bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inter-generational nuclear crosstalk links the control of gene expression to programmed genome rearrangements during theParameciumsexual cycle
Authors: Bazin-Gélis Mélanie , Eleftheriou Evangelia , Zangarelli Coralie , Lelandais Gaëlle , Sperling Linda , Arnaiz Olivier , Bétermier Mireille 
Published: April 2023

ABSTRACTMultinucleate cells are found in many eukaryotes, but how multiple nuclei coordinate their functions is still poorly understood. In the cytoplasm of the ciliateParamecium tetraurelia, two micronuclei (MIC) serving sexual reproduction coexist with a somatic macronucleus (MAC) dedicated to gene expression. During sexual processes, the MAC is progressively destroyed while still ensuring transcription and new MACs develop from copies of the zygotic MIC. Several gene clusters are successively induced and switched off before vegetative growth resumes. Concomitantly, programmed genome rearrangements (PGR) remove transposons and their relics from the new MACs. Development of the new MACs is controlled by the old MAC, since the latter expresses genes involved in PGR, including thePGMgene encoding the essential PiggyMac endonuclease that cleaves the ends of eliminated sequences. Using RNA deep sequencing and transcriptome analysis, we show that impairing PGR up-deregulates key PGR genes, together with ∼600 other genes possibly also involved in PGR. Among these genes, 42% are no longer induced when no new MACs are formed, including 180 genes that are co-expressed withPGMunder all tested conditions. We propose that bi-directional crosstalk between the two coexisting generations of MACs links gene expression to the progression of MAC development.
Phenotype prediction using biologically interpretable neural networks on multi-cohort multi-omics data
Authors: van Hilten Arno , van Rooij Jeroen ,   BIOS consortium, Ikram M. Arfan , Niessen Wiro. J. , van Meurs Joyce. B.J. , Roshchupkin Gennady V. 
Published: April 2023

AbstractIntegrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability, and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA-expression and CpG methylation data from blood of the BIOS consortium(4 population cohorts, N_total=2940). In a cohort-wise cross validation setting, the consistency of the diagnostic performance and interpretation was assessed.Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI, 0.90 - 1.00) and interpretation revealed the involvement of well-replicated genes such asAHRR, GPR15andLRRN3. LDL-level predictions only generalized in a single cohort with an R2of 0.07 (95% CI, 0.05 - 0.08). Age was infered with a mean error of 5.16 (95% CI, 3.97 - 6.35) years with the genesCOL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2andCD34consistently predictive. In general, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks.We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.
Topographical analysis of immune cell interactions reveals a biomechanical signature for immune cytolysis
Authors: de Jesus Miguel , Settle Alexander H. , Vorselen Daan , Gaetjens Thomas K. , Galiano Michael , Wong Yung Yu , Fu Tian-Ming , Santosa Endi , Winer Benjamin Y. , Tamzalit Fella , Wang Mitchell S. , Bao Zhirong , Sun Joseph C. , Shah Pavak , Theriot Julie A. , Abel Steven M. , Huse Morgan 
Published: April 2023

ABSTRACTImmune cells live intensely physical lifestyles characterized by structural plasticity, mechanosensitivity, and force exertion. Whether specific immune functions require stereotyped patterns of mechanical output, however, is largely unknown. To address this question, we used super-resolution traction force microscopy to compare cytotoxic T cell immune synapses with contacts formed by other T cell subsets and macrophages. T cell synapses were globally and locally protrusive, which was fundamentally different from the coupled pinching and pulling of macrophage phagocytosis. By spectrally decomposing the force exertion patterns of each cell type, we associated cytotoxicity with compressive strength, local protrusiveness, and the induction of complex, asymmetric interfacial topographies. These features were further validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, direct imaging of synaptic secretory events, andin silicoanalysis of interfacial distortion. We conclude that T cell-mediated killing and, by implication, other effector responses are supported by specialized patterns of efferent force.
GWAS and genomic selection for marker-assisted development of sucrose enriched soybean cultivars
Authors: Riaz Awais , Raza Qasim , Kumar Anuj , Dean Derek , Chiwina Kenani , Phiri Theresa Makawa , Thomas Julie , Shi Ainong 
Published: April 2023

