bluuebunny/crossref_metadata_2025 huggingface dataset:
GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States
Authors: Vidal Igor , Zheng Qizhi , Hicks Jessica L. , Chen Jiayu , Platz Elizabeth A. , Trock Bruce J. , Kulac Ibrahim , Baena-Del Valle Javier , Sfanos Karen S. , Ernst Sarah , Jones Tracy , Glavaris Stephanie , Nelson William G. , Yegnasubramanian Srinivasan , De Marzo Angelo M.
Published: September 2020

GSTP1 is a member of the Glutathione-S-transferase (GSTS) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on TMAs with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). The increased percentage of GSTP1 positive cases in Black men was present only in ERG positive cases. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTPI-positive tumor cells. This is the first report revealing that the GSTPI-positive prostate cancer subset is substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men.
Microfluidic nano-scale qPCR enables ultra-sensitive detection of SARS-CoV-2
Authors: Xie Xin , Gjorgjieva Tamara , Attieh Zaynoun , Dieng Mame Massar , Arnoux Marc , Khair Mostafa , Moussa Yasmine , Al Jallaf Fatima , Rahiman Nabil , Jackson Christopher A. , Victoria Zyrone , Zafar Mohammed , Ali Raghib , Piano Fabio , Gunsalus Kristin C. , Idaghdour Youssef
Published: September 2020

Background

A major challenge in controlling the COVID-19 pandemic is the high false-negative rate of the commonly used standard RT-PCR methods for SARS-CoV-2 detection in clinical samples. Accurate detection is particularly challenging in samples with low viral loads that are below the limit of detection (LoD) of standard one- or two-step RT-PCR methods.

Methods

We implement a three-step approach for SARS-CoV-2 detection and quantification that employs reverse transcription, targeted cDNA preamplification and nano-scale qPCR based on the Fluidigm 192.24 microfluidic chip. We validate the method using both positive controls and nasopharyngeal swab samples.

Results

Using SARS-CoV-2 synthetic RNA and plasmid controls, we demonstrate that the addition of a preamplification step enhances the LoD of the Fluidigm method by 1,000-fold, enabling detection below 1 copy/μl. We applied this method to analyze 182 clinical NP swab samples previously diagnosed using a standard RT-qPCR protocol (91 positive, 91 negative) and demonstrate reproducible detection of SARS-CoV-2 over five orders of magnitude (< 1 to 106viral copies/μl). Crucially, we detect SARS-CoV-2 with relatively low viral load estimates (<1 to 40 viral copies/μl) in 17 samples with negative clinical diagnosis, indicating a potential false negative rate of 18.7% by clinical diagnostic procedures.

Conclusion

The three-step nano-scale RT-qPCR method can robustly detect SARS-CoV-2 in samples with relatively low viral loads (< 1 viral copy/μl) and has the potential to reduce the false negative rate of standard RT-PCR-based diagnostic tests for SARS-CoV-2 and other viral infections.

We test, implement and report the results of a microfluidic RT-qPCR assay system involving sequential RT, preamplification and nano-scale qPCR that can robustly detect SARS-CoV-2 in clinical samples with viral loads less than 1 copy/ul.
COVID-19 Seroprevalence in Baixada Santista Metropolitan Area – Brazil
Authors: Batista Karina Barros Calife , Caseiro Marcos Montani , Barros Cláudia Renata , Martins Lourdes Conceição , Chioro Arthur , de Araújo Evaldo Stanislau Affonso , Calvo Marcos , Pereira Luiz Alberto Amador
Published: September 2020

Background

COVID-19 reached Brazil in February 2020 after spreading throughout Asia and Europe. The disease first struck in Brazil’s major cities, affecting high-income groups, subsequently spreading to the socially-vulnerable outlying areas. The objective of this preliminary study was to the estimate the seroprevalence of COVID-19 in the Baixada Santista Metropolitan Area - RMBS, to inform policies for prevention and preparation of primary care, hospital services, hospital beds, intensive and critical care in a bid to reduce lethality.

Methods

This study is the first of a four-phase cross-sectional survey to include all cities within the Baixada Santista metropolitan area. The probabilistic population-based sample was based on a 7% prevalence with a 2% delta, a 5% level of significance and 90% power, and considered the estimated population, stratified by age, gender and city. The sample was randomized in each city and street selection was based on data drawn from the 2010 Brazilian census. The serology test was chosen from the available test kits approved by the National Health Agency (ANS) of the National Health Surveillance Agency (ANVISA), for the detection of SARS-CoV-2 antibodies. Information on socioeconomic characteristics, health service use, symptoms and adherence to social distancing measures was collected. All variables were expressed as absolute and relative frequencies and confidence intervals.

Results

The final sample comprised 2,342 respondents with a mean age of 37.78 (±19.98) years and equal gender distribution. Respondents predominantly lived in an abode with 4 or more rooms, 71.9% had an income of ≤3 minimum wages and no formal employment. Over half of the sample reported being reliant on the National Health Service (SUS) for health care, while 26.5% held private health insurance. Social distancing was practiced by 61.4% of respondents who answered this question. Seroprevalence measured was 1.4% for a 95% CI (0.93-1.93) based on mathematical estimates, with a ratio of 15 actual infections for every case notified, and lethality of 0.48%.

