenced by regulatory light chain (RLC) phosphorylation. However, in simple eukaryotes such as fission yeast Schizosaccharomyces pombe, regulation of CAR dynamics by RLC phosphorylation seems dispensable. We found that redundant phosphorylation at Ser35 of the S. pombe RLC homolog Rlc1 by the p21-activated kinases Pak1 and Pak2, modulates Myosin II Myo2 activity and becomes essential for cytokinesis and cell growth during respiration. Previously, we showed that the Stress Activated Protein Kinase Pathway (SAPK) MAPK Sty1 controls fission yeast CAR integrity by downregulating formin For3 levels (Gomez-Gil et al.,2020). Here we report that reduced availability of formin For3-nucleated actin filaments for the CAR is the main reason for the required control of myosin II contractile activity by RLC phosphorylation during respiration-induced oxidative stress. Hence, recovery of For3 levels with antioxidants bypasses the control of Myosin II function regulated by RLC phosphorylation to allow cytokinesis and cell proliferation during respiration. Therefore, a fine-tuned interplay between Myosin II function by Rlc1 phosphorylation and environmentally controlled actin filament availability is critical for a successful cytokinesis in response to a switch to a respiratory carbohydrate metabolism.
Predicting Peptide HLA-II Presentation Using Immunopeptidomics, Transcriptomics and Deep Multimodal Learning
Authors: ElAbd Hesham , Wendorff Mareike , Koudelka Tomas , Hentschker Christian , Kamps Ann-Kristin , Prieß Christoph , Wienbrandt Lars , Degenhardt Frauke , Steiert Tim A. , Bacher Petra , Mathur Piyush , Ellinghaus David , Völker Uwe , Tholey Andreas , Lenz Tobias L. , Franke Andre
Published: September 2022

The human leukocyte antigen (HLA) class II proteins present peptides to CD4+T cells through an interaction with T cell receptors (TCRs). Thus, HLA proteins are key players in shaping immunogenicity and immunodominance. Nevertheless, factors governing peptide presentation by HLA-II proteins are still poorly understood. To address this problem, we profiled the blood transcriptome and immunopeptidome of 20 healthy individuals and integrated the profiles with publicly available immunopeptidomics datasets. In depth multi-omics analysis identified expression levels and subcellular locations as import sequence-independent features governing presentation. Levering this knowledge, we developed the Peptide Immune Annotator Multimodal (PIA-M) tool, as a novel pan multimodal transformer-based framework that utilises sequence-dependent along with sequence-independent features to model presentation by HLA-II proteins.PIA-Millustrated a consistently superior performance relative to existing tools across two independent test datasets (area under the curve: 0.93 vs. 0.84 and 0.95 vs. 0.86), respectively. Besides achieving a higher predictive accuracy,PIA-Mwith its Rust-based pre-processing engine, had significantly shorter runtimes.PIA-Mis freely available with a permissive licence as a standalone pipeline and as a webserver (https://hybridcomputing.ikmb.uni-kiel.de/pia). In conclusion,PIA-Menables a new state-of-the-art accuracy in predicting peptide presentation by HLA-II proteinsin vivo.
Microstructural and mechanical insight into atherosclerotic plaques– an ex vivo DTI study to better assess plaque vulnerability
Authors: Tornifoglio B , Johnston R. D. , Stone A. J. , Kerskens C. , Lally C.
Published: September 2022

Non-invasive microstructural characterisation has the potential to determine the stability, or lack thereof, of atherosclerotic plaques and ultimately aid in better assessing plaques’ risk to rupture. If linked with mechanical characterisation using a clinically relevant imaging technique, mechanically sensitive rupture risk indicators could be possible. This study aims to provide this link – between a clinically relevant imaging technique and mechanical characterisation within human atherosclerotic plaques. Ex vivo diffusion tensor imaging, mechanical testing, and histological analysis were carried out on human carotid atherosclerotic plaques. DTI-derived tractography was found to yield significant mechanical insight into the mechanical properties of more stable and more vulnerable microstructures. Coupled with insights from digital image correlation and histology, specific failure characteristics of different microstructural arrangements furthered this finding. More circumferentially uniform microstructures failed at higher stresses and strains when compared to samples which had multiple microstructures, like those seen in a plaque cap. The novel findings in this study motivate diagnostic measures which use non-invasive characterisation of the underlying microstructure of plaques to determine their vulnerability to rupture.

