bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Study to Evaluate the Possible Efficacy and Safety of Antibodies Combination (casirivimab and imdevimab) versus standard antiviral therapy as antiviral agent against Corona virus 2 infection in hospitalized COVID-19 patients
Authors: Hassan Ahmed H. , Hegazy Sahar K. , Radwan Samar T. 
Published: August 2022

AbstractIntroductionCorona Virus-induced disease – 2019 (COVID-19) pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now. With ending of the 2021 year, various advances in pharmacotherapy against COVID-19 have emerged.Regarding antiviral therapy, Casirivimab and imdevimab antibody combination is a type of new immunotherapy against COVID-19. Standard antiviral therapy against COVID-19 includes Remdesivir and Favipravir.Aim of StudyTo compare the efficacy and safety of antibodies cocktail (casirivimab and imdevimab), Remdesivir, and Favipravir in the COVID-19 patientsPatients and Population265 hospitalized COVID-19 patients were used to represent the COVID-19 population and were assigned into three groups in a ratio of (1:2:2) respectively, Group (A) received REGN3048-3051(Antibodies cocktail (casirivimab and imdevimab), group (B) received remdesivir, and group (C) received favipravir.MethodsThe study design is a single-blind non-Randomized Controlled Trial (non-RCT). The drugs of the study are owned by Mansoura University Hospital (MUH) and prescribed by chest diseases lectures of the faculty of medicine-Mansoura University. The duration of the study is about 6 months after ethical approval.Results and discussionCasirivimab and imdevimab achieve less 28-day mortality rate, less mortality at hospital discharge, more negative swab cases, less need for O2 therapy and IMV, less duration of this need, less hospital and ICU stay, less case progression as presented by lower World Health Organization (WHO) scale and better multi-organ functions as presented by lower Sequential Organ Function Assessment (SOFA) score than Remdesivir and Favipravir.ConclusionFrom all of these results, it is concluded that Group A (Casirivimab & imdevimab) has more favorable clinical outcomes than B (remdesivir) & C (favipravir) intervention groups.Clinical Trial Registration:NCT05502081, 16/08/2022,Clinicaltrials.gov, retrospectively registered
#ChronicPain: Automatic establishment of a chronic pain cohort from social media using machine learning for studying opioid-alternative therapies
Authors: Lakamana Sahithi , Guo Yuting , Ge Yao , Leslie Abimbola , Okunromade Omolola , Yang Yuan-Chi , Gonzalez-Polledo Elena , Perrone Jeanmarie , McKenzie-Brown Anne , Sarker Abeed 
Published: August 2022

AbstractDue to the high economic and public health burden of chronic pain, and the risk of public health consequences of opioid-based treatments, there is a need to identify effective alternative therapies. The evidence basis for many alternative therapies is weak or nonexistent. Social media presents a unique opportunity to gather large-scale knowledge about such therapies self-reported by sufferers themselves. We attempted to (i) verify the presence of largescale chronic pain-related chatter on Twitter, (ii) develop natural language processing (NLP) and machine learning for automatically detecting chronic pain sufferers, and (iii) identify the types of chronic pain-related information reported by them. We collected data from Twitter using chronic pain-related hashtags and keywords. We manually performed binary annotation of a sample of 4998 posts to indicate if they were self-reports of chronic pain experiences or not, and obtained inter-annotator agreement of 0.82 (Cohen’s kappa). We trained and evaluated several state-of-the-art transformer-based text classification models using the annotated data. The RoBERTa model outperformed all others (F1 score = 0.84; 95% CI: 0.80-0.89), and we used this model to classify a large number of unlabeled posts. We identified 22,795 self-reported chronic pain sufferers and collected their past posted data. Via manual and NLP-driven analyses, we found information about but not limited to alternative treatments, sufferers’ sentiments about treatments, side effects, and self-management strategies. Our social media-based approach will result in an automatically growing massive cohort over time, and the data can be leveraged to identify self-reported effective alternative therapies for diverse chronic pain types.
Model for FRET sensors of allosteric switchable modulator proteins for the determination of allosteric parameters
Authors: Babel Heiko 
Published: August 2022