Conclusion

Results revealed a flattening of the epidemiological curve in the region and high underreporting of cases.
An analysis of genetic diversity actions, indicators and targets in 114 National Reports to the Convention on Biological Diversity
Authors: Hoban Sean , Campbell Catriona , da Silva Jessica , Ekblom Robert , Funk W Chris , Garner Brittany , Godoy Jose A , Kershaw Francine , MacDonald Anna , Mergeay Joachim , Minter Melissa , O'Brien David , Paz-Vinas Ivan , Pearson Sarah Kim , Perez-Espona Silvia , Potter Kevin , Russo Isa-Rita , Segelbacher Gernot , Vernesi Cristiano , Hunter Margaret E
Published: September 2020

Genetic diversity is critically important for all species-domesticated and wild- to adapt to environmental change, and for ecosystem resilience to extreme events. International agreements such as the Convention on Biological Diversity (CBD) have committed to conserve and sustainably and equitably use all levels of biodiversity-genes, species and ecosystems-globally. However, assessment and monitoring of genetic diversity are often overlooked, and there are large knowledge and policy gaps regarding genetic diversity conservation. In this study, we present the first quantitative analysis of genetic diversity assessments conducted by Parties to the CBD. We conducted a detailed, systematic analysis of 114 CBD 5th (submitted 2014) and 6th (submitted 2018) National Reports to quantitatively assess actions, progress on targets, values and indicators related to genetic diversity. First, we found that the importance of genetic diversity is recognised by most Parties to the CBD, and that recognition increased over time. However, genetic targets mainly addressed genetic diversity within cultivated plants, farm animals, and crop wild relatives, with little focus on other wild species. Also, actions for conserving genetic diversity primarily concernedex-situfacilities and policy, rather than monitoring and intervention for maintaining genetic diversityin situ. The most commonly used indicators of genetic diversity status were the number of genetic resources in conservation facilities, number of threatened breeds, and Red List Index, which are not well correlated to genetic erosion in most species -- highlighting that genetic change is poorly monitored by current indicators. Lastly, analyses of genetic data observations, indigenous use and knowledge of genetic diversity, and strategies being developed and implemented to conserve genetic diversity are highly under-reported. We make several recommendations for the post-2020 CBD Biodiversity Framework to improve awareness, assessment, and monitoring, and facilitate consistent and complete reporting of progress of genetic diversity in future National Reports.

Article Impact Statement

An analysis of genetic diversity in CBD National Reports neglects non-domesticated species and demonstrates need for sufficient indicators.
Serotonergic Effects on Interoception
Authors: Livermore James J A , Holmes Clare L , Moga Gyorgy , Adamatzky Kristian , Critchley Hugo D , Garfinkel Sarah N , Campbell-Meiklejohn Daniel
Published: September 2020

Interoception is the signalling, perception, and interpretation of internal physiological states. Much of the psychopharmacology of interoception is still undiscovered. However, psychiatric disorders associated with changes of interoception, including depressive, anxiety, and eating disorders are often treated with selective serotonin reuptake inhibitors (SSRIs). The causal effect of acute changes of serotonin transmission on interoceptive cognition was tested by a within-participant, crossover, placebo-controlled study. Forty-seven healthy human volunteers (31 female, 16 male) were tested both on and off a 20mg oral dose of the commonly prescribed SSRI citalopram. For each randomly ordered session, participants made judgments on the synchrony of their heartbeat to auditory tones and expressed confidence in each of these judgments. Citalopram enhanced insight into the likelihood that one’s interoceptive judgment had been correct, driven primarily by enhanced confidence for correct responses. This effect was independent of measured cardiac and subjective effects of the drug. This novel result is evidence that acute serotonin changes can alter metacognitive insight into the reliability of inferences based on interoceptive information, which is a foundation for considering effects of serotonin on cognition and emotion in terms of effective top-down regulation of interoceptive influence on mental states.
Sex change in aquarium systems establishes the New Zealand spotty wrasse (Notolabrus celidotus) as a temperate model species for the investigation of sequential hermaphroditism
Authors: Goikoetxea A , Muncaster S , Todd EV , Lokman PM , Robertson HA , De Farias e Moraes CE , Damsteegt EL , Gemmell NJ
Published: September 2020

