bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility and Potential of Transcriptomic Analysis Using the NanoString nCounter Technology to Aid the Classification of Rejection in Kidney Transplant Biopsies
Authors: Varol Hilal , Ernst Angela , Cristoferi Iacopo , Arns Wolfgang , Baan Carla C. , van Baardwijk Myrthe , van den Bosch Thierry , Eckhoff Jennifer , Harth Ana , Hesselink Dennis A. , van Kemenade Folkert J. , de Koning Willem , Kurschat Christine , Minnee Robert C. , Mustafa Dana A. , Reinders Marlies E.J. , Shahzad-Arshad Shazia P. , Snijders Malou L.H. , Stippel Dirk , Stubbs Andrew P. , von der Thüsen Jan , Wirths Katharina , Becker Jan U. , Clahsen-van Groningen Marian C.
Published: November 2022

Background.

Transcriptome analysis could be an additional diagnostic parameter in diagnosing kidney transplant (KTx) rejection. Here, we assessed feasibility and potential of NanoString nCounter analysis of KTx biopsies to aid the classification of rejection in clinical practice using both the Banff-Human Organ Transplant (B-HOT) panel and a customized antibody-mediated rejection (AMR)–specific NanoString nCounter Elements (Elements) panel. Additionally, we explored the potential for the classification of KTx rejection building and testing a classifier within our dataset.

Methods.

Ninety-six formalin-fixed paraffin-embedded KTx biopsies were retrieved from the archives of the ErasmusMC Rotterdam and the University Hospital Cologne. Biopsies with AMR, borderline or T cell–mediated rejections (BLorTCMR), and no rejection were compared using the B-HOT and Elements panels.

Results.

High correlation between gene expression levels was found when comparing the 2 chemistries pairwise (r = 0.76–0.88). Differential gene expression (false discovery rate; P < 0.05) was identified in biopsies diagnosed with AMR (B-HOT: 294; Elements: 76) and BLorTCMR (B-HOT: 353; Elements: 57) compared with no rejection. Using the most predictive genes from the B-HOT analysis and the Element analysis, 2 least absolute shrinkage and selection operators–based regression models to classify biopsies as AMR versus no AMR (BLorTCMR or no rejection) were developed achieving an receiver-operating–characteristic curve of 0.994 and 0.894, sensitivity of 0.821 and 0.480, and specificity of 1.00 and 0.979, respectively, during cross-validation.

Conclusions.

Transcriptomic analysis is feasible on KTx biopsies previously used for diagnostic purposes. The B-HOT panel has the potential to differentiate AMR from BLorTCMR or no rejection and could prove valuable in aiding kidney transplant rejection classification.
Reports of deaths are an exaggeration: German (PCR-test-positive) fatality counts during the SARS-CoV-2 era in the context of all-cause mortality
Authors: Rockenfeller Robert , Günther Michael , Mörl Falk
Published: November 2022

As of March 2020, counts of SARS-CoV-2-related (‘CoViD-19’) deaths have been key numbers for justifying severe political, social, and economical measures put into action by authorities world-wide. A particular focus thereby was the concomitant excess mortality (EM), i.e. fatalities above the normally expected all-cause mortality (AM). Recent reports and studies, inter alia by the WHO, estimated the SARS-CoV-2-related EM in Germany between 2020 and 2021 as high as 200,000. In this study, we attempt to scrutinise these numbers by putting them into the context of German AM since the year 2000.

To this end, we propose two straightforward, low-parametric models to estimate German AM, and thus EM, for the years 2020 and 2021 as well as the flu seasons 2020/21 and 2021/22. Additionally, we give a forecast of the AM expected in 2022. After having derived age-cohort-specific mortality rates out of historical data, weighted with their corresponding demographic proportion, EM is obtained by subtracting (model-)calculated AM counts from observed ones. For Germany, we find even an overall negative EM (‘under-mortality’) of about -18,500 for the year 2020, and a minor positive EM of about 7,000 for 2021, unveiling that officially communicated EM numbers are a great exaggeration. Further, putting CoViD-19 “cases” (defined by positive PCR test outcomes) and their related death counts into the context of AM, we are able to estimate how many Germans have dieddue torather thanwithCoViD-19; an analysis not provided by the appropriate authority, the RKI. Thereby, varying governmental PCR test strategies are shown to heavily obscure reliable estimations of SARS-CoV-2-related EM, particularly within the second year of the proclaimed pandemic.
Blink rate measuredin situdecreases while reading from printed text or digital devices, regardless of task duration, complexity or working distance
Authors: Chidi-Egboka Ngozi Charity , Jalbert Isabelle , Chen Jiaying , Briggs Nancy E. , Golebiowski Blanka
Published: November 2022

Purpose

To compare blinking measuredin situduring various tasks and examine relationships with ocular surface symptoms. Day-to-day repeatability of blink rate and interblink interval was assessed.

Methods

Twenty-four students (28.6±6.3 years; 8M:16F) completed six reading tasks (printed text, laptop, TV, smartphone, smartphone at 50% brightness, smartphone with complex text), and two non-reading tasks (conversation, walking) in a randomised cross-over study. Ocular surface symptoms and clinical signs were assessed. Blink rate and interblink interval were measured using a wearable eye tracking headset. Blink parameters were compared across tasks and time (linear mixed model and post hoc comparisons with Bonferroni correction). Associations between blinking, symptoms, ocular surface, and clinical signs were assessed (Spearman’s correlation). The smartphone reading task was completed twice to determine coefficient of repeatability.

