bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between City-wide Lockdown and COVID-19 Hospitalization Rates in Multigenerational Households in New York City
Authors: Ghosh Arnab K. , Venkatraman Sara , Reshetnyak Evgeniya , Rajan Mangala , An Anjile , Chae John K. , Unruh Mark A. , Abramson David , DiMaggio Charles , Hupert Nathaniel
Published: September 2021

Background

City-wide lockdowns and school closures have demonstrably impacted COVID-19 transmission. However, simulation studies have suggested an increased risk of COVID-19 related morbidity for older individuals inoculated by house-bound children. This study examines whether the March 2020 lockdown in New York City (NYC) was associated with higher COVID-19 hospitalization rates in neighborhoods with larger proportions of multigenerational households.

Methods

We obtained daily age-segmented COVID-19 hospitalization counts in each of 166 ZIP code tabulation areas (ZCTAs) in NYC. Using Bayesian Poisson regression models that account for spatiotemporal dependencies between ZCTAs, as well as socioeconomic risk factors, we conducted a difference-in-differences study amongst ZCTA-level hospitalization rates from February 23 to May 2, 2020. We compared ZCTAs in the lowest quartile of multigenerational housing to other quartiles before and after the lockdown.

Findings

Among individuals over 55 years, the lockdown was associated with higher COVID-19 hospitalization rates in ZCTAs with more multigenerational households. The greatest difference occurred three weeks after lockdown: Q2 vs. Q1: 54% increase (95% Bayesian credible intervals: 22 – 96%); Q3 vs. Q1: 48%, (17 – 89%); Q4 vs. Q1: 66%, (30 – 211%). After accounting for pandemic-related population shifts, a significant difference was observed only in Q4 ZCTAs: 37% (7 –76%).

Interpretation

By increasing house-bound mixing across older and younger age groups, city-wide lockdown mandates imposed during the growth of COVID-19 cases may have inadvertently, but transiently, contributed to increased transmission in multigenerational households.

Funding

National Center for Advancing Translational Sciences; Clinical and Translational Science Center at Weill Cornell Medical College.
Immunogenicity of Pfizer mRNA COVID-19 vaccination followed by J&J adenovirus COVID-19 vaccination in two CLL patients
Authors: Lyski Zoe L. , Kim Sunny , Lee David Xthona , Sampson David , Raué Hans P. , Raghunathan Vikram , Ryan Debbie , Brunton Amanda E. , Slifka Mark K. , Messer William B. , Spurgeon Stephen E.
Published: September 2021

Importance

Individuals with Chronic Lymphocytic Leukemia have significant immune disfunction, often further disrupted by treatment. While currently available COVID-19 vaccinations are highly effective in immunocompetent individuals, they are often poorly immunogenic in CLL patients. It is important to understand the role heterologous boost would have in patients who did not respond to the recommended two-dose mRNA vaccine series with a SARS-CoV-2 specific immune response

Objective

To characterize the immune response of two CLL patients who failed to seroconvert after initial mRNA vaccine series following a third, heterologous, COVID-19 vaccination with Ad26.COV2.S.

Design

Two subjects with CLL were enrolled in an IRB-approved observational longitudinal cohort study of the immune response to COVID-19 vaccination. After enrollment, they received a third vaccination with Ad26.COV2.S. Blood was drawn prior to original vaccination series, four weeks after mRNA vaccination, and again four weeks after third vaccination.

Setting

Eligible subjects were approached by oncologist overseeing CLL treatment and informed about study, at time of enrollment subjects consented to join the cohort study.

Participants

Sixteen subjects enrolled in the larger CLL cohort study, of whom two subjects received a third COVID-19 vaccination and were included in this analysis. Subject 1 is CLL treatment naive, while Subject 2 is currently on active treatment.

Main Outcome(s) and Measure(s)

SARS-CoV-2 specific immune response, including plasma antibodies, memory B-cells, CD4 and CD8 T-cells were assessed prior to vaccination (baseline) as well as post vaccination series and post third dose.

Results

Of the two subjects who received Ad26.COV2.S doses, Subject 1 seroconverted, had RBD-specific memory B-cells as well as spike-specific CD4 T-cells while Subject 2 did not. Both subjects had a spike-specific CD8 T-cell response after original mRNA vaccination series that was further boosted after third dose (Subject 1), or remained stable (Subject 2).

Conclusions and Relevance

The results of this study, however small, is especially promising to CLL individuals who did not seroconvert following initial mRNA vaccination series. Especially those that are treatment naive, not currently in active treatment, or who may consider vaccination before beginning active treatment.
Genome-wide by environment interaction study of stressful life events and hospital-treated depression in the iPSYCH2012 sample
Authors: Suppli Nis P. , Andersen Klaus K. , Agerbo Esben , Rajagopal Veera M. , Appadurai Vivek , Coleman Jonathan R. I. , Breen Gerome , Bybjerg-Grauholm Jonas , Bækvad-Hansen Marie , Pedersen Carsten B. , Pedersen Marianne G. , Thompson Wesley K. , Munk-Olsen Trine , Benros Michael E. , Als Thomas D. , Grove Jakob , Werge Thomas , Børglum Anders D. , Hougaard David M. , Mors Ole , Nordentoft Merete , Mortensen Preben B. , Musliner Katherine L.
Published: September 2021

Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. We conducted a genome-wide environment interaction study in 18,532 depression cases from hospital-based settings and 20,184 population-representative non-cases from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability and child maltreatment were identified from population-based registers and operationalized as a time-varying count variable (0-4+). Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. The analyses yielded three novel, genome-wide significant (P < 5 × 10-8) loci located in the ATP-binding cassette transporter C 1 (ABCC1) gene, in the A-kinase anchor protein 6 (AKAP6) gene, and near the Major facilitator superfamily domain 1 (MFSD1) gene, as well as 50 loci of suggestive significance. These top 3 hits did not replicate in a case-control sample of depression drawn from the UK Biobank. These results suggest that there may be individual genetic variants that confer risk for or protection against clinical depression only in the presence of stressful life events; however, replication in a sample with similar design and ascertainment methods is needed before any firm conclusions can be drawn. Future gene-by-stress research in depression should focus on establishing even larger collaborative genome-wide environment interaction studies to attain sufficient power.
The international and intercontinental spread and expansion of antimicrobial-resistant Salmonella Typhi
Authors: da Silva Kesia Esther , Tanmoy Arif Mohammad , Pragasam Agila Kumari , Iqbal Junaid , Islam Sajib Mohammad Saiful , Mutreja Ankur , Veeraraghavan Balaji , Tamrakar Dipesh , Qamar Farah Naz , Dougan Gordon , Bogoch Isaac , Seidman Jessica C , Shakya Jivan , Vaidya Krista , Carey Megan E. , Shrestha Rajeev , Irfan Seema , Baker Stephen , Luby Steve P. , Cao Yanjia , Dyson Zoe Anne , Garrett Denise O. , John Jacob , Kang Gagandeep , Hooda Yogesh , Saha Samir K. , Saha Senjuti , Andrews Jason R.
Published: September 2021

The emergence of increasingly antimicrobial-resistant (AMR) Salmonella enterica serovar Typhi (S. Typhi) threatens to undermine effective treatment and control. Here, aiming to investigate the temporal and geographic patterns of emergence and spread of AMR S. Typhi, we sequenced 3,489 S. Typhi isolated from prospective surveillance in South Asia and combined these with a global collection of 4,169 S. Typhi genomes. Our analysis revealed that independent acquisition of plasmids and homoplastic mutations conferring AMR have occurred repeatedly in multiple lineages of S. Typhi, predominantly arising in South Asia. We found evidence of frequent international and intercontinental transfers of AMR S. Typhi, followed by rapid expansion and replacement of antimicrobial-susceptible clades.
Heterologous prime-boost immunization with CoronaVac and Convidecia
Authors: Li Jingxin , Hou Lihua , Guo Xiling , Jin Pengfei , Wu Shipo , Zhu Jiahong , Pan Hongxing , Wang Xue , Song Zhizhou , Wan Jingxuan , Cui Lunbiao , Li Junqiang , Wang Xuewen , Jin Lairun , Liu Jingxian , Shi Fengjuan , Xu Xiaoyu , Chen Yin , Zhu Tao , Chen Wei , Zhu Fengcai
Published: September 2021

Background

The safety and immunogenicity of heterologous prime-boost COVID-19 vaccine regimens with one shot of a recombinant adenovirus type-5-vectored COVID-19 vaccine Convidecia has not been reported.

Methods

We conducted a randomized, controlled, observer-blinded trial of heterologous prime-boost immunization with CoronaVac and Convidecia in healthy adults 18-59 years of age. Eligible participants who were primed with one or two doses of CoronaVac were randomly assigned at a 1:1 ratio to receive a booster dose of Convidecia or CoronaVac. Participants were masked to the vaccine received but not to the three-dose or two-dose regimen. The occurrences of adverse reactions within 28 days after the vaccination were documented. The geometric mean titers of neutralizing antibodies against live SARS-CoV-2 virus were measured at 14 and 28 days after the booster vaccination.

Results

Between May 25 and 26, 2021, a total of 300 participants were enrolled. Participants who received a booster shot with a heterologous dose of Convidecia reported increased frequencies of solicited injection-site reactions than did those received a homogeneous dose of CoronaVac, but frequencies of systemic reactions. The adverse reactions were generally mild to moderate. The heterologous immunization with Convidecia induced higher live viral neutralizing antibodies than did the homogeneous immunization with CoronaVac (197.4[167.7, 232.4] vs. 33.6[28.3, 39.8] and 54.4[37. 9, 78.0] vs. 12.8[9.3, 17.5]) at day 14 in the three- and two-dose regimen cohort, respectively.

