Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation.

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.

miR-21-5p-loaded bone mesenchymal stem cell-derived exosomes repair ovarian function in autoimmune premature ovarian insufficiency by targeting MSX1.

RESEARCH QUESTION: What is the effect of micro-RNA (miR)-21-5p-loaded bone marrow mesenchymal stem cell-derived exosomes (miR-21-Exo) on autoimmune premature ovarian insufficiency (POI)? DESIGN: The Cell Counting Kit 8 (CCK8) assay, fluorescence-activated cell sorting, western blotting, quantitative reverse transcriptase (qRT)-PCR and enzyme-linked immunosorbent assay (ELISA) verified the effect of miR-21-Exo on interferon-γ (IFN-γ)-induced KGN cells. qRT-PCR, western blotting and dual-luciferase reporter gene assays verified that miR-21-Exo mediated Msh homeobox 1 (MSX1) regulation of the Notch signalling pathway and that miR-21 interacted directly with MSX1. The effects of miR-21-Exo on the ovaries were verified by monitoring of the oestrous cycle, haematoxylin and eosin staining, follicle counts, ELISA, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL), western blotting and qRT-PCR. RESULTS: The results showed that miR-21-Exo promoted IFN-γ-induced KGN cell proliferation and hormone synthesis, and inhibited apoptosis. Using dual-luciferase reporter gene assays, miR-21 and MSX1 were shown to have direct interactions. Moreover, the findings elucidated that miR-21-Exo inhibited cell apoptosis and promoted hormone synthesis by mediating MSX1 to regulate the Notch signalling pathway. miR-21-Exo restored the ovarian structure in a mouse model of autoimmune POI, promoted endocrine function and proliferation, and inhibited apoptosis and inflammation in vivo. CONCLUSIONS: This study demonstrates that miR-21-Exo regulates the MSX1-mediated Notch signalling pathway to inhibit granulosa cell apoptosis and improve hormone synthesis function, providing insight into a potential mechanism of molecular therapy for the treatment of autoimmune POI.

Boron-Containing Mesoporous Silica Nanoparticles with Effective Delivery and Targeting of Liver Cancer Cells for Boron Neutron Capture Therapy.

Nanocarriers have been researched comprehensively for the development of novel boron-containing agents in boron neutron capture therapy (BNCT). We designed and synthesized a multifunctional mesoporous silica nanoparticle (MSN)-based boron-containing agent. The latter was coated with a lipid bilayer (LB) and decorated with SP94 peptide (SFSIIHTPILPL) on the surface as SP94-LB@BA-MSN. The latter incorporated boric acid (BA) into hydrophobic mesopores, coated with an LB, and modified with SP94 peptide on the LB. SP94-LB@BA-MSN enhanced nano interface tumor-targeting ability but also prevented the premature release of drugs, which is crucial for BNCT because adequate boron content in tumor sites is required. SP94-LB@BA-MSN showed excellent efficacy in the BNCT treatment of HepG-2 cells. In animal studies with tumor-bearing mice, SP94-LB@BA-MSN exhibited a satisfactory accumulation at the tumor site. The boron content reached 40.18 ± 5.41 ppm in the tumor site 4 h after injection, which was 8.12 and 15.51 times higher than those in mice treated with boronated phenylalanine and those treated with BA. For boron, the tumor-to-normal tissue ratio was 4.41 ± 1.13 and the tumor-to-blood ratio was 5.92 ± 0.45. These results indicated that nanoparticles delivered boron to the tumor site effectively while minimizing accumulation in normal tissues. In conclusion, this composite (SP94-LB@BA-MSN) shows great promise as a boron-containing delivery agent for the treatment of hepatocellular carcinoma using BNCT. These findings highlight the potential of MSNs in the field of BNCT.

Separate gut-brain circuits for fat and sugar reinforcement combine to promote overeating.

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits is poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for the detection of dietary fats and sugars. Using activity-dependent genetic capture of vagal neurons activated in response to gut infusions of nutrients, we demonstrate the existence of separate gut-brain circuits for fat and sugar sensing that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases nigrostriatal dopamine release and overeating compared with fat or sugar alone. This work provides new insights into the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.

Self-Supervised Fragment Alignment With Gaps.