Results

Blink rate was lower (mean 10.7±9.7 blinks/min) and interblink interval longer (mean 9.6±8.7s) during all reading tasks compared to conversation (mean 32.4±12.4 blinks/min; 1.5±0.6s) and walking (mean 31.3±15.5 blinks/min; 1.9±1.3s) (p<0.001). There were no significant differences in blink parameters between any of the reading tasks, nor between conversation and walking. Changes in blinking occurred within one minute of starting the task. No associations were evident between blink rate or interblink interval and ocular surface symptoms or signs. Coefficient of repeatability was ±12.4 blinks/min for blink rate and ±18.8s for interblink interval.

Conclusion

Spontaneous blinking can be reliably measuredin situ. Blink rate was reduced and interblink interval increased during reading compared to conversation and walking. Changes in blinking were immediate and sustained, and not associated with ocular surface symptoms or signs.
Behavioural Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain- (-Related) Phenotypes in Rats with Bone Cancer
Authors: Segelcke Daniel , Linnemann Jan , Pradier Bruno , Kronenberg Daniel , Stange Richard , Richter Helene , Görlich Dennis , Baldini Nicola , Di Pompo Gemma , Verri Waldiceu A. , Avnet Sofia , Pogatzki-Zahn Esther
Published: November 2022

Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. To uncover the mechanisms underlying CIBP, using rodent models is the most common approach; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative relevant pain in patients. In order to improve the accuracy and strength of the preclinical experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a homecage monitoring assay (HCM).

Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of CIBP-phenotype, including evoked and non-evoked based assays and HCM.

Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and different) in males. In addition, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex.

This multimodal battery allows an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalisability of results and provide information for targeted drug development in the future.
3D spheroid-microvasculature-on-a-chip for tumor-endothelium mechanobiology interplay
Authors: Zhang Yingqi , Jiang Fengtao , Zhao Yunduo Charles , Cho Ann-Na , Fang Guocheng , Cox Charles D. , Zreiqat Hala , Lu Zu Fu , Lu Hongxu , Ju Lining Arnold
Published: November 2022

In the final step of cancer metastasis, tumor cells become lodged in a distant capillary bed, where they can undergo extravasation and form a secondary tumor. While increasing evidence suggests blood/lymphatic flow and shear stress play a critical role in the tumor extravasation process, there is a lack of systematic and biomechanical approaches to recapitulate sophisticated 3D microtissue interactions within the controllable hydrodynamic microenvironment. Here, we report a simple-to-use 3D spheroid-microvasculature-on-a-chip (SMAC) model. Under static and controlled flow conditions, the SMAC recapitulates the biomechanical crosstalk between heterogeneous tumor spheroids and the endothelium in a high-throughput and quantitative manners. As anin vitrometastasis mechanobiology model, we discover 3D spheroid-induced endothelial compression and cell-cell junction degradation in the process of tumor migration and expansion. Lastly, we examine the shear stress effects on the endothelial orientation, polarization as well as the tumor spheroid expansion. Taken together, our SMAC model offers a miniaturized, cost-efficient and versatile platform for future investigation on metastasis mechanobiology, enhanced permeability and retention effect and even personalized therapeutic evaluation.
Computational investigations in inhibition of alcohol/aldehyde dehydrogenase in lignocellulosic hydrolysates
Authors: Kumar Karan , Siddiqa Azeeza , Pragati  , Chandane Priti , Yadav Saanya , Kori Mahima , Shivram A , Barbora Lepakshi , Moholkar Vijayanand S.
Published: November 2022

Second generation alcoholic biofuels synthesis from lignocellulosic biomass (LB) consists three steps viz., pre-treatment, detoxification, and fermentation. This dilute acid pre-treatment process generates several compounds like acids, aldehydes, ketones, oxides and their phenolic derivatives that are potential inhibitors of some of the crucial enzymes in the metabolic pathway of ABE fermentation. With application of hybrid quantum mechanics/ molecular mechanics (QM/MM) approach, our aim is to discern the molecular mechanism of inhibition of keyAADsacross solventogenic species. The objectives of present study are: (1) identification and homology modelling of keyAADs; (2) validation, quality assessment and physiochemical characterization of the modelled enzymes; (3) identification, construction and optimization of chemical structure of potent microbial inhibitors in LH; and (4) applications of hybrid QM/MM simulations to profile the molecular interactions between microbial inhibitors and keyAADs. Our computational investigation has revealed various important facets of inhibition of theAADenzymes, which could guide structural biologist in designing efficient and robust enzymes. Moreover, our methodology also provides a general framework which could applied for deciphering the molecular mechanism of inhibition behaviour of other enzymes.

