bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic prediction with whole-genome sequence data in intensely selected pig lines
Authors: Ros-Freixedes Roger , Johnsson Martin , Whalen Andrew , Chen Ching-Yi , Valente Bruno D , Herring William O , Gorjanc Gregor , Hickey John M
Published: February 2022

Background

Early simulations indicated that whole-genome sequence data (WGS) could improve genomic prediction accuracy and its persistence across generations and breeds. However, empirical results have been ambiguous so far. Large data sets that capture most of the genome diversity in a population must be assembled so that allele substitution effects are estimated with high accuracy. The objectives of this study were to use a large pig dataset to assess the benefits of using WGS for genomic prediction compared to using commercial marker arrays, to identify scenarios in which WGS provides the largest advantage, and to identify potential pitfalls for its effective implementation.

Methods

We sequenced 6,931 individuals from seven commercial pig lines with different numerical size. Genotypes of 32.8 million variants were imputed for 396,100 individuals (17,224 to 104,661 per line). We used BayesR to perform genomic prediction for eight complex traits. Genomic predictions were performed using either data from a marker array or variants preselected from WGS based on association tests.

Results

The prediction accuracy with each set of preselected WGS variants was not robust across traits and lines and the improvements in prediction accuracy that we achieved so far with WGS compared to marker arrays were generally small. The most favourable results for WGS were obtained when the largest training sets were available and used to preselect variants with statistically significant associations to the trait for augmenting the established marker array. With this method and training sets of around 80k individuals, average improvements of genomic prediction accuracy of 0.025 were observed in within-line scenarios.

Conclusions

Our results showed that WGS has a small potential to improve genomic prediction accuracy compared to marker arrays in intensely selected pig lines in some settings. Thus, although we expect that more robust improvements could be attained with a combination of larger training sets and optimised pipelines, the use of WGS in the current implementations of genomic prediction should be carefully evaluated on a case-by-case basis against the cost of generating WGS at a large scale.
Identification of cell types in multiplexed in situ images by combining protein expression and spatial information using CELESTA reveals novel spatial biology
Authors: Zhang Weiruo , Li Irene , Reticker-Flynn Nathan E. , Good Zinaida , Chang Serena , Samusik Nikolay , Saumyaa Saumyaa , Li Yuanyuan , Zhou Xin , Liang Rachel , Kong Christina S. , Le Quynh-Thu , Gentles Andrew J. , Sunwoo John B. , Nolan Garry P. , Engleman Edgar G. , Plevritis Sylvia K.
Published: February 2022

Advances in multiplexed in situ imaging are revealing important insights in spatial biology. However, cell type identification remains a major challenge in imaging analysis, with most existing methods involving substantial manual assessment and subjective decisions for thousands of cells. We propose a novel machine learning algorithm, CELESTA, which uses both cell’s protein expression and spatial information to identify cell type of individual cells. We demonstrate the performance of CELESTA on multiplexed immunofluorescence in situ images of colorectal cancer and head and neck cancer. Using the cell types identified by CELESTA, we identify tissue architecture associated with lymph node metastasis in HNSCC, which we validate in an independent cohort. By coupling our in situ spatial analysis with single-cell RNA-sequencing data on proximal sections of the same tissue specimens, we identify and validate cell-cell crosstalk associated with lymph node metastasis, demonstrating the power of spatial biology to reveal clinically-relevant cellular interactions.
Curvelet Transform-based Sparsity Promoting Algorithm for Fast Ultrasound Localization Microscopy
Authors: You Qi , Trzasko Joshua D. , Lowerison Matthew R. , Chen Xi , Dong Zhijie , Chandra Sekaran Nathiya Vaithiyalingam , Llano Daniel A. , Chen Shigao , Song Pengfei
Published: February 2022

Ultrasound localization microscopy (ULM) based on microbubble (MB) localization was recently introduced to overcome the resolution limit of conventional ultrasound. However, ULM is currently challenged by the requirement for long data acquisition times to accumulate adequate MB events to fully reconstruct vasculature. In this study, we present a curvelet transform-based sparsity promoting (CTSP) algorithm that improves ULM imaging speed by recovering missing MB localization signal from data with very short acquisition times. CTSP was first validated in a simulated microvessel model, followed by the chicken embryo chorioallantoic membrane (CAM), and finally, in the mouse brain. In the simulated microvessel study, CTSP robustly recovered the vessel model to achieve an 86.94% vessel filling percentage from a corrupted image with only 4.78% of the true vessel pixels. In the chicken embryo CAM study, CTSP effectively recovered the missing MB signal within the vasculature, leading to marked improvement in ULM imaging quality with a very short data acquisition. Taking the optical image as reference, the vessel filling percentage increased from 2.7% to 42.2% using 50ms of data acquisition after applying CTSP. CTSP used 80% less time to achieve the same 90% maximum saturation level as compared with conventional MB localization. We also applied CTSP on the microvessel flow speed maps and found that CTSP was able to use only 1.6s of microbubble data to recover flow speed images that have similar qualities as those constructed using 33.6s of data. In the mouse brain study, CTSP was able to reconstruct the majority of the cerebral vasculature using 1-2s of data acquisition. Additionally, CTSP only needed 3.2s of microbubble data to generate flow velocity maps that are comparable to those using 129.6s of data. These results suggest that CTSP can facilitate fast and robust ULM imaging especially under the circumstances of inadequate microbubble localizations.
Multiple mechanisms mediate the suppression of motion vision during escape maneuvers in flying Drosophila
Authors: Fischer Philippe J. , Schnell Bettina
Published: February 2022

