bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial context predicts SARS-CoV-2 prevalence in patients and the hospital built environment
Authors: Marotz Clarisse , Belda-Ferre Pedro , Ali Farhana , Das Promi , Huang Shi , Cantrell Kalen , Jiang Lingjing , Martino Cameron , Diner Rachel E. , Rahman Gibraan , McDonald Daniel , Armstrong George , Kodera Sho , Donato Sonya , Ecklu-Mensah Gertrude , Gottel Neil , Salas Garcia Mariana C. , Chiang Leslie Y. , Salido Rodolfo A. , Shaffer Justin P. , Bryant MacKenzie , Sanders Karenina , Humphrey Greg , Ackermann Gail , Haiminen Niina , Beck Kristen L. , Kim Ho-Cheol , Carrieri Anna Paola , Parida Laxmi , Vázquez-Baeza Yoshiki , Torriani Francesca J. , Knight Rob , Gilbert Jack A. , Sweeney Daniel A. , Allard Sarah M.
Published: November 2020

Synergistic effects of bacteria on viral stability and transmission are widely documented but remain unclear in the context of SARS-CoV-2. We collected 972 samples from hospitalized patients with coronavirus disease 2019 (COVID-19), their health care providers, and hospital surfaces before, during, and after admission. We screened for SARS-CoV-2 using RT-qPCR, characterized microbial communities using 16S rRNA gene amplicon sequencing, and contextualized the massive microbial diversity in this dataset through meta-analysis of over 20,000 samples. Sixteen percent of surfaces from COVID-19 patient rooms were positive, with the highest prevalence in floor samples next to patient beds (39%) and directly outside their rooms (29%). Although bed rail samples increasingly resembled the patient microbiome over time, SARS-CoV-2 was detected less there (11%). Despite viral surface contamination in almost all patient rooms, no health care workers contracted the disease, suggesting that personal protective equipment was effective in preventing transmissions. SARS-CoV-2 positive samples had higher bacterial phylogenetic diversity across human and surface samples, and higher biomass in floor samples. 16S microbial community profiles allowed for high SARS-CoV-2 classifier accuracy in not only nares, but also forehead, stool, and floor samples. Across distinct microbial profiles, a single amplicon sequence variant from the genus Rothia was highly predictive of SARS-CoV-2 across sample types and had higher prevalence in positive surface and human samples, even compared to samples from patients in another intensive care unit prior to the COVID-19 pandemic. These results suggest that bacterial communities may contribute to viral prevalence both in the host and hospital environment.

One Sentence Summary

Microbial classifier highlights specific taxa predictive of SARS-CoV-2 prevalence across diverse microbial niches in a COVID-19 hospital unit.
Anthropometrics: A forgotten gem in clinical assessment of obesity
Authors: Bhatti R , Warshow U M. , Joumaa M , ElSaban M , Nawaz F , Khamis A H
Published: November 2020

Background

According to World Health Organization (WHO), United Arab Emirates (UAE) has one of the highest prevalence rates of obesity in the Middle East at 34%. There is a paralleled rise in the incidence of related metabolic conditions, particularly type 2 diabetes, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Body mass index (BMI) alone is an insufficient marker of abdominal adiposity and addition of waist circumference (WC) can help to assess the cardiometabolic risk.

Aim

To study the prevalence of obesity related diseases in a multidisciplinary weight management program and determine the relationship to obesity anthropometric indices.

Methods

This is a cross-sectional study conducted at Mediclinic Parkview Hospital in Dubai, UAE. 308 patients have been evaluated from January 2019 until September 2019 as part of a multi-disciplinary weight management program. Key demographics, anthropometrics, and clinical data was analyzed using Statistical Package for Social Sciences software version 25 (SPSS Inc., Chicago, IL).

Results

Three hundred and eight patients taking part in the weight management program were studied. The population was constituted of 103 (33%) males and 205 (67%) females. The mean age was 41 years (±9.6) with a median BMI of 34.5 (±6.7) and 33.7 (±7.8) for males and females respectively. Mean waist circumference was 113.4 cm (±23.3) and 103.5 cm (±16.2), fat percent was 33.7% (±11.6) and 45 (±6.8), fat mass was 41 kg (±15.2) and 41.1 (±14.1), and visceral fat was 6.5 kg (±3.2) and 3.1 (±1.8), for males and females respectively. The population was heterogeneous with 38 nationalities. BMI strongly correlated with waist circumference (male; female, r=0.67; r=0.72) and visceral fat (male; female, r=0.89; r=0.78). Further, waist circumference was significantly associated with risk of diabetes, hypertension, and NAFLD.