Highlights

Homology modelling of 7alcohol/aldehyde dehydrogenase(AAD) in solventogenicClostridia

Identification and structural optimization of potent microbial inhibitors in lignocellulosic hydrolysates

QM/MM simulations to profile the molecular interactions between 10 inhibitors and 7AADs

Discernment of the molecular mechanism of inhibition of keyalcohol/aldehyde dehydrogenase

A methodological framework for deciphering the molecular mechanism of enzyme inhibition
Prolific non-research authors in high impact scientific journals: meta-research study
Authors: Ioannidis John P.A.
Published: November 2022

Journalistic papers published in high impact journals can be very influential, especially in hot fields. This meta-research analysis aimed to evaluate the publication profiles, impact, and disclosures of conflicts of interest of non-research authors who had published >200 Scopus-indexed papers in Nature, Science, PNAS, Cell, BMJ, Lancet, JAMA or New England Journal of Medicine. 154 prolific authors were identified, 148 of whom had published 67,825 papers in their main affiliated journal in a non-researcher capacity. Of 25 massively prolific authors with over 700 publications in one of these journals, only 3 had a PhD degree in any subject matter. Only 2 of the 25 disclosed potential conflicts with some specificity. The practice of assigning so much power to non-researchers in shaping scientific discourse should be further debated and disclosures of potential conflicts of interest should be emphasized.
High levels of detection of non-pneumococcal species ofStreptococcusin saliva from adults in the USA
Authors: Hislop Maikel S. , Allicock Orchid M. , Thammavongsa Darani A. , Mbodj Sidiya , Nelson Allison , Shaw Albert C. , Weinberger Daniel M. , Wyllie Anne L.
Published: November 2022

Background

While the sensitivity of detection of pneumococcal carriage can be improved by testing respiratory tract samples with qPCR, concerns have been raised regarding the specificity of this approach. We therefore investigated the reliability of the widely-usedlytAqPCR assay when applied to saliva samples from older adults in relation to a more specific qPCR assay (piaB).

Methods

During the autumn/winter seasons of 2018/2019 and 2019/2020, saliva was collected at multiple timepoints from 103 healthy adults aged 21-40 (n=34) and ≥64 (n=69) years. Following culture-enrichment, extracted DNA was tested using qPCR forpiaBandlytA. By sequencing the variable region ofrpsB(S2-typing), we identified the species of bacteria isolated from samples testinglytA-positive only.

Results

While 30/344 (8.7%) saliva samples (16.5% individuals) tested qPCR-positive for bothpiaBandlytA, 52 (15.1%) samples testedlytA-positive only. No samples testedpiaB-positive only. Through extensive re-culture of the 32lytA-positive samples collected in 2018/2019, we isolated 23 strains (from 8 samples, from 5 individuals) that were also qPCR-positive for onlylytA. Sequencing determined thatStreptococcus mitisandStreptococcus infantiswere predominantly responsible for thislytA-positive qPCR signal.

Conclusions

We identified a comparatively large proportion of samples generating positive signals with the widely usedlytA-qPCR and identified non-pneumococcal streptococcal species responsible for this signal. This highlights the importance of testing for the presence of multiple gene targets in tandem for reliable and specific detection of pneumococcus in respiratory tract samples.
AN INTEGRATED APPROACH TO CARDIOVASCULAR DISEASE IN HOMELESS INDIVIDUALS: A QUALITATIVE STUDY
Authors: Bark Pippa , Ramasawmy Mel , Hayward Andrew , Luchenski Serena A , Aldridge Robert , Burridge Stan , Banerjee Amitava
Published: November 2022

Background

Homelessness is associated with an increased risk of cardiovascular disease (CVD), beyond impact of socioeconomic status. CVD is preventable and treatable, with barriers to both for homeless people. Those with lived experience of homelessness and health professionals with relevant expertise can help to understand and address these barriers.

Objectives

To understand and make recommendations to improve CVD care in homeless populations through those with lived experience and professional expertise.

Method

Four focus groups were conducted in March-July 2019. Three groups included people currently or previously homeless, each attended by a cardiologist (AB), a health services researcher (PB) and an “expert by experience” (SB) who coordinated participants. One group included multidisciplinary health and social care professionals in and around London to explore solutions.

Participants

The three homeless groups included 16 men and 9 women, aged 20- 60 years, of whom 24 were homeless and currently living in hostels and 1 rough sleeper. At least 14 discussed sleeping rough at some point.

Results

Participants were aware of CVD risks and relevance of healthy habits but identified barriers to prevention and health access, starting with disorientation affecting planning and self-care, lack of facilities for food, hygiene, and exercise, and experiences of discrimination.

Conclusions

CVD care for those experiencing homelessness should account for fundamental problems of the environment, be co-designed with service users and cover key principles: flexibility, public and staff education, integration of support, and advocacy for health service rights.
Performance comparison of reusable versus disposable colonoscopes:a non-inferiority Trial
Authors: Wei Mingtong , Liang Chenghai , Ruan Huaqiang , Liao Guolin , Peng Peng , Li Xin , Zou Jun , Liu Shiquan , Cao Ge , Qin Mengbin , Huang Jiean
Published: November 2022

Objective

We herein compared the performance of reusable and disposable colonoscopes in patients scheduled to undergo colonoscopy with a view of preventing patient cross-infection, protecting the safety of clinical medical staff, reducing the risk of infection, and minimizing the decontamination process, particularly during the coronavirus disease 2019 pandemic.

