bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction
Authors: Maestri Evan , Duszka Kalina , Kuznetsov Vladimir A
Published: March 2021

Systematic analysis of calorie restriction (CR) mechanisms and pathways in cancer biology has not been carried out, leaving therapeutic benefits unclear. Using a systems biology approach and metadata analysis, we studied gene expression changes in the response of normal mouse duodenum mucosa (DM) to short-term (2-weeks) 25% CR as a biological model. We found a high similarity of gene expression profiles in human and mouse DM tissues. Surprisingly, 26% of the 467 CR responding differential expressed genes (DEGs) in mice consist of cancer-associated genes—most never studied in CR contexts. The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways (MRP) that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest a misbalance in telomere maintenance and activation of metabolic pathways playing dual (anti-cancer and pro-oncogenic) roles. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor immune evasion controls. Thus, CR induces MRP suppressing multiple immune mechanics and activating oncogenic pathways, potentially driving pre-malignant and cancer states. These findings change the paradigm regarding the anti-cancer role of CR and may initiate specific treatment target development.
Probable omnigenic effect and evolutionary insights of aerobic adaptation allele OsNCED2Ton qDTY12.1 effecting grain yield under reproductive stage drought stress in rice
Authors: Parameswaran C , Cayalvizhi B , Sanghamitra S , Anandan N , Lal K Jawahar , Devanna BN , Awadhesh K , Kishor J , Bandita S , Niranjana B , Biswaranjan B
Published: March 2021

Yield associated quantitative trait loci (qDTY) under drought stress provides significant advantage for grain yield in rice. The major, stable qDTY12.1 was identified in a mapping population developed from upland cultivars Vandana and Way Rarem. Further, introgression line comprising of qDTY12.1 genomic region was characterized to have multiple genes (NAM, DECUSSATE) regulating the drought tolerance under severe drought stress substantiated through recently proposed omnigenic model for complex traits. Recently, plastid localized NCED2Tallele present within the qDTY12.1 genomic region was characterized for conferring aerobic adaptation in lowland varieties. Since, NCED2Tis evolutionary fixed in upland cultivars and Vandana was found to have the favorable allele of NCED2T, we hypothesized that this favorable allele might confer omnigenic effect on qDTY12.1 genes. Our evolutionary analysis using non synonymous SNPs present in genes namely NCED, NAM, and DECUSSATE and qDTY12.1 genomic regions showed specific grouping of Vandana with upland cultivars only for NCED gene and its adjoining genomic regions. However, non synonymous SNPs in NAM and DECUSSATE genes and its adjoining genomic regions of drought tolerant varieties were closely related and grouped together in the phylogenetic analysis. Moreover, ecotype specific differentiation and greater nucleotide difference with wild relatives was also observed for DECUSSATE gene in rice. This finding indicates differential evolution of qDTY12.1 regions for upland and drought tolerance and omnigenic effect of NCED2Tgene in qDTY12.1. Further, we propose a breeding model for enhancing genetic gain for yield under severe drought stress by incorporation of NCEDT, qDTY12.1 and other drought tolerant QTLs for membrane stability in rice.
Single-Cell Spatial Proteomics Analyses of Head and Neck Squamous Cell Carcinoma Reveal Tumor Heterogeneity and Immune Architectures Associated with Clinical Outcome
Authors: Blise Katie E. , Sivagnanam Shamilene , Banik Grace L. , Coussens Lisa M. , Goecks Jeremy
Published: March 2021

There is increasing evidence that the spatial organization of cells within the tumor-immune microenvironment (TiME) of solid tumors influences survival and response to therapy in numerous cancer types. Here, we report results and demonstrate the applicability of quantitative single-cell spatial proteomics analyses in the TiME of primary and recurrent human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) tumors. Single-cell compositions of a nine patient, primary and recurrent (n=18), HNSCC cohort is presented, followed by deeper investigation into the spatial architecture of the TiME and its relationship with clinical variables and progression free survival (PFS). Multiple spatial algorithms were used to quantify the spatial landscapes of immune cells within TiMEs and demonstrate that neoplastic tumor-immune cell spatial compartmentalization, rather than mixing, is associated with longer PFS. Mesenchymal (αSMA+) cellular neighborhoods describe distinct immune landscapes associated with neoplastic tumor-immune compartmentalization and improved patient outcomes. Results from this investigation are concordant with studies in other tumor types, suggesting that trends in TiME cellular heterogeneity and spatial organization may be shared across cancers and may provide prognostic value in multiple cancer types.
Female fruitflies use gustatory cues to exhibit reproductive plasticity in response to the social environment
Authors: Fowler E.K. , Leigh S. , Rostant W.G. , Thomas A. , Bretman A. , Chapman T.
Published: March 2021

