Browse Articles

Regioselective Migratory Ring Expansion of Heterole‐Fused Norcaradienes for Modular Access to Azulene‐Incorporated Thienoacenes

ABSTRACT In this study, we report a sterically steered, thermally driven [1,5]‐C shift (“carbon‐walking”) of congested heterole‐fused norcaradienes (NCDs), generated in situ by tetramethylguanidine (TMG) catalyzed intramolecular hydroheteroarylation of heterole‐substituted alkynylcyclopropanes, coupled by Cope ring expansion to give highly functionalized cycloheptatrienes (CHTs). Further cyclopentannulation of the CHT ring with the aroyl substituents via either formal reductive or oxidative Nazarov cyclization enables modular access to diverse azulene‐incorporated thienoacenes as promising candidates for organic materials. DFT and experimental mechanistic investigations reveal that this organocatalytic intramolecular hydroheteroarylation is initiated by an unprecedented aromatic yne Cope rearrangement facilitating by a subsequent rate‐determining TMG‐mediated proton transfer. The resulting dearomatized heterole‐fused CHT species then isomerize via Cope ring contraction to isolable heterole‐fused NCDs. Upon heating, the differential steric environments around the two shared cyclopropyl carbon centers steer a stereoinvertive carbon‐walking process of such heterole‐fused NCDs, coupled with Cope ring expansion, to furnish the final skeleton‐rearranged CHTs. Beyond its synthetic versatility, the synergy between the challenging aromatic yne Cope rearrangement and base‐mediated proton transfer unlocks an otherwise inaccessible base‐catalyzed intramolecular hydroheteroarylation of propargylic‐proton‐free alkynes.

Rational Molecular Design to Improve Digital Polymer Readout in Aerolysin‐Based Nanopore Sequencing

ABSTRACT Nanopore sequencing is a promising method for decoding synthetic digital polymers, but translocation signals are often complex. This study examines the influence of macromolecular design on the accuracy of nanopore sequencing. Nine phosphoramidite monomers were synthesized and used in automated solid‐phase chemistry to generate a broad library of sequence‐defined poly(phosphodiesters) with varying chain lengths and sequences. The molecular uniformity of the polymers was confirmed by mass spectrometry and ion‐exchange HPLC. Evaluation using aerolysin‐based sensing allowed for the analysis of how key molecular parameters, such as monomer hydrophilicity, size, rigidity, and bulkiness, affect translocation events. This analysis enabled the selection of an optimal binary alphabet for nanopore sequencing, comprising a main‐chain cyclohexane 1,4‐dimethyl spacer for bit‐0 and a benzyl side chain for bit‐1. Using a machine learning approach, distinct polymer lengths and sequences could be identified. These results offer a novel pathway toward achieving low‐loss, repeatable, and reliable sequencing of information‐encoding synthetic polymers, thereby advancing the potential of nanopore technology for digital data storage.

Contemporary Management of Relapsed or Refractory Chronic Lymphocytic Leukemia

Relapsed or refractory (RR) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presents increasing therapeutic complexity in the era of targeted agents. Frontline use of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax-based fixed-duration (FD) or minimal residual disease–guided regimens has led to deeper remissions, yet many patients will eventually require subsequent therapy. Management of first relapse should integrate clinical status, prior therapy, progression kinetics, and assessment for Richter transformation, along with genomic re-evaluation (particularly acquired resistance mutations and TP53 aberrations). Multiple effective options exist for relapsing disease. Second-generation cBTKi (acalabrutinib, zanubrutinib) continuous therapy provides durable disease control with improved tolerability over ibrutinib, whereas continuous venetoclax monotherapy or FD venetoclax-rituximab achieves high response rates and prolonged remission, with retreatment feasible for selected patients. Noncovalent BTKis (ncBTKis) such as pirtobrutinib offer meaningful activity in patients previously exposed to cBTKi. Cellular therapies, particularly lisocabtagene maraleucel, have demonstrated substantial efficacy in heavily pretreated patients, and allogeneic hematopoietic cell transplantation remains an option for select individuals with double-class refractory disease. Emerging therapies—including BTK degraders, next-generation BCL2 inhibitors, and bispecific antibodies—will likely reshape the therapeutic landscape for RR CLL/SLL. With broadening treatment options for RR CLL/SLL, optimal sequencing requires consideration of disease biology, depth and duration of prior response, comorbidities, toxicity profiles, patient preferences, and logistical factors. As therapeutic options expand, individualized treatment planning and clinical trial participation remain essential for improving outcomes in RR CLL/SLL.

