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Iron in HSCs: too much of a good thing
Genetic variability and multivariate analysis of quantitative traits in advanced crosses and accessions of cotton (Gossypium hirsutum) in Ethiopia
Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer
A randomized trial of GVHD prophylaxis in haploidentical PBSC transplantation: ATG, PTCy, and low-dose combination therapy
Abstract The optimal graft-versus-host disease (GVHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation remains controversial. In this open-label, phase 3 study, patients aged 14 to 70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose antithymocyte globulin (ATG; 5 mg/kg) plus posttransplant cyclophosphamide (PTCy; 50 mg/kg; referred to as ATG/PTCy), standard-dose ATG (total dose, 10 mg/kg), or a PTCy-based (total dose, 100 mg/kg) regimen for GVHD prophylaxis. The coprimary end points were the cumulative incidence (CI) of grade 2 to 4 acute GVHD (aGVHD) by day 100 and GVHD-free, relapse-free survival at 1 year after transplant. A total of 407 patients were randomized to receive an ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GVHD prophylaxis. By day +100, the CI of grade 2 to 4 aGVHD did not differ significantly among the 3 groups (P = .210). Although the overall incidence of chronic GVHD (cGVHD) was comparable across all groups (P = .110), the 2-year CI of moderate-to-severe cGVHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups than the PTCy group (28.3%), without reaching statistical significance (P = .095). No significant differences were observed in survival outcomes among the 3 groups. Notably, the CI of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group than in the other groups (P< .001). This trial suggested that the 3 GVHD prophylaxis strategies presented similar efficacy in preventing grade 2 to 4 aGVHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.
Carcass traits and gastrointestinal morphological responses to rumen-protected methionine supplementation in grazing beef heifers under tropical conditions
Abstract This study evaluated the effects of rumen-protected metabolizable methionine (RPM) supplementation on performance, carcass traits, ruminal morphometry, cecal histology, and meat quality of crossbred heifers finished on Urochloa brizantha pastures during the rainy-to-dry seasonal transition. Forty-eight 18-month-old ½ Nellore × ½ Angus heifers (380 ± 44 kg) were assigned to three supplementation strategies: a control treatment (T1) receiving an energy–protein supplement without methionine; T2 receiving the same supplement plus 3 g/animal per day of RPM; and T3 receiving 3 g/day of RPM combined with a more gradual increase in concentrate supplementation over the 140-day grazing period. RPM supplementation did not affect final body weight or average daily gain throughout the experimental period. However, heifers receiving RPM supplementation (T2 and T3) showed greater ribeye area and lower Biceps femoris fat thickness than the control treatment. Ruminal morphometry revealed a greater number of papillae in RPM-supplemented animals, although absorptive surface area and other ruminal histological measurements were not affected by treatment. In the cecum, the most pronounced responses were observed in T3, which showed lower lesion scores and fewer goblet and disrupted goblet cells than the other treatments. Meat quality evaluations indicated greater marbling scores in RPM-supplemented heifers without changes in tenderness or cooking loss. In conclusion, RPM supplementation was associated with changes in carcass traits, ruminal morphometric variables, and cecal histological responses in grazing beef heifers under tropical conditions. The most pronounced cecal responses occurred in the treatment combining RPM supplementation with gradual concentrate adaptation, although the experimental design does not allow complete separation of the effects of methionine supplementation and feeding-management strategy.
A family of archaeal hibernation factors that bind in tandem and protect ribosomes in dormant cells
Abstract Under nutrient limitation or stress, ribosome hibernation factors inactivate and protect ribosomes. Although ribosome hibernation plays an important role in microbes, we lack a complete understanding of this process in archaea. Here, we identify a family of hibernation factors, which we designate as single ribosomal subunit inhibitors (SriA-SriD), from the methanogenic archaeon Methanosarcina acetivorans . All four sri genes are encoded in an operon and each Sri protein inhibits protein synthesis in vitro. Deletion of sri genes in M. acetivorans impaired growth recovery after prolonged stationary phase and also led to depletion of the small ribosomal subunit. Cryo-EM structures show that Sri proteins bind to the ribosome in tandem and form conserved protein-protein interfaces. Sri is broadly distributed across archaeal phyla and sri genes frequently co-occur. Together, these findings establish Sri proteins as a distinct group of hibernation factors that protect ribosomes during dormancy and expand our understanding of ribosome hibernation in archaea.
Sutimlimab vs B-cell–targeted therapy in cold agglutinin disease: which is the optimal approach?
Abstract Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by monoclonal immunoglobulin M autoantibodies that bind to red blood cells and trigger hemolysis through activation of the classical complement pathway. Cold agglutinins are produced by a clonal population of lymphocytes, recognized by the World Health Organization as a low-grade lymphoproliferative disorder. Traditional therapy relied on B-cell–targeted immunosuppression with rituximab, which mainly yielded partial responses in approximately half of the patients. The combination of rituximab with fludarabine or bendamustine significantly increased and prolonged response rates, although with a substantial infectious risk. Sutimlimab, the first C1s complement inhibitor, has shown efficacy in rapidly and sustainably increasing hemoglobin levels, reducing hemolysis, and significantly improving quality of life. However, the drug does not act on the B-cell clone and does not decrease cold agglutinins. Therefore, several unmet needs remain, including identifying patients who can discontinue sutimlimab while maintaining remission, developing combination strategies effective against cold-induced symptoms, and improving infection prevention and control of hemolytic flares. This perspective article briefly recapitulates the pathophysiology of CAD, outlines the evolution of its treatment landscape, and focuses on the role of sutimlimab, including its clinical positioning, therapeutic benefits, and management considerations, offering insights into optimizing care for patients with this challenging condition.
