bluuebunny/crossref_metadata_2025 huggingface dataset:
Viability, task switching, and fall avoidance of the simplest dynamic walker
Authors: Patil Navendu S. , Dingwell Jonathan B. , Cusumano Joseph P.
Published: January 2022

Humans display great versatility when performing goal-directed tasks while walking. However, the extent to which such versatility helps with fall avoidance remains unclear. We recently demonstrated a functional connection between the motor regulation needed to achieve task goals (e.g. maintaining walking speed) and a simple walker’s ability to reject large disturbances. Here, for the same model, we identify the viability kernel—the state space region in which the walker can step forever via at least one sequence of push-off inputs per state. We further find that only a few basins of attraction of the speed-regulated walker’s steady-state gaits can fully cover the viability kernel. This highlights a potentially important role of task-level motor regulation in fall avoidance. Therefore, we posit an adaptive hierarchical control/regulation strategy that switches between different task-level regulators to avoid falls. Our hierarchical task switching controller only requires a target value of the regulated observable—a ‘task switch’—at each walking step, each chosen from a small, predetermined collection. Because humans have typically already learned to perform such tasks during nominal walking conditions, this suggests that the ‘information cost’ of biologically implementing such controllers for the nervous system, including cognitive demands in humans, could be relatively low.
Transcriptomic and functional genetic evidence for distinct ecophysiological responses across complex life cycle stages
Authors: Freda Philip J. , Toxopeus Jantina , Dowle Edwina J. , Ali Zainab M. , Heter Nicholas , Lambert-Collier Rebekah L. , Sower Isaiah , Tucker Joseph C. , Morgan Theodore J. , Ragland Gregory J.
Published: January 2022

Organisms with complex life cycles demonstrate a remarkable ability to change their phenotypes across development, presumably as an evolutionary adaptation to developmentally variable environments. Developmental variation in environmentally sensitive performance, and thermal sensitivity in particular, has been well documented in holometabolous insects. For example, thermal performance in adults and juvenile stages exhibit little genetic correlation (genetic decoupling) and can evolve independently, resulting in divergent thermal responses. Yet, we understand very little about how this genetic decoupling occurs. We tested the hypothesis that genetic decoupling of thermal physiology is driven by fundamental differences in physiology between life stages, despite a potentially conserved Cellular Stress Response. We used RNAseq to compare transcript expression in response to a cold stressor in Drosophila melanogaster larvae and adults and used RNAi (RNA interference) to test whether knocking down nine target genes differentially affected larval and adult cold tolerance. Transcriptomic responses of whole larvae and adults during and following exposure to -5°C were largely unique both in identity of responding transcripts and in temporal dynamics. Further, we found no relationship between stage-specificity and tissue-specificity of transcripts, suggesting that the differences are not simply driven by differences in tissue composition across development. In addition, RNAi of target genes resulted in largely stage-specific and sometimes sex-specific effects on cold tolerance. The combined evidence suggests that thermal physiology is largely stage-specific at the level of gene expression, and thus natural selection may be acting on different loci during the independent thermal adaptation of different life stages.

Summary Statement

RNAseq and gene knockout via transgenic RNAi lines suggest that physiological responses to low temperatures are largely distinct across life stages of the fly Drosophila melanogaster.
UbE3-APA: A Bioinformatic Strategy to Elucidate Ubiquitin E3 Ligase Activities in Quantitative Proteomics Study
Authors: Gong Yao , Chen Yue
Published: January 2022

Motivation

Ubiquitination is widely involved in protein homeostasis and cell signaling. Ubiquitin E3 ligases are critical regulators of ubiquitination that recognize and recruit specific ubiquitination targets for the final rate-limiting step of ubiquitin transfer reactions. Understanding the ubiquitin E3 ligase ac-tivities will provide knowledge in the upstream regulator of the ubiquitination pathway and reveal po-tential mechanisms in biological processes and disease progression. Recent advances in mass spec-trometry-based proteomics have enabled deep profiling of ubiquitylome in a quantitative manner. Yet, functional analysis of ubiquitylome dynamics and pathway activity remains challenging.

Results

Here, we developed a UbE3-APA, a computational algorithm and stand-alone python-based software for Ub E3 ligase Activity Profiling Analysis. Combining an integrated annotation database with statistical analysis, UbE3-APA identifies significantly activated or suppressed E3 ligases based on quantitative ubiquitylome proteomics datasets. Benchmarking the software with published quantitative ubiquitylome analysis confirms the genetic manipulation of SPOP enzyme activity through overexpres-sion and mutation. Application of the algorithm in the re-analysis of a large cohort of ubiquitination proteomics study revealed the activation of PARKIN and the co-activation of other E3 ligases in mito-chondria depolarization-induced mitophagy process. We further demonstrated the application of the algorithm in the DIA-based quantitative ubiquitylome analysis.

