Stress and diet are known to synergistically promote risks of obesity but the underlying neural basis remains elusive. Corticotropin-releasing hormone neurons in the paraventricular hypothalamus (PVHCRH) are stress responsive and release both CRH and glutamate. Here we generated a mouse model with gain or loss of release in CRH or glutamate from PVHCRH neurons. While these models showed no changes in body weight when fed chow, they exhibited contrasting effects when fed high-fat high-caloric diets (HFD). Whereas disrupting glutamate release from PVHCRH neurons led to diet-induced obesity (DIO), that of CRH caused no impact. Conversely, augmented CRH release led to DIO while that of glutamate caused no impact. The observed DIO in both cases was associated with an increased drive for HFD, but without obvious changes in behavioral signs of anxiety. Our results suggest PVHCRH neurons as a key mediator for the exerbated DIO induced by maladaptive stress responses.

The fractional quantum Hall effect at half-filled Landau levels provides a promising route to unusual topological phases that may host non-Abelian excitations, but these states are often fragile and difficult to control experimentally. Here, we report the observation of a cascade of even-denominator fractional quantum Hall states at fillings ν = -5/2, -7/2, -9/2, -11/2 and -13/2, alongside numerous odd-denominator states in mixed-stacked pentalayer graphene-a system characterized by intertwined quadratic and cubic band dispersions. These even-denominator states emerge from two distinct intra-zeroth Landau levels and exhibit displacement-field tunability. At half fillings, continuous quantum phase transitions between even-denominator states, magnetic Bloch states, and composite Fermi liquids are clearly identified upon tuning external fields. Numerical calculations support possible Moore-Read type pairing for even-denominator states, although direct probes of their exchange statistics remain important for future experiments. These results establish mixed-stacked graphene as a versatile platform for tunable correlated topological phases.

Preeclampsia (PE) is a severe pregnancy disorder caused by placental dysfunction. Protein O-fucosylation is a type of protein post translational modification that is catalyzed by protein O-fucosyltransferases (poFUTs). However, the role and underlying mechanisms of O-fucosylation/poFUT1 in PE remain elusive. Here, we revealed a lower level of poFUT1 in the plasma and placental tissues of PE patients than in normal pregnancy (NP) women. Moreover, poFUT1 deletion induced PE-like phenotypes in a mouse model. Mechanistically, we globally screened O-fucosylated proteins and identified EDIL3 with an O-fucosylation site at threonine 88. Furthermore, O-fucosylation-EDIL3 can directly interact with LIFR on trophoblasts, consequently activating the STAT3 signaling pathway, promoting the invasion and vascular remodeling ability of trophoblasts. Conversely, de-O-fucosylation-EDIL3 aggravated PE-like phenotypes by attenuating placental development in vitro and in vivo. Our data elucidate the function of poFUT1/O-fucosylation EDIL3/LIFR axis during placental development, providing glycol-based target for diagnostic and therapeutic of preeclampsia.

Non-wetting viscous drops are unusually quick compared to wetting ones, owing to the conjunction of non-wetting (which minimizes the contact with the substrate) and rotation (which minimizes the dissipation inside the liquid). Here, we report the existence of a threshold in driving force above which the speed of these objects increases about tenfold compared to previous models and experiments. We find that this effect is due to a dynamic reduction of the contact, that minimizes even more the interaction with the substrate but can also render the dynamics non-stationary - a consequence of the geometrical transformations of fast revolving drops. Paradoxically, viscosity enables this regime by impeding rapid contact equilibration, thereby reducing substrate interactions in fast-moving drops.

