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Abstract Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Abstract Background Retinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients. Methods This prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients. Results RBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71–22.92) versus 9.59 (6.57–13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P 0.7. Conclusion Plasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.

Abstract Background Pure red cell aplasia (PRCA) in neuromyelitis optica spectrum disorder (NMOSD) has not been reported before. This study presents a patient with NMOSD who developed PRCA. Case presentation A 54-year-old female was admitted in January 2023 for dysuria and progressive numbness and weakness of lower limbs. She had difficulty standing and walking in a straight line. Both lower limbs were positive for the Babinski and Chaddock signs. MRI showed abnormal signals in the spinal cord. Aquaporin-4-IgG (AQP-4-IgG) was positive (1:320), and NMOSD was confirmed. Intravenous immunoglobulin and methylprednisolone were given, and the symptoms improved. She received maintenance treatment with methylprednisolone tablets, and the dosage was gradually reduced. She was readmitted for fatigue, palpitations, and shortness of breath in May 2023. Bone marrow aspiration and biopsy showed elevated erythroid precursors and erythroid hypoplasia, with normal megakaryocytes and myeloid precursors. Chest CT showed no mediastinal lymph node enlargement or thymoma. PRCA secondary to NMOSD was diagnosed. Recombinant human erythropoietin was given. Her condition improved after 1.5 months, as indicated by blood cell count and imaging. Conclusions This case suggests that PRCA can be secondary to NMOSD. A comprehensive immune function and bone marrow evaluation might be necessary if abnormal blood cells are found while managing NMOSD.

Plant immunity is largely governed by nucleotide-binding leucine-rich repeat receptor (NLR). Here, we examine the molecular activation and inhibition mechanisms of the wheat CC-type NLR Yr10CG, a previously proposed candidate for the Yr10 resistance gene. Though recent studies have identified YrNAM as the true Yr10 gene, Yr10CG remains an important NLR in understanding NLR-mediated immunity in wheat. In this study, we found that the overexpression of either the full-length Yr10CG or its CC domain in Nicotiana benthamiana did not trigger cell death, suggesting a robust autoinhibitory mechanism within Yr10CG. However, we observed that mutations in the conserved MHD motif, specifically D502G, activated Yr10CG and induced cell death. Structural modeling indicated that this mutation disrupted key interactions within the MHD motif, promoting local flexibility and activation. We further explored the effector recognition potential of Yr10CG by creating chimeric proteins with Sr50 domains, revealing that both the NB-ARC and LRR domains are necessary for effector recognition, while the CC domain likely functions in downstream immune signaling. Additionally, disrupting membrane localization through an L11E mutation abolished Yr10CG self-activation, suggesting a requirement for membrane association in immune activation. Our findings contribute to the understanding of CC-NLR activation and autoinhibition mechanisms, highlighting the potential of Yr10CG in NLR engineering for crop resistance improvement.

Objective: The olfactory bulb (OB) codes for sensory information and contributes to the control of energy metabolism by regulating foraging and cephalic phase responses. Mitral cells are the main output neurons of the OB. The glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) system in the OB (GLP-1OB) has been shown to be a major regulator of mitral cell activity but its function in vivo is unclear. Therefore, we investigated the role of GLP-1OB in foraging behavior and odor-evoked Cephalic Phase Insulin Release (CPIR). Methods and results: By fluorescent labeling, we confirmed the presence of GLP-1 producing neurons and the expression of GLP-1R in the mouse OB. In response to food odor presentation, we collected blood, quantified plasma insulin by ELISA and showed the existence of an odor-evoked CPIR in lean mice but its absence in obese animals. Expression of shRNA against preproglucagon mRNA in the OB resulted in blunted CPIR in lean mice. Injecting Exendin (9-39), a GLP-1R antagonist, into the OB of lean mice also resulted in decreased CPIR. Since parasympathetic cholinergic input to the pancreas is known to be partly responsible for CPIR, we systemically administered the muscarinic M3 receptor antagonist 4-DAMP which resulted in a reduced odor-evoked CPIR. Finally, local injection of Exendin (9-39) in the OB extinguished olfactory foraging in lean mice whereas the injection of the GLP-1R agonist Exendin-4 rescued the loss of foraging behavior in obese mice. Conclusions: Our results demonstrate that GLP-1OB controls olfactory foraging and is required for odor-evoked CPIR. We describe a new crucial brain function for GLP-1 and GLP-1R expressed within the brain.

Objective: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT2CR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here. Methods: We profiled PPG neurons in the nucleus of the solitary tract (PPGNTS) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGNTS neurons for obesity medication effects on food intake by virally ablating PPGNTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. Results: We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTS clusters and that lorcaserin significantly activated PPGNTS neurons. Accordingly, ablation of PPGNTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPGNTS 5-HT2CR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy. Conclusions: These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGNTS neurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HT2CR agonists.

The obligate biotrophic fungus Puccinia striiformis f. sp. tritici, which causes yellow (stripe) rust disease, is among the leading biological agents resulting in tremendous yield losses on global wheat productions per annum. The combatting strategies include, but are not limited to, fungicide applications and the development of resistant cultivars. However, evolutionary pressure drives rapid changes, especially in its “effectorome” repertoire, thus allowing pathogens to evade and breach resistance. The extracellular and intracellular effectors, predominantly secreted proteins, are tactical arsenals aiming for many defense processes of plants. Hence, the identity of the effectors and the molecular mechanisms of the interactions between the effectors and the plant immune system have long been targeted in research. The obligate biotrophic nature of P. striiformis f. sp. tritici and the challenging nature of its host, the wheat, impede research on this topic. Next-generation sequencing and novel prediction algorithms in bioinformatics, which are accompanied by in vitro and in vivo validation approaches, offer a speedy pace for the discovery of new effectors and investigations of their biological functions. Here, we briefly review recent findings exploring the roles of P. striiformis f. sp. tritici effectors together with their cellular/subcellular localizations, host responses, and interactors. The current status and the challenges will be discussed. We hope that the overall work will provide a broader view of where we stand and a reference point to compare and evaluate new findings.