How I treat autoimmune neutropenia in adults

Autoimmune neutropenia (AiN) in adults is rare when compared to children. It occurs predominantly in female patients and in individuals with other autoimmune conditions. Anti‑neutrophil antibodies are detected in ~50% of patients with AiN, and it is not clear whether this reflects testing limitations or cell-mediated (rather than antibody-mediated) mechanisms of neutrophil destruction. Unlike the commonly self‑limited pediatric disease, adult AiN is generally chronic. The degree of neutropenia and the clinical severity is highly variable, and most patients remain asymptomatic and free of infection despite absolute neutrophil counts (ANC) persistently lower than 500 /uL. As most patients do well despite their neutropenia, observation and supportive care are generally preferred over active treatment. Where necessary, empiric treatment recommendations have stemmed from small numbers of cases. Therapy focuses on boosting endogenous neutrophil production, reducing immune-mediated destruction, or eliminating pathogenic autoantibodies. Clinical response is highly variable, and second-line therapies, including T‑cell-directed approaches, can be effective, supporting a role for cell-mediated mechanisms of neutrophil destruction in a subset of patients. Emerging strategies, such as plasma cell-targeted therapies, modulation of cytokine signaling pathways, and complement blockade also show promise. Collaboration and discussion around this rare condition is critical to enhance treatment algorithms.

AI models of unstable flow exhibit hallucination

Harnessing neoantigen-specific T cells for precision immunotherapy in hematologic malignancies

Abstract Antigen-specific T-cell immunotherapies are transforming the treatment landscape of hematologic malignancies. Neoantigen-specific therapies that exploit the ability of endogenous T-cell receptors (TCRs) to recognize tumor-derived peptides in an HLA-restricted context differ mechanistically from modalities employing chimeric antigen receptor T cells, which target surface antigens in an HLA-independent manner. In contrast to approaches targeting tumor-associated antigens, neoantigen-specific strategies offer more precise tumor selectivity and reduced off-target toxicity. Advances in immunogenomics, immunopeptidomics, and functional validation have accelerated the identification of both personalized and recurrent neoantigens, and high-resolution sequencing technologies have further facilitated the characterization of their cognate TCRs, which are currently being explored for developing TCR-engineered T-cell therapies. Early-phase clinical trials in hematologic malignancies demonstrate that neoantigen-specific strategies are safe and feasible across multiple hematologic cancers, with ongoing studies actively assessing the immunogenicity, clinical efficacy, and durability of these approaches. This review synthesizes recent preclinical and clinical advances in the discovery, validation, and therapeutic exploitation of neoantigen-specific strategies in blood cancers, highlighting translational insights for prioritizing immunogenic neoantigens. Emphasis is placed on identifying biological and technological barriers that limit the therapeutic efficacy of neoantigen-specific immunotherapies, with the goal of distilling actionable insights to guide their development in hematologic malignancies.

The MCAA-YOLO + XPBI integrated model provides a hybrid intelligent measurement method for predicting the body weight of Hu sheep

Balancing risk: anemia or albuminuria when using ACEi/ARB?