AbstractFRET-sensors are a well-established method to investigate protein-protein interactions. To determine how FRET-sensor can be employed for the study of switchable allosteric modulator proteins (SAMPs) I extend a previously established model for enzymatic SAMPs to include a FRET-sensor system. Using this model, I determine the prerequisites for using FRET to investigate modulator-regulator interaction. The model shows, that under saturating stimulus conditions only a trimolecular complex contributes to the measured FRET value. How the signal is relayed by the modulator can be investigated by comparing FRET values of unstimulated and signal-saturated sensor systems. Finally, to determine the allosteric mode of signal transduction the natural logarithm of the ratio of stimulated and unstimulated FRET efficiencies is a useful metric.
Dynamic Disulfide Bond Topologies in von-Willebrand-Factor’s C4-Domain Undermine Platelet Binding
Authors: Kutzki Fabian , Butera Diego , Lay Angelina J. , Maag Denis , Chiu Joyce , Woon Heng-Giap , Kubař Tomáš , Elstner Marcus , Aponte-Santamaría Camilo , Hogg Philip J. , Gräter Frauke 
Published: August 2022

SummaryBackgroundThe von Willebrand Factor (vWF) is a key player in regulating hemostasis through adhesion of platelets to sites of vascular injury. It is a large multi-domain mechano-sensitive protein stabilized by a net of disulfide bridges. Binding to platelet integrin is achieved by the vWF-C4 domain which exhibits a fixed fold, even under conditions of severe mechanical stress, but only if critical internal disulfide bonds are closed.ObjectiveTo quantitatively determine C4’s disulfide topologies and their implication in vWF’s platelet-binding function via integrin.MethodsWe employed a combination of classical Molecular Dynamics and quantum mechanical simulations, mass spectrometry, site-directed mutagenesis, and platelet binding assays.ResultsWe quantitatively show that two disulfide bonds in the vWF-C4 domain, namely the two major force-bearing ones, are partially reduced in human blood. Reduction leads to pronounced conformational changes within C4 that considerably affect the accessibility of the RGD-integrin binding motif, and thereby impair integrin-mediated platelet binding. Our combined approach also reveals that reduced species in the C4 domain undergo specific thiol/disulfide exchanges with the remaining disulfide bridges, in a process in which mechanical force may increase the proximity of specific reactant cysteines, further trapping C4 in a state of low integrin-binding propensity. We identify a multitude of redox states in all six vWF-C domains, suggesting disulfide bond reduction and swapping to be a general theme.ConclusionOverall, our data put forward a mechanism in which disulfide bonds dynamically swap cysteine partners and control the interaction of vWF with integrin and potentially other partners, thereby critically influencing its hemostatic function.EssentialsPlatelet integrins interact with the disulfide-bonded C4 domain of von Willebrand FactorThe redox state of vWF-C4’s disulfide bonds is studied by molecular simulations and experimentsTwo bonds are reduced causing C4 unfolding and disulfide swappingOpening of disulfide bonds impairs integrin-mediated platelet binding
An automation workflow for high-throughput manufacturing and analysis of scaffold-supported 3D tissue arrays
Authors: Cao Ruonan , Li Nancy T , Cadavid Jose L , Latour Simon , Tan Cassidy M , McGuigan Alison P 
Published: August 2022

AbstractThe success rate of bringing novel cancer therapies to the clinic remains extremely low due to the lack of relevant pre-clinical culture models that capture the complexity of human tumours. Patient-derived organoids have emerged as a useful tool to model patient and tumour heterogeneity to begin addressing this need. Scaling these complex culture models while enabling stratified analysis of different cellular sub-populations remains a challenge, however. One strategy to enable higher throughput organoid cultures that also enables easy image-based analysis is the Scaffold-supported Platform for Organoid-based Tissues (SPOT) platform. SPOT allows the generation of flat, thin and dimensionally-defined microtissues in both 96- and 384-well plate footprints and is compatible with tumour organoid culture and downstream image-based readouts. SPOT manufacturing is currently a manual process however, limiting the use of SPOT to perform larger-scale screening. In this study, we integrate and optimize an automation approach to generate tumour-mimetic 3D engineered microtissues in SPOT using a liquid handler, and show comparable within-sample and between-sample variation as the standard manual manufacturing process. Furthermore, we develop a liquid handler-supported whole-cell extraction protocol and as a proof-of-value demonstration, we generate 3D complex tissues containing different proportions of tumour and stromal cells and perform single-cell-based end-point analysis to demonstrate the impact of co-culture on the tumour cell population specifically. We also demonstrate we can incorporate primary patient-derived organoids into the pipeline to capture patient-level tumour heterogeneity. We envision that this automated workflow integrated with 96/384-SPOT and multiple cell types and patient-derived organoid models will provide opportunities for future applications in high-throughput screening for novel personalized therapeutic targets. This pipeline also allows the user to assess dynamic cell responses using high-content longitudinal imaging or downstream single-cell-based analyses.
Intestinal permeability and peripheral immune cell composition are altered by pregnancy and adiposity at mid- and late-gestation in the mouse
Authors: Ribeiro Tatiane A. , Breznik Jessica A. , Kennedy Katherine M. , Yeo Erica , Kennelly Brianna K. E. , Jazwiec Patrycja A. , Patterson Violet S. , Bellissimo Christian J. , Anhê Fernando F. , Schertzer Jonathan D. , Bowdish Dawn M. E. , Sloboda Deborah M. 
Published: August 2022

AbstractIt is clear that the gastrointestinal tract influences metabolism and immune function. Most studies to date have used male test subjects, with a focus on effects of obesity and dietary challenges. Despite significant physiological adaptations that occur across gestation, relatively few studies have examined pregnancy-related gut function. In this study, we investigated the impacts of pregnancy and adiposity on maternal intestinal epithelium morphology, in vivo intestinal permeability, and peripheral blood immunophenotype, using control (CTL) and high-fat (HF) fed non-pregnant female mice and pregnant mice at mid-(embryonic day (E)14.5) and late (E18.5) gestation. We found that small intestine length increased between non-pregnant mice and dams at late-gestation, but ileum villus length, and ileum and colon crypt depths and goblet cell numbers remained similar. Compared to CTL-fed mice, HF-fed mice had reduced small intestine length, ileum crypt depth and villus length. Goblet cell numbers were only consistently reduced in HF-fed non-pregnant mice. Pregnancy increased in vivo gut permeability, with a greater effect at mid-versus late-gestation. Non-pregnant HF-fed mice had greater gut permeability, and permeability was also increased in HF-fed pregnant dams at mid but not late-gestation. The impaired maternal gut barrier in HF-fed dams at mid-gestation coincided with changes in maternal blood and bone marrow immune cell composition, including an expansion of circulating inflammatory Ly6Chigh monocytes. In summary, pregnancy has temporal effects on maternal intestinal structure and barrier function, and on peripheral immunophenotype, which are further modified by HF diet-induced maternal adiposity.
Spatial compartmentalization of signalling imparts source-specific functions on secreted factors
Authors: Groppa E , Martini P , Derakhshan N , Theret M , Ritso M , Tung LW , Wang YX , Soliman H , Hamer M , Stankiewicz L , Eisner C , Le Nevé E , Chang C , Yi L , Yuan JH , Kong S , Weng C , Adams J , Chang L , Peng A , Blau HM , Romualdi C , Rossi FMV 
Published: August 2022

