bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychosocial and Behavioral Responses and SARS-CoV-2 Transmission Prevention Behaviors while Working during the COVID-19 Pandemic
Authors: Senerat Araliya M. , Pope Zachary , Rydell Sarah , Mullan Aidan , Roger Veronique , Pereira Mark A.
Published: May 2021

Background

The impact of coronavirus disease-2019 (COVID-19) on psychosocial and behavioral responses of the non-healthcare workforce is unknown. This study investigated these outcomes in this population during the pandemic while also evaluating transmission prevention behavior implementation at the workplace.

Methods

We deployed the baseline questionnaire of a prospective online survey from November 2020-February 2021 to U.S.-based employees. The survey included questions on psychosocial and behavioral responses in addition to transmission prevention behaviors (e.g., mask wear). Select questions asked employees to report perceptions and behaviors ‘before’ and ‘during’ the COVID-19 pandemic. Data were analyzed descriptively and stratified by work from home (WFH) percentage.

Results

In total, 3,607 employees completed the survey from eight companies. Most participants (70.0%) averaged ≥90% of their time WFH during the pandemic. Employees reported increases in stress (54.0%), anxiety (57.4%), fatigue (51.6%), and feeling unsafe (50.4%) from before to during the pandemic, while feeling a lack of companionship (60.5%) and isolation from others (69.3%). Productivity was perceived to decrease, and non-work screen time and alcohol consumption to increase, for 43.0%, 50.7%, and 25.1% of employees, respectively, from before to during the pandemic. Adverse changes were worse among those with lower WFH percentages. Most employees reported wearing a mask (98.2%), washing hands regularly (95.7%), and physically distancing (93.6%) when at workplace.

Conclusion

Results suggested worsened psychosocial and behavioral outcomes from before to during the COVID-19 pandemic and higher transmission prevention behavior implementation among non-healthcare employees. Observations provide novel insight into how the COVID-19 pandemic has impacted non-healthcare employees.
Individuals who were mildly symptomatic following infection with SARS-CoV-2 B.1.1.28 have neutralizing antibodies to the P.1 variant
Authors: Mendes-Correa Maria Cassia , Villas-Boas Lucy S. , Bierrenbach Ana Luiza , de Paula Anderson , Tozetto-Mendoza Tania Regina , Leal Fabio E. , Freire Wilton , Paiao Heuder Gustavo Oliveira , Ferraz Andrea B C , Witkin Steven S.
Published: May 2021

Objectives

To evaluate if antibodies induced by infection with a different SARS-CoV-2 virus strain neutralize the P.1 variant.

Methods

Convalescent sera from 60 individuals following a documented SARS-CoV-2 infection were assayed for neutralizing antibody titer against both strains.

Results

Fifty-six and 50 sera were positive for neutralizing antibodies against the ancestral and P.1 strains, respectively. Neutralization titers were higher against the ancestral strain, but in the majority of patients differences did not differ by more than a single dilution.

Conclusions

Neutralizing antibodies that were generated following infection with SARS-CoV-2 B.1.1.28 were effective in vitro, against the SARS-CoV-2 P.1. variant.
Investigation of gene-environment interactions in relation to tic severity
Authors: Abdulkadir Mohamed , Yu Dongmei , Osiecki Lisa , King Robert A. , Fernandez Thomas V. , Brown Lawrence W. , Cheon Keun-Ah , Coffey Barbara J. , Garcia-Delgar Blanca , Gilbert Donald L. , Grice Dorothy E. , Hagstrøm Julie , Hedderly Tammy , Heyman Isobel , Hong Hyun Ju , Huyser Chaim , Ibanez-Gomez Laura , Kim Young Key , Kim Young-Shin , Koh Yun-Joo , Kook Sodahm , Kuperman Samuel , Leventhal Bennett , Madruga-Garrido Marcos , Maras Athanasios , Mir Pablo , Morer Astrid , Münchau Alexander , Plessen Kerstin J. , Roessner Veit , Shin Eun-Young , Song Dong-Ho , Song Jungeun , Visscher Frank , Zinner Samuel H. , Mathews Carol A. , Scharf Jeremiah M. , Tischfield Jay A. , Heiman Gary A. , Dietrich Andrea , Hoekstra Pieter J.
Published: May 2021

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N=518) design. We assessed 98 single nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate gene-studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.
Is mRankin scale correlated with mTICI? A systematic review and meta-regression on RCTs and registries
Authors: De Rubeis Gianluca , Pampana Enrico , Prosperini Luca , Fabiano Sebastiano , Bertaccini Luca , Anticoli Sabrina , Saba Luca , Gasperini Claudio , Cotroneo Enrico
Published: May 2021

Background and Purpose

mTICI ≥2b/3 is one of the strongest positive predictors of mRS ≤2. Quantitative analysis is poorly investigated. Reconcile results from RCT and registries is still a challenge.

