Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis.

Innate immunological signals induced by pathogen- and/or damage-associated molecular patterns are essential for adaptive immune responses, but it is unclear if the brain has a role in this process. Here we found that while the abundance of tumor-necrosis factor (TNF) quickly increased in the brain of mice following bacterial infection, intra-brain delivery of TNF mimicked bacterial infection to rapidly increase the number of peripheral lymphocytes, especially in the spleen and fat. Studies of various mouse models revealed that hypothalamic responses to TNF were accountable for this increase in peripheral lymphocytes in response to bacterial infection. Finally, we found that hypothalamic induction of lipolysis mediated the brain's action in promoting this increase in the peripheral adaptive immune response. Thus, the brain-fat axis is important for rapid linkage of innate immunity to adaptive immunity.

Hypothalamic Menin regulates systemic aging and cognitive decline.

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Author Correction: Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

The microarray data generated and analysed in this Article have been uploaded to the Gene Expression Omnibus (GEO) under accession number GSE113383 . Accordingly, the 'Data availability' section of the Methods of the original Article has been rephrased online.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.

Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice.

Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (Fmr1-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway. However, a role for autophagy in the pathophysiology of FXS is, as yet, unclear. Here we show that autophagic flux, a functional readout of autophagy, and biochemical markers of autophagy are down-regulated in hippocampal neurons of fragile X mice. We further show that enhanced activity of mammalian target of rapamycin complex 1 (mTORC1) and translocation of Raptor, a defining component of mTORC1, to the lysosome are causally related to reduced autophagy. Activation of autophagy by delivery of shRNA to Raptor directly into the CA1 of living mice via the lentivirus expression system largely corrects aberrant spine structure, synaptic plasticity, and cognition in fragile X mice. Postsynaptic density protein (PSD-95) and activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), proteins implicated in spine structure and synaptic plasticity, respectively, are elevated in neurons lacking fragile X mental retardation protein. Activation of autophagy corrects PSD-95 and Arc abundance, identifying a potential mechanism by which impaired autophagy is causally related to the fragile X phenotype and revealing a previously unappreciated role for autophagy in the synaptic and cognitive deficits associated with fragile X syndrome.

Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke.

Diabetes is a major stroke risk factor and is associated with poor functional recovery after stroke. Accumulating evidence indicates that the worsened outcomes may be due to hyperglycemia-induced cerebral vascular complications, especially disruption of the blood-brain barrier (BBB). The present study tested a hypothesis that the activation of hypoxia inducible factor-1 (HIF-1) was involved in hyperglycemia-aggravated BBB disruption in an ischemic stroke model. Non-diabetic control and Streptozotocin-induced type I diabetic mice were subjected to 90min transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Our results demonstrated that hyperglycemia induced higher expression of HIF-1α and vascular endothelial growth factor (VEGF) in brain microvessels after MCAO/reperfusion. Diabetic mice showed exacerbated BBB damage and tight junction disruption, increased infarct volume as well as worsened neurological deficits. Furthermore, suppressing HIF-1 activity by specific knock-out endothelial HIF-1α ameliorated BBB leakage and brain infarction in diabetic animals. Moreover, glycemic control by insulin abolished HIF-1α up-regulation in diabetic animals and reduced BBB permeability and brain infarction. These findings strongly indicate that HIF-1 plays an important role in hyperglycemia-induced exacerbation of BBB disruption in ischemic stroke. Endothelial HIF-1 inhibition warrants further investigation as a therapeutic target for the treatment of stroke patients with diabetes.

Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity.

Autophagy is a conserved cellular mechanism that enables the degradation and recycling of cellular organelles and proteins via the lysosomal pathway. In neurodevelopment and maintenance of neuronal homeostasis, autophagy is required to regulate presynaptic functions, synapse remodeling, and synaptic plasticity. Deficiency of autophagy has been shown to underlie the synaptic and behavioral deficits of many neurological diseases such as autism, psychiatric diseases, and neurodegenerative disorders. Recent evidence reveals that dysregulated autophagy plays an important role in the initiation and progression of neuroinflammation, a common pathological feature in many neurological disorders leading to defective synaptic morphology and plasticity. In this review, we will discuss the regulation of autophagy and its effects on synapses and neuroinflammation, with emphasis on how autophagy is regulated by epigenetic mechanisms under healthy and diseased conditions.

HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells.

Experimental evidence from human patients and animal models of diabetes has demonstrated that hyperglycemia increases blood-brain barrier (BBB) permeability, which is associated with increased risk of neurological dysfunction. However, the mechanism underlying high glucose-induced BBB disruption is not understood. Here we investigated the role of hypoxia-inducible factor-1 (HIF-1) in high glucose-induced endothelial permeability in vitro using mouse brain microvascular endothelial cells (b.End3). Our results demonstrated that high glucose (30 mM) upregulated the protein level of HIF-1α, the regulatable subunit of HIF-1, and increased the transcriptional activity of HIF-1 in the endothelial cells. At the same time, high glucose increased the paracellular permeability associated with diminished expression and disrupted continuity of tight junction proteins occludin and zona occludens protein-1 (ZO-1) of the endothelial cells. Upregulating HIF-1 activity by cobalt chloride increased the paracellular permeability of the endothelial cells exposed to normal glucose (5.5 mM). In contrast, downregulating HIF-1 activity by HIF-1α inhibitors and HIF-1α specific siRNA ameliorated the increased paracellular permeability and the alterations of distribution pattern of occludin and ZO-1 induced by high glucose. In addition, high glucose increased expression of vascular endothelial growth factor (VEGF), a downstream gene of HIF-1. Inhibiting VEGF improved the expression pattern of occludin and ZO-1, and attenuated the endothelial leakage. Furthermore, key results were confirmed in human brain microvascular endothelial cells. These results strongly indicate that HIF-1 plays an important role in high glucose-induced BBB dysfunction. The results will help us understand the molecular mechanisms involved in hyperglycemia-induced BBB dysfunction and neurological outcomes.

Transcriptomic clock predicts vascular changes of prodromal diabetic retinopathy.

Diabetic retinopathy is a common complication of long-term diabetes and that could lead to vision loss. Unfortunately, early diabetic retinopathy remains poorly understood. There is no effective way to prevent or treat early diabetic retinopathy until patients develop later stages of diabetic retinopathy. Elevated acellular capillary density is considered a reliable quantitative trait present in the early development of retinopathy. Hence, in this study, we interrogated whole retinal vascular transcriptomic changes via a Nile rat model to better understand the early pathogenesis of diabetic retinopathy. We uncovered the complexity of associations between acellular capillary density and the joint factors of blood glucose, diet, and sex, which was modeled through a Bayesian network. Using segmented regressions, we have identified different gene expression patterns and enriched Gene Ontology (GO) terms associated with acellular capillary density increasing. We developed a random forest regression model based on expression patterns of 14 genes to predict the acellular capillary density. Since acellular capillary density is a reliable quantitative trait in early diabetic retinopathy, and thus our model can be used as a transcriptomic clock to measure the severity of the progression of early retinopathy. We also identified NVP-TAE684, geldanamycin, and NVP-AUY922 as the top three potential drugs which can potentially attenuate the early DR. Although we need more in vivo studies in the future to support our re-purposed drugs, we have provided a data-driven approach to drug discovery.

Optimal wavelength band clustering for multispectral iris recognition.

This work explores the possibility of clustering spectral wavelengths based on the maximum dissimilarity of iris textures. The eventual goal is to determine how many bands of spectral wavelengths will be enough for iris multispectral fusion and to find these bands that will provide higher performance of iris multispectral recognition. A multispectral acquisition system was first designed for imaging the iris at narrow spectral bands in the range of 420 to 940 nm. Next, a set of 60 human iris images that correspond to the right and left eyes of 30 different subjects were acquired for an analysis. Finally, we determined that 3 clusters were enough to represent the 10 feature bands of spectral wavelengths using the agglomerative clustering based on two-dimensional principal component analysis. The experimental results suggest (1) the number, center, and composition of clusters of spectral wavelengths and (2) the higher performance of iris multispectral recognition based on a three wavelengths-bands fusion.

CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X.

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca2+-permeable to GluA2-containing, Ca2+-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance-a common theme in FXS and other autism spectrum disorders.

Donor-derived vasculature is required to support neocortical cell grafts after stroke.

Neural precursor cells (NPCs) transplanted into the adult neocortex generate neurons that synaptically integrate with host neurons, supporting the possibility of achieving functional tissue repair. However, poor survival and functional neuronal recovery of transplanted NPCs greatly limits engraftment. Here, we test the hypothesis that combining blood vessel-forming vascular cells with neuronal precursors improves engraftment. By transplanting mixed embryonic neocortical cells into adult mice with neocortical strokes, we show that transplant-derived neurons synapse with appropriate targets while donor vascular cells form vessels that fuse with the host vasculature to perfuse blood within the graft. Although all grafts became vascularized, larger grafts had greater contributions of donor-derived vessels that increased as a function of their distance from the host-graft border. Moreover, excluding vascular cells from the donor cell population strictly limited graft size. Thus, inclusion of vessel-forming vascular cells with NPCs is required for more efficient engraftment and ultimately for tissue repair.

Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes.

Epidemiological and clinical studies have long shown that exposure to high levels of heavy metals are associated with increased risks of neurodegenerative diseases. It is widely accepted that autophagic dysfunction is involved in pathogenesis of various neurodegenerative disorders; however, the role of heavy metals in regulation of macroautophagy/autophagy is unclear. Here, we show that manganese (Mn) induces a decline in nuclear localization of TFEB (transcription factor EB), a master regulator of the autophagy-lysosome pathway, leading to autophagic dysfunction in astrocytes of mouse striatum. We further show that Mn exposure suppresses autophagic-lysosomal degradation of mitochondria and induces accumulation of unhealthy mitochondria. Activation of autophagy by rapamycin or TFEB overexpression ameliorates Mn-induced mitochondrial respiratory dysfunction and reactive oxygen species (ROS) generation in astrocytes, suggesting a causal relation between autophagic failure and mitochondrial dysfunction in Mn toxicity. Taken together, our data demonstrate that Mn inhibits TFEB activity, leading to impaired autophagy that is causally related to mitochondrial dysfunction in astrocytes. These findings reveal a previously unappreciated role for Mn in dysregulation of autophagy and identify TFEB as a potential therapeutic target to mitigate Mn toxicity. ABBREVIATIONS: BECN1: beclin 1; CTSD: cathepsin D; DMEM: Dulbecco's Modified Eagle Medium; GFAP: glial fibrillary acid protein; GFP: green fluorescent protein; HBSS: hanks balanced salt solution; LAMP: lysosomal-associated membrane protein; LDH: lactate dehydrogenase; Lys Inh: lysosomal inhibitors; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; Mn: manganese; MTOR: mechanistic target of rapamycin kinase; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PI: propidium iodide; ROS: reactive oxygen species; s.c.: subcutaneous; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB.

Deaf and Hard of Hearing Students' Understanding of Causal and Adversative Connectives in Sentence Reading.

Deaf and hard of hearing (DHH) students tend to experience delayed development of grammatical skills in written language. However, much remains unknown about the mechanism behind this phenomenon. In the present study, the researchers used a self-paced moving-window reading task to investigate DHH students' understanding of causal and adversative connectives in Chinese. The students were similar to a hearing control group in their comprehension of the relationship between the clauses in a causal sentence. However, the DHH students were more likely than their hearing peers to find it harder to understand adversative connectives than causal connectives. More studies are needed to reveal how DHH students deal with other syntactic structures that are particularly difficult for them to learn. Educators should pay close attention to creating learning environments in which DHH students can acquire those syntactic structures in the process of using language.

Autophagy and synaptic plasticity: epigenetic regulation.