SummaryEfficient regeneration requires multiple cell types acting in a coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profiled the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. A time-resolved computational model of interactions was generated, and VEGFA-driven endothelial engagement was identified as a key differentiating feature in models of successful and failed regeneration. In addition, it revealed that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we deleted VEGFA from two cell types residing in close proximity, stromal and myogenic progenitors. By comparing responses to different types of damage, we found that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks.HighlightsLigand-receptor signaling redundancy during skeletal muscle regenerationInflammatory cells, and muscle and fibro/adipogenic progenitors produce VEGFAVEGFA from muscle progenitors control their proliferation after muscle damageVEGFA from FAP controls angiogenesis only after ischemic damageeTOC blurbGroppa et al. performed a novel time-resolved bioinformatics analysis that revealed extensive ligand-receptor redundancy among the cell types contributing to skeletal muscle regeneration. They focused on one of these pathways, and showed that VEGFA from different cell types has distinct roles in regeneration.
Axon arrival times and physical occupancy establish visual projection neuron integration on developing dendrites in theDrosophilaoptic glomeruli
Authors: McFarland Brennan W. , Jang HyoJong , Smolin Natalie , Hina Bryce W. , Parisi Michael J. , Davis Kristen C. , Mosca Timothy J. , Godenschwege Tanja A. , Nern Aljoscha , Kurmangaliyev Yerbol Z. , von Reyn Catherine R. 
Published: August 2022

SUMMARYBehaviorally relevant, higher order representations of an animal’s environment are built from the convergence of visual features encoded in the early stages of visual processing. Although developmental mechanisms that generate feature encoding channels in early visual circuits have been uncovered, relatively little is known about the mechanisms that direct feature convergence to enable appropriate integration into downstream circuits. Here we explore the development of a collision detection sensorimotor circuit inDrosophila melanogaster, the convergence of visual projection neurons (VPNs) onto the dendrites of a large descending neuron, the giant fiber (GF). We find VPNs encoding different visual features establish their respective territories on GF dendrites through sequential axon arrival during development. Physical occupancy, but not developmental activity, is important to maintain territories. Ablation of one VPN results in the expansion of remaining VPN territories and functional compensation that enables the GF to retain responses to ethologically relevant visual stimuli. GF developmental activity, observed using a pupal electrophysiology preparation, appears after VPN territories are established, and likely contributes to later stages of synapse assembly and refinement. Our data highlight temporal mechanisms for visual feature convergence and promote the GF circuit and theDrosophilaoptic glomeruli, where VPN to GF connectivity resides, as a powerful developmental model for investigating complex wiring programs and developmental plasticity.
Neutralizing Antibody to Omicron BA.1, BA.2 and BA.5 in COVID-19 Patients
Authors: Linderman Susanne L. , Lai Lilin , Bocangel Gamarra Estefany L. , Mohr Nicholas M. , Gibbs Kevin W. , Steingrub Jay S. , Exline Matthew C. , Shapiro Nathan I. , Frosch Anne E. , Qadir Nida , Edupuganti Srilatha , Surie Diya , Tenforde Mark W. , Davis-Gardner Meredith E. , Chappell James D. , Lau Max S Y , McElrath M. Juliana , Lauring Adam S. , Suthar Mehul S. , Patel Manish M. , Self Wesley H. , Ahmed Rafi 
Published: August 2022

AbstractNeutralizing antibody plays a key role in protective immunity against COVID-19. As increasingly distinct variants circulate, debate continues regarding the value of adding novel variants to SARS-CoV-2 vaccines. In this study, we have analyzed live virus neutralization titers against WA1, Delta, BA.1, BA.2, and BA.5 in 187 hospitalized patients infected with Delta or Omicron strains. This information will be useful in selection of the SARS-CoV-2 strains to include in an updated vaccine. Our results show that unvaccinated Delta infected patients made a highly biased neutralizing antibody response towards the infecting Delta strain with slightly lower responses against the WA1 strain, but with strikingly lower titers against BA.1, BA.2, and BA.5. Delta infected patients that had been previously vaccinated with the WA1 containing COVID vaccine made equivalent responses to WA1 and Delta strains, but still had very low neutralizing antibody responses to Omicron strains. In striking contrast, both unvaccinated and vaccinated Omicron patients exhibited a more balanced ratio of Omicron virus neutralization compared to neutralization of ancestral strains. Interestingly, Omicron patients infected with BA.1 or BA.2 had detectable neutralizing antibody titers to BA.5, but these titers were lower than neutralization titers to BA.1 and BA.2. Taken together, these results suggest that inclusion of the Omicron BA.5 strain in a SARS-CoV-2 vaccine would be beneficial in protection against the widely circulating BA.5 variant.DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Automated large-scale AMD progression prediction using machine-read OCT biomarkers
Authors: Rudas Akos , Chiang Jeffrey N. , Corradetti Giulia , Rakocz Nadav , Halperin Eran , Sadda Srinivas R. 
Published: August 2022