During voluntary behaviors, animals need to disable any reflexes that could interfere with the intended movements. With the optomotor response, for example, flies stabilize a straight flight path by correcting for unintended deviations sensed as panoramic motion of the surround. HS cells of the fly are thought to mediate optomotor responses to horizontal motion. During spontaneous flight turns, an efference copy acts on HS cells with the right sign to counteract the visual input elicited by the fly’s own behavior. Here, we investigated HS cell activity during looming-elicited turns in flying Drosophila. We show that looming stimuli themselves can influence the processing of panoramic motion stimuli in HS cells and that in addition, an inhibitory efference copy suppresses excitatory motion responses during turns, but only in a subset of HS cells. In conclusion, our findings support the notion that processing of sensory information is finely tuned to behavioral context.
Evolutionary responses of energy metabolism, development, and reproduction to artificial selection for increasing heat tolerance inDrosophila subobscura
Authors: Mesas Andrés , Castañeda Luis E.
Published: February 2022

Adaptations to warming conditions exhibited by ectotherms include increasing heat tolerance but also metabolic changes to reduce maintenance costs (metabolic depression), which can allow them to redistribute the energy surplus to biological functions close to fitness. Currently, there is evidence that energy metabolism evolves in response to warming conditions but we know little about how the rate of temperature change during heat stress determines the evolutionary response of metabolism and the consequences on life-history traits. Here, we evaluated the evolutionary response of energy metabolism (metabolic rate and activity of enzymes of the glucose-6-phosphate branchpoint) and life-history traits to artificial selection for increasing heat tolerance inDrosophila subobscura, using two different thermal selection protocols for heat tolerance: slow and fast ramping protocols. We found that the increase in heat thermal tolerance was associated with a reduction of the hexokinase activity in the slow-ramping selected lines, and a slight reduction of the glucose-6-phosphate dehydrogenase activity in the fast-ramping selected lines. We also found that the evolution of increased heat tolerance increased the early fecundity in selected lines and increased the egg-to-adult viability only in the slow-ramping selected lines. However, heat tolerance evolution was not associated with changes in the metabolic rate in selected populations. This work shows heat tolerance can evolve under different thermal scenarios but with different evolutionary outcomes on associated traits depending on the intensity of thermal stress. Therefore, spatial and temporal variability of thermal stress intensity should be taken into account to understand and predict the adaptive response to ongoing and future climatic conditions.
Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
Authors: Garretti Francesca , Monahan Connor , Sloan Nicholas , Bergen Jamie , Shahriar Sanjid , Kim Seon Woo , Sette Alessandro , Cutforth Tyler , Kanter Ellen , Agalliu Dritan , Sulzer David
Published: February 2022

Enteric symptoms, including constipation, are hallmarks of prodromal Parkinson’s disease (PD) that can appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein-(α-syn)-derived epitopes. One epitope, α-syn32-46, binds with strong affinity to the HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report that α-syn32-46immunization in a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation leading to loss of enteric neurons, damage of enteric dopaminergic neurons, constipation and weight loss. α-Syn32-46immunization activates innate and adaptive immune gene signatures in the gut and induces changes in CD4+TH1/ TH17 transcriptome that resemble tissue resident memory cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn32-46and HLA-DRB1*15:0 is critical for gut inflammation and CD4+T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD.

HIGHLIGHTS AND eTOC Blurb

α-syn32-46immunization of an HLA-DRB1*15:01 mouse triggers weight loss and constipation.

α-syn32-46immunizations induce gut inflammation, loss of enteric neurons and damage to dopaminergic neurons.

α-syn32-46immunization induces innate and adaptive immune responses in the gut.

Depletion of CD4+, but not CD8+, T cells partially rescues enteric neural loss.

An interaction between α-syn32-46and HLA-DRB1*15:01 is critical for this model of prodromal PD.