In neurons, autophagy is crucial to proper axon guidance, vesicular release, dendritic spine architecture, spine pruning and synaptic plasticity and, when dysregulated, is associated with brain disorders, including autism spectrum disorders, and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Once thought to play a housekeeping function of removing misfolded proteins or compromised organelles, neuronal autophagy is now regarded as a finely tuned, real time surveillance and clearance system crucial to synaptic integrity and function. Here we review the role of autophagy in synaptic plasticity and its regulation by epigenetic mechanisms.

Classification of hyperspectral medical tongue images for tongue diagnosis.

Human tongue is one of the important organs of the body, which carries abound of information of the health status. The images of the human tongue that are used in computerized tongue diagnosis of traditional Chinese medicine (TCM) are all RGB color images captured with color CCD cameras currently. However, this conversional method impedes the accurate analysis on the subjects of tongue surface because of the influence of illumination and tongue pose. To address this problem, this paper presents a novel approach to analyze the tongue surface information based on hyperspectral medical tongue images with support vector machines. The experimental results based on chronic Cholecystitis patients and healthy volunteers illustrate its effectiveness.

Mesh parameterization by minimizing the synthesized distortion metric with the coefficient-optimizing algorithm.

The parameterization of a 3D mesh into a planar domain requires a distortion metric and a minimizing process. Most previous work has sought to minimize the average area distortion, the average angle distortion, or a combination of these. Typical distortion metrics can reflect the overall performance of parameterizations but discount high local deformations. This affects the performance of postprocessing operations such as uniform remeshing and texture mapping. This paper introduces a new metric that synthesizes the average distortions and the variances of both the area deformations and the angle deformations over an entire mesh. Experiments show that, when compared with previous work, the use of synthesized distortion metric performs satisfactorily in terms of both the average area deformation and the average angle deformation; furthermore, the area and angle deformations are distributed more uniformly. This paper also develops a new iterative process for minimizing the synthesized distortion, the coefficient-optimizing algorithm. At each iteration, rather than updating the positions immediately after the local optimization, the coefficient-optimizing algorithm first update the coefficients for the linear convex combination and then globally updates the positions by solving the Laplace system. The high performance of the coefficient-optimizing algorithm has been demonstrated in many experiments.

Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis.

Metabolic homeostasis is regulated by the brain, but whether this regulation involves learning and memory of metabolic information remains unexplored. Here we use a calorie-based, taste-independent learning/memory paradigm to show that Drosophila form metabolic memories that help in balancing food choice with caloric intake; however, this metabolic learning or memory is lost under chronic high-calorie feeding. We show that loss of individual learning/memory-regulating genes causes a metabolic learning defect, leading to elevated trehalose and lipid levels. Importantly, this function of metabolic learning requires not only the mushroom body but also the hypothalamus-like pars intercerebralis, while NF-κB activation in the pars intercerebralis mimics chronic overnutrition in that it causes metabolic learning impairment and disorders. Finally, we evaluate this concept of metabolic learning/memory in mice, suggesting that the hypothalamus is involved in a form of nutritional learning and memory, which is critical for determining resistance or susceptibility to obesity. In conclusion, our data indicate that the brain, and potentially the hypothalamus, direct metabolic learning and the formation of memories, which contribute to the control of systemic metabolic homeostasis.

Mesh simplification with hierarchical shape analysis and iterative edge contraction.

This paper presents a novel mesh simplification algorithm. It decouples the simplification process into two phases: shape analysis and edge contraction. In the analysis phase, it imposes a hierarchical structure on a surface mesh by uniform hierarchical partitioning, marks the importance of each vertex in the hierarchical structure, and determines the affected regions of each vertex at the hierarchical levels. In the contraction phase, it also divides the simplification procedure into two steps: half-edge contraction and optimization. In the first step, memoryless quadric metric error and the importance of vertices in the hierarchical structure are combined to determine one operation of half-edge contraction. In the second step, it repositions the vertices in the half-edge simplified mesh by minimizing the multilevel synthesized quadric error on the corresponding affected regions from the immediately local to the more global. The experiments illustrate the competitive results.