bluuebunny/crossref_metadata_2025_split huggingface dataset:
HLA Mismatches Identified by a Novel Algorithm Predict Risk of Antibody-mediated Rejection From De Novo Donor-specific Antibodies
Authors: Zhang Xiaohai , Reinsmoen Nancy L. , Kobashigawa Jon A. 
Published: July 2024

Background.
The development of de novo donor-specific antibodies (dnDSA) and antibody-mediated rejection (AMR) remains a barrier to long-term graft and patient survival. Most dnDSA are directed against mismatched donor HLA-DQ antigens. Here, we describe a novel algorithm, which we have termed categorical amino acid mismatched epitope, to evaluate HLA-DQ mismatches.

Methods.
In this algorithm, amino acid residues of HLA-DQ protein were categorized into 4 groups based on their chemical characteristics. The likelihood of categorically mismatched peptides presented by the recipient’s HLA-DRB1 was expressed as a normalized value, %Rank score. Categorical HLA-DQ mismatches were analyzed in 386 heart transplant recipients who were mismatched with their donors at the HLA-DQB1 locus.

Results.
We found that the presence of DQB1 mismatches with %Rank score ≤1 was associated with the development of dnDSA (P = 0.002). Furthermore, dnDSA increased the risk of AMR only in recipients who had DQ mismatches with %Rank score ≤1 (hazard ratio = 5.8), but the freedom from AMR was comparable between recipients with dnDSA and those without dnDSA if %Rank scores of DQ mismatching were >1.

Conclusions.
These results suggest that HLA-DQ mismatches evaluated by the categorical amino acid mismatched epitope algorithm can stratify the risk of development of dnDSA and AMR in heart transplant recipients.
Clinical Management and Outcomes of Nontuberculous Mycobacterial Infections in Solid Organ Transplant Recipients: A Multinational Case-control Study
Authors: López-Medrano Francisco , Carver Peggy L. , Rutjanawech Sasinuch , Aranha-Camargo Luis F. , Fernandes Ruan , Belga Sara , Daniels Shay-Anne , Mueller Nicolas J. , Burkhard Sara , Theodoropoulos Nicole M. , Postma Douwe F. , van Duijn Pleun J. , Arnaiz de las Revillas Francisco , Pérez del Molino-Bernal Concepción , Hand Jonathan , Lowe Adam , Bodro Marta , Vanino Elisa , Fernández-Cruz Ana , Ramos-Martínez Antonio , Makek Mateja Jankovic , Bou Mjahed Ribal , Manuel Oriol , Kamar Nassim , Calvo-Cano Antonia , Rueda-Carrasco Laura , Muñoz Patricia , Álvarez-Uría Ana , Pérez-Recio Sandra , Sabé Núria , Rodríguez-Álvarez Regino , Silva José Tiago , Mularoni Alessandra , Vidal Elisa , Alonso-Titos Juana , del Rosal Teresa , Classen Annika Y. , Goss Charles W. , Agarwal Mansi , Mejía-Chew Carlos ,   on behalf of the EMOTE (Epidemiology, Management and Outcomes of Non-tuberculous Mycobacteria Infections in Transplant Recipients in Europe and America) study group
Published: July 2024

Background.
The management and outcomes of nontuberculous mycobacterial (NTM) infections in solid organ transplant (SOT) recipients are poorly characterized. We aimed to describe the management and 1-y mortality of these patients.

Methods.
Retrospective, multinational, 1:2 matched case-control study included SOT recipients aged 12 y old or older diagnosed with NTM infection between January 1, 2008, and December 31, 2018. Controls were matched on transplanted organs, NTM treatment center, and posttransplant survival at least equal to the time to NTM diagnosis. The primary aim was 1-y mortality after NTM diagnosis. Differences between cases and controls were compared using the log-rank test, and Cox regression models were used to identify factors associated with mortality at 12 mo among cases.