Parkinson’s disease (PD) patients exhibit elevated number of circulating T cells that recognize α-synuclein-(α-syn)- epitopes, particularly during early disease stages. One epitope, α-syn32-46, interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garrettiet al. show that α-syn32-46immunization of a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, a loss of enteric neurons, constipation and weight loss, suggesting a critical role for α-syn autoimmunity in HLA-DRB1*15:01 carriers in prodromal PD.
The Ca2+-gated Cl- channel TMEM16A amplifies capillary pericyte contraction reducing cerebral blood flow after ischemia
Authors: Korte Nils , Ilkan Zeki , Pearson Claire , Pfeiffer Thomas , Singhal Prabhav , Rock Jason , Sethi Huma , Gill Dipender , Attwell David , Tammaro Paolo
Published: February 2022

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activates chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplifies the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction and pericyte death, reduces neutrophil stalling and improves cerebrovascular reperfusion. Genetic analysis implicates altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function, and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia.
Evidence for evolutionary adaptation of mixotrophic nanoflagellates to warmer temperatures
Authors: Lepori-Bui Michelle , Paight Christopher , Eberhard Ean , Mertz Conner M. , Moeller Holly V.
Published: February 2022

Mixotrophs, organisms that combine photosynthesis and heterotrophy to gain energy, play an important role in global biogeochemical cycles. Metabolic theory predicts that mixotrophs will become more heterotrophic with rising temperatures, potentially creating a positive feedback loop that accelerates carbon dioxide accumulation in the atmosphere. Studies testing this theory have focused on phenotypically plastic (short-term) thermal responses of mixotrophs. However, as small organisms with short generation times and large population sizes, mixotrophs may rapidly evolve in response to climate change. Here we present data from a 3-year experiment quantifying the evolutionary response of two mixotrophic nanoflagellates to temperature. We found evidence for adaptive evolution through increasing growth rates in the obligately mixotrophic strain, but not in the facultative mixotroph. All lineages showed trends of increased carbon use efficiency, flattening of thermal reaction norms, and a return to homeostatic gene expression. Generally, mixotrophs evolved reduced photosynthesis and higher grazing with increased temperatures, suggesting that evolution may act to exacerbate mixotrophs’ effects on global carbon cycling.
Insights in the complex DegU, DegS, Spo0A regulation system of Paenibacillus polymyxa by CRISPR-Cas9-based targeted point mutations
Authors: Meliawati Meliawati , May Tobias , Eckerlin Jeanette , Heinrich Daniel , Herold Andrea , Schmid Jochen
Published: February 2022

Despite being unicellular organisms, bacteria undergo complex regulation mechanisms which coordinate different physiological traits. Among others, DegU, DegS, and Spo0A are the pleiotropic proteins which govern various cellular responses and behaviors. However, the functions and regulatory networks between these three proteins are rarely described in the highly interesting bacterium Paenibacillus polymyxa. In this study, we investigate the roles of DegU, DegS, and Spo0A by introduction of targeted point mutations facilitated by a CRISPR-Cas9-based system. In total, five different mutant strains were generated: the single mutants DegU Q218*, DegS L99F, Spo0A A257V, the double mutant DegU Q218* DegS L99F, and the triple mutant DegU Q218* DegS L99F Spo0A A257V. Characterization of the wild type and the engineered strains revealed differences in swarming behavior, genetic competence, sporulation, and viscosity formation of the culture broth. In particular, the double mutant DegU Q218* DegS L99F showed significant increase in regard to the genetic competence as well as a stable exopolysaccharides formation. Furthermore, we highlight similarities and differences of the roles of DegU, DegS, and Spo0A between P. polymyxa and related species. Finally, this study provides novel insights in the complex regulatory system of P. polymyxa DSM 365.

Importance

To date, only limited knowledge is available on how complex cellular behaviors are regulated in P. polymyxa. In this study, we investigate three regulatory proteins which play a role in governing different physiological traits. Precise targeted point mutations are introduced to their respective genes by employing a highly efficient CRISPR-Cas9-based system. Characterization of the strains revealed some similarities, but also differences, with the model bacterium Bacillus subtilis in regard to the regulation of cellular behaviors. Furthermore, we identified several strains which have superior performance in comparison to the wild type strain. Overall, our study provides novel insights which will be of importance in understanding how multiple cellular processes are regulated in Paenibacillus species.
The urothelial transcriptomic response to interferon gamma predicts T1 recurrence-free and basal/squamous muscle-invasive bladder cancer survival and better targeted strategies for immune checkpoint blocking
Authors: Baker Simon C. , Mason Andrew S. , Slip Raphael G. , Eriksson Pontus , Sjödahl Gottfrid , Trejdosiewicz Ludwik K , Southgate Jennifer
Published: February 2022

Intravesical Bacillus Calmette-Guérin vaccine (BCG) is an established immunotherapeutic in bladder cancer (BlCa), provoking inflammation leading to tumour-specific immunity. Immune checkpoint blockers such as anti-PD-L1 have potential for enhancing tumour-specific lymphocyte-mediated cytotoxicity in BCG-refractive or advanced disease. In both cases, Interferon-gamma (IFNγ) plays a central role. We investigated the transcriptomic response of normal human urothelium to IFNγ to disentangle mechanisms of BCG and anti-PD-L1 therapy failure.

