bluuebunny/crossref_metadata_2025 huggingface dataset:
Proposal of Lactococcus garvieae subsp. bovis Varsha and Nampoothiri 2016 as a later heterotypic synonym of Lactococcus formosensis Chen et al. 2014 and Lactococcus formosensis subsp. bovis comb. nov.
Authors: Zhang Hong Xia , Tian Wen Li , Gu Chun Tao
Published: August 2021

Currently,

Lactococcus garvieae

contains two subspecies:

L. garvieae

subsp.

bovis

and

L. garvieae

subsp.

garvieae

. In a study by Varsha and Nampoothiri, high pheS (99.7 %) and rpoA (99.6 %) sequence similarities indicated that

L. garvieae

subsp.

bovis

and

Lactococcus formosensis

probably have a close taxonomic relationship; low pheS (92.2 %) and rpoA (97.8 %) sequence similarities and relatively low DNA–DNA hybridization value (75.8 %) indicated that

L. garvieae

subsp.

bovis

and

L. garvieae

subsp.

garvieae

probably represent two different species. In the present study, the taxonomic relationships between

L. garvieae

subsp.

bovis

,

L. garvieae

subsp.

garvieae

and

L. formosensis

were re-examined based on sequence analyses of 16S rRNA, pheS, recA, rpoA and rpoB genes, average nucleotide identity (ANI), digital DNA–DNA hybridization (dDDH) values, average amino acid identity (AAI), fatty acid methyl ester analysis and phenotypic characterization.

L. garvieae

subsp.

bovis

LMG 30663T exhibited 97.3 % ANI, 78.3 % dDDH and 96.4 % AAI values to

L. formosensis

NBRC 109475T, higher than the threshold for species demarcation (95–96, 70 and 95–96 %, respectively), indicating that

L. garvieae

subsp.

bovis

LMG 30663T and

L. formosensis

NBRC 109475T belong to the same species.

L. garvieae

subsp.

bovis

LMG 30663T had 91.2 % ANI, 43.3 % dDDH and 92.9–93.0% AAI values with the type strain of

L. garvieae

subsp.

garvieae

, indicating that they represent two different species. Because

L. formosensis

has been proposed and validated before

L. garvieae

subsp.

bovis

,

L. garvieae

subsp.

bovis

is transferred to

L. formosensis

as

L. formosensis

subsp. bovis comb. nov. The type strain of

L. formosensis

subsp. bovis is BSN307T (=DSM 100577T=MCC 2824T=KCTC 21083T=LMG 30663T). The type strain of

L. formosensis

subsp. formosensis is 516T (=NBRC 109475T=BCRC 80576T).
Radiosensitivity Index (RSI) is not fit to be used for dose-adjustments: a pan-cancer analysis
Authors: Mistry Hitesh
Published: August 2021

Radiotherapy has been striving to find markers of radiotherapy sensitivity for decades. In recent years the community has spent significant resources on exploring the wide range of omics data-sets to find that elusive perfect biomarker. One such candidate termed the Radiosensitivity Index, RSI for short, has been heavily publicized as a marker suitable for making dose-adjustments in the clinical setting. However, none of the analyses conducted, thus far, has assessed whether RSI explains enough of the outcome variance to elucidate a dose-response empirically. Here we re-analyze a pan-cancer data-set and find that RSI is no better than random chance at explaining outcome variance, overall survival times. For completeness, we then assessed whether RSI captured a sufficient amount of outcome variance to elucidate a dose-response, it did not. These results suggest that like the initial in-vitro analysis 12 years previously RSI is not a marker of radiotherapy sensitivity and is thus not fit to be used in any dose-adjustment algorithms.
Genetic assessments of breast cancer risk that do not account for polygenic background are incomplete and lead to incorrect preventative strategies
Authors: Busby George B. , Craig Paul , Yousfi Nesrine , Hebbalkar Saurabh , Di Domenico Paolo , Bottà Giordano
Published: August 2021

Breast cancer is the most common cancer among women and is a leading cause of cancer mortality worldwide. There is a significant genetic component to breast cancer risk which is the result of both rare pathogenic mutations and common genome-wide variation. However, the penetrance of pathogenic mutations varies widely and their frequency is low, both at a population level and amongst breast cancer cases. Polygenic risk scores, which aggregate the effect of hundreds to millions of common genome-wide variants offer a way to further understand the contribution of genetics to disease risk. Here we analyse genome-wide data from 221,479 women and 90,307 high coverage exomes to understand how rare and common variation affect lifetime breast cancer risk. We show that PRS strongly modulates the penetrance of mutations in 8 breast cancer susceptibility genes. For example, lifetime risk in BRCA1 carriers with low polygenic risk is almost one third that of carriers with high PRS (26% v 69% in the bottom and top PRS deciles, respectively). Adding family history of breast cancer provides additional stratification on the potential outcome of disease in carriers of rare mutations. PRS also identifies a significant fraction of the population at equivalent risk to carriers of moderate impact pathogenic variants and who are an order of magnitude more common at a population level. These results have important implications for breast cancer risk mitigation strategies, indicating that the genetic risk of breast cancer is determined by both monogenic mutation and polygenic background, and that assessments of genetic risk for breast cancer risk that do not consider the polygenic background are imprecise and unreliable.
First-in-human autologous oral mucosal epithelial sheet transplantation to prevent anastomotic re-stenosis in congenital esophageal atresia
Authors: Fujino Akihiro , Fuchimoto Yasushi , Baba Yoshiyuki , Isogawa Nobutaka , Iwata Takanori , Arai Katsuhiro , Abe Makoto , Kanai Nobuo , Takagi Ryo , Maeda Masanori , Umezawa Akihiro
Published: August 2021