Results.
In 85 patients and 169 controls, the median age at the time of SOT was 54 y (interquartile range, 40–62 y), 59% were men, and the lungs were the most common site of infection after SOT (57.6%). One-year mortality was significantly higher in cases than in controls (20% versus 3%; P < 0.001), and higher mortality was associated with lung transplantation (hazard ratio 3.27; 95% confidence interval [1.1-9.77]; P = 0.034). Median time (interquartile range) from diagnosis to treatment initiation (20 [4–42] versus 11 [3–21] d) or the reduction of net immunosuppression (36% versus 45%, hazard ratio 1.35 [95% CI, 0.41-4.43], P = 0.618) did not differ between survivors and those who died.

Conclusions.
NTM disease in SOT recipients is associated with a higher mortality risk, especially among lung transplant recipients. Time to NTM treatment and reduction in net immunosuppression were not associated with mortality.
Prediction of Hemolytic Peptides and their Hemolytic Concentration (HC50)
Authors: Rathore Anand Singh , Kumar Nishant , Choudhury Shubham , Mehta Naman Kumar , Raghava Gajendra P. S. 
Published: July 2024

AbstractSeveral peptide-based drugs fail in clinical trials due to their toxicity or hemolytic activity against red blood cells (RBCs). Existing methods predict hemolytic peptides but not the concentration (HC50) required to lyse 50% of RBCs. In this study, we developed a classification model and regression model to identify and quantify the hemolytic activity of peptides. Our models were trained and validated on 1924 peptides with experimentally determined HC50 against mammalian RBCs. Analysis indicates that hydrophobic and positively charged residues were associated with higher hemolytic activity. Our classification models achieved a maximum AUC of 0.909 using a hybrid model of ESM-2 and a motif-based approach. Regression models using compositional features achieved R of 0.739 with R² of 0.543. Our models outperform existing methods and are implemented in the web-based platform HemoPI2 and standalone software for designing hemolytic peptides with desired HC50 values (http://webs.iiitd.edu.in/raghava/hemopi2/).HighlightsDeveloped classification and regression models to predict hemolytic activity and HC50 values of peptides.A hybrid model combining machine learning and motif prediction excels in accuracy.Benchmarking of the existing classification methods on independent datasets.Web server, standalone software, and pip package for hemolytic activity prediction of peptides/proteins.
DNA Methylation Age Acceleration Mediates the Relationship between Systemic Inflammation and Cognitive Impairment
Authors: Tejera César Higgins , Zhu Peiyao , Ware Erin B. , Hicken Margaret T. , Zawistowski Matthew , Kobayashi Lindsay C. , Seblova Dominika , Manly Jennifer , Mukherjee Bhramar , Bakulski Kelly M. 
Published: July 2024

BackgroundChronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk is understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship.MethodsIn a subset of the 2016 wave of the Health and Retirement Study (n=3,346, age>50), we employed logistic regression to estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and both Langa-Weir classified cognitive impairment non-dementia and dementia, respectively. We calculated DNA methylation age acceleration residuals by regressing GrimAge on chronologic age. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell type proportions.ResultsThe prevalence of cognitive impairment was 16%. In the fully-adjusted model, participants with a doubling of IL-6 levels had 1.12 (95% CI: 1.02-1.22) times higher odds of cognitive impairment. Similar associations were found for CRP and IGF-1. Participants with a doubling of IL-6 levels had 0.77 (95% CI: 0.64, 0.90) years of GrimAge acceleration. In mediation analyses with each cytokine as predictor separately, 17.7% (95% CI: 7.0%, 50.9%) of the effect of IL-6 on cognitive impairment was mediated through DNA methylation age acceleration. Comparable mediated estimates were found for CRP and IGF-1.ConclusionsSystemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.
Negatively charged α-Synuclein condensate modulates partitioning of molecules
Authors: Yang Qingqing , Chen Shunfa , Zhang Pengfei , Lu Zhonghua , Chang Shuwen , Wong Leo E. 
Published: July 2024

