bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unveiling Novel Hyperglycosylated Analog of Human Erythropoietin: A Comprehensive Computational Exploration
Authors: Thahsin Naima , Khan Khairul Islam , Sakib Mohammad Nazmus , Rahman Mohammad Shahedur 
Published: October 2024

AbstractIntroductionThe capability of human erythropoietin (hEPO) to treat anemia by stimulating erythropoiesis, has made it become one of the world’s leading biopharmaceuticals. An effective way to improve the efficiency of recombinant hEPO drugs is increasing glycosylation which can increase its serum half-life and thereby it’sin vivobiological activity. In this context, the objective of the present study was to explore potential glycosylation sites in hEPO to develop new hyperglycosylated analogous drug.Materials and MethodsA rational computational strategy was executed to select compatible region of hEPO for inserting N-linked glycosylation consensus motif (N-X-S/T), thus designing a number of analogs. The 3D models of the analogs were constructed by homology modeling and validated by variousin silicotools. The probability of glycosylation was checked and hyperglycosylated models of the selected analogs were developed. Molecular docking and molecular dynamics simulation were performed to select the best analog.ResultsAmong 40 analogs designed in this study, Analog-71.1 showed most promising results. Four possible sites of this analog showed good probability for glycosylation. According to the molecular docking study, the analog obtained high docking score (2313.711) and formed highest number of (25) hydrogen bonds with erythropoietin receptors, which indicated strong and stable interaction with the receptors. Moreover, the steady trajectory of RMSD, Rgyr, RMSF and other findings obtained from MD simulation confirmed the structural stability of the analog.ConclusionsOur overall study has selected Analog-71.1 as a potential candidate to develop new analogous drug with enhanced efficiency, which needs further experimental analyses.
Interpretable multi-omics integration with UMAP embeddings and density-based clustering
Authors: Castellano-Escuder Pol , Zachman Derek K. , Han Kevin , Hirschey Matthey D. 
Published: October 2024

AbstractIntegrating high-dimensional cellular multi-omics data is crucial for understanding various layers of biological control. Single ‘omic methods provide important insights, but often fall short in handling the complex relationships between genes, proteins, metabolites and beyond. Here, we present a novel, non-linear, and unsupervised method called GAUDI (Group Aggregation via UMAP Data Integration) that leverages independent UMAP embeddings for the concurrent analysis of multiple data types. GAUDI uncovers non-linear relationships among different omics data better than several state-of-the-art methods. This approach not only clusters samples by their multi-omic profiles but also identifies latent factors across each omics dataset, thereby enabling interpretation of the underlying features contributing to each cluster. Consequently, GAUDI facilitates more intuitive, interpretable visualizations to identify novel insights and potential biomarkers from a wide range of experimental designs.
Tuning Insulin Receptor Signaling UsingDe NovoDesigned Agonists
Authors: Wang Xinru , Cardoso Sarah , Cai Kai , Venkatesh Preetham , Hung Albert , Ng Michelle , Hall Catherine , Coventry Brian , Lee David , Chowhan Rishabh , Gerben Stacey , Li Jie , An Weidong , Hon Mara , Accili Domenico , Bai Xiaochen , Choi Eunhee , Baker David 
Published: October 2024

