The rockefeller university

Interferon-gamma (IFN1) is critical for immunity against intra-macrophagic pathogens, signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway to induce a tyrosinephosphorylation cascade that ensures a potent immune response. Excessive JAK-STAT signaling can drive hyperinflammation and autoimmunity; thus, signaling is tightly and selectively regulated by the IFN1-induci-ble protein, suppressor of cytokine signaling 1 (SOCS1). SOCS1 inhibits signaling by directly blocking JAK kinase activity. Here, we identified a SOCS1-interacting partner, ankyrin repeat and pleckstrin homology domain 2 (ARAP2), that fine-tunes SOCS1 function. We report that tyrosine 415 in ARAP2 binds the SOCS1-Src homology 2 (SH2) domain and limits the ability of SOCS1 to inhibit IFN1 signaling. Our findings show that ARAP2 promotes the IFN1 response through a phosphorylation-dependent interaction with the negative regulator SOCS1, and this exacerbates inflammation in a mouse model of influenza virus infection.

The COVID-19 pandemic has increased public reliance on natural treatments, particularly in regions with strong cultural ties to herbal medicine or limited access to conventional healthcare. Globally, surveys have reported heightened use of plant-based remedies and dietary supplements, perceived as safe and effective. In Israel, this trend was evident within an integrative healthcare system that combines conventional and complementary medicine. The public demonstrated significant interest in herbal remedies and supplements to boost immunity and manage pandemic-induced stress. Natural compounds with anti-inflammatory and antiviral properties offer potential pharmacological benefits, warranting clinical investigation. However, restrictive trial criteria hinder broader applicability of findings. To address this gap, we evaluated the effects of bioactive dietary supplements on COVID-19 severity and duration through an online survey. Among respondents, Boswellia emerged as the most popular supplement. Disease duration in Boswellia users was significantly reduced (11.8 +/- 7.1 days) compared to untreated cases or those taking other supplements (18.0 +/- 9.7 days). Known as frankincense, Boswellia's gum resin has traditionally been used for its anti-inflammatory properties. Its bioactive compounds, boswellic acids and incensole acetate, inhibit cytokines like TNF alpha, IL-1 beta, and IL-6, implicated in COVID-19-related cytokine storms and ARDS. Preliminary clinical and laboratory studies suggest Boswellia's potential as an anti-inflammatory and antiviral agent. Laboratory experiments corroborated these findings, demonstrating that cultures infected with 229e virus, as measured by qPCR. Boswellia extracts also decreased viral RNA levels by up to 75% without adverse effects on cell viability and inhibited TMPRSS2 activity, a key protease for viral entry. These findings underscore Boswellia's therapeutic potential, combining anti-inflammatory and antiviral mechanisms, and support further investigation into its use as a complementary treatment for COVID-19.

Climate and land use change have increased human-wildlife interactions, potentially reducing wild species density and prompting behavioral adaptations to urbanized environments. It is still debated if behavioral responses are mainly the result of phenotypic plasticity or if they were driven by anthropic selective pressures, especially in small populations where genetic drift is strong. Our study focused on the small Apennine brown bear population (Ursus arctos marsicanus), which has coexisted with humans in Central Italy for millennia. We characterized genomic diversity and identified adaptation signals distinctive to this population by comparing newly generated and published whole-genome resequencing data from Apennine, Central European, and North American brown bears. Apennine brown bears exhibited reduced genomic diversity, higher inbreeding, and larger realized genetic load compared to other brown bears. We showed that Apennine brown bears possess a unique genomic diversity pattern including selective signatures at genes associated with reduced aggressiveness (eg DCC, SLC13A5). Within these genes, most of the newly discovered variants were located in noncoding regions and some of them were predicted to alter splicing factor binding sites, highlighting the contribution of noncoding variation in shaping complex phenotypes. Our results support the hypothesis that human-induced selection has promoted behavioral changes even in small- and long-isolated populations, reducing conflicts and contributing to the long-term persistence of a large mammal species and its coexistence with humans.

Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein alpha (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18 kDa and the norepinephrine transporter, respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.

Myeloid cells-including monocytes, macrophages, dendritic cells, and granulocytes-are critical architects of the tumor microenvironment, in which they exert diverse functions ranging from immunosuppressive to immunostimulatory. Advances in single-cell omics and high-dimensional immune profiling have unveiled the remarkable heterogeneity and plasticity of these cells, revealing lineage-specialized functions that shape cancer immunity. These discoveries have sparked growing interest in therapeutically targeting myeloid cells as a next-generation strategy in cancer immunotherapy. As a complementary or alternative approach to T cell-centered immunotherapies, myeloid-directed therapies offer unique opportunities to reprogram the immune landscape, enhance antitumor responses, and overcome resistance mechanisms. In this review, we highlight recent discoveries in myeloid cell biology in cancer and discuss emerging therapeutic targets, with an emphasis on antibody-based therapies that have reached clinical development. We further provide perspective on translational challenges to implement these approaches into the clinic and discuss how Fc-engineering and rational antibody design can optimize myeloid cell engagement and amplify their immune effector functions. Together, these advances position myeloid-directed immunotherapies as a promising approach to enhance the efficacy and durability of cancer treatment.

The gut conveys nutritional, mechanical, and microbial signals to the brain to regulate physiology and behavior. Writing in Nature, Liu et al. reveal a colonic neuropod-vagus circuit that senses bacterial flagellin, highlighting microbial input as a rapid driver of feeding control and expanding paradigms of communication between the gut and the brain.

Mosquitoes, the world's deadliest animal, exemplify single-mating systems where females mate only once in their lifetime, making mate choice critically important for reproductive success and mosquito control. Despite this importance, the mechanisms behind mosquito mating and what prevents the female from mating again remain poorly understood. To address this gap, we developed a dual-color fluorescent sperm system in invasive Aedes aegypti mosquitoes and quantified mating patterns, confirming that 86%-96% of females mate only once. Using behavioral tracking of mating pairs, deep learning, and quantitative analysis at increasing resolution, we discovered that females actively control mating initiation through a previously undescribed behavior: genital tip elongation. This female response is triggered by rapidly evolving male genital structures, creating a lock-and-key mechanism that determines mating success. Comparative analysis revealed that Aedes albopictus, separated from Aedes aegypti by similar to 35 million years of evolution, employs a similar female-controlled system. Strikingly, we found that Aedes albopictus males bypass female control when attempting cross-species matings with Aedes aegypti females, but not with conspecific females. This "lock-picking" ability, combined with the known sterility induced by cross-species matings, could explain how Aedes albopictus competitively displaces Aedes aegypti populations in overlapping territories. Our findings redefine mosquito reproduction as a female-controlled process and establish a quantitative framework for investigating the molecular and neurobiological mechanisms underlying mating control and species competition in these globally important disease vectors.