Conclusions

The heterologous prime-boost regimen with Convidecia after the priming with CoronaVac was safe and significantly immunogenic than a homogeneous boost with CoronaVac (ClinicalTrials.gov, numberNCT04892459).
Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health
Authors: Gadd Danni A , Hillary Robert F , McCartney Daniel L , Shi Liu , Stolicyn Aleks , Robertson Neil , Walker Rosie M , McGeachan Robert I , Campbell Archie , Xueyi Shen , Barbu Miruna C , Green Claire , Morris Stewart W , Harris Mathew A , Backhouse Ellen V , Wardlaw Joanna M , Steele J Douglas , Oyarzún Diego A , Muniz-Terrera Graciela , Ritchie Craig , Nevado-Holgado Alejo , Chandra Tamir , Hayward Caroline , Evans Kathryn L , Porteous David J , Cox Simon R , Whalley Heather C , McIntosh Andrew M , Marioni Riccardo E
Published: September 2021

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4,058 plasma proteins are performed (N=774), identifying 2,928 CpG-protein associations after adjustment for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N=1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.
Functional respiratory capacity in the elderly after COVID-19 – a pilot study
Authors: Pereira Filipe Alexandre , Tomás Maria Teresa
Published: September 2021

Background

The pandemic spread of SARS-CoV-2 has led to an unprecedented outbreak of viral pneumonia. Despite the current focus of worldwide research being the characterization of post-COVID-19 sequelae, the level of functional impact that this disease causes in the elderly who have presented moderate, severe or critical manifestations is still unknown.

Objective

To identify the main consequences/sequelae on functional respiratory capacity in the elderly after CoViD-19.

Methodology

A cross-sectional study was carried out in the community. Functional aerobic capacity (2min step test), dyspnea perception (modified Medical Research Council Dyspnea Questionnaire), respiratory and peripheral muscle strength (maximum inspiratory and expiratory pressure, grip strength) and the Frailty Index (Clinical Fragility Scale) were assessed in 25 community-dwelling individuals aged ≥65 years, who have had a diagnosis of CoViD-19 for up to 6 months, and in an equal number of elderly people with the same characteristics without a known diagnosis of CoViD-19.

Results

The elderly with a diagnosis of CoViD-19 up to 6 months presented a decrease in the values of maximum inspiratory pressure (p=0.001) and maximum expiratory pressure (p=0.015), in aerobic capacity (p<0.001) with significant presence of desaturation on exertion (p<0.001), and increased values of dyspnea perception (p=0.001) and Frailty Index (p=0.026).

Conclusion

Significant changes were found in the functional respiratory capacity of elderly patients diagnosed with CoViD-19 for up to 6 months, when compared with elderly individuals without a known diagnosis of CoViD-19. It is not possible to extrapolate the results obtained to the Portuguese population, however these results may be an important indicator in the characterization of sequelae in the elderly after infection by SARS-CoV-2.
Is life-course neighbourhood deprivation associated with frailty and frailty progression from age 70 to 82 in the Lothian Birth Cohort 1936?
Authors: Baranyi Gergő , Welstead Miles , Corley Janie , Deary Ian J. , Muniz-Terrera Graciela , Redmond Paul , Shortt Niamh , Taylor Adele , Ward Thompson Catharine , Cox Simon , Pearce Jamie
Published: September 2021

Background

Neighbourhood features have been postulated as key predictors of frailty. However, evidence is mainly limited to cross-sectional studies without indication of long-term impact and developmental timing of the exposures. This study explored how neighbourhood social deprivation (NSD) across the life course is associated with frailty and frailty progression among older Scottish adults.

Methods

Participants (n=323) were from the Lothian Birth Cohort 1936 with historical measures of NSD in childhood (1936-1955), early adulthood (1956-1975) and mid-to-late adulthood (1976-2014). Frailty was measured five times between the ages of 70 and 82 years using the Frailty Index. Confounder-adjusted life-course models were assessed using a structured modelling approach with least angle regression; associations were estimated for frailty at baseline using linear regression, and for frailty progression using linear mixed-effects models.

Results

Accumulation was the most appropriate life-course model for males; greater accumulated NSD was associated with higher frailty at age 70 (b=0.017; 95%CI: 0.005, 0.029;P=0.007) with dominant exposure times in childhood and mid-to-late adulthood. Among females, mid-to-late adulthood sensitive period was the best-fit life-course model and higher NSD in this period was associated with widening frailty trajectories between age 70 and 82 (b=0.005; 95%CI: 0.0004, 0.009,P=0.033).

Conclusions

This is the first investigation of the life-course impact of neighbourhood deprivation on frailty in a cohort of older adults with residential information across their lives. Future research should explore neighbourhood mechanisms linking deprivation to frailty. Policies designed to address neighbourhood deprivation and inequalities across the full life course may support healthy ageing.

Key messages

Neighbourhood context might be associated with old-age frailty, but existing investigations are mainly based on cross-sectional data with limited understanding of the relative importance of exposure timing during the life course.

Using a structured approach, we investigated how neighbourhood social deprivation across the life course is associated with frailty, and frailty progression, in a sample of older Scottish adults.

Among males, accumulated neighbourhood social deprivation was moderately associated with frailty at age 70 but not with subsequent frailty trajectories; widening frailty trajectories between age 70 and 82 conditional on deprivation during mid-to-late adulthood were identified among females.

