bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning from harmonized peptide libraries enables retention time prediction of diverse post translational modifications
Authors: Wilburn Damien Beau , Shannon Ariana E. , Spicer Vic , Richards Alicia L. , Yeung Darien , Swaney Danielle L. , Krokhin Oleg V. , Searle Brian C. 
Published: June 2023

AbstractIn proteomics experiments, peptide retention time (RT) is an orthogonal property to fragmentation when assessing detection confidence. Advances in deep learning enable accurate RT prediction for any peptide from sequence alone, including those yet to be experimentally observed. Here we present Chronologer, an open-source software tool for rapid and accurate peptide RT prediction. Using new approaches to harmonize and false-discovery correct across independently collected datasets, Chronologer is built on a massive database with >2.2 million peptides including 10 common post-translational modification (PTM) types. By linking knowledge learned across diverse peptide chemistries, Chronologer predicts RTs with less than two-thirds the error of other deep learning tools. We show how RT for rare PTMs, such as OGlcNAc, can be learned with high accuracy using as few as 10-100 example peptides in newly harmonized datasets. This iteratively updatable workflow enables Chronologer to comprehensively predict RTs for PTM-marked peptides across entire proteomes.
POST-COVID ORTHOPAEDIC ELECTIVE RESOURCE PLANNING USING SIMULATION MODELLING
Authors: Harper Alison , Monks Thomas , Wilson Rebecca , Redaniel Maria Theresa , Eyles Emily , Jones Tim , Penfold Chris , Elliott Andrew , Keen Tim , Pitt Martin , Blom Ashley , Whitehouse Michael , Judge Andrew 
Published: June 2023

ABSTRACTObjectivesTo develop a simulation model to support orthopaedic elective capacity planning.MethodsAn open-source, generalisable discrete-event simulation was developed, including a web-based application. The model used anonymised patient records between 2016-2019 of elective orthopaedic procedures from an NHS Trust in England. In this paper, it is used to investigate scenarios including resourcing (beds and theatres) and productivity (lengths-of-stay, delayed discharges, theatre activity) to support planning for meeting new NHS targets aimed at reducing elective orthopaedic surgical backlogs in a proposed ring fenced orthopaedic surgical facility. The simulation is interactive and intended for use by health service planners and clinicians.ResultsA higher number of beds (65-70) than the proposed number (40 beds) will be required if lengths-of-stay and delayed discharge rates remain unchanged. Reducing lengths-of-stay in line with national benchmarks reduces bed utilisation to an estimated 60%, allowing for additional theatre activity such as weekend working. Further, reducing the proportion of patients with a delayed discharge by 75% reduces bed utilisation to below 40%, even with weekend working. A range of other scenarios can also be investigated directly by NHS planners using the interactive web app.ConclusionsThe simulation model is intended to support capacity planning of orthopaedic elective services by identifying a balance of capacity across theatres and beds and predicting the impact of productivity measures on capacity requirements. It is applicable beyond the study site and can be adapted for other specialties.Strengths and Limitations of this studyThe simulation model provides rapid quantitative estimates to support post-COVID elective services recovery toward medium-term elective targets.Parameter combinations include changes to both resourcing and productivity.The interactive web app enables intuitive parameter changes by users while underlying source code can be adapted or re-used for similar applications.Patient attributes such as complexity are not included in the model but are reflected in variables such as length-of-stay and delayed discharge rates.Theatre schedules are simplified, incorporating the five key orthopaedic elective surgical procedures.
Principles for Optimal Window Size Selection for Infant and Adult EEG Connectivity Analysis
Authors: Santamaria Lorena , Canales-Johnson Andres , Noreika Valdas , Leong Victorial 
Published: June 2023