Methods

We randomly divided patients meeting the enrollment criteria into reusable and disposable colonoscopy groups; the success rate of photographing customary anatomical sites with a non-inferiority margin of -8% was the primary endpoint. Secondary endpoints were the adenoma detection rate, operation time, endoscopic image quality score, endoscopic mucosal resection (EMR) success rate, and adverse events.

Results

We recruited patients who were treated using reusable or disposable (n = 45, each) colonoscopes. Both groups had 100% success rate for capturing images of customary anatomical sites, with no between-group differences. The lower limit of 95% CI was - 7.8654%, which was greater than the non-inferiority threshold of -8%. The disposable group had a significantly lower average image quality score (26.09 ±1.33 vs. 27.44±0.59,P< 0.001) than the reusable group. The groups did not significantly differ in maneuverability, safety, or device failure/defect rate. Theen-blocEMR success rate was 100% in both groups. EMR took significantly longer in the disposable group (466.18 s±180.56 svs. 206.32 s±109.54 s,P< 0.001). The incidence of EMR-related bleeding and perforation did not significantly differ between the groups.

Conclusions

Disposable colonoscope endoscopy is safe and feasible for endoscopy examinations and EMR.
Meta-analysis of public RNA sequencing data revealed potential key genes associated with reproductive division of labor in social Hymenoptera and termites
Authors: Toga Kouhei , Bono Hidemasa
Published: November 2022

Eusociality in insects has evolved independently many times. One of the most notable characteristics of eusociality is the reproductive division of labor. In social insects, the reproductive division of labor is accomplished by queens and workers. Transcriptome analyses of queens and workers have been conducted for various eusocial species. However, the genes that regulate the reproductive division of labor across all or multiple eusocial species have not yet been fully elucidated. Therefore, we conducted a meta-analysis using publicly available RNA-sequencing data from four major groups of social insects. In this meta-analysis, we collected 258 pairs (queen vs. worker) of RNA-sequencing data from 34 eusocial species. The meta-analysis identified a total of 20 genes that were differentially expressed in queens or workers. Out of these, 12 genes have not previously been reported to be involved in the reproductive division of labor. Functional annotation of these 20 genes in other organisms revealed that they could be regulators of behaviors and physiological states related to the reproductive division of labor. These 20 genes, revealed using massive datasets of numerous eusocial insects, may be key regulators of the reproductive division of labor.
Convergent evolution in silico reveals shape and dynamic principles of directed locomotion
Authors: Biazzi Renata B , Fujita André , Takahashi Daniel Y
Published: November 2022

Active, directed locomotion on the ground is present in many phylogenetically distant species. Bilateral symmetry and modularity of the body are common traits often associated with improved directed locomotion. Nevertheless, both features result from natural selection, which is contingent (history-dependent) and multifactorial (several factors interact simultaneously). Based solely on the unique natural history on Earth, it is difficult to conclude that bilateral symmetry and modularity of the body are required traits for an improved locomotion ability as they can result from chance or be related to other body functions. As a way to avoid these caveats, we propose using physics-based simulations of 3D voxel-based soft robots evolved under different evolutionary scenarios to test the necessity of both traits for sustained and effective displacement on the ground. We found that an intermediate number of body modules (appendages) and high body symmetry are evolutionarily selected regardless of gravitational environments, robot sizes, and genotype encoding. Therefore, we conclude that both traits are strong candidates for universal principles related to improved directed locomotion.
Predicting Lifespan-Extending Chemical Compounds with Machine Learning and Biologically Interpretable Features
Authors: Ribeiro Caio , Farmer Christopher K. , de Magalhães João Pedro , Freitas Alex A.
Published: November 2022

Recently, there has been a growing interest in the development of pharmacological interventions targeting ageing, as well as on the use of machine learning for analysing ageing-related data. In this work we use machine learning methods to analyse data from DrugAge, a database of chemical compounds (including drugs) modulating lifespan in model organisms. To this end, we created four datasets for predicting whether or not a compound extends the lifespan ofC. elegans(the most frequent model organism in DrugAge), using four different types of predictive biological features, based on compound-protein interactions, interactions between compounds and proteins encoded by ageing-related genes, and two types of terms annotated for proteins targeted by the compounds, namely Gene Ontology (GO) terms and physiology terms from the WormBase’s Phenotype Ontology. To analyse these datasets we used a combination of feature selection methods in a data pre-processing phase and the well-established random forest algorithm for learning predictive models from the selected features. The two best models were learned using GO terms and protein interactors as features, with predictive accuracies of about 82% and 80%, respectively. In addition, we interpreted the most important features in those two best models in light of the biology of ageing, and we also predicted the most promising novel compounds for extending lifespan from a list of previously unlabelled compounds.
Instantaneous antidepressant effect of lateral habenula deep brain stimulation in rats studied with functional magnetic resonance imaging
Authors: Li Gen , Bo Binshi , Wang Puxin , Qian Peixing , Li Mingzhe , Li Yuyan , Tong Chuanjun , Zhang Kaiwei , Zhang Baogui , Jiang Tianzi , Liang Zhifeng , Duan Xiaojie
Published: November 2022