Animals can exhibit remarkable reproductive plasticity in response to their social surroundings, with profound fitness consequences. The study of such plasticity in females, particularly in same-sex interactions, has been severely neglected. Here we measured the impact of variation in the pre-mating social environment on reproductive success in females and tested the underlying mechanisms involved. We used theDrosophila melanogastermodel system to test the effect of varying female group size prior to mating and deployed physical and genetic methods to manipulate the perception of different social cues and sensory pathways. We found that socially isolated females were significantly more likely to retain unfertilised eggs before mating, but to show the opposite pattern and lay significantly more fertilised eggs in the 24h after mating, in comparison to grouped females. More than 48h of exposure to other females was necessary for this socially-induced plasticity to be expressed. Neither olfactory nor visual cues were involved in mediating these responses. Instead, we found that females detected other females through direct contact with the deposits they leave behind, even in the absence of eggs. The results demonstrate that females show striking reproductive plasticity in response to their social surroundings and that the nature of their plastic reproductive responses, and the cues they use, differ markedly from those of males. The results emphasise the stark contrasts in how each sex realises reproductive success.
The Genetic Basis of Differential Autodiploidization in Evolving Yeast Populations
Authors: Tung Sudipta , Bakerlee Christopher W. , Phillips Angela M. , Nguyen Ba Alex N. , Desai Michael M.
Published: March 2021

Spontaneous whole-genome duplication, or autodiploidization, is a common route to adaptation in experimental evolution of haploid budding yeast populations. The rate at which autodiploids fix in these populations appears to vary across strain backgrounds, but the genetic basis of these differences remains poorly characterized. Here we show that the frequency of autodiploidization differs dramatically between two closely related laboratory strains ofSaccharomyces cerevisiae, BY4741 and W303. To investigate the genetic basis of this difference, we crossed these strains to generate hundreds of unique F1 segregants and tested the tendency of each segregant to autodiplodize across hundreds of generations of laboratory evolution. We find that variants in theSSD1gene are the primary genetic determinant of differences in autodiploidization. We then used multiple laboratory and wild strains ofS. cerevisiaeto show that clonal populations of strains with a functional copy ofSSD1autodiploidize more frequently in evolution experiments, while knocking out this gene or replacing it with the W303 allele reduces autodiploidization propensity across all genetic backgrounds tested. These results suggest a potential strategy for modifying rates of spontaneous whole-genome duplications in laboratory evolution experiments in haploid budding yeast. They may also have relevance to other settings in which eukaryotic genome stability plays an important role, such as biomanufacturing and the treatment of pathogenic fungal diseases and cancers.
Alphaproteobacteria facilitateTrichodesmiumcommunity trimethylamine utilization
Authors: Conover Asa E. , Morando Michael , Zhao Yiming , Semones Jacob , Hutchins David A. , Webb Eric A.
Published: March 2021

In the surface waters of the warm oligotrophic ocean, filaments and aggregated colonies of the nitrogen (N)-fixing cyanobacteriumTrichodesmiumcreate microscale nutrient-rich oases. These hotspots fuel primary productivity and harbor a diverse consortium of heterotrophs. Interactions with associated microbiota can affect the physiology ofTrichodesmium, often in ways that have been predicted to support its growth. Recently, it was found that trimethylamine (TMA), a globally-abundant organic N compound, inhibits N2fixation in cultures ofTrichodesmiumwithout impairing growth rate, suggesting thatTrichodesmiumreceives nitrogen from TMA. In this study,15N-TMA DNA stable isotope probing (SIP) of aTrichodesmiumenrichment was employed to further investigate TMA metabolism and determine if TMA-N is incorporated directly or secondarily via cross-feeding facilitated by microbial associates. Herein we identify two members of the marineRoseobacterclade (MRC) of Alphaproteobacteria as the likely metabolizers of TMA and provide genomic evidence that they converted TMA into a more readily available form of N, e.g., NH4+, which was subsequently used byTrichodesmiumand the rest of the community. The results implicate microbiome-mediated carbon (C) and N transformations in modulating N2fixation, and thus highlight the involvement of host-associated heterotrophs in global biogeochemical cycling.
Human primary visual cortex shows larger population receptive fields for binocular disparity-defined stimuli
Authors: Alvarez Ivan , Hurley Samuel A. , Parker Andrew J. , Bridge Holly
Published: March 2021

1

The visual perception of 3D depth is underpinned by the brain’s ability to combine signals from the left and right eyes to produce a neural representation of binocular disparity for perception and behavior. Electrophysiological studies of binocular disparity over the past two decades have investigated the computational role of neurons in area V1 for binocular combination, while more recent neuroimaging investigations have focused on identifying specific roles for different extrastriate visual areas in depth perception. Here we investigate the population receptive field properties of neural responses to binocular information in striate and extrastriate cortical visual areas using ultra-high field fMRI. We measured BOLD fMRI responses while participants viewed retinotopic-mapping stimuli defined by different visual properties: contrast, luminance, motion, correlated and anti-correlated stereoscopic disparity. By fitting each condition with a population receptive field model, we compared quantitatively the size of the population receptive field for disparity-specific stimulation. We found larger population receptive fields for disparity compared with contrast and luminance in area V1, the first stage of binocular combination, which likely reflects the binocular integration zone, an interpretation supported by modelling of the binocular energy model. A similar pattern was found in region LOC, where it may reflect the role of disparity as a cue for 3D shape. These findings provide insight into the binocular receptive field properties underlying processing for human stereoscopic vision.
Winter rye cover cropping changes squash (Cucurbita pepo) phyllosphere microbiota and reduces Pseudomonas syringae symptoms
Authors: Maglione Rémi , Ciotola Marie , Cadieux Mélanie , Toussaint Vicky , Laforest Martin , Kembel Steven W.
Published: March 2021