Image alignment and registration methods typically rely on visual correspondences across common regions and boundaries to guide the alignment process. Without them, the problem becomes significantly more challenging. Nevertheless, in real world, image fragments may be corrupted with no common boundaries and little or no overlap. In this work, we address the problem of learning the alignment of image fragments with gaps (i.e., without common boundaries or overlapping regions). Our setting is unsupervised, having only the fragments at hand with no ground truth to guide the alignment process. This is usually the situation in the restoration of unique archaeological artifacts such as frescoes and mosaics. Hence, we suggest a self-supervised approach utilizing self-examples which we generate from the existing data and then feed into an adversarial neural network. Our idea is that available information inside fragments is often sufficiently rich to guide their alignment with good accuracy. Following this observation, our method splits the initial fragments into sub-fragments yielding a set of aligned pieces. Thus, sub-fragmentation allows exposing new alignment relations and revealing inner structures and feature statistics. In fact, the new sub-fragments construct true and false alignment relations between fragments. We feed this data to a spatial transformer GAN which learns to predict the alignment between fragments gaps. We test our technique on various synthetic datasets as well as large scale frescoes and mosaics. Results demonstrate our method's capability to learn the alignment of deteriorated image fragments in a self-supervised manner, by examining inner image statistics for both synthetic and real data.

Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation.

The hippocampus (HPC), traditionally known for its role in learning and memory, has emerged as a controller of food intake. While prior studies primarily associated the HPC with food intake inhibition, recent research suggests a critical role in appetitive processes. We hypothesized that orexigenic HPC neurons differentially respond to fats and/or sugars, potent natural reinforcers that contribute to obesity development. Results uncover previously-unrecognized, spatially-distinct neuronal ensembles within the dorsal HPC (dHPC) that are responsive to separate nutrient signals originating from the gut. Using activity-dependent genetic capture of nutrient-responsive HPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific preference through different mechanisms. Sugar-responsive neurons encode an appetitive spatial memory engram for meal location, whereas fat-responsive neurons selectively enhance the preference and motivation for fat intake. Collectively, these findings uncover a neural basis for the exquisite specificity in processing macronutrient signals from a meal that shape dietary choices.

Ventral hippocampus neurons encode meal-related memory.

The ability to encode and retrieve meal-related information is critical to efficiently guide energy acquisition and consumption, yet the underlying neural processes remain elusive. Here we reveal that ventral hippocampus (HPCv) neuronal activity dynamically elevates during meal consumption and this response is highly predictive of subsequent performance in a foraging-related spatial memory task. Targeted recombination-mediated ablation of HPCv meal-responsive neurons impairs foraging-related spatial memory without influencing food motivation, anxiety-like behavior, or escape-mediated spatial memory. These HPCv meal-responsive neurons project to the lateral hypothalamic area (LHA) and single-nucleus RNA sequencing and in situ hybridization analyses indicate they are enriched in serotonin 2a receptors (5HT2aR). Either chemogenetic silencing of HPCv-to-LHA projections or intra-HPCv 5HT2aR antagonist yielded foraging-related spatial memory deficits, as well as alterations in caloric intake and the temporal sequence of spontaneous meal consumption. Collective results identify a population of HPCv neurons that dynamically respond to eating to encode meal-related memories.

Long-term fencing can't benefit plant and microbial network stability of alpine meadow and alpine steppe in Three-River-Source National Park.

A great number of fencing facilities has been established in Three-River-Source National Park. However, with the transformation of wild animals into the main consumers of grassland ecosystem and the increasing years of fence (>15 years), whether the fence still has a positive effect on grassland ecosystem has become controversial. Therefore, taking the alpine steppe and alpine meadow in Three-River-Source National Park as the case study, this study focused on the effects of long-term enclosure on different ecological components by investigating plant communities, soil physical and chemical characteristics and soil microbial characteristics (16S, ITS). Furthermore, we evaluated the ecological benefits of long-term fencing based on the stability of plant communities and microbial networks. We found that fencing did not significantly promote the stability of plant community in different grassland types. The analysis of bacteria-fungal symbiotic network indicated that fencing significantly reduced the stability of soil microbial network in alpine meadows. The results of structural equation showed that the microbial community was indirectly affected by the changes of soil moisture content (SMC) and soil total nutrient content in the alpine steppe, and the stability of microbial network was significantly correlated with the diversity of fungal community. In alpine meadows, fencing indirectly affected soil microbial community by changing SMC and pH. High SMC was not conducive to microbial network stability, while high plant community stability was beneficial to microbial network stability. Network stability was remarkably related to bacterial community composition and diversity, as well as fungal community diversity. Therefore, in Three-River-Source National Park, the positive effects of long-term fencing on various components in different grassland types are weak, especially the negative effects on the stability of soil microbial community in alpine meadows may also weaken the stability of the ecosystem, which is not conducive to the ecological protection of grassland ecosystem.

Spatial-temporal variations of forest and grassland phenology in the Yellow River Basin during 2000-2018.

