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| Open AccessA role for nNOS in mediating stress and female sexual behavior in mice
Developmental stress can detrimentally affect adult female reproductive behavior, influencing sexual receptivity and fertility. Recent work has demonstrated neuronal nitric oxide (NO) synthase (nNOS)-promoted NO release in the ventromedial hypothalamus as a nexus between pre-pubertal stress and adult sexual behavior in mice.
- Konstantina Chachlaki
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Article
| Open AccessLSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice
Even though glucocorticoids are potent anti-inflammatory agents, they can cause muscle wasting. Here, the authors show that targeting the glucocorticoid receptor coactivator LSD1 limits muscle loss without reducing the drugs’ efficiency on the immune system.
- Qingshuang Cai
- , Rajesh Sahu
- & Delphine Duteil
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Article
| Open AccessDietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion
Enteroendocrine cells in the gut sense food to regulate feeding behavior. Here, the authors show in Drosophila L-glutamate reduces the frequency of calcium oscillations in enteroendocrine cells and decreases the release of NPF, thereby reducing the activation of a pair of anorexic enteric neurons.
- Junjun Gao
- , Song Zhang
- & Zheng Guo
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Article
| Open AccessBIN1 knockdown rescues systolic dysfunction in aging male mouse hearts
Cardiac dysfunction is a hallmark of aging in humans and mice. Here, the authors show that by restoring youthful Bridging Integrator 1 (BIN1) protein levels in the hearts of 24-month-old mice in vivo cardiac systolic function is rejuvenated, and the aging phenotype partially reversed within two weeks.
- Maartje Westhoff
- , Silvia G. del Villar
- & Rose E. Dixon
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Article
| Open AccessBacterial peptidoglycan acts as a digestive signal mediating host adaptation to diverse food resources in C. elegans
Here, by using a food digestion model in C. elegans, the authors identify a mechanism by which bacterial peptidoglycan (PGN) interacts with Bacterial Colonization Factor-1 (BCF-1) triggering C. elegans to expand its ability to consume a wide range of foods in their natural environment.
- Fanrui Hao
- , Huimin Liu
- & Bin Qi
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Article
| Open AccessConjunctive encoding of exploratory intentions and spatial information in the hippocampus
The hippocampus maps space, but its role in encoding investigatory intentions is unclear. Here the authors show that certain CA1 neurons encode both spatial information and animals’ intention to explore, depending on input from lateral entorhinal cortex.
- Yi-Fan Zeng
- , Ke-Xin Yang
- & Ning Zhou
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Article
| Open AccessLipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis
Oxidative stress triggers lipid accumulation in cells by sequestering triglycerides in lipid droplets. Here, the authors show that lipopolysaccharide-binding protein interacts with redox sensor PRDX4 to control lipid-redox balance and promotes triglyceride accumulation in droplets by capturing unsaturated lipids.
- Qilun Zhang
- , Xuting Shen
- & Haoshu Fang
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Article
| Open AccessProtein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis
Vascular protein disulfide isomerase (PDI) regulates thrombosis and targeting extracellular PDI remains a promising antithrombotic approach. Here, the authors show that PDI cleaves allosteric disulfides on histidine-rich glycoprotein to influence its functions during coagulation and thus fine-tune the kinetics of thrombus formation.
- Keyu Lv
- , Shuai Chen
- & Chao Fang
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Article
| Open AccessMultisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
Repetitive audio-visual stimulation, or sensory flicker, can modulate oscillations in a non-invasive manner. Here the authors demonstrate the potential of flicker in individuals with epilepsy undergoing intracranial seizure monitoring.
- Lou T. Blanpain
- , Eric R. Cole
- & Annabelle C. Singer
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Article
| Open AccessAn Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress
In this study, Vergani-Junior et al. show that increased expression of the argonaute ALG-1 in long-lived worms improves oxidative stress resistance through the modulation of microRNAs that downregulate the protein disulfide isomerase pathway.
- Carlos A. Vergani-Junior
- , Raíssa De P. Moro
- & Marcelo A. Mori
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Article
| Open AccessStress increases hepatic release of lipocalin 2 which contributes to anxiety-like behavior in mice
Cross talk between periphery and the central nervous system may contribute to stress associated behaviours. Here the authors identified liver-derived lipocalin 2 as a peripheral factor that elicits anxiety-like behaviours via modulating medial prefrontal neural activity.