AbstractNeural connectivity analysis is often performed on continuous data that has been discretized into temporal windows of a fixed length. However, the selection of an optimal window length is non-trivial, and depends on the properties of the connectivity metric being used as well as the effects of interest within the data (e.g. developmental or inter-brain effects). A systematic investigation of these factors, and objective criteria for window size selection are currently missing in the literature, particularly in regard to pediatric datasets. Here, we provide a principled examination of the effect of window size on optimization of signal to noise ratio for linear and non-linear EEG connectivity, as applied to infant, adult and dyadic (infant-adult) datasets. We employed a linear weighted phase lag index (wPLI), and a nonlinear weighted symbolic mutual information (wSMI) metric to assess brain connectivity for each dataset. Our results showed a clear polar dissociation between linear and non-linear metrics, as well as between infant and adult datasets in optimal window size. Further, optimal dyadic (infant-adult) window size settings defaulted to one or the partner rather than reflecting an intermediate compromise. Given the specificity of these results (i.e. there was no single window size that was optimal for all contrasts), we conclude that a formal analysis of optimal window size may be useful prior to conducting any new connectivity analysis. Here, we recommend guiding principles, performance metrics and decision criteria for optimal and unbiased window size selection.
Rewiring protein binding specificity in paralogous DRG/DFRP complexes
Authors: Westrip Christian A. E. , Smerdon Stephen J , Coleman Mathew L. 
Published: June 2023

SummaryThe Developmentally Regulated GTP-binding (DRG) proteins are an ancient subfamily of GTPases implicated in the regulation of translation and cell growth. In eukaryotes, there are two paralogs: DRG1 and DRG2, both of which have a conserved binding partner called DRG family regulatory protein 1 and 2 (DFRP1 and DFRP2), respectively. These binding partners are required for the function of DRGs, including their stabilisation at the protein level. Moreover, DFRPs interact with their respective DRG via a conserved region called the DFRP domain. Despite being highly similar, DRG1 and DRG2 have strict binding specificity for their respective DFRP. Using AlphaFold generated structure models of the human DRG/DFRP complexes, we have biochemically characterised their interactions and identified interface residues involved in determining specificity. This analysis revealed that as few as five mutations in DRG1 are able to switch its binding from DFRP1 to DFRP2. We show how two DRG1 residues in the core of the interface are most important for specifying the interaction with DFRP1 over DFRP2. We also demonstrate that whilst DFRP1 can stimulate the GTPase activity of DRG1, DFRP2 binding cannot. Overall, this work provides new insight into the structural determinants responsible for the binding specificities of the DRG:DFRP translation factor complexes, which are known to be essential for normal development in mice and humans.
Unraveling the Efficiency of Non-Navigated 2D Intraoperative Ultrasound in Glioma Surgery: Challenging the Demand for Increased Technological Sophistication in Intraoperative Imaging
Authors: Cepeda Santiago , García-García Sergio , Arrese Ignacio , Sarabia Rosario 
Published: June 2023

ABSTRACTBackgroundIn an era characterized by rapid progression in neurosurgical technologies, traditional tools such as the non-navigated two-dimensional intraoperative ultrasound (nn-2D-IOUS) risk being overshadowed. Against this backdrop, this study endeavors to provide a comprehensive and rigorous assessment of the clinical efficacy and surgical relevance of nn-2D-IOUS, specifically in the context of glioma resections.MethodsThis retrospective study undertaken at a single center evaluated 99 consecutive, non-selected patients diagnosed with both high-grade and low-grade gliomas. The primary objective was to assess the proficiency of nn-2D-IOUS in generating satisfactory image quality, identifying residual tumor tissue, and its influence on the extent of resection. To validate these results, early postoperative MRI data served as the reference standard.ResultsThe nn-2D-IOUS exhibited a high level of effectiveness, successfully generating good quality images in 79% of the cases evaluated. With a sensitivity rate of 68% and a perfect specificity of 100%, nn-2D-IOUS unequivocally demonstrated its utility in intraoperative tumor detection. Notably, in cases where total tumor removal was the surgical objective, a resection exceeding 95% of the initial tumor volume was achieved in 86% of patients. Additionally, in cases where residual tumor was not detected by nn-2D-IOUS, the mean volume of undetected tumor tissue was remarkably minimal, averaging at 0.29 cm3.ConclusionOur study provides compelling evidence supporting the invaluable role and efficacy of nn-2D-IOUS in glioma surgery. The results underscore the potential of harnessing traditional, cost-effective technologies such as nn-2D-IOUS to achieve enhanced surgical outcomes, even in the face of more advanced alternatives. These insights carry significant implications, particularly for resource-constrained settings, emphasizing the importance of optimizing the use of existing tools to improve patient care in a practical and efficient manner.
Phylodynamics Uncovers the Transmission of Antibiotic-ResistantEscherichia colibetween Canines and Humans in an Urban Environment
Authors: Walas Nikolina , Müller Nicola F. , Parker Emily , Henderson Abigail , Capone Drew , Brown Joe , Barker Troy , Graham Jay P. 
Published: June 2023