The stunning sexual transformation commonly triggered by age, size or social context in some fishes is one of the best examples of phenotypic plasticity thus far described. To date our understanding of this process is dominated by studies on a handful of subtropical and tropical teleosts, often in wild settings because sex change has been challenging to achieve in captivity. Here we have established the protogynous New Zealand spotty wrasse, Notolabrus celidotus, as a temperate model for the experimental investigation of sex change. Captive fish were induced to change sex using either aromatase inhibition or manipulation of social groups. Complete transition from female to male occurred over 60 days and time-series sampling was used to quantify changes in hormone production, gene expression and gonadal cellular anatomy using radioimmunoassay, nanoString nCounter mRNA and histological analyses, respectively. Early-stage decreases in plasma 17β-estradiol (E2) concentrations or gonadal aromatase (cyp19a1a) expression were not detected in spotty wrasse, despite these being commonly associated with the onset of sex change in subtropical and tropical protogynous (female-to-male) hermaphrodites. In contrast, expression of the masculinising factor amh (anti-Müllerian hormone) increased during early sex change, implying a potential role as a proximate trigger for masculinisation. Expression of male-related genes responsible for androgen production cyp11c1 and hsd11b2 increased from mid sex change. Gonadal expression of the glucocorticoid and mineralocorticoid receptors nr3c1 and nr3c2, putative mediators of the stress hormone cortisol, increased in late stages of sex change. Collectively, these data provide a foundation for the spotty wrasse as a temperate teleost model to study sex change and cell fate in vertebrates.

Summary statement

The spotty wrasse, Notolabrus celidotus, is a new temperate model for the study of vertebrate sex change, this work characterises endocrine and genetic markers based on laboratory induced sex change.
Amplitude of circadian rhythms becomes weaker in the north, but there is no cline in the period of rhythm in a beetle
Authors: Abe Masato S. , Matsumura Kentarou , Yoshii Taishi , Miyatake Takahisa
Published: September 2020

Many species show rhythmicity in activity, from the timing of flowering in plants to that of foraging behaviour in animals. The free-running periods and amplitude (sometimes called strength or power) of circadian rhythms are often used as indicators of biological clocks. Many reports have shown that these traits highly geographically variable, and interestingly, they often show latitudinal or altitudinal clines. In many cases, the higher the latitude is, the longer the free-running circadian period (i.e., period of rhythm) in insects and plants. However, reports of positive correlations between latitude or longitude and circadian rhythm traits, including free-running periods, the power of the rhythm and locomotor activity, are limited to certain taxonomic groups. Therefore, we collected a cosmopolitan stored-product pest species, the red flour beetleTribolium castaneum, in various parts of Japan and examined its rhythm traits, including the power of the rhythm and period of the rhythm, which were calculated from locomotor activity. The analysis revealed that power was significantly lower for beetles collected in northern areas compared with southern areas in Japan. However, it is worth noting that the period of circadian rhythm did not show any clines; specifically, it did not vary among the sampling sites, despite the very large sample size (n = 1585). We discuss why these cline trends were observed inT. castaneum.
Idiosyncratic Tower of Babel: Individual differences in word meaning representation increase along abstractness
Authors: Wang Xiaosha , Bi Yanchao
Published: September 2020

Humans primarily rely on language to communicate, based on a shared understanding of the basic building blocks of communication: words. However, words also have idiosyncratic aspects of meaning. Do we mean the same things when we use the same words? Classical philosophers disagreed on this point, speculating that words have more similar meanings across individuals if they are either more experiential (John Locke) or more abstract (Bertrand Russell). Here, we empirically characterize the individual variation pattern of 90 words using both behavioral and neuroimaging measures. We show that the magnitude of individual meaning disagreement is a function of how much language or sensory experience a word associates with, and this variation increases with abstractness of a word. Uncovering the cognitive and neural origins of word meaning disagreements across individuals has implications for potential mechanisms to modulate such disagreements.
Temporal and genomic analysis of additive genetic variance in breeding programmes
Authors: Lara Letícia A. de C. , Pocrnic Ivan , Gaynor R. Chris , Gorjanc Gregor
Published: September 2020

This study demonstrates a framework for temporal and genomic analysis of additive genetic variance in a breeding programme. Traditionally we used specific experimental designs to estimate genetic variance for a specific group of individuals and a general pedigree-based model to estimate genetic variance for pedigree founders. However, with the pedigree-based model we can also analyse temporal changes in genetic variance by summarising sampled realisations of genetic values from a fitted model. Here we extend this analysis to a marker-based model and build a framework for temporal and genomic analyses of genetic variance. The framework involves three steps: (i) fitting a marker-based model to data, (ii) sampling realisations of marker effects from the fitted model and for each sample calculating realisations of genetic values, and (iii) calculating variance of the sampled genetic values by time and genome partitions. Genome partitions enable estimation of contributions from chromosomes and chromosome pairs and genic and linkage-disequilibrium variances. We demonstrate the framework by analysing data from a simulated breeding programme involving a complex trait with additive gene action. We use the full Bayesian and empirical Bayesian approaches to account for the uncertainty due to model fitting. We also evaluate the use of principal component approximation. Results show good concordance between the simulated and estimated variances for temporal and genomic analyses and give insight into genetic processes. For example, we observe reduction of genic variance due to selection and drift and buildup of negative linkage-disequilibrium (the Bulmer effect) due to directional selection. In this study the popular empirical Bayesian approach estimated the variances well but it underestimated uncertainty of the estimates. The principal components approximation biases estimates, in particular for the genic variance. This study gives breeders a framework to analyse genetic variance and its components in different stages of a programme and over time.
Anatomy, transcription dynamics and evolution of wheat ribosomal RNA loci deciphered by a multi-omics approach
Authors: Tulpová Zuzana , Kovařík Aleš , Toegelová Helena , Navrátilová Pavla , Kapustová Veronika , Hřibová Eva , Vrána Jan , Macas Jiří , Doležel Jaroslav , Šimková Hana
Published: September 2020