Cover cropping is a soil conservation practice that may reduce the impacts of the economically important pathogen Pseudomonas syringae on crops including squash (Cucurbita pepo). To date, no studies have directly quantified the effect of rye cover crops on P. syringae populations, nor on the bacterial community of squash leaves. In this work, we tested the hypothesis that the protective effects of cover cropping on squash may be mediated by cover cropping effects on the plant’s microbiota that in turn protects against P. syringae. Using combined 16S sequencing and culture-based approaches, we showed that rye cover cropping protects squash against P. syringae, by decreasing pathogen population size on squash leaves and increasing fruit health and marketability at harvest. We also found evidence of a strong effect of rye cover crops on bacterial communities of the squash phyllosphere. Those findings were more striking early in the growing season. Finally, we identified numerous phyllosphere bacteria belonging to the genera Sphingomonas, Methylobacterium and Pseudomonas that were promoted by rye cover crops. Overall, our findings suggest cover cropping is effective for the sustainable management of P. syringae on squash and may provide a reservoir of potential microbial biocontrol agents colonizing the phyllosphere.
Single-trial-based Temporal Principal Component Analysis on Extracting Event-related Potentials of Interest for an Individual Subject
Authors: Zhang Guanghui , Li Xueyan , Lu Yingzhi , Tiihonen Timo , Chang Zheng , Cong Fengyu
Published: March 2021

Temporal principal component analysis (t-PCA) has been widely used to extract event-related potentials (ERPs) at the group level of multiple subjects’ ERP data. The t-PCA is, however, poorly employed to isolate ERPs from single-trial data of an individual subject. Additionally, the effects of varied trial numbers on the yields of t-PCA have not been systematically examined. To fill both gaps, in an emotional experiment (22 subjects), we use t-PCA and Promax rotation to extract interesting P2/N2 from single-trial data of each subject with consecutive increasingly trial numbers (from 10 to 42) and all trials, respectively. Besides, time-domain analysis and other two group t-PCA strategies (trial-averaged and single-trial) are also employed to isolate ERPs of interest from all subjects. The results indicate that the proposed technique produces the internal consistent measure of N2 from few trials (i.e., 19) as from all trials compared with the other three approaches (more than 30 trials). As for P2, all approaches yield internal-subject consistent effect after approximately 33 trials are included in the average, but Cronbach’s alpha values for the proposed technique are higher than the other two group PCA strategies over varied trials. Combined, the yields provide evidence that the proposed approach may efficiently temporally filter the data to extract more reliable and stable ERPs for an individual subject.
Release, rescue and recycling: termination of translation in mammalian mitochondria
Authors: Kummer Eva , Schubert Katharina Noel , Schönhut Tanja , Scaiola Alain , Ban Nenad
Published: March 2021

The mitochondrial translation system originates from a bacterial ancestor but has substantially diverged in the course of evolution. Here, we use single particle cryo-EM as a screening tool to identify mitochondrial translation termination mechanisms and to describe them in molecular detail. We show how mitochondria release factor 1a releases the nascent chain from the ribosome when it encounters the canonical stop codons UAA and UAG. Furthermore, we define how the peptidyl-tRNA hydrolase ICT1 acts as a rescue factor on mitoribosomes that have stalled on truncated messages to recover them for protein synthesis. Finally, we present near-atomic models detailing the process of mitochondrial ribosome recycling, to explain how a dedicated elongation factor, mtEFG2, has specialized for cooperation with the mitochondrial ribosome recycling factor to dissociate the mitoribosomal subunits at the end of the translation process. (134 words)
Natural spring water gargle and direct RT-PCR for the diagnosis of COVID-19 (COVID-SPRING study)
Authors: Dumaresq Jeannot , Coutlée François , Dufresne Philippe J. , Longtin Jean , Fafard Judith , Bestman-Smith Julie , Bergevin Marco , Vallières Emilie , Desforges Marc , Labbé Annie-Claude
Published: March 2021