Conclusion

The study has confirmed the high prevalence rates of obesity related diseases in a private hospital setting in a multinational cohort of obese patients. BMI and waist circumference are the most representative measures of obesity in our population and correlate with abdominal adiposity and obesity related diseases. Further studies will play a part in assessing the benefit of these measures during weight reduction interventions.
Community factors and excess mortality in first wave of the COVID-19 pandemic
Authors: Davies Bethan , Parkes Brandon L , Bennett James , Fecht Daniela , Blangiardo Marta , Ezzati Majid , Elliott Paul
Published: November 2020

Risk factors for increased risk of death from Coronavirus Disease 19 (COVID-19) have been identified1,2 but less is known on characteristics that make communities resilient or vulnerable to the mortality impacts of the pandemic. We applied a two-stage Bayesian spatial model to quantify inequalities in excess mortality at the community level during the first wave of the pandemic in England. We used geocoded data on all deaths in people aged 40 years and older during March-May 2020 compared with 2015-2019 in 6,791 local communities. Here we show that communities with an increased risk of excess mortality had a high density of care homes, and/or high proportion of residents on income support, living in overcrowded homes and/or high percent of people with a non-White ethnicity (including Black, Asian and other minority ethnic groups). Conversely, after accounting for other community characteristics, we found no association between population density or air pollution and excess mortality. Overall, the social and environmental variables accounted for around 15% of the variation in mortality at community level. Effective and timely public health and healthcare measures that target the communities at greatest risk are urgently needed if England and other industrialised countries are to avoid further widening of inequalities in mortality patterns during the second wave.
Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice
Authors: Healy Sara A. , Anderson Charles , Swihart Bruce J. , Mwakingwe Agnes , Gabriel Erin E. , Decederfelt Hope , Hobbs Charlotte V. , Rausch Kelly M. , Zhu Daming , Muratova Olga , Herrera Raul , Scaria Puthupparampil V. , MacDonald Nicholas J. , Lambert Lynn E. , Zaidi Irfan , Coelho Camila H. , Renn Jonathan P. , Wu Yimin , Narum David L. , Duffy Patrick E.
Published: November 2020

Background

Vaccines that block human-to-mosquitoPlasmodiumtransmission are needed for malaria eradication and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced significant serum functional activity in both US and Malian adults. However, antibody titers declined rapidly, and transmission-reducing activity required four vaccine doses. Functional immunogenicity and durability must be improved before advancing TBV further in clinical development. We hypothesized that the pre-fertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.

Methods

Transmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel®,and administered to mice, rhesus macaques, and humans. Antibody titers were measured by ELISA and transmission-reducing activity was assess by the Standard Membrane Feeding Assay.

Results

Pfs25-EPA/Alhydrogel®and Pfs230D1-EPA/Alhydrogel®induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In U.S. adults, two vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel® recipients but no significant activity in five Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.

Conclusion

The complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.

Trial Registration

ClinicalTrials.govNCT02334462

Funding

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
A simple direct RT-LAMP SARS-CoV-2 saliva diagnostic
Authors: Flynn Michael J. , Snitser Olga , Flynn James , Green Samantha , Yelin Idan , Szwarcwort-Cohen Moran , Kishony Roy , Elowitz Michael B.
Published: November 2020

Widespread, frequent testing is essential for curbing the ongoing COVID-19 pandemic. Because its simplicity makes it ideal for widely distributed, high throughput testing, RT-LAMP provides an attractive alternative to RT-qPCR. However, most RT-LAMP protocols require the purification of RNA, a complex and low-throughput bottleneck that has often been subject to reagent supply shortages. Here, we report an optimized RT-LAMP-based SARS-CoV-2 diagnostic protocol for saliva and swab samples. In the protocol we replace RNA purification with a simple sample preparation step using a widely available chelating agent, as well as optimize key protocol parameters. When tested on clinical swab and saliva samples, this assay achieves a limit of detection of 105viral genomes per ml, with sensitivity close to 90% and specificity close to 100%, and takes 45 minutes from sample collection to result, making it well suited for a COVID-19 surveillance program.
The effectiveness of early diagnostic tools for neural lesions in leprosy An observational cohort study
Authors: Cegana Luciano Henrique Vieira , Nardi Susilene Maria Tonelli , Pascoeto Luciana , Paschoal Vania Del Arco
Published: November 2020

Cegana LHV, Nardi SMT, Pascoeto L, Paschoal VDA. The effectiveness of early diagnostic tools for neural lesions in leprosy. 37p. MANUSCRIPT, 2020. https://doi.org/10.1101/2020.11.19.20234963

Introduction

Leprosy can cause different lesions in peripheral nerves and inervatory structures.

Objectives

To analyse the effectiveness of evaluation protocols used to identify neural lesions in leprosy such as Degree of Physical Disability (DPD), Simplified Neurological Assessment (SNA) and propose to use Neurodynamic Assessment (NDA).

Method

Descriptive analytical study, associative, with 27 individuals treated in two outpatient leprosy clinics in São Paulo State, between 2017 and 2019, and 27 individuals from the paired control group. The Mann-Whitney, Multivariate Linear Regression and association between variables and P<0.05 values were used.