Background and Aims

Three out of four RNA components of ribosomes are encoded by 45S rDNA loci, whose transcripts are processed into 18S, 5.8S and 26S ribosomal RNAs. The loci are organized as long head-to-tail tandem arrays of nearly identical units spanning over several megabases of sequence. Due to this peculiar structure, the number of rRNA genes, their sequence composition and expression status remain unclear, especially in complex polyploid genomes harbouring multiple loci. Here we conducted a complex study to decipher structure and activity of both major and minor rRNA loci in hexaploid bread wheat (Triticum aestivum).

Methods

We employed an original, multi-omics approach, combining chromosome flow sorting and optical mapping with transcriptome and methylome sequencing.

Key Results

The former two techniques enabled unbiased quantification of rDNA units in particular loci of the wheat genome. Total number of rRNA genes organized in tandem arrays was 4388, with 64.1, 31.4, 3.9 and 0.7% located in short arms of chromosomes 6B, 1B, 5D and 1A, respectively. At the expression level, only 1B and 6B loci contributed to transcription at roughly 2:1 ratio. The 1B:6B ratio varied among five analysed tissues (embryo, coleoptile, root tip, primary leaf, mature leaf), being the highest (2.64:1) in mature leaf and lowest (1.72:1) in coleoptile. Cytosine methylation was considerably higher in CHG contexts in the silenced 5D locus compared to the active 1B and 6B loci.

Conclusions

A fine genomic organization and tissue-specific expression of rRNA loci were deciphered, for the first time, in a complex polyploid species. We documented various mechanisms of rRNA dosage control, including gene elimination and stable inactivation related to nucleolar subdominance of A and D-genome loci, and a subtle, developmentally regulated silencing of one of the major loci. The results are discussed in the context of wheat evolution and transcription regulation.
Grazing impacts on ground beetle (Coleoptera: Carabidae) abundance and diversity on a semi-natural grassland
Authors: Pozsgai Gabor , Quinzo-Ortega Luis , Littlewood Nick A.
Published: September 2020

Semi-natural grasslands are commonly managed as a grazing resource for domestic livestock but, due to their unique biodiversity, they are also of conservation interest. Numerous drivers have impacted on the status of these grasslands in recent decades, most importantly changing grazing management strategies. These changes have the potential to affect the biodiversity associated with these habitats, including on some rich invertebrate assemblages. Responses, however, are often dissimilar between different invertebrate taxa.

We investigated the responses of ground beetles to different grazing regimes within a long-term grazing experiment on upland semi-natural grassland in Scotland. Although there was substantial overlap between ground beetle assemblages in different grazing treatments, species richness, mean abundance and Shannon diversity of ground beetles were significantly lower in ungrazed plots than in plots subject to high- or low-intensity sheep grazing. Ground beetle abundance (but not species richness or diversity) were lower in ungrazed plots compared to those with low-intensity mixed grazing by sheep and cattle. However, no differences were identified in abundance, species richness or diversity between the three grazed treatments.

Our results suggest that ground beetles may show different responses to grazing compared to responses of some other invertebrate groups and demonstrates the difficulty of carrying out management for a multi-taxon benefit.
Haplotype-resolved genome assembly enables gene discovery in the red palm weevilRhynchophorus ferrugineus
Authors: Dias Guilherme B. , Altammami Musaad A. , El-Shafie Hamadttu A.F. , Alhoshani Fahad M. , Al-Fageeh Mohamed B. , Bergman Casey M. , Manee Manee M.
Published: September 2020

The red palm weevilRhynchophorus ferrugineus(Coleoptera: Curculionidae) is an economically-important invasive species that attacks multiple species of palm trees around the world. A better understanding of gene content and function inR. ferrugineushas the potential to inform pest control strategies and thereby mitigate economic and biodiversity losses caused by this species. Using 10x Genomics linked-read sequencing, we produced a haplotype-resolved diploid genome assembly forR. ferrugineusfrom a single heterozygous individual with modest sequencing coverage (~62x). Benchmarking against conserved single-copy Arthropod orthologs suggests both pseudo-haplotypes in ourR. ferrugineusgenome assembly are highly complete with respect to gene content, and do not suffer from haplotype-induced duplication artifacts present in a recently published hybrid assembly for this species. Annotation of the larger pseudo-haplotype in our assembly provides evidence for 23,413 protein-coding loci inR. ferrugineus, including over 13,000 predicted proteins annotated with Gene Ontology terms and over 6,000 loci independently supported by high-quality Iso-Seq transcriptomic data. Our assembly also includes 95% ofR. ferrugineuschemosensory, detoxification and neuropeptide-related transcripts identified previously using RNA-seq transcriptomic data, and provides a platform for the molecular analysis of these and other functionally-relevant genes that can help guide management of this widespread insect pest.
RetroCHMP3 Blocks Budding of Enveloped Viruses Without Blocking Cytokinesis
Authors: Rheinemann Lara , Downhour Diane Miller , Bredbenner Kate , Mercenne Gaelle , Davenport Kristen A. , Schmitt Phuong Tieu , Necessary Christina R. , McCullough John , Schmitt Anthony P. , Simon Sanford M. , Sundquist Wesley I. , Elde Nels C.
Published: September 2020