The purpose was to evaluate the numeric correlation between mTICI≥2b/3 and mRS≤2 in RCT and registries.

Methods

Literature research was performed on Pubmed for studies in 2015-2020. mTICI, mRS and sample size were recorded. Exclusion criteria were monocentric study, not-human and not-English. Studies quality were assessed with MINORS and RoB2. Meta-logistic and meta-linear regressions were used to correlate mTICI and mRS in both RCTs and registries. Z-test was used for comparing coefficients between RCTs and registries.

Results

Twenty-six studies were evaluated (13 registries; 14 RCTs) for 24423 patients (21914 from registries [average per registry 1685±1277]; 2509 from RCTs [average per RCT 179±160]). RCTs involved anterior circulation only, 7/13 (53.8%) registries considered also posterior one.

The OR of obtaining a mRS≤2 for a singular increased of mTICI ≥2b rate was 1.65 (CI95% 1.22-2.01) for all studies, 1.65 (CI95% 1.10-2.46) for RCTs and 1.50 (CI95% 1.00-2.23) for registries. mTICI≥2b and mRS had a positive correlation with a coefficient of 0.49 (CI95% 0.19-0.80, p=0.001) for all studies, 0.54 (CI95% 0.09-1.00) for RCTs and 0.42 (CI 95% 0.04-0.81) for registries. No differences were found in the coefficients between RCTs and registries (p=0.63; p=0.65; respectively).

Conclusions

Unitary increased of mTICI≥2b rate correspond to an augment of mRS≤2 by 0.50 (CI95% 0.19-0.89) with OR of obtaining mRS≤2 of 1.65 (CI95% 1.22-2.01), without significantly differences in coefficients.
Clustered Mendelian Randomization analyses identifies distinct and opposing pathways in the causal association between insulin-like growth factor-1 and type 2 diabetes mellitus
Authors: Wang Wenyi , Tesfay Ephrem Baraki , van Dijk Ko Willems , Bartke Andrzej , van Heemst Diana , Noordam Raymond
Published: May 2021

Aims/hypothesis

There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of type 2 diabetes. Here, we investigated the association between IGF-1 and type 2 diabetes using a combination of multivariable-adjusted and (clustered) Mendelian Randomization (MR) analyses in the UK Biobank.

Methods

We conducted Cox proportional hazard analyses in 451,232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13,247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent SNPs associated with IGF-1. Given the heterogeneity between the causal estimates of individual instruments (P-value for Q statistic=4.03e-145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by overrepresentation analyses.

Results

In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes (HR: 1.31; CI: 1.23-1.39). In contrast, in the two-sample MR analyses, higher genetically-influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of causal effect estimates, six clusters associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth-hormone signaling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity.

Conclusion

The IGF-1 associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of causal effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.
A Model to Introduce Medical Students to the Use of Artificial Intelligence and Genomics for Precision Medicine
Authors: Alderson Philip O. , Donlin Maureen J. , Morrison Lynda A.
Published: May 2021

Objective

Despite the significant medical impact of artificial intelligence (AI) in healthcare, emergence of AI-related topics in medical curricula has been slow. The authors sought to introduce pre-clinical students to the importance of AI methodologies and medical applications using modular short courses focused on active learning with precision medicine as a primary use case.

Materials and Methods

A short elective course was designed to introduce first-year students to how various bioinformatic and AI-related processes work and how they help classify medical data, facilitate genomic analysis and predict clinical outcomes. The course covers gene sequencing and variants, neural networks, natural language processing, medical computer vision and the limitations and ethical concerns related to use of AI in precision medicine. Online content serves as major source material. After a faculty-led introduction, sessions focus on teams of students who present course content to one another and lead discussions with faculty guidance. A related short AI course focused on gene variants was given to the entire second-year class.

Results

The elective course has been taken by 74 first- year students over 8 consecutive semesters (2017-2021). The course achieved average satisfaction scores of 4.4/5.0 (n = 13) when the active learning approach became dominant in 2018. Students were able to describe accurately how bioinformatics and AI make personalized medicine possible. Students also did well on the gene variants exercise given to the entire second year class (2018), but the full class short AI course was not continued in subsequent years. Students have created a school-approved interest group in medical AI.