AbstractThe role of canines in transmitting antibiotic resistant bacteria to humans in the urban environment is poorly understood. To elucidate this role, we utilized genomic sequencing and phylogenetics to characterize the burden and transmission dynamics of antibiotic resistantEscherichia coli(ABR-Ec) cultured from canine and human feces present on urban sidewalks in San Francisco, California. We collected a total of fifty-nine ABR-Ec from human (n=12) and canine (n=47) fecal samples from the Tenderloin and South of Market (SoMa) neighborhoods of San Francisco. We then analyzed phenotypic and genotypic antibiotic resistance (ABR) of the isolates, as well as clonal relationships based on cgMLST and single nucleotide polymorphisms (SNPs) of the core genomes. Using Bayesian inference, we reconstructed the transmission dynamics between humans and canines from multiple local outbreak clusters using the marginal structured coalescent approximation (MASCOT). Overall, we found human and canine samples to carry similar amounts and profiles of ABR genes. Our results provide evidence for multiple transmission events of ABR-Ec between humans and canines. In particular, we found one instance of likely transmission from canines to humans as well as an additional local outbreak cluster consisting of one canine and one human sample. Based on this analysis, it appears that canine feces act as an important reservoir of clinically relevant ABR-Ec within the urban environment. Our findings support that public health measures should continue to emphasize proper canine feces disposal practices, access to public toilets and sidewalk and street cleaning.Importance:Antibiotic resistance inE. coliis a growing public health concern with global attributable deaths projected to reach millions annually. Current research has focused heavily on clinical routes of antibiotic resistance transmission to design interventions while the role of alternative reservoirs such as domesticated animals remain less well understood. Our results suggest canines are part of the transmission network that disseminates high-risk multidrug resistance inE. coliwithin the urban San Francisco community. As such, this study highlights the need to consider canines, and potentially domesticated animals more broadly, when designing interventions to reduce the prevalence of antibiotic resistance in the community. Additionally, it showcases the utility of genomic epidemiology to reconstruct the pathways by which antimicrobial resistance spreads.
The effect of linker conformation on performance and stability of a two-domain lytic polysaccharide monooxygenase
Authors: Forsberg Zarah , Stepnov Anton A. , Tesei Giulio , Wang Yong , Buchinger Edith , Kristiansen Sandra K. , Aachmann Finn L. , Arleth Lise , Eijsink Vincent G. H. , Lindorff-Larsen Kresten , Courtade Gaston 
Published: June 2023

AbstractA considerable number of lytic polysaccharide monooxygenases (LPMOs) and other carbohydrate-active enzymes are modular, with catalytic domains being tethered to additional domains, such as carbohydrate-binding modules, by flexible linkers. While such linkers may affect the structure, function, and stability of the enzyme, their roles remain largely enigmatic, as do the reasons for natural variation in length and sequence. Here, we have explored linker functionality using the two-domain cellulose-activeScLPMO10C fromStreptomyces coelicoloras a model system. In addition to investigating the wild-type enzyme, we engineered three linker variants to address the impact of both length and sequence and characterized these using SAXS, NMR, MD simulations, and functional assays. The resulting data revealed that, in the case ofScLPMO10C, linker length is the main determinant of linker conformation and enzyme performance. Both the wild-type and a serine-rich variant, which have the same linker length, demonstrated better performance compared to those with either a shorter or longer linker. A highlight of our findings was the substantial thermostability observed in the serine-rich variant. Importantly, the linker affects thermal unfolding behavior and enzyme stability. In particular, unfolding studies show that the two domains unfold independently when mixed, while the full-length enzyme shows one cooperative unfolding transition, meaning that the impact of linkers in biomass processing enzymes is more complex than mere structural tethering.
Demonstration that sublinear dendrites enable linearly non-separable computations
Authors: Cazé Romain D. , Tran-Van-Minh Alexandra , Gutkin Boris S. , DiGregorio David A. 
Published: June 2023