The available treatments for depression have substantial limitations, including low response rates and substantial lag time before a response is achieved. We applied deep brain stimulation (DBS) to the lateral habenula (LHb) of two rat models of depression (Wistar Kyoto rats and lipopolysaccharide-treated rats) and observed an immediate (within seconds to minutes) alleviation of depressive-like symptoms with a high response rate. Simultaneous functional magnetic resonance imaging (fMRI) conducted on the same sets of depressive rats used in behavioral tests revealed DBS-induced activation of multiple regions in afferent and efferent circuitry of the LHb. The activation levels of brain regions connected to the medial LHb (M-LHb) was correlated with the extent of behavioral improvements. Rats with more medial stimulation sites in the LHb exhibited greater antidepressant effects than those with more lateral stimulation sites. These results indicated that the antidromic activation of the limbic system and orthodromic activation of the monoaminergic systems connected to the M-LHb played a critical role in the rapid antidepressant effects of LHb-DBS. This study indicates that M-LHb-DBS might act as a valuable, rapid-acting antidepressant therapeutic strategy for treatment-resistant depression and demonstrates the potential of using fMRI activation of specific brain regions as biomarkers to predict and evaluate antidepressant efficacy.
No evidence for an effect of chronic boat noise on the fitness of reared water fleas
Authors: Prosnier Loïc , Rojas Emilie , Médoc Vincent
Published: November 2022

Abstract

Among the numerous questions about human impacts on ecosystems, there is a growing interest for acoustic pollution. First studies on underwater acoustic pollution focused, and showed effects, on vertebrates’ behaviours. Knowledge on the effects on invertebrates is more limited and there is a huge lack concerning zooplankton species, although widely used as bioindicators in chemical pollution. Consequently, it is critical to assess the impact of noise on zooplankton’s fitness (survival and fecundity). Here, isolated water fleas,Daphnia magna, were reared from birth to death in the presence or absence of motorboat noises. Effects on lifespan and clonal offspring production (e.g., clutch size, number of offspring produced along life) were assessed and chronic exposure to boat noise did not affectDaphnia’s fitness. The spectral and temporal features of the sounds could explain the results. This study highlights the importance of integrating noise pollution into ecotoxicological research to understand, and prevent, human impacts on communities.
Soil metatranscriptomics: An improved RNA extraction method toward functional analysis using nanopore direct RNA sequencing
Authors: Poursalavati Abdonaser , Javaran Vahid J. , Laforest-Lapointe Isabelle , Fall Mamadou L.
Published: November 2022

Soil microbes play an undeniable role in sustainable agriculture, plant health, and soil management. A deeper understanding of soil microbial composition and function has been gained through next-generation sequencing. While soil metagenomics has provided valuable information about microbial diversity, issues stemming from RNA extraction, low RNA abundance in some microbial populations (e.g., viruses), and mRNA enrichment have slowed the progress of soil metatranscriptomics. A variety of soil RNA extraction methods have been developed so far. Yet none of the available protocols can obtain RNA with high quality, purity, and yield for third-generation sequencing. This latter requires RNA with high quality and large quantities (with no or low contamination, such as humic acids). Also, use of commercial kits for in-batch soil RNA extraction is quite expensive, and these commercial kits lack buffer composition details, which prevents the optimization of protocols for different soil types. An improved and cost-effective method for extracting RNAs from mineral and organic soils is presented in this paper. An acidic sodium acetate buffer and phosphate buffer with modifications to bead-beating and nucleic acid precipitation lead to higher RNA yields and quality. Using this method, we obtained almost DNA-free RNA. By using nanopore’s direct RNA sequencing, the extracted contamination-free RNAs were successfully sequenced. Lastly, taxonomic groups such as bacteria, fungi, archaea, and viruses were classified and profiled as well as functional annotation of the datasets was carried out using an in-house customized bioinformatics workflow.
Safety and immunogenicity of SARS-CoV-2 self-amplifying RNA vaccine expressing anchored RBD: a randomised, observer-blind, phase 1 study
Authors: Akahata Wataru , Sekida Takashi , Nogimori Takuto , Ode Hirotaka , Tamura Tomokazu , Kono Kaoru , Kazami Yoko , Washizaki Ayaka , Masuta Yuji , Suzuki Rigel , Matsuda Kenta , Komori Mai , Morey Amber , Ishimoto Keiko , Nakata Misako , Hasunuma Tomoko , Fukuhara Takasuke , Iwatani Yasumasa , Yamamoto Takuya , Smith Jonathan F , Sato Nobuaki
Published: November 2022

BACKGROUND

VLPCOV-01 is a lipid nanoparticle-encapsulated self-amplifying RNA (saRNA) vaccine that expresses a membrane-anchored receptor-binding domain (RBD) derived from the SARS-CoV-2 spike protein.

METHODS

A phase 1 study of VLPCOV-01 was conducted at Medical Corporation Heishinkai OPHAC Hospital, Japan. Participants aged 18 to 55 or ≥65 years who had completed two doses of the BNT162b2 mRNA vaccine 6 to 12 months previously were randomised to receive one intramuscular vaccination of 0·3, 1·0, or 3·0 μg VLPCOV-01, 30 μg BNT162b2, or placebo between February 16, 2022, and March 17, 2022. Solicited adverse events were collected up to 6 days post-administration. Interim immunogenicity analyses included SARS-CoV-2 IgG and neutralising antibody titres. Follow-up for safety and immunogenicity evaluation is ongoing. (The trial is registered: jRCT2051210164).

