bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative plasma proteomics identifies metallothioneins as a marker of acute-on-chronic liver failure associated acute kidney injury
Authors: Acharya Pragyan , Saha Rohini , Quadri Javed Ahsan , Sarwar Saba , Khan Maroof Ahmad , Sati Hem Chandra , Gauniyal Nidhi , Shariff Ahmadullah , Swaroop Shekhar , Pathak Piyush , Shalimar  
Published: January 2023

BackgroundAcute kidney injury (AKI) considerably increases the risk of short-term mortality in acute-on-chronic liver failure (ACLF) but predicting AKI is not possible with existing tools. Our study aimed at de novo discovery of AKI biomarkers in ACLF.MethodsThis observational study had two phases- (A) Discovery phase in which quantitative proteomics was carried-out with day-of-admission plasma from ACLF patients who initially had no-AKI but either progressed to AKI (n=10) or did not (n=9) within 7 days of admission and, (B) Validation phase in which selected biomarkers from the discovery phase were validated by ELISA in a larger set of ACLF plasma samples (n=93) followed by sub-group analyses.ResultsPlasma proteomics revealed 56 differentially expressed proteins in ACLF patients who progressed to AKI vs those who did not. The metallothionein protein-family was upregulated in patients who progressed to AKI and was validated by ELISA as significantly elevated in both- (i) ACLF-AKI vs no-AKI (p-value ≤ 0.0001) and (ii) progression to AKI vs no-progression to AKI (p-value ≤ 0.001). AUROC for AKI vs no-AKI was 0.786 (p-value ≤0.001) and for progression to AKI vs no-progression to AKI was 0.7888 (p-value ≤0.001). Kaplan-Meier analysis revealed that ACLF patients with plasma MT concentration &gt;5.83 ng/mL had a high probability of developing AKI by day 7 (p-value ≤0.0001). High expression of metallothionein genes was found in post-mortem liver biopsies of ACLF patients.ConclusionDay-of-admission measurements of plasma metallothionein can act as predictive biomarkers of AKI in ACLF.
Mathematical modelling of the waning of anti-RBD IgG SARS-CoV-2 antibody titers after a two-dose BNT162b2 mRNA vaccination
Authors: Cimas Francisco J. , Torres Javier , Ontañón Jesús , de Cabo Carlos , Lozano Julia , Requena María Ángeles , Blas Joaquín , Rodríguez-García José Luis , Mas Antonio , Solera Javier 
Published: January 2023

BackgroundAfter exposure to SARS-CoV-2 and/or vaccination there is an increase in serum antibody titers followed by a non-linear waning. Our aim was to find out if this waning of antibody titers would fit to a mathematical model.MethodsWe analyzed anti-RBD (receptor binding domain) IgG antibody titers and the breakthrough infections over a ten-month period following the second dose of the mRNA BNT162b2 (Pfizer-BioNtech.) vaccine, in a cohort of 54 health-care workers (HCWs) who were either never infected with SARS-CoV-2 (naïve, nHCW group, n=27) or previously infected with the virus (experienced, eHCW group, n=27). Two mathematical models, exponential and power law, were used to quantify antibody waning kinetics, and we compared the relative quality of the goodness of fit to the data between both models was compared using the Akaik Information Criterion.ResultsWe found that the waning slopes were significantly more pronounced for the naïve when compared to the experienced HCWs in exponential (p-value: 1.801E-9) and power law (p-value: 9.399E-13) models. The waning of anti-RBD IgG antibody levels fitted significantly to both exponential (average-R2: 0.957 for nHCW and 0.954 for eHCW) and power law (average-R2: 0.991 for nHCW and 0.988 for eHCW) models, with a better fit to the power law model. In the nHCW group, titers would descend below an arbitrary 1000-units threshold at a median of 210.6 days (IQ range: 74.2). For the eHCW group, the same risk threshold would be reached at 440.0 days (IQ range: 135.2) post-vaccination.ConclusionTwo parsimonious models can explain the anti-RBD IgG antibody titer waning after vaccination. Regardless of the model used, eHCWs have lower waning slopes and longer persistence of antibody titers than nHCWs. Consequently, personalized vaccination booster schedules should be implemented according to the individual persistence of antibody levels.
Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages
Authors: Drummer Charles , Saaoud Fatma , Jhala Nirag C. , Cueto Ramon , Sun Yu , Xu Keman , Shao Ying , Lu Yifan , Shen Huimin , Yang Ling , Zhou Yan , Yu Jun , Wu Sheng , Snyder Nathaniel W. , Hu Wenhui , Zhuo Jia ‘Joe’ , Zhong Yinghui , Jiang Xiaohua , Wang Hong , Yang Xiaofeng 
Published: January 2023