Computational assessment of cold thermal energy storage improvement using hybrid nanofluid cooling and metal foam media
Surface energy-driven perpendicular gradient structure in flexible composite dielectrics for high-temperature capacitive energy storage
Kinetic Regulation of Anionic Redox Reaction Voltage by Metastable Over‐Lithiated Surface Shells Formation for High‐Energy‐Density Batteries
ABSTRACT Anionic redox reaction (ARR) has emerged as a pivotal mechanism to support next‐generation of high‐energy‐density batteries. While extensive efforts have focused on elucidating the origin of ARR‐induced additional capacity, ARR operating voltage constitutes the limiting factor for its practical applications. Particularly, voltage hysteresis between charge‐discharge brings poor energy efficiency. This work investigates key factors determining ARR operating voltage in Li 1.17 Ti 0.58 Ni 0.25 O 2 (LTNO), a unique model system enabled by its well‐isolated ARR plateau around 2.0 V. By combining in situ XRD, TEM, sXAS, and RIXS, the kinetic regulation of both transition metal redox and ARR voltages is validated. For the very first time, depth‐resolved Li 1s XPS and Li‐K sXAS are combined to trace Li distribution profile and occupation sites. A metastable over‐lithiated shell forms on the LTNO surface, where the extra surface Li‐ions occupy tetrahedral coordination. Such a surface shell exerts a large energy barrier for Li‐ion transfer and leads to an extremely low ARR plateau. Furthermore, the kinetics‐regulated ARR voltage may work in other cathodes, where voltage decay in Li‐rich layered cathode can be kinetically dominated in long‐term cycle. These findings provide new insights into understanding the ARR operating mechanism, and guidelines for optimizing ARR performance can be proposed via facilitating Li transfer kinetics.
Genotype-immunophenotype relationships in <i>NPM1</i> -mutated AML clonal evolution uncovered by single-cell multiomic analysis
Abstract Acute myeloid leukemia (AML) is a multiclonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single-cell molecular profiling and immunophenotyping on 43 samples from 32 patients with NPM1 (nucleophosmin 1)–mutated AML at different time points in disease progression. Here, we show that diagnosis and relapse AML samples display similar clonal architecture patterns, but signaling mutations drive increased clonal complexity, specifically at relapse, which correlates with overall survival. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on front-line AML therapy identified dynamic clonal and immunophenotypic changes consistent with the genotype-immunophenotype relationships we identified.
Inhibition of osteoarthritis progression with freshly thawed small umbilical cord-derived fast proliferating cells in a rat model
Quantum Fisher information as a thermal probe in frustrated magnets through insights from quantum spin ice
IRF2 is an essential transcription factor with pathogenic and prognostic impact in multiple myeloma
Abstract Multiple myeloma (MM), the second most prevalent hematologic malignancy, remains incurable, highlighting the need to identify molecular drivers of disease progression and new therapies. Using a CRISPR-Cas9 library screening approach in MM cells, we identified 22 essential transcription factors (TFs), including members of the interferon regulatory factor (IRF) family. Remarkably, in addition to the well-known IRF4, IRF2 emerged as a critical TF in MM. Cleavage under targets and release using nuclease (CUT&RUN) experiments demonstrated that IRF2 binds extensively to chromatin, both independently and in cooperation with IRF1 and IRF4. Although IRF2-unique regions were predominantly associated with active promoters, regions bound by IRF2/1/4 were biased toward introns. Functionally, IRF2 contributes to MM cell survival by suppressing necroptosis and promoting cell migration. Notably, IRF2-dependent transcriptional dysregulation was evident in precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), suggesting a role in early disease evolution. In addition to its role as an early factor, IRF2 levels also seem to influence disease progression, as MMs with higher expression demonstrated worse progression-free survival (PFS) and overall survival (OS) in both univariate and multivariate analyses, even after adjusting for common MM genetic risk factors. In conclusion, IRF2 constitutes an underappreciated essential TF involved in the pathogenesis and clinical behavior of MM. Its inhibition leads to dysregulation of key signaling pathways in MM pathogenesis, highlighting its potential as a therapeutic target.
Electronic structure–activity relationships of adenine-based istradefylline derivatives investigated by DFT, topological analysis, and exploratory neuronal excitability modeling
Author Correction: A broadly protective antibody targeting gammaherpesvirus gB
Integrative cross-sample alignment and spatially differential gene analysis for spatial transcriptomics
From bench to broken brains: freeze-dried platelets
Understanding the role of burnout on nurses’ quit intentions in the context of healthcare organizations of Hungary
Abstract Nurse burnout and workforce attrition represent critical challenges for healthcare organizations worldwide. This study examines how job demands and job resources are associated with burnout and how burnout relates to psychological factors shaping nurses’ intention to remain in the profession. Drawing on the Job Demands–Resources (JD–R) model and the theory of planned behavior (TPB), the research integrates organizational and behavioral perspectives to explain retention processes in hospital nursing. Empirical data were collected through a cross-sectional quantitative survey among 288 hospital nurses employed in public and private healthcare institutions in Hungary. Structural equation modelling was applied to test the relationships between relevant variables. The results indicate that workload has a strong positive association with burnout, while autonomy and regular supportive feedback function as important protective resources. Burnout was significantly associated with less favorable attitudes toward remaining in the profession and lower perceived behavioral control, both of which were strong predictors of intention to stay. The findings highlight the importance of addressing both organizational working conditions and psychological mechanisms when seeking to improve nurse retention.
Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress
Abstract Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer’s disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.