Many enveloped viruses require the endosomal sorting complexes required for transport (ESCRT) pathway to exit infected cells. This highly conserved pathway mediates essential cellular membrane fission events, which restricts the acquisition of adaptive mutations to counteract viral co-option. Here, we describe duplicated and truncated copies of the ESCRT-III factor CHMP3 that block ESCRT-dependent virus budding and that arose independently in New World monkeys and mice. When expressed in human cells, these retroCHMP3 proteins potently inhibit release of retroviruses, paramyxoviruses, and filoviruses. Remarkably, retroCHMP3 proteins have evolved to reduce interactions with other ESCRT-III factors and to have little effect on cellular ESCRT processes, revealing routes for decoupling cellular ESCRT functions from viral exploitation. The repurposing of duplicated ESCRT-III proteins thus provides a mechanism to generate broad-spectrum viral budding inhibitors without blocking highly conserved essential cellular ESCRT functions.
Theta oscillations shift towards optimal frequency for cognitive control
Authors: Senoussi Mehdi , Verbeke Pieter , Desender Kobe , De Loof Esther , Talsma Durk , Verguts Tom
Published: September 2020

Cognitive control is supported by theta band (4-7Hz) neural oscillations coordinating neural populations for task implementation. Task performance has been shown to depend on theta amplitude but a second critical aspect of theta oscillations, its peak frequency, has mostly been overlooked. Using modelling, behavioral and electrophysiological recordings, we show that theta oscillations adapt to task demands by shifting towards the optimal frequency.
Rab2 is a potent new target for enhancing autophagy in the treatment of Parkinson’s disease
Authors: Szinyákovics Janka , Kiss Eszter , Keresztes Fanni , Vellai Tibor , Kovács Tibor
Published: September 2020

Macroautophagy is a lysosomal-dependent degradational pathway of eukaryotic cells, during which toxic, unnecessary, and damaged intracellular components are broken down. Autophagic activity declines with age, and this change could contribute to the accumulation of intracellular damage at advanced ages, causing cells to lose their functionality and vitality. This could be particularly problematic in post-mitotic cells include neurons, the mass destruction of which leads to different neurodegenerative diseases.

We aim to discover new regulation points where autophagy could be specifically activated, and test these potential drug targets in Drosophila neurodegenerative disease models. One possible way to activate autophagy is through the enhancement of autophagosome-lysosome fusion to become autolysosome. This fusion is regulated by HOPS (homotypic fusion and protein sorting) and SNARE (Snap receptor) complexes. The HOPS complex forms a bridge between lysosome and autophagosome with the assistance of small GTPase Rab (Ras-associated binding) proteins. Thus, Rab proteins are essential for autolysosome maturation, and among Rab proteins, Rab2 is required for the degradation of autophagic cargo.

Our results revealed that GTP-locked (constitutively active) Rab2 (Rab2 CA) expression reduces the levels of the autophagic substrate p62/Ref2P in dopaminergic neurons, and improved the climbing ability of animals during aging. The expression of Rab2 CA also increased lifespan in a Parkinson’s disease model (human mutant alpha-synuclein [A53T] overexpressed animals). In these animals, Rab2 CA expression significantly increased autophagic degradation as compared to control. These results may reveal a new, more specific drug target for autophagic activation treating today’s incurable neurodegenerative diseases.
A hybrid stochastic-deterministic approach to explore multiple infection and evolution in HIV
Authors: Kreger Jesse , Komarova Natalia L. , Wodarz Dominik
Published: September 2020

To study viral evolutionary processes within patients, mathematical models have been instrumental. Yet, the need for stochastic simulations of minority mutant dynamics can pose computational challenges, especially in heterogeneous systems where very large and very small subpopulations coexist. Here, we describe a hybrid stochastic-deterministic algorithm to simulate mutant evolution in large viral populations, such as acute HIV-1 infection, and further include the multiple infection of cells. We demonstrate that the hybrid method can approximate the fully stochastic dynamics with sufficient accuracy at a fraction of the computational time, and quantify evolutionary end points that cannot be expressed by deterministic models, such as the mutant distribution or the probability of mutant existence at a given infected cell population size. We apply this method to study the role of multiple infection and intracellular interactions among different virus strains (such as complementation and interference) for mutant evolution. Multiple infection is predicted to increase the number of mutants at a given infected cell population size, due to a larger number of infection events. We further find that viral complementation can significantly enhance the spread of disadvantageous mutants, but only in select circumstances: it requires the occurrence of direct cell-to-cell transmission through virological synapses, as well as a substantial fitness disadvantage of the mutant, most likely corresponding to defective virus particles. This, however, likely has strong biological consequences because defective viruses can carry genetic diversity that can be incorporated into functional virus genomes via recombination. Through this mechanism, synaptic transmission in HIV might promote virus evolvability.
An improved mode of running PASTA
Authors: Yang Qikai , Warnow Tandy
Published: September 2020