IntroductionNon-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it’s still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD.MethodsTo examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11–/– mice.Results and DiscussionOur results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics—glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.
Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19
Authors: Borrmann Melanie , Brandes Florian , Kirchner Benedikt , Klein Matthias , Billaud Jean-Noël , Reithmair Marlene , Rehm Markus , Schelling Gustav , Pfaffl Michael W. , Meidert Agnes S. 
Published: January 2023

BackgroundDegradation of the endothelial protective glycocalyx layer during COVID-19 infection leads to shedding of major glycocalyx components. These circulating proteins and their degradation products may feedback on immune and endothelial cells and activate molecular signaling cascades in COVID-19 associated microvascular injury. To test this hypothesis, we measured plasma glycocalyx components in patients with SARS-CoV-2 infection of variable disease severity and identified molecular signaling networks activated by glycocalyx components in immune and endothelial cells.MethodsWe studied patients with RT-PCR confirmed COVID-19 pneumonia, patients with COVID-19 Acute Respiratory Distress Syndrome (ARDS) and healthy controls (wildtype, n=20 in each group) and measured syndecan-1, heparan sulfate and hyaluronic acid. The in-silico construction of signaling networks was based on RNA sequencing (RNAseq) of mRNA transcripts derived from blood cells and of miRNAs isolated from extracellular vesicles from the identical cohort. Differentially regulated RNAs between groups were identified by gene expression analysis. Both RNAseq data sets were used for network construction of circulating glycosaminoglycans focusing on immune and endothelial cells.ResultsPlasma concentrations of glycocalyx components were highest in COVID-19 ARDS. Hyaluronic acid plasma levels in patients admitted with COVID-19 pneumonia who later developed ARDS during hospital treatment (n=8) were significantly higher at hospital admission than in patients with an early recovery. RNAseq identified hyaluronic acid as an upregulator of TLR4 in pneumonia and ARDS. In COVID-19 ARDS, syndecan-1 increased IL-6, which was significantly higher than in pneumonia. In ARDS, hyaluronic acid activated NRP1, a co-receptor of activated VEGFA, which is associated with pulmonary vascular hyperpermeability and interacted with VCAN (upregulated), a proteoglycan important for chemokine communication.ConclusionsCirculating glycocalyx components in COVID-19 have distinct biologic feedback effects on immune and endothelial cells and result in upregulation of key regulatory transcripts leading to further immune activation and more severe systemic inflammation. These consequences are most pronounced during the early hospital phase of COVID-19 before pulmonary failure develops. Elevated levels of circulating glycocalyx components may early identify patients at risk for microvascular injury and ARDS. The timely inhibition of glycocalyx degradation could provide a novel therapeutic approach to prevent the development of ARDS in COVID-19.
New insight into Salpa thompsoni distribution via glider-borne acoustics
Authors: Hann Ashley M. , Bernard Kim S. , Kohut Josh , Oliver Matthew J. , Statscewich Hank 
Published: January 2023