Availability

Source code and binaries are freely available for download at URL:https://github.com/Chenlab-UMN/Ub-E3-ligase-Activity-Profiling-Analysis, implemented in python and supported on Linux and MS Windows

Contact

yuechen@umn.edu

Supplementary information

Supplementary data are available.
Pain-related learning signals in the human insula
Authors: Horing Björn , Büchel Christian
Published: January 2022

Pain is not only a perceptual phenomenon, but also a preeminent learning signal. In reinforcement learning models, prediction errors (PEs) play a crucial role, i.e. the mismatch between expectation and sensory input. In particular, advanced learning models require the representation of different types of PEs, namely signed PEs (whether more or less pain was expected) to specify the direction of learning, and unsigned PEs (the absolute deviation from an expectation) to adapt the learning rate. The insula has been shown to play an important role in pain intensity coding and in signaling surprise. However, mainly unsigned PEs could be identified in the anterior insula. It remains an open question whether these PEs are specific to pain, and whether signed PEs are also represented in the insula.

To answer these questions, 47 subjects learned associations of two conditioned stimuli (CS) with four unconditioned stimuli (US; painful heat or loud sound, of one low and one high intensity each) while undergoing functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. CS-US associations reversed multiple times between intensities and between sensory modalities, generating frequent PEs.

SCRs indicated comparable nonspecific characteristics of the two modalities. fMRI analyses focusing on the insular and opercular cortices contralateral to painful stimulation showed that activation in the anterior insula correlated with unsigned intensity PEs. Importantly, this unsigned PE signal was similar for pain and aversive sounds and also modality PEs, indicating an unspecific aversive surprise signal. Conversely, signed pain intensity PE signals were modality-specific and located in the dorsal posterior insula, an area previously implicated in pain intensity processing.

Previous studies have identified abnormal insula function and abnormal learning as potential causes of pain chronification. Our findings link these results and suggest one potential mechanism, namely a misrepresentation of learning relevant prediction errors in the insular cortex.
The value of vaccine booster doses to mitigate the global impact of the Omicron SARS-CoV-2 variant
Authors: Hogan Alexandra B , Wu Sean L , Doohan Patrick , Watson Oliver J , Winskill Peter , Charles Giovanni , Barnsley Gregory , Riley Eleanor M , Khoury David S , Ferguson Neil M , Ghani Azra C
Published: January 2022

Vaccines have played a central role in mitigating severe disease and death from COVID-19 in the past 12 months. However, efficacy wanes over time and this loss of protection is being compounded by the emergence of the Omicron variant. By fitting an immunological model to population-level vaccine effectiveness data, we estimate that neutralizing antibody titres for Omicron are reduced by 3.9-fold (95% CrI 2.9–5.5) compared to the Delta variant. Under this model, we predict that 90 days after boosting with the Pfizer-BioNTech vaccine, efficacy against severe disease (admission to hospital) declines to 95.9% (95% CrI 95.4%–96.3%) against the Delta variant and 78.8% (95% CrI 75.0%–85.1%) against the Omicron variant. Integrating this immunological model within a model of SARS-CoV-2 transmission, we demonstrate that the size of the Omicron wave will depend on the degree of past exposure to infection across the population, with relatively small Omicron waves in countries that previously experienced a large Delta wave. We show that booster doses can have a major impact in mitigating the epidemic peak, although in many settings it remains possible that healthcare capacity could still be challenged. This is particularly the case in “zero-COVID” countries where there is little prior infection-induced immunity and therefore epidemic peaks will be higher. Where dose supply is limited, targeting boosters to the highest risk groups to ensure continued high protection in the face of waning immunity is of greater benefit than giving these doses as primary vaccination to younger age-groups. In many settings it is likely that health systems will be stretched, and it may therefore be necessary to maintain and/or reintroduce some level of NPIs to mitigate the worst impacts of the Omicron variant as it replaces the Delta variant.
Pharmaceutical Payments to Japanese Certificated Hematologists: A Retrospective Analysis of Personal Payments from Pharmaceutical Companies between 2016 and 2019
Authors: Kusumi Eiji , Murayama Anju , Kamamoto Sae , Kawashima Moe , Yoshida Makoto , Saito Hiroaki , Sawano Toyoaki , Yamashita Erika , Tanimoto Tetsuya , Ozaki Akihiko
Published: January 2022

Background

A growing and significant financial relationship exist between physicians and pharmaceutical companies. However, little is known about the characteristics and trends of personal payments from pharmaceutical companies to hematologists. This study was aimed to evaluate the financial relationship between hematology specialists and pharmaceutical companies in Japan between 2016 and 2019.

Methods

Descriptive analyses were performed to evaluate personal payments from 92 major pharmaceutical companies to all board-certificated hematologists in Japan. Furthermore, trend of payments over four years were evaluated by generalized estimating equations.

Results

Among the 4,183 hematology specialists, 2,706 (64.7%) received a total of US$36,291,434 (¥3,955,766,292). The personal payments were worth $13,411 (standard deviation: $34,856) on average, with a median of $2,471 (Interquartile range: $851 $9,677) over the four-year period, respectively. Only the top 10% of specialists accounted for 76.8% of the total payments. The average payment values constantly increased from $4,259 to $5,574 between 2016 and 2019, with a significant mean annual increase rate of 11.2% (95%CI: 9.1% 13.4%). The proportion of hematology specialists with payments also slightly increased by 1.8% (95%CI: 0.6% 3.0%) per year.