SummaryBinding of insulin to the insulin receptor (IR) induces conformational changes in the extracellular portion of the receptor that lead to activation of the intracellular kinase domain and the AKT and MAPK pathways, and downstream modulation of glucose metabolism and cell proliferation. We reasoned that designed agonists that induce different conformational changes in the receptor might induce different downstream responses, which could be useful both therapeutically and to shed light on how extracellular conformation is coupled to intracellular signaling. We usedde novoprotein design to first generate binders to individual IR extracellular domains, and then to fuse these together in different orientations and with different conformational flexibility. We describe a series of synthetic agonists that signal through the IR that differ from insulin and from each other in the induction of receptor autophosphorylation, MAPK activation, intracellular trafficking, and cell proliferation. We identify designs that are more potent than insulin causing much longer lasting reductions in glucose levels, and that retain signaling activity on disease-causing receptor mutants that do not respond to insulin. These results inform our understanding of how changes in receptor conformation and dynamics are transmitted to downstream signaling, and our synthetic agonists have considerable therapeutic potential for diabetes and severe insulin resistance syndromes.HighlightsComputational design yielded super agonists, partial agonists, and antagonists of IR.De novoagonists induce a distinct IR active conformation.Designed agonists tune IR signaling by modulating conformational dynamics of activated IR.Designed agonists are more potent than insulin, reducing glucose levels longer and activating disease-causing IR mutants.
Antibody-Fab and -Fc features promoteMycobacterium tuberculosisrestriction
Authors: Grace Patricia S. , Peters Joshua M. , Sixsmith Jaimie , Lu Richard , Luedeman Corinne , Fenderson Brooke A. , Vickers Andrew , Slein Matthew D. , Irvine Edward B. , McKitrick Tanya , Wei Mo-Hui , Cummings Richard D. , Wallace Aaron , Cavacini Lisa A. , Choudhary Alok , Proulx Megan K. , Sundling Christopher , Källenius Gunilla , Reljic Rajko , Ernst Joel D. , Casadevall Arturo , Locht Camille , Pinter Abraham , Sasseti Christopher M. , Bryson Bryan D. , Fortune Sarah M. , Alter Galit 
Published: October 2024

AbstractMycobacterium tuberculosis (Mtb),the causative agent of tuberculosis (TB), is a leading cause of death by an infectious disease globally, with no efficacious vaccine. Antibodies are implicated inMtbcontrol, but the mechanisms of antibody action remain poorly understood. We assembled a library of TB monoclonal antibodies (mAb) and screened for the ability to restrictMtbin mice, identifying protective antibodies targeting known and novel antigens. To dissect the mechanism of mAb-mediatedMtbrestriction, we optimized a protective lipoarabinomannan-specific mAb through Fc-swapping.In vivoanalysis of these Fc-variants revealed a critical role for Fc-effector function inMtbrestriction. Restrictive Fc-variants altered distribution ofMtbacross innate immune cells. Single-cell transcriptomics highlighted distinctly activated molecular circuitry within innate immune cell subpopulations, highlighting early activation of neutrophils as a key signature of mAb-mediatedMtbrestriction. Therefore, improved antibody-mediated restriction ofMtbis associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.
Transgenerational effects alter the fitness consequences and genetic architecture of phenotypic plasticity and its regulatory pathways
Authors: Bogan Samuel N. , Strader Marie E. , Hofmann Gretchen E. 
Published: October 2024

AbstractParental exposure to environmental stress can influence phenotypic plasticity by offspring developing under that stressor. Transgenerational effects may also reshape natural selection on developmental plasticity by influencing its fitness consequences and expression of its genetic variation. We tested these hypotheses in the purple sea urchinStrongylocentrotus purpuratus, an invertebrate exposed to coastal upwelling (periods of low temperature and pH impacting biomineralization and performance). We conditioned parents and larvae to experimental upwelling and integrated RNA-seq, phenotyping of body size and biomineralization, and measured fitness-correlated traits in a quantitative genetic experiment. Larvae developing under upwelling induced widespread differential expression (DE), decreased biomineralization, and reduced body size. We detected fitness benefits for increased biomineralization and reduced size under upwelling indicative of adaptive plasticity, but only when larvae were spawned from parents exposed to upwelling. Larval DE was largely associated with adaptive phenotypic plasticity. Negative genetic correlation in DE was abundant between genes associated with adaptive plasticity. However, genetic correlations in DE associated with body size plasticity were significantly more positive in larvae from upwelling-exposed parents. These results show that transgenerational effects modify the fitness landscape and genetic architecture of phenotypic plasticity and its regulatory pathways.
Addressing domain shift in deep learning: Challenges and insights from plant disease diagnosis and flower recognition
Authors: Sun Jianqiang 
Published: October 2024