Salpa thompsoniis an ephemerally abundant pelagic tunicate in the waters of the Southern Ocean that makes significant contributions to carbon flux and nutrient recycling in the region. WhileS. thompsoni, hereafter referred to as “salps”, was historically described as a polar-temperate species with a latitudinal range of 40 – 60°S, observations of salps in coastal waters of the Western Antarctic Peninsula have become more common in the last 50 years. There is a need to better understand the variability in salp densities and vertical distribution patterns in Antarctic waters to improve predictions of their contribution to the global carbon cycle. We used acoustic data obtained from an echosounder mounted to an autonomous underwater Slocum glider to investigate the anomalously high densities of salps observed in Palmer Deep Canyon, at the Western Antarctic Peninsula, in the austral summer of 2020. Acoustic measurements of salps were made synchronously with temperature and salinity recordings (all made on the glider downcasts), and asynchronously with chlorophyll-ameasurements (made on the glider upcasts and matched to salp measurements by profile) across the depth of the water column near Palmer Deep Canyon for 60 days. Using this approach, we collected high-resolution data on the vertical and temporal distributions of salps, their association with key water masses, their diel vertical migration patterns, and their correlation with chlorophyll-a. While salps were recorded throughout the water column, they were most prevalent in Antarctic Surface Water. A peak in vertical distribution was detected from 0 – 50 m regardless of time of day or point in the summer season. We found salps did not undergo diel vertical migration in the early season, but following the breakdown of the remnant Winter Water layer in late January, marginal diel vertical migration was initiated and sustained through to the end of our study. There was a significant, positive correlation between salp densities and chlorophyll-a. To our knowledge, this is the first high resolution assessment of salp spatial (on the vertical) and temporal distributions in the Southern Ocean as well as the first to use glider-borne acoustics to assess salpsin situ.
The occurrence of humpback whales across the Hawaiian archipelago revealed by fixed and mobile acoustic monitoring
Authors: Lammers Marc O. , Goodwin Beth , Kügler Anke , Zang Eden J. , Harvey Matt , Margolina Tetyana , Martinez Jonathan A. , Merkens Karlina , Hatch Leila T. 
Published: January 2023

The occurrence of humpback whales (Megaptera novaeangliae) across the 2600 km of Hawaiian archipelago, which include the remote atolls, banks, and seamounts of Papahānaumokuākea Marine National Monument (PMNM), remains poorly understood. Previous surveys for humpback whales beyond the main Hawaiian Islands have been scarce due to limited access and the challenging winter conditions typically found in PMNM when whales are present. To overcome these limitations, a combination of moored acoustic recorders and a Wave Glider autonomous surface vehicle were used to acoustically monitor eight locations and survey approximately 1500 km of the Hawaiian archipelago for the occurrence of humpback whale song during the 2019-2020 breeding season. Relative song prevalence was established using a machine learning tool and by quantifying the level of song chorusing. A generalized additive model framework was applied to understand the associations between habitat variables and humpback whale song occurrence, and sound propagation modeling was performed to examine whether acoustic propagation influenced observed patterns. Whale song was recorded at all monitored and surveyed locations across the archipelago, albeit in varying amounts. Among the locations monitored with moored recorders, the highest and most sustained seasonal chorusing levels were measured off Maui followed by French Frigate Shoals (Kānemilohai), Hawaii Island, Middle Bank, Oahu, Kauai, Gardner Pinnacles (Pūhāhonu) and Pearl and Hermes Reef (Holoikauaua), respectively. The Wave Glider mission to PMNM revealed that song prevalence was highest at Middle Bank and gradually decreased further to the northwest, reaching a minimum at Gardner Pinnacles (Pūhāhonu). However, song occurrence increased again at Raita Bank, remaining high between Raita Bank and the Northampton Seamounts. The results reveal that nearly the entire Hawaiian archipelago is exploited by humpback whales during the winter and early spring months. Moreover, song occurrence patterns suggest that there may be more structure in the distribution of whales in PMNM than previously known and raises questions about whether multiple subpopulations occur across the archipelago.
EphH, a unique epoxide hydrolase encoded by Rv3338 is involved in the survival of Mycobacterium tuberculosis under in vitro stress and vacuolar pH-induced changes
Authors: Garg Tanu , Das Swetarka , Singh Shriya , Imran Mohmmad , Mukhopadhyay Atri , Gupta Umesh D. , Chopra Sidharth , Dasgupta Arunava 
Published: January 2023