Statements and Declarations

The authors have no competing interests or declarations to declare.

Graphical abstract
Biologically informed variational autoencoders allow predictive modeling of genetic and drug induced perturbations
Authors: Doncevic Daria , Herrmann Carl
Published: September 2022

Variational Autoencoders (VAE) have rapidly increased in popularity in biological applications and have already successfully been used on many omic datasets. Their latent space provides a low dimensional representation of input data, and VAEs have been applied for example for clustering of single-cell transcriptomic data. However, due to their non-linear nature, the patterns that VAEs learn in the latent space remain obscure. To shed light on the inner workings of VAE and enable direct interpretability of the model through its structure, we designed a novel VAE, OntoVAE (Ontology guided VAE) that can incorporate any ontology in its latent space and decoder part and, thus, provide pathway or phenotype activities for the ontology terms. In this work, we demonstrate that OntoVAE can be applied in the context of predictive modeling, and show its ability to predict the effects of genetic or drug induced perturbations using different ontologies and both, bulk and single-cell transcriptomic datasets. Finally, we provide a flexible framework which can be easily adapted to any ontology and dataset.
Host infection dynamics and disease induced mortality modify species contributions to the environmental reservoir
Authors: Laggan Nichole A. , Parise Katy L. , White J. Paul , Kaarakka Heather M. , Redell Jennifer A. , DePue John E. , Scullon William H. , Kath Joseph , Foster Jeffrey T. , Kilpatrick A. Marm , Langwig Kate E. , Hoyt Joseph R.
Published: September 2022

Environmental pathogen reservoirs exist for many globally important diseases and can fuel epidemics, influence pathogen evolution, and increase the threat of host extinction. Species composition can be an important factor that shapes reservoir dynamics and ultimately determines the outcome of a disease outbreak. However, disease induced mortality can change species communities, indicating that species responsible for environmental reservoir maintenance may change over time. Here we examine reservoir dynamics ofPseudogymnoascus destructans,the fungal pathogen that causes white-nose syndrome in bats. We quantified changes in pathogen shedding, infection prevalence and intensity, host abundance, and the subsequent propagule pressure imposed by each species over time. We find that highly shedding species are important during pathogen invasion, but contribute less over time to environmental contamination as they also suffer the greatest declines. Less infected species remain more abundant, resulting in equivalent or higher propagule pressure. More broadly, we demonstrate that high infection intensity and subsequent mortality during disease progression can reduce the contributions of high shedding species to long-term pathogen maintenance.
Transcriptional immunogenomic analysis reveals distinct immunological clusters in pediatric nervous system tumours
Authors: Nabbi Arash , Beck Pengbo , Delaidelli Alberto , Oldridge Derek A. , Sudhaman Sumedha , Zhu Kelsey , Cindy Yang S.Y. , Mulder David T. , Bruce Jeffrey P. , Paulson Joseph N. , Raman Pichai , Zhu Yuankun , Resnick Adam C. , Sorensen Poul H. , Sill Martin , Brabetz Sebastian , Lambo Sander , Malkin David , Johann Pascal D. , Kool Marcel , Jones David T.W. , Pfister Stefan M. , Jäger Natalie , Pugh Trevor J.
Published: September 2022

To inform immunotherapy approaches in children, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve pediatric nervous system tumours (pedNST) spanning 12 cancer types from three public data sets. Within pedNST, we uncovered four broad immune clusters: Pediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Excluded (17%). We validated these clusters using immunohistochemistry, methylation immune inference, and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune-cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Given the heterogeneity within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.
SRSF2 is required for mRNA splicing and spermatogenesis
Authors: Lei Wen-Long , Du Zongchang , Meng Tie-Gang , Su Ruibao , Li Yuan-Yuan , Liu Wenbo , Sun Si-Min , Liu Meng-Yu , Hou Yi , Zhang Chun-Hui , Gui Yaoting , Schatten Heide , Han Zhiming , Liu Chenli , Wang Zhen-Bo , Qian Wei-Ping , Sun Qing-Yuan
Published: September 2022