AbstractDeep learning models have demonstrated potential in plant disease diagnosis and flower recognition; however, their real-world application is hindered by domain shift—where models trained on one dataset underperform when tested on datasets collected in different conditions. This study assessed the cross-dataset generalization of deep learning models, including ResNet, EfficientNet, Inception, and MobileNet, using multiple tomato disease and flower datasets. While models achieved high accuracy when trained and validated on the same dataset, their performance declined significantly when evaluated on different datasets, underscoring the impact of domain variability. This performance degradation was consistent across all model architectures, suggesting that domain shift cannot be addressed through model architecture alone. The results emphasize the need for more diverse and representative datasets to mitigate variability in agricultural data and enhance the practical utility of deep learning models in agricultural applications.
Thermal Adaptation of Cytosolic Malate Dehydrogenase Revealed by Deep Learning and Coevolutionary Analysis
Authors: Shukla D , Martin J , Morcos F , Potoyan DA 
Published: October 2024

AbstractProtein evolution has produced enzymes that maintain stability and function across various thermal environments. While sequence variation, structural dynamics, and intermolecular interactions are known to influence an enzyme’s thermal adaptation, how these factors collectively govern stability and function across diverse temperatures remains unresolved. Cytosolic malate dehydrogenase (cMDH), a citric acid cycle enzyme, is an ideal model for studying these mechanisms due to its temperature-sensitive flexibility and broad presence in species from diverse thermal environments. In this study, we employ techniques inspired by deep learning and statistical mechanics to uncover how sequence variation and structural dynamics shape patterns of cMDH’s thermal adaptation. By integrating coevolutionary models with variational autoencoders (VAE), we generate a latent generative landscape (LGL) of cMDH sequence space, enabling us to explore evolutionary pathways and predict fitness using direct coupling analysis (DCA). Structural predictions via AlphaFold and molecular dynamics simulations further illuminate how variations in hydrophobic interactions and conformational flexibility contribute to the thermal stability of warm- and cold-adapted cMDH orthologs. The integrative computational framework employed in this study provides powerful insights into protein adaptation at both sequence and structural levels, offering new perspectives on the evolution of thermal stability and creating avenues for the rational design of proteins with optimized thermal properties for biotechnological applications.
Long-Term Effects of Working Memory Retrieval From Prioritized and Deprioritized States
Authors: Born Frieda , Spitzer Bernhard 
Published: October 2024

AbstractWhich factors determine whether information temporarily held in working memory (WM) is transferred to long-term memory (LTM)? Previous work has shown that retrieving (“testing”) memories from LTM can benefit their future LTM recall. Here, we examined the extent to which a benefit for subsequent LTM may also occur after retrieval from WM, depending on whether the WM contents were retrieved from a prioritized or deprioritized state. In three experiments, we combined variants of a novel visual WM paradigm with a subsequent surprise LTM recall test. We found a LTM benefit of WM testing both for prioritized and deprioritized WM contents, which, interestingly, was stronger for the deprioritized information. This pattern showed similarly across experiments with different priority manipulations. Subsequent LTM benefits generally occurred after WM testing with a recall-like test format (continuous report), but not after simple WM comparisons against a probe. The surprisingly larger LTM benefit for deprioritized WM contents may reflect enhanced encoding of the participants’ own subjective WM report – as opposed to the originally presented sample information – into LTM.
Tunneling Nanotubes Between Bone Marrow Stromal Cells Support Transmitophagy and Resistance to Apoptosis in Myeloma
Authors: Solimando Antonio Giovanni , Di Palma Francesco , Desantis Vanessa , Vacca Angelo , Svelto Maria , Pisani Francesco 
Published: October 2024

AbstractHere we show that under oxygen-glucose deprivation (OGD), multiple myeloma cells transfer dysfunctional mitochondria to bone marrow stromal cells (BMSCs) for degradation (transmitophagy). These mitochondria are then transferred between BMSCs via tunneling nanotubes contributing to myeloma survival in OGD.
Reporter CRISPR screens deciphercis- andtrans-regulatory principles at theXistlocus
Authors: Schwämmle Till , Noviello Gemma , Kanata Eleni , Froehlich Jonathan J. , Bothe Melissa , Altay Aybuge , Scouarnec Jade , Feng Vivi-Yun , Vingron Martin , Schulz Edda G. 
Published: October 2024