The study of vegetation phenology is of great significance for understanding global climate change. The Yellow River basin has a wide spatial range and a complex ecological environment. The phenological characteristics of forest and grassland need further clarification. Based on the MODIS-EVI data from 2000 to 2018, we extracted the phenology of forest and grassland in the Yellow River basin using piecewise logistic and double logistic phenological models with the corresponding curvature change extremum method and derivative method, respectively. The temporal and spatial variations of phenological parameters were analyzed. The start of growing season (SOS) was at 90-165 day of year (DOY), and gradually delayed from southeast to northwest. The increase of 100 m elevation delayed SOS 0.94 d, and the SOS of forest was earlier than that of grassland. The end of growing season (EOS) was at 270-315 DOY, which delayed from west to southeast. For every 100 m increase in altitude, the EOS advanced 0.63 d, with EOS of forest being later than that of grassland. The length of growing season (LOS) was 110-230 d, which shortened gradually from southeast to northwest. The LOS of forest was larger than that of grassland. During the study, SOS showed an advance trend from 2000 to 2018 with a rate of 4.1 d·(10 a)-1, and the proportion of spatial advance area was 73.2%. There was an obvious advance in the central part of the basin. EOS generally showed a significant postponement trend with a rate of 2.3 d·(10 a)-1, and the proportion of spatially delayed area was 63.4%, the phenological advance and delay of forest was less stronger than that of grassland. LOS showed a significant prolongation trend with a rate of 6.4 d·(10 a)-1, and the proportion of spatial extension was 71.8%. The piecewise Logistic and double Logistic phenological models and the corresponding curvature extremum method and derivative method were suitable for the extraction of natural vegetation in the Yellow River Basin. The overall LOS of forest and grassland showed a prolonging trend, which was shortened with the increases of altitude. The LOS of forest was longer than that of grassland in the study area.

Computed tomography findings, associated factors, and management of pulmonary nodules in 54,326 healthy individuals.

Introduction: To investigate the pulmonary nodules detected by low-dose computed tomography (LDCT), identified factors affecting the size and number of pulmonary nodules (single or multiple), and the pulmonary nodules diagnosed and management as lung cancer in healthy individuals. Methods: A retrospective analysis was conducted on 54,326 healthy individuals who received chest LDCT screening. According to the results of screening, the detection rates of pulmonary nodules, grouped according to the size and number of pulmonary nodules (single or multiple), and the patients' gender, age, history of smoking, hypertension, and diabetes were statistically analyzed to determine the correlation between each factor and the characteristics of the nodules. The pulmonary nodules in healthy individuals diagnosed with lung cancer were managed with differently protocols. Results: The detection rate of pulmonary nodules was 38.8% (21,055/54,326). The baseline demographic characteristics of patients with pulmonary nodules were: 58% male and 42% female patients, 25.7% smoking and 74.3% nonsmoking individuals, 40-60 years old accounted for 49%, 54.8% multiple nodules, and 45.2% single nodules, and ≤5-mm size accounted for 80.4%, 6-10 mm for 18.2%, and 11-30 mm for 1.4%. Multiple pulmonary nodules were more common in hypertensive patients. Diabetes is not an independent risk factor for several pulmonary nodules. Of all patients with lung nodules, 26 were diagnosed with lung cancer, accounting for 0.1% of all patients with pulmonary nodules, 0.6% with nodules ≥5 mm, and 2.2% with nodules ≥8 mm, respectively. Twenty-six patients with lung cancer were treated with surgical resection (57.7%), microwave ablation (MWA, 38.5%), and follow-up (3.8%). Conclusions: LDCT was suitable for large-scale pulmonary nodules screening in healthy individuals, which was helpful for the early detection of suspicious lesions in the lung. In addition to surgical resection, MWA is an option for early lung cancer treatment.

Cell membrane camouflaged cerium oxide nanocubes for targeting enhanced tumor-selective therapy.

Anticancer therapies with profound efficacy but negligible toxicity are a fundamental pursuit that has been made humanly possible through either targeting or tumor-selective therapeutic (TST) approaches. Herein, we developed a targeting-enhanced tumor-selective cancer therapy aimed at integrating the two approaches by preparing cerium oxide (CeO2) nanocubes with glucose oxidase (GOx) modified on the cube surface and cancer cell membrane (CCM) camouflaged outside. The immune escape and homotypic binding of camouflaged CCM enable targeted delivery of the resultant CeO2-GOx@CCM nanoparticles mostly into cancer tissue, while its acidic environment (pH < 6.6) activated a cascade reaction, in which the glucose was first catalyzed by GOx into H2O2 and then by CeO2 into highly cytotoxic ˙OH killing cancer cells. In the case of off-targeting, when very few CeO2-GOx@CCM nanoparticles were accidentally delivered into normal tissue, its neutral pH environment (pH = 7.4) triggered a protective reaction, in which the H2O2 generated was catalyzed by CeO2 into non-toxic H2O and O2. Both in vitro and in vivo results demonstrated that this targeting-enhanced TST achieved the most remarkable antitumor performance with negligible toxic side effects.

Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a rare kidney disease caused by APOE mutations. The aim of this study was to correlate the genetic and clinical features of LPG. METHODS: Totally eight LPG patients were recruited in this study and Sanger sequencing of APOE was performed for all available family members. Clinical and histological features were analyzed. A literature review of LPG was also conducted. RESULTS: Genetic analysis revealed five patients with APOE-Kyoto, two with APOE-Osaka/Kurashiki, and one with APOE-Chicago mutations. LPG patients with urine protein reduced more than 50% had a slower decrease in renal function than those with less urine protein reduction (estimated glomerular filtration rate reduction rate -5.0 ± 0.8 vs. 1.5 ± 0.7 ml/min per 1.73 m2 ⋅month-1 , p = .03). We then enrolled 95 LPG patients from previous studies and this study. LPG patients had higher blood pressure (mean arterial pressure: 109.4 ± 19.4 vs. 94.4 ± 11.1 mmHg, p < .001) than the control group. Interestingly, patients with APOE mutations in the LDL receptor binding region had higher serum apolipoprotein E (apoE) levels [ln(apoE): 2.7 ± 0.4 vs. 2.0 ± 0.5 mg/dl, p < .001] in comparison to other domains. CONCLUSION: Here, we report for the first time APOE-Osaka/Kurashiki and APOE-Chicago mutations in the Chinese population. LPG was associated with higher blood pressure and serum apoE levels were higher in patients with mutations in LDL receptor binding region. In addition, the findings further indicated that treatment of proteinuria might slow down renal function progression in these patients.

Photothermal Generation of Oxygen-Irrelevant Free Radicals with Simultaneous Suppression of Glutathione Synthesis for an Enhanced Photonic Thermodynamic Cancer Therapy.

Reactive oxygen species (ROS) as one kind of oxygen-dependent toxic free radical has been widely adopted in ROS-mediated therapies (RMT). However, two shackles, known as tumor hypoxia and high intratumor glutathione (GSH) levels, respectively, limit RMT as the former prevents ROS from generating, while the latter scavenges the ROS generated. Herein, we developed a novel nanoplatform to simultaneously overcome the two shackles by facile preparation of mesoporous carbon nanospheres (MCNs) with AIBI and raloxifene loaded inside as an initiator and inhibitor, respectively, and phase-change materials (PCMs) capped outside as gatekeepers. Upon 808 nm NIR light irradiation, the photothermal effect of MCNs melted PCMs causing the loaded AIBI and raloxifene to be released, during which the AIBI was further decomposed into oxygen-irrelevant radicals to kill cancer cells, while the raloxifene suppressed GSH synthesis, synergistically enabling an enhanced photonic thermodynamic cancer therapy.

Protection from Amyloid ß Peptide-Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor.

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.

Transplantation of umbilical cord mesenchymal stem cells into mice with focal segmental glomerulosclerosis delayed disease manifestation.

BACKGROUND: Familial focal segmental glomerulosclerosis (fFSGS) is difficult to treat, and stem cell transplantation is one of the most promising approaches for treating this condition. According to the novel mutation site found in our FSGS family, we established a novel animal model of FSGS to explore the application of stem cell therapy in FSGS. METHODS: The animal model used in this experiment was p.Gly1617Valfs X15 (C57BL/6) mutant mice. This mutation was first found in a focal segmental glomerulosclerosis (FSGS) family undergoing renal biopsy in our department. The mouse model was then constructed via CRISPR/Cas9 genomic editing technology. Then, the animals were injected with human umbilical cord mesenchymal stem cells (UCMSC) through the tail vein and regularly followed up to determine phenotypic changes in urine protein quantities, serum creatinine and histological outcomes. RESULTS: Compared with the positive control group, the levels of urinary protein and serum creatine were decreased significantly after UCMSC transplantation. HE staining images revealed a delay in glomerular sclerosis. Moreover, the secretion of the type IV collagen α3 chain was significantly increased compared with the positive control group, as shown by using immunofluorescence microscopic observation, and electron microscopy proved that the podocytes and basement membrane recovered well from the damage. The intervention also resulted in enhanced IL-22 expression. CONCLUSIONS: UCMSC transplantation may be a potential treatment for FSGS, and IL-22 may play an important role in this process. Further studies are needed to reveal the underlying mechanism.

Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice.

Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.

IgA Nephropathy Susceptibility Loci and Disease Progression.

BACKGROUND AND OBJECTIVES: At least 20 susceptibility loci of IgA nephropathy have been identified by genome-wide association studies to date. Whether these loci were associated with disease progression is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled 613 adult patients with IgA nephropathy for a follow-up of ≥12 months. All 20 IgA nephropathy susceptibility loci were selected and their tag single nucleotide polymorphisms (SNPs) were genotyped. After strict quality control, 16 SNPs and 517 patients with IgA nephropathy were eligible for subsequent analysis. Progression was defined as ESKD or 50% decrease in eGFR. A stepwise Cox regression analysis of all SNPs on Akaike information criterion was performed to select the best model. RESULTS: A four-SNP model, rs11150612 (ITGAM-ITGAX), rs7634389 (ST6GAL1), rs2412971 (HORMAD2), and rs2856717 (HLA-DQ/DR), was selected as the best predictive model. The genetic risk score calculated on the basis of the four SNPs was independently associated with disease progression before (hazard ratio [HR], 1.65; 95% confidence interval [95% CI], 1.29 to 2.12) and after adjustment by a recently reported clinical model (HR, 1.29; 95% CI, 1.03 to 1.62) or clinical-pathologic model (HR, 1.35; 95% CI, 1.03 to 1.77). Compared with low genetic risk, patients with middle genetic risk had a 2.12-fold (95% CI, 1.33 to 3.40) increase of progression risk, whereas patients with high genetic risk had 3.61-fold (95% CI, 2.00 to 6.52) progression risk increase. In addition, incorporation of genetic risk score could potentially increase discrimination of the clinical model (c-statistic increase from 0.83 to 0.86) or the clinical-pathologic model (c-statistic increase from 0.82 to 0.85) in predicting 5-year progression risk. CONCLUSIONS: The four-SNP genetic risk score was independently associated with IgA nephropathy progression and could enhance the performance of clinical and clinical-pathologic risk models.

trans-Resveratrol ameliorates anxiety-like behaviors and fear memory deficits in a rat model of post-traumatic stress disorder.

trans-Resveratrol, a natural polyphenol enriched in grape seed and skin, has been extensively investigated for its antioxidant, anti-inflammatory and anti-psychiatric properties. The present study examined the effects of trans-resveratrol on ameliorating anxiety-like behaviors and fear memory deficits induced by time-dependent sensitization (TDS) procedure, which is a classical animal model for mimicking posttraumatic stress disorder (PTSD). The results suggested that trans-resveratrol at doses of 10, 20 and 40 mg/kg (via gavage, i.g.) reversed TDS-induced decreases in the percentage of time spent in the center of arena, the open arm entries and time spent in the open arms in the open field and elevated plus maze tests. It also decreased the percentage of freezing time in the contextual fear paradigm that was increased in TDS treated rats. Further study suggested that TDS-induced abnormality in the limbic hypothalamus-pituitary-adrenal gland (L-HPA) axis was reversed by trans-resveratrol, i.e. it reversed increased adrenal gland index and corticotropin-releasing factor (CRF) levels, and rescued the differential expression of glucocorticoid receptor (GR) in the hypothalamus, hippocampus and amygdala. Neurobiological studies suggested that trans-resveratrol increased phosphorylation of cAMP response element binding protein (pCREB) and brain derived neurotrophic factor (BDNF) levels, which were decreased in rats subjected to TDS. These results provide compelling evidence that trans-resveratrol protects neurons against PTSD-like stress insults by regulation of L-HPA axis function and activation of downstream neuroprotective molecules, such as pCREB and BDNF expression.

Calculating the number of cluster heads based on the rate-distortion function in wireless sensor networks.

Due to limited resources in wireless sensor nodes, energy efficiency is considered as one of the primary constraints in the design of the topology of wireless sensor networks (WSNs). Since data that are collected by wireless sensor nodes exhibit the characteristics of temporal association, data fusion has also become a very important means of reducing network traffic as well as eliminating data redundancy as far as data transmission is concerned. Another reason for data fusion is that, in many applications, only some of the data that are collected can meet the requirements of the sink node. In this paper, we propose a method to calculate the number of cluster heads or data aggregators during data fusion based on the rate-distortion function. In our discussion, we will first establish an energy consumption model and then describe a method for calculating the number of cluster heads from the point of view of reducing energy consumption. We will also show through theoretical analysis and experimentation that the network topology design based on the rate-distortion function is indeed more energy-efficient.