- Lan Yan
- , Fengzhen Yang
- & Li Zhang
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Article
| Open AccessPaternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring
The dietary factors causing varying intergenerational responses are not fully identified. Here, the authors show that the relative proportion of protein, fats, and carbohydrates in paternal diets before conception differentially influences the phenotype of the next-generation offspring on energy metabolism and behaviour.
- Angela Jane Crean
- , Alistair McNair Senior
- & Stephen James Simpson
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Article
| Open AccessCold-induced FOXO1 nuclear transport aids cold survival and tissue storage
How tissues adapt to extreme cold is not well understood. Here, the authors discover a mechanism that promotes FOXO1-mediated cold survival gene transcription at low temperatures, with potential implications for long-term tissue storage for transplantation.
- Xiaomei Zhang
- , Lihao Ge
- & Jingxing Ou
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Article
| Open AccessObesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk
Obesity represents a risk factor for cancer and compromises immune function, however the mechanisms linking the two together are not fully known. Here authors show in a mouse sarcoma model that obesity increases tumour incidence, impairs intra-tumoral T cell immunity but paradoxically increases sensitivity to immune therapy via impairing immunoediting.
- Alexander Piening
- , Emily Ebert
- & Ryan M. Teague
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Article
| Open AccessInvolution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution. Here, the authors demonstrate that physiologic aging induced involution and thermogenic dysfunction result from pyroptotic signalling activation.
- Xiaofan Yu
- , Gabrielle Benitez
- & Daorong Feng
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Article
| Open AccessTM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction
Adipose tissue adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Here, the authors show that the deletion of TM4SF19 expressed in lipid-associated macrophages, enhances the clearance of dying adipocytes, thereby improving local and systemic insulin sensitivity as well as energy expenditure.
- Cheoljun Choi
- , Yujin L. Jeong
- & Yun-Hee Lee
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Article
| Open AccessMapping cell-to-tissue graphs across human placenta histology whole slide images using deep learning with HAPPY
Placenta histopathology for maternal and newborn health is highly specialised and time consuming. Here, authors present a deep learning pipeline for quantifying cells and tissues in placenta whole slide images, revealing biological and clinical insights.
- Claudia Vanea
- , Jelisaveta Džigurski
- & Christoffer Nellåker
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Article
| Open AccessNaked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
| Open AccessActivation of the insulin receptor by insulin-like growth factor 2
IGF2 has a distinct binding affinity for two insulin receptor (IR) isoforms and mimics insulin’s function. Here, the authors present the activation mechanism of IR by IGF2 and reveal the molecular basis for IGF2’s different affinity for two IR isoforms.
- Weidong An
- , Catherine Hall
- & Eunhee Choi
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Article
| Open AccessMyosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads
Myosin-binding protein C (MyBP-C) resides and interacts with the myosin filaments in striated muscle and regulates contraction via an unclear mechanism. Here, the authors demonstrate that MyBP-C regulates the performance of myosin heads.
- Anthony L. Hessel
- , Nichlas M. Engels
- & Samantha P. Harris
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Article
| Open AccessSNX8 enables lysosome reformation and reverses lysosomal storage disorder
Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.
- Xinran Li
- , Cong Xiang
- & Xin-Hua Feng
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Article
| Open AccessOsteocyte mitochondria regulate angiogenesis of transcortical vessels
Osteocytes are the key cellular components of cortical bone. Here they show that osteocytes transfer mitochondria to the endothelial cells of transcortical vessels (TCVs), which promotes angiogenesis and increases function of the TCV network.
- Peng Liao
- , Long Chen
- & Junjie Gao
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Article
| Open AccessTrimethylamine N-oxide impairs β-cell function and glucose tolerance
β-Cell dysfunction is a hallmark of type 2 diabetes. Here, the authors show that trimethylamine N-oxide (TMAO (a microbiota metabolite)) induces β-cell dysfunction and type 2 diabetes in mice through NLRP3 inflammasome activation and calcium transients.
- Lijuan Kong
- , Qijin Zhao
- & Pingping Li
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Article
| Open AccessHepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver
The liver is segregated into spatially organized areas that serve distinct functions, though how these zones are patterned remains unclear. Here they show that mTORC1 controls spatial segregation of liver metabolic functions via modulation of Wnt signaling, and find that impaired zonation is also observed in pigs given total parenteral nutrition.