RNA splicing plays significant roles in fundamental biological activities. However, our knowledge about the roles of alternative splicing and underlying mechanisms during spermatogenesis is limited. Here, we report that Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf2 by Stra8-Cre caused complete infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 disrupted differentiation and meiosis initiation of spermatogonia. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF2 regulatory networks play critical roles in several major events including reproductive development, spermatogenesis, meiotic cell cycle, synapse organization, DNA recombination, chromosome segregation, and male sex differentiation. Furthermore, SRSF2 affected expression and alternative splicing of Stra8, Stag3 and Atr encoding critical factors for spermatogenesis in a direct manner. Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.
Cis-regulatory variation in relation to sex and sexual dimorphism inDrosophila melanogaster
Authors: Mishra Prashastha , Barrera Tania S. , Grieshop Karl , Agrawal Aneil F.
Published: September 2022

Much of sexual dimorphism is likely due to sex-biased gene expression, which results from differential regulation of a genome that is largely shared between males and females. Here we use allele-specific expression to explorecis-regulatory variation inDrosophila melanogasterin relation to sex. We develop a Bayesian framework to infer the transcriptome-wide joint distribution ofcis-regulatory effects across the sexes. We use this approach to quantify transcriptome-wide sex differences incis-regulatory effects as well as examine patterns ofcis-regulatory variation with respect to two other levels of variation in sexual dimorphism: (i) across genes varying in their degree of sex-biased expression, and (ii) among tissues that vary in their degree of dimorphism (e.g., relatively low dimorphism in heads vs high dimorphism in gonads). We uncover evidence of widespreadcis-regulatory variation in all tissues examined, with female-biased genes being especially enriched for this variation. A sizeable proportion ofcis-regulatory variation is inferred to have sex-specific effects, with sex-dependentciseffects being much more frequent in gonads than in heads. Finally, we detect some genes with reversed allelic imbalance between the sexes. Such variants could provide a mechanism for sex-specific dominance reversals, a phenomenon important for sexually antagonistic balancing selection.
T cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL-1 and TNFα Inflammation
Authors: Cho Nam Woo , Guldberg Sophia M. , Nabet Barzin Y. , Yu Jie Zeng , Kim Eun Ji , Hiam-Galvez Kamir J. , Yee Jacqueline L. , DeBarge Rachel , Tenvooren Iliana , Ashitey Naa Asheley , Lynce Filipa , Dillon Deborah A. , Rosenbluth Jennifer M. , Spitzer Matthew H.
Published: September 2022

Resistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells increased in ICI-resistant tumors following treatment as did neutrophils, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL-1 Receptor 1 (IL1R1), enabling a synergistic response to IL-1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting neutrophils. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα bothin vitroandin vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a novel mechanism of ICI resistance, wherein treatment-induced T cell activity can drive resistance in tumors responsive to IL-1 and TNFα, with important therapeutic implications.

Statement of Significance

Although T cell-infiltrated cancers are frequently resistant to immune checkpoint inhibitor therapies, mechanisms of resistance beyond T cell exhaustion remain unclear. Here, we reveal the functional significance of tumor- infiltrating T cells in resistant tumors, which surprisingly instruct immunosuppressive inflammation in mouse and human cancers responsive to IL-1 and TNFα.
Conserved coexpression at single cell resolution across primate brains
Authors: Suresh Hamsini , Crow Megan , Jorstad Nikolas , Hodge Rebecca , Lein Ed , Dobin Alexander , Bakken Trygve , Gillis Jesse
Published: September 2022