Conclusions

This experience shows that AI-related materials can be sustainably introduced into pre- clinical medical education with precision medicine as the primary use case. This modular course design and content could be adapted easily for educational use in medical subspecialties and other health professions.
Design and Formative Evaluation of a Voice-based Virtual Coach for Problem-Solving Treatment
Authors: Kannampallil Thomas , Ronneberg Corina R. , Wittels Nancy , Kumar Vikas , Lv Nan , Smyth Joshua M. , Gerber Ben S. , Kringle Emily , Johnson Jillian A. , Yu Philip , Steinman Lesley E. , Ajilore Olu , Ma Jun
Published: May 2021

Artificial intelligence (AI)-based voice technology offers considerable promise in healthcare; however, its application for behavioral therapy in a real-world or research setting has yet to be determined. We describe the design and evaluation of 1Lumen™, a fully functional voice-only virtual coach that delivers evidence-based, problem-solving treatment (PST) for patients with mild-to-moderate depression and/or anxiety. Participants (N=26) completed surveys and semi-structured interviews after two therapy sessions with Lumen. Participants found Lumen to provide high pragmatic usability and favorable user experience, with marginal task load during interactions. Participants emphasized its on-demand accessibility and the delivery of a complex PST task with a simplistic structure for achieving therapy goals. Suggestions for improvement included streamlining and improved personalization and pacing of conversations and providing additional context during therapy sessions. Lumen offers a realistic and cognitively plausible verbal interaction that can potentially lead to personalized and accessible mental health care, filling a gap in traditional mental health services.
MiR-139-5p is a causal biomarker for type 2 diabetes; Results from genome-wide microRNA profiling and Mendelian randomization analysis in a population-based study
Authors: Mens Michelle M.J. , Mustafa Rima , Ahmadizar Fariba , Ikram M. Arfan , Evangelou Marina , Kavousi Maryam , Dehghan Abbas , Ghanbari Mohsen
Published: May 2021

MicroRNAs (miRNAs) have emerged as key regulators of gene expression. Differential expression of miRNAs has been linked to diabetes, but underlying pathways remain poorly understood. We performed genome-wide miRNAs profiling and tested the causal associations between miRNAs and type 2 diabetes in the general population. Subsequently, we investigated target genes and metabolites of miRNAs to provide insight into the metabolic disturbances that emerge with type 2 diabetes. Between 2002 and 2005, plasma levels of 2083 circulatory miRNAs were profiled in 1900 participants (mean age 71.4 years) of the population-based Rotterdam Study cohort. The associations of 591 well-expressed miRNAs with prevalent and incident type 2 diabetes were examined until 2015. Two-sample Mendelian Randomization (MR) was conducted to investigate the causal associations and miRNA-target genes and metabolites were studied in relation to type 2 diabetes. At baseline, higher plasma levels of miR-139-5p and miR-193a-5p were associated (FDR<0.05) with prevalent type 2 diabetes (n=253 cases). During a follow-up of >9.0 years, 209 participants developed type 2 diabetes. Plasma levels of miR-99a-5p, miR-4664-3p, miR-29a-3p, miR-122-5p, and miR-125b-5p were significantly associated with incident type 2 diabetes (n=209). Two-sample MR confirmed a causal effect for miR-139-5p (MR-IWV-beta=0.10, p=3.51×10−4) on type 2 diabetes. We found several target genes and metabolites that could link miR-139-5p to pathways underlying type 2 diabetes. Our study indicates a causal relationship between miR-139-5p and type 2 diabetes and suggests this miRNA as a plasma biomarker of type 2 diabetes.
Current challenges of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence studies among blood donors: A scoping review
Authors: Saeed Sahar , Uzicanin Samra , Lewin Antoine , Lieshout-Krikke Ryanne , Faddy Helen , Erikstrup Christian , Osiowy Carla , Seed Clive , Steele Whitney , Davidson Katy , Custer Brian , O’Brien Sheila
Published: May 2021

Background

Blood donors are increasingly being recognized as an informative resource for surveillance. We aimed to review and characterize SARS-CoV-2 seroprevalence studies conducted using blood donors to investigate methodology and provide guidance for future research.

Methods

We conducted a scoping review of peer-reviewed and preprint publications between January 2020 to January 2021. Two reviewers used standardized forms to extract seroprevalence estimates and data on methodology pertaining to population sampling, periodicity, assay characteristics and antibody kinetics. National data on cumulative incidence and social distancing policies were extracted from publicly available sources and summarized.

Results

Thirty-three studies representing 1,323,307 blood donations from 20 countries worldwide were included (sample size per study ranged from 22 to 953,926 donations). Seroprevalence rates ranged from 0% to 76% (after adjusting for waning antibodies). Overall, less than 1 in 5 studies reported standardized seroprevalence rates to reflect the demographics of the general population. Stratification by age and sex were most common (64% of studies), followed by region (48%). 52% of studies reported seroprevalence at a single time point. Overall, 27 unique assay combinations were identified, 55% of studies used a single assay and only 39% adjusted seroprevalence rates for imperfect test characteristics. Among the eight nationally representative studies case detection was most underrepresented in Kenya (1:1264).

