bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modelling count data with partial differential equation models in biology
Authors: Simpson Matthew J , Murphy Ryan J , Maclaren Oliver J 
Published: September 2023

AbstractPartial differential equation (PDE) models are often used to study biological phenomena involving movement-birth-death processes, including ecological population dynamics and the invasion of populations of biological cells. Count data, by definition, is non-negative, and count data relating to biological populations is often bounded above by some carrying capacity that arises through biological competition for space or nutrients. Parameter estimation, parameter identifiability, and making model predictions usually involves working with a measurement error model that explicitly relating experimental measurements with the solution of a mathematical model. In many biological applications, a typical approach is to assume the data are normally distributed about the solution of the mathematical model. Despite the widespread use of the standard additive Gaussian measurement error model, the assumptions inherent in this approach are rarely explicitly considered or compared with other options. Here, we interpret scratch assay data, involving migration, proliferation and delays in a population of cancer cells using a reaction–diffusion PDE model. We consider relating experimental measurements to the PDE solution using a standard additive Gaussian measurement error model alongside a comparison to a more biologically realistic binomial measurement error model. While estimates of model parameters are relatively insensitive to the choice of measurement error model, model predictions for data realisations are very sensitive. The standard additive Gaussian measurement error model leads to biologically inconsistent predictions, such as negative counts and counts that exceed the carrying capacity across a relatively large spatial region within the experiment. Furthermore, the standard additive Gaussian measurement error model requires estimating an additional parameter compared to the binomial measurement error model. In contrast, the binomial measurement error model leads to biologically plausible predictions and is simpler to implement. We provide open source Julia software onGitHubto replicate all calculations in this work, and we explain how to generalise our approach to deal with coupled PDE models with several dependent variables through a multinomial measurement error model, as well as pointing out other potential generalisations by linking our work with established practices in the field of generalised linear models.
Rapid and cost-effective epitope mapping using PURE ribosome display coupled with next-generation sequencing and bioinformatics
Authors: Jia Beixi , Ojima-Kato Teruyo , Kojima Takaaki , Nakano Hideo 
Published: September 2023

AbstractA novel, efficient and cost-effective approach for epitope identification of an antibody has been developed using a ribosome display platform. This platform, known as PURE ribosome display, utilizes anEscherichia coli-based reconstituted cell-free protein synthesis system (PURE system). It stabilizes the mRNA-ribosome-peptide complex via a ribosome-arrest peptide sequence. This system was complemented by next-generation sequencing (NGS) and an algorithm for analyzing binding epitopes. To showcase the effectiveness of this method, selection conditions were refined using the anti-PA tag monoclonal antibody with the PA tag peptide as a model. Subsequently, a random peptide library was constructed using 10 NNK triplet oligonucleotides via the PURE ribosome display. The resulting random peptide library-ribosome-mRNA complex was selected using a commercially available anti-HA (YPYDVPDYA) tag monoclonal antibody, followed by NGS and bioinformatic analysis. Our approach successfully identified the “DVPDY” sequence as an epitope within the hemagglutinin amino acid sequence, which was then experimentally validated. This platform provided a valuable tool for investigating continuous epitopes in antibodies.
A key role of pectin demethylation-mediated cell wall Na+retention in regulating differential salt stress resistance in allotetraploid rapeseed genotypes
Authors: Zhou Ting , Wu Peng-jia , Chen Jun-fan , Du Xiao-qian , Feng Ying-na , Yue Cai-peng , Huang Jin-yong , Hua Ying-peng 
Published: September 2023

AbstractAllotetraploid rapeseed (Brassica napusL.) is highly susceptible to salt stress, a worldwide limiting factor that causes severe losses in seed yield. Genetic variations in the resistance against salt stress found in rapeseed genotypes emphasizes the complex response architecture. Westar is ubiquitously used as a major transgenic receptor, and ZS11 is widely grown as a high production and good quality cultivar. In this study, Westar was identified to outperform than ZS11 under salt stress. Through cell component isolation, non-invasive micro-test, X-ray energy spectrum analysis, and ionomic profiling characterization, pectin demethylation was found to be a major regulator for differential salt resistance between Westar and ZS11. Integrated analyses of genome-wide DNA variations, differentially expression profiling, and gene co-expression network identifiedBnaC9.PME47, encoding pectin methyl esterase, as a positive regulator mainly responsible for salt stress resistance.BnaC9.PME47, located in two reported QTLs regions for salt resistance, was strongly induced by salt stress and localized on the cell wall. Natural variation of the promoter regions conferred higher expression ofBnaC9.PME47in Westar than in other salt-sensitive rapeseed genotypes. Loss-of-function ofAtPME47resulted in the hypersensitivity of Arabidopsis plants to salt stress. This study facilitates a more comprehensive understanding of the differential morpho-physiological and molecular responses to salt stress and abundant genetic diversity in rapeseed genotypes, and the integrated multiomics analyses provide novel insights regarding the rapid dissection of quantitative trait genes responsible for nutrient stresses in plant species with complex genomes.
Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection
Authors: Loehr Amanda R. , Timmerman Dennis M. , Liu Michelle , Gillis Ad J.M. , Matthews Melia , Bloom Jordana C. , Nicholls Peter K. , Page David C. , Miller Andrew D. , Looijenga Leendert H.J. , Weiss Robert S. 
Published: September 2023

ABSTRACTMalignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs and informative biomarkers for several diseases. In humans, miRNAs of the miR-371-373 cluster are detectable in the serum of patients with malignant TGCTs and outperform existing serum protein markers for both initial diagnosis and subsequent disease monitoring. We previously developed a genetically engineered mouse model featuring malignant mixed TGCTs consisting of pluripotent embryonal carcinoma (EC) and differentiated teratoma that, like the corresponding human malignancies, originate in utero and are highly chemosensitive. Here, we report that miRNAs in the mouse miR-290-295 cluster, homologs of the human miR-371-373 cluster, were detectable in serum from mice with malignant TGCTs but not from tumor-free control mice or mice with benign teratomas. miR-291-293 were expressed and secreted specifically by pluripotent EC cells, and expression was lost following differentiation induced by the drug thioridazine. Notably, miR-291-293 levels were significantly higher in the serum of pregnant dams carrying tumor-bearing fetuses compared to that of control dams. These findings reveal that expression of the miR-290-295 and miR-371-373 clusters in mice and humans, respectively, is a conserved feature of malignant TGCTs, further validating the mouse model as representative of the human disease. These data also highlight the potential of serum miR-371-373 assays to improve patient outcomes through early TGCT detection, possibly even prenatally.
Supercharging carbohydrate-binding module alone enhances endocellulase thermostability, binding, and activity on cellulosic biomass
Authors: DeChellis Antonio , Nemmaru Bhargava , Sammond Deanne , Douglass Jenna , Patil Nivedita , Reste Olivia , Chundawat Shishir P. S. 
Published: September 2023

ABSTRACTLignocellulosic biomass recalcitrance to enzymatic degradation necessitates high enzyme loadings incurring large processing costs for industrial-scale biofuels or biochemicals production. Manipulating surface charge interactions to minimize non-productive interactions between cellulolytic enzymes and plant cell wall components (e.g., lignin or cellulose) via protein supercharging has been hypothesized to improve biomass biodegradability, but with limited demonstrated success to date. Here we characterize the effect of introducing non-natural enzyme surface mutations and net charge on cellulosic biomass hydrolysis activity by designing a library of supercharged family-5 endoglucanase Cel5A and its native family-2a carbohydrate binding module (CBM) originally belonging to an industrially relevant thermophilic microbeThermobifida fusca. A combinatorial library of 33 mutant constructs containing different CBM and Cel5A designs spanning a net charge range of −52 to 37 was computationally designed using Rosetta macromolecular modelling software. Activity for all mutants was rapidly characterized as soluble cell lysates and promising mutants (containing mutations either on the CBM, Cel5A catalytic domain, or both CBM and Cel5A domains) were then purified and systematically characterized. Surprisingly, often endocellulases with mutations on the CBM domain alone resulted in improved activity on cellulosic biomass, with three top-performing supercharged CBM mutants exhibiting between 2–5-fold increase in activity, compared to native enzyme, on both pretreated biomass enriched in lignin (i.e., corn stover) and isolated crystalline/amorphous cellulose. Furthermore, we were able to clearly demonstrate that endocellulase net charge can be selectively fine-tuned using protein supercharging protocol for targeting distinct substrates and maximizing biocatalytic activity. Additionally, several supercharged CBM containing endocellulases exhibited a 5–10 °C increase in optimal hydrolysis temperature, compared to native enzyme, which enabled further increase in hydrolytic yield at higher operational reaction temperatures. This study demonstrates the first successful implementation of enzyme supercharging of cellulolytic enzymes to increase hydrolytic activity towards complex lignocellulosic biomass derived substrates.
Examining DNA Breathing with pyDNA-EPBD
Authors: Kabir Anowarul , Bhattarai Manish , Rasmussen Kim Ø. , Shehu Amarda , Usheva Anny , Bishop Alan R , Alexandrov Boian S 
Published: September 2023

