👤 Tobias Rausch

Obesity and Alzheimer’s disease (AD) are epidemiologically associated. The locus coeruleus (LC)—the brain’s primary and most significant source of norepinephrine—is one of the earliest sites of neurodegeneration in AD. The LC participates in feeding behavior through connections with the hypothalamus. The cellular composition of the LC has been characterized at single-cell resolution. However, the constituent cellular signatures of genes related to energy homeostasis—such as the melanocortin pathway genes—in the LC are unclear. We performed single-nucleus RNA sequencing and spatial transcriptomics (Visium) in the human LC, and HiPlex RNAscope in the LC of mice. The melanocortin pathway gene The online version contains supplementary material available at 10.1186/s40478-026-02287-x. Show less

Pain is common among adults with heart failure (HF), but pain subtypes and associated biomarkers are understudied. The aims were to: 1) characterize chronic pain severity, neuropathic pain quality, locations, and subtypes; and 2) compare pain severity and levels of biomarkers among pain subtypes. An exploratory aim was to correlate levels of biomarkers with pain severity. This pilot descriptive study included cross-sectional data from 60 adults with HF and chronic pain. Pain was evaluated using the PainDETECT questionnaire. Blood biomarkers included interleukin (IL)-10, IL-18, IL-1β, IL-33, IL-6, IL-8, tumor necrosis factor (TNF)-α, brain-derived neurotrophic factor, leptin, adiponectin, and C-reactive protein. Descriptive statistics, Chi-square test of homogeneity, one-way analysis of variance, and Spearman correlation were used for analyses. The mean age was 70.45 (SD 7.92) years. The sample consisted of 63.3% women and 65.0% White race. Participants primarily reported nociceptive pain only (73.3%) with fewer reporting neuropathic pain only (6.7%) and mixed pain (20.0%). Current and 4-week mean pain severity scores were highest in the mixed pain subtype (p both <.05). No biomarkers were significantly different across the pain subtypes, but lower lL-10 (p=.049), and IL-33 (p=.014), were associated with higher pain severity. In this study, chronic pain and its association with underlying biomarkers were characterized. Future research with a larger sample is needed to understand the unique contributions of biomarkers with targeted pain phenotypes. Show less

Acute Myeloid Leukemia (AML) with rearranged PICALM::MLLT10 is a rare and poorly characterized entity. Here, we describe a patient with this rearrangement, and compare this case to the literature. We observed a trend towards young age, male sex, extramedullary involvement (particularly mediastinal myelosarcoma), trisomy 4, trisomy 19 and aberrant CD7-expression. It was suggested that upregulation of DOT1l or BMI1 is a key effector for subsequent leukemogenesis. However, molecular data are not available for most published cases. Interestingly, two different EZH2-mutations were detected in our case, while generally being rare in AML, which is concordant with recent reports on the occurrence of EZH2mut in this AML subtype. As a synergistic effect of BMI1 and EZH2 has already been demonstrated in other neoplasms, we hypothesize that acquiring an EZH2 mutation might be a crucial proliferation advantage in PICALM::MLLT10 positive cells. This may explain the high percentage of EZH2 mutated cases in this entity, but also supports the hypothesis of BMI1-mediated leukemogenesis. Show less

Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease  legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R. Show less

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825. Show less

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep Show less

While nuclear lamina abnormalities are hallmarks of human diseases, their interplay with epigenetic regulators and precise epigenetic landscape remain poorly understood. Here, we show that loss of the lysine acetyltransferase MOF or its associated NSL-complex members KANSL2 or KANSL3 leads to a stochastic accumulation of nuclear abnormalities with genomic instability patterns including chromothripsis. SILAC-based MOF and KANSL2 acetylomes identified lamin A/C as an acetylation target of MOF. HDAC inhibition or acetylation-mimicking lamin A derivatives rescue nuclear abnormalities observed in MOF-deficient cells. Mechanistically, loss of lamin A/C acetylation resulted in its increased solubility, defective phosphorylation dynamics and impaired nuclear mechanostability. We found that nuclear abnormalities include EZH2-dependent histone H3 Lys 27 trimethylation and loss of nascent transcription. We term this altered epigenetic landscape "heterochromatin enrichment in nuclear abnormalities" (HENA). Collectively, the NSL-complex-dependent lamin A/C acetylation provides a mechanism that maintains nuclear architecture and genome integrity. Show less