AbstractDevelopmental genes are controlled by an ensemble ofcis-acting regulatory elements (REs), which in turn respond to multipletrans-acting transcription factors (TFs). Understanding how acis-regulatory landscape integrates information from many dynamically expressed TFs has remained a challenge. We develop a combined CRISPR-screening approach using endogenous RNA and RE-reporters as readouts. Applied to theXistlocus, crucial for X-chromosome inactivation in females, this method allows us to comprehensively identify Xist-controlling TFs and map their TF-RE wiring. We find a group of transiently expressed TFs that regulate proximal REs, driving the binary activation of Xist expression. These basal activators are more highly expressed in cells with two X chromosomes, potentially driving female-specific Xist upregulation. A second set of developmental TFs is upregulated later during differentiation and targets distal REs. This regulatory axis is crucial to achieve high levels of Xist RNA, which is necessary for X-chromosome inactivation. Our findings support a model for developmental gene regulation in which factors targeting proximal REs drive binary ON-OFF decisions, while factors interacting with distal REs control the transcription output.
Aligning Funding Models with Clinical Practice: Phases of Neonatal Care and the Link with Activity-Based Funding
Authors: Mordaunt Dylan A 
Published: October 2024

AbstractObjectiveTo explore the potential impact of partitioning neonatal unit funding into acute and sub-acute/non-acute care (SNAP) types, within a level 6 neonatal unit under the Independent Health and Aged Care Pricing Authority (IHACPA) National Efficient Price (NEP) Funding Model.MethodsIn a 12-month retrospective cohort from our neonatal unit, we simulated the effect of a care type change to SNAP. We then explored the trend in this activity type over the past 20 years.Results341 patients with a length of stay greater than 10 days were identified from FY 2021-22. Modelling estimates that between 51 and 175 episodes could have a SNAP opportunity. When moderated, this corresponds with an uplift of between AUD $0.3 - 1.7M, based on 2023-24 value and NEP price.ConclusionsUtilisation of a SNAP care-type change has the potential for a considerable uplift in funding for level 6 neonatal units, supporting service sustainability. This may be of use for other units, whilst the neonatal funding model continues to be reviewed and optimized by IHACPA. Implementation in our context, would require changes to both local and state funding management systems, as well as alterations in the Electronic Medical Record (EMR).
Pilot randomized controlled trial of acetylsalicylic acid to reduce cerebral microembolism in Chagas heart failure
Authors: Castello-Branco Renan Carvalho , de Santana Cárita Victoria Carvalho , Botelho Victor L. P. P. , deSousa Paulo R. S. P. , Nunes Maria C.P. , Furie Karen L. , Oliveira-Filho Jamary 
Published: October 2024

AbstractBackgroundChagas disease is an important cause of heart failure (HF) and stroke, affecting over six million people. High intensity transient signals (HITS) are detected on transcranial Doppler (TCD) in patients with Chagas disease, but the effect of antithrombotic treatment on HITS is unknown. The aim of this study was to evaluate whether acetylsalicylic acid (ASA) reduces the frequency and number of HITS in patients with chagasic HF.MethodsProof-of-principle pilot prospective, randomized, open and blinded endpoint clinical trial (PROBE), where patients with both Chagas and HITS were randomized 2:1 to ASA 300 mg for seven days and standard HF treatment or standard HF treatment alone (control group). The primary outcome was the proportion of HITS after one week, analyzed using chi-squared test.Results373 patients with HF were evaluated, HITS occurred in 22/190 (12%) chagasic patients and in 16/183 (8%) non-chagasic patients (p=0.531). Twelve of the 22 (54%) chagasic patients were randomized to treatment with ASA (n = 8) or without ASA (n = 4). Two patients in the control group (50%) persisted with HITS after 7 days of treatment, compared to none in the ASA group, p=0.028. Median number of HITS decreased from 3.5 to 0 with ASA (p=0.012) and 4.0 to 0.5 in the control group (p=0.095), with no significant between-group difference (p=0.262). No adverse events were reported.ConclusionIn this pilot clinical trial, ASA reduced the proportion of HITS in patients with Chagas disease HF.
Exploring the Decisional Needs of Patients living with Subacromial Pain Syndrome: a qualitative needs assessment study
Authors: Bengtsen Samantha Charmaine , Zadro Joshua Robert , Rathleff Michael Skovdal , Foster Nadine E , Thomsen Janus Laust , Olesen Jens Lykkegaard , Søndergaard Jens , Lyng Kristian Damgaard 
Published: October 2024