AbstractMotivationThe two strands of the DNA double helix locally and spontaneously separate and recombine in living cells due to the inherent thermal DNA motion.This dynamics results in transient openings in the double helix and is referred to as “DNA breathing” or “DNA bubbles.” The propensity to form local transient openings is important in a wide range of biological processes, such as transcription, replication, and transcription factors binding. However, the modeling and computer simulation of these phenomena, have remained a challenge due to the complex interplay of numerous factors, such as, temperature, salt content, DNA sequence, hydrogen bonding, base stacking, and others.ResultsWe present pyDNA-EPBD, a parallel software implementation of the Extended Peyrard-Bishop-Dauxois (EPBD) nonlinear DNA model that allows us to describe some features of DNA dynamics in detail. The pyDNA-EPBD generates genomic scale profiles of average base-pair openings, base flipping probability,DNA bubble probability, and calculations of the characteristically dynamic length indicating the number of base pairs statistically significantly affected by a single point mutation using the Markov Chain Monte Carlo (MCMC) algorithm.
Perceptual uncertainty explains activation differences between audiovisual congruent speech and McGurk stimuli
Authors: Dong Chenjie , Noppeney Uta , Wang Suiping 
Published: September 2023

AbstractFace-to-face communication relies on the integration of acoustic speech signals with the corresponding facial articulations. While the McGurk illusion is widely used as an index of audiovisual speech integration, critics argue that it arises from perceptual processes that differ categorically from natural speech recognition. Conversely, Bayesian theoretical frameworks suggest that both the illusory McGurk and the veridical audiovisual congruent speech percepts result from probabilistic inference based on noisy sensory signals. According to these models, the inter-sensory conflict in McGurk stimuli may only increase observers’ perceptual uncertainty. This functional magnetic resonance imaging (fMRI) study presented participants (20 male and 24 female) with audiovisual congruent, incongruent, and McGurk stimuli along with their unisensory counterparts in a syllable categorization task. Behaviorally, observers’ response entropy was greater for McGurk compared to congruent audiovisual stimuli. At the neural level, McGurk stimuli increased activations in a widespread neural system, extending from the inferior frontal sulci (IFS) to the pre-supplementary motor area (pre-SMA) and insulae, typically involved in cognitive control processes. Crucially, in line with Bayesian theories these activation increases were fully accounted for by observers’ perceptual uncertainty as measured by their response entropy. Our findings suggest that McGurk and congruent speech processing rely on shared neural mechanisms, thereby supporting the McGurk illusion as a valid measure of natural audiovisual speech perception.Significance StatementEffective face-to-face communication relies on integrating acoustic speech signals with the corresponding facial articulations. While McGurk illusion is extensively used to study audiovisual speech perception, recent critiques argue that it may be categorically different from typical speech recognition because of the conflict between the audiovisual inputs. This study demonstrates that McGurk stimuli increase activations in a network of regions typically involved in cognitive control. Crucially, the activation differences between McGurk and normal speech stimuli could be fully accounted for by the variation in observers’ perceptual uncertainties. Our results suggest that McGurk and congruent audiovisual speech stimuli rely on shared neural mechanisms – thereby supporting the validity of the McGurk illusion as a tool for studying natural audiovisual speech perception.
Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing
Authors: Bard Angela M. , Clark Lindsay V. , Cosgun Erdal , Aldinger Kimberly A. , Timms Andrew , Quina Lely A. , Lavista Ferres Juan M. , Jardine David , Haas Elisabeth A. , Becker Tatiana M , Pagan Chelsea M , Santani Avni , Martinez Diego , Barua Soumitra , McNutt Zakkary , Nesbitt Addie , Mitchell Edwin A , Ramirez Jan-Marino 
Published: September 2023

AbstractPurposeTo gain insights into potential genetic factors contributing to the infant’s vulnerability to Sudden Unexpected Infant Death (SUID).MethodsWhole Genome Sequencing (WGS) was performed on 145 infants that succumbed to SUID, and 576 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences.ResultsVariants of interest were identified in 86 genes, 63.4% of our cohort. Seventy-one of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria (Figure 1).ConclusionOur study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID.
A Bayesian approach to identifying the role of hospital structure and staff interactions in nosocomial transmission of SARS-CoV-2
Authors: Bridgen Jessica R.E. , Lewis Joseph M. , Todd Stacy , Taegtmeyer Miriam , Read Jonathan M. , Jewell Chris P. 
Published: September 2023

AbstractNosocomial infections threaten patient safety, and were widely reported during the COVID-19 pandemic. Effective hospital infection control requires a detailed understanding of the role of different transmission pathways, yet these are poorly quantified. Using patient and staff data from a large UK hospital we demonstrate a method to infer unobserved epidemiological event times efficiently and disentangle the infectious pressure dynamics by ward. A stochastic individual-level, continuous-time state-transition model was constructed to model transmission of SARS-CoV-2, incorporating a dynamic staff-patient contact network as time-varying parameters. A Metropolis-Hastings MCMC algorithm was used to estimate transmission rate parameters associated with each possible source of infection, and the unobserved infection and recovery times. We found that the total infectious pressure exerted on an individual in a ward varied over time, as did the primary source of transmission. There was marked heterogeneity between wards; each ward experienced unique infectious pressure over time. Hospital infection control should consider the role of between-ward movement of staff as a key infectious source of nosocomial infection for SARS-CoV-2. With further development, this method could be implemented routinely for real-time monitoring of nosocomial transmission and to evaluate interventions.
Recapturing the Initial Clinical Benefit of TMS in a Major Depressive Episode: a Retrospective Analysis in a Veteran Cohort
Authors: Laufer Jeremy , Olmsted Alisa , Sampair Irina , Madore Michelle , Yoon Jong , Hack Laura , Keller Corey J. 
Published: September 2023