Exposure of differentiated human urothelium to IFNγ resulted in upregulated MHC class I and class II and de novo expression of CXCL9-11 chemokine genes. Normal urothelium expressed only immuno-inhibitory B7 family members: PD-L1 expression was induced by IFNγ, whereas VISTA was expressed constitutively.

A urothelial IFNγ response gene set was derived and used for unsupervised clustering of tumours, which predicted longer recurrence-free survival in non-muscle invasive bladder cancer (NMIBC). In muscle invasive bladder cancer (MIBC), the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak/absent.

Normal urothelium has few resident lymphocytes. Tumour cell killing requires recruitment and activation of IFNγ-secreting pro-inflammatory/cytotoxic lymphocytes while surmounting both innate (VISTA) and upregulated (PD-L1) inhibitory mechanisms. This study offers supportive evidence for strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.

Patient Summary

Immunotherapy brings promise of harnessing a patient’s own immune system to seek and destroy malignant cells, but it has yet to deliver widespread clinical benefit. We exposed human urothelium to interferon gamma, a key messenger of the immune system and identified a novel signature of 33 genes that predicted cancers with better outcomes. Our study revealed alternative strategies for targeting checkpoint proteins to improve immunotherapy in the future.
An assessment of the vaccination of school-aged children in England
Authors: Keeling Matt J. , Moore Sam E.
Published: February 2022

Background

Children and young persons are known to have a high number of close interactions, often within the school environment, which can facilitate rapid spread of infection; yet for SARS-CoV-2 it is the elderly and vulnerable that suffer the greatest health burden. Vaccination, initially targeting the elderly and vulnerable but later expanded to the entire adult population, has been transformative in the control of SARS-CoV-2 in England. However, early concerns over adverse events and the lower risk associated with infection in younger individuals means that the expansion of the vaccine programme to those under 18 year of age needs to be rigorously and quantitatively assessed.

Methods

Here, using a bespoke mathematical model matched to case and hospital data for England, we consider the potential impact of vaccinating 12-17 and 5-11 year olds. This analysis is reported from an early model (generated in June 2021) that formed part of the evidence base for the decisions in England, and a later model (from November 2021) that benefits from a richer understanding of vaccine efficacy, greater knowledge of the Delta variant wave and uses data on the rate of vaccine administration. For both models we consider the population wide impact of childhood vaccination as well as the specific impact on the age-group targeted for vaccination.

Results

Projections from June suggested that an expansion of the vaccine programme to those 12-17 years old could generate substantial reductions in infection, hospital admission and deaths in the entire population, depending on population behaviour following the relaxation of control measures. The benefits within the 12-17 year old cohort were less marked, saving between 656 and 1077 (95% prediction interval 281-2260) hospital admissions and between 22 and 38 (95% PI 9-91) deaths depending on assumed population behaviour. For the more recent model, the benefits within this age group are reduced, saving on average 631 (95% PI 304-1286) hospital admissions and 11 (95% PI 5-28) deaths for 80% vaccine uptake, while the benefits to the wider population represent a reduction of 8-10% in hospital admissions and deaths. The vaccination of 5-11 year olds is projected to have a far smaller impact, in part due to the later roll-out of vaccines to this age-group.

Conclusions

Vaccination of 12-17 year olds and 5-11 year olds is projected to generate a reduction in infection, hospital admission and deaths for both the age-groups involved and the population in general. For any decision involving childhood vaccination, these benefits needs to be balanced against potential adverse events from the vaccine, the operational constraints on delivery and the potential for diverting resources from other public health campaigns.
Causal relationship between Environmental Enteric Dysfunction (EED), WaSH practices and growth failure in children from Rukwa-Tanzania
Authors: Modern Grantina , Mpolya Emmanuel , Sauli Elingarami
Published: February 2022

This was a hospital based prospective cohort study aimed at assessing causal relationship between environmental enteric dysfunction (EED), WaSH practices and growth failure in children aged between 1-2 years from Rukwa, Tanzania, using univariate and multivariate logistic regression models. We found very significant causal relationship between growth failure and combined water availability (p=0.0055), toilet sharing by parents/caregivers (OR= 2.632, CI: 1.156 - 6.233, p=0.023 from univariate analysis, and OR=4.067, CI: 1.484 - 12.206, p=0.008 from multivariate analysis), and handwashing by parents/caregivers before food (OR=3.363, CI: 0.928 -11.454, p=0.05 from univariate analysis and OR=15.038, CI:2.422 - 115.8, p=0.005 from multivariate analysis). This significant causal relationship may be linked to increased diarrheal incidence and intestinal worm infections among the studied children, which may then lead to inadequate absorption of nutrients and subsequent growth failure. The findings herein should therefore improve policy and programs designed to deliver targeted intervention strategies in Tanzania, to also identify and include other entry points for managing child growth failure and improving WaSH practices.
Anterior Connectivity Critical for Recovery of Connected Speech after Stroke
Authors: Ding Junhua , Schnur Tatiana T.
Published: February 2022