We prospectively compared natural spring water gargle to combined oro-nasopharyngeal swab (ONPS) for the diagnosis of coronavirus disease 2019 (COVID-19) in paired clinical specimens (1005 ONPS and 1005 gargles) collected from 987 unique early symptomatic as well as asymptomatic individuals from the community. Using a direct RT-PCR method with the Allplex™ 2019-nCoV Assay (Seegene), the clinical sensitivity of the gargle was 95.3% (95% confidence interval [CI], 90.2 to 98.3%) and was similar to the sensitivity of the ONPS (93.8%; 95% CI, 88.2 to 97.3%), despite significantly lower viral RNA concentration in gargles, as reflected by higher cycle threshold values. No single specimen type detected all COVID-19 cases. SARS-CoV-2 RNA was stable in gargles at room temperature for at least 7 days. The simplicity of this sampling method coupled with the accessibility of spring water are clear advantages in a pandemic situation where testing frequency, turnaround time and shortage of consumables and trained staff are critical elements.
A survey of current anticoagulation patient education practices and development
Authors: Jones Aubrey E. , Saunders John , Vazquez Sara , Fagerlin Angela , Witt Daniel M.
Published: March 2021

Introduction

Anticoagulants are high-risk medications widely used to prevent and treat thrombotic events, resulting in a need for adequate patient education to minimize harm. While anticoagulant patient education interventions can improve knowledge and surrogate outcomes, they may not represent current practice. Our objective was to determine provider perceptions of anticoagulation patient education at their institution.

Methods

A quantitative survey was distributed through a national professional organization and across several health systems. Questions included educational delivery methods, perceived effectiveness, evaluation of patient knowledge, development of patient education, and demographics.

Results

The 61 survey respondents were 79.0% female, 86.2% white, and an average age of 43. Most respondents (95%) complete patient education interventions in one session. Providers reviewed educational topics in 37% of daily patient interactions. 59% of respondents reported reasons for not performing patient knowledge checks included no formal process requiring knowledge checks, lack of time, and forgetting. The majority (93.4%) reported their patient education process was somewhat or very effective. The main reason underlying perceived less effective patient education was too much information in one session. Thirty-four respondents had some knowledge of patient education development at their institution. Most of these (82.9%) indicated their educational process’s development relied on expert opinion. In comparison, 22.9% indicated utilizing user-based design, and 10 (28.9%) respondents used learning theories.

Conclusion

While most providers felt patient education was effective, they reported reviewing education with patients daily. The lack of formal knowledge checks and best practices in developing patient education tools are significant gaps to address.
Reducing the Cost of Rapid Antigen Tests through Swab Pooling and Extraction in a Device
Authors: Berking Tim , Lorenz Sabrina G. , Ulrich Alexander , Greiner Joachim , Richert Clemens
Published: March 2021

The COVID-19 pandemic places a significant stress on the viral testing capabilities of many countries. The value of rapid point-of-care (PoC) antigen tests is becoming increasingly clear, but implementing frequent large scale testing is costly. We have developed an inexpensive device for pooling swabs, extracting specimens, and detecting viral antigens with a commercial lateral flow assay detecting the nucleocapsid protein of SARS-CoV-2 as antigen. The holder of the device can be produced locally through 3D printing. The extraction and the elution can be performed with the entire set-up encapsulated in a transparent bag, minimizing the risk of infection for the operator. With 6 swabs holding approx. 0.1 mL specimen each and 0.35 mL extraction buffer, 43±6 % (n= 8) of the signal for an individual extraction of a positive control standard was obtained. Image analysis still showed a signal-to-noise ratio of ≥ 7 upon further eight-fold dilution. Our current total cost of materials is below $ 2 per tested person or 20% of our cost for an individual PoC test. These findings suggest that pooling can make frequent testing more affordable for schools, universities and other institutions, without decreasing sensitivity to an unacceptable level. Further validation of the method is required.
Magnesium Treatment on Methylation Changes of Transmembrane Serine Protease 2 (TMPRSS2)
Authors: Fan Lei , Zhu Xiangzhu , Zheng Yinan , Zhang Wei , Seidner Douglas L , Ness Reid , Murff Harvey J , Yu Chang , Huang Xiang , Shrubsole Martha J , Hou Lifang , Dai Qi
Published: March 2021

Background

The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike (S) protein priming.

Objectives

To test the hypothesis that Mg treatment leads to DNA methylation changes in TMPRSS2.

Methods

This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized.

Results

We found that 12-week of personalized Mg treatment significantly increased 5-mC methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to placebo arm (decreased by 0.1%) in those aged < 65 years old. The difference remained statistically significant after adjusting for age, sex and baseline methylation as well as FDR correction (FDR-adjusted P =0.014). Additionally, Mg treatment significantly reduced 5-hmC level at cg26337277 (close proximity to TSS200 and 5’UTR, promoter) by 2.3% compared to increases by 7.1% in the placebo arm after adjusting for covariates in those aged < 65 years old (P=0.003). The effect remained significant at FDR of 0.10 (adjusted P value=0.088).