Gendered experiences of living in deprived areas from childhood onwards may contribute to frailty which should be considered in policies supporting healthy ageing.
Effective connectivity reveals distinctive patterns in response to others’ genuine affective experience of disgust as compared to pain
Authors: Zhao Yili , Zhang Lei , Rütgen Markus , Sladky Ronald , Lamm Claus
Published: September 2021

Empathy is significantly influenced by the identification of others’ emotions. In a recent study, we have found increased activation in the anterior insular cortex (aIns) that could be attributed to affect sharing rather than perceptual saliency, when seeing another person genuinely experiencing pain as opposed to merely acting to be in pain. In that prior study, effective connectivity between aIns and the right supramarginal gyrus (rSMG) was revealed to track what another person really feels. In the present study, we used a similar paradigm to investigate the corresponding neural signatures in the domain of empathy for disgust - with participants seeing others genuinely sniffing unpleasant odors as compared to pretending to smell something disgusting. Consistent with the previous findings on pain, we found stronger activations in aIns associated with affect sharing for genuine disgust compared with pretended disgust. However, instead of rSMG we found engagement of the olfactory cortex. Using dynamic causal modeling (DCM), we estimated the neural dynamics of aIns and the olfactory cortex between the genuine and pretended conditions. This revealed an increased excitatory modulatory effect for genuine disgust compared to pretended disgust. For genuine disgust only, brain-to-behavior regression analyses highlighted a link between the observed modulatory effect and the perspective-taking empathic trait. Altogether, the current findings complement and expand our previous work, by showing that perceptual saliency alone does not explain responses in the insular cortex. Moreover, it reveals that different brain networks are implicated in a modality-specific way when sharing the affective experiences associated with pain vs. disgust.
Community science designed ribosomes with beneficial phenotypes
Authors: Krüger Antje , Watkins Andrew M. , Wellington-Oguri Roger , Romano Jonathan , Kofman Camila , DeFoe Alysse , Kim Yejun , Anderson-Lee Jeff , Fisker Eli , Townley Jill , participants Eterna , d’Aquino Anne E. , Das Rhiju , Jewett Michael C.
Published: September 2021

Functional design of ribosomes with mutant ribosomal RNA (rRNA) could expand opportunities for understanding molecular translation, building cells from the bottom-up, and engineering ribosomes with altered capabilities. However, such efforts have been hampered by cell viability constraints, an enormous combinatorial sequence space, and limitations on large-scale, 3D design of RNA structures and functions. To address these challenges, we developed an integrated community science and experimental screening approach for rational design of ribosomes. This approach couples Eterna, an online video game that crowdsources RNA sequence design to community scientists in the form of puzzles, within vitroribosome synthesis, assembly, and translation in multiple design-build-test-learn cycles. We applied our framework to discover mutant rRNA sequences that improve protein synthesisin vitroand cell growthin vivo, relative to wild type ribosomes, under diverse environmental conditions. This work provides new insights into ribosome rRNA sequence-function relationships, with implications for synthetic biology.
Machine learning techniques to derive bioclimatic classifications for Colombia ☆
Authors: Rios Richard , Noguera-Urbano Elkin A. , Espinosa Jairo , Ochoa Jose Manuel
Published: September 2021

Bioclimatic classifications seek to divide a study region into geographic areas with similar bioclimatic characteristics. In this study we proposed two bioclimatic classifications for Colombia using machine learning techniques. We firstly characterized the precipitation space of Colombia using principal component analysis. Based on Lang classification, we then projected all background sites in the precipitation space with their corresponding categories. We sequentially fit logistic regression models to reclassify all background sites in the precipitation space with six redefined Lang categories. New categories were the used to define a new modified Lang and Caldas-Lang classifications.
Serine Starvation Silences Estrogen Receptor Signaling through Histone Hypoacetylation
Authors: Li Albert M. , Li Yang , He Bo , Jiang Haowen , Ramirez Yaniel , Zhou Meng-Ning , Lu Chao , Gruber Joshua J. , Rankin Erinn B. , Ye Jiangbin
Published: September 2021

Estrogen receptor (ER) plays important roles in regulating normal development and female reproductive system function. Loss of ER pathway activity is a hallmark of breast cancer progression, associated with accelerated tumor proliferation and resistance to endocrine therapy. How ER loss occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in solid tumors, downregulates estrogen receptor alpha (ERα) expression, represses transcriptional targets such as progesterone receptor (PR), and reduces sensitivity to antiestrogens, suggesting a transition of ER-positive (ER+) breast cancer cells to an ER/PR-negative (ER-/PR-) state. ER downregulation under serine starvation is accompanied by a global loss of histone acetylation. These chromatin changes are driven by metabolic reprogramming triggered by serine starvation, particularly lower glucose flux through glycolysis and the TCA cycle, leading to reduced acetyl-CoA levels and histone hypoacetylation. Supplementation with acetate or glycerol triacetate (GTA), precursors of acetyl-CoA, restores H3K27 acetylation and ERα expression under serine starvation. Therefore, a major consequence of serine starvation in breast cancer could be global chromatin changes that influence lineage-specific gene expression.
A hybrid capture RNA bait set for resolving genetic and evolutionary relationships in angiosperms from deep phylogeny to intraspecific lineage hybridization
Authors: Waycott Michelle , van Dijk Kor-jent , Biffin Ed
Published: September 2021