Conclusion

As of December 11, 2020, 79% of studies reported seroprevalence rates <10%; thresholds far from reaching herd immunity. In addition to differences in community transmission and diverse public health policies, study designs and methodology were likely contributing factors to seroprevalence heterogeneity.
COGNITIVE ADVERSE EFFECTS OF LACOSAMIDE IN PATIENTS WITH LOCALIZATION RELATED
EPILEPSY - A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Modi Sophia B , Asha S , Iype Thomas , Libu G K , Rajan Reeja
Published: May 2021

Newer antiepileptic drugs (AEDs) offer favourable safety profiles than the
previously used AEDs. Despite the introduction of many AEDs, a large number of
patients continue to suffer from uncontrolled partial-onset seizures which have
considerable impact on a patient’s quality of life. Lacosamide (LCM) is a third
generation AED approved for adjunctive use in partial-onset seizures. Patients
with epilepsy frequently experience cognitive dysfunctions due to a variety of
factors. Because AEDs are the major therapeutic modality for epilepsy, the
adverse effects of AEDs on cognition are important.

Objectives

To assess the adverse effects of lacosamide on cognition among patients
with localization related epilepsy to whom lacosamide is given as adjuvant
therapy.

METHODOLOGY

An open labelled prospective observational study in 22 patients who
suffered from localization related epilepsy.

Results

Average Initial seizure frequency per month was 3.56 (SD 2.58) and
median frequency 2.5 seizures per month. Range being 1-8 per month. At the
final followup at 6months, only 2 persons experienced seizure and that too
only single episodes. The difference in frequency is statistically
significant (Wilcoxon Signed Ranks TestP <0.001). All the pre and post
lacosamide cognition scores showed statistically significant positive
correlation in this study.

Conclusion

Excellent seizure control is observed in patients with refractory
localization related epilepsy treated with lacosamide. Also, lacosamide has
no serious adverse effects or drug interactions. In this study, it is
observed that unlike many AEDs, lacosamide contributed to significant
improvement in cognition and can improve the quality of life in such
patients.
Global mapping of RNA homodimers in living cells
Authors: Gabryelska Marta M , Kudla Grzegorz
Published: May 2021

RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding of RNA homodimerization has been hampered by the lack of systematicin vivodetection methods. Here we show that PARIS, COMRADES, and other RNA proximity ligation methods can detect RNA homodimers transcriptome-wide as “overlapping” chimeric reads that contain more than one copy of the same sequence. Analysing published proximity ligation datasets, we show that RNA:RNA homodimers mediated by direct base-pairing interactions are rare across the transcriptome, but highly enriched in specific transcripts, including U8 snoRNA, U2 snRNA and a subset of tRNAs. Analysis of data from virus-infected cells reveals homodimerization of SARS-CoV-2 and Zika genomes, mediated by specific palindromic sequences located within protein-coding regions of N protein in SARS-CoV-2 and NS2A gene in Zika. We speculate that regions of viral genomes involved in homodimerization may constitute effective targets for antiviral therapies.
Short 5′ UTR enables optimal translation of plant virus tricistronic RNA via leaky scanning
Authors: Fujimoto Yuji , Keima Takuya , Hashimoto Masayoshi , Hagiwara-Komoda Yuka , Hosoe Naoi , Nishida Shuko , Nijo Takamichi , Oshima Kenro , Verchot Jeanmarie , Namba Shigetou , Yamaji Yasuyuki
Published: May 2021

Regardless of the general model of translation in eukaryotic cells, a number of studies suggested that many of mRNAs encode multiple proteins. Leaky scanning, which supplies ribosomes to downstream open reading frames (ORFs) by read-through of upstream ORFs, is the most major regulatory mechanism to translate polycistronic mRNAs. However, the general regulatory factors controlling leaky scanning and their biological relevance have rarely been elucidated, with exceptions such as the Kozak sequence. Here, we have analyzed the strategy of a plant RNA virus to translate three movement proteins from a single RNA molecule through leaky scanning. The in planta and in vitro results indicate that significantly shorter 5′ UTR of the most upstream ORF promotes leaky scanning, potentially finetuning the translation efficiency of the three proteins in a single RNA molecule to optimize viral propagation. Moreover, in plant endogenous mRNAs, we found that shorter UTRs were more frequently observed in uORFs of polycistronic mRNAs. We propose that the promotion of leaky scanning induced by a short 5′ UTR (LISH), together with the Kozak sequence, is a conserved gene regulation mechanism not only in viruses but also in eukaryotes.
Genome and transcriptome analysis of the beet armywormSpodoptera exiguareveals targets for pest control
Authors: Simon Sabrina , Breeschoten Thijmen , Jansen Hans J. , Dirks Ron P. , Schranz M. Eric , Ros Vera I.D.
Published: May 2021

Background

The genusSpodoptera(Lepidoptera: Noctuidae) includes some of the most infamous insect pests of cultivated plants includingSpodoptera frugiperda,Spodoptera lituraandSpodoptera exigua. To effectively develop targeted pest control strategies for diverseSpodopteraspecies, genomic resources are highly desired. To this aim, we provide the genome assembly and developmental transcriptome comprising all major life stages ofS. exigua, the beet armyworm.Spodoptera exiguais a polyphagous herbivore that can feed from > 130 host plants including several economically important crops.

