The rockefeller university

Wang et al. recently reported that during helminth infection, innate lymphoid cell (ILC)-derived IL-13 is sensed by gut neurons, which in turn secretes CGRP to inhibit ILC2 proliferation and anti-helminth responses. Hence, this study demonstrates a bidirectional crosstalk between enteric neurons and immune cells that regulates type-2 immunity.

Apolipoprotein E (APOE) has multiple functions in metabolism and immunoregulation. Its common germ line variants APOE2, APOE3, and APOE4 give rise to 3 functionally distinct gene products. Previous studies reported yin-yang roles of APOE2 and APOE4 in immunological processes, but their effects in hematopoietic stem cell transplantation (HSCT) have never been studied. We performed APOE genotyping in 2 contemporary cohorts of 348 and 447 patients with acute myeloid leukemia who had received allogeneic HSCT and evaluated the associations of recipient and donor APOE genetic variations with posttransplant outcomes. Patients who carried at least 1 APOE2 allele had a higher risk of posttransplant death than APOE4 carriers in the discovery (hazard ratio [HR], 2.09; P = .024) and validation cohorts (HR, 1.96; P = .040). Detrimental APOE2 effects were driven by an increased risk of severe chronic graft-versus-host disease (GVHD; adjusted HR [HRadj], 1.85; P = .034) and nonrelapse death (HRadj, 1.72; P = .044). In non-APOE2 recipients, transplantation of an APOE2-positive allograft was associated with an increased incidence of grade 3 to 4 acute GVHD (HRadj, 2.82; P = .012) and severe chronic GVHD (HRadj, 2.54; P = .022) compared with APOE2-negative grafts. In summary, the APOE2 allele, typically considered a longevity gene in the general population, was associated with a higher risk of acute GVHD (HRadj, 2.75; P = .002), chronic GVHD (HRadj, 2.57; P = .001), and posttransplant mortality (HRadj, 1.79; P = .004), when present in either the host or transplanted from the donor.

Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n = 137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n = 50, IHC). In contrast, high RRAS expression (cohort 4, n = 252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/ RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3Ahigh-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n = 49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.

Neuronal maturation is guided by changes in the chromatin landscape that control developmental gene expression programs. Histone bivalency, the co-occurrence of activating and repressive histone modifications, has emerged as an epigenetic feature of developmentally regulated genes during neuronal maturation. Although initially associated with early embryonic development, recent studies have shown that histone bivalency also exists in differentiated and mature neurons. In this review, we discuss methods to study bivalency in specific populations of neurons and summarize emerging studies on the function of bivalency in central nervous system neuronal maturation and in adult neurons.

Outbreaks of chilblains were reported during the COVID-19 pandemic. Given the essential role of type I interferon (I-IFN) in protective immunity against SARS-CoV-2 and the association of chilblains with inherited type I interferonopathies, we hypothesized that excessive I-IFN responses to SARS-CoV-2 might underlie the occurrence of chilblains in this context. We identified a transient I-IFN signature in chilblain lesions, accompanied by an acral infiltration of activated plasmacytoid dendritic cells (pDCs). Patients with chilblains were otherwise asymptomatic or had mild disease without seroconversion. Their leukocytes produced abnormally high levels of I-IFN upon TLR7 stimulation with agonists or ssRNA viruses-particularly SARS-CoV-2-but not with DNA agonists of TLR9 or the dsDNA virus HSV-1. Moreover, the patients' pDCs displayed cell-intrinsic hyperresponsiveness to TLR7 stimulation regardless of TLR7 levels. Inherited TLR7 or I-IFN deficiency confers a predisposition to life-threatening COVID-19. Conversely, our findings suggest that enhanced TLR7 activity in predisposed individuals could confer innate, pDC-mediated, sterilizing immunity to SARS-CoV-2 infection, with I-IFN-driven chilblains as a trade-off.