Connected speech recovers to different degrees across people after left hemisphere stroke, but white matter predictors of differential recovery from the acute stage of stroke are unknown. We assessed changes in lexical-syntactic aspects of connected speech in a longitudinal analysis of 40 individuals (18 females) from the acute stage of left hemisphere stroke (within an average 4 days post-stroke) to subacute (within 2 months) and chronic stages (early: 6 months, late: 1 year) while measuring the extent of acute lesions on white matter tracts to identify tracts predictive of recovery. We found that acute damage to the frontal aslant tract led to decreased recovery of the fluency and structural complexity of connected speech during the year following left hemisphere stroke. Results were independent of baseline performance, overall lesion volume, and the proportion damage to tract-adjacent gray matter. This longitudinal analysis from acute to chronic stroke provides the first evidence that recovery of fluent and structurally complex spontaneous connected speech requires intact left frontal connectivity via the frontal aslant tract. That the frontal aslant tract was critical for recovery at early as well as later stages of stroke demonstrates that anterior connectivity plays a lasting and important role for the reorganization of function related to the successful production of connected speech.
Sibling Experiences of Adverse Childhood Experiences: A Scoping Review
Authors: Donagh Ben , Taylor Julie , Mushaikni Muna al , Bradbury-Jones Caroline
Published: February 2022

Adverse childhood experiences (ACEs) are traumatic events during childhood known to affect health and wellbeing across the life-span. The purpose of this scoping review was to understand what we currently know about the experiences of siblings living with ACEs. Sibling relationships are unique, and for some the most enduring we experience. These relationships can be categorised by love and warmth, however, can also be a point of escalating conflict and problems. This scoping review was conducted following Arksey and O’Malley’s (2005) methodological framework, complemented by the PAGER framework (Bradbury-Joneset al, 2021), offering a structured approach to the review’s analysis and reporting through presenting thePatterns,Advances,Gaps, andEvidence for practice andResearch. In June 2020 we searched 12 databases, with 11,469 results. Articles were screened for eligibility by the review team leaving a total of 148 articles meeting the inclusion criteria. Findings highlighted five main patterns: (1) the influence of birth order (older siblings shielding younger); (2) the influence of sibling relationships (lack of research exploring sibling types outside of biological siblings); (3) identifying siblings experiencing ACEs (when one sibling experiences adversity, it is likely that their other siblings also do, or experience vicariously); (4) siblings who cause harm (siblings harming other siblings is often normalised and minimised, especially by parents); (5) focus on individual ACEs (the majority of studies explore ACEs in isolation). Our findings suggest future research would benefit from an increase in theoretical understanding and exploration of different types of sibling relationships (full, step, half).
Unpicking the Gordian knot: Mendelian randomization to elucidate the risk factors for infectious diseases, using EBV as a model pathogen
Authors: Muckian Marisa D. , Wilson James. F , Taylor Graham S. , Stagg Helen R. , Pirastu Nicola
Published: February 2022

Background

Why particular individuals are more at risk of a given infectious disease than others has been a topic of interest for scientists, clinicians, and polymaths for millennia. Complex webs of factors-sociodemographic, clinical, genetic, environmental-intersect, rendering causality difficult to decipher. We aimed to demonstrate the ability of Mendelian Randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of infectious diseases, using Epstein Barr Virus (EBV) as a model pathogen.

Methods

We mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8,422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal.

Results

Our GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed educational attainment, number of sexual partners, and smoking as causal risk factors for EBV serostatus.

Conclusions

Our study demonstrates the power of MR to decipher complex webs of putative risk factors and determine which are causal for the acquisition of an infectious disease. The factors identified for EBV will be important for vaccine deployment.

Key messages

The risk of infectious disease acquisition is dependent on many interacting sociodemographic, lifestyle, clinical, genetic, environmental, and national and international health governance factors.

Traditional epidemiological studies of these risk factors are often hindered by issues of confounding and therefore whether a given putative risk factor is causally associated with infection acquisition is difficult to decipher.

Using Epstein Barr Virus (EBV) as a model pathogen, we demonstrate the power of Mendelian randomization to understand if putative risk factors are causal, while controlling for confounding.