Conclusions

Most Japanese board-certified hematology specialists received substantial personal payments. These payments are becoming increasingly more prevalent and greater among hematology specialists.
PLWHA’s Perspective on Community Stigma for Getting Social Support and Improving Life Quality in the Digital Era
Authors: Erwansyah Rio Ady , Rumambo Pandin Moses Glorino
Published: January 2022

Community stigma against HIV/AIDS is still a problem that must be faced by people living with HIV/AIDS (PLWHA). The existence of stigmatization and discrimination received by PLWHA causes the lack of social support they get. Social support is very important for PLWHA to improve their quality of life. In this digital era where the development of technology and social media is an alternative for PLWHA to get social support online through their community, by sharing information and experiences. This systematic review was conducted through Scopus, Science Direct, ProQuest, and SAGE. The selection of articles followed inclusion criteria, including articles published in the last five years and published in English and discussing perspectives on stigma. Articles published not in English and articles with unclear literature reviews were excluded from this study. The PRISMA flow chart and JBI assessment checklist were used to assess the risk of bias and article quality. 20 relevant articles will be reviewed. The results of the study found that in this digital era PLWHA can take advantage of technological developments and social media to improve their quality of life by getting social support through the online communities they follow.
Genetic Susceptibility to Atrial Fibrillation Identified via Deep Learning of 12-lead Electrocardiograms
Authors: Wang Xin , Khurshid Shaan , Choi Seung Hoan , Friedman Sam , Weng Lu-Chen , Reeder Christopher , Pirruccello James P. , Singh Pulkit , Lau Emily S. , Venn Rachael , Diamant Nate , Achille Paolo Di , Philippakis Anthony , Anderson Christopher D. , Ho Jennifer E. , Ellinor Patrick T. , Batra Puneet , Lubitz Steven A.
Published: January 2022

Artificial intelligence (AI) models applied to 12-lead electrocardiogram (ECG) waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. We hypothesized that there may be a genetic basis for ECG-AI based risk estimates. We applied an ECG-AI model for predicting incident AF to ECGs from 39,986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk. We identified three signals (P<5×10−8) at established AF susceptibility loci marked by the sarcomeric gene TTN, and sodium channel genes SCN5A and SCN10A. We also identified two novel loci near the genes VGLL2 and EXT1. In contrast, a GWAS of risk estimates from a clinical variable model indicated a different genetic profile. Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel, and height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways.
COVID-19 breakthrough infection after inactivated vaccine induced robust antibody responses and cross-neutralization of SARS-CoV-2 variants, but less immunity against omicron
Authors: Suntronwong Nungruthai , Yorsaeng Ritthideach , Puenpa Jiratchaya , Auphimai Chompoonut , Thongmee Thanunrat , Vichaiwattana Preeyaporn , Kanokudom Sitthichai , Duangchinda Thaneeya , Chantima Warangkana , Pakchotanon Pattarakul , Assawakosri Suvichada , Nilyanimit Pornjarim , Klinfueng Sirapa , Wongsrisang Lakkhana , Srimuan Donchida , Thatsanatorn Thaksaporn , Sudhinaraset Natthinee , Wanlapakorn Nasamon , Poovorawan Yong
Published: January 2022

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the waning of immunity in vaccinated individuals is resulting in increased numbers of SARS-CoV-2 breakthrough infections. This study investigated binding antibody responses and neutralizing activities against SARS-CoV-2 variants in patients with COVID-19 who had been fully vaccinated with CoronaVac (n = 78), individuals who had been fully vaccinated with CoronaVac but had not contracted COVID-19 (n = 170), and individuals who had received AZD1222 as a third vaccination (n = 210). Breakthrough infection was generally detected approximately 88 days after the second CoronaVac vaccination (interquartile range 68–100) days. Blood samples were collected at median of 34 days after infection. Binding antibody levels in sera from patients with breakthrough infection were significantly higher than those in individuals who had received AZD1222 as a third vaccination. However, neutralizing activities against wild-type and variants including alpha (B.1.1.7), beta (B.1.351), and delta (B.1.617.2) were comparable in patients with breakthrough infections and individuals who received a third vaccination with AZD1222, which activities are exceeding 90%. Omicron (B.1.1.529) was neutralized less effectively by serum from breakthrough infection patients, with a 6.3-fold reduction compared to delta variants. The study suggests that breakthrough infection after two doses of an inactivated vaccine can induce neutralizing antibody against omicron. Further investigation is needed to assess the long-term persistence of antibody against omicron variant.
Outcomes after radioiodine treatment for thyrotoxicosis
Authors: Bolland Mark J , Croxson Michael S
Published: January 2022

Background

Radioiodine is commonly prescribed as a permanent treatment for thyrotoxicosis. At ADHB, Auckland, New Zealand, radioiodine dose is individualised by the prescribing physician according to patient characteristics.

Aims

We investigated the outcomes of this approach.

Methods

We identified all patients receiving radioiodine for thyrotoxicosis at ADHB in 2015 and retrieved relevant clinical details.