FINDINGS

92 healthy adults were enrolled, with 60 participants receiving VLPCOV-01. No serious adverse events were reported up to 26 weeks, and no prespecified trial-halting events were met. VLPCOV-01 induced robust IgG titres against SARS-CoV-2 RBD protein that were maintained up to 26 weeks in non-elderly participants, with geometric means ranging from 5037 (95% CI 1272–19,940) at 0·3 μg to 12,873 (95% CI 937–17,686) at 3 μg, in comparison to 3166 (95% CI 1619–6191) with 30 μg BNT162b2. Among elderly participants, IgG titres at 26 weeks post-vaccination with 3 μg VLPCOV-01 were 9865 (95% CI 4396–22138) compared to 4183 (95% CI 1436–12180) following vaccination with 30 μg BNT162b2. Pseudovirus neutralising antibody responses were observed against multiple SARS-CoV-2 variants and strongly correlated with anti-SARS-CoV-2 IgG (r=0·950, p<0·001).

INTERPRETATION

VLPCOV-01 is immunogenic following low dose administration, with anti-SARS-CoV-2 immune responses comparable to BNT162b2. These findings support further development of VLPCOV-01 as a COVID-19 booster vaccine and the potential for saRNA vectors as a vaccine platform.

FUNDING

Supported by AMED, Grant No. JP21nf0101627.
Is anxiety a pathway to Alcohol Use Disorders? A phenome-wide association study of theGABRA2coding variant rs279858
Authors: Merikangas Alison K. , Kember Rachel L. , Plawecki Martin H. , Kamarajan Chella , Chan Grace , Bauer Lance , Meyers Jacquelyn L. , Nurnberger John I. , Kramer John , Porjesz Bernice , Edenberg Howard J. , Almasy Laura
Published: November 2022

Alcohol use disorders (AUDs) and related electrophysiological endophenotypes have been associated with theGABRA2gene. However, the causal variants inGABRA2and their mechanisms of influence on AUD and its correlates have not been established. Here we investigate the phenotypic spectrum of aGABRA2coding variant (rs279858) through a phenome-wide association study (PheWAS) in two open-source datasets.

We applied the PheWAS approach to identify a broad range of phenotypes associated with rs279858 in the MRC IEU OpenGWAS PheWAS and the Open Targets Genetics Portal. These databases extend the array of phenotypes beyond those available in electronic health records (EHR) to include numerous non-medical phenotypes and traits. We then followed up the results from those exploratory associations by examining the genetic correlations between our “top hits” and alcohol- and smoking-related phenotypes.

In both data sources, rs279858 (C effect allele) was associated with anxiety-related phenotypes, including reduced risk-taking behavior and an increase in nervous feelings, as well as reduced number of lifetime sexual partners. Follow-up analyses revealed that these phenotypes were genetically correlated with each other and with alcohol- and smoking-related phenotypes.

This work illustrates the utility of the PheWAS approach, particularly for phenotypes that extend beyond those that are typically captured in EHR data. In fact, the associations described here are all behavioral rather than clinical phenotypes. We postulate that these traits may be related to anxiety or behavioral inhibition that has been identified as a risk factor for AUD, and may represent pathophysiological intermediaries betweenGABRA2and AUD.
The Bidirectional Relationship Between Head Injuries and Conduct Problems: Longitudinal Modelling of a Population-Based Birth Cohort Study
Authors: Carr Hannah R. , Hall James E. , Eisenbarth Hedwig , Brandt Valerie C.
Published: November 2022

Childhood head injuries and conduct problems increase the risk of aggression and criminality and are well-known correlates. However, the direction and timing of their association and the role of their demographic risk factors remain unclear. This study investigates the bidirectional links between both from 3 to 17 years while revealing common and unique demographic risks.

A total of 7,140 participants (51% female; 83.9% White ethnicity) from the Millennium Cohort Study were analysed at 6 timepoints from age 3 to 17. Conduct problems were parent-reported for ages 3 to 17 using the Strengths and Difficulties Questionnaire (SDQ) and head injuries at ages 3 to 14. A cross-lagged path model estimated the longitudinal bidirectional effects between the two whilst salient demographic risks were modelled cumulatively at three ecological levels (child, mother, and household).

Conduct problems at age 7 promoted head injuries between 7 and 11 (Z= .07;SE= .03; 95% CI, .01-.12), and head injuries then promoted conduct problems at age 14 (ß= .07;SE= .03; 95% CI, .01-.12). Head injuries were associated with direct child-level risk until 7 years, whereas conduct problems were associated with direct risks from all ecological levels up until 17 years.