ABSTRACTTheory predicts that nonlinear summation of synaptic potentials within dendrites allows neurons to perform linearly non-separable computations (LNSCs). Using Boolean analysis approaches, we predicted that both supralinear and sublinear synaptic summation could allow single neurons to implement a type of LNSC, the feature binding problem (FBP), which does not require inhibition contrary to the XOR. Notably, sublinear dendritic operations enable LNSCs when scattered synaptic activation generates increased somatic spike output. However, experimental demonstrations of scatter-sensitive neuronal computations have not yet been described. Using glutamate uncaging onto cerebellar molecular layer interneurons, we show that scattered synaptic-like activation of dendrites evoked larger compound EPSPs than clustered synaptic activation, generating a higher output spiking probability. Moreover, we also demonstrate that single interneurons can indeed implement the FBP. We use a biophysical model to predict under what conditions a neuron can implement the FBP and what leads to failures. Experimental results agree with the model-determined conditions and hence validate our protocol as a solid benchmark for a neuron to implement linearly non-separable computations. Since sublinear synaptic summation is a property of passive dendrites we expect that many different neuron types can implement LNSCs.
In vitro modelling of anterior primitive streak patterning with human pluripotent stem cells identifies the path to notochord progenitors
Authors: Robles-Garcia M. , Thimonier C. , Angoura K. , Ozga E. , MacPherson H. , Blin G. 
Published: June 2023

AbstractNotochord progenitors (NotoPs) represent a scarce yet crucial embryonic cell population, playing important roles in embryo patterning and eventually giving rise to the cells that form and maintain intervertebral discs. The mechanisms regulating NotoPs emergence are unclear. This knowledge gap persists due to the inherent complexity of cell fate patterning during gastrulation, particularly within the anterior primitive streak (APS), where NotoPs first arise alongside other important progenitors including neuro-mesodermal and endodermal progenitors.To gain insights into this process, we use micropatterning together with FGF and the WNT pathway activator CHIR9901, to guide the development of human embryonic stem cells into reproducible patterns of APS cell fates. We show that small variations in CHIR9901 dosage dictate the downstream dynamics of endogenous TGFbeta signalling which in turn controls cell fate decisions. We show that sustained NODAL signalling induces endoderm while NODAL inhibition is needed for NMP specification. Furthermore, we unveil a crosstalk between TGFbeta and WNT signaling pathways, wherein TGFbeta inhibition enhances WNT activity. Finally, we demonstrate that the timely inhibition of TGFbeta signalling is imperative for the emergence of NotoPs.Our work elucidates the signalling regimes underpinning NotoPs emergence and provides novel insights into the regulatory mechanisms controlling the balance of APS cell fates during gastrulation.
A prospective two-year longitudinal follow-up study depicting humoral and cell-mediated immune responses in Covaxin vaccinated individuals
Authors: Tripathy Archana , Podder Sreeparna , Sradhanjali Swatishree , Bhattacharya Debdutta , Pati Sanghamitra , Raghav Sunil K. 
Published: June 2023