Results

The 419 Mb beet armyworm genome was sequenced from a femaleS. exiguapupa. Using a hybrid genome sequencing approach (Nanopore long read data and Illumina short read), a high-quality genome assembly was achieved (N50=1.1 Mb). An official gene set (OGS, 18,477 transcripts) was generated by automatic annotation and by using transcriptomic RNA-seq data sets of 18S. exiguasamples as supporting evidence. In-depth analyses of developmental stage-specific expression in combination with gene tree analyses of identified homologous genes across Lepidoptera genomes revealed potentialSpodoptera-specific genes of interest such as mg7 and REPAT46 upregulated during 1stand 3rdinstar larval stages for targeted pest-outbreak management.

Conclusions

The beet armyworm genome sequence and developmental transcriptome covering all major developmental stages provides critical insights into the biology of this devastating polyphagous insect pest species with a worldwide distribution. In addition, comparative genomic analyses across Lepidoptera significantly advance our knowledge to further control other invasiveSpodopteraspecies and reveals potential lineage-specific target genes for pest control strategies.
SCOUR: A stepwise machine learning framework for predicting metabolite-dependent regulatory interactions
Authors: Lee Justin Y. , Nguyen Britney , Orosco Carlos , Styczynski Mark P.
Published: May 2021

Background

The topology of metabolic networks is both well-studied and remarkably well-conserved across many species. The regulation of these networks, however, is much more poorly characterized, though it is known to be divergent across organisms – two characteristics that make it difficult to model metabolic networks accurately. While many computational methods have been built to unravel transcriptional regulation, there have been few approaches developed for systems-scale analysis and study of metabolic regulation. Here, we present a stepwise machine learning framework that applies established algorithms to identify regulatory interactions in metabolic systems based on metabolic data: Stepwise Classification Of Unknown Regulation, or SCOUR.

Results

We evaluated our framework on both noiseless and noisy data, using several models of varying sizes and topologies to show that our approach is generalizable. We found that, when testing on data under the most realistic conditions (low sampling frequency and high noise), SCOUR could identify reaction fluxes controlled only by the concentration of a single metabolite (its primary substrate) with high accuracy. The positive predictive value (PPV) for identifying reactions controlled by the concentration of two metabolites ranged from 32-88% for noiseless data, 9.2-49% for either low sampling frequency/low noise or high sampling frequency/high noise data, and 6.6-27% for low sampling frequency/high noise data, with results typically sufficiently high for lab validation to be a practical endeavor. While the PPVs for reactions controlled by three metabolites were lower, they were still in most cases significantly better than random classification.

Conclusions

SCOUR uses a novel approach to synthetically generate the training data needed to identify regulators of reaction fluxes in a given metabolic system, enabling metabolomics and fluxomics data to be leveraged for regulatory structure inference. By identifying and triaging the most likely candidate regulatory interactions, SCOUR can drastically reduce the amount of time needed to identify and experimentally validate metabolic regulatory interactions. As high-throughput experimental methods for testing these interactions are further developed, SCOUR will provide critical impact in the development of predictive metabolic models in new organisms and pathways.
Sequence and functional characterization of a public HIV-specific antibody clonotype
Authors: Murji Amyn A. , Raju Nagarajan , Qin Juliana S , Kaldine Haajira , Janowska Katarzyna , Fechter Emilee Friedman , Mapengo Rutendo , Scheepers Cathrine , Setliff Ian , Acharya Priyamvada , Morris Lynn , Georgiev Ivelin S.
Published: May 2021

Public antibody clonotypes shared among multiple individuals have been identified for several pathogens. However, little is known about the limits of what constitutes a public clonotype. Here, we characterize the sequence and functional properties of antibodies from a public HIV-specific clonotype comprising sequences from 3 individuals. Our results showed that antigen specificity for the public antibodies was modulated by the VH, but not VL, germline gene. Non-native pairing of public heavy and light chains from different donors resulted in antibodies with consistent antigen specificity, suggesting functional complementation of sequences within the public antibody clonotype. The strength of antigen recognition appeared to be dependent on the specific antibody light chain used, but not on other sequence features such as germline or native-antibody sequence identity. Understanding the determinants of antibody clonotype “publicness” can provide insights into the fundamental rules of host-pathogen interactions at the population level, with implications for clonotype-specific vaccine development.
Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin
Authors: Ocsenas Oliver , Reimand Jüri
Published: May 2021

Background

Regional distribution of somatic mutations in cancer genomes associates with DNA replication timing (RT) and chromatin accessibility (CA), however normal tissues and cell lines have contributed these insights while associations with the epigenomes of primary cancers remain uncharacterized.