Results

The test that most captured the neurological alterations was the SNA, with 22 (81.5%) in the upper limbs (ULs) and 25 (92.6%) in the lower limbs (LLs), followed by the NDA, with 20 (74.1%) in the ULs and 11 (40.7%) in the LLs. The DPD showed handicap in the hands of 16 (59.2%) individuals and in the feet of 17 (62.9%) individuals, and they have expressed sensitivity. DPD showed agreement with SNA in 21 (77.8%) of the cases in ULs (p=0.010) and 19 (70,4%) of the cases in LLs (p=0.060). DPD and NDA showed that in 19 (70.4%) of the patients evaluated there was concordance of results in ULs (p=0.143); 9 (33.3%) in LLs (p=0.125). SNA and the NDA in the ULs found agreement in 21 (77.8%); 11 (40.7%) (p=0.786) in the LLs.

Conclusion

The three assessment instruments are specific and will hardly produce false positive tests. DPD can produce more false negatives than SNA. If there is an instrument to be chosen, it should be the SNA, since it is more sensitive, more accurate and has a less negative likelihood ratio. Neurodynamic tests were positive in 7.4% of individuals while there were still no changes in the SNA; afterwards, these changes appeared.

Descriptors

Neural mobilization; Leprosy; Peripheral nerves; Disability; Pain; Physical therapy.
A framework to model global, regional, and national estimates of intimate partner violence
Authors: Maheu-Giroux Mathieu , Sardinha Lynnmarie , Stöckl Heidi , Meyer Sarah , Godin Arnaud , Alexander Monica , García-Moreno Claudia
Published: November 2020

Abstract

Background

Accurate and reliable estimates of violence against women statistics form the backbone of monitoring efforts to eliminate these human right violations and public health concerns. Estimating the prevalence of intimate partner violence (IPV) is challenging due to variations in case definition and recall period, surveyed populations, partner definition, level of age disaggregation, and survey representativeness, among others. In this paper, we aim to develop a sound and flexible statistical modeling framework for global, regional, and national IPV statistics.

Methods

We modeled IPV within a Bayesian multilevel modeling framework, accounting for heterogeneity of age groups using age-standardization, and age patterns and time trends using splines functions. Survey comparability is achieved using adjustment factors which are estimated using exact matching and their uncertainty accounted for. Both in-sample and out-of-sample comparisons are used for model validation, including posterior predictive checks. Post-processing of models’ outputs is performed to aggregate estimates at different geographic levels and age groups.

Results

A total of 307 unique studies conducted between 2000-2018, from 154 countries/territories/areas, and totaling nearly 1.8 million unique women responses informed lifetime IPV. Past year IPV had similar number of studies (n=332), countries represented (n=159), and individual responses (n=1.8 million). Roughly half of IPV observations required some adjustments. Posterior predictive checks suggest good model fit to data and out-of-sample comparisons provided reassuring results with small median prediction errors and appropriate coverage of predictions’ intervals.

Conclusions

The proposed modeling framework can pool both national and sub-national surveys, account for heterogeneous age groups and age trends, accommodate different surveyed population, adjust for differences in survey instruments, and efficiently propagate uncertainty to model outputs. By describing this model to reproducible levels of details, the accurate interpretation and responsible use of estimates for global monitoring of violence against women elimination efforts are supported, as part of the Sustainable Development Goals.
Resources allocation explains the differential roles of RBS and promoter strengths in cell mass distribution and optimal protein expression productivity
Authors: Nóbel Fernando , Picó Jesús
Published: November 2020

Design of synthetic genetic circuits without considering the impact of host–circuit interactions results in an inefficient design process and lengthy trial-and-error iterations to appropriately tune the expression levels. Microorganisms have evolved to reach an optimal use of cellular resources. This balance is perturbed by circuit-host interactions resulting from the interaction among the cell environment from which the cell takes substrates, its metabolism, and the needs of exogenous synthetic genetic circuit introduced in the cell host. The resulting competition for common shared cell resources introduces spurious dynamics leading to problems of malfunctioning of the synthetic circuit due to lack of enough cellular resources. Therefore, there is an increasing interest in development of methods for model-based design of synthetic gene circuits considering host-circuit interactions. Here we present a small-size model of gene expression dynamics in bacterial cells accounting for host-circuit interactions. For each gene, the model defines the cellular resources recruitment strength as the key functional coefficient that allows to explain the distribution of resources among the host and the genes of interest and the relationship between the usage of resources and cell growth. This functional coefficient explicitly takes into account the availability of resources and lab-accessible gene characteristics, such as promoter and ribosome binding site (RBS) strengths and capture their interplay with the availability of free cell resources. In spite of its simplicity, the model is able to explain the differential role of promoter and RBS strengths in the distribution of protein mass and the optimal protein expression productivity with remarkable fit to the experimental data from the literature forE. coli. This makes the model amenable for model-based circuit design purposes. Moreover, the model also allows to understand why endogenous ribosomal and non-ribosomal genes have evolved different strategies in the expression space.
Isolation thresholds for curbing SARS-CoV-2 resurgence
Authors: Yakob Laith
Published: November 2020