AbstractBackgroundRepetitive transcranial magnetic stimulation (TMS) is now widely accepted as an effective non-pharmacologic treatment for treatment-resistant depression. However, whether repeated acute TMS courses can recapture the antidepressant effects of the initial acute course is still an open question, especially in the Veteran population. We present here a retrospective analysis of a specialty clinic within the Veteran Affairs Hospital System to help address this question.AimsFollowing an acute treatment course of TMS, we sought to determine the treatment response of a subsequent TMS course. We hypothesized that those who responded to an initial acute TMS course would respond in a similar manner to a subsequent treatment course.Methods116 cases referred for evaluation for TMS between September 2017 to April 2021 were reviewed. 63 Veterans completed at least one acute course of TMS and 12 completed at least two courses and met inclusion criteria for this review. Symptoms were evaluated via self-reported scales at baseline and weekly throughout treatment. Clinical response to subsequent treatment (>50% symptom reduction as measured by the PHQ-9) was compared to initial treatment response.ResultsOf the initial treatment responders (n = 6), all six responded to a second acute course, with an 85.3% symptom reduction. Of the initial treatment nonresponders (n = 6), three responded to a second acute course. Exploratory regression analysis predicted change in depression symptoms (PHQ-9) during a second TMS course using initial treatment response, time into treatment, and baseline symptom severity. Together, these factors explained 72% of the variance. No adverse events were reported in those who completed a second course, and the Veterans tolerated the treatment well.ConclusionsOur findings support the growing understanding that a second acute TMS treatment course for treatment-resistant depression is safe, well-tolerated, and effective in initial responders and some non-responders. Despite multiple confounders in a naturalistic setting, robust initial treatment response was sustained in a second acute course. Low power limits generalizability, and larger powered, prospective studies are needed.
High burden of anti-microbial resistance among neonatal blood stream infections in Southeast Asia: results of the NeoSEAP study
Authors: R Dickson Benjamin F , Putri Nina Dwi , Adrizain Riyadi , Kartina Leny , Villaneuva Uy Maria Esterlita , Gunaratna Gayana , Le Chau , Tran Hoang , Xuân Hương Nguyễn , Sukarja Distayay , Yuniati Tetty , Utomo Martono , Kieu Trinh Nguyen Thi , Thanh Thuy Hoang Nguyen , Cam Tu Tran Thi , Hong Le Tuyet , Fong Siew Moy , Harrison Michelle , M Williams Phoebe C 
Published: September 2023

AbstractBackgroundProgress on neonatal sepsis has remained modest in recent decades and is threatened by the global rise of antimicrobial resistance. The Southeast Asian region has a high burden of both neonatal sepsis and antimicrobial resistance. Despite this, their remains a lack of robust epidemiological data on the causes of neonatal sepsis and the prevalence of AMR in the region.MethodsWe evaluated the causes of neonatal sepsis and AMR burden in 10 sites across five countries in South and Southeast Asia (Sri Lanka, Indonesia, The Philippines, Malaysia and Vietnam). Retrospective data on all blood cultures collected from neonates between 1stJanuary 2019 – 31stDecember 2020 were extracted from laboratory records. Data were also collected on the availability of clinical resources, the implementation of infection prevention and control strategies, and antimicrobial prescribing practices.FindingsA total of 1,528 blood cultures were positive for significant isolates over the study period. Gram-negative pathogens predominated (1,163/1,528, 76.1%) with the most frequently isolated pathogensKlebsiellaspp. (408/1,528, 26.7%) andAcinetobacterspp. (261/1,528, 17.08%) Among Gram-negative Enterobacteriaceae pooled resistance to ampicillin, gentamicin, third-generation cephalosporins (ceftriaxone and/or cefotaxime) and carbapenems was 75% (193/257), 59% (393/665), 67% (441/655) and 18.6% (125/672). For Gram negative non-Enterobacteriaceae resistance to gentamicin and carbapenems was 76.6% (326/282) and 69.7% (207/297).InterpretationNeonatal sepsis among study sites was caused predominantly by Gram-negative pathogens and associated with high levels of non-susceptibility to common empirical treatment regimes.