Abstractα-Synuclein (αSyn) aggregation via liquid-liquid phase separation has recently emerged as a crucial mechanism underlying amyloid fibril formation implicated in Parkinson’s disease. However, comprehensive investigations of the physico-chemical properties of αSyn condensate remains incomplete. Here, we showed that αSyn condensate possesses a highly negative electrostatic potential that spans the whole condensate. This property causes differential partitioning of dye-labeled αSyn as well as fluorescent molecules by an order of magnitude depending on their net charges. Consistent with this, the phase separation propensity of αSyn is governed by a delicate balance between self-association of αSyn and electrostatic repulsion, hence is antagonized by excess negative charge. We further demonstrated that, in differentiated neuron-like SH-SY5Y cells, αSyn also forms negatively charged condensate. Our results highlighted the significant impact of αSyn condensate’s electrostatic potential on molecular partitioning, hence calling for close examination of the electrostatic property of other biomolecular condensates.
Stress relaxation rates of myocardium from failing and non-failing hearts
Authors: Gionet-Gonzales Marissa , Gathman Gianna , Rosas Jonah , Kunisaki Kyle Y. , Inocencio Dominique Gabriele P. , Hakami Niki , Milburn Gregory N. , Pitenis Angela A. , Campbell Kenneth S. , Pruitt Beth L. , Stowers Ryan S. 
Published: July 2024

AbstractThe heart is a dynamic pump whose function is influenced by its mechanical properties. The viscoelastic properties of the heart, i.e. its ability to exhibit both elastic and viscous characteristics upon deformation, influence cardiac function. Viscoelastic properties change during heart failure (HF), but, direct measurements of failing and non-failing myocardial tissue stress relaxation under constant displacement are lacking. Further, how consequences of tissue remodeling, such as fibrosis and fat accumulation, alter the stress relaxation remains unknown. To address this gap, we conducted stress relaxation tests on porcine myocardial tissue to establish baseline properties of cardiac tissue. We found porcine myocardial tissue to be fast relaxing, characterized by stress relaxation tests on both a rheometer and microindenter. We then measured human left ventricle (LV) epicardium and endocardium human tissue from non-failing, ischemic HF, and non-ischemic HF patients by microindentation. We found that the ischemic HF had slower stress relaxation than non-failing endocardium; and that slower stress relaxing tissues were correlated with increased collagen deposition and increased α-smooth muscle actin (α-SMA) stress fibers, a marker of fibrosis and cardiac fibroblast activation, respectively. In the epicardium, we found that ischemic HF had faster stress relaxation than non-ischemic HF and non-failing; and that faster stress relaxation correlated with Oil Red O staining, a marker for adipose tissue. These data show that changes in stress relaxation vary across the different layers of the heart during ischemic vs. non-ischemic HF. These findings reveal how the viscoelasticity of the heart changes, which will lead to better modeling of cardiac mechanics for in vitro and in silico HF models.
Enhancing the Reverse Transcriptase Function in Taq Polymerase via AI-driven Multiparametric Rational Design
Authors: Tomilova Yulia E. , Russkikh Nikolay E. , Yi Igor M. , Shaburova Elizaveta V. , Tomilov Viktor N. , Pyrinova Galina B. , Brezhneva Svetlana O. , Tikhonyuk Olga S. , Gololobova Nadezhda S. , Popichenko Dmitriy V. , Arkhipov Maxim O. , Bryzgalov Leonid O. , Brenner Evgeny V. , Artyukh Anastasia A. , Shtokalo Dmitry N. , Antonets Denis V. , Ivanov Mikhail K. 
Published: July 2024

