Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

The psychological and physiological effects of integrated cognitive-behavioral and biofeedback therapy on panic disorder: A randomized controlled trial.

BACKGROUND: Cognitive-behavioral therapy (CBT) and biofeedback therapy are commonly regarded as effective treatment modalities for panic disorder. The aim of this study was to establish a Taiwanese version of an integrated cognitive-behavioral and biofeedback therapy (ICB) and examine its effects on panic disorder using psychological and physiological indicators. METHODS: Thirty patients with panic disorder were enrolled in this study. They were randomly assigned to either the ICB group (n = 15) or the treatment as usual (TAU) group (n = 15). The intervention consisted of six sessions, conducted once a week. Psychological indicators were measured at baseline (prior to intervention), week 3, and week 6, while physiological indicators were measured at baseline and week 6. The psychological indicators included five scales, with the Panic Disorder Severity Scale (PDSS) being the primary measure. The physiological indicators included respiratory sinus arrhythmia (RSA) and skin conductance, which respectively represent parasympathetic and sympathetic activity. RESULTS: Considering all participants, PDSS scores significantly decreased over time, but the difference between the ICB and TAU groups did not reach statistical significance. Among the physiological indicators, resting-state RSA and RSA under relaxation showed significant between-group differences over time, with the ICB group demonstrating a more pronounced improvement in RSA. CONCLUSION: In the context of existing pharmacological treatments, the benefits of ICB for panic disorder may not be observable through psychological indicators. However, it can lead to enhancement of parasympathetic activity as evidenced by the physiological indicators.

A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers.

The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

Establishment of trimester-specific thyroid stimulating hormone and free thyroxine reference interval in pregnant Chinese women using the Beckman Coulter UniCel™ DxI 600.

BACKGROUND: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals are essential for screening and diagnosing thyroid dysfunction during pregnancy. The aim of this study was to establish method- and trimester-specific TSH and FT4 reference intervals in pregnant Chinese women using the Beckman Coulter UniCel™ DxI 600. METHODS: A cross-sectional dataset analysis was performed. A total of 3507 participants were recruited, and 2743 were eligible for analysis to set reference intervals. TSH, FT4, and thyroid peroxidase antibody (TPOAb) levels were analyzed with the Beckman Coulter UniCel™ DxI 600 Access® immunoassay system. Ranges between the 2.5th and 97.5th percentiles were defined as reference intervals for TSH and FT4. RESULTS: The calculated reference intervals for the first, second, and third trimesters were TSH: 0.06-3.13, 0.07-4.13 and 0.15-5.02 mIU/L, respectively, and FT4: 8.72-15.22, 7.10-13.55 and 6.16-12.03 pmol/L, respectively. CONCLUSIONS: Our reference intervals for TSH and FT4 are distinct from the ranges reported in the DxI 600 instruction manual and previously reported data, confirming the importance of method-specific reference intervals.

Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis.

Previous studies have focused on the association of a gene (EPHX1) encoding microsomal epoxide hydrolase with the carcinogenesis of hepatocellular carcinoma (HCC). In the present study, we performed a meta-analysis to systematically summarize the possible association between EPHX1 genetic polymorphisms and the risk for HCC. We conducted a search of case-control studies on the associations of EPHX1 genetic polymorphisms with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Wanfang database in China, and the Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with EPHX1 genetic polymorphism was estimated by pooled odds ratios and 95% confidence intervals. Thirteen studies were included in the present meta-analysis. Our results showed that, for the two polymorphisms (337 T > C and 416A > G) of EPHX1 gene, neither allele frequency nor genotype distributions were associated with risk for HCC in all genetic models (all P > 0.05). This meta-analysis suggests that EPHX1 genetic polymorphisms were not associated with the risk of HCC.

TERT mediates the U-shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function.

BACKGROUND: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. METHODS: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 µL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. RESULTS: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 µM) promoted NSC proliferation in vitro, while the stress level of GCs (10 µM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. CONCLUSION: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.