AbstractSucrose concentration in soy-derived foods is becoming a seminal trait for the production of food-grade soybeans. However, limited scientific knowledge is reported on this increasingly important breeding objective. In this study, 473 genetically diverse soybean germplasm accessions and 8,477 high-quality single nucleotide polymorphisms (SNPs) markers were utilized to pinpoint genomic regions associated with seed sucrose contents through a genome-wide association study (GWAS). A total of 75 significant SNPs (LOD ≥6.0) were identified across GLM, FarmCPU and BLINK models, including four stable and novel SNPs (Gm03_45385087_ss715586641, Gm06_10919443_ss715592728, Gm09_45335932_ss715604570 and Gm14_10470463_ss715617454). Gene mining near 20 kb flanking genomic regions of four stable SNPs identified 23 candidate genes with the majority of them highly expressed in soybean seeds and pod shells. A sugar transporter encoding major facilitator superfamily gene (Glyma.06G132500) showing the highest expression in pod shells was also identified. Moreover, selection accuracy, efficiency and favorable alleles of 75 significantly associated SNPs were estimated for their utilization in soybean breeding programs. Furthermore, genomic predictions with three different scenarios revealed better feasibility of GWAS-derived SNPs for selection and improvement of seed sucrose concentration. These results could facilitate plant breeders in marker-assisted breeding and genomic selection of sucrose-enriched food-grade soybean cultivars for the global soy-food industry.
The pAblo·pCasso self-curing vector toolset for unconstrained cytidine and adenine base-editing in Gram-negative bacteria
Authors: Kozaeva Ekaterina , Nielsen Zacharias S. , Nieto-Domínguez Manuel , Nikel Pablo I. 
Published: April 2023

ABSTRACTA synthetic biology toolkit, exploiting clustered regularly interspaced short palindromic repeats (CRISPR) and modified CRISPR-associated protein (Cas) base-editors, was developed for genome engineering in Gram-negative bacteria. Both a cytidine base-editor (CBE) and an adenine base-editor (ABE) have been optimized for precise single-nucleotide modification of plasmid and genome targets. CBE comprises a cytidine deaminase conjugated to a Cas9 nickase fromStreptococcus pyogenes(SpnCas9), resulting in C→T (or G→A) substitutions. Conversely, ABE consists of an adenine deaminase fused toSpnCas9 for A→G (or T→C) editing. Several nucleotide substitutions were achieved using these plasmid-borne base-editing systems and a novel protospacer adjacent motif (PAM)-relaxedSpnCas9 (SpRY) variant. Base-editing was validated inPseudomonas putidaand other Gram-negative bacteria by inserting prematureSTOPcodons into target genes, thereby inactivating both fluorescent proteins and metabolic (antibiotic-resistance) functions. The functional knockouts obtained by engineeringSTOPcodonsviaCBE were reverted to the wild-type genotype using ABE. Additionally, a series of induction-responsive vectors was developed to facilitate the curing of the base-editing platform in a single cultivation step, simplifying complex strain engineering programs without relying on homologous recombination and yielding plasmid-free, modified bacterial cells.Abstract Figure
Collaborative nowcasting of COVID-19 hospitalization incidences in Germany
Authors: Wolffram Daniel , Abbott Sam , an der Heiden Matthias , Funk Sebastian , Günther Felix , Hailer Davide , Heyder Stefan , Hotz Thomas , van de Kassteele Jan , Küchenhoff Helmut , Müller-Hansen Sören , Syliqi Diellë , Ullrich Alexander , Weigert Maximilian , Schienle Melanie , Bracher Johannes 
Published: April 2023