Division of labour (DoL) is of prime importance in the success of social insects in various ecosystems and benefits their colonies by increasing efficiency and productivity. This review summarizes more than three decades of experimental evidence collected towards understanding the emergence and maintenance of division of labour in the Indian tropical paper wasp Ropalidia marginata. This primitively eusocial species provides an interesting variation between newly founded colonies and mature colonies in terms of the behavioural mechanisms regulating division of labour. Newly founded colonies rely on physical dominance behaviour for establishing division of labour. Workers in mature post-emergence colonies continue to implement physical dominance as a way to regulate non-reproductive division of labour in a decentralized manner, while the queens switch to chemical regulation of worker reproduction. We discuss experiments that build evidence toward establishing R. marginata as an important model for understanding the origin and maintenance of division of labour.This article is part of the theme issue 'Division of labour as key driver of social evolution'.

Background/Objectives: Acne vulgaris is a skin disorder that affects millions worldwide, with Cutibacterium acnes playing a key role in its inflammation. Antibiotics reduce C. acnes and inflammation, but growing antibiotic resistance has limited their efficacy. Additionally, other common acne treatments with bactericidal activity, like benzoyl peroxide, cause irritation, dryness, and peeling. To fulfill the unmet need for alternative therapies, our strategy focused on identifying potent phage lysins and/or their derived cationic peptides. Methods: The C-terminal cationic antimicrobial peptide of the Prevotella intermedia phage lysin PlyPi01 was synthesized along with several sequence-engineered variants in an attempt to enhance their bactericidal efficacy. In vitro bacterial killing assays evaluated the potency of the lysin-derived peptide derivatives against C. acnes and Staphylococcus aureus, another skin bacterium associated with acne. Antibacterial activity was assessed both in conditions simulating the human skin and in combination with retinoids. Results: The variant peptide P156 was engineered by adding arginine residues at both the N- and C-terminal ends of the parental peptide PiP01. P156 was highly potent and eradicated all tested strains of C. acnes and S. aureus. P156 acted rapidly (>5-log kill in 10 min), further reducing the potential of resistance development. Additionally, P156 maintained its potency under conditions (e.g., temperature, pH, and salt concentration) observed on the skin surface and in hair follicles, as well as in combination with retinoid-all without being toxic to human cells. Conclusions: These collective findings position P156 as a promising topical drug for clinical applications to control acne vulgaris.

Gene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This is exemplified by the phosphate-sensing transcription factor Pho4, which requires phosphorylation for nuclear export by the yeast exportin Msn5. Here, we present a high resolution cryogenic-electron microscopy structure showing the phosphorylated 35-residue nuclear export signal of Pho4, which binds the concave surface of Msn5 through two Pho4 phospho-serines that align with two Msn5 basic patches. These findings characterize a mechanism of phosphate-specific recognition mediated by a non-classical signal distinct from that for Exportin-1. Furthermore, the discovery that unliganded Msn5 is autoinhibited explains the positive cooperativity of Pho4/Ran-binding and proposes a mechanism for Pho4's release in the cytoplasm. These findings advance our understanding of the diversity of signals that drive nuclear export and how cargo phosphorylation is crucial in regulating nuclear transport and controlling cellular signaling pathways.

Kr & uuml;ppel-like factor 4 (KLF4) is a highly conserved zinc-finger transcription factor involved in cellular processes such as development, differentiation, and cell cycle regulation. Previous studies show that mouse embryonic fibroblasts (MEFs) null for Klf4 exhibit increased genomic instability. While KLF4 is regarded as a tumor suppressor in many human cancers, its role in DNA repair mechanisms remains unknown. In this study, cultured MEFs wild type (+/+) and null (-/-) for Klf4 and human carcinoma colorectal (RKO) cells were studied as a model for human colorectal cancer. Etoposide, a chemotherapeutic topoisomerase II poison, was employed to investigate KLF4's role in DNA damage repair. Following etoposide treatment, immunostaining and Western blotting revealed cells expressing Klf4 exhibited lower levels of gamma-H2AX, a biomarker for DNA damage, compared to cells without Klf4. Moreover, after DNA damage, cells expressing Klf4 exhibited increased levels of BRCA1 and Rad51, known tumor suppressor genes. Finally, genes involved in DNA damage response (DDR), ATR, and Chk1 were upregulated in cells containing functional KLF4, offering a possible mechanism for KLF4's role in mediating DDR. Our results indicate that KLF4 plays a crucial role in maintaining genetic stability by enhancing cell DDR, supporting previous findings that KLF4 functions as a tumor suppressor.