IntroductionMycobacterium tuberculosis (Mtb), one of the deadliest human pathogen, has evolved with different strategies of survival inside the host, leading to a chronic state of infection. Phagosomally residing Mtb encounters a variety of stresses, including increasing acidic pH. To better understand the host-pathogen interaction, it is imperative to identify the role of various genes involved in the survivability of Mtb during acidic pH environment.MethodsBio-informatic and enzymatic analysis were used to identify Mtb gene, Rv3338, as epoxide hydrolase. Subsequently, CRISPRi knockdown strategy was used to decipher its role for Mtb survival during acidic stress, nutrient starvation and inside macrophages. Confocal microscopy was used to analyse its role in subverting phagosomal acidification within macrophage.ResultsThe present work describes the characterization of Rv3338 which was previously known to be associated with the aprABC locus induced while encountering acidic stress within the macrophage. Bio-informatic analysis demonstrated its similarity to epoxide hydrolase, which was confirmed by enzymatic assays, thus, renamed EphH. Subsequently, we have deciphered its indispensable role for Mtb in protection from acidic stress by using the CRISPRi knockdown strategy. Our data demonstrated the pH dependent role of EphH for the survival of Mtb during nutrient starvation and in conferring resistance against elevated endogenous ROS levels during stress environment.ConclusionTo the best of our knowledge, this is the first report of an EH of Mtb as a crucial protein for bacterial fitness inside the host, a phenomenon central to its pathogenesis.
In silico analyses of diversity and dissemination of antimicrobial resistance genes and mobile genetics elements, for plasmids of enteric pathogens
Authors: Algarni Suad , Han Jing , Gudeta Dereje D. , Khajanchi Bijay K. , Ricke Steven C. , Kwon Young Min , Rhoads Douglas D. , Foley Steven L. 
Published: January 2023

IntroductionThe antimicrobial resistance (AMR) mobilome plays a key role in the dissemination of resistance genes encoded by mobile genetics elements (MGEs) including plasmids, transposons (Tns), and insertion sequences (ISs). These MGEs contribute to the dissemination of multidrug resistance (MDR) in enteric bacterial pathogens which have been considered as a global public health risk.MethodsTo further understand the diversity and distribution of AMR genes and MGEs across different plasmid types, we utilized multiple sequence-based computational approaches to evaluate AMR-associated plasmid genetics. A collection of 1,309 complete plasmid sequences from Gammaproteobacterial species, including 100 plasmids from each of the following 14 incompatibility (Inc) types: A/C, BO, FIA, FIB, FIC, FIIA, HI1, HI2, I1, K, M, N, P except W, where only 9 sequences were available, was extracted from the National Center for Biotechnology Information (NCBI) GenBank database using BLAST tools. The extracted FASTA files were analyzed using the AMRFinderPlus web-based tools to detect antimicrobial, disinfectant, biocide, and heavy metal resistance genes and ISFinder to identify IS/Tn MGEs within the plasmid sequences.Results and DiscussionIn silico prediction based on plasmid replicon types showed that the resistance genes were diverse among plasmids, yet multiple genes were widely distributed across the plasmids from enteric bacterial species. These findings provide insights into the diversity of resistance genes and that MGEs mediate potential transmission of these genes across multiple plasmid replicon types. This notion was supported by the observation that many IS/Tn MGEs and resistance genes known to be associated with them were common across multiple different plasmid types. Our results provide critical insights about how the diverse population of resistance genes that are carried by the different plasmid types can allow for the dissemination of AMR across enteric bacteria. The results also highlight the value of computational-based approaches and in silico analyses for the assessment of AMR and MGEs, which are important elements of molecular epidemiology and public health outcomes.
Evaluation of anakinra in the management of patients with COVID-19 infection: A randomized clinical trial
Authors: Elmekaty Eman Zeyad I. , Maklad Aya , Abouelhassan Rawan , Munir Waqar , Ibrahim Mohamed Izham Mohamed , Nair Arun , Alibrahim Rim , Iqbal Fatima , Al Bishawi Ahmad , Abdelmajid Alaaeldin , Aboukamar Mohamed , Hadi Hamad Abdel , Khattab Mohammed Abu , Al Soub Hussam , Al Maslamani Muna 
Published: January 2023