Neuronal nitric oxide synthase is an endogenous negative regulator of glucocorticoid receptor in the hippocampus.

The hippocampus is rich in both glucocorticoid receptor (GR) and neuronal nitric oxide synthase (nNOS). But the relationship between the two molecules under physiological states remains unrevealed. Here, we report that nNOS knockout mice display increased GR expression in the hippocampus. Both systemic administration of 7-Nitroindazole (7-NI), a selective nNOS activity inhibitor, and selective infusion of 7-NI into the hippocampus resulted in an increase in GR expression in the hippocampus. Moreover, KCl exposure, which can induce overexpression of nNOS, resulted in a decrease in GR protein level in cultured hippocampal neurons. Moreover, blockade of nNOS activity in the hippocampus leads to decreased corticosterone (CORT, glucocorticoids in rodents) concentration in the plasma and reduced corticotrophin-releasing factor expression in the hypothalamus. The results indicate that nNOS is an endogenous inhibitor of GR in the hippocampus and that nNOS in the hippocampus may participate in the modulation of Hypothalamic-Pituitary-Adrenal axis activity via GR.

[Construction of biofilm formation related mutants in Vibrio parahaemolyticus].

OBJECTIVE: To construct the mutants of biofilm related genes in Vibrio parahaemolyticus and confirm the mutants. METHODS: The homologous upstream and downstream flanking fragments of target gene were amplified by using PCR, and the fusion homologous fragment was amplified by using the two flanking fragments as template. Then the fusion homologous fragment was digested by restriction enzyme and cloned into suicide plasmid pDS132. The recombinant plasmid was transferred into Vibrio parahaemolyticus RIMD 2210633 through conjugation. The mutants were screened and identified by PCR and the phenotype of one mutant was analyzed in order to verify that the mutants were constructed successfully. RESULTS: Six recombinant plasmids carrying the fusion homologous fragments of genes vbfR, crp, hns, swrZ, swrT and cpsR respectively were constructed and identified by PCR. The amplification products of 1190, 1128, 1136, 953, 1242 and 1112 bp were obtained respectively. The six mutants (ΔvbfR, Δcrp, Δhns, ΔswrZ, ΔswrT and ΔcpsR) were constructed using recombinant plasmids. Verified by PCR, the size of amplification products of mutants (1190, 1128, 1136, 953, 1242 and 1112 bp respectively) was less (610, 739, 421, 542, 427 and 1367 bp respectively) than the corresponding positive control. Meanwhile, none of the products was amplified using the primers locating on the target gene. One mutant Δhns was selected to test the ability of biofilm formation. The result showed that the ability of biofilm formation of mutant Δhns was increased compared with the wild type. CONCLUSION: Six mutants of biofilm related genes in Vibrio parahaemolyticus were constructed and tested by molecular and phenotype experiment to confirm that the mutants were constructed successfully.

Extending Normative Data of the Paced Auditory Serial Addition Test to Account for Preliminary Psychometric Properties among Elderly Individuals in Taiwan.

OBJECTIVE: The Paced Auditory Serial Addition Test (PASAT) is widely used to assess cognitive performance in clinical settings. However, availability of normative data for Revised Version of PASAT (PASAT-R) is often constrained by sample size among elderly individuals. In this study, we sought to establish normative data for PASAT-R for elderly individuals in Taiwan. METHODS: This study recruited 166 individuals aged over 65 years stratified in accordance with the general population in terms of demographic characteristics, including age, educational level, and sex. We assessed PASAT-R test results in terms of psychometric properties. RESULTS: PASAT-R demonstrated good internal consistency and test-retest reliability. Performance on PASAT-R was correlated with performance on the criterion tests. Performance on PASAT-R was negatively correlated with age and positively correlated with educational level. This study provides normative data for PASAT-R for elderly Taiwanese individuals. CONCLUSIONS: PASAT-R is applicable to neuropsychological assessment among elderly Taiwanese individuals.