AbstractThere are majorly two variants of SARS-CoV-2 vaccine that were employed worldwide on emergency basis to contain the COVID-19 pandemic i.e., RNA based or adenovirus construct based Spike protein expression system which was broadly used and the inactivated virus particle composition. Due to emergency usage starting from the onset of 2021, the immunogenicity data pertaining to long term effects of these vaccines is unexplored. Therefore, in this study we assessed the immunogenicity analysis of Covaxin (BBV152), an inactivated virus-based vaccine for a longitudinal time-span of two years. We investigated the humoral and cell-mediated immune responses in 250 subjects for two years by estimating the RBD specific IgG titres and CD4+/CD8+ T-cell responses. We found that anti-RBD IgG titres that were almost reaching at the basal levels within a year of 2nd dose of vaccination, went significantly high immediately after Omicron infection wave in January 2022. Moreover, the pseudo-virus neutralization by the serum of these subjects showed concordant and drastic increase in virus neutralization activity. At the same time, mild or no symptoms were observed in individuals infected with Omicron variant of SARS-CoV-2. These observations strongly suggested that Omicron variant could have been the best SARS-CoV-2 variant for effective vaccine formulations to generate robust protective immune response along with lesser side effects. Interestingly, the CD4+ and CD8+T-cell activity in Covaxin vaccinees depicted mild to moderate but sustained responses. The spike peptivator pool activated PBMCs of vaccinees depicted an enhancement of CD4+ and CD8+ antigenic responses after 2ndand 3rddose of vaccine administration. In comparison to Covishield, the antibody and T-cell responses were found to be milder in BBV152 vaccinees. This milder antibody and T-cell response could be the reason behind no or less side effects with BBV152 administration than other RNA based vaccines. Overall, our study is one of the first studies profiling the longitudinal humoral and T-cell responses of inactivated virus-based vaccines like COVAXIN, which was predominantly used in India and neighbouring Southeast Asian countries.
Spirometry performance quality and lung function pattern during pregnancy; should testing conditions and interpretation criteria be re-evaluated?
Authors: Ruhighira Jacktan J , Mashili Fredirick L , Tungu Alexander M , Kibusi Stephen 
Published: June 2023

AbstractIntroductionDespite the prevalence of respiratory disorders in the gravid state, and the crucial role of spirometry in respiratory medicine, its utility for assessing lung function during pregnancy remains infrequent. Putative reasons for this include reservations regarding spirometry performance and its potential influence on test outcomes, although the literature documenting such concerns is insufficient. This study sought to evaluate whether variations in spirometry test performance could impact the diagnosis of pulmonary function patterns throughout gestation.MethodsWe used spirometry data from a cross-sectional study of 120 pregnant and 114 non-pregnant women who underwent spirometry with uniform instructions given to all subjects. Data were subjected to chi-square testing and subsequently evaluated through logistic regression analysis.ResultsThe acceptable performance rate among pregnant participants was 77.3%, with the most common quality grade being C (37.5%). Pregnant individuals exhibited 2.1 times the odds of achieving a B grade (p=0.037, 95% CI=1.0-4.2) and 4.1 times the odds of achieving an F grade (p=0.02, 95% CI=1.6-9.9) instead of an A grade. Additionally, they manifested 2.9 times the odds of generating unsatisfactory performance (p=0.007, 95% CI=1.3-6.1) compared to non-pregnant participants. Also, pregnant participants displayed 2.5 times the odds of exhibiting a restrictive pattern (p=0.021, 95% CI=1.1-5.7); but pattern classification was not associated with quality grades.ConclusionDespite the higher likelihood of suboptimal spirometry quality, the observed pattern classification remains as expected physiologically, suggesting that spirometry is still a valid tool for assessing lung function in pregnancy.
YAP/TAZ enhance P-body formation to promote tumorigenesis
Authors: Shen Xia , Peng Xiang , Guo Yuegui , Dai Zhujiang , Cui Long , Yu Wei , Liu Yun , Liu Chen-Ying 
Published: June 2023

AbstractThe role of Processing bodies (P-bodies) in tumorigenesis and tumor progression is not well understood. Here, we showed that the oncogenes YAP/TAZ promote P-body formation in a series of cancer cell lines. Mechanistically, both transcriptional activation of the P- body-related genes SAMD4A, AJUBA, and WTIP and transcriptional suppression of the tumor suppressor gene PNRC1 are involved in enhancing the effects of YAP/TAZ on P- body formation in CRC cells. By reexpression of PNRC1 or knockdown of P-body core genes (DDX6, DCP1A, and LSM14A), we determined that disruption of P-bodies attenuates cell proliferation, cell migration and tumor growth induced by overexpression of YAP5SAin CRC. Analysis of a pancancer CRISPR screen database (DepMap) revealed codependencies between YAP/TEAD and the P-body core genes and correlations between the mRNA levels of SAMD4A, AJUBA, WTIP, PNRC1 and YAP target genes. Our study suggests that the P-body is a new downstream effector of YAP/TAZ, which implies that reexpression of PNRC1 or disruption of P-bodies is a potential therapeutic strategy for tumors with active YAP.