- Ana Belén Plata-Gómez
- , Lucía de Prado-Rivas
- & Alejo Efeyan
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Article
| Open AccessAn organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome
Endocrinologists have traditionally focused on studying one hormone or organ system at a time. Here the authors use transcriptomic data from the mouse lemur to globally characterize primate hormonal signaling, describing hormone sources and targets, identifying conserved and primate specific regulation, and elucidating principles of the network.
- Shixuan Liu
- , Camille Ezran
- & James E. Ferrell Jr.
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Article
| Open AccessmicroRNA-33 controls hunger signaling in hypothalamic AgRP neurons
AgRP neurons regulate feeding behavior by promoting signals of hunger. Here, the authors show that miR-33, represses the activity of AgRP neurons, and selective loss of miR-33 in AgRP neurons promotes obesity and metabolic dysfunction in mice.
- Nathan L. Price
- , Pablo Fernández-Tussy
- & Carlos Fernández-Hernando
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Article
| Open AccessA single-cell atlas of Drosophila trachea reveals glycosylation-mediated Notch signaling in cell fate specification
Studying Drosophila trachea development can inform the mechanisms of growth of all tubular structures. Here, the authors generate a transcriptomic cell atlas of the developing fly trachea and establish roles for Notch signaling, which may be disrupted by diet-induced glycosylation.
- Yue Li
- , Tianfeng Lu
- & Hai Huang
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Article
| Open AccessFunctional analysis of the human perivascular subarachnoid space
Functional implications of subarachnoid space anatomy remain unclear. Here, the authors show by human in vivo imaging that an intrathecal tracer propagates antegrade along the major cerebral arteries within a perivascular subarachnoid space facilitating tracer passage towards the brain.
- Per Kristian Eide
- & Geir Ringstad
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Article
| Open AccessALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice
Cardiac macrophage contributes to the onset of cardiac fibrosis, but the underneath mechanisms remain unclear. Here the authors show that mouse cardiac macrophages from circulating monocytes may trans-differentiate into myofibroblast under hypertensive conditions for fibrosis development, with an AKLBH5/IL11 molecular axis modulating this macrophage-to-myofibroblast transition.
- Tao Zhuang
- , Mei-Hua Chen
- & Cheng-Chao Ruan
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Article
| Open AccessNDUFS4 regulates cristae remodeling in diabetic kidney disease
Mitochondrial Ndufs4, a subunit of complex I, is a regulator of the electron transport chain. Here, the authors show that forced expression of Ndufs4 in podocytes improves the assembly of respiratory supercomplexes, maintains cristae integrity, and mitigates the progression of diabetic kidney disease
- Koki Mise
- , Jianyin Long
- & Farhad R. Danesh
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Article
| Open AccessA GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis
The endometrium is activated by the pregnancy hormones estrogen and progesterone to facilitate embryo implantation, and errors in endometrial responsiveness can lead to reduced fertility or endometriosis. Here they show that GREB1 interacts with hormone receptors in the endometrium, leading to normal or pathological consequences depending on the hormones involved.
- Sangappa B. Chadchan
- , Pooja Popli
- & Ramakrishna Kommagani
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Article
| Open AccessThe proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
In the kidney, maintaining permeability of the filtration barrier is critical. Here, Sachs W. et al show that homeostasis of podocytes and glomerular endothelial cells relies on differing proteasome constitutions which orchestrate endocytic activity in addition to protein degradation.
- Wiebke Sachs
- , Lukas Blume
- & Catherine Meyer-Schwesinger
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessCellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Upon physiological injury, hepatocytes transdifferentiate into biliary epithelial cells, a process involving molecular rewiring. Here, authors show that Sox4 organizes the early steps, acting as a pioneer factor to decommission hepatocyte enhancers and open chromatin around biliary genes.
- Takeshi Katsuda
- , Jonathan H. Sussman
- & Ben Z. Stanger
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Article
| Open AccessDirect contribution of the sensory cortex to the judgment of stimulus duration
The neural substrates of time perception are still unclear. Here, the authors show that as rats judged tactile stimuli, optogenetic manipulation of somatosensory cortex systematically altered perception of stimulus intensity and of duration, unveiling a multiplexed code.