PASTA is a method for estimating alignments and trees that has been able to provide excellent accuracy on large sequence datasets. By design, PASTA operates using iteration, in which the tree from the previous iteration is used to inform a divide-and-conquer strategy during which a new alignment is computed on the sequence dataset, and then a new maximum likelihood tree is estimated on the new alignment. In its default setting, PASTA runs for three iterations and returns that alignment/tree pair from the last iteration. Here we use both biological and simulated nucleotide datasets to show that returning the alignment/tree pair that has the best maximum likelihood score improves on the default usage.
Cystic proliferation of embryonic germ stem cells is necessary to reproductive success and normal mating behavior in medaka
Authors: Arias Padilla Luisa F. , Castañeda-Cortés Diana C. , Rosa Ivana F. , Nóbrega Rafael Henrique , Fernandino Juan I.
Published: September 2020

The production of an adequate number of gametes in both sexes is necessary for normal reproduction, for which the regulation of proliferation from early gonadal development to adulthood is key. Cystic proliferation of embryonic stem germ cells prior the onset of gametogenesis is an especially important step prior to the beginning of meiosis. However, in vertebrates, the molecular regulators of cystic proliferation remain unknown. Here, we report thatndrg1b, a member of the N-myc downstream regulated family, is an important regulator of cystic proliferation in medaka. We generated mutants ofndrg1bthat led to a disruption of proliferation type II, independently of the TGF-β signaling pathway. This loss of cystic proliferation was observed from embryogenic to adult stages, impacting the success of gamete production and reproductive parameters such as spawning and fertilization. Interestingly, the depletion of cystic proliferation of thendrg1bmutant also impacted male sexual behavior, with a decrease of mating vigor. These data illustrate why it is also necessary to consider gamete production capacity in order to analyze reproductive behavior.

HIGHLIGHTS

Ndrg1b is involved in the regulation of cystic proliferation in gonad from embryo to adulthood.

The cystic proliferation is independently of the TGF-β signaling pathway.

Decrease of production of gametes declines reproductive success for both sexes.

Reduction of cystic proliferation declines male sexual behavior, with a decrease of mating vigor.
From Face-to-Face to Online Modality: Implications for Undergraduate Learning While the World is Temporarily Closed in the Age of COVID-19
Authors: Hacisalihoglu Gokhan
Published: September 2020

The second half of the Spring 2020 semester has been an unprecedented time globally due to the ongoing coronavirus disease 2019 (COVID-19). COVID-19 pandemic has forced more than one billion students out of school, has disrupted the world and led all university courses switched to online instruction social distancing actions taken to limit the spread of the virus. The aim of the present study is to evaluate the pandemic related changes for undergraduate students, to assess their perspectives related to their learning, experiences in two courses, and to discuss the far-reaching potential implications for the upcoming summer and fall semesters. An electronic survey was conducted to gather data on the student perceptions and learning characteristics of this transition from face-to-face (F2F) to online at a medium-sized university in the Southeast in the Spring 2020 semester. Nearly 88% of the participants indicated that the COVID-19 pandemic impacted their education, while 19% indicated that they prefer online over F2F learning. Furthermore, the online modality significantly increased attendance in General Biology I. Our study also showed that the usage of live conferencing and digital applications increased due to the pandemic. The current research fills the gap in the existing literature by providing the first study on the effects of the ongoing COVID-19 pandemic on undergraduate learning and experiences in the most unique dual modality of the Spring 2020 semester.
Polygenic Scores for Plasticity: A New Tool for Studying Gene-Environment Interplay
Authors: Johnson Rebecca , Sotoudeh Ramina , Conley Dalton
Published: September 2020