MYST lysine acetyltransferases (KATs) are a class of epigenetic enzymes critical for cellular function that constitute an emerging therapeutic target in cancer. Recently, several drug-like MYST inhibitors have been reported that show promise in preclinical models as well as in clinical trials of breast cancer. Understanding the specificity of these molecules is critical for their effective use as chemical probes. Here we apply an integrated profiling strategy to systematically define the potency and selectivity of drug-like MYST KAT inhibitors. First, we use optimized chemoproteomic profiling and histone acetylation biormarkers to study the industry-developed KAT inhibitor PF-9363. This reveals dose-dependent engagement of native KAT complexes, with hierarchical inhibition following the order KAT6A/B > KAT7 » KAT8 > KAT5. This pattern of target engagement is shared by the clinical candidate PF-8144. Next, we demonstrate how PF-9363's ability to disrupt capture of MYST complex members in chemoproteomic experiments can be leveraged to identify uncharacterized candidate members of these complexes, including the transcription factor FOXK2. Applying insights from these studies to WM-8014, WM-1119 and WM-3835, which have been extensively applied in the literature as MYST probes, highlights unexpected cross-inhibition and suggests a framework for how these small molecules and biomarkers may be applied to differentiate KAT6A/B and KAT7-dependent phenotypes. Finally, we benchmark the activity of PF-9363 in the NCI-60 cell line screen, providing evidence that its ability to engage KAT8 at elevated concentrations can drive acute growth inhibition. Collectively, our studies indicate the potential for MYST KAT inhibitors, including clinical candidates, to exhibit dose-dependent target engagement reminiscent of kinase inhibitors. The assays and biomarkers described here should find broad utility in assessing selective target engagement by this inhibitor class.

Charge density waves are a widespread collective electronic order in quantum materials, furnishing key insights into symmetry breaking and competing phases. However, their dynamic control with external fields remains a significant challenge. Here, we report deterministic and hysteretic switching of unidirectional charge density wave orientation via in-plane magnetic field rotation in magnetic kagome metal GdTi3Bi4. Atomically resolved spectroscopy shows two types of 3a0 × 1a0 charge density wave domains, Q1 and Q2 oriented 60° apart along two distinct crystallographic directions and separated by atomically sharp domain walls. Rotating the magnetic field drives reversible transitions between these charge density wave configurations, exhibiting a robust C2-symmetric phase diagram with pronounced hysteresis. This hysteretic switching is mediated by a field-dependent reorientation of underlying antiferromagnetic spins, revealing a tunable energy landscape with stable and metastable states and modulates the electronic charge order via spin-lattice coupling. Our findings not only demonstrate the switching of charge density wave configurations by in-plane magnetic field but also reveal the mechanism of coupling between charge density wave and magnetic fields, offering new insights into charge density wave manipulation and versatile platform for developing a spin-mediated multistate spin-charge coupling memory and programmable quantum devices.

Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as adistinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.

CD4+ T cells are key drivers of immune-mediated tissue damage and participate in complex cellular interactions that perpetuate chronic inflammation. However, the specific subsets of pathogenic CD4+ T cells and their non-immune cell partners are less well characterized. Here, we use a mouse model of primary Sjögren disease (pSjD) and identify CD153+CD4+ T cells as critical drivers of inflammation during the early stages of autoimmune pathology. We describe a CD153+CD4+ T cell-CD30+ tissue-resident fibroblast interaction that promotes fibroblast proliferation and chemokine secretion, further driving immune cell infiltration and thereby amplifying the autoimmune response. Importantly, deletion of CD153 in CD4+ T cells or neutralization of fibroblast-derived chemokines reduces lymphocytic infiltration and significantly halts autoimmune-like pathology. The CD153-CD30 axis positively correlates with disease severity in human patients. Thus, our results describe a pathogenic, therapeutically targetable CD153+CD4+ T cell-CD30+ fibroblast axis that perpetuates chronic inflammation in pSjD.

Systematic whole-protein screening and comprehensive profiling of antigen-specific CD4+ T cells are crucial for advancing vaccine design and cancer immunotherapies, yet remain technically challenging. Here, we present a high-throughput platform that utilizes large-scale class II single-chain trimer libraries to detect antigen-specific CD4+ T cells, while simultaneously profiling their antigen specificity, TCRα/β sequences, MHC restriction, whole transcriptomes, and patient/timepoint origins at single-cell resolution. Upon rigorous platform validation, we screened the full SARS-CoV-2 spike receptor binding domain in a longitudinal cohort of 22 participants, identifying 2,188 antigen-specific CD4+ T cells and showing key metrics defining the immunogenicity of class II-restricted viral antigens. We further extended the platform to whole-protein screening of HPV-16 E6/E7 in a cohort of precancerous patients, indicating HPV-specific CD4 TCRs that, upon extensive characterization, demonstrate strong therapeutic potential. By integrating high-throughput antigen screening with high-dimensional, multi-modal cellular characterization, our approach provides detailed insight into CD4+ T cell immunity, potentially guiding vaccine design and next-generation TCR-based cancer immunotherapies.

Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers and enable the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes analyzed using this pipeline highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While α and β cell composition influenced insulin and glucagon secretory traits, the abundance of δ cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and β cell replacement therapy.