Better understanding of infectious disease risk factors using Mendelian randomization can inform vaccine strategies and deployment e.g. by identifying priority populations for vaccination.
Interactions among 17 respiratory pathogens: a cross-sectional study using clinical and community surveillance data
Authors: Burstein Roy , Althouse Benjamin M. , Adler Amanda , Akullian Adam , Brandstetter Elizabeth , Cho Shari , Emanuels Anne , Fay Kairsten , Gamboa Luis , Han Peter , Huden Kristen , Ilcisin Misja , Izzo Mandy , Jackson Michael L. , Kim Ashley E. , Kimball Louise , Lacombe Kirsten , Lee Jover , Logue Jennifer K. , Rogers Julia , Chung Erin , Sibley Thomas R. , Van Raay Katrina , Wenger Edward , Wolf Caitlin R. , Boeckh Michael , Chu Helen , Duchin Jeff , Rieder Mark , Shendure Jay , Starita Lea M. , Viboud Cecile , Bedford Trevor , Englund Janet A. , Famulare Michael
Published: February 2022

Background

Co-circulating respiratory pathogens can interfere with or promote each other, leading to important effects on disease epidemiology. Estimating the magnitude of pathogen-pathogen interactions from clinical specimens is challenging because sampling from symptomatic individuals can create biased estimates.

Methods

We conducted an observational, cross-sectional study using samples collected by the Seattle Flu Study between 11 November 2018 and 20 August 2021. Samples that tested positive via RT-qPCR for at least one of 17 potential respiratory pathogens were included in this study. Semi-quantitative cycle threshold (Ct) values were used to measure pathogen load. Differences in pathogen load between monoinfected and coinfected samples were assessed using linear regression adjusting for age, season, and recruitment channel.

Results

21,686 samples were positive for at least one potential pathogen. Most prevalent were rhinovirus (33·5%), Streptococcus pneumoniae (SPn, 29·0%), SARS-CoV-2 (13.8%) and influenza A/H1N1 (9·6%). 140 potential pathogen pairs were included for analysis, and 56 (40%) pairs yielded significant Ct differences (p < 0.01) between monoinfected and co-infected samples. We observed no virus-virus pairs showing evidence of significant facilitating interactions, and found significant viral load decrease among 37 of 108 (34%) assessed pairs. Samples positive with SPn and a virus were consistently associated with increased SPn load.

Conclusions

Viral load data can be used to overcome sampling bias in studies of pathogen-pathogen interactions. When applied to respiratory pathogens, we found evidence of viral-SPn facilitation and several examples of viral-viral interference. Multipathogen surveillance is a cost-efficient data collection approach, with added clinical and epidemiological informational value over single-pathogen testing, but requires careful analysis to mitigate selection bias.
Bi-steric mTORC1-selective Inhibitors activate 4EBP1 reversing MYC-induced tumorigenesis and synergize with immunotherapy
Authors: Mahauad-Fernandez Wadie D. , Yang Yu Chi , Lai Ian , Park Jangho , Yao Lilian , Evans James W. , Burnett G. Leslie , Gill Adrian , Smith Jacqueline A. M. , Singh Mallika , Felsher Dean W.
Published: February 2022

The MYC oncogene is causally involved in the pathogenesis of most types of human cancer but it remains therapeutically untargeted. The mTORC1 protein complex regulates cap-dependent translation through 4EBP1 and S6K and thereby, downstream MYC protein expression. However, to date, agents such as rapalogs that selectively target mTORC1 (as compared to mTORC2) fail to reactivate 4EBP1 and thus, to block MYCin vivo.In contrast, agents that nonselectively inhibit both protein complexes of the mTOR pathway, mTORC1 and mTORC2, can activate 4EBP1, but often suffer from a lack of tolerability includingin vivohepatotoxicity and immunosuppression. Here, we report the anti-tumor activity of bi-steric mTORC1-selective inhibitors, including Revolution Medicines’ clinical candidate RMC-5552, that potently and selectively target mTORC1 over mTORC2. In an autochthonous transgenic mouse model of MYC-amplified and MYC-driven hepatocellular carcinoma (HCC), representative bi-steric mTORC1-selective inhibitors suppress translation initiation via activation of 4EBP1, thereby suppressing MYC protein expression and blocking tumor growth. Furthermore, in human HCC samples, the low levels of 4EBP1 and MYC is correlated with immune reactivation. Immunohistochemistry, CIBERSORT, and CODEX reveal that selective mTORC1 inhibition results in activation of both CD4+ T cell- and NKp46+ NK cell-mediated immune surveillance. Moreover, bi-steric mTORC1-selective inhibitors synergize with α-PD-1 to induce sustained tumor regression, with immune cell degranulation and release of perforins and granzyme B. These agents also exhibit anti-tumor activity in human patient-derived xenografts of HCC, colorectal cancer, head and neck cancer, and ovarian cancer harboring genomic amplifications inMYC. We infer that selective mTORC1 inhibition is a potential therapeutic strategy to drive effective MYC inactivation in cancer, and the consequent restoration of immune surveillance against neoplasia.
Chronic Alcohol Consumption Alters Home-Cage Behaviors and Responses to Ethologically Relevant Predator Tasks in Mice
Authors: Neira Sofia , Hassanein Leslie A. , Stanhope Christina M. , Buccini Michelle C. , D’Ambrosio Shannon L. , Flanigan Meghan E. , Haun Harold L. , Boyt Kristen M. , Bains Jaideep S. , Kash Thomas L.
Published: February 2022