Background

Congenital esophageal atresia postoperative anastomotic stricture occurs in 30-50% of cases. Patients with severe dysphagia are treated with endoscopic balloon dilatation (EBD) and/or local injection of steroids, but many patients continue to experience frequent stricture. In this study, we investigated the transplantation of autologous oral mucosa-derived cell sheets (epithelial cell sheets) as a prophylactic treatment for congenital esophageal atresia postoperative anastomotic stricture.

Methods

Epithelial cell sheets were fabricated from a patient’s oral epithelial tissue, and their safety was confirmed by quality control tests. The epithelial cell sheets were transported under controlled conditions from the fabrication facility to the transplantation facility and successfully transplanted onto the lacerations caused by EBD using a newly developed transplantation device for pediatric patients. The safety of the transplantation was confirmed by follow-up examinations over 48 weeks.

Results

The number of EBDs required after transplantation and the number of days between EDBs were recorded. Before transplantation, EBDs were performed approximately every two weeks, whereas after transplantation, the interval was extended to a maximum of four weeks. The patient was also aware of a reduction in dysphagia.

Conclusions

This study suggests that cell sheet transplantation might be effective in preventing anastomotic stricture after surgery for congenital esophageal atresia. We chose this very severe case for the first clinical study in humans. Future studies are needed to identify cases in which cell sheet transplantation is most effective and to determine the appropriate timeframes for transplantation.
Tau spreading is driven by neuronal connectivity in primary tauopathies - evidence from tau-PET and histopathology
Authors: Franzmeier Nicolai , Brendel Matthias , Beyer Leonie , Kovacs Gabor , Arzberger Thomas , Kurz Carolin , Respondek Gesine , Lukic Milica Jecmenica , Biel Davina , Rubinski Anna , Frontzkowski Lukas , Finze Anika , Palleis Carla , Joseph Emanuel , Weidinger Endy , Katzdobler Sabrina , Song Mengmeng , Biechele Gloria , Kern Maike , Scheifele Maximilian , Rauchmann Boris-Stephan , Perneczky Robert , Rullman Michael , Patt Marianne , Schildan Andreas , Barthel Henryk , Sabri Osama , Rumpf Jost J. , Schroeter Matthias L. , Classen Joseph , Villemagne Victor , Seybl John , Stephens Andrew W. , Lee Edward B. , Coughlin David G. , Giese Armin , Grossman Murray , McMillan Corey T. , Gelpi Ellen , Molina-Porcel Laura , Compta Yaroslau , van Swieten John C. , Laat Laura Donker , Troakes Claire , Al-Sarraj Safa , Robinson John L. , Xie Sharon X. , Irwin David J. , Roeber Sigrun , Herms Jochen , Simons Mikael , Bartenstein Peter , Lee Virginia M. , Trojanowski John Q. , Levin Johannes , Höglinger Günter U. , Ewers Michael ,   For the German Imaging Initiative for Tauopathies (GII4T) & the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2021

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.
A Longitudinal Normative Dataset and Protocol for Speech and Language Biomarker Research
Authors: Schwoebel James W. , Schwartz Joel , Warrenburg Lindsay A. , Brown Roland , Awasthi Ashi , New Austin , Butler Monroe , Moss Mark , Pissadaki Eleftheria K.
Published: August 2021