Results

222 patients were prescribed radioiodine: 147 (66%) for Graves’ disease, 58 (26%) for toxic nodular goitre, and 17 (8%) for solitary toxic nodule. For Graves’ disease, 80% had one radioiodine dose (first dose median 550 MBq, range 200-1000 MBq; total dose 200-2400 MBq), 92% had the thyrotoxicosis cured, and 83% required thyroxine post-radioiodine. For toxic nodular goitre, 93% had one dose (median 550 MBq, range 400-1000 MBq, total dose 400-1800 MBq), 93% were cured and 22% required thyroxine. For solitary toxic nodule, all had one dose (median 550 MBq, range 500-550 MBq), all were cured and 35% required thyroxine. In 69/222 (31%) patients (35% of individuals with Graves’ disease, 17% with toxic nodular goitre, and 47% with solitary toxic nodule), the most recent TSH (mean 3.2 years post-radioiodine) was elevated (30% TSH >10 mu/L, 70% TSH 4-10 mu/L).

Conclusions

Following radioiodine treatment, >90% of individuals have the thyrotoxicosis cured, but hypothyroidism is usual in Graves’ disease and occurs in 22-35% in toxic nodular goitre or solitary toxic nodule. Many individuals taking thyroxine after radioiodine have suboptimally controlled hypothyroidism.
CBioProfiler: a web and standalone pipeline for cancer biomarker and subtype characterization
Authors: Liu Xiaoping , Wang Zisong , Shi Hongjie , Li Sheng , Wang Xinghuan
Published: January 2022

Cancer is a leading cause of death worldwide, and the identification of biomarkers and subtypes that can predict the long-term survival of cancer patients is essential for their risk stratification, treatment, and prognosis. However, there are currently no standardized tools for exploring cancer biomarkers or subtypes. In this study, we introduce CBioProfiler, a web server and standalone application that includes two pipelines for analyzing cancer biomarkers and subtypes. The cancer biomarker pipeline consists of five modules for identifying and annotating cancer survival-related biomarkers using multiple machine learning survival algorithms. The subtype pipeline includes three modules for data preprocessing, subtype identification using multiple unsupervised machine learning methods, and subtype evaluation and validation. CBioProfiler also includes a novel R package, CuratedCancerPrognosisData, which has reviewed, curated, and integrated gene expression data and clinical data from 268 gene expression studies of 43 common blood and solid tumors, including data from 47,686 clinical samples. The web server is available athttps://www.cbioprofiler.com/andhttps://cbioprofiler.znhospital.cn/CBioProfiler/, and the standalone app and source code can be found athttps://github.com/liuxiaoping2020/CBioProfiler.
Polyfunctional IL-17A+ MAIT cells are expanded in the peripheral blood of patients with HLA-B27+ axial spondyloarthritis
Authors: Lefton Micah , Sharma Nihaarika , Patel Akash R. , Sparks Jeffrey A. , Ermann Joerg
Published: January 2022

Objectives

Studies in axial spondyloarthritis (axSpA) have yielded conflicting results regarding the identity of the major IL-17A-producing lymphocyte populations. The goal of this study was to comprehensively assess the production of IL-17A and related cytokines by peripheral blood lymphocytes in axSpA.

Methods

Peripheral blood mononuclear cells were isolated from patients with axSpA and healthy controls matched for age, sex and HLA-B27 status. Unstimulated cells and cells activated with PMA/Ionomycin were analyzed by 25-parameter fluorescent flow cytometry. Data were analyzed by hierarchical gating, UMAP and SPICE.

Results

Except for a reduced frequency of mucosal-associated invariant T (MAIT) cells and natural killer (NK) cells, there were no other significant differences in abundance of major lymphocyte populations in axSpA patients compared with controls. Increased IL-17A production in axSpA was observed in total non-B lymphocytes and in MAIT cells. The fraction of MAIT cells expressing the tissue residency markers CD69 and CD103 was increased in axSpA. CD103 positive MAIT cells were enriched for IL-17A producers. axSpA patients demonstrated an expansion of MAIT cell subsets producing IL-17A, IL-17F, GM-CSF and TNF. This expansion was only observed in HLA-B27+ patients.

Conclusions

We document an expansion of polyfunctional IL-17A+ MAIT cells in the peripheral blood of HLA-B27+ patients with axSpA. These results are consistent with the implied role of intestinal dysbiosis or inflammation in axSpA pathogenesis.

Key messages

What is already known about this subject?

Various IL-17A-producing lymphocyte populations have been implicated in the pathogenesis of axSpA.

What does this study add?

Polyfunctional MAIT cells capable of producing IL-17A, IL-17F, GM-CSF and TNF are expanded in the peripheral blood of HLA-B27+ patients with axSpA.

How might this impact on clinical practice or future developments?

Overproduction of IL-17A by MAIT cells is the most consistent finding of peripheral blood lymphocyte studies in axSpA.

Our data support the pathogenetic link between intestinal and axial inflammation in axSpA.
Impact of pre-breeding feeding practices on rabbit mammary gland development at mid-pregnancy
Authors: Hue-Beauvais C , Bébin K , Robert R , Gardan-Salmon D , Maupin M , Brun N , Aujean E , Jaffrezic F , Simon S , Charlier M , Le Provost F
Published: January 2022

Abstract

Optimizing rabbit does preparation during early life to improve reproductive potential is a major challenge for breeders. Does selected for reproduction have specific nutritional needs, which may not be supplied with the common practice of feed restriction during rearing in commercial rabbit production. Nutrition during early life was already known to influence metabolism, reproduction and mammary gland development later in life, in particular during pregnancy. The aim of this study was to analyze the impact of four different feeding strategies in the early life of rabbit females (combination of high or moderate feed restriction from 5 to 9 weeks of age with restricted or ad libitum feeding regime from 9 to 12 weeks of constituting the pubertal period) on their growth, reproductive capacities and mammary development at mid-pregnancy.