Self-instigated isolation is heavily relied on to curb SARS-CoV-2 transmission. Accounting for uncertainty in the latent and prepatent periods, as well as the proportion of infections that remain asymptomatic, the limits of this intervention at different phases of infection resurgence are estimated. We show that by October 2020, SARS-CoV-2 transmission rates in England had already begun exceeding levels that could be interrupted using this intervention alone, lending support to the second national lockdown on November 5th 2020.
Experience of the COVID-19 pandemic in rural Odisha, India: knowledge, preventative actions, and impacts on daily life
Authors: Bauza Valerie , Sclar Gloria D. , Bisoyi Alokananda , Owens Ajilé , Ghugey Apurva , Clasen Thomas
Published: November 2020

We conducted 131 semi-structured phone interviews with householders in rural Odisha, India to explore participants’ COVID-19 related knowledge, perceptions, and preventative actions, as well as how the pandemic was impacting their daily life, economic and food security, and the village-level response. Interviews were conducted with 73 heads of household, 37 primary caregivers, and 21 members of village water and sanitation committees from 43 rural villages in Ganjam and Gajapati districts in Odisha state. The study took place between May-July 2020 throughout various lockdown restrictions and at a time when many migrant workers were returning to their villages. Most respondents could name at least one correct symptom of COVID-19 (75%), but there was lower knowledge about causes of the disease and high-risk groups, and overall COVID-19 knowledge was lowest among caregivers. Respondents reported high compliance with important preventative measures, including staying home as much as possible (94%), social distancing (91%), washing hands frequently (96%), and wearing a facial mask (95%). Additionally, many respondents reported job loss (31%), financial challenges (93%), challenges related to staying home whether as a preventative measure or due to lockdowns (57%), changes in types and/or amount of food consumed (61%), and adverse emotional effects as a result of the pandemic and lockdown. We also provide detailed summaries of qualitative responses to allow for deeper insights into the lived experience of villagers during this pandemic. Although the research revealed high compliance with preventative measures, the pandemic and associated lockdowns also led to many challenges and hardships faced in daily life particularly around job loss, economic security, food security, and emotional wellbeing. The results underscore the vulnerability of marginalized populations to the pandemic and the need for measures that increase resilience to large-scale shocks.
A CDK-regulated chromatin segregase promoting chromosome replication
Authors: Chacin Erika , Bansal Priyanka , Reusswig Karl-Uwe , Diaz-Santin Luis M. , Ortega Pedro , Vizjak Petra , Gómez-González Belen , Müller-Planitz Felix , Aguilera Andrés , Pfander Boris , Cheung Alan C.M. , Kurat Christoph F.
Published: November 2020

The replication of chromosomes during S phase is critical for cellular and organismal function. Replicative stress can result in genome instability, which is a major driver of cancer. Yet how chromatin is made accessible during eukaryotic DNA synthesis is poorly understood.

Here, we report the identification of a novel class of chromatin remodeling enzyme, entirely distinct from classical SNF2-ATPase family remodelers. Yta7 is a AAA+-ATPase that assembles into ~ 1 MDa hexameric complexes capable of segregating histones from DNA. Yta7 chromatin segregase promotes chromosome replication bothin vivoandin vitro. Biochemical reconstitution experiments using purified proteins revealed that Yta7’s enzymatic activity is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK). S-CDK phosphorylation stimulates ATP hydrolysis by Yta7, promoting nucleosome disassembly and chromatin replication.

Our results present a novel mechanism of how cells orchestrate chromatin dynamics in co-ordination with the cell cycle machinery to promote genome duplication during S phase.
Likelihood Approximation Networks (LANs) for Fast Inference of Simulation Models in Cognitive Neuroscience
Authors: Fengler Alexander , Govindarajan Lakshmi N. , Chen Tony , Frank Michael J.
Published: November 2020

In cognitive neuroscience, computational modeling can formally adjudicate between theories and affords quantitative fits to behavioral/brain data. Pragmatically, however, the space of plausible generative models considered is dramatically limited by the set of models with known likelihood functions. For many models, the lack of a closed-form likelihood typically impedes Bayesian inference methods. As a result, standard models are evaluated for convenience, even when other models might be superior. Likelihood-free methods exist but are limited by their computational cost or their restriction to particular inference scenarios. Here, we propose neural networks that learn approximate likelihoods for arbitrary generative models, allowing fast posterior sampling with only a one-off cost for model simulations that is amortized for future inference. We show that these methods can accurately recover posterior parameter distributions for a variety of neurocognitive process models. We provide code allowing users to deploy these methods for arbitrary hierarchical model instantiations without further training.
Transmission and protection against re-infection in the ferret model with the SARS-CoV-2 USA-WA1/2020 reference isolate
Authors: Patel Devanshi R. , Field Cassandra J. , Septer Kayla M. , Sim Derek G. , Jones Matthew J. , Heinly Talia A. , McGraw Elizabeth A. , Sutton Troy C
Published: November 2020

SARS-CoV-2 has initiated a global pandemic and vaccines are being rapidly developed. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory transmission was poor to only 1/4 contact animals. To assess the durability of immunity, ferrets were re-challenged 28 or 56 days post-primary infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets against infection, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the SARS-CoV-2 USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity.