Dentate nNOS accounts for stress-induced 5-HT1A receptor deficiency: Implication in anxiety behaviors.

BACKGROUND: Anxiety is a common disorder with high social burden worldwide. Dysfunction of serotonin-1A receptor (5-HT1A receptor) in the dentate gyrus (DG) of the hippocampus has been predominantly implicated in the anxiety behavior. However, the molecular mechanism underlying the deficiency of postsynaptic 5-HT1A receptor in regulating anxiety behavior remains unclear. METHODS: Using pharmacological and genetic methods, we investigated the role of detate nNOS in 5-HT1A receptor decline and anxiety behavior induced by chronic mild stress (CMS) in mice. RESULTS: Here we showed that local elevation of glucocorticoids in the DG accounted for chronic stress-induced anxiety behavior. Neuronal nitric oxide synthase (nNOS) mediated chronic stress-induced downregulation of 5-HT1A receptor in the DG through peroxynitrite anion (ONOO•) pathway but not cyclic guanosine monophosphate (cGMP) pathway. By using pharmacological tool drugs and nNOS knockout mice, we found that nNOS in the DG played a key role in chronic stress-induced anxiety behavior. CONCLUSIONS: These findings uncovered an important role of nNOS-5-HT1A receptor pathway in the DG of the hippocampus in chronic stress-induced anxiety. Accordingly, we developed a "dentate nNOS-5-HT1A receptor closed-loop" theory (stress-glucocorticoids-nNOS-Nitric oxide-ONOO•-5-HT1A receptor -nNOS) of stress-related anxiety.

[Setup and Microbial Community Analysis of ANAMMOX System for Landfill Leachate Treatment Coupling Partial Nitrification-Denitrification Process].

In order to upgrade the current shortcut nitrification and denitrification process for landfill leachate treatment and to stimulate nitrification-denitrification coupled with anaerobic ammonia oxidation (ANAMMOX) at a landfill, an ANAMMOX process was started using an up-flow anaerobic sludge bed (UASB) reactor seeded with nitrification and denitrification sludge. The performances of the reactor were investigated, including the nitrogen loading and nitrogen removal rates. Moreover, Illumina Miseq sequencing was conducted to analyze the microbial community dynamics under long-term operation on a molecular level. The results showed that the ANAMMOX reactor was successfully started in 149 days. The total nitrogen loading rate reached 4000.00 mg·(L·d)-1, and the total nitrogen removal rate reached 3885.76 mg·(L·d)-1 after stable operation. The average ammonium and nitrite removal efficiencies were more than 95%. In 250 days, the Planctomycetes in the reactor experienced rapid growth, and its abundance reached 54.94%. The abundance of Candidatus Kuenenia reached 49.66%. The upgrading process of landfill leachate treatment by coupling ANAMMOX based on short-cut nitrification and denitrification was confirmed to be feasible.

GPR30-mediated estrogenic regulation of actin polymerization and spatial memory involves SRC-1 and PI3K-mTORC2 in the hippocampus of female mice.

AIMS: The G-protein-coupled estrogen receptor GPR30 (also referred to as GPER) has been implicated in the estrogenic regulation of hippocampal plasticity and spatial memory; however, the molecular mechanisms are largely unclear. METHODS: In this study, we initially examined the levels of GPR30 in the hippocampus of postnatal, ovariectomy (OVX)- and letrozole (LET)-treated female mice. Under G1, G15, and/or OVX treatment, the spatial memory, spine density, levels of ERα, ERß, and SRC-1, selected synaptic proteins, mTORC2 signals (Rictor and p-AKT Ser473), and actin polymerization dynamics were subsequently evaluated. Furthermore, G1, G15, and/or E2 combined with SRC-1 and/or PI3K inhibitors, actin cytoskeleton polymerization modulator JPK, and CytoD treatments were used to address the mechanisms that underlie GPR30 regulation in vitro. Finally, mTORC2 activator A-443654 (A4) was used to explore the role of mTORC2 in GPR30 regulation of spatial memory. RESULTS: The results showed that high levels of GPR30 were detected in the adult hippocampus and the levels were downregulated by OVX and LET. OVX induced an impairment of spatial memory, and changes in other parameters previously described were reversed by G1 and mimicked by G15. Furthermore, the E2 effects on SRC-1 and mTORC2 signals, synaptic proteins, and actin polymerization were inhibited by G15, whereas G1 effects on these parameters were inhibited by the blockade of SRC-1 or PI3K; the levels of synaptic proteins were regulated by JPK and CytoD. Importantly, G15-induced actin depolymerization and spatial memory impairment were rescued by mTORC2 activation with A4. CONCLUSIONS: Taking together, these results demonstrated that decreased GPR30 induces actin depolymerization through SRC-1 and PI3K/mTORC2 pathways and ultimately impairs learning and memory, indicating its potential role as a therapeutic target against hippocampus-based, E2-related memory impairments.