The findings suggest a sensitive period at 7 to 11 years for the bidirectional relationship shared between head injuries and conduct problems. They suggest that demographic risks for increased head injuries play an earlier role than they do for conduct problems. Both findings have implications for intervention timing.
Discovery and biosynthetic assessment ofStreptomyces ortussp nov. isolated from a deep-sea sponge
Authors: Williams Sam E. , Back Catherine R. , Best Eleanor , Mantell Judith , Stach James E. M. , Williams Tom A. , Race Paul R. , Curnow Paul
Published: November 2022

The deep sea is known to host novel bacteria with the potential to produce a diverse array of undiscovered natural products. Understanding these bacteria is thus of broad interest in ecology and could also underpin applied drug discovery, specifically in the area of antimicrobials. Here, we isolate a new strain ofStreptomycesfrom the tissue of the deep-sea spongePolymastia corticatacollected at a depth of 1869 m from the Gramberg seamount in the Atlantic Ocean. This strain, which was given the initial designation A15ISP2-DRY2T, has a genome size of 9.29 Mb with a GC content of 70.83%. Phylogenomics determined that A15ISP2-DRY2Trepresents a novel species within the genusStreptomycesas part of theStreptomyces aurantiacusclade. The biosynthetic potential of A15ISP2-DRY2Twas assessed relative to other members of theaurantiacusclade via comparative gene cluster family (GCF) analysis. This revealed a clear congruent relationship between phylogeny and GCF content. A15ISP2-DRY2Tcontains six unique GCFs absent elsewhere in the clade. Culture-based assays were used to demonstrate the antibacterial activity of A15ISP2-DRY2Tagainst two drug-resistant human pathogens. We thus determine A15ISP2-DRY2Tto be a novel bacterial species with considerable biosynthetic potential and propose the systematic nameStreptomyces ortussp. nov.

Impact Statement

TheStreptomycesgenus has contributed more to our antibiotic arsenal than any other group of bacteria or fungi. Despite decades of exploration, global analysis has suggested they still possess more undiscovered biosynthetic diversity than any other bacterial group. Isolating novel species ofStreptomycesis therefore a priority for antibiotic discovery. Here we isolate a novel strain from a deep-sea sponge and use comparative cluster analysis to identify six biosynthetic clusters unique to our deep-sea strain. This work demonstrates the utility of continuing to isolate novelStreptomycesstrains for antibiotic discovery and, for the first time, we used species tree-gene cluster tree reconciliation to assess the contribution of vertical evolution on the biosynthetic gene cluster content ofStreptomyces.
Improving orthologous signal and model fit in datasets addressing the root of the animal phylogeny
Authors: McCarthy Charley GP , Mulhair Peter O , Siu-Ting Karen , Creevey Christopher J , O’Connell Mary J
Published: November 2022

There is conflicting evidence as to whether Porifera (sponges) or Ctenophora (comb jellies) comprise the root of the animal phylogeny. Support for either a Porifera-sister or Ctenophore-sister tree has been extensively examined in the context of model selection, taxon sampling and outgroup selection. The influence of dataset construction is comparatively understudied. We re-examine five animal phylogeny datasets that have supported either root hypothesis using an approach designed to enrich orthologous signal in phylogenomic datasets. We find that many component orthogroups in animal datasets fail to recover major animal lineages as monophyletic with the exception of Ctenophora, regardless of the supported root. Enriching these datasets to retain orthogroups recovering ≥3 major lineages reduces dataset size by up to 50% while retaining underlying phylogenetic information and taxon sampling. Site- heterogeneous phylogenomic analysis of these enriched datasets recovers both Porifera-sister and Ctenophora-sister positions, even with additional constraints on outgroup sampling. Two datasets which previously supported Ctenophora-sister support Porifera-sister upon enrichment. All enriched datasets display improved model fitness under posterior predictive analysis. While not conclusively rooting animals at either Porifera or Ctenophora, our results indicate that dataset size and construction as well as model fit influence animal root inference.
BIOLOGICAL DIAGNOSTICS OF THE ECOLOGICAL STATE OF URBAN ECOSYSTEMS
Authors: Galaktionova L.V. , Terekhova N.A. , Vedeneeva N.G.
Published: November 2022

Annotation

The processes of urbanization and the development of industrial production entail active environmental pollution with pollutants of various nature. The existing analytical methods for their determination in natural media make it possible to reveal their concentration. But in conditions of complex soil pollution, this approach does not give a complete picture of their total impact on living organisms. In the course of the study, an assessment was made of the ecological state of soils in large administrative and industrial centers of the Southern Urals (the cities of Orenburg and Mednogorsk) in terms of their phytotoxicity and enzymatic activity. On the territory of the objects of study, soil samples were taken from a layer of 0-20 cm in various functional zones. Phytotoxicity was assessed using a wheat test culture, and indicators of urease and catalase activity were used to assess biological activity. The calculation of the integral indicator of the ecological state on their basis showed the development of processes of degradation of the soil cover of cities under the influence of urbanization.
Does AlphaFold predict the spatial structure of a protein from physics or recognize it (its main parts and their association) using databases?
Authors: Finkelstein Alexei V.
Published: November 2022