BACKGROUND: The underlying mechanisms of atherosclerosis and strategies for identifying high cardiovascular risk in psoriasis are incompletely understood. Platelet activity is increased in psoriasis and induces vascular dysfunction. We investigated the platelet phenotype and platelet transcriptome as one potential mechanism to explain cardiovascular risk in psoriasis. METHODS: Psoriasis and controls underwent platelet aggregation and activation studies and platelet RNA sequencing to generate a psoriasis platelet transcriptomic score. The relationship between the platelet transcriptomic score and cardiovascular risk was assessed by arterial stiffness, coronary calcium, and longitudinally in an independent cohort of high cardiovascular-risk individuals undergoing lower extremity arterial revascularization. RESULTS: Psoriasis subjects (n=73; median age, 51 years; body surface area of psoriasis, 3%) compared with controls (n=56; median age, 41 years) trended older (P=0.08) and had greater body mass index (P=0.01) and higher hs-CRP (high-sensitivity C-reactive protein) values (P=0.01). Platelet aggregation in response to collagen (P=0.0049) and ADP (P=0.033), and leukocyte-, neutrophil-, and lymphocyte-platelet aggregates (P<0.05 for each comparison) were all higher in psoriasis versus controls. Platelet RNA sequencing comparing 51 patients with psoriasis with 39 controls identified 329 upregulated and 345 downregulated genes (P<0.05). Pathway analysis identified dysregulated platelet activation, apoptosis, VEGF (vascular endothelial growth factor), interferon, senescence, IL (interleukin)-1, and clotting cascade signaling between psoriasis and controls. Using a phenotypic rank-based scoring methodology, a psoriasis platelet transcriptomic score comprised of 142 genes differentiated psoriasis from controls. This score correlated with arterial stiffness (r=0.26; P=0.031) and coronary calcium (r=0.58; P=0.0069). In a separate cohort of high cardiovascular-risk patients undergoing lower extremity arterial revascularization, the psoriasis platelet transcriptomic score associated with incident myocardial infarction (adjusted hazard ratio, 3.7 [95% CI, 1.4-10.1]; P=0.015). CONCLUSIONS: Platelet aggregation and activation are increased in patients with controlled psoriatic disease, with the platelet transcriptome associated with proinflammatory, proatherothrombotic pathways, and cardiovascular risk. Our results warrant further investigation of platelet involvement promoting heightened cardiovascular disease in psoriasis.

Radioimmunotherapy using Ac-225, a highly cytotoxic alpha-particle emitter, has potential for treating advanced breast cancer, especially human epidermal growth factor receptor 2 (HER2)-positive cases. We use a pretargeted radioimmunotherapy (PRIT) approach consisting of a 3-step intravenous regimen (step 1: bispecific anti-HER2/anti-DOTA antibody; step 2: clearing agent; step 3: Ac-225-radiolabeled Proteus DOTA, or [Ac-225]Ac-Pr). Our goal was to establish curative Ac-225-PRIT with high therapeutic indices. Methods: The impact of [Ac-225]Ac-Pr specific activity was evaluated in the BT-474 breast xenograft model. We tested the effects of [Ac-225]Ac-Pr dosing during PRIT on tumor-targeting efficiency and tissue biodistribution. Using a Ac-225-PRIT regimen consisting of a ratio of 1.19 nmol of bispecific antibody to 0.60-0.66 nmol of [Ac-225]Ac-Pr, we evaluated therapy in the BT-474 model and a patient-derived xenograft model. BT-474-tumor-bearing mice were treated with 1 or 2 cycles of Ac-225-PRIT (37 kBq/cycle) separated by 1 wk. A dose escalation study was performed on the BT-474 model to establish an absorbed radiation dose of approximately 40 Gy (relative biological effectiveness [RBE], 5) as a nephrotoxic dose, as no such histologic findings were observed in prior studies at the 20.7-Gy (RBE, 5) renal dose level. Results: In the BT-474 model, 100% (20/20) achieved complete responses and histologic cure in 17 of 20 (85%) of the treated animals. One-cycle and 2-cycle treatments were equally effective. Treatments were well tolerated, with no chronic radiation toxicity documented during necropsy at 175 d. Dosimetry estimates (RBE, 5) per 37 kBq administered for tumors and kidneys were 210 and 3.5 Gy, respectively. In the patient-derived xenograft model, a single Ac-225-PRIT treatment led to 60% (3/5) complete response and prolonged survival (>93 d) versus no treatment (30 d; P = 0.0185). Lastly, a Ac-225-PRIT regimen was identified that induces severe chronic nephrotoxicity (41.4 Gy/592 kBq; RBE, 5). Conclusion: Safe and effective Ac-225-PRIT regimens were developed in 2 preclinical models of advanced HER2-positive human breast cancer with tumor cure without dose-limiting nephrotoxicity. This study establishes crucial preclinical dosimetry benchmarks for Ac-225-PRIT and provides a compelling rationale for its advancement into the clinic.