Outcomes of interest to demographers—fertility; health; education—are the product of both an individual’s genetic makeup and his or her social environment. Yet Gene × Environment research (GxE) currently deploys a limited toolkit on the genetic side to study gene-environment interplay: polygenic scores (PGS, or what we call mPGS) that reflect the influence of genetics on levels of an outcome. The purpose of the present paper is to develop a genetic summary measure better suited for GxE research. We develop what we callvariance polygenic scores(vPGS), or polygenic scores that reflect genetic contributions to plasticity in outcomes. The first part of the analysis uses the UK Biobank (N ~ 326,000 in the training set) and the Health and Retirement Study (HRS) to compare four approaches for constructing polygenic scores for plasticity. The results show that widely-used methods for discovering which genetic variants affect outcome variability fail to serve as distinctive new tools for GxE. Then, using the polygenic scores that do capture distinctive genetic contributions to plasticity, we analyze heterogeneous effects of a UK education reform on health and educational attainment. The results show the properties of a new tool useful for population scientists studying the interplay of nature and nurture and for population-based studies that are releasing polygenic scores to applied researchers.
Loss of mitochondrial protease CLPP activates type I interferon responses through the mtDNA-cGAS-STING signaling axis
Authors: Torres-Odio Sylvia , Lei Yuanjiu , Gispert Suzana , Maletzko Antonia , Key Jana , Menissy Saeed , Wittig Ilka , Auburger Georg , West A. Phillip
Published: September 2020

Caseinolytic mitochondrial matrix peptidase proteolytic subunit, CLPP, is a serine protease that degrades damaged or misfolded mitochondrial proteins. CLPP null mice exhibit growth retardation, deafness, and sterility, resembling human Perrault syndrome (PS), but also display immune system alterations. However, the molecular mechanisms and signaling pathways underlying immunological changes in CLPP null mice remain unclear. Here we report the steady state activation of type I interferon (IFN-I) signaling and antiviral gene expression in CLPP deficient cells and tissues. Depletion of the cyclic GMP-AMP (cGAS)-Stimulator of Interferon Genes (STING) DNA sensing pathway ablates heightened IFN-I responses and abrogates the broad viral resistance phenotype of CLPP null cells. Moreover, we report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations. Pharmacological and genetic approaches to deplete mtDNA or inhibit cytosolic release markedly reduce antiviral gene expression, implicating mtDNA stress as the driver of IFN-I signaling in CLPP null mice. Our work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have implications for understanding myriad human diseases involving CLPP dysregulation.
Label-free Isolation and Single Cell Biophysical Phenotyping Analysis of Primary Cardiomyocytes Using Inertial Microfluidics
Authors: Tavassoli Hossein , Rorimpandey Prunella , Kang Young Chan , Carnell Michael , Brownlee Chris , Pimanda John E , Chan Peggy P.Y. , Chandrakanthan Vashe
Published: September 2020

To advance our understanding of cardiomyocyte identity and function, we need appropriate tools to isolate pure primary cardiomyocytes. We have developed a label-free method to purify viable cardiomyocytes from mouse neonatal hearts using a simple inertial microfluidics biochip. Cardiomyocytes were sorted from neonatal hearts and isolated to >90% purity and their physico-mechanical properties were evaluated using real time deformability cytometry. Purified cardiomyocytes were viable and retained their identity and function as depicted by expression of cardiac specific markers and contractility. Furthermore, we showed that cardiomyocytes have a distinct physico-mechanical phenotype that could be used as an intrinsic biophysical marker to distinguish these cells from other cell types within the heart. Taken together, this cardiomyocyte isolation and phenotyping method could serve as a valuable tool to progress our understanding of cardiomyocyte identity and function, which will ultimately benefit many diagnostic development and cardiac treatment studies.
A Maize Practical Haplotype Graph Leverages Diverse NAM Assemblies
Authors: Franco Jose A. Valdes , Gage Joseph L. , Bradbury Peter J. , Johnson Lynn C. , Miller Zachary R. , Buckler Edward S. , Romay M. Cinta
Published: September 2020

As a result of millions of years of transposon activity, multiple rounds of ancient polyploidization, and large populations that preserve diversity, maize has an extremely structurally diverse genome, evidenced by high-quality genome assemblies that capture substantial levels of both tropical and temperate diversity. We generated a pangenome representation (the Practical Haplotype Graph, PHG) of these assemblies in a database, representing the pangenome haplotype diversity and providing an initial estimate of structural diversity. We leveraged the pangenome to accurately impute haplotypes and genotypes of taxa using various kinds of sequence data, ranging from WGS to extremely-low coverage GBS. We imputed the genotypes of the recombinant inbred lines of the NAM population with over 99% mean accuracy, while unrelated germplasm attained a mean imputation accuracy of 92 or 95% when using GBS or WGS data, respectively. Most of the imputation errors occur in haplotypes within European or tropical germplasm, which have yet to be represented in the maize PHG database. Also, the PHG stores the imputation data in a 30,000-fold more space-efficient manner than a standard genotype file, which is a key improvement when dealing with large scale data.
DARPP-32 Distinguishes a Subset of Adult-Born Neurons in Zebra Finch HVC
Authors: Aronowitz Jake V , Kirn John R , Pytte Carolyn L , Aaron Gloster B
Published: September 2020