Unlike food intake, which remains regular, mean body weight gain was inversely proportional to the dietary restriction applied over the considered periods. The feeding strategies in place for the four groups had no effect on the reproductive parameters of the females at mid-pregnancy, as opposed to certain metabolic parameters such as cholesterolemia, that decreased with dietary intake at puberty (p≤0.05). Furthermore, restriction programs have impacted mammary tissular structures at mid-pregnancy. The expression of lipid metabolism enzymes (Fatty acid synthase N and Stearoyl co-A desaturase) is also increased in mammary epithelial tissue at mid-pregnancy by the dietary strategies implemented (p≤0.05). Moreover, milk gene expression, used as differentiation markers, indicates a better mammary epithelial development regarding further lactation, in the case of the less restrictive strategies during early life period, especially the higher feeding allowance. Our results highlight the importance of investigating feeding conditions of young female rabbits and nutrition in early life rearing, in order to provide specific recommendations for optimizing lactation and thus preventing neonatal mortality of the offspring.
Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice
Authors: Gargareta Vasiliki-Ilya , Reuschenbach Josefine , Siems Sophie B. , Sun Ting , Piepkorn Lars , Mangana Carolina , Späte Erik , Goebbels Sandra , Huitinga Inge , Möbius Wiebke , Nave Klaus-Armin , Jahn Olaf , Werner Hauke B.
Published: January 2022

Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP and SEPTIN8 correlates well with that in C57Bl/6N- mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein-2 (PMP2), which was specific to human CNS myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes includingPmp2, Tspan2andGjc3. Species-dependent diversity of oligodendroglial mRNA-expression and myelin protein composition can be informative when translating from mouse models to humans.
How Glutamate Promotes Liquid-liquid Phase Separation and DNA Binding Cooperativity ofE. coliSSB Protein
Authors: Kozlov Alexander G. , Cheng Xian , Zhang Hongshan , Shinn Min Kyung , Weiland Elizabeth , Nguyen Binh , Shkel Irina A. , Zytkiewicz Emily , Finkelstein Ilya J. , Thomas Record M. , Lohman Timothy M.
Published: January 2022

E. colisingle-stranded-DNA binding protein (EcSSB) displays nearest-neighbor (NN) and non-nearest-neighbor (NNN)) cooperativity in binding ssDNA during genome maintenance. NNN cooperativity requires the intrinsically-disordered linkers (IDL) of the C-terminal tails. Potassium glutamate (KGlu), the primaryE. colisalt, promotes NNN-cooperativity, while KCl inhibits it. We find that KGlu promotes compaction of a single polymeric SSB-coated ssDNA beyond what occurs in KCl, indicating a link of compaction to NNN-cooperativity.EcSSB also undergoes liquid-liquid phase separation (LLPS), inhibited by ssDNA binding. We find that LLPS, like NNN-cooperativity, is promoted by increasing [KGlu] in the physiological range, while increasing [KCl] and/or deletion of the IDL eliminate LLPS, indicating similar interactions in both processes. From quantitative determinations of interactions of KGlu and KCl with protein model compounds, we deduce that the opposing effects of KGlu and KCl on SSB LLPS and cooperativity arise from their opposite interactions with amide groups. KGlu interacts unfavorably with the backbone (especially Gly) and side chain amide groups of the IDL and therefore promotes amide-amide interactions in LLPS and NNN-cooperativity. By contrast, KCl interacts favorably with these amide groups and therefore inhibits LLPS and NNN-cooperativity. These results highlight the importance of salt interactions in regulating the propensity of proteins to undergo LLPS.
Elevation of Clavibacter michiganensis subsp. californiensis to species level as Clavibacter californiensis sp. nov., merging and re-classification of Clavibacter michiganensis subsp. chilensis and Clavibacter michiganensis subsp. phaseoli as Clavibacter chilensis sp. nov. based on complete genome in-silico analyses
Authors: Arizala Dario , Dobhal Shefali , Alvarez Anne M. , Arif Mohammad
Published: January 2022