Importance

The SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.
Neuromorphological changes following selection for tameness and aggression in the Russian fox-farm experiment
Authors: Hecht Erin E. , Kukekova Anna , Gutman David A. , Acland Greg , Preuss Todd M. , Trut Lyudmila
Published: November 2020

The Russian fox-farm experiment is an unusually long-running and well-controlled study designed to replicate wolf-to-dog domestication. As such, it offers an unprecedented window onto the neural mechanisms governing the evolution of behavior. Here we report adaptations to gray matter morphology resulting from selection for tameness vs. aggressive response toward humans. Contrasting with prior work in other domesticated species, tame foxes did not show reduced brain volume. Rather, gray matter volume in both the tame and aggressive strains was increased relative to foxes bred without selection on behavior. Furthermore, tame- and aggressive-enlarged regions overlapped substantially, including portions of motor, somatosensory, and prefrontal cortex, amygdala, hippocampus, and cerebellum. We also observed differential morphological covariation across distributed gray matter networks. In one prefrontal-hypothalamic network, this covariation differentiated the tame and aggressive foxes together from the conventional strain. These findings indicate that selection for opposite behaviors can influence brain morphology in a similar way.
Crosstalk between repair pathways elicits Double-Strand Breaks in alkylated DNA: implications for the action of temozolomide
Authors: Fuchs Robert P. , Isogawa Asako , Paulo Joao A. , Onizuka Kazumitsu , Takahashi Tatsuro , Amunugama Ravindra , Duxin Julien , Fujii Shingo
Published: November 2020

Temozolomide (TMZ), a DNA methylating agent, is the primary chemotherapeutic drug used in glioblastoma treatment. TMZ induces mostly N-alkylation adducts (N7-methylguanine and N3-methyladenine) and some O6-methylguanine (O6mG). Current models propose that during DNA replication, thymine is incorporated across from O6mG, promoting a futile cycle of mismatch repair (MMR) that leads to DNA double strand breaks (DSBs). To revisit the mechanism of O6mG processing, we reacted plasmid DNA with N-Methyl-N-nitrosourea (MNU), a temozolomide mimic, and incubated it in Xenopus egg extracts. We show that in this system, mismatch repair (MMR) proteins are enriched on MNU-treated DNA and we observe robust, MMR-dependent, repair synthesis. Our evidence also suggests that MMR, initiated at O6mG:C sites, is strongly stimulated incisby repair processing of other lesions, such as N-alkylation adducts. Importantly, MNU-treated plasmids display DSBs in extracts, the frequency of which increased linearly with the square of alkylation dose. We suggest that DSBs result from two independent repair processes, one involving MMR at O6mG:C sites and the other involving BER acting at a nearby N-alkylation adducts. We propose a new, replication-independent mechanism of action of TMZ, that operates in addition to the well-studied cell cycle dependent mode of action.
Forensic features and genetic legacy of the Baloch population of Pakistan and the Hazara population across Durand-line revealed by Y chromosomal STRs
Authors: Adnan Atif , Wen Shao-Qing , Rakha Allah , Alghafri Rashed , Nazir Shahid , Rehman Muhammad , Wang Chuan-Chao , Lu Jie
Published: November 2020

Hazara population across Durand-line has experienced extensive interaction with Central Asian and East Asian populations. Hazara individuals have typical Mongolian facial appearances and they called themselves descendants of Genghis Khan’s army. The people who speak the Balochi language are called Baloch. Previously, a worldwide analysis of Y-chromosomal haplotype diversity for rapidly mutating (RM) Y-STRs and with PowerPlex Y23 System (Promega Corporation Madison, USA) kit was created with collaborative efforts, but Baloch and Hazara population from Pakistan and Hazara population from Afghanistan were missing. A limited data with limited number of markers and samples is available which poorly define these populations. So, in the current study, Yfiler Plus PCR Amplification Kit loci were examined in 260 unrelated Hazara individuals from Afghanistan, 153 Hazara individuals, and 111 Balochi individuals from Baluchistan Pakistan. For the Hazara population from Afghanistan and Pakistan overall, 380 different haplotypes were observed on these 27 Y-STR loci, gene diversities ranged from 0.51288 (DYS389I) to 0.9257 (DYF387S1) and haplotype diversity was 0.9992 +/- 0.0004. For the Baloch population, every individual was unique at 27 Y-STR loci, gene diversity ranged from 0.5718 (DYS460) to 0.9371(DYF387S1). Twelve haplotypes shared between 178 individuals while only two haplotypes among these twelve were shared between 87 individuals in Hazara populations. Rst and Fst pairwise genetic distance analyses, multidimensional scaling (MDS) plot, Neighbor-joining (NJ) tree, linear discriminatory analysis (LDA), and median-joining network (MJNs) were performed, which shed light on the history of Hazara and Baloch populations. Interestingly null alleles were observed at DYS448 with specific mutation patterns in Hazara populations. The results of our study showed that the Yfiler Plus PCR Amplification Kit marker set provided substantially stronger discriminatory power in the Baloch population of Pakistan and the Hazara population across the Durand-line.
Patient-derived Glioblastoma Stem cells transfer mitochondria through Tunneling Nanotubes in Tumor Organoids
Authors: Pinto Giulia , Saenz-de-Santa-Maria Inés , Chastagner Patricia , Perthame Emeline , Delmas Caroline , Toulas Christine , Moyal-Jonathan-Cohen Elizabeth , Brou Christel , Zurzolo Chiara
Published: November 2020

Glioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSLCs). Also, tumor networking and intercellular communication play a major role in driving GBM therapy-resistance. Tunneling Nanotubes (TNTs), thin membranous open-ended channels connecting distant cells, have been observed in several types of cancer, where they emerge to drive a more malignant phenotype. Here, we investigated whether GBM cells are capable to intercommunicate by TNTs. Two GBM stem-like cells (GSLCs) were obtained from the external and infiltrative zone of one GBM from one patient. We show, for the first time, that both GSLCs, grown in classical 2D culture and in 3D-tumor organoids, formed functional TNTs which allowed mitochondria transfer. In the organoid model, recapitulative of several tumor’s features, we observed the formation of a network between cells constituted of both Tumor Microtubes (TMs), previously observedin vivo, and TNTs. In addition, the two GSLCs exhibited different responses to irradiation in terms of TNT induction and mitochondria transfer, although the correlation with the disease progression and therapy-resistance needs to be further addressed. Thus, TNT-based communication is active in different GSLCs derived from the external tumoral areas associated to GBM relapse, and we propose that they participate together with TMs in tumor networking.
Computational cell cycle analysis of single cell RNA-Seq data
Authors: Moussa Marmar , Măndoiu Ion I.
Published: November 2020

The variation in gene expression profiles of cells captured in different phases of the cell cycle can interfere with cell type identification and functional analysis of single cell RNA-Seq (scRNA-Seq) data. In this paper, we introduce SC1CC (SC1 CellCycle analysis tool), a computational approach for clustering and ordering single cell transcriptional profiles according to their progression along cell cycle phases. We also introduce a new robust metric, Gene Smoothness Score (GSS) for assessing the cell cycle based order of the cells. SC1CC is available as part of the SC1 web-based scRNA-Seq analysis pipeline, publicly accessible athttps://sc1.engr.uconn.edu/.
A comprehensive analysis of the global human gut archaeome from a thousand genome catalogue
Authors: Chibani Cynthia Maria , Mahnert Alexander , Borrel Guillaume , Almeida Alexandre , Werner Almut , Brugere Jean-Francois , Gribaldo Simonetta , Finn Robert D. , Schmitz Ruth A. , Moissl-Eichinger Christine
Published: November 2020

The human gut microbiome plays an important role in health and disease, but the archaeal diversity therein remains largely unexplored. Here we report the pioneering analysis of 1,167 non-redundant archaeal genomes recovered from human gastrointestinal tract microbiomes across countries and populations. We identified three novel genera and 15 novel species including 52 previously unknown archaeal strains. Based on distinct genomic features, we warrant the split of the Methanobrevibacter smithii clade into two separate species, with one represented by the novel Candidatus M. intestini. Patterns derived from 1.8 million proteins and 28,851 protein clusters coded in these genomes showed a substantial correlation with socio-demographic characteristics such as age and lifestyle. We infer that archaea are actively replicating in the human gastrointestinal tract and are characterized by specific genomic and functional adaptations to the host. We further demonstrate that the human gut archaeome carries a complex virome, with some viral species showing unexpected host flexibility. Our work furthers our current understanding of the human archaeome, and provides a large genome catalogue for future analyses to decipher its role and impact on human physiology.
A conserved strategy for inducing appendage regeneration
Authors: Abrams Michael J. , Tan Fayth , Basinger Ty , Heithe Martin , Li Yutian , Raffiee Misha , Leahy Patrick , Dabiri John O. , Gold David A. , Goentoro Lea
Published: November 2020

Can limb regeneration be induced? Few have pursued this question, and an evolutionarily conserved strategy has yet to emerge. This study reports a strategy for inducing regenerative response in appendages, which works across three species that span the animal phylogeny. In Cnidaria, the frequency of appendage regeneration in the moon jellyfishAureliawas increased by feeding with the amino acid L-leucine and the growth hormone insulin. In insects, the same strategy induced tibia regeneration in adultDrosophila. Finally, in mammals, L-leucine and sucrose administration induced digit regeneration in adult mice, including dramatically from mid-phalangeal amputation. The conserved effect of L-leucine and insulin/sugar suggests a key role for energetic parameters in regeneration induction. The simplicity by which nutrient supplementation can induce appendage regeneration provides a testable hypothesis across animals.
Correlative transmission electron microscopy and high-resolution hard X-ray fluorescence microscopy of cell sections to measure trace elements concentrations at the organelle level
Authors: Suárez Vanessa Tardillo , Gallet Benoit , Chevallet Mireille , Jouneau Pierre-Henri , Tucoulou Rémi , Veronesi Giulia , Deniaud Aurélien
Published: November 2020