Alcohol use disorders (AUD) are the most prevalent substance use disorders worldwide. Considering recent reports indicating an increase in alcohol use particularly in females, it is vital to understand how alcohol history impacts behavior. Animal model research on withdrawal-associated affective states tends to focus on males, forced alcohol paradigms, and a few traditional anxiety/stress tests. While this has been essential, heavy alcohol use triggers adverse withdrawal-related affective states that can influence how people respond to a large variety of life events and stressors. To this end, we show that behaviors in the home-cage, open field, looming disc, and robogator predator threat task, which vary in task demand and intensity, are altered in mice with a history of voluntary alcohol consumption. In alcohol-exposed males, behaviors in the home cage, a low anxiety baseline environment, suggest increased vigilance/exploration. However, in the open field and robogator task, which induce heightened arousal and task demands, a more hesitant/avoidant phenotype is seen. Female alcohol mice show no behavioral alterations in the home cage and open field test, however, in the looming disc task, which mimics an overhead advancing predator and forces a behavioral choice, we see greater escape responses compared to water controls, indicative of active stress coping behaviors. This suggests females may begin to show alcohol-induced alterations as task demands increase. To date, few drugs have advanced past clinical trials for the treatment of AUD, and those that have are predominately used in life-threatening situations only. No treatments exist for ameliorating negative withdrawal related states, which could aid in harm reduction related to heavy alcohol use. Understanding how withdrawal alters a variety of behavioral responses that are linked to stress coping can widen our understanding of alcohol abuse and lead us closer to better therapeutics to help individuals with AUD.
Distinct mechanisms of germ cell factor regulation for an inductive germ cell fate
Authors: Foster Stephany , Oulhen Nathalie , Fresques Tara , Zaki Hossam , Wessel Gary
Published: February 2022

Specification of primordial germ cells (PGCs), the lineage which gives rise to eggs and sperm, is essential for sexually reproducing organisms. The mechanism by which animals specify their PGCs generally falls into two categories: inherited or inductive. The inductive mechanism, used by mammals, relies on cell signaling interactions to direct a subset of embryonic cells to a germ cell fate. Previous work suggested that sea star embryos, which develop in simple culture and are markedly transparent, also use inductive mechanisms to specify their germline. The germ cell factors Nanos and Vasa become restricted during early development into a localized region of cells within the posterior enterocoel (PE), the presumptive germline. Nodal signaling was observed to negatively regulate Vasa and Nanos mRNAs outside of the PE and restrict the germline to the PE. Here we employed single cell RNA sequencing to identify the transcriptional program of germ cells and their changes during development. We never see Nodal pathway members within Nanos/Vasa positive cells in the region known to give rise to the PE, and instead see members of the Wnt-signaling pathway and the FoxY family of transcription factors. We learned that Wnt and Delta/Notch signaling enhances expression of both Nanos and Vasa, whereas a test of cell interactions reveals that Nanos and Vasa are regulated distinctly. This work provides insights into the sequence of events that leads to PGC specification and enables deeper mechanistic studies in a tractable in vivo model.

Highlights

Single-cell RNA-sequencing of sea star embryos demonstrates temporal differences in cell fate commitment among echinoderms.

Sea urchin and sea star embryos appear to ascribe their germ line by two extreme different mechanisms but share similar pathways in regulation of the germline genes.

Expression of the germline factors, Vasa and Nanos, is regulated by distinct mechanisms in the sea star.

Germline induction in the sea star uses similar signaling mechanisms as mammals.
IL-34 deficiency impairs FOXP3+ Treg function and increases susceptibility to autoimmunity
Authors: Freuchet Antoine , Salama Apolline , Bézie Séverine , Tesson Laurent , Rémy Séverine , Humeau Romain , Règue Hadrien , Flippe Léa , Peterson Pärt , Vimond Nadège , Usal Claire , Ménoret Séverine , Heslan Jean-Marie , Duteille Franck , Blanchard Frédéric , Giral Magali , Colonna Marco , Anegon Ignacio , Guillonneau Carole
Published: February 2022