Conclusion

Among individuals aged younger than 65 years with the Ca:Mg intake ratios equal to or over 2.6, reducing Ca:Mg ratios to around 2.3 increased 5-mC modifications (i.e. cg16371860) and reduced 5-hmC modifications (i.e. cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention for the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.
Immunodominant B cell epitope in a hotspot mutation site and mechanism of immune escape for SARS-CoV-2
Authors: Oliveira Jamille Ramos , Machado Rafael Rahal G. , Arcuri Helen Andrade , Magawa Jhosiene Yukari , Daher Isabela Pazotti , Urbanski Alysson Henrique , Händel Schmitz Gabriela Justamante , Silva Roberto Carlos Vieira , Durigon Edison Luiz , Boscardin Silvia Beatriz , Rosa Daniela Santoro , Schechtman Deborah , Nakaya Helder I , Cunha-Neto Edecio , Gadermaier Gabriele , Coelho Verônica , Santos Keity Souza , Kalil Jorge
Published: March 2021

Recent SARS-CoV-2 variants pose important concerns due to their higher transmissibility (1) and escape (2) from previous infections or vaccine-induced neutralizing antibodies (nAb). The receptor binding domain (RBD) of the Spike protein is a major nAb target (3), but data on its B cell epitopes are still lacking. Using a peptide microarray, we identified an immunodominant epitope (S415-429) recognized by 68% of sera from 71 convalescent Brazilians infected with the ancestral variant. In contrast with previous studies, we have identified a linear IgG and IgA antibody binding epitope within the RBD. IgG and IgA antibody levels for this epitope positively correlated with nAb titers, suggesting a potential target of antibody neutralizing activity. Interestingly, this immunodominant RBD region harbors the mutation hotspot site K417 present in P.1 (K417T) and B.1.351 (K417N) variants. In silico simulation analyses indicate impaired RBD binding to nAb in both variants and that a glycosylation in the B.1.351 417N could further hinder antibody binding as compared to the K417T mutation in P.1. This is in line with published data showing that nAb from either convalescents or anti-CoV-2 vaccinees are less effective towards B.1.351 than for P.1. Our data support the occurrence of immune pressure and selection involving this immunodominant epitope that may have critically contributed to the recent COVID-19 marked rise in Brazil and South Africa, and pinpoint a potential additional immune escape mechanism for SARS-CoV-2.
The Use/Abuse of Oral Contraceptive Pills Among Males: A Mixed-Method Explanatory Sequential Study Over Jordanian Community Pharmacists
Authors: Barakat Muna M. , Al-Qudah Raja’a A. , Akour Amal , Abu-Asal Mona , Thiab Samar , Dallal Bashi Yahya H.
Published: March 2021

Background

Oral contraceptive pills (OCPs) are considered one of the most important birth control methods in the world. However, these pills were designed for female administration rather than males. This study was designed to investigate patterns of OCPs use and abuse among Jordanian males, according to the community pharmacists’ observations.

Method

A mixed-method explanatory sequential study was conducted using an online self - administered survey and semi-structured in-depth interviews for community pharmacists. The interviews were utilized using a conceptual framework. Inductive thematic analysis and descriptive/regression analyses were completed using Nvivo and SPSS, respectively.

Results

A total of 158 questionnaire responses and 22 interviews were included in our analysis. Around half (48.4%) of the questionnaire responses confirmed that males could use OCPs for hair growth enhancement, muscle gain and acne treatment 12.7%, 31.7% and 4.4%, respectively. Through the interviews, the majority of the pharmacists highlighted that most of the males use OCPs for bodybuilding purposes, according to recommendations by their coaches at the gym. The most abused OCPs containing estrogen (Ethinyl estradiol) and progestins (Drospirenone or Levonorgestrel).

Conclusion

This study provided insight into unexpected uses of OCPs by males in Jordan. Community pharmacists have a crucial role in the management of OCPs use and abuse, However, restricted regulations and monitoring must be released and implemented on the community to limit such practices.
Population Impact and Efficiency of Improvements to HIV PrEP Under Conditions of High ART Coverage among San Francisco Men Who Have Sex with Men
Authors: Le Guillou Adrien , Buchbinder Susan , Scott Hyman , Liu Albert , Havlir Diane , Scheer Susan , Jenness Samuel M.
Published: March 2021

Background

Key components of Ending the HIV Epidemic (EHE) plan include increasing HIV antiretroviral therapy (ART) and HIV preexposure prophylaxis (PrEP) coverage. One complication to addressing this service delivery challenge is the wide heterogeneity of HIV burden and healthcare access across the U.S. It is unclear how the effectiveness and efficiency of expanded PrEP will depend on different baseline ART coverage.

Methods

We used a network-based model of HIV transmission for men who have sex with men (MSM) in San Francisco. Model scenarios increased varying levels of PrEP coverage relative under current empirical levels of baseline ART coverage and two counterfactual levels. We assessed the effectiveness of PrEP with the cumulative percent of infections averted (PIA) over the next decade and efficiency with the number needed to treat (NNT) by PrEP required to avert one HIV infection.

Results

In our projections, only the highest levels of combined PrEP and ART coverage achieved the EHE goals. Increasing PrEP coverage up to 75% showed that PrEP effectiveness was higher at higher baseline ART coverage with the PIA ranging from 61% in the lowest baseline ART coverage population to 75% in the highest ART coverage. The efficiency declined with increasing ART (NNT range from 41 to 113).