Results

Here we model megabase-scale mutation burden in whole cancer genomes using ∼900 CA and RT profiles of primary cancers, normal tissues, and cell lines. CA profiles of primary cancers, rather than normal tissues, predict regional mutagenesis in most cancer types. Regional mutation burden associates with the CA profiles of matching cancer types, indicating tissue-specific determinants of mutagenesis. However, mutagenesis in squamous cell and lymphoid cancers instead associates with RT profiles. Mutational signatures also show tissue-specific associations with cancer epigenomes, especially for carcinogen-induced and unannotated signatures. Lastly, while each cancer type includes certain frequently-mutated genomic regions exceeding epigenome-informed predictions of mutation burden, these regions show a pan-cancer convergence to biological processes involved in development and cancer. Thus, modelling excess mutations using epigenomes highlights known cancer driver genes as well as frequently mutated non-coding regions.

Conclusions

The dominant association of regional mutation burden with cancer epigenomes suggests that many passenger mutations are determined by the epigenetic landscapes of transformed cells and may occur later in tumor evolution. CA-informed models help find cancer genes and pathways with positive selection and highlight regions where additional mutation burden is contributed by local mutational processes. This study underlines the complex interplay of mutational processes, genome function and evolution in cancer and tissues of origin.
Lukea gen. nov. (Monodoreae-Annonaceae) with two new species of shrub from the forests of the Udzungwas, Tanzania & Kaya Ribe, Kenya
Authors: Cheek Martin , Luke W.R. Quentin , Gosline George
Published: May 2021

A new genus, Lukea Gosline & Cheek (Annonaceae), is erected for two new species to science, Lukea quentinii Cheek & Gosline from Kaya Ribe, S.E. Kenya, and Lukea triciae Cheek & Gosline from the Udzungwa Mts, Tanzania. Lukea is characterised by a flattened circular bowl-shaped receptacle-calyx with a corolla of three petals that give the buds and flowers a unique appearance in African Annonaceae. Both species are extremely rare shrubs of small surviving areas of lowland evergreen forest under threat of habitat degradation and destruction and are provisionally assessed as Critically Endangered and Endangered respectively using the IUCN 2012 standard. Both species are illustrated and mapped. Material of the two species had formerly been considered to be possibly Uvariopsis Engl. & Diels, and the genus Lukea is placed in the Uvariopsis clade of the Monodoreae (consisting of the African genera Uvariodendron (Engl. & Diels) R.E.Fries, Uvariopsis, Mischogyne Exell, Dennettia Bak.f., and Monocyclanthus Keay).

The clade is characterised by often conspicuous, finely reticulate quaternary nervation and incomplete or absent connective shields (in Annonaceae the connective shield is usually complete). Morphologically Lukea is distinct for its broad, turbinate, fleshy pedicel, a synapomorphy. It appears closest to the West African monotypic Monocyclanthus, sharing a trait unusual in the Annonaceae: the calyx in both genera forms a shallow bowl (calyx lobes are absent or vestigial), barely enclosing the base of the petals at anthesis, and persisting as a living, leathery disc at least until the fruit is mature. The placement of Lukea within the Uvariopsis clade is discussed.
Early Detection of Tau Pathology
Authors: Parekh Parag , Badachhape Andrew , Mu Qingshan , Bhavane Rohan , Srivastava Mayank , Stupin Igor , Bhandari Prajwal , Devkota Laxman , Eriksen Jason , Tanifum Eric , Ghaghada Ketan , Annapragada Ananth
Published: May 2021

While a definitive Alzheimer’s disease (AD) diagnosis remains a post-mortem exercise, the ATN Research Framework proposed by the National Institute on Aging and the Alzheimer’s Association utilizes a score representing the presence of amyloid deposits (A), tau deposits (T) and neuronal degeneration markers (N), with A+T+ necessary for a positive diagnosis. Current detection of tau pathology lags amyloid detection by years and by the time both markers are detected the disease is fairly advanced. We describe the development of a new generation of molecular imaging probes forin vivodetection of cells undergoing abnormal phosphorylation representing the initial stages of pTau pathology, potentially enabling a very early stage diagnosis of AD. We describe a novel nanoparticle formulation that binds such abnormally phosphorylating cells in a mouse model of tau pathology, enabling invivovisualization of the hyperphosphorylative state by magnetic resonance imaging. Our results demonstrate the potential of this novel platform to identify a correlative marker signifying the development of future tau pathology, and has implications for early-stage diagnosis of Alzheimer’s disease.
Error minimization and specificity could emerge in a genetic code as by-products of prebiotic evolution
Authors: Janzen Evan , Shen Yuning , Liu Ziwei , Blanco Celia , Chen Irene A.
Published: May 2021