AbstractModification of natural enzymes to introduce new properties and enhance existing ones is a central challenge in bioengineering. This study is focused on the development of Taq polymerase mutants that show enhanced reverse transcriptase (RTase) activity while retaining other desirable properties such as fidelity, 5′-3′ exonuclease activity, effective deoxyuracil incorporation, and tolerance to locked nucleic acid (LNA)-containing substrates. Our objective was to use AI-driven rational design combined with multiparametric wet-lab analysis to identify and validate Taq polymerase mutants with an optimal combination of these properties. The experimental procedure was conducted in several stages: 1) On the basis of a foundational paper, we selected 18 candidate mutations known to affect RTase activity across six sites. These candidates, along with the wild type, were assessed in the wet lab for multiple properties to establish an initial training dataset. 2) A ridge regression model was trained on this dataset to predict the enzymes’ properties. This model enabled us to select 14 new candidates for further experimental testing. 3) We refined our predictive model using Gaussian process regression and trained it on an expanded dataset now including 33 data points. 4) Leveraging the refined model, we screenedin silicoover 27 million potential mutations, thus selecting 16 for detailed wet-lab evaluation. Through this iterative data-driven approach, we identified 18 enzymes that not only manifested considerably enhanced RTase activity but also retained a balance of other required properties. These enhancements were generally accompanied by lower Kd, moderately reduced fidelity, and greater tolerance to noncanonical substrates, thereby illustrating a strong interdependence among these traits. Several enzymes validated via this procedure were effective in single-enzyme real-time reverse-transcription PCR setups, implying their utility for the development of new tools for real-time reverse-transcription PCR technologies, such as pathogen RNA detection and gene expression analysis. This study illustrates how AI can be effectively integrated with experimental bioengineering to enhance enzyme functionality systematically. Our approach offers a robust framework for designing enzyme mutants tailored to specific biotechnological applications. The results of our biological activity predictions for mutated Taq polymerases can be accessed athttps://huggingface.co/datasets/nerusskikh/taqpol_insilico_dms.
Rice JASMONIC ACID OXIDASES (OsJAO) control resting jasmonate metabolism to promote development and repress basal immune responses
Authors: Ndecky Simon , Malherbe Ludivine , Villette Claire , Chalvon Véronique , Meusnier Isabelle , Beltran-Valencia Dennisse , Baumberger Nicolas , Riemann Michael , Kroj Thomas , Champion Antony , Heitz Thierry 
Published: July 2024

AbstractRecent research has established that catabolic conversions within the jasmonate pathway have significant consequences on hormone signaling output. In dicotyledonous plants, the jasmonic acid oxidase (JAO) catabolic route is endowed with a regulatory function by diverting jasmonic acid (JA) towards hydroxylation, at the expense of its conjugation into the bioactive jasmonoyl-isoleucine (JA-Ile) hormone. Here we functionally characterized the JAO pathway in rice (Oryza sativa) and demonstrate its prevalent function in promoting growth and attenuating JA responses in vegetative tissues. The rice genome contains four JAO-related homologs of which three generated hydroxy-JAin vitroand reverted the high defense phenotype when expressed in the Arabidopsisjao2-2mutant. By generating and analyzing a series of single to quadruple ricejaomutants, we show the incremental effect of gradual JAO depletion on JA metabolism, basal defense levels, growth inhibition, fitness and global metabolic reprogramming. JAO-deficient lines were significantly growth-retarded at the juvenile stage, while recovering a near wild-type vegetative development after three months, where they exhibited a enhanced resistance to virulent and avirulent strains ofMagnaporthe oryzae, the causal agent of fungal blast disease. Our findings identify the JAO pathway as an integral component of rice JA homeostasis and an important determinant of the growth-defense tradeoff. They demonstrate its conserved regulatory function in monocots and open possibilities for modulating selectively basal JA responses in a major cereal crop. Natural variation in JAO activity could also be explored as a mechanism underlying varying levels of JA signaling output in rice.
Differential responses in the core, active site and peripheral regions of cytochrome c peroxidase to extreme pressure and temperature
Authors: Zawistowski Rebecca K. , Crane Brian R. 
Published: July 2024