Novel multi-gene targeted capture probes have been developed with the objective of obtaining multi-locus high quality sequence reads across any angiosperm lineage. Using existing genomic and transcriptomic data, two independent single assay probe/bait sets have been developed, the first targeting conserved exons from 20 low copy nuclear genes (OzBaits_NR V1.0) and the second, 19 plastid gene regions (OZBaits_CP V1.0). These ‘universal’ bait sets can efficiently generate DNA sequence data that are suitable for systematics and evolutionary studies of flowering plants. The bait sets can be ordered as Daicel-Arbor Sciences custom myBaits. We demonstrate the utility of the bait set in consistently recovering the targeted genomic regions across an evolutionarily broad range of angiosperm taxa.
Sequence conservation and structural features that are common within TRP channels
Authors: Cabezas-Bratesco Deny , Colenso Charlotte K. , Zavala Katina , Granata Danielle , Carnevale Vincenzo , Opazo Juan C. , Brauchi Sebastian E.
Published: September 2021

TRP proteins are a large family of cation selective channels, surpassed in variety only by voltage-gated potassium channels. Detailed molecular mechanisms governing how membrane voltage, ligand binding, or temperature can induce conformational changes promoting the open state of the channel are still missing for TRP channels. Aiming to unveil distinctive structural features common to the transmembrane domains within the TRP family, we performed bioinformatic analyses over a large set of TRP channel genes. Here we report a discrete and exceptionally conserved set of residues. This fingerprint is composed of eleven residues localized at equivalent three-dimensional positions in TRP channels from the different subtypes. Moreover, these amino acids are arranged in three groups, connected by a set of aromatics located at the core of the transmembrane structure. We hypothesize that differences in the connectivity between these different groups of residues harbors the apparent differences in coupling strategies used by TRP subgroups.
Evidence of structural rearrangements and variability in pESI(like) megaplasmids of S.Infantis by resolving the pESI-like ESBL-producing variants
Authors: Alba Patricia , Carfora Virginia , Feltrin Fabiola , Iurescia Manuela , Diaconu Elena Lavinia , Cordaro Gessica , Dell’Aira Elena , Marani Ilaria , Giacomi Angelo , Franco Alessia , Battisti Antonio
Published: September 2021

The increasing prevalence of pESI(like)-positive, multidrug-resistant (MDR) S. Infantis in Europe is a cause of major concern. As previously demonstrated, the pESI(like) megaplasmid is not only a carrier of antimicrobial resistant (AMR) genes (at least tet, dfr and sul genes), but also harbours several virulence and fitness genes, and toxin/antitoxin systems that enhance its persistence in the S. Infantis host.

In this study, five prototype pESI(like) plasmids, of either CTX-M-1 or CTX-M-65 ESBL producing strains, were long-read sequenced using Oxford Nanopore Technology (ONT) and their complete sequences were resolved. Comparison of the structure and gene content of the five sequenced plasmids, and further comparison with previously published pESI(like) sequences, indicated that although the sequence of such pESI(like) “mosaic” plasmids remains almost identical, their structures appear different and composed of regions inserted or transposed after different events.

The results obtained in this study are essential to better understand the plasticity and the evolution of the pESI(like) megaplasmid, and therefore to better address risk management options and policy decisions to fight against AMR and MDR in Salmonella and other food-borne pathogens.
SETDB1 Fuels the Lung Cancer Phenotype by Modulating Epigenome, 3D Genome Organization and Chromatin Mechanical Properties
Authors: Zakharova Vlada V. , Magnitov Mikhail D. , Del-Maestro Laurence , Ulianov Sergey V. , Glentis Alexandros , Ulyanik Burhan , Williart Alice , Karpukhina Anna , Demidov Oleg , Joliot Veronique , Vassetzky Yegor S. , Mège René-Marc , Piel Matthieu , Razin Sergey V. , Ait-Si-Ali Slimane
Published: September 2021

Imbalance in the finely orchestrated system of chromatin-modifying enzymes is a hallmark of many pathologies such as cancers, since causing the affection of the epigenome and transcriptional reprogramming. Here, we demonstrate that a loss-of-function mutation (LOF) of the major histone lysine methyltransferase SETDB1 possessing oncogenic activity in lung cancer cells leads to broad changes in the overall architecture and mechanical properties of the nucleus through genome-wide redistribution of heterochromatin, which perturbs chromatin spatial compartmentalization. Together with the enforced activation of the epithelial expression program, cytoskeleton remodeling, reduced proliferation rate and restricted cellular migration, this leads to the reversed oncogenic potential of lung adenocarcinoma cells. These results emphasize an essential role of chromatin architecture in the determination of oncogenic programs and illustrate a relationship between gene expression, epigenome, 3D genome and nuclear mechanics.
eIF6 rebinding dynamically couples ribosome maturation and translation
Authors: Jaako Pekka , Faille Alexandre , Tan Shengjiang , Wong Chi C. , Escudero-Urquijo Norberto , Castro-Hartmann Pablo , Wright Penny , Hilcenko Christine , Adams David J. , Warren Alan J.
Published: September 2021