Immune homeostasis requires fully functional Tregs with a stable phenotype to control autoimmunity. Although IL-34 is a cytokine first described as mainly involved in monocyte cell survival and differentiation, we recently described its expression by CD8+ Tregs in a rat model of transplantation tolerance and by activated FOXP3+ CD4+ and CD8+ Tregs in human healthy individuals. However, its role in autoimmunity and potential in human diseases remain to be determined. Here we report that the absence of expression of IL-34 in Il34-/- rodents leads to an unstable phenotype, with production of multiple auto-antibodies, exacerbated under inflammatory conditions with increased susceptibility to DSS- and TNBS-colitis in deficient animals. Moreover, we strikingly revealed the inability of Il34-/- CD4+ Tregs to protect Il2rg-/- rats from a wasting disease induced by transfer of pathogenic cells, in contrast to Il34+/+ CD4+ Tregs. We also showed that IL-34 treatment delayed EAE in mice as well as GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, we show that presence of IL-34 in the serum is associated with a longer rejection-free period in kidney transplanted patients. Altogether, our data emphasize on the crucial necessity of IL-34 for immune homeostasis and for CD4+ Tregs suppressive function. Our data also shows the therapeutic potential of IL-34 in human transplantation and auto-immunity.
Reward contingency gates selective cholinergic suppression of amygdala neurons
Authors: Kimchi Eyal Y. , Burgos-Robles Anthony , Matthews Gillian A. , Chakoma Tatenda , Patarino Makenzie , Weddington Javier , Siciliano Cody A. , Yang Wannan , Foutch Shaun , Simons Renee , Fong Ming-fai , Jing Miao , Li Yulong , Polley Daniel B. , Tye Kay M.
Published: February 2022

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward – even in prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs.In vivoelectrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex (PFC). Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic-receptor-signaling, while also facilitating firing in GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.
GSK2556286 is a novel antitubercular drug candidate effective in vivo with the potential to shorten tuberculosis treatment
Authors: Nuermberger Eric L. , Martínez-Martínez Maria Santos , Sanz Olalla , Urones Beatriz , Esquivias Jorge , Soni Heena , Tasneen Rokeya , Tyagi Sandeep , Li Si-Yang , Converse Paul J. , Boshoff Helena I. , Robertson Gregory T , Besra Gurdyal S , Abrahams Katherine A. , Upton Anna M , Mdluli Khisimuzi , Boyle Gary W , Turner Sam , Fotouhi Nader , Cammack Nicholas C. , Siles Juan Miguel , Alonso Marta , Escribano Jaime , Lelievre Joel , Pérez-Herrán Esther , Bates Robert H. , Maher-Ewards Gareth , Barros David , Ballell Lluís , Jiménez Elena
Published: February 2022

As a result of a high-throughput compound screening campaign of Mycobacterium tuberculosis infected macrophages, a new preclinical drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (IC50 = 0.07 µM), is active against extracellular bacteria in cholesterol-containing culture media and exhibits no cross-resistance with known antitubercular drugs. In addition, it has shown efficacy in different mouse models of tuberculosis (TB) and has an adequate safety profile in two preclinical species. These features indicate a compound with a novel mode of action, although still not fully defined, that is effective against both multidrug or extensively-resistant (M/XDR) and drug-sensitive (DS) M. tuberculosis with the potential to shorten the duration of treatment in novel combination drug regimens.

One Sentence Summary

GSK2556286 is a novel preclinical drug candidate for the treatment of tuberculosis with a new mode of action potentially able to contribute to the shortening of TB chemotherapy.
The Effect of Cryo-auriculotherapy on Post-Operative Pain Management following Rotator Cuff Surgery: A Randomized, Placebo-Controlled Study
Authors: Chelly Jacques E. , Orebaugh Steven L. , Rodosky Mark W. , Groff Yram J. , Norton Brittany E. , Monroe Amy L. , Alimi David , Sadhasivam Senthilkumar K. , Vogt Keith M.
Published: February 2022

Background

In the context of the current opioid crisis, there is a growing interest in evaluating non-pharmacological solutions to manage post-operative pain. Evidence supports the concept that auriculotherapy may provide significant analgesia

Objective

Investigating the efficacy of cryo-auriculotherapy to reduce postoperative opioid consumption following a rotator cuff surgery.

Settings

Academic medical center, USA

Methods

This trial was registered to Clinicaltrials.gov (NCT03860259). A total of 39 subjects undergoing rotator cuff surgery and randomized to receive either an active cryo-auriculotherapy treatment (Auriculotherapy; n=20) or a placebo treatment (placebo; n=19) were included in the analysis. For each cryo-auriculotherapy subject, the treatment was performed in the recovery room. The primary endpoint was overall opioid consumption (oral morphine equivalent = OME). Secondary endpoints included pain and overall non-narcotic analgesic consumption on postoperative day 5, patient satisfaction and function recovery using the 12-Item Short Form Health Survey (SF-12), time to discharge from the recovery room and the hospital and patient satisfaction, as well as the number of subjects from each group readmitted because of pain-related issues.

Results

The use of cryo-auriculotherapy was associated with a 35% decrease in total opioid requirement over the first five-day recovery period and a 15% decrease in pain with movement. Pain with movement in the auriculotherapy group remained lower compared to the placebo group for at least 14 days (4.47 ± 2.12 vs 5.84 ± 2.39, respectively; p=0.0394).

Conclusions

Our data suggests that cryo-auriculotherapy represents an alternative to opioids in patients undergoing rotator-cuff surgery.