Enhanced cognitive function in humans is hypothesized to result from cortical expansion and increased cellular diversity. However, the mechanisms that drive these phenotypic differences remain poorly understood, in part due to the lack of high-quality cellular resolution data in human and non-human primates. Here, we take advantage of single cell expression data from the middle temporal gyrus of five primates (human, chimp, gorilla, macaque and marmoset) to identify 57 homologous cell types and generate cell-type specific gene coexpression networks for comparative analysis. While ortholog expression patterns are generally well conserved, we find 24% of genes with extensive differences between human and non-human primates (3383/14,131), which are also associated with multiple brain disorders. To validate these observations, we perform a meta-analysis of coexpression networks across 19 animals, and find that a subset of these genes have deeply conserved coexpression across all non-human animals, and strongly divergent coexpression relationships in humans (139/3383, <1% of primate orthologs). Genes with human-specific cellular expression and coexpression networks (like NHEJ1, GTF2H2, C2 and BBS5) typically evolve under relaxed selective constraints and may drive rapid evolutionary change in brain function.

One Sentence Summary

Cross-primate middle temporal gyrus single cell expression data reveals patterns of conservation and divergence that can be validated with population coexpression networks.
Onecut1partially contributes to the liver progenitor cell transition and acquisition of metastatic potential in hepatocellular carcinoma
Authors: Liu Yu , Higashitsuji Hiroaki , Itoh Katsuhiko , Yamaguchi Kanji , Umemura Atsushi , Itoh Yoshito , Fujita Jun
Published: September 2022

Metastasis-initiating cells are considered to originate from stem cell-like cancer cells. In hepatocellular carcinoma, liver progenitor-like cells are reported to be derived from hepatocytes, indicating the possible acquisition of metastatic potential during hepatocyte-to-cholangiocyte transdifferentiation. Consistent with the expression pattern observed during ductal plate formation, we revealed an LPC transition withOnecut1accumulation both during hepatocyte-to-cholangiocyte transdifferentiation and in a cell model. This event may be associated with transient acquisition of metastatic potential.
The logic of recurrent circuits in the primary visual cortex
Authors: Oldenburg Ian Antón , Hendricks William D. , Handy Gregory , Shamardani Kiarash , Bounds Hayley A. , Doiron Brent , Adesnik Hillel
Published: September 2022

Recurrent cortical activity sculpts visual perception by refining, amplifying, or suppressing incoming visual signals. Despite the importance of recurrent circuits for cortical processing, the basic rules that govern how nearby cortical neurons influence each other remains enigmatic. We used two-photon holographic optogenetics to activate ensembles of neurons in Layer 2/3 of the primary visual cortex (V1) in the absence of external stimuli to isolate the impact of local recurrence from external inputs. We find that the spatial arrangement and the stimulus feature preference of both the stimulated and the target ensemble jointly determine the net effect of recurrent activity, defining the cortical activity patterns that drive competition versus facilitation in L2/3 circuits. Computational modeling suggests that a combination of highly local recurrent excitatory connectivity and selective convergence onto inhibitory neurons give rise to these principles of recurrent activity. Our data and modeling reveal that recurrent activity can have varied impact, but a logic emerges through an understanding of the precise spatial distribution and feature preference of the multicellular pattern of activity.
Whole-genome sequencing and single acute toxicity of heavy metal to Photobacterium kishitanii FJ21
Authors: Yin Shuzheng , Yi Zilong , Liu Jia , Liu Gang , Fang Jun
Published: September 2022

In this study, the growth morphology of FJ21 strain was observed, and its 16S rRNA and whole genome were sequenced. Then, related software was used to make genome assembly, gene structure and function annotation, genome phylogenetic tree analysis, genome collinearity analysis and prediction of secondary metabolic gene cluster analysis. Finally, the single acute toxicity of five heavy metals to FJ21 strain was detected. There were luxC, luxD, luxA, luxB, luxF, luxE and luxG genes in FJ21, and the protein encoded by lux operon had certain hydrophilicity. The genome of this strain FJ21 contains a chromosome with a total length of 4853277bp and a GC content of 39.23%. The genome of FJ21 was compared with that of Photobacterium kishitanii ATCCBAA-1194, Photobacterium phosphoreum JCM21184, Photobacterium aquimaris LC2-065, Photobacterium malacitanum CECT9190, and Photobacterium carnosum TMW 2.2021. The average nucleotide identity(ANI), tetra nucleotide signatures (Tetra), comparative genome, and phylogenetic analysis proposed that FJ21 is a strain of Photobacterium kishitanii. In the acute toxicity test, the toxicity of heavy metals to the strain FJ21 is Pb(NO3)2 > ZnSO4·7H2O > CdCl2·2.5H2O > CuSO4·5H2O > K2Cr2O7.
Joint Likelihood-Free Inference of the Number of Selected SNPS and the Selection Coefficient in an Evolving Population
Authors: Xu Yuehao , Futschik Andreas , Dutta Ritabrata
Published: September 2022