Protein synthesis is a cyclical process consisting of translation initiation, elongation, termination and ribosome recycling. The release factors SBDS and EFL1 (both mutated in the leukaemia predisposition disorder Shwachman-Diamond syndrome) license entry of nascent 60S ribosomal subunits into active translation by evicting the anti-association factor eIF6 from the 60S intersubunit face. Here, we show that in mammalian cells, eIF6 holds all free cytoplasmic 60S subunits in a translationally inactive state and that SBDS and EFL1 are the minimal components required to recycle these 60S subunits back into additional rounds of translation by evicting eIF6. Increasing the dose of eIF6 in mice in vivo impairs terminal erythropoiesis by sequestering post-termination 60S subunits in the cytoplasm, disrupting subunit joining and attenuating global protein synthesis. Our data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukaemia predisposition disorder.
Integrating convolution and self-attention improves language model of human genome for interpreting non-coding regions at base-resolution
Authors: Yang Meng , Huang Haiping , Huang Lichao , Zhang Nan , Wu Jihong , Yang Huanming , Mu Feng
Published: September 2021

Interpretation of non-coding genome remains an unsolved challenge in human genetics due to impracticality of exhaustively annotate biochemically active elements in all conditions. Deep learning based computational approaches emerge recently to help interpretating non-coding regions. Here we present LOGO (Language of Genome), a self-attention based contextualized pre-trained language model containing only 2 self-attention layers with 1 million parameters as a substantially light architecture that applies self-supervision techniques to learn bidirectional representations of unlabeled human reference genome. LOGO is then fine-tuned for sequence labelling task, and further extended to variant prioritization task via a special input encoding scheme of alternative alleles followed by adding a convolutional module. Experiments show that LOGO achieves 15% absolute improvement for promoter identification and up to 4.5% absolute improvement for enhancer-promoter interaction prediction. LOGO exhibits state-of-the-art multi-task predictive power on thousands of chromatin features with only 3% parameterization benchmarking against fully supervised model, DeepSEA and 1% parameterization against a recent BERT-based language model for human genome. For allelic-effect prediction, locality introduced by one dimensional convolution shows improved sensitivity and specificity for prioritizing non-coding variants associated with human diseases. In addition, we apply LOGO to interpret type 2 diabetes (T2D) GWAS signals and infer underlying regulatory mechanisms. We make a conceptual analogy between natural language and human genome and demonstrate LOGO is an accurate, fast, scalable, and robust framework to interpret non-coding regions for global sequence labeling as well as for variant prioritization at base-resolution.
Phase-amplitude coupling and phase synchronization between medial temporal, frontal and posterior brain regions support episodic autobiographical memory recall
Authors: Roehri Nicolas , Bréchet Lucie , Seeber Martin , Pascual-Leone Alvaro , Michel Christoph M.
Published: September 2021

Episodic autobiographical memory (EAM) is a complex cognitive function that emerges from the coordination of specific and distant brain regions. Specific brain rhythms, namely theta and gamma oscillations and their synchronization, are thought of as putative mechanisms enabling EAM. Yet, the mechanisms of inter-regional interaction in the EAM network remain unclear in humans at the whole brain level. To investigate this, we analyzed EEG recordings of participants instructed to retrieve autobiographical episodes. EEG recordings were projected in the source space, and time-courses of atlas-based brain regions-of-interest (ROIs) were derived. Directed phase synchrony in high theta (7-10 Hz) and gamma (30-80 Hz) bands and high theta-gamma phase-amplitude coupling were computed between each pair of ROIs. Using network-based statistics, a graph-theory method, we found statistically significant networks for each investigated mechanism. In the gamma band, two sub-networks were found, one between the posterior cingulate cortex (PCC) and the medial temporal lobe (MTL) and another within the medial frontal areas. In the high theta band, we found a PCC to ventromedial prefrontal cortex (vmPFC) network. In phase-amplitude coupling, we found the high theta phase of the left MTL biasing the gamma amplitude of posterior regions and the vmPFC. Other regions of the temporal lobe and the insula were also phase biasing the vmPFC. These findings suggest that EAM, rather than emerging from a single mechanism at a single frequency, involves precise spatio-temporal signatures mapping on distinct memory processes. We propose that the MTL orchestrates activity in vmPFC and PCC via precise phase-amplitude coupling, with vmPFC and PCC interaction via high theta phase synchrony and gamma synchronization contributing to bind information within the PCC-MTL sub-network or valuate the candidate memory within the medial frontal sub-network.
Determinants of directionality and efficiency of the ATP synthase Fo motor at atomic resolution
Authors: Marciniak Antoni , Chodnicki Pawel , Hossain Kazi A , Slabonska Joanna , Czub Jacek
Published: September 2021