The Gram-positive Clavibacter genus is currently divided into seven species (C. michiganensis, C. nebraskensis, C. capsici, C. sepedonicus, C. tessellarius, C. insidiosus and C. zhangzhiyongii) and three subspecies (C. michiganensis subsp. californiensis, C. michiganensis subsp. chilensis and C. michiganensis subsp. phaseoli). Recent studies have indicated that the taxonomic rank of the subspecies must be re-evaluated. In this research, we assessed the taxonomy position of the three C. michiganensis subspecies and clarified the taxonomic nomenclature of other 75 Clavibacter strains. The complete genomes of the type strains of the three Clavibacter subspecies, type strain of C. tessellarius and C. nebraskensis A6096 were sequenced using PacBio RSII technology. Application of whole-genome-based computational approaches such as average nucleotide identity (ANI), digital DNA-DNA hybridization (dDDH), multi-locus sequence analysis (MLSA) of seven housekeeping genes (acnA, atpD, bipA, icdA, mtlD, recA and rpoB), phylogenomic tree reconstructed from 1,028 core genes, and ANI-based phylogeny pinpointed conclusive evidence to raise C. michiganensis subsp. californiensis to the species status. These results led us to propose the establishment of C. californiensis sp. nov. as a species with its type strain C55ᵀ (=CFBP 8216ᵀ=ATCC BAA-2691ᵀ). Moreover, the orthologous and in-silico dot plot analyses, along with the aforementioned bioinformatic strategies, revealed a high degree of homology between C. michiganensis subsp. chilensis and C. michiganensis subsp. phaseoli. Based on these outcomes, we proposed to combine both subspecies into a single taxon and elevate its rank to the species level as C. chilensis sp. nov., with ZUM3936ᵀ (= ATCC BAA-2690ᵀ = CFBP 8217ᵀ) as the type strain.
Development of an HIV reporter virus that identifies latently infected CD4+T cells
Authors: Kim Eun Hye , Manganaro Lara , Schotsaert Michael , Brown Brian D. , Mulder Lubbertus C.F. , Simon Viviana
Published: January 2022

There is no cure for HIV infection as the virus establishes a latent reservoir, which escapes highly active antiretroviral treatments. One major obstacle is the difficulty to identify cells that harbor latent proviruses. We devised a novel viral vector that carries a series of versatile reporter molecules that are expressed in an LTR-dependent or LTR-independent manner and allows to accurately distinguish productive from latent infection. Using primary human CD4+T cells, we show that transcriptionally silent proviruses make up over 50% of all infected cells. These latently infected cells harbor proviruses, but lack evidence for viral transcription. LTR silent integrations occurred to variable degrees in all CD4+T-subsets examined with CD4+TEMand CD4+Tregdisplaying the highest frequency. Viral vectors such as the one described here, permit interrogation HIV latency at a single-cell resolution, revealing mechanisms of latency establishment and allowing for the characterization of effective latency reversing agents.
MicroRNA Detection in Biological Media Using a Split Aptamer Platform
Authors: Wang Liming , Hast Kern , Aggarwal Tushar , Baci Melih , Hong Jonathan , Izgu Enver Cagri
Published: January 2022

Intercellular microRNA (miRNA)-based communication has been implicated in a wide array of functional and dysfunctional biological processes. This has raised attention to the potential use of miRNAs as biomarkers for disease diagnosis and prognosis and produced interest in their detection. Though the list of clinically significant miRNA biomarkers is rapidly expanding, it remains challenging to adapt current tools to investigate new targets in biological environments. Systematic approaches for the rapid development of miRNA biosensors are valuable to reduce this disparity. We describe here a methodology for developing aptamer-based fluorescent biosensors that can specifically detect miRNAs in biological environments, including culture medium from HeLa cells, human serum, and human plasma. This methodology includes the semi-rational design of the hybridization between a pair of split DNA aptamer oligonucleotides and the miRNA target to build a pool of potential sensor designs, and the screening of this pool for designs with high signal-to-background ratio and sequence selectivity. The method uses natural oligonucleotides without chemical modification, and is effective in buffer, 10%, and 30% (v/v) biological media. Following this approach, we developed sensors that detect three miRNA targets (miR-19b, miR-21, and miR-92a) at concentrations as low as 5 nM without amplification and are selective against single-nucleotide mutants. This work expands upon the current design principles of nucleic acid-based biosensors and provides a method to rapidly develop diagnostic tools for novel and niche miRNA targets of interest.
Omicron-associated changes in SARS-CoV-2 symptoms in the United Kingdom
Authors: Vihta Karina-Doris , Pouwels Koen B. , Peto Tim EA , Pritchard Emma , House Thomas , Studley Ruth , Rourke Emma , Cook Duncan , Diamond Ian , Crook Derrick , Clifton David A. , Matthews Philippa C. , Stoesser Nicole , Eyre David W. , Walker Ann Sarah ,   the COVID-19 Infection Survey team
Published: January 2022

Background

The SARS-CoV-2 Delta variant has been replaced by the highly transmissible Omicron BA.1 variant, and subsequently by Omicron BA.2. It is important to understand how these changes in dominant variants affect reported symptoms, while also accounting for symptoms arising from other co-circulating respiratory viruses.

Methods

In a nationally representative UK community study, the COVID-19 Infection Survey, we investigated symptoms in PCR-positive infection episodes vs. PCR-negative study visits over calendar time, by age and vaccination status, comparing periods when the Delta, Omicron BA.1 and BA.2 variants were dominant.

Results

Between October-2020 and April-2022, 120,995 SARS-CoV-2 PCR-positive episodes occurred in 115,886 participants, with 70,683 (58%) reporting symptoms. The comparator comprised 4,766,366 PCR-negative study visits (483,894 participants); 203,422 (4%) reporting symptoms. Symptom reporting in PCR-positives varied over time, with a marked reduction in loss of taste/smell as Omicron BA.1 dominated, maintained with BA.2 (44%/45% 17 October 2021, 16%/13% 2 January 2022, 15%/12% 27 March 2022). Cough, fever, shortness of breath, myalgia, fatigue/weakness and headache also decreased after Omicron BA.1 dominated, but sore throat increased, the latter to a greater degree than concurrent increases in PCR-negatives. Fatigue/weakness increased again after BA.2 dominated, although to a similar degree to concurrent increases in PCR-negatives. Symptoms were consistently more common in adults aged 18-65 years than in children or older adults.