AbstractAge-related Macular Degeneration (AMD) is a major cause of irreversible vision loss in individuals over 55 years old in the United States. While anti-vascular growth factor injections can be used to treat macular neovascularization (MNV), there are currently no treatments available to halt or reverse geographic atrophy, which is the late-stage of nonneovascular AMD. There is a great interest in detecting early biomarkers associated with a higher risk for AMD progression in order to design early intervention clinical trials. The annotation of structural biomarkers on optical coherence tomography (OCT) B-scans is a laborious, complex and time-consuming process, and discrepancies between human graders can introduce variability into this assessment.To address this issue, a deep-learning model (SLIVER-net) was proposed, which could identify AMD biomarkers on structural OCT volumes with high precision and without human supervision. However, the validation was performed on a small dataset, and the true predictive power of these detected biomarkers in the context of a large cohort has not been evaluated. In this retrospective cohort study, we perform the largest-scale validation of these biomarkers to date. We also assess how these features combined with other EHR data (demographics, comorbidities, etc) affect and/or improve the prediction performance relative to known factors. Our hypothesis is that these biomarkers can be identified by a machine learning algorithm without human supervision, in a way that they preserve their predictive nature.The way we test this hypothesis is by building several machine learning models utilizing these machine-read biomarkers, and assessing their added predictive power. We found that not only can we show that the machine-read OCT B-scan biomarkers are predictive of AMD progression, we also observe that our proposed combined OCT and EHR data-based algorithm significantly outperforms the state-of-the-art solution in clinically relevant metrics and provides actionable information which has the potential to improve patient care. In addition, it provides a framework for automated large-scale processing of OCT volumes, making it possible to analyze vast archives without human supervision.
Proteomics Investigation of Diverse Serological Patterns in COVID-19
Authors: Liang Xiao , Sun Rui , Wang Jing , Zhou Kai , Li Jun , Chen Shiyong , Lyu Mengge , Li Sainan , Xue Zhangzhi , Shi Yingqiu , Xie Yuting , Zhang Qiushi , Yi Xiao , Pan Juan , Wang Donglian , Xu Jiaqin , Zhu Hongguo , Zhu Guangjun , Zhu Jiansheng , Zhu Yi , Zheng Yufen , Shen Bo , Guo Tiannan 
Published: August 2022

AbstractSerum antibodies IgM and IgG are elevated during COVID-19 to defend against viral attack. Atypical results such as negative and abnormally high antibody expression were frequently observed whereas the underlying molecular mechanisms are elusive. In our cohort of 144 COVID-19 patients, 3.5% were both IgM and IgG negative whereas 29.2% remained only IgM negative. The remaining patients exhibited positive IgM and IgG expression, with 9.3% of them exhibiting over 20-fold higher titers of IgM than the others at their plateau. IgG titers in all of them were significantly boosted after vaccination in the second year. To investigate the underlying molecular mechanisms, we classed the patients into four groups with diverse serological patterns and analyzed their two-year clinical indicators. Additionally, we collected 111 serum samples for TMTpro-based longitudinal proteomic profiling and characterized 1494 proteins in total. We found that the continuously negative IgM and IgG expression during COVID-19 were associated with mild inflammatory reactions and high T cell responses. Low levels of serum IgD, inferior complement 1 activation of complement cascades, and insufficient cellular immune responses might collectively lead to compensatory serological responses, causing overexpression of IgM. Serum CD163 was positively correlated with antibody titers during seroconversion. This study suggests that patients with negative serology still developed cellular immunity for viral defense, and that high titers of IgM might not be favorable to COVID-19 recovery.