Fo subcomplex of ATP synthase is an membraneembedded rotary motor that converts proton motive force into mechanical energy. Despite a rapid increase in the number of high-resolution structures, the mechanism of tight coupling between proton transport and motion of the rotary c-ring remains elusive. Here, using extensive all-atom free energy simulations, we show how the motor’s directionality naturally arises from the interplay between intra-protein interactions and energetics of protonation of the c-ring. Notably, our calculations reveal that the strictly conserved arginine in the a-subunit (R176) serves as a jack-of-all-trades: it dictates the direction of rotation, controls the protonation state of the proton-release site and separates the two proton-access half-channels. Therefore, arginine is necessary to avoid slippage between the proton flux and the mechanical output and guarantees highly efficient energy conversion. We also provide mechanistic explanations for the reported defective mutations of R176, reconciling the structural information on the Fo motor with previous functional and single-molecule data.
Synthetic reconstruction of the hunchback promoter specifies the role of Bicoid, Zelda and Hunchback in the dynamics of its transcription
Authors: Fernandes Goncalo , Tran Huy , Andrieu Maxime , Diaw Youssoupha , Romero Carmina Perez , Fradin Cécile , Coppey Mathieu , Walczak Aleksandra M. , Dostatni Nathalie
Published: September 2021

For over 40 years, the Bicoid-hunchback (Bcd-hb) system in the fruit fly embryo has been used as the model to study how positional information in morphogen concentration gradients is robustly translated into step-like responses. A body of quantitative comparisons between theory and experiment have since questioned the initial paradigm that the sharp hb transcription pattern emerges solely from diffusive biochemical interactions between the Bicoid transcription factor and the gene promoter region. Several alternative mechanisms have been proposed, such as additional sources of positional information, positive feedback from Hb proteins or out-of-equilibrium transcription activation.

By using the MS2-MCP RNA-tagging system and analysing in real time, the transcription dynamics of synthetic reporters for Bicoid and/or its two partners Zelda and Hunchback, we show that all the hb expression pattern features and temporal dynamics are compatible with an equilibrium model with a short decay length Bicoid activity gradient as a sole source of positional information. Meanwhile, Bicoid’s partners speed-up the process by different means: Zelda lowers the Bicoid concentration threshold required for transcriptional activation while Hunchback reduces burstiness and increases the polymerase firing rate.
Non-Gaussian, transiently anomalous and ergodic self-diffusion of flexible dumbbells in crowded two-dimensional environments: coupled translational and rotational motions
Authors: Klett Kolja , Cherstvy Andrey G. , Shin Jaeoh , Sokolov Igor M. , Metzler Ralf
Published: September 2021

We employ Langevin-dynamics simulations to unveil non-Brownian and non-Gaussian center-of-mass self-diffusion of massive flexible dumbbell-shaped particles in crowded two-dimensional solutions. We also study the intra-dumbbell dynamics due to the relative motion of the two constituent elastically-coupled disks. Our main focus is on effects of the crowding fractionϕand the particle structure on the diffusion characteristics. We evaluate the time-averaged mean-squared displacement (TAMSD), the displacement probability-density function (PDF) and the displacement autocorrelation function (ACF) of the dimers. For the TAMSD at highly crowded conditions of dumbbells, e.g., we observe a transition from the short-time ballistic behavior, via an intermediate subdiffusive regime, to long-time Brownian-like spreading dynamics. The crowded system of dimers exhibits two distinct diffusion regimes distinguished by the scaling exponent of the TAMSD, the dependence of the diffusivity onϕ, and the features of the displacement-ACF. We attribute these regimes to a crowding-induced transition from a viscous to a viscoelastic diffusion medium upon growingϕ. We also analyze the relative motion in the dimers, finding that largerϕsuppress their vibrations and yield strongly non-Gaussian PDFs of rotational displacements. For the diffusion coefficientsD(ϕ) of translational and rotational motion of the dumbbells an exponential decay withϕfor weak and a power-lawD(ϕ) ∝ (ϕ–ϕ⋆)2.4for strong crowding is found. A comparison of simulation results with theoretical predictions forD(ϕ) is discussed and some relevant experimental systems are overviewed.
Open-Access STRS Database Of Populations From The 1000 Genomes Project Using High Coverage Phase 3 Data
Authors: Frontanilla Tamara Soledad , Valle-Silva Guilherme , Ayala Jesus , Mendes-Junior Celso Teixeira
Published: September 2021

Accurate STR genotyping from next-generation sequencing (NGS) data has been challenging. Haplotype inference and phasing for STRs (HipSTR) was specifically developed to deal with genotyping errors and obtain reliable STR genotypes from whole-genome sequencing datasets. The objective of this investigation was to perform a comprehensive genotyping analysis of a set of STRs of broad forensic interest from the 1000 Genomes populations and release a reliable open-access STR database to the forensic genetics community. A set of 22 STR markers were analyzed using the CRAM files of the 1000 Genomes Project Phase 3 high-coverage (30x) dataset generated by the New York Genome Center (NYGC). HipSTR was used to call genotypes from 2,504 samples from 26 populations organized into five groups: African, East Asian, European, South Asian, and admixed American. The D21S11 marker could not be detected in the present study. Moreover, the Hardy-Weinberg equilibrium analysis, coupled with a comprehensive analysis of allele frequencies, revealed that HipSTR could not identify longer Penta E (and Penta D at a lesser extent) alleles. This issue is probably due to the limited length of sequencing reads available for genotype calling, resulting in heterozygote deficiency. Notwithstanding that, AMOVA, a clustering analysis using STRUCTURE, and a Principal Coordinates Analysis revealed a clear-cut separation between the four major ancestries sampled by the 1000 Genomes Consortium (AFR, EUR, EAS, SAS). Meanwhile, the AMOVA results corroborated previous reports that most of the variance is (97.12%) observed within populations. This set of analyses revealed that except for larger Penta D and Penta E alleles, allele frequencies and genotypes defined by HipSTR from the 1000 Genomes Project phase 3 data and offered as an open-access database are consistent and highly reliable.
Selective signatures and high genome-wide diversity in traditional Brazilian manioc (Manihot esculentaCrantz) varieties
Authors: Alves-Pereira Alessandro , Zucchi Maria I. , Clement Charles R. , Viana João P. G. , Pinheiro José B. , Veasey Elizabeth A. , Souza Anete P.
Published: September 2021

