bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterozygous deleterious MUTYH variants as a driver for tumorigenesis
Authors: Barreiro Rodrigo Araujo Sequeira , Sabbaga Jorge , Rossi Benedito M. , Achatz Maria Isabel W , Camargo Anamaria A , Asprino Paula F , Galante Pedro A F
Published: June 2021

MUTYH is a glycosylase involved in the base excision repair of the DNA. Biallelic mutations in the MUTYH gene cause the autosomal recessive condition known as MUTYH-associated adenomatous polyposis and increase colorectal cancer risk. However, the cancer risk associated with germline variants in individuals carrying only one MUTYH defective allele is controversial and based on studies involving few samples. Here, we described a comprehensive investigation of monoallelic deleterious MUTYH carriers among approximately 10,400 patients across 33 different tumor types and more than 117 thousand samples of normal individuals. Our results indicate MUTYH deficiency in heterozygosity can lead to tumorigenesis through a mechanism of Loss Of Heterozygosity (LOH) of the functional MUTYH allele. We confirmed that the frequency of damaging MUTYH monoallelic variant carriers is higher in individuals with cancer than in the general population, though its frequency is not homogeneous among tumor types. We also demonstrate that MUTYH related mutational signature is elevated only in those patients with loss of the functional allele. We also find that MUTYH characteristic base substitution (C>A) increases stop codon generation and we identify key genes affected during tumorigenesis. In conclusion, we propose that deleterious germline monoallelic MUTYH variant carriers are at a higher risk of developing tumors, especially those types with frequent LOH events, such as adrenal adenocarcinoma.
Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project
Authors: Wilcox Emma , Harrison Steven M. , Lockhart Edward , Voelkerding Karl , Lubin Ira M. ,   ClinGen Expert Panels, Rehm Heidi L. , Kalman Lisa , Funke Birgit
Published: June 2021

Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.
Polymorphism of NAT2, PXR, ABCB1, and GSTT1 genes among tuberculosis patients of North Eastern States of India
Authors: Meitei Heikrujam Nilkanta , Pandey Anupama , Faruquee Hossain Md. , Thokchom Maria , Athokpam Sonia , Guha Hritusree , Das Ranjit , Saha Sourav , Kupa Rukuwe-u , Kapfo Wetetsho , Keppen Joshua , Mohapatara Amit Kumar , Priyadarsini Haripriya , Koijam Arunkumar Singh , Dasgupta Arunabha , Goswami Bidhan , Thong Aseno , Meru Kezhasino , Konyak Wungyong , Gupta Dinesh , Das Anjan , Khamo Vinotsole , Huidrom Lokhendro Singh , Haobam Sunita , Nanda Ranjan Kumar , Haobam Reena
Published: June 2021

Background

Anti-tuberculosis drug-induced liver injury (AT-DILI) in tuberculosis (TB) patients has been linked to polymorphisms in genes encoding drug metabolism enzymes and proteins.

Objective

This study aimed to monitor polymorphisms of NAT2, PXR, ABCB1, and GSTT1 genes in TB patients from three states (Manipur, Tripura, and Nagaland) in the North Eastern Region of India.

Methods

Genomic DNA was isolated from the whole blood samples of TB patients (n=219; Manipur:139; Tripura: 60; Nagaland: 20). The TaqMan allelic discrimination assay and statistical tools were used to investigate single nucleotide polymorphisms (SNP) patterns in NAT2, PXR, ABCB1, and GSTT1 genes.

Results

In the study population, ten distinct genotypes of the NAT2 gene and single variation in the PXR, ABCB1, and GSTT1 genes were identified. A strong linkage disequilibrium (LD) was observed between rs1801280 and rs1799931 of the NAT2 gene. Majority of the study populations were intermediate (~46.1%), rest were either slow acetylators (~35.6%) or fast acetylators. Interestingly, ~55% of the TB patients in Tripura were slow acetylators and majority in Manipur and Nagaland were of intermediate acetylator genotypes. For all of the markers investigated, the population had a greater prevalence of ancestral alleles and genotypes. According to a combinational study of the genotypes linked to AT-DILI, ~26.1% of the population possessed the risk genotypes.

Conclusion

These TB patients from north eastern states of India were found as carriers of the ancestral alleles and genotypes. And the risk for AT-DILI during TB treatment is low. Expanding such studies with additional markers and larger sample sizes will be useful to generate precise population-specific pharmacogenomics details for efficient TB management.
Genetic and early environmental predictors of adulthood self-reports of trauma
Authors: Peel Alicia J. , Purves Kirstin L. , Baldwin Jessie R. , Breen Gerome , Coleman Jonathan R.I. , Pingault Jean-Baptiste , Skelton Megan , Kuile Abigail R. ter , Danese Andrea , Eley Thalia C.
Published: June 2021

Background

Evidence suggests that retrospective self-reports of childhood trauma are associated with a greater risk of psychopathology in adulthood than are prospective measures. However, it remains unclear why retrospectively reported trauma confers a greater risk for poor outcomes. Investigating the heritable characteristics and environmental adversities associated with measures of self-reported trauma could increase understanding of this risk pathway to psychopathology.

Methods

Our sample included 3,963 unrelated individuals from the Twins Early Development Study. We tested whether polygenic scores for 21 psychiatric, cognitive, anthropometric and personality traits were associated with childhood emotional and physical abuse retrospectively self-reported in adulthood. To assess the presence of gene-environment correlation, we investigated whether these associations remained after controlling for composite scores of environmental adversity between birth and age 16.

Results

Retrospectively self-reported childhood trauma was associated with polygenic scores for autism spectrum disorder (ASD), body mass index and risky behaviours. When composite scores of environmental adversity were included in one model, only associations with parent-reported environmental adversity in middle childhood, self-reported environmental adversity in early adolescence and the polygenic score for ASD remained significant.

Conclusions

Retrospective self-reports of childhood trauma are associated with heritable characteristics of the reporter. Genetic predisposition to ASD may increase liability to experiencing or interpreting events as traumatic. Associations between genetic predisposition for risky behaviour and high BMI with self-reported childhood trauma may be environmentally-mediated. Studies of the association between retrospectively self-reported childhood trauma and later life outcomes should consider that genetically-influenced reporter characteristics may confound associations, both directly and through gene-environment correlation.
Second wave of COVID-19 in India could be predicted with genomic surveillance of SARS-CoV-2 variants coupled with epidemiological data: A tool for future
Authors: Kumar Ashutosh , Asghar Adil , Dwivedi Prakhar , Kumar Gopichand , Narayan Ravi K. , Jha Rakesh K. , Parashar Rakesh , Sahni Chetan , Pandey Sada N.
Published: June 2021

India recently witnessed a devastating second wave of COVID-19, which peaked by the end of the first week of May 2021. We aimed to understand formation and spread of the second wave in the country. We analyzed time series distribution of the genomic sequence data for SARS-CoV-2 and correlated that with the epidemiological data for new cases and deaths, for the corresponding period of the second wave. Further we analyzed the phylodynamics of the circulating SARS-CoV-2 variants in the Indian population in the period of study. Our analysis shows that the first indications of arrival of the second wave were observable by the end of January 2021, and by the end of March, 2021 it was clearly indicated. B.1.617 lineage variants drove the wave, particularly B.1.617.2 (a.k.a. delta variant). Based on the observations of this study, we propose that genomic surveillance of the SARS-CoV-2 variants augmented with epidemiological data can be a promising tool for forecasting imminent COVID-19 waves.
A systematic review assessing the potential for release of vector species from competition following insecticide-based population suppression ofAnophelesspecies in Africa
Authors: Qureshi Alima , Connolly John B.
Published: June 2021

Background

While insecticide-based vector control can effectively target vector species in areas of high malaria endemicity, such asAnopheles gambiaein Africa, residual disease transmission can occur. Understanding the potential role of competitive displacement between vector species could inform both current insecticide-based vector control programmes and the development of future complementary interventions.

Methods

A systematic review was conducted to identify studies of insecticide-based vector control ofAnophelesspecies in Africa that reported indices for absolute densities of vector species. After screening against inclusion, exclusion and risk of bias criteria, studies were assigned to three categories based on whether they showed population density changes involving decreases in two or more vector species (D), increases in two or more vector species (I), or increases in one vector species concomitant with decreases in another vector species (ID). Category ID studies could thus provide evidence consistent with the release of vector species from competition following the insecticide-based population suppression ofAnophelesspecies.

Results

Of 5,569 papers identified in searches, 30 were selected for quantitative and qualitative analysis. Nineteen studies were assigned to category D and 1 study to category I. Ten studies categorised as ID provided evidence ranging from weak to persuasive that release from competition could have contributed to changes in species composition. Category ID showed no statistical differences from category D for reductions in malaria transmission and levels of insecticide resistance, but did so for insecticide type, pyrethroids being associated with category ID. A qualitative assessment identified 5 studies that provided the most convincing evidence that release from competition could have contributed to changes in species composition.

Conclusion

This review identified evidence that insecticide-based reductions in the density ofAnophelesspecies in Africa could facilitate the release of other vector species from competition. While it remains uncertain whether this evidence is representative of most entomological sequelae from the use insecticide-based vector control in the field, 5 studies provided persuasive evidence that insecticide use could lead, at least under some circumstances, to competitive release of non-targeted vector species. These results should inform current and future integrated vector management approaches to malaria control.
Determinants of adherence to COVID-19 preventive behaviours in Canada: Results from the iCARE Study
Authors: Lavoie Kim L. , Gosselin-Boucher Vincent , Stojanovic Jovana , Voisard Brigitte , Szczepanik Geneviève , Boyle Jacqueline A. , Belanger-Gravel Ariane , Bacon Simon L. ,   for the iCARE Study Team
Published: June 2021

Objective

Key to slowing the spread of SARS-Cov-2 is adherence to preventive behaviours promoted through government policies, which may be influenced by policy awareness, attitudes and concerns about the virus and its impacts. This study assessed determinants of adherence to major coronavirus preventive behaviours, including demographics, attitudes and concerns, among Canadians during the first pandemic wave.

Methods

As part of the iCARE study (www.iCAREstudy.com), we weighted data from two population-based, online surveys (April and June, 2020) of Canadian adults. Questions tapped into behaviour change constructs. Multivariate regression models identified determinants of adherence.

Results

Data from 6,008 respondents (51% female) were weighted for age, sex, and province. Awareness of government policies was high at both time points (80-99%), and adherence to prevention behaviours was high in April (87.5%-93.5%) but decreased over time, particularly for avoiding social gatherings (68.1%). Adherence was worse among men, those aged 25 and under, and those currently working. Aligned with the Health Beliefs Model, perceptions of the importance of prevention behaviours and the nature of people’s COVID-19-related concerns were highly predictive of adherence. Interestingly, health and social/economic concerns predicted better adherence, but having greater personal financial concerns predicted worse adherence at both time points.

Conclusion

Adherence to COVID-19 prevention behaviours was worse among men, younger adults, and workers, and deteriorated over time. Perceived importance of prevention behaviours measures and health and social/economic concerns predicted better adherence, but personal financial concerns predicted worse adherence. Results have implications for tailoring policy and communication strategies during subsequent pandemic waves.
SARS-CoV-2-antibody response in health care workers after vaccination or natural infection in a longitudinal observational study
Authors: Herzberg Jonas , Vollmer Tanja , Fischer Bastian , Becher Heiko , Becker Ann-Kristin , Honarpisheh Human , Guraya Salman Yousuf , Strate Tim , Knabbe Cornelius
Published: June 2021

Background

Following a year of development, several vaccines have been approved to contain the global COVID-19 pandemic. Real world comparative data on immune response following vaccination or natural infection are rare.

Methods

We conducted a longitudinal observational study in employees at a secondary care hospital affected by the COVID-19 pandemic. Comparisons were made about the presence of anti-SARS-CoV-2 immunglobulin G (IgG) antibody ratio after natural infection, or vaccination with one or two doses of BioNTech/Pfizer (BNT162b2), or one dose of AstraZenca (Vaxzevria) vaccine.

Results

We found a 100% humoral response rate in participants after 2 doses of BNT162b2 vaccine. The antibody ratio in participants with one dose BNT162b2 and Vaxzevria did not differ significantly to those with previous PCR-confirmed infection, whereas this was significantly lower in comparison to two doses of BioNTech/Pfizer. We could not identify a correlation with previous comorbidities, obesity or age within this study. Smoking showed a negative effect on the antibody response (p=0.006)

Conclusion

Our data provide an overview about humoral immune response after natural SARS-CoV-2 infection or following vaccination, and supports the usage of booster vaccinations, especially in patients after a natural SARS-CoV-2 infection.
A Survey of the Smokefree Status of Pedestrian-Only Spaces in 10 New Zealand Local Government Areas
Authors: Wilson Nick , Gurram Niveditha , Grout Leah , Thomson George
Published: June 2021

Aim

To describe the smokefree status and signage of outdoor pedestrian-only plazas/malls/boulevards in 10 New Zealand local government (council) areas.

Methods

The 10 council areas were a convenience sample. Council websites were examined for smokefree policies and a systematic attempt was made to identify the five largest pedestrian-only sites with permanent seating in each council area (10 sites each for two larger cities). Field visits were conducted to all selected sites.

Results

Smokefree policies with components covering smokefree outdoor plazas/malls/boulevards were common (80%; 8/10 councils), albeit with some gaps (eg, around signage and vaping policy). A total of 60 relevant pedestrianised sites with permanent seating were identified and surveyed. Of these 63% were officially designated smokefree. Smokefree signage was only present in 15% (9/60) of all the sites and in 24% (9/38) of the designated smokefree sites. In these designated sites the average number of smokefree signs was only 1.4 (range: 0 to 14). Issues identified with the signs included small size, being only a small part of a larger other sign, limited use of te reo Māori wording, and not covering vaping. At sites where tables were present, 12% had ash trays on the tables (none where smokefree).

Conclusions

Smokefree plazas/malls/boulevards in this survey had multiple policy and signage deficiencies that are inconsistent with achieving the national smokefree goal for 2025. There is scope to address these issues with an upgrade to the national smokefree law.
Modeling and reviewing analysis of the COVID-19 epidemic in Algeria with diagnostic shadow
Authors: Jia Jiwei , Liu Siyu , Liu Yawen , Shan Ruitong , Zennir Khaled , Zhang Ran
Published: June 2021

In this paper, we formulate a special epidemic dynamic model to describe the transmission of COVID-19 in Algeria. We derive the threshold parameter control reproduction number, and present the effective control reproduction number (Rc(t)) as a real-time index for evaluating the epidemic under different control strategies. Due to the limitation of the reported data, we redefine the number of accumulative confirmed cases with diagnostic shadow and then use the processed data to do the optimal numerical simulations. According to the control measures, we divide the whole research period into six stages. And then the corresponding medical resource estimations and the average effective control reproduction numbers for each stage are given. Meanwhile, we use the parameter values which are obtained from the optimal numerical simulations to forecast the whole epidemic tendency under different control strategies.
SARS-COV-2 VIRUS INFECTED PATIENT IDENTIFICATION THROUGH CANINE OLFACTIVE DETECTION ON AXILLARY SWEAT SAMPLES
Authors: Grandjean Dominique , Gallet Capucine , Lecoq-Julien Clotilde , Sarkis Riad , Muzzin Quentin , Roger Vinciane , Roisse Didier , Dirn Nicolas , Levert Clément , Breton Erwan , Galtat Arnaud , Forget Alexandre , Charreaudeau Sébastien , Gasmi Fabien , Jean-Baptiste Caroline , Petitjean Sébastien , Hamon Katia , Duquesne Jean-Michel , Coudert Chantal , Tourtier Jean-Pierre , Billy Christophe , Wurtz Jean-Marc , Chauvin Anthony , Eyer Xavier , Ziani Sabrina , Prevel Laura , Cherubini Ilaria , Khelili-Houas Enfel , Hausfater Pierre , Devillier Philippe , Desquilbet Loïc
Published: June 2021

Facing the COVID-19 pandemic, testing individuals in order to promptly isolate positive people is one of the key actions. One approach to rapid testing might be to consider the olfactory capacities of trained detection dogs in order to develop a non-invasive, rapid and cheap mass detection approach, through the Volatile Organic Compounds (VOCs) signature of SARS-CoV-2 infection.

The goal of this study was to determine the individual values of sensitivity and specificity of trained dogs when performing olfactory detection of COVID-19 on axillary sweat samples. Seven dogs were used to sniff a total of 218 samples (62 COVID-19 positive and 156 COVID-19 negative samples), based on a randomised and double-blinded protocol carried out on olfaction cone line-ups. To ensure a wide olfactory range as close as possible to operational conditions, the samples were retrieved from 13 different sites.

Sensitivities varied from 87% to 94% for 6 dogs, and were above 90% for 3 of them. Only one dog, whose sensitivity was 60%, was not selected to subsequently enter the operational stage. Specificities varied from 78% to 92%, with 6 dogs over 85% and 4 dogs over 90%.

Based on the calculated sensitivity and specificity for each dog, positive and negative predictive values (PPV and NPV) were calculated according to several prevalence rates of SARS-CoV-2 scenarii, and were compared to PPV and NPV of an “almost perfect” diagnostic tool. For 6 out of the 7 dogs, and for a prevalence rate of SARS-CoV-2 lower or equal than 40%, the NPV of the dogs were virtually the same as the one of the “almost perfect” tool. Along with other studies on olfactory detection of COVID-19 by dogs these positive and encouraging results suggest that olfactory dogs may play an important part in mass COVID-19 pre-testing situations.
Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) Alters Transcriptional Profiles, Lipid Metabolism and Behavior in Zebrafish Larvae
Authors: Saad Noha , Bereketoglu Ceyhun , Pradhan Ajay
Published: June 2021

Plasticizers are commonly used in different consumer goods and personal care products to provide flexibility, durability and elasticity to polymers. Due to their reported toxicity, the use of several plasticizers including phthalates has been regulated and/or banned from the market. Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) is an alternative plasticizer that was introduced to replace toxic plasticizers. Increasing global demand and lack of information regarding toxicity and safety assessment of DINCH have raised the concern to human and animal health. Hence, in the present study, we investigated the adverse effects of DINCH (at concentrations ranging from 0.01 to 10 μM) in early developmental stages of zebrafish using different endpoints such as hatching rate, developmental abnormalities, lipid metabolism, behavior analysis and gene expression. We found that DINCH caused hatching delay in a dose-dependent manner and altered the expression of genes involved in stress response. Lipid staining using Oil Red O stain showed a slight lipid accumulation around the yolk, brain, eye and neck with increasing concentration. Genes associated with lipid metabolism such as fatty acid synthesis, β-oxidation, elongation, lipid transport were significantly altered by DINCH. Behavioral analysis of larvae demonstrated a distinct locomotor activity including distance and acceleration upon exposure to DINCH both in light and dark. Genes involved in cholesterol biosynthesis and homeostasis were also affected by DINCH indicating possible developmental neurotoxicity. The present data shows that DINCH could induce physiological and metabolic toxicity to aquatic organisms. Hence, further analyses and environmental monitoring on DINCH should be conducted to determine its safety and toxicity levels.
Ultrasound mediated cellular deflection results in cellular depolarization
Authors: Vasan Aditya , Orosco Jeremy , Magaram Uri , Duque Marc , Weiss Connor , Tufail Yusuf , Chalasani Sreekanth H , Friend James
Published: June 2021

Ultrasound has been used to manipulate cells in both humans and animal models. While intramembrane cavitation and lipid clustering have been suggested as likely mechanisms, they lack experimental evidence. Here we use high-speed digital holographic microscopy (to 100-kHz order) to visualize the cellular membrane dynamics. We show that neuronal and fibroblast membranes deflect about 150 nm upon ultrasound stimulation. Next, we develop a biomechanical model that predicts changes in membrane voltage after ultrasound exposure. Finally, we validate our model predictions using whole-cell patch clamp electrophysiology on primary neurons. Collectively, we show that ultrasound stimulation directly defects the neuronal membrane leading to a change in membrane voltage and subsequent depolarization. Our model is consistent with existing data and provides a mechanism for both ultrasound-evoked neurostimulation and sonogenetic control.
Determinants of haemosporidian single and co-infections risks in western paleartic birds
Authors: Pigeault Romain , Chevalier Mathieu , Cozzarolo Camille-Sophie , Baur Molly , Arlettaz Mathilde , Cibois Alice , Keiser André , Guisan Antoine , Christe Philippe , Glaizot Olivier
Published: June 2021

Co-infections with multiple pathogens are common in the wild and may act as a strong selective pressure on both host and parasite evolution. Yet, contrary to single infection, the factors that shape co-infection risk are largely under-investigated. Here, we explored the extent to which bird ecology and phylogeny impact single and co-infection probabilities by haemosporidian parasites using large datasets from museum collections and a Bayesian phylogenetic modelling framework. While both phylogeny and species attributes (e.g. size of the geographic range, life-history strategy, migration) were relevant predictors of co-infection risk, these factors were less pertinent in predicting the probability of being single infected. Our study suggests that co-infection risk is under a stronger deterministic control than single-infection risk. These results underscore the combined influence of host evolutionary history and species attributes in determining single and co-infection pattern providing new avenues regarding our ability to predict infection risk in the wild.
Delimitation of the Tick-Borne Flaviviruses. Resolving the Tick-Borne Encephalitis and Louping-Ill Virus Paraphyletic Taxa
Authors: Bondaryuk Artem N. , Andaev Evgeny I. , Dzhioev Yurij P. , Zlobin Vladimir I. , Tkachev Sergey E. , Bukin Yurij S.
Published: June 2021

The tick-borne flavivirus (TBFV) group contains at least 12 members where five of them are important pathogens of humans inducing diseases with varying severity (from mild fever forms to acute encephalitis). The taxonomy structure of TBFV is not fully clarified at present. In particular, there is a number of paraphyletic issues of tick-borne encephalitis virus (TBEV) and louping-ill virus (LIV). In this study, we aimed to apply different bioinformatic approaches to analyze all available complete genome amino acid sequences to delineate TBFV members at the species level. Results showed that the European subtype of TBEV (TBEV-E) is a distinct species unit. LIV, in turn, should be separated into two species. Additional analysis of the diversity of TBEV and LIV antigenic determinants also demonstrate that TBEV-E and LIV are significantly different from other TBEV subtypes. The analysis of available literature provided data on other virus phenotypic particularities that supported our hypothesis. So, within the TBEV+LIV paraphyletic group, we offer to assign four species to get a more accurate understanding of the TBFV interspecies structure according to the modern monophyletic conception.
Photosynthesis from stolen chloroplasts increases sea slug reproductive fitness
Authors: Cartaxana Paulo , Rey Felisa , Lekieffre Charlotte , Lopes Diana , Hubas Cedric , Spangenberg Jorge , Escrig Stephane , Jesus Bruno , Calado Goncalo , Domingues Rosario , Kuhl Michael , Calado Ricardo , Meibom Anders , Cruz Sonia
Published: June 2021

Some sea slugs are able to steal functional chloroplasts (kleptoplasts) from their algal food sources, but the role and relevance of photosynthesis to the animal host remain controversial. While some researchers claim that kleptoplasts are slowly digestible snacks, others advocate that they enhance the overall fitness of sea slugs much more profoundly. Our analysis show light-dependent incorporation of 13C and 15N in the albumen gland and gonadal follicles of the sea slug Elysia timida, representing translocation of photosynthates to kleptoplast-free reproductive organs. Long-chain polyunsaturated fatty acids with reported roles in reproduction were produced in the sea slug cells using labelled precursors translocated from the kleptoplasts. Finally, we report reduced fecundity of E. timida by suppressing kleptoplast photosynthesis. The present study provides the first thorough experimental evidence that photosynthesis enhances the reproductive fitness of kleptoplast-bearing sea slugs, confirming the biological relevance of this remarkable association between a metazoan and an algal-derived organelle.
Rhizospheric and endophyticPseudomonas aeruginosain edible vegetable plants share molecular and metabolic traits with clinical isolates
Authors: Ambreetha Sakthivel , Marimuthu Ponnusamy , Mathee Kalai , Balachandar Dananjeyan
Published: June 2021

Pseudomonas aeruginosa,a leading opportunistic pathogen causing hospital-acquired infections is predominantly present in agricultural settings. There are minimal attempts to examine the molecular and functional attributes shared by agricultural and clinical strains ofP. aeruginosa.This study aims to investigate the presence ofP. aeruginosain edible vegetable plants (including salad vegetables) and analyze the evolutionary and metabolic relatedness of the agricultural and clinical strains. Eighteen rhizospheric and endophyticP. aeruginosastrains were isolated from cucumber, tomato, eggplant, and chili directly from the farms. The identity of these strains was confirmed using biochemical, and molecular markers and their genetic and metabolic traits were compared with clinical isolates. DNA fingerprinting analyses and 16S rDNA-based phylogenetic tree revealed that the plant- and human-associated strains are evolutionarily related. Both agricultural and clinical isolates possessed plant-beneficial properties, including mineral solubilization (phosphorous, potassium, and zinc), ammonification, and the ability to release extracellular siderophore and indole-3 acetic acid. These findings suggest that rhizospheric and endophyticP. aeruginosastrains are genetically and functionally analogous to the clinical isolates. This study highlights the edible plants as a potential source for human and animal transmission ofP. aeruginosa.
Evidence for two distinct thalamocortical circuits in retrosplenial cortex
Authors: Lomi Eleonora , Mathiasen Mathias L. , Cheng Han Yin , Zhang Ningyu , Aggleton John P. , Mitchell Anna S. , Jeffery Kate J.
Published: June 2021

Retrosplenial cortex (RSC) lies at the interface between perceptual and memory networks in the brain and mediates between these, although it is not yet known how. It has two distinct subregions, granular (gRSC) and dysgranular (dRSC). The present study investigated how these subregions differ with respect to their electrophysiology and connections, as a step towards understanding their functions. gRSC is more closely connected to the hippocampal system, in which theta-band local field potential oscillations are prominent. We therefore compared theta-rhythmic single-unit activity between the two RSC subregions and found, mostly in gRSC, a subpopulation of non-directional cells with spiking activity strongly entrained by theta oscillations, suggesting a stronger coupling of gRSC to the hippocampal system. We then used retrograde tracers to examine whether differences in neural coding between RSC subregions might reflect differential inputs from the anterior thalamus, which is a prominent source of RSC afferents. We found that gRSC and dRSC differ in their afferents from two AV subfields: dorsomedial (AVDM) and ventrolateral (AVVL). AVVL targets both gRSC and dRSC, while AVDM provides a selective projection to gRSC. These combined results suggest the existence of two distinct but interacting RSC subcircuits: one connecting AVDM to gRSC that may comprise part of the cognitive hippocampal system, and the other connecting AVVL to both RSC regions that may link hippocampal and perceptual regions. We suggest that these subcircuits are distinct to allow for differential weighting during integration of converging sensory and cognitive computations: an integration that may take place in thalamus, RSC or both.

Highlights

The two retrosplenial cortex subregions, gRSC and dRSC, differ in their temporal firing characteristics and relation to theta oscillations.

There are differential afferents from the anteroventral thalamic nucleus to gRSC and dRSC, with the dorsomedial subnucleus projecting selectively to gRSC.

The anteroventral thalamus-retrosplenial cortex circuitry thus comprises two functionally and anatomically distinct but connected circuits, differentially connected to the hippocampal system, that may support the integration of cognitive and perceptual information.
Analysis of the Genetic Structure and Diversity of Upland Cotton Groups in Different Planting Areas Based on SNP Markers
Authors: Wang Jungduo , Zhang Zeliang , Gong Zhaolong , Liang Yajun , Ai Xiantao , Sang Zhiwei , Guo Jiangping , Li Xueyuan , Zheng Juyun
Published: June 2021

Genetic diversity, kinship and population genetic structure analyses of Gossypium hirsutum germplasm can provide a better understanding of the origin and evolution of G. hirsutum biodiversity. In this study, 1313331 SNP molecular markers were used to construct a phylogenetic tree of each sample using MEGAX, to perform population structure analysis by ADMIXTURE software and principal component analysis (PCA) by EIGENSOFT software, and to estimate relatedness using SPAGeDi. ADMIXTURE software divided the experimental cotton population into 16 subgroups, and the Gossypium hirsutum samples could be roughly clustered according to source place, but there were some overlapping characteristics among samples. The experimental cotton population was divided into six groups according to source to calculate the genetic diversity index (H), and the obtained value (0.306) was close to that for germplasm collected by others in China. Cluster 4 had a relatively high genetic diversity level (0.390). The degrees of genetic differentiation within the experimental cotton population groups were low (the population differentiation indexes ranged from 0.02368 to 0.10664). The genetic distance among cotton accessions varied from 0.000332651 to 0.562664014, with an average of 0.25240429. The results of this study may provide a basis for mining elite alleles and using them for subsequent association analysis.
Ageing red deer alter their spatial behaviour and become less social
Authors: Albery Gregory F , Clutton-Brock Tim H. , Morris Alison , Morris Sean , Pemberton Josephine M , Nussey Daniel H , Firth Josh A
Published: June 2021

Social relationships are important to many aspects of animals’ lives, and an individual’s connections may change over the course of their lifespan. Currently, it is unclear whether social connectedness declines within individuals as they age, and what the underlying mechanisms might be, so the role of age in structuring animal social systems remains unresolved, particularly in non-primates. Here, we describe senescent declines in social connectedness using 43 years of data in a wild, individually monitored population of a long-lived mammal (European red deer,Cervus elaphus). Applying a series of spatial and social network analyses, we demonstrate that these declines occur due to within-individual changes in social behaviour, with correlated changes in spatial behaviour (smaller home ranges and movements to lower-density, lower-quality areas). These findings demonstrate that within-individual socio-spatial behavioural changes can lead older animals in fission-fusion societies to become less socially connected, shedding light on the ecological and evolutionary processes structuring wild animal populations.
Stratum Lacunosum-moleculare Interneurons of the Hippocampus Coordinate Memory Encoding and Retrieval
Authors: Guo Jun , Oliveros Heankel Cantu , Oh So Jung , Liang Bo , Li Ying , Kavalali Ege T. , Lin Da-Ting , Xu Wei
Published: June 2021

Encoding and retrieval of memory are two processes serving distinct biological purposes but operating in highly overlapping brain circuits. It is unclear how the two processes are coordinated in the same brain regions, especially in the hippocampal CA1 region where the two processes converge at the cellular level. Here we find that the neuron-derived neurotrophic factor (NDNF)-positive interneurons at stratum lacunosum-moleculare (SLM) in CA1 play opposite roles in memory encoding and retrieval. These interneurons show high activities in learning and low activities in recall. Increasing their activity facilitates learning but impairs recall. They inhibit the entorhinal- but dis-inhibit the CA3- inputs to CA1 pyramidal cells and thereby either suppress or elevate CA1 pyramidal cells’ activity depending on animal’s behavioral states. Thus, by coordinating entorhinal- and CA3- dual inputs to CA1, these SLM interneurons are key to switching the hippocampus between encoding and retrieval modes.
SpotClean adjusts for spot swapping in spatial transcriptomics data
Authors: Ni Zijian , Prasad Aman , Chen Shuyang , Halberg Richard B. , Arkin Lisa , Drolet Beth , Newton Michael , Kendziorski Christina
Published: June 2021

Spatial transcriptomics (ST) is a powerful and widely-used approach for profiling genome-wide gene expression across a tissue with emerging applications in molecular medicine and tumor diagnostics. Recent spatial transcriptomics experiments utilize slides containing thousands of spots with spot-specific barcodes that bind mRNA. Ideally, unique molecular identifiers at a spot measure spot-specific expression, but this is often not the case owing to bleed from nearby spots, an artifact we refer to as spot swapping. We propose SpotClean to adjust for spot swapping and, in doing so, to increase the sensitivity and precision with which downstream analyses are conducted.
CODEC enables ‘single duplex’ sequencing
Authors: Bae Jin H. , Liu Ruolin , Nguyen Erica , Rhoades Justin , Blewett Timothy , Xiong Kan , Shea Douglas , Gydush Gregory , Tabrizi Shervin , An Zhenyi , Patel Sahil , Makrigiorgos G. Mike , Golub Todd R. , Adalsteinsson Viktor A.
Published: June 2021

Detecting mutations as rare as a single molecule is crucial in many fields such as cancer diagnostics and aging research but remains challenging. Third generation sequencers can read a double-stranded DNA molecule (a ‘single duplex’) in whole to identify true mutations on both strands apart from false mutations on either strand but with limited accuracy and throughput. Although next generation sequencing (NGS) can track dissociated strands with Duplex Sequencing, the need to sequence each strand independently severely diminishes its throughput. Here, we developed a hybrid method called Concatenating Original Duplex for Error Correction (CODEC) that combines the massively parallel nature of NGS with the single-molecule capability of third generation sequencing. CODEC physically links both strands to enable NGS to sequence a single duplex with a single read pair. By comparing CODEC and Duplex Sequencing, we showed that CODEC achieved a similar error rate (10−6) with 100 times fewer reads and conferred ‘single duplex’ resolution to most major NGS workflows.
A secondary metabolite drives intraspecies antagonism in a gut symbiont that is inhibited by cell wall acetylation
Authors: Özçam Mustafa , Oh Jee-Hwan , Tocmo Restituto , Acharya Deepa , Zhang Shenwei , Astmann Theresa , Heggen Mark , Ruiz-Ramírez Silvette , Li Fuyong , Cheng Christopher C. , Vivas Eugenio , Rey Federico E. , Claesen Jan , Bugni Tim , Walter Jens , van Pijkeren Jan-Peter
Published: June 2021

The mammalian microbiome encodes numerous secondary metabolite biosynthetic gene clusters, yet their role in microbe-microbe interactions is unclear. Here, we characterized two polyketide synthase gene clusters (funandpks) in the gut symbiontLimosilactobacillus reuteri.Thepks, but not thefuncluster, encodes antimicrobial activity. Forty-one out of 51L. reuteristrains tested are sensitive to Pks products, which was independent of strains’ host origin. The sensitivity to Pks was also established in intraspecies competition experiments in gnotobiotic mice. Comparative genome analyses between Pks-resistant and sensitive strains identified an acyltransferase gene (act) that is unique to Pks-resistant strains. Subsequent cell wall analysis of the wild-type and theactmutant strains showed that Act acetylates cell wall components. Thepksmutants lost their competitive advantage andactmutants lost their Pks resistancein vivo. Thus, our findings provide insight into how closely related gut symbionts can compete and co- exist in the gastrointestinal tract.
CRISPRa screen on a genetic risk locus shared by multiple autoimmune diseases identifies a dysfunctional enhancer that affects IRF8 expression through cooperative lncRNA and DNA methylation machinery
Authors: Zhou Tian , Zhu Xinyi , Ye Zhizhong , Wang Yongfei , Yao Chao , Xu Ning , Zhou Mi , Ma Jianyang , Qin Yuting , Shen Yiwei , Tang Yuanjia , Yin Zhihua , Xu Hong , Zhang Yutong , Zang Xiaoli , Ding Huihua , Yang Wanling , Guo Ya , Harley John B. , Namjou Bahram , Kaufman Kenneth M. , Kottyan Leah C. , Weirauch Matthew T. , Hou Guojun , Shen Nan
Published: June 2021

Dysregulated transcription factors represent a major class of drug targets that mediate the abnormal expression of many critical genes involved in SLE and other autoimmune diseases. Although strong evidence suggests that natural human genetic variation affects basal and inducible gene expression, it is still a considerable challenge to establish a biological link between GWAS-identified non-coding genetic risk variants and their regulated gene targets. Here, we combine genetic data, epigenomic data, and CRISPR activation (CRISPRa) assays to screen for functional variants regulating IRF8 expression. Using CRISPR-mediated deletion and 3D chromatin structure analysis, we demonstrate that the locus containing rs2280381 is a cell-type-specific distal enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter to modulate IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to differentially regulate AC092723.1 and IRF8 expression. Our work illustrates a strategy to define the functional genetic variants modulating transcription factor gene expression levels and identifies the biologic mechanism by which autoimmune diseases risk genetic variants contribute to the pathogenesis of disease.
Sustained replication of synthetic canine distemper virus defective genomesin vitroandin vivo
Authors: Tilston-Lunel Natasha L. , Welch Stephen R. , Nambulli Sham , de Vries Rory D. , Ho Gregory W , Wentworth David , Shabman Reed , Nichol Stuart T. , Spiropoulou Christina F. , de Swart Rik L. , Rennick Linda J. , Duprex W. Paul
Published: June 2021

Defective interfering (DI) genomes restrict viral replication and induce type-I interferon. Since DI genomes have been proposed as vaccine adjuvants or therapeutic antiviral agents, it is important to understand their generation, delineate their mechanism of action, develop robust production capacities, assess their safety andin vivolongevity and determine their long-term effects. To address this, we generated a recombinant (r) canine distemper virus (CDV) from an entirely synthetic molecular clone designed using the genomic sequence from a clinical isolate obtained from a free-ranging raccoon with distemper. rCDV was serially passagedin vitroto identify DI genomes that naturally arise during rCDV replication. Defective genomes were identified by Sanger and next-generation sequencing techniques and predominant genomes were synthetically generated and cloned into T7-driven plasmids. Fully encapsidated DI particles (DIPs) were then generated using a rationally attenuated rCDV as a producer virus to drive DI genome replication. We demonstrate these DIPs interfere with rCDV replication in a dose-dependent mannerin vitro. Finally, we show sustained replication of a fluorescent DIP in experimentally infected ferrets over a period of 14 days. Most importantly, DIPs were isolated from the lymphoid tissues which are a major site of CDV replication. Our established pipeline for detection, generation and assaying DIPs is transferable to highly pathogenic paramyxoviruses and will allow qualitative and quantitative assessment of the therapeutic effects of DIP administration on disease outcome.

Importance

Defective interfering (DI) genomes have long been considered inconvenient artifacts that suppressed viral replicationin vitro. However, advances in sequencing technologies have led to DI genomes being identified in clinical samples, implicating them in disease progression and outcome. It has been suggested that DI genomes could be harnessed therapeutically. Negative strand RNA virus research has provided a rich pool of natural DI genomes over many years and they are probably the best understoodin vitro. Here, we demonstrate identification, synthesis, production and experimental inoculation of novel CDV DI genomes in highly susceptible ferrets. These results provide important evidence that rationally designed and packaged DI genomes can survive the course of a wild-type virus infection.
Cysteine dependence in Lactobacillus iners constitutes a novel therapeutic target to modify the vaginal microbiota
Authors: Bloom Seth M , Mafunda Nomfuneko A , Woolston Benjamin M , Hayward Matthew R , Frempong Josephine F , Abai Aaron B , Xu Jiawu , Mitchell Alissa J , Westergaard Xavier , Hussain Fatima A , Xulu Nondumiso , Dong Mary , Dong Krista L , Gumbi Thandeka , Ceasar Xolisile , Rice Justin K , Choksi Namit , Ismail Nasreen , Ndung'u Thumbi , Ghebremichael Musie S , Balskus Emily P , Mitchell Caroline M , Kwon Douglas S
Published: June 2021

Vaginal microbiota composition affects several important reproductive health outcomes. Lactobacillus crispatus-dominant bacterial communities have favorable associations whereas anaerobe-dominant communities deficient of lactobacilli are linked to poor outcomes, including bacterial vaginosis (BV). Lactobacillus iners, the most abundant vaginal species worldwide, has adverse associations compared to L. crispatus, but standard metronidazole treatment for BV promotes L. iners-dominance, likely contributing to post-treatment relapse. L. iners is under-studied because it fails to grow in standard Lactobacillus media in vitro. Here we trace this in vitro phenotype to a species-specific cysteine requirement associated with limitations in cysteine-related transport mechanisms and show that vaginal cysteine concentrations correlate with Lactobacillus abundance in vivo. We demonstrate that cystine uptake inhibitors selectively impede L. iners growth and that combining an inhibitor with metronidazole thus promotes L. crispatus dominance of defined BV-like communities. These findings identify a novel target for therapeutic vaginal microbiota modulation to improve reproductive health.