Conclusions

Improving both PrEP and ART coverage would have a synergistic impact on HIV prevention even in a high baseline coverage city like San Francisco. Efforts should focus on narrowing the implementation gaps to achieve higher levels of PrEP retention and ART sustained viral suppression.
An international comparison of age and sex dependency of COVID-19 Deaths in 2020 - a descriptive analysis
Authors: Bauer Peter , Brugger Jonas , König Franz , Posch Martin
Published: March 2021

COVID-19 mortality, the number of reported COVID-19 deaths per 100,000 persons observed so far, is described in 15 European countries and the USA depending on age groups and sex for the full year 2020. It is contrasted to the corresponding historic all-cause mortality per year depending on age and sex observed in these countries. Although there are substantial differences in the age and sex dependency of COVID-19 mortality between countries, there are some common features: Exponential increase with age is a good model to describe and analyse both COVID-19 and all-cause mortality above an age of 40 years, where almost all COVID-19 death occur. Age dependency is stronger for COVID-19 mortality than for all-cause mortality, males have an excess risk compared to women which flattens off with increasing age. Also with regard to calendar time, there were differences in the age and sex dependency between countries with the common tendency that male excess risk of COVID-19 mortality was smaller in the second half of the year.
mTOR-activating mutations inRRAGDcause kidney tubulopathy and cardiomyopathy (KICA) syndrome
Authors: Schlingmann Karl P. , Jouret François , Shen Kuang , Nigam Anukrati , Arjona Francisco J. , Dafinger Claudia , Houillier Pascal , Jones Deborah P. , Kleinerüschkamp Felix , Oh Jun , Godefroid Nathalie , Eltan Mehmet , Güran Tülay , Burtey Stéphane , Parotte Marie-Christine , König Jens , Braun Alina , Bos Caro , Serra Maria Ibars , Rehmann Holger , Zwartkruis Fried J.T. , Renkema Kirsten Y. , Klingel Karin , Schulze-Bahr Eric , Schermer Bernhard , Bergmann Carsten , Altmüller Janine , Thiele Holger , Beck Bodo B. , Dahan Karin , Sabatini David , Liebau Max C. , Vargas-Poussou Rosa , Knoers Nine V.A.M. , Konrad Martin , Baaij Jeroen H.F. de
Published: March 2021

Background

Over the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, ±20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM).

Methods

Whole exome and genome sequencings were performed with various subsequent functional analyses of identifiedRRAGDvariants in vitro.

Results

In 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants inRRAGDthat mostly occurredde novo. Six of these patients additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant inRRAGDwas simultaneously identified in eight members of a large family with a similar renal phenotype.RRAGDencodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identifiedRRAGDvariants were shown to induce a constitutive activation of mTOR signalingin vitro,

Conclusions

Our findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

SIGNIFICANCE STATEMENT

Here, we report on heterozygous variants inRRAGDin patients with profound hypomagnesemia, renal salt wasting, nephrocalcinosis, and dilated cardiomyopathy. The identified RagD variants induce a constitutive activation of mTOR signalingin vitro. These findings not only establish a novel monogenic disorder of the kidney tubule, but demonstrate the essential role of mTOR signaling for distal tubular electrolyte handling and cardiac function.
From synaptic activity to human in vivo quantification of neurotransmitter dynamics: a neural modelling approach
Authors: Lea-Carnall Caroline A. , El-Deredy Wael , Williams Stephen R. , Stagg Charlotte J. , Trujillo-Barreto Nelson J.
Published: March 2021

Understanding the role of neurotransmitters glutamate and GABA during normal and abnormal brain function and under external stimulation in humans are critical neuroscientific and clinical goals. The recent development of functional 1H-Magnetic resonance spectroscopy (fMRS) has allowed us to study neuro-transmitter activityin vivofor the first time. However, the physiological basis of the observed fMRS signal remains unclear. It has been proposed that fMRS detects shifts in metabolite concentrations as they move from presynaptic vesicles, where they are largely invisible, to extracellular and cytosolic pools, where they are visible.

Here we bridge the gap between neural dynamics and fMRS by developing a mean-field model to link the neurotransmitter dynamics at the microscopic-level to the macroscopic-level imaging measurements. GABA and glutamate are described as cycling between three metabolic pools: in the vesicles; active in the cleft; or undergoing recycling in the astrocytic or neuronal cytosol. We interrogate the model by applying a current to manipulate the mean membrane potential and firing rate of the neural populations.

We find that by disregarding the contribution from the vesicular pool, our model predicts activity-dependent changes in the MRS signal, which are consistent with reported empirical findings. Further, we show that current magnitude and direction has a selective effect on the GABA/glutamate-MRS signal: inhibitory stimulation leads to reduction of both metabolites, whereas excitatory stimulation leads to increased glutamate and decreased GABA. In doing so, we link neural dynamics and fMRS and provide a mechanistic account for the activity-dependent change in the observed MRS signal.