Knowledge about crops’ genetic diversity is essential to promote effective use and conservation of their genetic resources, because genetic diversity enables farmers to adapt their crops to specific needs and is the raw material for breeding efforts. Currently, manioc (Manihot esculentassp.esculenta) is one of the most important food crops in the world and has the potential to help achieve food security in the context of on-going climate changes. In this study we assessed the patterns of genome-wide diversity of traditional Brazilian manioc varieties conserved in the gene bank of the Luiz de Queiroz College of Agriculture, University of São Paulo. We used single nucleotide polymorphisms to evaluate the organization of genetic diversity and to identify selective signatures contrasting varieties from different biomes with samples of manioc’s wild relativeM. esculentassp.flabellifolia. We identified signatures of selection putatively associated with resistance genes, plant development and response to abiotic stresses. This presumed adaptive variation might have been important for the initial domestication and for the crop’s diversification in response to cultivation in different environments. The neutral variation revealed high levels of genetic diversity within groups of varieties from different biomes and low to moderate genetic divergence among biomes. These results reflect the complexity of manioc’s biology and its evolutionary dynamics under traditional cultivation. Our results exemplify how the smallholder practices contribute to the conservation of manioc’s genetic resources, maintaining variation of potential adaptive significance and high levels of neutral genetic diversity.
Protein sequence sampling and prediction from structural data
Authors: Orellana Gabriel A. , Caceres-Delpiano Javier , Ibañez Roberto , Dunne Michael P. , Alvarez Leonardo
Published: September 2021

The increasing integration between protein engineering and machine learning has led to many interesting results. A problem still to solve is to evaluate the likelihood that a sequence will fold into a target structure. This problem can be also viewed as sequence prediction from a known structure.

In the current work, we propose improvements in the recent architecture of Geometric Vector Perceptrons [1] in order to optimize the sampling of sequences from a known backbone structure. The proposed model differs from the original in that there is: (i) no updating in the vectorial embedding, only in the scalar one, (ii) only one layer of decoding. The first aspect improves the accuracy of the model and reduces the use of memory, the second allows for training of the model with several tasks without incurring data leakage.

We treat the trained classifier as an Energy-Based Model and sample sequences by sampling amino acids in a non-autoreggresive manner in the empty positions of the sequence using energy-guided criteria and followed by random mutation optimization. We improve the median identity of samples from 40.2% to 44.7%.

An additional question worth investigating is whether sampled and original sequences fold into similar structures independent of their identity. We chose proteins in our test set whose sampled sequences show low identity (under 30%) but for which our model predicted favorable energies. We used AlphaFold [2, 3] and observed that the predicted structures for sampled sequences highly resemble the predicted structures for original sequences, with an average TM-score of 0.84.
Interpretable and tractable models of transcriptional noise for the rational design of single-molecule quantification experiments
Authors: Gorin Gennady , Vastola John J. , Fang Meichen , Pachter Lior
Published: September 2021

The question of how cell-to-cell differences in transcription rate affect RNA count distributions is fundamental for understanding biological processes underlying transcription. We argue that answering this question requires quantitative models that are both interpretable (describing concrete biophysical phenomena) and tractable (amenable to mathematical analysis). This enables the identification of experiments which best discriminate between competing hypotheses. As a proof of principle, we introduce a simple but flexible class of models involving a stochastic transcription rate coupled to a discrete stochastic RNA transcription and splicing process, and compare and contrast two biologically plausible hypotheses about transcription rate variation. One assumes variation is due to DNA experiencing mechanical strain, while the other assumes it is due to regulator number fluctuations. Although biophysically distinct, these models are mathematically similar, and we show they are hard to distinguish without comparing whole predicted probability distributions. Our work illustrates the importance of theory-guided data collection, and introduces a general framework for constructing and solving mathematically nontrivial continuous–discrete stochastic models.

Significance Statement

The interpretation of transcriptomic observations requires detailed models of biophysical noise that can be compared and fit to experimental data. Models of intrinsic noise, describing stochasticity in molecular reactions, and extrinsic noise, describing cell-to-cell variation, are particularly common. However, integrating and solving them is challenging, and previous results are largely limited to summary statistics. We examine two mechanistically grounded stochastic models of transcriptional variation and demonstrate that (1) well-known regimes naturally emerge in limiting cases, and (2) the choice of noise model significantly affects the RNA distributions, but not the lower moments, offering a route to model identification and inference. This approach provides a simple and biophysically interpretable means to construct and unify models of transcriptional variation.