The great success of the AlphaFold programs poses the following questions: (i) What is the main reason for this success? (ii) What exactly do AlphaFolds do:predictionof the 3D protein structure based on its amino acid sequence and knowledge of the protein physics orrecognitionof this 3D structure, based on the similarity between some parts of its amino acid sequence and parts of sequences with already known 3D structures? The answers given in this paper are: The main reason for the tremendous success of the AlphaFold is (i) the usage of huge protein databases, which already cover all or almost all of the protein superfamilies existing in nature; (ii) using these databases and the resulting multiple sequence alignments and coevolutionary information (like correlations in pairs and especially in triplets of amino acid residues in the contacting chain regions), AlphaFoldrecognizesa 3D structure of the examined amino acid sequence by a similarity of this sequence (or its parts) to related sequences with already known 3D structures. Concluding, I have to emphasize that this paper does not diminish the merit and utility of AlphaFold; it only explains the basis of its success.
Tetraspanner-based nanodomains modulate BAR domain-induced membrane curvature
Authors: Haase Daniel , Rasch Christiane , Keller Ulrike , Elting Annegret , Wittmar Julia , Janning Annette , Kahms Martin , Schuberth Christian , Klingauf Jürgen , Wedlich-Söldner Roland
Published: November 2022

Topography is a critical feature driving formation and dynamics of protein and lipid domains within biological membranes. The yeast plasma membrane (PM) has provided a powerful model system to study lateral domain formation, including characteristic BAR domain-induced PM furrows. Currently, it is not clear how the components involved in the establishment of these furrows cooperate to precisely regulate local PM topography. Here we report opposing functions for the Sur7 and Nce102 families of tetraspanner proteins in modulating membrane curvature and domain topography. Using STED nanoscopy and freeze-fracture EM we found that Sur7 tetraspanners form multimeric strands at the upper edges of PM furrows, which counteract the forces exerted by BAR domain proteins and prevent membrane tubulation. In contrast, Nce102 tetraspanners are located basal to the Sur7 proteins and promote BAR domain-induced curvature. The segregation of the two tetraspanner-based nanodomains is further supported by differential distribution of ergosterol to the upper edge of furrows and PIP2 lipids at the furrow base. These findings suggest a general role of tetraspanner proteins in sculpting local membrane domains.
Climatic refugia in the coldest neotropical hotspot, the Andean páramo
Authors: Peyre Gwendolyn , Lopez Catalina , Diaz Maria Daniela , Lenoir Jonathan
Published: November 2022

Aim

The Andean páramo is the most biodiverse high-mountain region on Earth and past glaciation dynamics during the Quaternary are greatly responsible for its plant diversification. Here, we aim at identifying potential climatic refugia since the Last Glacial Maximum (LGM) in the páramo, according to plant family, biogeographic origin, and life-form.

Location

The páramo region in the Northern Andes

Methods

We built species distribution models for 664 plant species to generate range maps under current and LGM conditions, using five General Circulation Models (GCMs). For each species and GCM, we identified potential (suitable) and potential active (likely still occupied) refugia where both current and LGM range maps overlap. We stacked and averaged the resulting refugia maps across species and GCMs to generate consensus maps for all species, plant families, biogeographic origins and life-forms. All maps were corrected for potential confounding effect due to species richness.

Results

We found refugia to be chiefly located in the southern and central páramos of Ecuador and Peru, especially towards the páramo ecotone with lower-elevation forests. However, we found additional specific patterns according to plant family, biogeographic origin and life-form. For instance, endemics showed refugia concentrated in the northern páramos.

Main conclusions

Our findings suggest that large and connected páramo areas, but also the transitional Amotape-Huancabamba zone with the Central Andes, are primordial areas for plant species refugia since the LGM. This study therefore enriches our understanding on páramo evolution and calls for future research on plant responses to future climate change.
Appetitive cue exposure increases neural reward responses without modulating temporal discounting
Authors: Knauth Kilian , Mathar David , Kuzmanovic Bojana , Tittgemeyer Marc , Peters Jan
Published: November 2022

When given a choice, humans and many animals prefer smaller but sooner over larger but later rewards, a tendency referred to as temporal discounting. Alterations in devaluation of future rewards have been reported in a range of maladaptive behaviors and clinical conditions. Although temporal discounting is highly stable over time and testing environments (e.g., laboratory vs. virtual reality), it is partly under contextual control. For example, highly appetitive cues such as erotic images might increase preferences for immediate rewards, although overall evidence remains mixed. Dopaminergic circuit activity and striatal dopamine concentrations are often assumed to drive increases in temporal discounting following appetitive cue-exposure, yet this was never explicitly tested. Here we examined cue-reactivity effects (erotic vs. neutral pictures) on subsequent temporal discounting in a pre-registered within-subjects study in healthy male participants (n=38). Functional magnetic resonance imaging (fMRI) assessed neural cue-reactivity, value-computations and choice-related effects. Preregistered analyses replicated previous findings of value coding in ventromedial prefrontal cortices, striatum and cingulate cortex. Likewise, as hypothesized, lateral prefrontal cortex activity increased during choices of delayed rewards, potentially reflecting cognitive control. As predicted, erotic vs. neutral cue exposure was associated with increased activity in attention and reward circuits. Contrary to our preregistered hypotheses, temporal discounting was largely unaffected by cue exposure. Likewise, cue-reactivity in key areas of the dopaminergic reward circuit (Nacc, VTA) was not significantly associated with changes in behavior. Our results indicate that behavioral effects of erotic cue exposure on temporal discounting might not be as unequivocal as previously thought and raise doubt on the hypothesis of an upregulated dopaminergic ramping mechanism, that might support myopic approach behavior towards immediate rewards.