- Sebastian Reinartz
- , Arash Fassihi
- & Mathew E. Diamond
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Article
| Open AccessReducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans
Synthesis of ribosomal RNA (rRNA) by Pol I sustains cell growth but is highly energy demanding. Here the authors show that curbing of Pol I activity lowers systemic energy utilization and delays metabolic aging by reducing triglyceride lipolysis and mitochondrial oxygen consumption.
- Samim Sharifi
- , Prerana Chaudhari
- & Maria Ermolaeva
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Article
| Open AccessRunx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo
Hematopoietic stem cells are supported by niche cells that help balance stem cell self-renewal and differentiation. Here they show that Runx1 deletion in the embryonic perivascular HSC niche impairs hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM.
- Zaniah N. Gonzalez Galofre
- , Alastair M. Kilpatrick
- & Mihaela Crisan
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Article
| Open AccessHigh resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing
Advancements in spatial transcriptomics technologies have enabled the analysis of gene expression at cellular resolution in situ. The authors applied direct RNA hybridization-based in situ sequencing (dRNA HybISS) and developed a computational tool, CellScopes, to study gene expression in mouse kidneys, identifying cellular changes and interactions during injury and repair.
- Haojia Wu
- , Eryn E. Dixon
- & Benjamin D. Humphreys
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Article
| Open AccessAdipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape
Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.
- Isabel Reinisch
- , Helene Michenthaler
- & Andreas Prokesch
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Article
| Open AccessMultigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification
The mechanisms through which multigenerational paternal obesity affects spermatogenesis in offspring remain poorly understood. Here, the authors show that it affects Wt1 m6A modifications, decreasing the fertility of offspring.
- Yong-Wei Xiong
- , Hua-Long Zhu
- & Hua Wang
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Article
| Open AccessPolar bear energetic and behavioral strategies on land with implications for surviving the ice-free period
Declining Arctic sea ice is increasing polar bear land use. Here, the authors follow 20 different polar bears on land over 3 years and measure daily energy expenditure finding that despite behavioural and diet plasticity the bears are at risk of starvation.
- Anthony M. Pagano
- , Karyn D. Rode
- & Charles T. Robbins
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Article
| Open AccessA common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis
Authors show that a common SNP upregulates endometrial Wnt4 expression and proimplantation genes in mouse proestrus and estrus. They suggest that this increases uterine permissiveness to embryo invasion, while decreasing resistance to invasion in reproductive cancers and endometriosis.
- Mihaela Pavličev
- , Caitlin E. McDonough-Goldstein
- & Louis Muglia
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Article
| Open AccessProtection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
- Camilla Lund
- , Pablo Ranea-Robles
- & Christoffer Clemmensen
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Article
| Open AccessThe impact of reproductive factors on the metabolic profile of females from menarche to menopause
Here, the authors explore the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits in over 65,000 UK Biobank to explore whether reproductive factors are likely to impact females’ metabolic profile later in life.
- Gemma L. Clayton
- , Maria Carolina Borges
- & Deborah A. Lawlor
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Article
| Open AccessRelaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status
Restoring mitochondrial function has emerged as a promising therapeutic strategy for diabetic retinopathy. Here, the authors show that mitochondrial hyperfusion blunts mitophagy during the disease process, and that rescuing this process pharmacologically confers retinal neuroprotection independent of an improved glycaemic status in type-1 diabetic mice.
- Aidan Anderson
- , Nada Alfahad
- & Jose R. Hombrebueno
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Article
| Open AccessIdentification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes
After partial liver resection, the remaining liver blood vessels receive more blood flow and get mechanically stretched. Here the authors show that MYDGF is released from the stretched cells of these liver vessels, and that it is required and sufficient to promote liver regeneration and cell proliferation.
- Linda Große-Segerath
- , Paula Follert
- & Eckhard Lammert
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Article
| Open AccessResolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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Article
| Open AccessSecretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice
The mechanism by which central secretin regulates metabolism is unclear. Here, the authors show that ventromedial hypothalamus-derived secretin maintains energy and bone homeostasis by controlling food intake and sympathetic nerve activity.
- Fengwei Zhang
- , Wei Qiao
- & Billy Kwok Chong Chow
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Article
| Open AccessThe liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity
Blood vessel integrity is critical to maintain brain health. Here, the authors show that both the liver and the muscles secrete HFE2, a protein that promotes blood vessel integrity in healthy animals and in an animal model for multiple sclerosis.
- Xue Fan Wang
- , Robin Vigouroux
- & Philippe P. Monnier