AbstractReal-time surveillance is a crucial element in the response to infectious disease outbreaks. However, the interpretation of incidence data is often hampered by delays occurring at various stages of data gathering and reporting. As a result, recent values are biased downward, which obscures current trends. Statistical nowcasting techniques can be employed to correct these biases, allowing for accurate characterization of recent developments and thus enhancing situational awareness. In this paper, we present a preregistered real-time assessment of eight nowcasting approaches, applied by independent research teams to German 7-day hospitalization incidences. This indicator played an important role in the management of the pandemic in Germany and was linked to levels of non-pharmaceutical interventions via certain thresholds. Due to its definition, in which hospitalization counts are aggregated by the date of case report rather than admission, German hospitalization incidences are particularly affected by delays and can take several weeks or months to fully stabilize. For this study, all methods were applied from 22 November 2021 to 29 April 2022, with probabilistic nowcasts produced each day for the current and 28 preceding days. Nowcasts at the national, state, and age-group levels were collected in the form of quantiles in a public repository and displayed in a dashboard. Moreover, a mean and a median ensemble nowcast were generated. We find that overall, the compared methods were able to remove a large part of the biases introduced by delays. Most participating teams underestimated the importance of very long delays, though, resulting in nowcasts with a slight downward bias. The accompanying uncertainty intervals were also too narrow for almost all methods. Averaged over all nowcast horizons, the best performance was achieved by a model using case incidences as a covariate and taking into account longer delays than the other approaches. For the most recent days, which are often considered the most relevant in practice, a mean ensemble of the submitted nowcasts performed best. We conclude by providing some lessons learned on the definition of nowcasting targets and practical challenges.
Investigating the causal interplay between sleep traits and risk of acute myocardial infarction: a Mendelian randomization study
Authors: Arora Nikhil , Bhatta Laxmi , Skarpsno Eivind Schjelderup , Dalen Håvard , Åsvold Bjørn Olav , Brumpton Ben Michael , Richmond Rebecca Claire , Strand Linn Beate 
Published: April 2023

AbstractBackgroundFew studies have investigated the joint effects of sleep traits on the risk of acute myocardial infarction (AMI). No previous study has used factorial Mendelian randomization (MR) which may reduce confounding, reverse causation and measurement error. Thus, it is prudent to study joint effects using robust methods to propose sleep-targeted interventions which lower the risk of AMI.MethodsThe causal interplay between combinations of two sleep traits (including insomnia symptoms, sleep duration or chronotype) on the risk of AMI was investigated using factorial MR. Genetic risk scores for each sleep trait were dichotomized at their median in UK Biobank (UKBB) and the second survey of the Trøndelag Health Study (HUNT2). A combination of two sleep traits constituting 4 groups were analysed to estimate the risk of AMI in each group using a 2×2 factorial MR design.ResultsIn UKBB, participants with high genetic risk for both insomnia symptoms and short sleep had the highest risk of AMI (hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.03, 1.18), although there was no evidence of interaction (relative excess risk due to interaction (RERI) 0.03; 95% CI −0.07, 0.12). These estimates were less precise in HUNT2 (HR 1.02; 95% CI 0.93, 1.13), possibly due to weak instruments. Participants with high genetic risk for both a morning chronotype and insomnia symptoms (HR 1.09; 95% CI 1.03, 1.17); and a morning chronotype and short sleep (HR 1.11; 95% CI 1.04, 1.19) had the highest risk of AMI in UKBB, although there was no evidence of interaction (RERI 0.03; 95% CI −0.06, 0.12; and RERI 0.05; 95% CI −0.05, 0.14, respectively). Chronotype was not available in HUNT2.ConclusionsThis study reveals no interaction effects between sleep traits on the risk of AMI, but all combinations of sleep traits increased the risk of AMI except those with long sleep. This indicates that the main effects of sleep traits on AMI are likely to be independent of each other.
ChatGPT Decision Support System: Utility in Creating Public Policy for Concussion/Repetitive Brain Trauma Associated With Neurodegenerative Diseases
Authors: Comrie Don 
Published: April 2023

AbstractThis article evaluates the ChatGPT decision support system’s utility for creating policies related to concussion and repetitive brain trauma associated with neurodegenerative disease risk. It is generally stable and fast. prompt/response pairs (n=259) were examined returning: six prompt response pairs that regenerated (2.31%); one Incorrect Answer; (.38%) one fragment (.38%). Its accuracy, validity, opacity, informational latency and vulnerability to manipulation limits its utility. ChatGPT’s data can be both out-of-date and incomplete which limits its utility use to subject matter experts analyzing expert statements. ChatGPT’s performance is affected by prompts involving stakeholder bias and litigation management, such as race. Nonetheless, ChatGPT demonstrated its ability to respond in both American and British/Australian English with ease. Overall, this study suggests that ChatGPT has limitations that need to be addressed before it can be widely used in decision-making related to concussion and repetitive brain trauma policies.
Patient consent for medical student pelvic exams under anesthesia: an exploratory retrospective chart review
Authors: Jushchyshyn Jessica A. , Mulugeta-Gordon Lakeisha , Curley Cara , Polite Florencia Greer , Merz Jon F. 
Published: April 2023

ABSTRACTBackgroundLegal requirements and clinical practices of securing patient consent for medical student pelvic examinations under anesthesia (EUA) vary widely, while ethical arguments and patients’ preferences for being asked for consent are well known.ObjectiveThis study was performed to examine patients’ choices to permit or refuse medical student pelvic EUAs during planned gynecologic procedures.Study DesignAn exploratory retrospective chart review of electronic consent forms at a single academic medical center, using contingency table and logistic regression to explore relationships between patient and provider characteristics and consent.ResultsElectronic consent forms were downloaded for a census of 4000 patients undergoing gynecologic surgery from September 2020 through calendar year 2022 and linked to anonymized medical record information, including patient age, race, religion, and insurance carrier, along with physician name. Physicians were coded by gender, departmental affiliation, and status (attending, resident, or fellow). Of the 4000 patients, 142 (3.6%) patients were removed from analysis because of uncertainty about the EUA consent. Of the remainder, 308 (8.0%) were asked for EUA consent more than once. Overall, of 3858 patients, 3308 (85.7%) consented every time asked and 550 (14.2%) refused or limited EUA consent at least once. Nine patients limited their consent to female students, and 2 patients refused medical student participation at all. Of the 308 asked more than once, 46 were not consistent. Exploratory multiple logistic regression Consent for pelvic exams under anesthesia analysis showed that patients identifying as Black or African American (OR=0.482, p<0.001) or Asian (OR=0.303, p<0.001), or of Moslem/Muslim/Islamic faith (OR=0.598, p=0.008) were substantially less likely to grant EUA consent than other patients. Moreover, male physicians were somewhat more likely to secure consent from patients than their female colleagues (OR=1.427, p=0.016).ConclusionsThe finding that some patients are more likely than others to refuse a pelvic EUA magnifies the dignitary harm from a nonconsensual invasion of intimate bodily integrity and perpetuates the historic wrongs visited upon vulnerable people of color and religious minorities. Patient’s rights to control over their own bodies can only be respected if their physicians take seriously the ethical obligation to inform their patients and ask them for permission.
A chromatin-associated regulator of RNA Polymerase III assembly at tRNA genes revealed by locus-specific proteomics
Authors: Breugel Maria Elize van , Kruijsbergen Ila van , Mittal Chitvan , Lieftink Cor , Brouwer Ineke , Brand Teun van den , Kluin Roelof J.C. , Menezes Renée , Welsem Tibor van , Cortona Andrea Del , Malik Muddassir , Beijersbergen Roderick , Lenstra Tineke L. , Verstrepen Kevin , Pugh B. Franklin , Leeuwen Fred van 
Published: April 2023

ABSTRACTTranscription of tRNA genes by RNA Polymerase III (RNAPIII) is tightly regulated by signaling cascades in response to nutrient availability. The emerging notion of differential tRNA gene regulation implies the existence of additional regulatory mechanisms. However, tRNA gene-specific regulatory factors have not been described. For that reason, we decoded the proteome of a single native tRNA gene locus in yeast. We observed dynamic reprogramming of the core RNAPIII transcription machinery upon nutrient perturbation. In addition, we identified Fpt1, a protein of unknown function. Fpt1 uniquely occupied tRNA genes but its occupancy varied and correlated with the efficiency of RNAPIII eviction upon nutrient perturbation. Decoding the proteome of a tRNA gene in the absence of Fpt1 revealed that Fpt1 promotes eviction of RNAPIII. Cells without Fpt1 also showed impaired shutdown of ribosome biogenesis genes upon nutrient perturbation. Our findings provide support for a chromatin-associated mechanism required for RNAPIII eviction from tRNA genes and for tuning an integrated physiological response to changing metabolic demands.Abstract Figure
High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue
Authors: Muller Alissa , Sullivan Jack , Schwarzer Wibke , Wang Mantian , Park-Windhol Cindy , Klingler Beryll , Matsell Jane , Hostettler Simon , Galliker Patricia , Duman Mert , Hou Yanyan , Balmer Pierre , Virág Tamás , Barrera Luis Alberto , Xu Quan , Magda Dániel Péter , Kilin Ferenc , Khadka Arogya , Quinodoz Mathieu , Hasler Pascal W. , Moreau Pierre-Henri , Fellmann Lyne , Azoulay Thierry , Cattaneo Marco , Picelli Simone , Grison Alice , Cowan Cameron S. , Janeschitz-Kriegl Lucas , Kusnyerik Ákos , Renner Magdalena , Nagy Zoltán Zsolt , Szabó Arnold , Rivolta Carlo , Scholl Hendrik P.N. , Bryson David , Ciaramella Giuseppe , Roska Botond , György Bence 
Published: April 2023

ABSTRACTStargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in theABCA4gene. We have designed a dual adeno-associated viral vector split-intein adenine base-editing strategy to correct the most common mutation inABCA4(c.5882G>A, p.G1961E). We optimizedABCA4base editing in human models, including retinal organoids, iPSC-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal- and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in non-human primates, with an average editing of 37% of photoreceptors and 73% of RPE cells in vivo. The high editing rates in primates make way for precise and efficient gene editing in other neurodegenerative ocular diseases.
Focal adhesions are controlled by microtubules through local contractility regulation
Authors: Aureille J. , Barnett S.F.H. , Arnal I. , Lafanechère L. , Low B.C. , Kanchanawong P. , Mogilner A. , Bershadsky A.D. 
Published: April 2023

ABSTRACTMicrotubules regulate cell polarity and migration by local activation of focal adhesion turnover, but the mechanism of this process is insufficiently understood. Molecular complexes containing KANK family proteins connect microtubules with the major component of focal adhesions, talin. Local optogenetic activation of KANK1-mediated links which promoted microtubule targeting to individual focal adhesion resulting in its centripetal sliding and rapid disassembly. The sliding is preceded by a local increase of traction force due to accumulation of myosin-II and actin in the proximity of the focal adhesion. Knockdown of Rho activator GEF-H1 prevented development of traction force and abolished sliding and disassembly of focal adhesion upon KANK activation. Other players participating in microtubule-driven KANK-dependent focal adhesion disassembly include kinases ROCK and PAK, as well as microtubules/focal adhesions associated proteins Kinesin-1, APC and αTAT. Finally, we propose a physical model of a microtubule-driven focal adhesion disruption involving local GEF-H1/RhoA/ROCK dependent activation of contractility which is consistent with experimental data.
Heterologous Expression and Characterization ofToxA1Haplotype from India and its Interaction withTsn1for Spot Blotch Susceptibility in Spring Wheat
Authors: Chaubey Ranjan Kumar , Thakur Dharamsheela , Navathe Sudhir , Sharma Sandeep , Mishra Vinod Kumar , Singh Pawan Kumar , Chand Ramesh 
Published: April 2023

AbstractBackgroundToxA, a necrotrophic effector protein, is present in the genome of fungal species likeParastagnospora nodorum,Pyrenophora tritici-repentisandBipolaris sorokiniana. Tsn1is the sensitivity gene in the host whose presence indicates more susceptibility toToxAcarrying pathogen, andToxA-Tsn1interaction follows an inverse gene-for-gene relationship.Methods and ResultsThe present study involved cloning and expressing theToxA1haplotype fromB. sorokiniana. It was found that the amplicon exhibited an expected product size of 471 bp. Sequence analysis of theToxA1nucleotide sequence revealed the highest identity, 99.79%, withP. tritici-repentis. The protein expression analysis showed peak expression at 16.5kDa. Phylogenetic analysis of theToxA1sequence from all theBipolarisisolates formed an independent clade along withP. tritici-repentisand diverged fromP. nodorum.ToxA-Tsn1interaction was studied in 18 wheat genotypes (11Tsn1and 7tsn1) at both seedling and adult stages, validating the inverse gene-for-gene relationship, as the toxin activity was highest in the K68 genotype (Tsn1) and lowest in WAMI280 (tsn1).ConclusionThe study indicates that the haplotypeToxA1is prevailing in the Indian population ofB. sorokiniana. It would be desirable for wheat breeders to select genotypes withtsn1locus for making wheat resistant to spot blotch.