BackgroundThe global COVID-19 pandemic led to substantial clinical and economic outcomes with catastrophic consequences. While the majority of cases has mild to moderate disease, minority of patients progress into severe disease secondary to the stimulation of the immune response. The hyperinflammatory state contributes towards progression into multi-organ failure which necessitates suppressive therapy with variable outcomes. This study aims to explore the safety and efficacy of anakinra in COVID-19 patients with severe disease leading to cytokine release syndromes.MethodsIn this open-label, multi-center, randomized clinical trial, patients with confirmed COVID-19 infection with evidence of respiratory distress and signs of cytokine release syndrome were randomized in 1:1 ratio to receive either standard of care (SOC) or anakinra (100 mg subcutaneously every 12 h for 3 days then 100 mg subcutaneously once daily for 4 days) in addition to SOC. The primary outcome was treatment success at day 14 as defined by the WHO clinical progression score of ≤3. Primary analysis was based upon intention-to-treat population, with value of p of &lt;0.05.ResultsOut 327 patients screened for eligibility, 80 patients were recruited for the study. The mean age was 49.9 years (SD = 11.7), with male predominance at 82.5% (n = 66). The primary outcome was not statistically different (87.5% (n = 35) in anakinra group vs. 92.5% (n = 37) in SOC group, p = 0.712; OR = 1.762 (95%CI: 0.39–7.93). The majority of reported adverse events were mild in severity and not related to the study treatment. Elevated aspartate aminotransferase was the only significant adverse event which was not associated with discontinuation of therapy.ConclusionIn patients with severe COVID-19 infection, the addition of anakinra to SOC treatment was safe but was not associated with significant improvement according to the WHO clinical progression scale. Further studies are warranted to explore patients’ subgroups characteristics that might benefit from administered therapy.Clinical Trial RegistrationTrial registration at ClinicalTrials.gov, identifier: NCT04643678.
Parameterization of a single H-bond in Orange Carotenoid Protein by atomic mutation reveals principles of evolutionary design of complex chemical photosystems
Authors: Moldenhauer Marcus , Tseng Hsueh-Wei , Kraskov Anastasia , Tavraz Neslihan N. , Yaroshevich Igor A. , Hildebrandt Peter , Sluchanko Nikolai N. , Hochberg Georg A. , Essen Lars-Oliver , Budisa Nediljko , Korf Lukas , Maksimov Eugene G. , Friedrich Thomas 
Published: January 2023

Introduction: Dissecting the intricate networks of covalent and non-covalent interactions that stabilize complex protein structures is notoriously difficult and requires subtle atomic-level exchanges to precisely affect local chemical functionality. The function of the Orange Carotenoid Protein (OCP), a light-driven photoswitch involved in cyanobacterial photoprotection, depends strongly on two H-bonds between the 4-ketolated xanthophyll cofactor and two highly conserved residues in the C-terminal domain (Trp288 and Tyr201).Method: By orthogonal translation, we replaced Trp288 in Synechocystis OCP with 3-benzothienyl-L-alanine (BTA), thereby exchanging the imino nitrogen for a sulphur atom.Results: Although the high-resolution (1.8 Å) crystal structure of the fully photoactive OCP-W288_BTA protein showed perfect isomorphism to the native structure, the spectroscopic and kinetic properties changed distinctly. We accurately parameterized the effects of the absence of a single H-bond on the spectroscopic and thermodynamic properties of OCP photoconversion and reveal general principles underlying the design of photoreceptors by natural evolution.Discussion: Such “molecular surgery” is superior over trial-and-error methods in hypothesis-driven research of complex chemical systems.