The emergence of the genetic code was a major transition in the evolution from a prebiotic RNA world to the earliest modern cells1. A prominent feature of the standard genetic code is error minimization, or the tendency of mutations to be unusually conservative in preserving biophysical features of the amino acid2–6. While error minimization is often assumed to result from natural selection, it has also been speculated that error minimization may be a by-product of emergence of the genetic code3. During establishment of the genetic code in an RNA world, self-aminoacylating ribozymes would enforce the mapping of amino acids to anticodons. Here we show that expansion of the genetic code, through co-option of ribozymes for new substrates, could result in error minimization as an emergent property. Using self-aminoacylating ribozymes previously identified during an exhaustive search of sequence space7, we measured the activity of thousands of candidate ribozymes on alternative substrates (activated analogs for tryptophan, phenylalanine, leucine, isoleucine, valine, and methionine). Related ribozymes exhibited preferences for biophysically similar substrates, indicating that co-option of existing ribozymes to adopt additional amino acids into the genetic code would itself lead to error minimization. Furthermore, ribozyme activity was positively correlated with specificity, indicating that selection for increased activity would also lead to increased specificity. These results demonstrate that by-products of the evolution and functional expansion of a ribozyme system could lead to adaptive properties of a genetic code. Such ‘spandrels’ could thus underlie significant prebiotic developments.
C. elegansDSB-3 Reveals Conservation and Divergence among Protein Complexes Promoting Meiotic Double-Strand Breaks
Authors: Hinman Albert W. , Yeh Hsin-Yi , Roelens Baptiste , Yamaya Kei , Woglar Alexander , Bourbon Henri-Marc G. , Chi Peter , Villeneuve Anne M.
Published: May 2021

Meiotic recombination plays dual roles in the evolution and stable inheritance of genomes: recombination promotes genetic diversity by reassorting variants, and it establishes temporary connections between pairs of homologous chromosomes that ensure for their future segregation. Meiotic recombination is initiated by generation of double-strand DNA breaks (DSBs) by the conserved topoisomerase-like protein Spo11. Despite strong conservation of Spo11 across eukaryotic kingdoms, auxiliary complexes that interact with Spo11 complexes to promote DSB formation are poorly conserved. Here, we identify DSB-3 as a DSB-promoting protein in the nematodeCaenorhabditis elegans. Mutants lacking DSB-3 are proficient for homolog pairing and synapsis but fail to form meiotic crossovers. Lack of crossovers indsb-3mutants reflects a requirement for DSB-3 in meiotic DSB formation. DSB-3 concentrates in meiotic nuclei with timing similar to DSB-1 and DSB-2 (predicted homologs of yeast/mammalian Rec114/REC114), and DSB-1, DSB-2, and DSB-3 are interdependent for this localization. Bioinformatics analysis and interactions among the DSB proteins support the identity of DSB-3 as a homolog of MEI4 in conserved DSB-promoting complexes. This identification is reinforced by colocalization of pairwise combinations of DSB-1, DSB-2, and DSB-3 foci in structured illumination microscopy images of spread nuclei. However, unlike yeast Rec114, DSB-1 can interact directly with SPO-11, and in contrast to mouse REC114 and MEI4, DSB-1, DSB-2 and DSB-3 are not concentrated predominantly at meiotic chromosome axes. We speculate that variations in the meiotic program that have co-evolved with distinct reproductive strategies in diverse organisms may contribute to and/or enable diversification of essential components of the meiotic machinery.

Significance Statement

Faithful inheritance of chromosomes during meiosis depends on the formation and repair of double-strand DNA breaks (DSBs), which are generated through the activity of a topoisomerase-like protein known as Spo11. Spo11 exhibits strong conservation throughout eukaryotes, presumably reflecting constraints imposed by its biochemical activity, but auxiliary proteins that collaborate with Spo11 to promote and regulate DSB formation are less well conserved. Here we investigate a cohort of proteins comprising a complex required for meiotic DSB formation inCaenorhabditis elegans, providing evidence for both conservation with and divergence from homologous complexes in other organisms. This work highlights the evolutionary malleability of protein complexes that serve essential, yet auxiliary, roles in fundamental biological processes that are central to reproduction.
Density Fluctuations Yield Distinct Growth and Fitness Effects in Single Bacteria
Authors: Nemati Shahla , Singh Abhyudai , Dhuey Scott D. , McDonald Armando , Weinreich Daniel M. , Vasdekis Andreas. E.
Published: May 2021

Single-cells grow by increasing their biomass and size. Here, we report that while mass and size accumulation rates of single Escherichia coli cells are exponential, their density fluctuates during growth. As such, the rates of mass and size accumulation of a single-cell are generally not the same, but rather cells differentiate into increasing one rate with respect to the other. This differentiation yields a previously unknown density homeostasis mechanism, which we support mathematically. Further, growth differentiation challenges ongoing efforts to predict single-cell reproduction rates (or fitness-levels), through the accumulation rates of size or mass. In contrast, we observe that density fluctuations can predict fitness, with only high fitness individuals existing in the high density fluctuation regime. We detail our imaging approach and the ‘invisible’ microfluidic arrays that critically enabled increased precision and throughput. Biochemical production, infections, and natural communities start from few, growing, cells, thus, underscoring the significance of density-fluctuations when considering non-genetic variability.
Modeling colicin operons as genetic arms in plasmid-genome conflicts
Authors: Sudhakari Pavithra Anantharaman , Ramisetty Bhaskar Chandra Mohan
Published: May 2021