Adult male zebra finches (Taeniopygia guttata) continually incorporate adult-born neurons into HVC, a telencephalic brain region necessary for the production of learned song. These neurons express immediate early genes during song production, suggesting a role for neurogenesis in song production throughout the lifespan. Half of these adult-born HVC neurons (HVC NNs) can be backfilled from the robust nucleus of the arcopallium (RA) and are a part of the vocal motor pathway underlying learned song production, but the other half do not backfill from RA, and they remain to be characterized. Here we used cell birth-dating, retrograde tract tracing, and immunofluorescence to demonstrate that half of all HVC NNs express thephosphoprotein DARPP-32, a protein associated with dopamine (DA) receptor expression. We also demonstrate that DARPP-32+ HVC NNs are contacted by tyrosine hydroxylase immunoreactive fibers suggesting that they receive catecholaminergic input, have transiently larger nuclei than DARPP-32− HVC NNs, and do not backfill from RA. Taken together, these findings help characterize a group of HVC NNs that have no apparent projections to RA and so far have eluded any positive identification other than HVC NN status.
Tissue specificity-aware TWAS (TSA-TWAS) framework identifies novel associations with metabolic, immunologic, and virologic traits in HIV-positive adults
Authors: Li Binglan , Veturi Yogasudha , Verma Anurag , Bradford Yuki , Daar Eric S. , Gulick Roy M. , Riddler Sharon A. , Robbins Gregory K. , Lennox Jeffrey L. , Haas David W. , Ritchie Marylyn D.
Published: September 2020

As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue specificity of transcriptional regulatory mechanisms. In a previous study from our group, this may have affected whether TWAS methods better identified associations in single tissues versus multiple tissues. We therefore designed simulation analyses to examine how the interplay between particular TWAS methods and tissue specificity of gene expression affects power and type I error rates for gene prioritization. We found that cross-tissue identification of expression quantitative trait loci (eQTLs) improved TWAS power. Single-tissue TWAS (i.e., PrediXcan) had robust power to identify genes expressed in single tissues, but, had high false positive rates for genes that are expressed in multiple tissues. Cross-tissue TWAS (i.e., UTMOST) had overall equal or greater power and controlled type I error rates for genes expressed in multiple tissues. Based on these simulation results, we applied a tissue specificity-aware TWAS (TSA-TWAS) analytic framework to look for gene-based associations with pre-treatment laboratory values from AIDS Clinical Trial Group (ACTG) studies. We replicated several proof-of-concept transcriptionally regulated gene-trait associations, includingUGT1A1(encoding bilirubin uridine diphosphate glucuronosyl transferase enzyme) and total bilirubin levels (p = 3.59×10−12), andCETP(cholesteryl ester transfer protein) with high-density lipoprotein cholesterol (p = 4.49×10−12). We also identified several novel genes associated with metabolic and virologic traits, as well as pleiotropic genes that linked plasma viral load, absolute basophil count, and/or triglyceride levels. By highlighting the advantages of different TWAS methods, our simulation study promotes a tissue specificity-aware TWAS analytic framework that revealed novel aspects of HIV-related traits.

publicly available.
Major functional bias for mitochondrial complexes in genome-wide CRISPR screens
Authors: Rahman Mahfuzur , Billmann Maximilian , Costanzo Michael , Aregger Michael , Tong Amy H. Y. , Chan Katherine , Ward Henry N. , Brown Kevin R. , Andrews Brenda J. , Boone Charles , Moffat Jason , Myers Chad L.
Published: September 2020

We present FLEX (Functionalevaluation of experimental perturbations), a pipeline that leverages several functional annotation resources to establish reference standards for benchmarking human genome-wide CRISPR screen data and methods for analyzing them. We apply FLEX to analyze data from the diverse cell line screens generated by the DepMap project. We identify a dominant mitochondria-associated signal, which our time-resolved CRISPR screens and analysis suggests may reflect screen dynamics and protein stability effects rather than genetic dependencies.
Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria
Authors: Yang Rui , Mele Federico , Worley Lisa , Langlais David , Rosain Jérémie , Benhsaien Ibithal , Elarabi Houda , Croft Carys A. , Doisne Jean-Marc , Zhang Peng , Weisshaar Marc , Jarrossay David , Latorre Daniela , Shen Yichao , Han Jing , Gruber Conor , Markle Janet , Al Ali Fatima , Rahman Mahbuba , Khan Taushif , Seeleuthner Yoann , Kerner Gaspard , Husquin Lucas T. , Maclsaac Julia L. , Jeljeli Mohamed , Ailal Fatima , Kobor Michael S. , Oleaga-Quintas Carmen , Roynard Manon , Bourgey Mathieu , El Baghdadi Jamila , Boisson-Dupuis Stéphanie , Puel Anne , Batteux Fréderic , Rozenberg Flore , Marr Nico , Pan-Hammarström Qiang , Bogunovic Dusan , Quintana-Murci Lluis , Carroll Thomas , Ma Cindy S , Abel Laurent , Bousfiha Aziz , Di Santo James P. , Glimcher Laurie H , Gros Philippe , Tangye Stuart G , Sallusto Federica , Bustamante Jacinta , Casanova Jean-Laurent
Published: September 2020

Inborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, includingIFNG, by altering chromatin accessibility and DNA methylation in CD4+T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2−γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit.