Navß2 Intracellular Fragments Contribute to Aß1-42-Induced Cognitive Impairment and Synaptic Deficit Through Transcriptional Suppression of BDNF.

A pathological hallmark of Alzheimer's disease (AD) is the region-specific accumulation of the amyloid-beta protein (Aß), which triggers aberrant neuronal excitability, synaptic impairment, and progressive cognitive decline. Previous works have demonstrated that Aß pathology induced aberrant elevation in the levels and excessive enzymatic hydrolysis of voltage-gated sodium channel type 2 beta subunit (Navß2) in the brain of AD models, accompanied by alteration in excitability of hippocampal neurons, synaptic deficits, and subsequently, cognitive dysfunction. However, the mechanism is unclear. In this research, by employing cell models treated with toxic Aß1-42 and AD mice, the possible effects and potential mechanisms induced by Navß2. The results reveal that Aß1-42 induces remarkable increases in Navß2 intracellular domain (Navß2-ICD) and decreases in both BDNF exons and protein levels, as well as phosphorylated tropomyosin-related kinase B (pTrkB) expression in cells and mice, coupled with cognitive impairments, synaptic deficits, and aberrant neuronal excitability. Administration with exogenous Navß2-ICD further enhances these effects induced by Aß1-42, while interfering the generation of Navß2-ICD and/or complementing BDNF neutralize the Navß2-ICD-conducted effects. Luciferase reporter assay verifies that Navß2-ICD regulates BDNF transcription and expression by targeting its promoter. Collectively, our findings partially elucidate that abnormal enzymatic hydrolysis of Navß2 induced by Aß1-42-associated AD pathology leads to intracellular Navß2-ICD overload, which may responsible to abnormal neuronal excitability, synaptic deficit, and cognition dysfunction, through its transcriptional suppression on BDNF. Therefore, this work supplies novel evidences that Navß2 plays crucial roles in the occurrence and progression of cognitive impairment of AD by transcriptional regulatory activity of its cleaved ICD.

Gut microbiota is necessary for pair-housing to protect against post-stroke depression in mice.

The goal of this study is to investigate the role of microbiota-gut-brain axis involved in the protective effect of pair-housing on post-stroke depression (PSD). PSD model was induced by occluding the middle cerebral artery (MCAO) plus restraint stress for four weeks. At three days after MCAO, the mice were restrained 2 h per day. For pair-housing (PH), each mouse was pair housed with a healthy isosexual cohabitor for four weeks. While in the other PH group, their drinking water was replaced with antibiotic water. On day 35 to day 40, anxiety- and depression-like behaviors (sucrose consumption, open field test, forced swim test, and tail-suspension test) were conducted. Results showed pair-housed mice had better performance on anxiety- and depression-like behaviors than the PSD mice, and the richness and diversity of intestinal flora were also improved. However, drinking antibiotic water reversed the effects of pair-housing. Furthermore, pair-housing had an obvious improvement in gut barrier disorder and inflammation caused by PSD. Particularly, they showed significant decreases in CD8 lymphocytes and mRNA levels of pro-inflammatory cytokines (TNF-a, IL-1ß and IL-6), while IL-10 mRNA was upregulated. In addition, pair-housing significantly reduced activated microglia and increased Nissl's body in the hippocampus of PSD mice. However, all these improvements were worse in the pair-housed mice administrated with antibiotic water. We conclude that pair-housing significantly improves PSD in association with enhanced functions of microbiota-gut-brain axis, and homeostasis of gut microbiota is indispensable for the protective effect of pair-housing on PSD.

[Impact of primary duodenogastric reflux and Helicobacter pylori infection on gastritis and antibiotic resistance in children]. / å„¿ç«¥åŽŸå‘æ€§åäºŒæŒ‡è‚ èƒƒåæµä¸Žå¹½é—¨èžºæ†èŒæ„ŸæŸ“å¯¹èƒƒç‚Žå’ŒæŠ—ç”Ÿç´ è€è¯æ€§çš„å½±å“.