Metals are essential to all forms of life and their concentration and distribution in the organisms are tightly regulated. Indeed, in their free form, metal ions are toxic. Therefore, an excess of physiologic metal ions or the uptake of non-physiologic metal ions can be highly detrimental for the organisms. It is thus fundamental to understand metals distribution and dynamics in physiologic or disrupted conditions, for instance in metal-related pathologies or upon environmental exposure to metals. Elemental imaging techniques can serve this purpose, by allowing the visualization and the quantification of metal species in a tissue or down to the interior of a cell. Among these techniques, synchrotron radiation-based X-ray fluorescence (SR-XRF) microscopy is the most sensitive to date, and great progresses were made to reach spatial resolutions as low as 20×20 nm2. Until recently, 2D XRF mapping was used on whole cells, thus summing up the signal from the whole thickness of the cell. In the last two years, we have developed a methodology to work on thin cell sections, in order to analyze the metal content at the level of the organelle. Herein, we propose a correlative method to couple SR-XRF to electron microscopy, with the aim to quantify the elemental content in an organelle of interest. As a proof-of-concept, the technique was applied to the analysis of mitochondria from hepatocytes exposed to silver nanoparticles. It was thus possible to identify mitochondria with higher concentration of Ag(I) ions compared to the surrounding cytosol. The versatility of the method makes it suitable to answer a large panel of biological questions, for instance related to metal homeostasis in biological organisms.
DNA methylation age analysis of rapamycin in common marmosets
Authors: Horvath Steve , Zoller Joseph A. , Haghani Amin , Lu Ake T. , Raj Ken , Jasinska Anna J. , Mattison Julie A. , Salmon Adam B.
Published: November 2020

Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging (“epigenetic clocks”). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets (Callithrix jacchus) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here, two epigenetic clocks for marmosets that are applicable to whole blood samples. We find that the human-marmoset clock for relative age exhibits moderately high age correlations in two other non-human primate species: vervet monkeys and rhesus macaques. In a separate cohort of marmosets, we tested whether intervention with rapamycin, a drug shown to extend lifespan in mice, would alter the epigenetic age of marmosets, as measured by the marmoset epigenetic clocks. These clocks did not detect significant effects of rapamycin on the epigenetic age of marmoset blood. The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). Overall, the epigenetic clocks developed here for the common marmoset are expected to be useful for age estimation of wild-born animals and for anti-aging studies in this species.
CM1-driven assembly and activation of Yeast γ-Tubulin Small Complex underlies microtubule nucleation
Authors: Brilot Axel F. , Lyon Andrew S. , Zelter Alex , Viswanath Shruthi , Maxwell Alison , MacCoss Michael J. , Muller Eric G. , Sali Andrej , Davis Trisha N. , Agard David A.
Published: November 2020

Microtubule (MT) nucleation is regulated by the γ-tubulin ring complex (γTuRC), conserved from yeast to humans. In Saccharomyces cerevisiae, γTuRC is composed of seven identical γ-tubulin small complex (γTuSC) sub-assemblies which associate helically to template microtubule growth. γTuRC assembly provides a key point of regulation for the MT cytoskeleton. Here we combine cross-linking mass spectrometry (XL-MS), X-ray crystallography and cryo-EM structures of both monomeric and dimeric γTuSCs, and open and closed helical γTuRC assemblies in complex with Spc110p to elucidate the mechanisms of γTuRC assembly. γTuRC assembly is substantially aided by the evolutionarily conserved CM1 motif in Spc110p spanning a pair of adjacent γTuSCs. By providing the highest resolution and most complete views of any γTuSC assembly, our structures allow phosphorylation sites to be mapped, surprisingly suggesting that they are mostly inhibitory. A comparison of our structures with the CM1 binding site in the human γTuRC structure at the interface between GCP2 and GCP6 allows for the interpretation of significant structural changes arising from CM1 helix binding to metazoan γTuRC.
Novel Cluster AZArthrobacterphages Powerpuff, Lego, and YesChef exhibit close functional relationships withMicrobacteriumphages
Authors: Kapinos Andrew , Aghamalian Pauline , Capehart Erika , Alag Anya , Angel Heather , Briseno Eddie , Farag Emily , Foster Hilory , Hakim Abbas , Hernandez-Casas Daisy , Huang Calvin , Lam Derek , Mendez Maya , Min Ashley , Nguyen Nikki , Ortiz Emily , Saldivar Lizbeth Shelly , Shannon Jack Arthur , Smith Rachel , Sridhar Mihika V. , Ta An , Theophilus Malavika C. , Ngo Ryan , Torres Canela , Reddi Krisanavane , Freise Amanda C. , Parker Jordan Moberg
Published: November 2020

Bacteriophages exhibit a vast spectrum of relatedness and there is increasing evidence of close genomic relationships independent of host genus. The variability in phage similarity at the nucleotide, amino acid, and gene content levels confounds attempts at quantifying phage relatedness, especially as more novel phages are isolated. This study describes three highly similar novelArthrobacter globiformisphages–Powerpuff, Lego, and YesChef–which were assigned to Cluster AZ using a nucleotide-based clustering parameter. Phages in Cluster AZ andMicrobacteriumCluster EH, as well as the formerMicrobacteriumsingleton Zeta1847, exhibited low nucleotide similarity but gene content similarity in excess of the recently adoptedMicrobacteriumclustering parameter, which resulted in the reassignment of Zeta1847 to Cluster EH. Additionally, Clusters AZ and EH phages encode a shared integrase indicative of a lysogenic life cycle; in the first experimental verification of a Cluster AZ phage’s life cycle, we show that phage Powerpuff is a true temperate phage and forms stable lysogens that exhibit immunity to superinfection by related phages, despite lacking identifiable repressors typically required for lysogenic maintenance and superinfection immunity. The ability of phage Powerpuff to undergo and maintain lysogeny suggests that other closely related phages encoding an integrase but lacking an identified repressor may be temperate as well. Our findings further highlight the importance of using multiple metrics to capture phage relatedness, provide additional evidence of significant shared phage genomic content spanning multiple actinobacterial host genera, and demonstrate the continued need for verification and characterization of life cycles in newly isolated phages.
THE VARIATION OF GENOME SITES ASSOCIATED WITH SEVERE COVID-19 ACROSS POPULATIONS: THE WORLDWIDE AND NATIONAL PATTERNS
Authors: Balanovsky Oleg , Petrushenko Valerie , Mirzaev Karin , Abdullaev Sherzod , Gorin Igor , Chernevskiy Denis , Agdzhoyan Anastasiya , Balanovska Elena , Alexander Kryukov , Sychev Dmitriy
Published: November 2020

Background

The knowledge of clinically relevant markers distribution might become a useful tool in COVID-19 therapy using personalized approach in the lack of unified recommendations for COVID-19 patients management during pandemic. We aimed to identify the frequencies and distribution patterns of rs11385942 and rs657152 polymorphic markers, associated with severe COVID-19, among populations of the world, as well at the national level within Russia. The study was also dedicated to reveal whether population frequencies of both polymorphic markers are associated with COVID-19 cases, recovery and death rates.

Methods

We genotyped 1883 samples from 91 ethnic populations from Russia and neighboring countries by rs11385942 and rs657152 markers. Local populations which were geographically close and genetically similar were pooled into 28 larger groups. In the similar way we compiled a dataset on the other regions of the globe using genotypes extracted or imputed from the available datasets (32 populations worldwide). The differences in alleles frequencies between groups were estimated and the frequency distribution geographic maps have been constructed. We run the correlation analysis of both markers frequencies in various populations with the COVID-19 epidemiological data on the same populations.

Findings

The cartographic analysis revealed that distribution of rs11385942 follows the West Eurasian pattern: it is frequent in Europeans, West Asians, and particularly in South Asians but rare or absent in all other parts of the globe. Notably, there is no abrupt changes in frequency across Eurasia but the clinal variation instead. The distribution of rs657152 is more homogeneous. Higher population frequencies of both risk alleles correlated positively with the death rate. For the rs11385942 we can state the tendency only (r=0,13, p=0.65), while for rs657152 the correlation was significantly high (r=0,59, p=0,02). These reasonable correlations were obtained on the Russian dataset, but not on the world dataset.

Interpretation

Using epidemiological statistics on Russia and neighboring countries we revealed the evident correlation of the risk alleles frequencies with the death rate from COVID-19. The lack of such correlations at the world level should be attributed to the differences in the ways epidemiological data have been counted in different countries. So that, we believe that genetic differences between populations make small but real contribution into the heterogeneity of the pandemic worldwide. New studies on the correlations between COVID-19 recovery/mortality rates and population’s gene pool are urgently needed.
Integrative Brain Transcriptome Analysis Links Complement Component 4 andHSPA2to theAPOEε2 Protective Effect in Alzheimer Disease
Authors: Panitch Rebecca , Hu Junming , Chung Jaeyoon , Zhu Congcong , Meng Gaoyuan , Xia Weiming , Bennett David A. , Lunetta Kathryn L. , Ikezu Tsuneya , Au Rhoda , Stein Thor D. , Farrer Lindsay A. , Jun Gyungah R.
Published: November 2020

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer’s disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135APOEε 2/ε 3 carriers. Complement pathway genesC4AandC4Bwere among the most significantly differentially expressed genes between ε 2/ε 3 AD cases and controls. We also identified anAPOEε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genesC4A, C4B, andHSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting thisAPOEε 2 related co-expression network may primarily be involved with tau pathology.HSPA2expression was oligodendrocyte specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect ofAPOEε2 for AD.