Although speech and language biomarker (SLB) research studies have shown methodological and clinical promise, some common limitations of these studies include small sample sizes, limited longitudinal data, and a lack of a standardized survey protocol. Here, we introduce the Voiceome Protocol and the corresponding Voiceome Dataset as standards which can be utilized and adapted by other SLB researchers. The Voiceome Protocol includes 12 types of voice tasks, along with health and demographic questions that have been shown to affect speech. The longitudinal Voiceome Dataset consisted of the Voiceome Protocol survey taken on (up to) four occasions, each separated by roughly three weeks (22.80 +/- 20.91 days). Of 6,650 total participants, 1,382 completed at least two Voiceome surveys. The results of the Voiceome Dataset are largely consistent with results from standard clinical literature, suggesting that the Voiceome Study is a high-fidelity, normative dataset and scalable protocol that can be used to advance SLB research.
The SARS-CoV-2 Alpha variant is associated with increased clinical severity of COVID-19 in Scotland: a genomics-based retrospective cohort analysis
Authors: Pascall David J. , Vink Elen , Blacow Rachel , Bulteel Naomi , Campbell Alasdair , Campbell Robyn , Clifford Sarah , Davis Chris , da Silva Filipe Ana , Sakka Noha El , Fjodorova Ludmila , Forrest Ruth , Goldstein Emily , Gunson Rory , Haughney John , Holden Matthew T.G. , Honour Patrick , Hughes Joseph , James Edward , Lewis Tim , Lycett Samantha , MacLean Oscar , McHugh Martin , Mollett Guy , Onishi Yusuke , Parcell Ben , Ray Surajit , Robertson David L , Shabaan Sharif , Shepherd James G. , Smollett Katherine , Templeton Kate , Wastnedge Elizabeth , Wilkie Craig , Williams Thomas ,   The COVID-19 Genomics UK (COG-UK) consortium, Thomson Emma C.
Published: August 2021

Objectives

The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this.

Methods

In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1stNovember 2020 and 30thJanuary 2021 were sequenced. We matched sequence data to clinical outcomes as the variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death.

Results

Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus non-Alpha variant).

Conclusions

The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.
Segregation of children into small groups for in-person learning during the COVID-19 pandemic
Authors: Muñoz-Nava Luis Manuel , Nahmad Marcos
Published: August 2021

The COVID-19 pandemic affected in-person learning worldwide due to fears that schools could contribute to the propagation of the virus within their communities. Using computational modeling, we compare the reopening of schools with mitigation measures with a strategy in which schoolchildren are segregated into small isolated groups or “bubbles,” where children physically interact without restrictions while receiving remote instruction from their teachers. This strategy is robust to common perturbations and is more flexible and stable than reopening of schools. Our modeling results and a real-world implementation of a bubbles program in an elementary school in Mexico City support that this strategy is an effective transition alternative, especially in communities with low vaccination rates or where operational costs associated to safely reopening schools cannot be afforded.
Classifying Refugee Status Using Common Features in EMR
Authors: Morrison Malia , Nobles Vanessa , Johnson-Agbakwu Crista E. , Bailey Celeste , Liu Li
Published: August 2021

Objective

Automated and accurate identification of refugees in healthcare databases is a critical first step to investigate healthcare needs of this vulnerable population and improve health disparities. This study developed a machine-learning method, named refugee identification system (RIS) that uses features commonly collected in healthcare databases to classify refugees and non-refugees.

Materials and Methods

We compiled a curated data set consisting of 103 refugees and 930 non-refugees in Arizona. For each person in the curated data set, we collected age, primary language, and noise-masked home address. We supplemented de-identified individual-level data with state-level refugee resettlement statistics and world language statistics, then performed feature engineering to convert primary language and masked address into quantitative features. Finally, we built a random forest model to classify refugee status.

Results

Evaluated on holdout testing data, RIS achieved a high classification accuracy of 0.97, specificity of 0.99, sensitivity of 0.85, positive predictive value of 0.88, and negative predictive value of 0.98. The receiver operating characteristic curve had an area under the curve value of 0.98. The source code is available at GitHub (https://github.com/liliulab/ris).

Discussion and Conclusion

RIS is an automated, accurate, and scalable method to predict refugee status. It uses only de-identified information to protect patient privacy. The computational framework is adaptable to address similar challenges in other States. Its application enables large-scale investigation of refugee healthcare needs and improvement of health disparities.
Changing incidence of invasive pneumococcal disease in infants less than 90 days of age before and after introduction of the 13-valent Pneumococcal Conjugate Vaccine in Blantyre, Malawi: a 14-year hospital based surveillance study
Authors: Koenraads Marianne , Swarthout Todd D. , Bar-Zeev Naor , Brown Comfort , Msefula Jacquline , Denis Brigitte , Dube Queen , Gordon Stephen B. , Heyderman Robert S. , Gladstone Melissa , French Neil
Published: August 2021

Background

Invasive pneumococcal disease (IPD) in young infants is uncommon but associated with high morbidity and mortality. Accurate data on the burden of IPD in young infants in low-income countries are lacking. We examined the burden of IPD in infants aged <90 days in Blantyre, Malawi over a 14 year period and evaluated the impact of the 12 November 2011 introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) on vaccine-serotype IPD (VT-IPD) in this population.

Methods

We conducted laboratory-based prospective IPD surveillance in infants aged <90 days admitted to Queen Elizabeth Central Hospital (QECH) in Blantyre between 2005 and 2018, including 7 years pre- and 7 years post-PCV13 introduction. IPD was defined as Streptococcus pneumoniae identified by culture from blood or cerebrospinal fluid. Serotypes were determined by multiplex PCR and latex agglutination testing.

Results

We identified 130 cases of culture-confirmed IPD in infants <90 days old between 2005-2018. Total IPD incidence was declining prior to PCV13 introduction. The mean incidence of IPD was significantly lower in the post-PCV era. Serotypes 5 (27.8%) and 1(15.6%), were most prevalent. Even after PCV13 introduction, VT-IPD remained dominant with serotype 5 accounting for 17.4% and serotype 1 for 13% of cases in young infants.

Conclusion

Vaccine serotypes were the main cause of IPD in neonates and young infants, both before and after PCV13 introduction. Further strategies need to be considered to protect this vulnerable population, including maternal or neonatal immunization and implementation of an alternative PCV schedule with a booster dose.

The incidence of invasive pneumococcal disease in infants in Blantyre, Malawi has declined over the past decade and more significantly after introduction of the pneumococcal conjugate vaccine. Vaccine serotypes have remained the main cause of disease in this population.
Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK
Authors: Pouwels Koen B. , Pritchard Emma , Matthews Philippa C. , Stoesser Nicole , Eyre David W. , Vihta Karina-Doris , House Thomas , Hay Jodie , Bell John I , Newton John N , Farrar Jeremy , Crook Derrick , Cook Duncan , Rourke Emma , Studley Ruth , Peto Tim , Diamond Ian , Walker A. Sarah ,   the COVID-19 Infection Survey Team
Published: August 2021

The effectiveness of BNT162b2, ChAdOx1, and mRNA-1273 vaccines against new SARS-CoV-2 infections requires continuous re-evaluation, given the increasingly dominant Delta variant. We investigated the effectiveness of the vaccines in a large community-based survey of randomly selected households across the UK. We found that the effectiveness of BNT162b2 and ChAd0x1 against any infections (new PCR positives) and infections with symptoms or high viral burden is reduced with the Delta variant. A single dose of the mRNA-1273 vaccine had similar or greater effectiveness compared to a single dose of BNT162b2 or ChAdOx1. Effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity following second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positives but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher among those vaccinated following a prior infection and younger adults. With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.
Symptoms and SARS-CoV-2 positivity in the general population in the UK
Authors: Vihta Karina-Doris , Pouwels Koen B. , Peto Tim , Pritchard Emma , Eyre David W. , House Thomas , Gethings Owen , Studley Ruth , Rourke Emma , Cook Duncan , Diamond Ian , Crook Derrick , Matthews Philippa C. , Stoesser Nicole , Walker Ann Sarah ,   the COVID-19 Infection Survey team
Published: August 2021

Background

Several community-based studies have assessed the ability of different symptoms to identify COVID-19 infections, but few have compared symptoms over time (reflecting SARS-CoV-2 variants) and by vaccination status.

Methods

Using data and samples collected by the COVID-19 Infection Survey at regular visits to representative households across the UK, we compared symptoms in new PCR-positives and comparator test-negative controls.

Results

From 26/4/2020-7/8/2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years (IQR 22-58)); 13,427 (48%) self-reported symptoms (“symptomatic positive episodes”). The comparator group comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms (“symptomatic negative visit”). Reporting of any symptoms in positive episodes varied over calendar time, reflecting changes in prevalence of variants, incidental changes (e.g. seasonal pathogens, schools re-opening) and vaccination roll-out. There was a small increase in sore throat reporting in symptomatic positive episodes and negative visits from April-2021. After May-2021 when Delta emerged there were substantial increases in headache and fever in positives, but not in negatives. Although specific symptom reporting in symptomatic positive episodes vs. negative visits varied by age, sex, and ethnicity, only small improvements in symptom-based infection detection were obtained; e.g. adding fatigue/weakness or all eight symptoms to the classic four symptoms (cough, fever, loss of taste/smell) increased sensitivity from 74% to 81% to 90% but tests per positive from 4.6 to 5.3 to 8.7.

Conclusions

Whilst SARS-CoV-2-associated symptoms vary by variant, vaccination status and demographics, differences are modest and do not warrant large-scale changes to targeted testing approaches given resource implications.

Within the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.
Long-Term Effectiveness of a Digital Therapeutic Intervention for Smoking Cessation: A Randomized Controlled Trial
Authors: Webb Jamie , Peerbux Sarrah , Ang Alfonso , Siddiq Sarim , Sherwani Yusuf , Ahmed Maroof , MacRae Hannah , Puri Hannah , Majeed Azeem , Glasner Suzette
Published: August 2021

Introduction

The present study evaluated the long-term effectiveness of Quit Genius (QG), an extended digital smoking cessation intervention.

Methods

Participants were adult smokers (N=556) recruited between January and November of 2019 via social media and referrals from primary care practices who were given nicotine replacement therapy and randomly assigned to Quit Genius (QG) (n=277), a cognitive behavioral therapy (CBT) based digital intervention or Very Brief Advice (VBA) (n=279), a face-to-face control intervention. Primary analyses (N=530), by intention-to-treat, compared QG and VBA on biochemically verified continuous 7-day abstinence at 4, 26, and 52 weeks post-quit date. Secondary outcomes included sustained abstinence, quit attempts, self-efficacy and mental well-being.