AbstractIn consideration of life in extreme environments, the effects of hydrostatic pressure on proteins at the atomic level have drawn substantial interest. Large deviations of temperature and pressure from ambient conditions can shift the free energy landscape of proteins to reveal otherwise lowly populated structural states and even promote unfolding. We report the crystal structure of the heme-containing peroxidase, cytochrome c peroxidase (CcP) at 1.5 and 3.0 kbar and make comparisons to structures determined at 1.0 bar and cryo-temperatures (100 K). Compressibility plateaus after 1.5 kbar and pressure produces anisotropic changes in CcP. CcP responds to pressure with volume declines at the periphery of the protein where B-factors are relatively high but maintains nearly intransient core structure and active site channels. Compression at the surface affects neither alternate side-chain conformers nor B-factors. Thus, packing in the core, which resembles a crystalline solid, limits motion and protects the active site, whereas looser packing at the surface preserves side-chain dynamics. Changes in active-site solvation and heme ligation reveal pressure sensitivity to protein-ligand interactions and reveal a potential docking site for the substrate peroxide.
Adaptation to water salinity changes: phenotypic plasticity meets and moulds carry-over effects in sea rock-pool mosquitoes
Authors: Cordeschi Giulia , Bisconti Roberta , Mastrantonio Valentina , Canestrelli Daniele , Porretta Daniele 
Published: July 2024

AbstractOrganisms living in highly variable environments are expected to exhibit a strong phenotypic variability within populations due to plastic responses to environmental fluctuations. Yet, this phenomenon is not commonly seen in nature, since compensatory mechanisms can promote phenotypic stability. Here, we hypothesized a potential compensatory effect that could result from the interaction between behavioural and morphological trait plasticity. These traits are highly responsive to environmental factors, and compelling research has demonstrated that behavioural plasticity can impact individual life history traits. In microcosm experiments, we analysed plasticity in body size, larval and pupal behaviour and carry-over effect across developmental stages in the sea rock-pool mosquitoAedes mariaein response to water salinity changes. Analyzing morphological traits, we found that larvae raised under increasing salinity were smaller than those raised under constant conditions. Additionally, a smaller body size at the pupal stage was observed, which indicated the presence of carry-over effects from the larval to pupal stages. However, no differences were observed in adult sizes between the two salinity conditions. When examining behavioural traits, we observed that higher salinity promoted plastic changes in larval activity behaviour and pupal diving behaviour. In particular, pupae exposed to increased salinity spent 20.6% less time underwater and performed fewer abdominal contractions than those under constant conditions. Since pupal energy expenditure is proportional to the time spent underwater, we suggest that the plastic pupal behaviour promoted compensatory energy allocation to growth, thereby reducing the carry-over effects from the pupal to the adult stage. This study emphasizes that plasticity at multiple traits during development can impact carry-over effects, ultimately leading to the convergence of adult phenotypes.
A family of bacterial Josephin-like deubiquitinases with an unusual cleavage mode
Authors: Hermanns Thomas , Kolek Susanne , Uthoff Matthias , de Heiden Richard A. , Mulder Monique P.C. , Baumann Ulrich , Hofmann Kay 
Published: July 2024

AbstractMany intracellular bacteria secrete deubiquitinase (DUB) effectors into eukaryotic host cells to keep the bacterial surface or the enclosing vesicle membrane free of ubiquitin marks. Here, we describe a new family of bacterial DUBs that is structurally related to eukaryotic Josephins, but contains members that catalyze a unique destructive substrate deubiquitination. These ubiquitin C-terminal clippases (UCCs) cleave ubiquitin before the C-terminal diGly motif, thereby truncating the modifier and leaving a remnant on the substrate. By comparing the crystal structures of substrate-bound clippases and a closely related conventional DUB, we identified the factors causing the shift and found them conserved in other clippases, including one highly specific for M1-linked ubiquitin chains. This new enzyme class has great potential as tools to study the ubiquitin system, in particular aspects involving branched chains.
Satellite glial contact enhances differentiation and maturation of human iPSC-derived sensory neurons
Authors: LeBlang Chelsey J. , Pazyra-Murphy Maria F. , Silagi Elizabeth S. , Dasgupta Srestha , Tsolias Marianna , Miller Toussaint , Petrova Veselina , Zhen Shannon , Jovanovic Vukasin , Castellano David , Gerrish Kathryn , Ormanoglu Pinar , Tristan Carlos , Singeç Ilyas , Woolf Clifford J. , Tasdemir-Yilmaz Ozge , Segal Rosalind A. 
Published: July 2024

AbstractSensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.