Key Points Summary

The recent development of functional 1H-Magnetic resonance spectroscopy (fMRS) has allowed us to study neurotransmitter activityin vivofor the first time in humans. However, the physiological basis of the observed fMRS signal is unclear.

It has been proposed that fMRS detects shifts in metabolite concentrations as they move from presynaptic vesicles, where they are largely invisible to MRS, to extracellular and cytosolic pools, where they are visible to MRS.

We test this hypothesis using a mean field model which links the neural dynamics of neurotransmitters at the microscopic-level to the macroscopic-level imaging measurements obtained in experimental studies.

By disregarding activity in the vesicular pool, our model can generate activity-dependent changes in the MRS signal in response to stimulation which are consistent with experimental findings in the literature.

We provide a mechanistic account for the activity-dependent change in observed neurotransmitter concentrations using MRS.
Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment
Authors: Fjæstad Klaire Yixin , Askehøj Rømer Anne Mette , Goitea Victor , Johansen Astrid Zedlitz , Thorseth Marie-Louise , Carretta Marco , Engelholm Lars Henning , Grøntved Lars , Junker Niels , Hargbøl Madsen Daniel
Published: March 2021

The nonselective beta blocker, propranolol, which for decades has been prescribed for treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis.

Here, we have investigated the anti-angiogenic properties of propranolol in the context of stimulating an anti-tumor immune response. We show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma tumors and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol-treatment leads to an upregulation of PD-L1 on tumor-associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy.

Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.
Bacterial filamentation drives colony chirality
Authors: Aranda-Díaz Andrés , Rodrigues Cecilia , Grote Alexandra , Sun Jiawei , Schreck Carl , Hallatschek Oskar , Souslov Anton , Möbius Wolfram , Huang Kerwyn Casey
Published: March 2021

Chirality is ubiquitous in nature, with consequences at the cellular and tissue scales. AsEscherichia colicolonies expand radially, an orthogonal component of growth creates a pinwheel-like pattern that can be revealed by fluorescent markers. To elucidate the mechanistic basis of this colony chirality, we investigated its link to left-handed, single-cell twisting duringE. colielongation. While chemical and genetic manipulation of cell width altered single-cell twisting handedness, colonies ceased to be chiral rather than switching handedness, and anaerobic growth altered colony chirality without affecting single-cell twisting. Chiral angle increased with increasing temperature even when growth rate decreased. Unifying these findings, we discovered that colony chirality was associated with the propensity for cell filamentation. Inhibition of cell division accentuated chirality under aerobic growth and generated chirality under anaerobic growth. Thus, regulation of cell division is intrinsically coupled to colony chirality, providing a mechanism for tuning macroscale spatial patterning.
Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model
Authors: Doan Thanh N. , McKinney Jay M. , Pucha Krishna A , Bernard Fabrice C. , Willett Nick J.
Published: March 2021

Osteoarthritis is a degenerative disease of synovial joints affecting all tissues, including the articular cartilage and underlying subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are commonly used to test the development of drugs, biomaterials, and cell therapies for treatment. The rat medial meniscus transection (MMT) model is a surgically induced post-traumatic osteoarthritis model and is one of the most commonly used models for therapeutic development; however, it is typically used to evaluate the efficacy of therapies to prevent disease development rather than testing the treatment of disease progression in already established disease. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes in rats at early-(3-weeks post-surgery), mid-(6-weeks post-surgery) and late-(12-weeks post-surgery) stages of osteoarthritis progression. Tibiae of MMT-operated animals showed loss of proteoglycan and fibrillation formation on articular cartilage surfaces as early as 3-weeks post-surgery. Using a contrast-enhanced μCT technique, quantitative, 3-dimensional analysis of the tibiae showed that the articular cartilage initially thickened at 3- and 6-weeks post-surgery and then decreased at 12-weeks post-surgery. This decrease in cartilage thickness corresponded with increased lesions in the articular cartilage, including fully degraded surfaces down to the subchondral bone layer. In this rat MMT model, subchondral bone thickening was significant at 6-weeks post-surgery and seem to follow cartilage damage. Osteophytes were found at 3-weeks post-surgery, which coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization suggesting that these marginal tissue growths most likely occurred through endochondral ossification. The use of the rat MMT model has predominantly been used out to 3-weeks, and most studies determine the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6 and 12 weeks resembled more severe phenotypes of human osteoarthritis. The mid- to late-stages of rat MMT model can be used to evaluate the therapeutic efficacy of novel treatments to treat the progression of established disease — since patients typically present in the clinic when the disease is established and becomes symptomatic, thus evaluating the efficacy of new treatments at the late stage will be important for eventual clinical translation.
A single synonymous nucleotide change impacts the male-killing phenotype of prophage WO genewmk
Authors: Perlmutter Jessamyn I. , Meyers Jane E. , Bordenstein Seth R.
Published: March 2021

