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.

How are systems supporting high-level cognition organized in the human brain? We hypothesize that cognitive processes involved in understanding people and places are implemented by distinct neural systems with parallel anatomical organization. We test this hypothesis using precision neuroimaging of individual human brains on diverse tasks involving perception and cognition in the domains of familiar people, places, and objects. We find that thinking about people and places elicits responses in distinct areas of high-level association cortex within the default mode network, spanning the frontal, parietal, and temporal lobes. Person-and place-preferring brain regions are systematically spatially adjacent across cortical zones. These areas have strongly domain-specific response profiles across visual, semantic, and episodic tasks and are specifically functionally connected to other parts of association cortex with like domain preference. Social and spatial networks remain anatomically separated at the apex of a unimodal-to-transmodal gradient across cortex and include regions with anatomical connections to the hippocampal formation. These results demonstrate the existence of parallel, domain-specific networks reaching the cortical apex.

The spatiotemporal regulation of morphogenetic signals, along with local tissue mechanics, guides morphogenesis and determines the shape of the embryo. However, how these signals integrate into developmental circuits remains poorly understood. Here, we developed a light-inducible strategy to induce BMP4 signaling with precise spatial coordinates in human pluripotent stem cells. Light-controlled BMP4 induces SMAD1-5 phosphorylation, resulting in amnion differentiation, and relies on a tension-dependent induction of WNT and NODAL for mesoderm differentiation. In response to BMP4 signaling, the mechanosensitive transcription factor YAP1 accumulates in the nucleus, where it represses WNT3 mRNA, regulating the induction of the three germ layers. Based on these findings, we developed a mathematical model that integrates tissue mechanics into morphogen dynamics, quantitatively explaining tissue-scale responses to BMP4 signaling. Thus, light induction of the morphogen BMP4 in human stem cell models elucidated the interplay between tissue mechanics and signaling at the onset of gastrulation.

Background: Polymicrobial sepsis is an infectious disease characterized by excessive inflammation and coagulation that is linked to more severe disease pathology, organ failure, and fatality. The plasma contact system is a protein cascade in the blood that can be activated by bacteria and contributes to both inflammation and coagulation. Objectives: To determine if inhibiting the plasma contact system by targeting highmolecular-weight kininogen (HK) can exert a protective effect on bacteria-induced coagulation. Methods: Polymicrobial cecal slurry (CS) was prepared from donor mice and used for ex vivo and in vivo experiments. CS was used in vivo to establish a murine model of polymicrobial sepsis. CS was incubated with mouse or human plasma ex vivo. Contact system activation was assessed by Western blot, and clotting was assessed spectroscopically. Our monoclonal antihuman HK antibody, 3E8, was used to determine how contact system inhibition could delay CS-induced coagulation ex vivo. Results: Polymicrobial CS activated the plasma contact system in vivo in mice and ex vivo in both mouse and human plasma. CS promoted coagulation in mouse and human plasma ex vivo. Treatment with our 3E8 anti-HK antibody protected against CS-induced contact system activation and coagulation. Conclusion: The plasma contact system was activated in the CS model of polymicrobial sepsis. Targeting HK in polymicrobial sepsis may have beneficial effects in limiting excessive coagulation and could represent a novel therapeutic avenue to promote survival in sepsis.

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.