Plasmids are acellular propagating entities that depend, as molecular parasites, on bacteria for propagation. The conflict between the bacterial genome and the parasitic plasmids allows the emergence of ‘genetic arms’ such as Colicin (Col) operons. Endonuclease Col operons encode three proteins; an endonuclease colicin (cleaves nucleic acids), an immunity protein (inactivates its cognate colicin), and lysis protein (aids in colicin release via host cell lysis). Col operons are efficient plasmid-maintenance systems; (i) the plasmid cured cells are killed by the colicins; (ii) damaged cells lyse and release the colicins that eliminate the competitors; and (iii) the released plasmids invade new bacteria. Surprisingly, some bacterial genomes have Col operons. The eco-evolutionary drive and physiological relevance of genomic Col operons are unknown. We investigated plasmidic and genomic Col operons using sequence analyses from an eco-evolutionary perspective. We found 1,248 genomic and plasmidic colicins across 30 bacterial genera. Although 51% of the genomes harbor colicins, the majority of the genomic colicins lacked a functional lysis gene, suggesting the negative selection of lethal genes. The immunity gene of the Col operon protects the cured host, thereby eliminating the metabolic burden due to plasmid. We show mutual exclusivity of Col operons on genomes and plasmids. We propose an ‘anti-addiction’ hypothesis for genomic colicins. Using a stochastic agent-based model, we show that the genomic colicins confer an advantage to the host genome in terms of immunity to the toxin and elimination of plasmid burden. Col operons are ‘genetic arms’ that regulate the ecological interplay of bacterial genomes and plasmids.
Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome
Authors: Ramaswamy Sathishkumar , Jain Ruchi , Naofal Maha El , Halabi Nour , Yaslam Sawsan , Taylor Alan , Tayoun Ahmad Abou
Published: May 2021

Genetic variation in populations of Middle Eastern origin remains highly underrepresented in most comprehensive genomic databases. This underrepresentation hampers the functional annotation of the human genome and challenges accurate clinical variant interpretation. To highlight the importance of capturing genetic variation in the Middle East, we aggregated whole exome and genome sequencing data from 2116 individuals in the Middle East and established the Middle East Variation (MEV) database. Of the high-impact coding (missense and loss of function) variants in this database, 53% were absent from the most comprehensive Genome Aggregation Database (gnomAD), thus representing a unique Middle Eastern variation dataset which might directly impact clinical variant interpretation. We highlight 39 variants with minor allele frequency >1% in the MEV database that were previously reported as rare disease variants in ClinVar and the Human Gene Mutation Database (HGMD). Furthermore, the MEV database consisted of 281 putative homozygous loss of function (LoF) variants, or complete knockouts, of which 31.7% (89/281) were absent from gnomAD. This set represents either complete knockouts of 83 unique genes in reportedly healthy individuals, with implications regarding disease penetrance and expressivity, or might affect dispensable exons, thus refining the clinical annotation of those regions. Intriguingly, 24 of those genes have several clinically significant variants reported in ClinVar and/or HGMD. Our study shows that genetic variation in the Middle East improves functional annotation and clinical interpretation of the genome and emphasizes the need for expanding sequencing studies in the Middle East and other underrepresented populations.
Ecologically pre-trained RNNs explain suboptimal animal decisions
Authors: Molano-Mazon Manuel , Shao Yuxiu , Duque Daniel , Yang Guangyu Robert , Ostojic Srdjan , de la Rocha Jaime
Published: May 2021

The strategies found by animals facing a new task are determined both by individual experience and by structural priors evolved to leverage the statistics of natural environments. Rats can quickly learn to capitalize on the trial sequence correlations of two-alternative forced choice (2AFC) tasks after correct trials, but consistently deviate from optimal behavior after error trials, when they waive the accumulated evidence. To understand this outcome-dependent gating, we first show that Recurrent Neural Networks (RNNs) trained in the same 2AFC task outperform rats as they can readily learn to use across-trial information both after correct and error trials. We hypothesize that, while RNNs can optimize their behavior in the 2AFC task without any a priori restrictions, rats’ strategy is constrained by a structural prior adapted to a natural environment in which rewarded and non-rewarded actions provide largely asymmetric information. When pre-training RNNs in a more ecological task with more than two possible choices, networks develop a strategy by which they gate off the across-trial evidence after errors, mimicking rats’ behavior. Population analyses show that the pre-trained networks form an accurate representation of the sequence statistics independently of the outcome in the previous trial. After error trials, gating is implemented by a change in the network dynamics which temporarily decouples the categorization of the stimulus from the across-trial accumulated evidence. Our results suggest that the suboptimal behavior observed in rats reflects the influence of a structural prior that reacts to errors by isolating the network decision dynamics from the context, ultimately constraining the performance in a 2AFC laboratory task.