Abstract

With the exact likelihood often intractable, likelihood-free inference plays an important role in the field of population genetics. Indeed, several methodological developments in the context of Approximate Bayesian Computation (ABC) were inspired by population genetic applications. Here we explore a novel combination of recently proposed ABC tools that can deal with high dimensional summary statistics and apply it to infer selection strength and the number of selected loci for data from experimental evolution. While there are several methods to infer selection strength that operate on a single SNP level, our window based approach provides additional information about the selective architecture in terms of the number of selected positions. This is not trivial, since the spatial correlation introduced by genomic linkage leads to signals of selection also at neighboring SNPs. A further advantage of our approach is that we can easily provide an uncertainty quantification using the ABC posterior. Both on simulated and real data, we demonstrate a promising performance. This suggests that our ABC variant could also be interesting in other applications.
Does a history of co-occurrence predict plant performance, community productivity, or invasion resistance?
Authors: Agneray Alison C. , Forister Matthew L. , Parchman Thomas L. , Leger Elizabeth A.
Published: September 2022

A history of species co-occurrence in plant communities is hypothesized to lead to greater niche differentiation, more efficient resource partitioning, and more productive, resistant communities as a result of evolution in response to biotic interactions. We asked if individual species or community responses differed when communities were founded with species sharing a history of co-occurrence (sympatric) or with species originating from different locations (allopatric). Using shrub, grass, and forb species from six locations in the western Great Basin, USA, we compared establishment, productivity, reproduction, phenology, and resistance to invaders for experimental communities with either sympatric or allopatric associations. Each community type was planted with six taxa in outdoor mesocosms, measured over three growing seasons, and invaded with the annual grassBromus tectorumin the final season. For most populations, the allopatric or sympatric status of neighbors was not important. However, in some cases it was beneficial for some species from some locations to be planted with allopatric neighbors, while others benefited from sympatric neighbors, and some of these responses had large effects. For instance, theElymuspopulation that benefited the most from allopatry grew 50% larger with allopatric neighbors than in single origin mesocosms. This response affected invasion resistance, asB. tectorumbiomass was strongly affected by productivity and phenology ofElymusspp., as well asPoa secunda. Our results demonstrate that while community composition can in some cases affect plant performance in semi-arid plant communities, assembling sympatric communities is not sufficient to ensure high ecosystem services. Instead, we observed a potential interaction between sampling effects and evolutionary history that can create invasion resistant allopatric communities.
Single cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia
Authors: Robinson Troy M. , Bowman Robert L. , Persaud Sonali , Liu Ying , Gao Qi , Zhang Jingping , Sun Xiaotian , Miles Linde A. , Cai Sheng F. , Sciambi Adam , Llanso Aaron , Famulare Christopher , Goldberg Aaron , Dogan Ahmet , Roshal Mikhail , Levine Ross L. , Xiao Wenbin
Published: September 2022

Measurable residual disease (MRD), defined as the population of cancer cells which persists following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia (AML) and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones and normal precursors remains a challenge with current MRD tools. Herein, we developed a single cell (sc) MRD assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated scDNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/pre-leukemic and leukemic cells surviving AML therapy.

Statement of significance

ScMRD assay integrates mutation and immunophenotype at single cell resolution and therefore distinguishes clonal hematopoiesis/preleukemic vs. leukemic clones. This study serves as a framework for identifying high-risk MRD clones and improving our understanding of both the molecular drivers and vulnerabilities of therapy resistant AML clones.