AbstractBackgroundThere are a variety of different treatments for patients living with subacromial pain syndrome (SAPS). All treatments have small to moderate effect sizes, and it is challenging when healthcare practitioners and patients need to decide on which treatment options to choose. The aim of this study was to explore and understand the decisional needs of patients with SAPS, to inform and support the decision-making process.MethodsA qualitative research study, using semi-structured individual interviews with patients with SAPS. The interview guide was informed by the Ottawa Decision Support Framework (ODSF), previous research related to treatment decision-making, other decisional needs assessment studies, and inputs from patients with SAPS and healthcare practitioners. Data were analysed by using reflexive thematic text analysis and ODSF. The analysis was conducted in NVivo 12.ResultsWe invited 22 participants of which 17 (age 22-71 years) took part in the study. We found three main themes related to individual decisional needs in the context of decision-making: 1) The necessity of certainty and adequate information as fundamental prerequisites for effective decision-making, 2) The importance of person-centred care to achieve a desirable decision, and 3) The need for a supportive environment to facilitate adaptation and acceptance of the decision.ConclusionThe decision-making process faced by patients with SAPS is complex and involves several decisional needs. Our findings highlight the importance of healthcare professionals identifying and addressing patients’ decisional needs in consultations with patients with SAPS.ImplicationsOur study provides guidance to clinical practice in terms of increased understanding of the decisional needs experienced by patients with SAPS. Furthermore, these results should inform future development of decision aids for patients with SAPS.HighlightsSubacromial pain syndrome is a complex condition, demanding a thorough decision-making processWe identified several concrete decisional needs through the Ottawa Decision Support Framework and further provided in-depth knowledge on key themes related to certainty, patient-centeredness, and support.Our study provides information of designing a decision aid supporting shared decision-making in future studies.
Pre-pandemic national immunisation programme strength and health workforce capacity improved routine immunisation resilience during the COVID-19 pandemic
Authors: Evans Beth , Kaiser Laurent , Keiser Olivia , Jombart Thibaut 
Published: October 2024

AbstractBackgroundThe adverse impact of the COVID-19 pandemic on Routine Immunisation (RI) coverage has been well-documented: most countries experienced backsliding or stagnation in coverage. Qualitative surveys indicated potential causes of such declines, including reduced health care seeking behaviour, lockdowns, and overwhelmed health systems.MethodsWe investigate determinants of RI resilience during COVID-19 at a national level for 119 countries from 2020 to 2022, using publicly available data on pre-pandemic immunisation programme performance, health workforce capacity, health systems strength, health financing, global health security preparedness, COVID-19 burden, COVID-19 containment, economic, and health policy responses, population mobility changes, and country wealth. We employ a mixed methods approach: stepwise linear regression based on a causal inference framework, and Random Forest regression to identify potential nonlinear interactions and collinear effects.ResultsWe provide evidence that stronger pre-pandemic immunisation programmes and more health workers, once above minimum thresholds (about 83% Diphtheria-Tetanus-Pertussis third-dose coverage and 60 health workers per 10,000 population), are associated with improved RI resilience. Random Forest analysis suggests health financing and health system strength impact RI resilience. COVID-19 vaccinations and pandemic policies were not associated with RI coverage changes, implying – reassuring – these acute responses did not interrupt routine services. In addition to these findings, a large fraction of variation in pandemic RI resilience remains unexplained, highlighting the need for further research on RI performance determinants.ConclusionOur findings underscore the role of robust immunisation programmes and sufficiently sized health workforces in mitigating RI disruption during global health crises once above minimum thresholds. Reassuringly, we do not find evidence that COVID-19 vaccination campaigns nor pandemic containment policies impacted RI performance – counter to qualitative survey indications. We encourage continued efforts to identify RI disruption determinants to inform the evidence base for public health practitioners globally.