Results

Seven-day point prevalence abstinence from weeks 4 through 52 ranged from 27% to nearly 45% among those who received QG, and from 13% to 29% for those in VBA. Continuous 7-day abstinence at 26 and 52 weeks occurred in 27.2% and 22.6% of QG participants, respectively, relative to 16.6% and 13.2% of VBA participants; QG participants were more likely to remain abstinent than those in VBA (Relative Risk [RR]= 1.71, 95% CI 1.17-2.50; p=0.005).

Conclusions

This study provides evidence for the long-term effectiveness of an extended digital therapeutic intervention.

Implications

The long-term effectiveness of digital smoking cessation interventions has not been well-studied. This study established the long-term effectiveness of an extended CBT-based intervention; results may inform implementation of scalable, cost-effective approaches to smoking cessation in the health system.
Cytotoxic T cells are silenced to induce disease tolerance in human malaria
Authors: Sandoval Diana Muñoz , Bach Florian A. , Ivens Alasdair , Harding Adam C. , Smith Natasha L. , Mazurczyk Michalina , Themistocleous Yrene , Edwards Nick J. , Silk Sarah E. , Barrett Jordan R. , Cowan Graeme J.M. , Napolitani Giorgio , Savill Nicholas J. , Draper Simon J. , Minassian Angela M. , Nahrendorf Wiebke , Spence Philip J.
Published: August 2021

Immunity to severe malaria is acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance remains unknown. We developed a human re-challenge model of falciparum malaria in which healthy adult volunteers were infected three times over a 12 month period to track the development of disease tolerance in real-time. We found that parasitemia triggered a hardwired emergency host response that led to systemic inflammation, pyrexia and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, a single infection was sufficient to reprogramme T cell activation and reduce the number and diversity of effector cells upon re-challenge. Crucially, this did not silence stem-like memory cells but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerised hosts were thus able to prevent collateral tissue damage in the absence of anti-parasite immunity.
Emergence and phenotypic characterization of C.1.2, a globally detected lineage that rapidly accumulated mutations of concern
Authors: Scheepers Cathrine , Everatt Josie , Amoako Daniel G. , Tegally Houriiyah , Wibmer Constantinos Kurt , Mnguni Anele , Ismail Arshad , Mahlangu Boitshoko , Lambson Bronwen E. , Richardson Simone I. , Martin Darren P. , Wilkinson Eduan , San James Emmanuel , Giandhari Jennifer , Manamela Nelia , Ntuli Noxolo , Kgagudi Prudence , Cele Sandile , Pillay Sureshnee , Mohale Thabo , Ramphal Upasana , Naidoo Yeshnee , Khumalo Zamantungwa T. , Kwatra Gaurav , Gray Glenda , Bekker Linda-Gail , Madhi Shabir A. , Baillie Vicky , Van Voorhis Wesley C. , NGS-SA  , Treurnicht Florette K. , Venter Marietjie , Mlisana Koleka , Wolter Nicole , Sigal Alex , Williamson Carolyn , Hsiao Nei-yuan , Msomi Nokukhanya , Maponga Tongai , Preiser Wolfgang , Makatini Zinhle , Lessells Richard , Moore Penny L. , de Oliveira Tulio , von Gottberg Anne , Bhiman Jinal N.
Published: August 2021

Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The emergence of C.1.2, associated with a high substitution rate, includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 VOC/VOIs. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta showed high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2.
An ultra-low dose of Δ9-tetrahydrocannabinol improves Alzheimer’s Disease-related cognitive deficits
Authors: Nitzan K. , Ellenbogen L. , Beniamin T. , Sarne Y. , Doron R
Published: August 2021

Alzheimer’s disease (AD) is the most common form of dementia. AD has a physical, emotional, and economic impact on the patients and their families and society at large. More than a decade since its discovery, there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional-high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC elevated Sirtuin-1 (Sirt-1) levels in the brain and ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Our working hypothesis suggests that ULD-THC can prevent and even reverse AD pathology. In this preliminary study, we saw that a single injection of ULD-THC alleviated cognitive impairments of a mice model for AD, 5xFAD mice. Our work may establish the foundations for the development of a pharmaceutical preparation for the treatment of AD patients, thus, bringing the ULD-THC treatment closer to clinical application.
Self-assembly of pericentriolar material in interphase cells lacking centrioles
Authors: Chen Fangrui , Wu Jingchao , Iwanski Malina K. , Jurriens Daphne , Sandron Arianna , Pasolli Milena , Puma Gianmarco , Kromhout Jannes Z. , Yang Chao , Nijenhuis Wilco , Kapitein Lukas C. , Berger Florian , Akhmanova Anna
Published: August 2021

Abstract

The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on PCM binding to centrioles, PCM self-association and dynein­mediated PCM transport, but the self-assembly properties of PCM in interphase cells are poorly understood. Here, we used experiments and modeling to study centriole-independent features of interphase PCM assembly. We showed that when centrioles are lost due to PLK4 depletion or inhibition, dynein-based PCM transport and PCM self-clustering are sufficient to form a single compact MTOC, which generates a dense radial microtubule array. Interphase PCM self-assembly depends on γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152 or CEP192. Formation of a compact acentriolar MTOC is inhibited by AKAP450-dependent PCM recruitment to the Golgi or by randomly organized CAMSAP2-stabilized microtubules, which keep PCM mobile and prevent its coalescence. Linking of CAMSAP2 to a minus-end-directed motor leads to the formation of an MTOC, but MTOC compaction requires cooperation with pericentrin-containing self-clustering PCM. Our data reveal that interphase PCM contains a set of components that can self-assemble into a compact structure and organize microtubules, but PCM self-organization is sensitive to motor-and microtubule-based rearrangement.
Environment symmetry drives a multidirectional code in rat retrosplenial cortex
Authors: Zhang Ningyu , Grieves Roddy M. , Jeffery Kate J.
Published: August 2021

A class of neurons showing bidirectional tuning in a two-compartment environment was recently discovered in dysgranular retrosplenial cortex (dRSC). We investigated here whether these neurons possess a more general environmental symmetry-encoding property, potentially useful in representing complex spatial structure. We report that directional tuning of dRSC neurons reflected environment symmetry in onefold, twofold and fourfold-symmetric environments: this was the case not just globally, but also locally within each sub-compartment. Thus, these cells use environmental cues to organize multiple directional tuning curves, which perhaps sometimes combine via interaction with classic head direction cells. A consequence is that both local and global environmental symmetry are simultaneously encoded even within local sub-compartments, which may be important for cognitive mapping of the space beyond immediate perceptual reach.

One Sentence Summary

Retrosplenial directionally tuned neurons encode global environment symmetry even in local sub-compartments.
FEDERATED MORPHOMETRY FEATURE SELECTION FOR HIPPOCAMPAL MORPHOMETRY ASSOCIATED BETA-AMYLOID AND TAU PATHOLOGY
Authors: Wu Jianfeng , Dong Qunxi , Zhang Jie , Su Yi , Wu Teresa , Caselli Richard J. , Reiman Eric M. , Ye Jieping , Lepore Natasha , Chen Kewei , Thompson Paul M. , Wang Yalin ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2021

Amyloid-β (Aβ) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimer’s disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of Aβ/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with Aβ/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two ADNI cohorts to understand hippocampal alterations that relate to Aβ/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89x speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum andcornu ammonis1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal Aβ/tau. As potential biomarkers for Aβ/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between Aβ/tau burden and hippocampal morphometry.
Direct capture and sequencing reveal ultra-short single-stranded DNA in biofluids
Authors: Cheng Lauren Y. , Dai Peng , Wu Lucia R. , Zhang David Yu
Published: August 2021

Direct capture and sequencing revealed a new DNA population in biofluids, named ultra-short single-stranded DNA (ussDNA), which was neglected by conventional DNA extraction and sequencing approaches. Evaluation of the size distribution and abundance of ussDNA in biofluids manifested generality of its presence in human, animal, and plants. Red blood cells were found to contain abundant ussDNA with enriched functional elements, and thus possesses great potential as a novel DNA biomarker.
Monodopsis and Vischeria genomes elucidate the biology of eustigmatophyte algae
Authors: Yang Hsiao-Pei , Wenzel Marius , Hauser Duncan A. , Nelson Jessica M. , Xu Xia , Eliáš Marek , Li Fay-Wei
Published: August 2021

Members of eustigmatophyte algae, especially Nannochloropsis, have been tapped for biofuel production owing to their exceptionally high lipid content. While extensive genomic, transcriptomic, and synthetic biology toolkits have been made available for Nannochloropsis, very little is known about other eustigmatophytes. Here we present three near-chromosomal and gapless genome assemblies of Monodopsis (60 Mb) and Vischeria (106 Mb), which are the sister groups to Nannochloropsis. These genomes contain unusually high percentages of simple repeats, ranging from 12% to 21% of the total assembly size. Unlike Nannochloropsis, LINE repeats are abundant in Monodopsis and Vischeria and might constitute the centromeric regions. We found that both mevalonate and non-mevalonate pathways for terpenoid biosynthesis are present in Monodopsis and Vischeria, which is different from Nannochloropsis that has only the latter. Our analysis further revealed extensive spliced leader trans-splicing in Monodopsis and Vischeria at 36-61% of genes. Altogether, the high-quality genomes of Monodopsis and Vischeria not only serve as the much-needed outgroups to advance Nannochloropsis research, but also shed new light on the biology and evolution of eustigmatophyte algae.
Integrative Genome Modeling Platform reveals essentiality of rare contact events in 3D genome organizations
Authors: Boninsegna Lorenzo , Yildirim Asli , Polles Guido , Quinodoz Sofia A. , Finn Elizabeth , Guttman Mitchell , Zhou Xianghong Jasmine , Alber Frank
Published: August 2021

A multitude of sequencing-based and microscopy technologies provide the means to unravel the relationship between the three-dimensional (3D) organization of genomes and key regulatory processes of genome function. However, it remains a major challenge to systematically integrate all available data sources to characterize the nuclear organization of genomes across different spatial scales. Here, we develop a multi-modal data integration approach to produce genome structures that are highly predictive for nuclear locations of genes and nuclear bodies, local chromatin compaction, and spatial segregation of functionally related chromatin.

By performing a quantitative assessment of the predictive power of genome structures generated from different data combinations, we demonstrate that multimodal data integration can compensate for systematic errors and missing values in some of the data and thus, greatly increases accuracy and coverage of genome structure models. We also show that alternative combinations of different orthogonal data sources can converge to models with similar predictive power. Moreover, our study reveals the key contributions of low-frequency inter-chromosomal contacts (e.g., “rare” contact events) to accurately predicting the global nuclear architecture, including the positioning of genes and chromosomes. Overall, our results highlight the benefits of multi-modal data integration for genome structure analysis, available through the Integrative Genome structure Modeling (IGM) software package that we introduce here.
Experimental safety testing shows that the NSAID tolfenamic acid is not toxic to Gyps vultures in India at concentrations likely to be encountered in cattle carcasses
Authors: Chandramohan S , Mallord John W. , Manickam Kesavan , Sharma A. K. , Mahendran K. , Gupta Reena , Chutia Krishna , Mathes Karikalan , Pawde Abhijit , Prakash Nikita V. , Ravichandran P. , Saikia Debasish , Shringarpure Rohan , Timung Avinash , Galligan Toby H. , Green Rhys E. , Prakash Vibhu M.
Published: August 2021

Population declines of Gyps vultures across the Indian subcontinent were caused by unintentional poisoning by the non-steroidal anti-inflammatory drug (NSAID) diclofenac. Subsequently, a number of other NSAIDs have been identified as toxic to vultures, while one, meloxicam, is safe at concentrations likely to be encountered by vultures in the wild. Other vulture-safe drugs need to be identified to reduce the use of those toxic to vultures. We report on safety-testing experiments on the NSAID tolfenamic acid on captive vultures of three Gyps species, all of which are susceptible to diclofenac poisoning. Firstly, we estimated the maximum level of exposure (MLE) of wild vultures and gave this dose to 38 Near Threatened G. himalayensis by oral gavage, with 15 control birds dosed with benzyl alcohol (the carrier solution for tolfenamic acid). Two birds given tolfenamic acid died with elevated uric acid levels and severe visceral gout, while the remainder showed no adverse clinical or biochemical signs. Secondly, four G. himalayensis were fed tissues from water buffaloes which had been treated with double the recommended veterinary dose of tolfenamic acid prior to death and compared to two birds fed uncontaminated tissue; none suffered any clinical effects. Finally, two captive Critically Endangered vultures, one G. bengalensis and one G. Indicus, were given the MLE dose by gavage and compared to two control birds; again, none suffered any clinical effects. The death of two G. himalayensis may have been an anomaly due to i) the high dose level used and ii) the high ambient temperatures at the time of the experiment. Tolfenamic acid is likely to be safe to Gyps vultures at concentrations encountered by wild birds and could therefore be promoted as a safe alternative to toxic NSAIDs. It is manufactured in the region, and is increasingly being used to treat livestock.
Cyclic loading regime considered beneficial does not protect injured and interleukin-1-inflamed cartilage from post-traumatic osteoarthritis
Authors: Eskelinen ASA , Florea C , Tanska P , Hung HK , Frank EH , Mikkonen S , Nieminen P , Julkunen P , Grodzinsky AJ , Korhonen RK
Published: August 2021

Post-traumatic osteoarthritis is a degenerative musculoskeletal condition where homeostasis of articular cartilage is perturbated by lesions and inflammation, leading to abnormal tissue-level loading. These mechanisms have rarely been included simultaneously inin vitroosteoarthritis models. We modeled the early disease progression in bovine cartilage regulated by the coaction of(1)mechanical injury,(2)pro-inflammatory interleukin-1α challenge, and(3)cyclic loading mimicking walking and considered beneficial (15% strain, 1 Hz). Surprisingly, cyclic loading did not protect cartilage from accelerated glycosaminoglycan loss over 12 days of interleukin-1-culture despite promoting aggrecan biosynthesis. Our time-dependent data suggest that this loading regime could be beneficial in the first days following injury but later turn detrimental in interleukin-1-inflamed cartilage. Consequently, early anti-catabolic drug intervention may inhibit, whereas cyclic loading during chronic inflammation may promote osteoarthritis progression. Our data on the early stages of post-traumatic osteoarthritis could be utilized in the development of countermeasures for disease progression.
Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection
Authors: Iida Kei , Ajiro Masahiko , Muramoto Yukiko , Takenaga Toru , Denawa Masatsugu , Kurosawa Ryo , Noda Takeshi , Hagiwara Masatoshi
Published: August 2021

Background

The rapidly accumulating disease susceptibility information collected from coronavirus disease (COVID-19) patient genomes must be urgently utilized to develop therapeutic interventions for SARS-CoV-2 infection. Chromosome 12q24.13, which encodes the 2’-5’-oligoadenylate synthetase (OAS) family of proteins that sense viral genomic RNAs and trigger an antiviral response, is identified as one of the genomic regions that contains SNPs associated with COVID-19 severity. A high-risk SNP identified at the splice acceptor site of OAS1 exon 6 is known to change the proportions of the various splicing isoforms and the activity of the enzyme.

Methods

We employed in-silico motif search and RNA pull-down assay to define a factor responsible for the OAS1 splicing. Next, we rationally selected a candidate for slicing modulator to modulate this splicing.

Results

We found that inhibition of CDC-like kinase with a small chemical compound induces switching of OAS1 splice isoforms in human lung cells. In this condition, increased resistance to SARS-CoV-2 infection, enhanced RNA degradation, and transcriptional activation of interferon β1, were also observed.

Conclusions

The results indicate the possibility of using chemical splicing modifiers aided by genome-based precision medicine to boost the innate immune response against SARS-CoV-2 infection.
An NLR Integrated Domain toolkit to identify plant pathogen effector targets
Authors: Landry David , Mila Isabelle , Sabbagh Cyrus Raja Rubenstein , Zaffuto Matilda , Pouzet Cécile , Tremousaygue Dominique , Dabos Patrick , Deslandes Laurent , Peeters Nemo
Published: August 2021

Plant resistance genes (or NLR “Nod-like Receptors”) are known to contain atypical domains procuring them with a decoy capacity. Some of these integrated domains (or ID) allow the plant to lure the virulence determinants (“effectors”) of pathogens and triggering a specific NLR immune reaction.

In this work, our goal was to generate a library of known IDs that could be screened with plant pathogen effectors in order to identify putative new effector virulence targets and NLR-effector pairs.

We curated the IDs contained in NLRs from seven model and crop plant species. We cloned 52 IDs representing 31 distinct Pfam domains. This library was screened for interaction by yeast-two-hybrid with a set of 31 conservedRalstonia solanacearumtype III effectors. This screening and the furtherin plantainteraction assay allowed us to identify three interactions, involving different IDs (kinase, DUF3542, WRKY) and two type III effectors (RipAE and PopP2).

PopP2 was found to physically interact with ID#85, an atypical WRKY domain integrated in the GmNLR-ID85 NLR protein from Soybean. Using a imaging method in living plant cells, we showed that PopP2 associates with ID#85 in the nucleus. But unlike the known WRKY-containing Arabidopsis RRS1-R NLR receptor, this newly identified soybean WRKY domain could not be acetylated by PopP2 and its atypical sequence (WRKYGKR) also probably renders it inefficient in plant immunity triggering.

This ID toolkit is available for screening with other plant pathogen effectors and should prove useful to discover new effectors targets and potentially engineer new plant resistance genes.
Presence and Stability of SARS-CoV-2 on Environmental Currency and Money Cards
Authors: Newey Colleen , Olausson Abigail T , Applegate Alyssa , Reid Ann Aubrey , Robison Richard A , Grose Julianne H.
Published: August 2021

The highly contagious nature of SARS-CoV-2 has led to several studies on the transmission of the virus. A little studied potential fomite of great concern in the community is currency, which has been shown to harbor microbial pathogens in several studies. Since the onset of the COVID-19 pandemic, many businesses in the United States have limited the use of banknotes in favor of credit cards. However, SARS-CoV-2 has shown greater stability on plastic in several studies.  Herein, the stability of SARS-CoV-2 at room temperature on banknotes, money cards and coins was investigated. In vitro studies with live virus suggested SARS-CoV-2 was highly unstable on banknotes, showing an initial rapid reduction in viable virus and no viral detection by 24 hours. In contrast, SARS-CoV-2 was far more stable on money cards with live virus detected after 48 hours. Environmental swabbing of currency and money cards on and near the campus of Brigham Young University supported these results, with no detection of SARS-CoV-2 RNA on banknotes, and a low level on money cards. No viable virus was detected on either. These preliminary results suggest that the use of money cards over banknotes in order to slow the spread of this virus may be ill-advised. These findings should be investigated further through larger environmental studies involving more locations.