Wolbachiaare the most widespread bacterial endosymbionts in animals. Within arthropods, these maternally-transmitted bacteria can selfishly hijack host reproductive processes to increase the relative fitness of their transmitting females. One such form of reproductive parasitism called male killing, or the selective killing of infected males, is recapitulated to degrees by transgenic expression of theWO-mediated killing(wmk) gene. Here, we characterize the genotype-phenotype landscape ofwmk-induced male killing inD.melanogasterusing transgenic expression. While phylogenetically distantwmkhomologs induce no sex-ratio bias, closely-related homologs exhibit complex phenotypes spanning no death, male death, or death of all hosts. We demonstrate that alternative start codons, synonymous codons, and notably a single synonymous nucleotide inwmkcan ablate killing. These findings reveal previously unrecognized features of transgenicwmk-induced killing and establish new hypotheses for the impacts of post-transcriptional processes in male killing variation. We conclude that synonymous sequence changes are not necessarily silent in nested endosymbiotic interactions with life-or-death consequences.
kinesin recruitment by adapter SKIP on melanosomes is dynamically controlled by LC3B phosphorylation
Authors: Subramaniam Yogaspoorthi , Murthy Divya , Raja Desingu Ayyappa , Ramkumar Amrita , Sivasubbu Sridhar , McEwan David G , Gokhale Rajesh S , Natarajan Vivek T
Published: March 2021

Anterograde melanosome transport is essential for adaptive skin tanning response. However, the molecular components involved, their interplay and regulation by external cues in melanosome transport remain under-explored. Silencing of kinesin motors revealed that several members including the established KIF5B and a novel candidate KIF1B, mediate melanosome movement. The camouflage behaviour of zebrafish embryos induced by incident light or α -MSH requires kif1b, suggesting a conserved melanosome transport machinery across vertebrates. Interestingly, the peri-nuclear melanosome accumulation upon kinesin knockdown is recapitulated by the silencing of autophagy effector MAP1LC3B (LC3B). Pull-down assays identified KIF1B, but not KIF5B, to be the LC3B-associated kinesin. LC3B binds the adapter SKIP via its LIR docking region that is proximal to Thr12 residue, a site for phosphorylation by Protein Kinase A. We demonstrate that phosphorylation of LC3B at Thr12 is stimulated by α-MSH, which potentiates the anterograde melanosome transport. Thereby, our study, identifies a novel kinesin motor KIF1B for melanosome movement and establishes LC3B as the key molecular component that facilitates α-MSH responsive mobilization of melanosomes.

Key Highlights

Kinesin screen reveals non-redundant use of KIF5B, KIF1B motors for melanosome transport

kif1b is required for camouflage response in zebrafish and melanosome movement in mammals

N-terminal region of LC3B interacts with adapter SKIP and couples kinesin KIF1B

α-MSH activates PKA-mediated phosphorylation of LC3B to potentiate anterograde movement

Significance

Melanosomes are lysosome related organelles containing melanin pigment, that are synthesized in melanocytes and transferred to the recipient keratinocytes of skin. This involves long range melanosome movement within melanocytes to reach cell periphery for the transfer to follow. Physiologically, UV protection involves local secretion of melanocyte stimulating hormone (α-MSH) that acts on melanocytes to promote skin tanning response. Herein, we investigate the components involved in this process and establish that the melanosome movement is dynamically controlled byα-MSH through phosphorylation of LC3B. These findings establish the mechanism behind the rapid distribution of melanosomes during tanning response and provide opportunity to intervene for sun protection.
Deeplasmid: Deep learning accurately separates plasmids from bacterial chromosomes
Authors: Andreopoulos William B , Geller Alexander M , Lucke Miriam , Balewski Jan , Clum Alicia , Ivanova Natalia , Levy Asaf
Published: March 2021

Plasmids are mobile genetic elements that play a key role in microbial ecology and evolution by mediating horizontal transfer of important genes, such as antimicrobial resistance genes. Many microbial genomes have been sequenced by short read sequencers and have resulted in a mix of contigs that derive from plasmids or chromosomes. New tools that accurately identify plasmids are needed to elucidate new plasmid-borne genes of high biological importance. We have developed Deeplasmid, a deep learning tool for distinguishing plasmids from bacterial chromosomes based on the DNA sequence and its encoded biological data. It requires as input only assembled sequences generated by any sequencing platform and assembly algorithm and its runtime scales linearly with the number of assembled sequences. Deeplasmid achieves an AUC-ROC of over 93%, and it was much more precise than the state-of-the-art methods. Finally, as a proof of concept, we used Deeplasmid to predict new plasmids in the fish pathogenYersinia ruckeriATCC 29473 that has no annotated plasmids. Deeplasmid predicted with high reliability that a long assembled contig is part of a plasmid. Using long read sequencing we indeed validated the existence of a 102 Kbp long plasmid, demonstrating Deeplasmid’s ability to detect novel plasmids.

Availability

The software is available with a BSD license:deeplasmid.sourceforge.io. A Docker container is available on DockerHub under: billandreo/deeplasmid.

Contact

wandreopoulos@lbl.govalevy@mail.huji.ac.il