Conclusions

Increases in sore throat (also common in the general community), and a marked reduction in loss of taste/smell, make Omicron harder to detect with symptom-based testing algorithms, with implications for institutional and national testing policies.

In a UK community study, loss of taste/smell was markedly less commonly reported with Omicron BA.1/BA.2 than Delta SARS-CoV-2 infections, with smaller declines in reported shortness of breath, myalgia and fatigue/weakness, but increases in sore throat, challenging symptom-based testing algorithms.
Booster vaccination to curtail COVID-19 resurgence - population-level implications of the Israeli campaign
Authors: Gavish Nir , Yaari Rami , Huppert Amit , Katriel Guy
Published: January 2022

Israel was one of the first countries to administer mass vaccination. Consequently, it was among the first countries to experience significant breakthrough infections due to the waning of vaccine-induced immunity, which led to a resurgence of the epidemic. To mitigate the outbreak, Israel launched a pioneering booster campaign. Israel’s success in curtailing the Delta resurgence while imposing only mild non-pharmaceutical interventions has been instrumental in influencing the decision of many countries to initiate a booster campaign. By constructing a detailed mathematical model and calibrating it to the Israeli data, we expand our understanding of the impact of the booster campaign from the individual to the population level. We use the calibrated model to explore counterfactual scenarios in which the booster vaccination campaign is altered and to assess the direct and indirect effects in the different scenarios. Our results point to the vast benefits of vaccinating younger age groups that are not at a high risk of developing severe disease but play an important role in transmission. We further show that when the epidemic is exponentially growing the success of the booster campaign is highly sensitive to the timing of its initiation. Hence a rapid response is an important factor in reducing disease burden using booster vaccination.
Parallel evolution of amphioxus and vertebrate small-scale gene duplications
Authors: Brasó-Vives Marina , Marlétaz Ferdinand , Echchiki Amina , Mantica Federica , Acemel Rafael D. , Gómez-Skarmeta José L. , Hartasánchez Diego A. , Targa Lorlane L. , Pontarotti Pierre , Tena Juan J. , Maeso Ignacio , Escriva Hector , Irimia Manuel , Robinson-Rechavi Marc
Published: January 2022

Background

Amphioxus are non-vertebrate chordates characterized by a slow morphological and molecular evolution. They share the basic chordate body-plan and genome organization with vertebrates but lack their 2R whole-genome duplications and their developmental complexity. For these reasons, amphioxus are frequently used as an outgroup to study vertebrate genome evolution and Evo-Devo. Aside from whole-genome duplications, genes continuously duplicate on a smaller scale. Small-scale duplicated genes can be found in both amphioxus and vertebrate genomes, while only the vertebrate genomes have duplicated genes product of their 2R whole-genome duplications. Here, we explore the history of small-scale gene duplications in the amphioxus lineage and compare it to small- and large-scale gene duplication history in vertebrates.

Results

We present a study of the European amphioxus (Branchiostoma lanceolatum) gene duplications thanks to a new, high-quality genome reference. We find that, despite its overall slow molecular evolution, the amphioxus lineage has had a history of small-scale duplications similar to the one observed in vertebrates. We find parallel gene duplication profiles between amphioxus and vertebrates, and conserved functional constraints in gene duplication. Moreover, amphioxus gene duplicates show levels of expression and patterns of functional specialization similar to the ones observed in vertebrate duplicated genes. We also find strong conservation of gene synteny between two distant amphioxus species, B. lanceolatum and B. floridae, with two major chromosomal rearrangements.

Conclusions

In contrast to their slower molecular and morphological evolution, amphioxus’ small-scale gene duplication history resembles that of the vertebrate lineage both in quantitative and in functional terms.
Enhancing Uterine Receptivity for Embryo Implantation through Controlled Collagenase Intervention
Authors: Zehorai Eldar , Gross Tamar , Shimshoni Elee , Hadas Ron , Adir Idan , Golani Ofra , Molodij Guillaume , Eitan Ram , Kadler Karl E. , Kollet Orit , Neeman Michal , Dekel Nava , Solomonov Inna , Sagi Irit
Published: January 2022

Successful embryo implantation within the uterine wall requires intricate endometrial remodeling. Impaired endometrial receptivity, a common cause of infertility, often results from ineffective remodeling processes. Here, we demonstrate that a single dose of human collagenase-1 administered into the mouse uterus enhances embryo implantation rates. Mechanistically, collagenase-1 induces remodeling of the endometrial extracellular matrix (ECM), leading to the degradation of collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors, such as VEGF, which facilitates local vascular permeability and angiogenesis. Furthermore, collagenase-1 treatment increases NK cell infiltration and elevates levels of the cytokine LIF, a key factor in embryo implantation. Remarkably, the overall structural integrity of the uterine tissue remains uncompromised, even in the presence of reduced tension in endometrial collagen fibers. To assess pre-clinical potential, in-uteri application of collagenase-1 successfully rescued implantation in mouse models subjected to heat stress and embryo transfer, conditions known for their adverse impact on implantation rates. Importantly, ex-vivo exposure of human uterine tissue to collagenase-1 induced collagen de-tensioning and the release of VEGF, demonstrating similar processes observed in the mouse settings, and the potential relevance of this treatment to human conditions. Our findings underscore the immense clinical potential and feasibility of collagenase treatment to enhance uterine receptivity for embryo implantation, offering a controlled and minimally invasive intervention. This innovative approach not only demonstrates the potential to enhance efficiency in livestock breeding but, more importantly, signifies a substantial promise in supporting medical interventions for human reproduction in clinical settings.
Fam49b dampens TCR signal strength to regulate survival of positively selected thymocytes
Authors: Park Chan-Su , Guan Jian , Rhee Peter , Gonzalez Federico , Coscoy Laurent , Robey Ellen A. , Shastri Nilabh , Sadegh-Nasseri Scheherazade
Published: January 2022

The fate of developing T cells is determined by the strength of T cell receptor (TCR) signal they receive in the thymus. This process is finely regulated through tuning of positive and negative regulators in thymocytes. The Family with sequence similarity 49 member B (Fam49b) protein is a newly discovered negative regulator of TCR signaling that has been shown to suppress Rac-1 activity in vitro in cultured T cell lines. However, the contribution of Fam49b to thymic development of T cells is unknown. To investigate this important issue, we generated a novel mouse line deficient in Fam49b (Fam49b-KO). We observed that Fam49b-KO double positive (DP) thymocytes underwent excessive negative selection, whereas the positive selection stage was unaffected. This altered development process resulted in significant reductions in CD4 and CD8 single positive thymocytes as well as peripheral T cells. Interestingly, a large proportion of the TCRγδ+ and CD8αα+TCRαβ+ gut intraepithelial T lymphocytes were absent in Fam49b-KO mice. Our results demonstrate that Fam49b dampens thymocytes TCR signaling in order to escape negative selection during development, uncovering the function of Fam49b as a critical regulator of selection process to ensure normal thymocyte development.
Chronic hyperglycemia drives alterations in macrophage effector function in pulmonary tuberculosis
Authors: Panda Sudhasini , Seelan Diravya M , Faisal Shah , Luthra Kalpana , Palanichamy Jayanth Kumar , Mohan Anant , Vikram Naval K , Gupta Neeraj Kumar , Ramakrishnan Lakshmy , Singh Archana
Published: January 2022

Background

The rising prevalence of Diabetes mellitus (DM) in high TB endemic countries has the potential to adversely affect sustainability of TB control since DM can lead to alterations in both innate and adaptive immune response constituting as a risk factor for development of active tuberculosis (TB). The impact of hyperglycemia on TB specific innate immune response in terms of macrophage functions remains poorly addressed.

Material and methods

Macrophage effector functions in diabetic and non-diabetic individuals with and without PTB infection as well as non-diabetic-uninfected controls (fifty individuals in each group) were assessed. Phagocytic capacity against BCG and surface expression of PRRs (CD11b, CD14, CD206, MARCO and TLR2) were measured via flow cytometry. Effector molecules (ROS and NO) were assessed via DCFDA and Griess reaction respectively.

Results

A systematic dysregulation in phagocytic capacity with concurrent alterations in expression pattern of key PRRs (CD11b, MARCO and CD206) and effector molecules (ROS and NO) was observed in diabetic individuals with PTB. These altered macrophage functions were positively correlated with increase in disease severity in diabetic individuals.

Conclusion

Our results highlight several key patterns of immune dysregulation against M.Tb under hyperglycemic conditions. A significant reduction in macrophage effector functions in infected diabetic individuals which further correlated with increase in disease severity reveals a negative impact of hyperglycemia with aetiology and pathological progression of TB.
Infection strategy and biogeography distinguish cosmopolitan groups of marine jumbo bacteriophages
Authors: Weinheimer Alaina R. , Aylward Frank O.
Published: January 2022

Recent research has underscored the immense diversity and key biogeochemical roles of large DNA viruses in the ocean. Although they are important constituents of marine ecosystems, it is often difficult to detect these viruses due to their large size and complex genomes. This is true for “jumbo” bacteriophages, which have genome sizes >200 kbp and large capsids reaching up to 0.45 μm in diameter. In this study, we sought to assess the genomic diversity and distribution of these bacteriophages in the ocean by developing a bioinformatic pipeline to generate and validate jumbo phage genomes from metagenomes. We recover 85 marine jumbo phages that ranged in size from 201-498 kilobases, and we examine their genetic similarities and biogeography together with a reference database of marine jumbo phage genomes. By analyzing Tara Oceans metagenomic data we show that jumbo phages are less common in <0.22 μm size fractions but are widespread in larger fractions, consistent with their large size. Our network-based analysis of gene sharing patterns reveals that jumbo bacteriophage belong to five genome clusters that are typified by diverse replication strategies, genomic repertoires, and potential host ranges. Our analysis of jumbo phage distributions in the ocean reveals that depth is a major factor shaping their biogeography, with some phage genome clusters exhibiting higher relative abundance in either surface or mesopelagic waters, respectively. Taken together, our findings demonstrate that jumbo phages are widespread community members in the ocean with complex genomic repertoires and ecological impacts that warrant further targeted investigation.