OBJECTIVES: To investigate the risk factors for Helicobacter pylori (HP) infection in children with primary duodenogastric reflux (DGR) and its impact on gastritis and antibioticresistance. METHODS: A retrospective analysis was performed on the clinical data of 2 190 children who underwent upper gastrointestinal endoscopy in Wuxi Children's Hospital from January 2019 to February 2022, among whom 308 children were diagnosed with primary DGR. According to the presence or absence of HP infection, the children were classified to HP infection group (53 children) and non-HP infection group (255 children). The risk factors for HP infection and its impact on the incidence rate and severity of gastritis were analyzed. According to the presence or absence of primary DGR, 331 children with HP infection were classified to primary DGR group (29 children) and non-primary DGR group (302 children), and then the impact of primary DGR with HP infection on antibiotic resistance was analyzed. RESULTS: The HP infection group had a significantly higher age than the non-HP infection group (P<0.05), and there was a significant difference in the age distribution between the two groups (P<0.05), while there were no significant differences in the incidence rate and severity of gastritis between the two groups (P>0.05). The multivariate logistic regression analysis showed that older age was a risk factor for HP infection in children with DGR (P<0.05). Drug sensitivity test showed that there were no significant differences in the single and combined resistance rates of metronidazole, clarithromycin, and levofloxacin between the primary DGR group and the non-primary DGR group (P>0.05). CONCLUSIONS: Older age is closely associated with HP infection in children with DGR. Primary DGR with HP infection has no significant impact on gastritis and antibiotic resistance in children.

Introducing Carborane Clusters into Crystalline Frameworks via Thiol-Yne Click Chemistry for Energetic Materials.

Crystalline frameworks represent a cutting-edge frontier in material science, and recently, there has been a surge of interest in energetic crystalline frameworks. However, the well-established porosity often leads to diminished output energy, necessitating a novel approach for performance enhancement. Thiol-yne coupling, a versatile metal-free click reaction, has been underutilized in crystalline frameworks. As a proof of concept, we herein demonstrate the potential of this approach by introducing the energy-rich, size-matched, and reductive 1,2-dicarbadodecaborane-1-thiol (CB-SH) into an acetylene-functionalized framework, Zn(AIm)2, via thiol-yne click reaction. This innovative decoration strategy resulted in a remarkable 46.6 % increase in energy density, a six-fold reduction in ignition delay time (4 ms) with red fuming nitric acid as the oxidizer, and impressive enhancement of stability. Density functional theory calculations were employed to elucidate the mechanism by which CB-SH promotes hypergolic ignition. The thiol-yne click modification strategy presented here permits engineering of crystalline frameworks for the design of advanced energetic materials.

Voluntary running wheel exercise induces cognitive improvement post traumatic brain injury in mouse model through redressing aberrant excitation regulated by voltage-gated sodium channels 1.1, 1.3, and 1.6.

Traumatic brain injury (TBI) leads to disturbed brain discharge rhythm, elevated excitability, anxiety-like behaviors, and decreased learning and memory capabilities. Cognitive dysfunctions severely affect the quality of life and prognosis of TBI patients, requiring effective rehabilitation treatment. Evidence indicates that moderate exercise after brain injury decreases TBI-induced cognitive decline. However, the underlying mechanism remains unelucidated. Our results demonstrate that TBI causes cognitive impairment behavior abnormalities and overexpression of Nav1.1, Nav1.3 and Nav1.6 proteins inside the hippocampus of mice models. Three weeks of voluntary running wheel (RW) exercise treatments before or/and post-injury effectively redressed the aberrant changes caused by TBI. Additionally, a 10% exercise-conditioned medium helped recover cell viability, neuronal sodium current and expressions of Nav1.1, Nav1.3 and Nav1.6 proteins across cultured neurons after injury. Therefore, the results validate the neuroprotection induced by voluntary RW exercise treatment before or/and post-TBI. The RW exercise-induced improvement in cognitive behaviors and neuronal excitability could be associated with correcting the Nav1.1, Nav1.3, and Nav1.6 expression levels. The current study proves that voluntary exercise is an effective treatment strategy against TBI. The study also highlights novel potential targets for rehabilitating TBI, including the Navs proteins.

Pretreatment with Bifidobacterium longum BAA2573 ameliorates dextran sulfate sodium (DSS)-induced colitis by modulating gut microbiota.

Objectives: Inflammatory bowel disease (IBD) is a chronic lifelong inflammatory disease. Probiotics such as Bifidobacterium longum are considered to be beneficial to the recovery of intestinal inflammation by interaction with gut microbiota. Our goals were to define the effect of the exclusive use of BAA2573 on dextran sulfate sodium (DSS)-induced colitis, including improvement of symptoms, alleviation of histopathological damage, and modulation of gut microbiota. Methods: In the present study, we pretreated C57BL/6J mice with Bifidobacterium longum BAA2573, one of the main components in an over-the-counter (OTC) probiotic mixture BIFOTO capsule, before modeling with DSS. 16S rDNA sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based non-targeted metabolomic profiling were performed with the collected feces. Results: We found that pretreatment of Bifidobacterium longum BAA2573 given by gavage significantly improved symptoms and histopathological damage in DSS-induced colitis mice. After the BAA2573 intervention, 57 genera and 39 metabolites were significantly altered. Pathway enrichment analysis demonstrated that starch and sucrose metabolism, vitamin B6 metabolism, and sphingolipid metabolism may contribute to ameliorating colitis. Moreover, we revealed that the gut microbiome and metabolites were interrelated in the BAA2573 intervention group, while Alistipes was the core genus. Conclusion: Our study demonstrates the impact of BAA2573 on the gut microbiota and reveals a possible novel adjuvant therapy for IBD patients.

The aptamer-based RNA-PROTAC.

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.

CoOOH nanosheets ensure ratiometric fluorescence assay of acetylcholinesterase.

Cobalt oxyhydroxide nanosheets (CoOOH) with peroxidase-like activity provide a promising probe for acetylcholinesterase (AChE) sensing through a ratiometric fluorescence strategy. Fluorescence of silicon quantum dots (SiQDs) at 457 nm was quenched by CoOOH on account of inner-filter effect (IFE). Meanwhile, the nonfluorescent o-phenylenediamine (OPD) was catalytically oxidized to 2,3-diaminophenazine (oxOPD) by CoOOH nanosheets with emission at 572 nm. The acetylcholine (ATCh) was catalytically hydrolyzed by AChE to enzymatic thiocholine (TCh), which decomposed CoOOH to Co2+, recovered the fluorescence of SiQDs and reduced the emission of oxOPD. Fluorescence ratio at F457/F572 serves as signal output for AChE detection within 5 × 10-5-0.05 and 0.05-10 U mL-1, with a limit of detection (LOD) of 3.2 × 10-5 U mL-1. The sensing strategy was applied for AChE assay in human blood and erythrocyte.

[Theoretical basis of ecology for the influence of global change on resources, environment, and ecosystems.] / å ¨çƒå˜åŒ–å¯¹èµ„æºçŽ¯å¢ƒåŠç”Ÿæ€ç³»ç»Ÿå½±å“çš„ç”Ÿæ€å­¦ç†è®ºåŸºç¡€.

With the deepening of global change research, the applied problems such as global change risk and response for social sustainable development, temporal and spatial allocation of resources and environmental elements and impact assessment of ecosystem are becoming a new trend in the research field of global change. Based on the ecological framework, we focused on clarifying the connotations of resources and the environment and their components. Resources refer to all substances consumed by organisms in the process of producing organic matter from inorganic matter and transferring energy and matter among organisms. These include inorganic resources (e.g., solar radiation, CO2, O2, water, and mineral elements) and organic resources (as a source of food for other organisms). In contrast, the environment can not be consumed or depleted by organisms. In addition, we described the components of global change and the associated variations of resources and environmental factors, as well as current research progress on the responses of ecosystem to global change. We scientifically described the processes and mechanisms of global change in terms of their influence on resources, the environment, and ecosystems within a theoretical framework based on ecological principles. Our goal was to provide a strong theoretical foundation for future research on coping with the risks of global change.

[Soil stoichiometry characteristics under different land use types in the Horqin Sandy Land, China]. / 科尔沁沙地不同土地利用类型土壤化学计量特征.

The stoichiometry characteristics of carbon (C), nitrogen (N), and phosphorus (P) is an important indicator of soil quality and ecosystem nutrient limitations. Exploring the effects of land use type and soil depth on soil nutrient stoichiometry can clarify soil nutrient cycling. In this study, we collected soil samples from sites with five different land use types (irrigated cropland, rainfed cropland, sandy grassland, fixed dunes, and mobile dunes) in the Horqin Sandy Land, and evaluated the influences of land use type and soil depth on the contents and stoichiometry characteristics of soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP). We found that: 1) SOC (3.23 g·kg-1), TN (0.37 g·kg-1), and TP (0.15 g·kg-1) contents and stoichiometry characteristics (C:N, C:P, N:P was 9.07, 25.56, 2.97, respectively) to a depth of 10 cm in the Horqin Sandy Land were significantly lower than the mean values of soils in China. 2) Soil stoichiometry characteristics differed significantly among land use types. The contents of SOC, TN, and TP to a depth of 100 cm were highest in irrigated cropland, followed by sandy grassland, rainfed cropland, fixed dunes, and mobile dunes. The C:N ratios in sandy grassland, irrigated cropland, and rainfed cropland were significantly higher than those in the fixed dune and mobile dune sites. C:P ratios in the sandy grassland, fixed dunes, irrigated cropland, and rainfed cropland were significantly higher than that in the mobile dunes. The N:P ratio differed little among the five land use types. 3) SOC and TN contents in the sandy grassland, fixed dunes, irrigated cropland, and rainfed cropland decreased with increasing soil depth. SOC, TN, and C:P in the mobile dunes and TP and C:N in all land use types showed no variation among depths. The C:P ratio of sandy grassland, fixed dunes, irrigated cropland, and rainfed cropland and the N:P ratio of sandy grassland decreased with increasing soil depth. 4) SOC, TN, and TP contents and the C:N ratio were significantly negatively correlated with the contents of medium and fine sands and with soil bulk density, but significantly positively correlated with silt+clay, and very fine sand contents. Desertification led to losses of SOC and nutrients in the Horqin Sandy Land, and exacerbated soil N deficiency. Inputs of water and ferti-lizer helped cropland to maintain a relatively high level of soil nutrients.

In vivo glial trans-differentiation for neuronal replacement and functional recovery in central nervous system.

The adult mammalian central nervous system (CNS) is deficient in intrinsic machineries to replace neurons lost in injuries or progressive degeneration. Various types of these neurons constitute neural circuitries wired to support vital sensory, motor, and cognitive functions. Based on the pioneer studies in cell lineage conversion, one promising strategy is to convert in vivo glial cells into neural progenitors or directly into neurons that can be eventually rewired for functional recovery. We first briefly summarize the well-studied regeneration-capable CNS in the zebrafish, focusing on their postinjury spontaneous reprogramming of the retinal Müller glia (MG). We then compare the signaling transductions, and transcriptional and epigenetic regulations in the zebrafish MGs with their mammalian counterparts, which perpetuate certain barriers against proliferation and neurogenesis and thus fail in MG-to-progenitor conversion. Next, we discuss emerging evidence from mouse studies, in which the in vivo glia-to-neuron conversion could be achieved with sequential or one-step genetic manipulations, such as the conversions from retinal MGs to interneurons, photoreceptors, or retinal ganglion cells (RGCs), as well as the conversions from midbrain astrocytes to dopaminergic or GABAergic neurons. Some of these in vivo studies showed considerable coverage of subtypes in the newly induced neurons and partial reestablishment in neural circuits and functions. Importantly, we would like to point out some crucial technical concerns that need to be addressed to convincingly show successful glia-to-neuron conversion. Finally, we present challenges and future directions in the field for better neural function recovery.

Notoginsenoside R1-Induced Neuronal Repair in Models of Alzheimer Disease Is Associated With an Alteration in Neuronal Hyperexcitability, Which Is Regulated by Nav.

Alzheimer disease is characterized by a progressive cognitive deficit and may be associated with an aberrant hyperexcitability of the neuronal network. Notoginsenoside R1 (R1), a major activity ingredient from Panax notoginseng, has demonstrated favorable changes in neuronal plasticity and induced neuroprotective effects in brain injuries, resulting from various disorders, however, the underlying mechanisms are still not well understood. In the present study, we aimed to explore the possible neuroprotective effects induced by R1 in a mouse model of AD and the mechanisms underlying these effects. Treatment with R1 significantly improved learning and memory functions and redressed neuronal hyperexcitability in amyloid precursor protein/presenilin-1 mice by altering the numbers and/or distribution of the members of voltage-gated sodium channels (Nav). Moreover, we determined whether R1 contributed to the regulation of neuronal excitability in Aß-42-injured cells. Results of our study demonstrated that treatment with R1 rescued Aß1-42-induced injured neurons by increasing cell viability. R1-induced alleviation in neuronal hyperexcitability might be associated with reduced Navß2 cleavage, which partially reversed the abnormal distribution of Nav1.1α. These results suggested that R1 played a vital role in the recovery of Aß1-42-induced neuronal injury and hyperexcitability, which is regulated by Nav proteins. Therefore, R1 may be a promising candidate in the treatment of AD.

COX5A Plays a Vital Role in Memory Impairment Associated With Brain Aging via the BDNF/ERK1/2 Signaling Pathway.

Cytochrome c oxidase subunit Va (COX5A) is involved in maintaining normal mitochondrial function. However, little is known on the role of COX5A in the development and progress of Alzheimer's disease (Martinez-Losa et al., 2018). In this study, we established and characterized the genomic profiles of genes expressed in the hippocampus of Senescence-Accelerated Mouse-prone 8 (SAMP8) mice, and revealed differential expression of COX5A among 12-month-aged SAMP8 mice and 2-month-aged SAMP8 mice. Newly established transgenic mice with systemic COX5A overexpression (51% increase) resulted in the improvement of spatial recognition memory and hippocampal synaptic plasticity, recovery of hippocampal CA1 dendrites, and activation of the BDNF/ERK1/2 signaling pathway in vivo. Moreover, mice with both COX5A overexpression and BDNF knockdown showed a poor recovery in spatial recognition memory as well as a decrease in spine density and branching of dendrites in CA1, when compared to mice that only overexpressed COX5A. In vitro studies supported that COX5A affected neuronal growth via BDNF. In summary, this study was the first to show that COX5A in the hippocampus plays a vital role in aging-related cognitive deterioration via BDNF/ERK1/2 regulation, and suggested that COX5A may be a potential target for anti-senescence drugs.

Infection within 2 weeks before liver transplantation closely related to prognosis of posttransplant infection: A single-center retrospective observational study in China.

BACKGROUND: Infections still represent the main factors influencing morbidity and mortality following liver transplantation. This study aimed to evaluate the incidence and risk factors for infection and survival after liver transplantation. METHODS: We retrospectively examined medical records in 210 liver recipients who underwent liver transplantation between April 2015 and October 2017 in our hospital. Clinical manifestations and results of pathogen detection test were used to define infection. We analyzed the prevalence, risk factors and prognosis of patients with infection. RESULTS: The median follow-up was 214 days; the incidence of infection after liver transplantation was 46.7% (n = 98) which included pneumonia (43.4%), biliary tract infection (21.9%), peritonitis (21.4%) and bloodstream infection (7.6%). Among the pathogens in pneumonia, the most frequently isolated was Acinetobacter baumanii (23.5%) and Klebsiella pneumoniae (21.2%). Model for end-stage liver disease (MELD) score (OR = 1.083, 95% CI: 1.045-1.123; P < 0.001), biliary complication (OR = 4.725, 95% CI: 1.119-19.947; P = 0.035) and duration of drainage tube (OR = 1.040, 95% CI: 1.007-1.074; P = 0.017) were independent risk factors for posttransplant infection. All-cause mortality was 11.0% (n = 23). The prognostic factors for postoperative infection in liver recipients were prior-transplant infection, especially pneumonia within 2 weeks before transplantation. Kaplan-Meier curves of survival showed that recipients within 2 weeks prior infection had a significantly lower cumulative survival rate compared with those without infection (65.2% vs. 90.0%; hazard ratio: 4.480; P < 0.001). CONCLUSIONS: Infection, especially pneumonia within 2 weeks before transplantation, complication with impaired renal function and MELD score after 7 days of transplantation was an independent prognostic factor for postoperative infection in liver transplant recipients.

Exercise-Induced Cognitive Improvement Is Associated with Sodium Channel-Mediated Excitability in APP/PS1 Mice.

Elevated brain activation, or hyperexcitability, induces cognitive impairment and confers an increased risk of Alzheimer's disease (AD). Blocking the overexcitation of the neural network may be a promising new strategy to prevent, halt, and even reverse this condition. Physical exercise has been shown to be an effective cognitive enhancer that reduces the risk of AD in elderly individuals, but the underlying mechanisms are far from being fully understood. We explored whether long-term treadmill exercise attenuates amyloid precursor protein (APP)/presenilin-1 (PS1) mutation-induced aberrant network activity and thus improves cognition by altering the numbers and/or distribution of voltage-gated sodium channels (Nav) in transgenic mice. APP/PS1 mice aged 2, 3.5, 5, 6.5, 8, and 9 months underwent treadmill exercise with different durations or at different stages of AD. The alterations in memory, electroencephalogram (EEG) recordings, and expression levels and distributions of Nav functional members (Nav1.1α, Nav1.2, Nav1.6, and Navß2) were evaluated. The results revealed that treadmill exercise with 12- and 24-week durations 1) induced significant improvement in novel object recognition (NOR) memory and Morris water maze (MWM) spatial memory; 2) partially reduced abnormal spike activity; and 3) redressed the disturbed cellular distribution of Nav1.1α, aberrant Navß2 cleavage augmentation, and Nav1.6 upregulation. Additionally, APP/PS1 mice in the 24-week exercise group showed better performance in the NOR task and a large decrease in Nav1.6 expression, which was close to the wild-type level. This study suggests that exercise improves cognition and neural activity by altering the numbers and distribution of hippocampal Nav in APP/PS1 mice. Long-term treadmill exercise, for about 24 weeks, starting in the preclinical stage, is a promising therapeutic strategy for preventing AD and halting its progress.

[Inter- and intra-annual dynamics of vegetation litter at different habitats in Horqin Sandy Land, China.] / ç§‘å°”æ²æ²™åœ°ä¸åŒç”Ÿå¢ƒæ¤è¢«å‡‹è½ç‰©å¹´é™ åŠå¹´å† åŠ¨æ€.

As one of the important pathways of material and energy flow between plant and soil system, litterfall plays a key role in the process of vegetation and soil restoration in ecologically fragile region. To explore the inter- and intra-annual dynamics of litter production and related regulatory factors at different habitats in sandy land ecosystem, we investigated the litter production during nine continuous growing seasons, while the air temperature and precipitation were measured over mobile dune, fixed dune, and grassland in Horqin Sandy Land. The results showed that annual litter production at different habitants were in the order of mobile dune (9.01 g·m-2) ＜ fixed dune (67.46 g·m-2) ＜ grassland (119.55 g·m-2). The inter-annual dynamics of litterfall fluctuated significantly, with a double-peak curve in fixed dune and "W" curve in grassland. The intra-annual variation of litterfall exhibited a "U" curve at all the three habitats, with peaks appearing in April and September, respectively. Precipitation and temperature had significant effects on the intra-annul dynamics of litterfall production in fixed sand dune and grassland, but had no significant effect on the inter-annual dynamics of litter production at three habitats. Temperature was the major factor affecting the dynamics of the litter fall during the growing season in Horqin Sandy Land.

The Agr Quorum Sensing System Represses Persister Formation through Regulation of Phenol Soluble Modulins in Staphylococcus aureus.

The opportunistic pathogen Staphylococcus aureus has become an increasing threat to public health. While the Agr quorum sensing (QS) system is a master regulator of S. aureus virulence, its dysfunction has been frequently reported to promote bacteremia and mortality in clinical infections. Here we show that the Agr system is involved in persister formation in S. aureus. Mutation of either agrCA or agrD but not RNAIII resulted in increased persister formation of stationary phase cultures. RNA-seq analysis showed that in stationary phase AgrCA/AgrD and RNAIII mutants showed consistent up-regulation of virulence associated genes (lip and splE, etc.) and down-regulation of metabolism genes (bioA and nanK, etc.). Meanwhile, though knockout of agrCA or agrD strongly repressed expression of phenol soluble modulin encoding genes psmα1-4, psmß1-2 and phenol soluble modulins (PSM) transporter encoding genes in the pmt operon, mutation of RNAIII enhanced expression of the genes. We further found that knockout of psmα1-4 or psmß1-2 augmented persister formation and that co-overexpression of PSMαs and PSMßs reversed the effects of AgrCA mutation on persister formation. We also detected the effects on persister formation by mutations of metabolism genes (arcA, hutU, narG, nanK, etc.) that are potentially regulated by Agr system. It was found that deletion of the ManNAc kinase encoding gene nanK decreased persister formation. Taken together, these results shed new light on the PSM dependent regulatory role of Agr system in persister formation and may have implications for clinical treatment of MRSA persistent infections.

Endogenous TGFß1 Plays a Crucial Role in Functional Recovery After Traumatic Brain Injury Associated with Smad3 Signal in Rats.

Transforming growth factor-ß 1 (TGFß1) has a diverse role in astrogliosis and neuronal survival, but the underlying mechanism remains to be elucidated, especially in traumatic brain injury (TBI). Here, we show that the expression of TGFß1 was increased in the pericontusional region, accompanied with astrogliosis and neuronal loss in TBI rats. Moreover, TGFß1 knockdown not only reduced the number of neurons and inhibited astrogliosis but also resulted in a significant neurological dysfunction in rats with TBI. Subsequently, Smad3, a key downstream signal of TGFß1, was involved in pericontusional region after TBI. These findings therefore indicate that TGFß1 is involved in neuroprotection and astrogliosis, via activation of down stream Smad3 signal in the brain after injury.

Endogenous neurotrophin-3 promotes neuronal sprouting from dorsal root ganglia.

In the present study, we investigated the role of endogenous neurotrophin-3 in nerve terminal sprouting 2 months after spinal cord dorsal root rhizotomy. The left L1-5 and L7-S2 dorsal root ganglia in adult cats were exposed and removed, preserving the L6 dorsal root ganglia. Neurotrophin-3 was mainly expressed in large neurons in the dorsal root ganglia and in some neurons in spinal lamina II. Two months after rhizotomy, the number of neurotrophin-3-positive neurons in the spared dorsal root ganglia and the density of neurite sprouts emerging from these ganglia were increased. Intraperitoneal injection of an antibody against neurotrophin-3 decreased the density of neurite sprouts. These findings suggest that endogenous neurotrophin-3 is involved in spinal cord plasticity and regeneration, and that it promotes axonal sprouting from the dorsal root ganglia after spinal cord dorsal root rhizotomy.