Application of iron nano-biofertilizers as a sustainable approach to enhance growth and micronutrient uptake in soybean

Expansion of functional human long-term HSCs through restraining excessive cell cycle activation

Ex vivo expansion of human hematopoietic stem cells (HSCs) holds promise for overcoming their limited availability, a major barrier to broader clinical application. Although recent advances in culture systems can increase HSC numbers, these conditions frequently impair self-renewal and induce myeloid bias, and the underlying molecular mechanisms remain poorly understood. Here, we performed single-cell multiome sequencing (scMultiome-seq) on human umbilical cord blood-derived CD34⁺ hematopoietic stem and progenitor cells to co-profile transcriptional and epigenetic adaptations within the same cells during ex vivo culture. Our analyses revealed reduced transcriptional and epigenetic HSC signatures, accompanied by markedly increased activity of myeloid-associated transcription factor motifs, providing molecular insight into the functional decline and myeloid bias of cultured HSCs. We further observed substantial functional heterogeneity among phenotypically defined HSCs following culture. To address these limitations, we established a niche-mimetic culture system that integrates intrinsic and extrinsic bone marrow regulatory cues, including pharmacologic inhibition of the m6A reader YTHDF2 using the small molecule Y13-27, a three-dimensional microenvironment, and N-cadherin-mediated adhesion. This condition (3D-NcadP-Y) robustly preserved long-term repopulating capacity. When combined with the self-renewal agonist UM729, the resulting platform (3D-NcadP-Y-UM) uniquely enabled the expansion of serially transplantable long-term HSCs with balanced multilineage potential. scMultiome-seq and cellular analyses demonstrated that this condition preserves transcriptional and epigenetic long-term HSC signatures, maintains multilineage-associated transcription factor motifs, and limits excessive cell-cycle activation. Together, these findings elucidate molecular mechanisms underlying culture-induced HSC dysfunction and establish a niche-mimetic strategy for expanding functional human long-term HSCs while preserving key features of stemness.

Adolescents’ status-dependent public and private conformity to prosocial and antisocial decisions in a public goods game

Abstract Peer influence is a central yet contested issue in adolescence, a developmental period marked by heightened social sensitivity. The present study examined how adolescents conform to prosocial and antisocial decisions of peers with different knowledge-based statuses in public or private contexts, while also considering gender and dispositional social conformity and prosocial tendencies. A total of 271 adolescents (132 boys, 139 girls; M  = 17, SD  = 1.495) were randomly assigned to one of the four experimental conditions. After completing dispositional conformity and prosocial tendencies questionnaires, they underwent a status manipulation task and then played a modified Public Goods Game. In general, adolescents conformed more strongly to high-status peers. Prosocial peer decisions prompted greater conformity in public contexts, whereas antisocial decisions primarily led to private conformity. These effects were further shaped by individual differences in emotional prosociality, compliance, and dispositional conformity. Higher emotional prosociality attenuated status-related differences in conformity and was associated with lower conformity among boys than girls. Greater compliance amplified girls’ conformity, particularly toward high-status and prosocial peers, whereas higher dispositional conformity widened the prosocial–antisocial conformity gap, especially in private contexts. These findings highlight the influential role of high-status peers and suggest that leveraging such influence may help promote prosocial behavior and reduce free riding.

Prior anticoagulation experience and bleeding risk with the factor XI inhibitor abelacimab in the AZALEA-TIMI 71 study

Abstract This prespecified AZALEA-TIMI 71 analysis showed that prior oral anticoagulation (OAC) experience indicates bleeding risk in atrial fibrillation. The factor XI inhibitor abelacimab reduced bleeding regardless of prior OAC experience, with potentially greater absolute benefit among OAC-naïve patients. This trial was registered at www.ClinicalTrials.gov as NCT04755283.

An explainable hierarchical capsule network framework for supporting expert sensory evaluation of herbal medicines with natural language generation

Stag2-dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome

Abstract The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. Although mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 coregulates divergent cell fates remains incompletely characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome (MDS) and myeloid leukemia of Down syndrome, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Therefore, we hypothesized that chromatin accessibility determines GATA1 cistrome specificity and lineage fate decisions. To understand the connection between chromatin accessibility and GATA1, we comprehensively studied erythropoiesis in Stag2Δ mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid differentiation, increased number of megakaryocyte progenitors, and increased megakaryocytes. RNA- and assay for transposase-accessible chromatin–sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Despite unchanged Gata1 expression, Gata1 occupancy was reprogrammed from erythroid to megakaryocyte targets with Fli1 motifs enriched at Stag2Δ Gata1 binding sites. Functionally, we observed that Stag2-deficient EryPs have a diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays, which was partially reversed with Fli1 knockdown. Human models and patients with primary MDS recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study establishes chromatin accessibility as a determinant of transcription factor binding specificity, revealing an accessibility-driven Gata1 retargeting mechanism underlying MDS dyserythropoiesis.

Author Correction: A machine learning method to process voice samples for identification of Parkinson’s disease

Between a clot and a hard place: role of FXIa inhibition

UVB-induced Ca2+ signaling orchestrates PPP3CA-AFF4 axis to promote cancer stem cell plasticity in melanoma

A quantitative definition of the clinical manifestations of GATA2 deficiency in adults

Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.

Evidence of predation events by marine mammals at offshore wind farms

Abstract Anthropogenic structures in the marine environment alter the availability and distribution of food for marine animals with potential consequences for individual fitness, population and community dynamics. Knowledge of how marine mammals’ behaviour or foraging activities are influence by existing wind farms is essential to predict the effect of future large-scale renewable energy development on local or regional populations. During acoustic tracking of demersal gadoid fish at two offshore wind farms in Scotland, six Atlantic cod were predated by a marine mammal close to or in the vicinity of turbine foundations. The distinct change in the temperature, depth and movement pattern of the acoustic tags allowed estimations of the time and location of predation (and likely predator) and provided details of post consumption behaviour. The detection of tags (predator) at multiple turbines within a relatively short period, post consumption, suggests the targeted use of turbine foundations as foraging sites where prey fish are known to aggregate. Moreover, the bias in predation of cod over haddock, and evidence for the cod being of higher energetic quality, provide rare evidence for prey selection by a marine mammal predator(s). These data provide further evidence for how wind farms and other introduced structures influence the behaviour of marine mammals with potential consequences for individuals and populations through changes in the distribution of prey. The ultimate consequences are to be determined but need consideration with the continued development of offshore wind farm sites.

Renin-angiotensin-aldosterone system inhibition exacerbates anemia in sickle cell disease

Abstract Renin-angiotensin-aldosterone system inhibitors (RAASi) are suggested for treating albuminuria in patients with sickle cell disease (SCD). RAASi may exacerbate anemia in the general population and those with diabetes through unclear mechanisms. The impact of RAASi on anemia in chronic hemolytic disorders, such as SCD, is unknown. In a cross-sectional analysis of 658 Walk-PHaSST participants, RAASi use was independently associated with lower hemoglobin concentrations, adjusting for age, sex, SCD genotype, estimated glomerular filtration rate, and erythroid-stimulating agent and hydroxyurea use (β, −0.46 ± 0.21; P = .032). In 2 longitudinal cohorts (University of Illinois Chicago, n = 24; multicenter losartan clinical trial, n = 32), RAASi therapy led to a reduction in hemoglobin concentrations compared with pretreatment values by −0.44 ± 0.14 g/dL (P = .006) and −0.53 ± 0.17 g/dL (P = .005), respectively. SCD mice treated with losartan demonstrated lower hemoglobin concentrations after 6 and 14 weeks (P< .001) and lower absolute reticulocyte counts by 14 weeks (P = .03) vs control mice without changes in circulating erythropoietin, interleukin-12p70 (IL-12p70), IL-3, or insulin-like growth factor 1 levels. Bone marrow cells from losartan-treated SCD mice had lower colony-forming units (P ≤ .09) with rescue of erythroid colony formation after exogenous erythropoietin supplementation (P = .02). Bone marrow histopathology demonstrated reduced erythroid relative to myeloid ratios in losartan-treated vs untreated SCD mice. Hemoglobin levels should be closely monitored when using RAASi in this high-risk population.