The Emerging Roles for Telomerase in the Central Nervous System.

Telomerase, a specialized ribonucleoprotein enzyme complex, maintains telomere length at the 3' end of chromosomes, and functions importantly in stem cells, cancer and aging. Telomerase exists in neural stem cells (NSCs) and neural progenitor cells (NPCs), at a high level in the developing and adult brains of humans and rodents. Increasing studies have demonstrated that telomerase in NSCs/NPCs plays important roles in cell proliferation, neuronal differentiation, neuronal survival and neuritogenesis. In addition, recent works have shown that telomerase reverse transcriptase (TERT) can protect newborn neurons from apoptosis and excitotoxicity. However, to date, the link between telomerase and diseases in the central nervous system (CNS) is not well reviewed. Here, we analyze the evidence and summarize the important roles of telomerase in the CNS. Understanding the roles of telomerase in the nervous system is not only important to gain further insight into the process of the neural cell life cycle but would also provide novel therapeutic applications in CNS diseases such as neurodegenerative condition, mood disorders, aging and other ailments.

Exogenous Tissue Inhibitor of Metalloproteinase-2 Affects Matrix Metalloproteinase-2 Expression in Conjunctival Filtering Blebs and Bleb Scarring in Rats.

OBJECTIVE: To examine the effect of tissue inhibitor of metalloproteinase-2 (TIMP-2) on conjunctival filtering bleb scarring. METHODS: A model of conjunctival filtering bleb was established whereby rats were injected with saline, blank adenoviral vector, or adenoviral vector carrying TIMP-2 into the bleb. Filtration bleb formation and matrix metalloproteinase-2 (MMP-2) expression were examined. RESULTS: All operated eyes formed obvious elevated blebs on day 1. In the normal saline group, empty plasmid group, and gene transfection group maintenance time of filtrating blebs was 5-14, 5-14, and 6-16 days, and average survival time was 8.24, 8.16, and 9.44 days, respectively. MMP-2 expression increased slightly in the gene transfection group at 3 and 5 days after surgery, reached a peak after 14 days, and then gradually decreased. MMP-2 expression was weakly positive in the normal conjunctival epithelium, but was hardly detected in the lamina propria. Seven days after surgery, the epithelium and lamina propria of the conjunctival filtering bleb exhibited strong positive expression in the empty plasmid group but only weak expression in the adenovirus group. CONCLUSION: Exogenous TIMP-2 interfered with local MMP-2 expression, delaying peak expression of MMP-2 and slowing the scarring of filtering blebs during wound healing of subconjunctival tissue.

The PPI network analysis of mRNA expression profile of uterus from primary dysmenorrheal rats.

To elucidate the mechanisms of molecular regulations underlying primary dysmenorrhea (PD), we used our previously published mRNA expression profile of uterus from PD syndrome rats to construct protein-protein interactions (PPI) network via STRING Interactome. Consequently, 34 subnetworks, including a "continent" (Subnetwork 1) and 33 "islands" (Subnetwork 2-34) were generated. The nodes, with relative expression ratios, were visualized in the PPI networks and their connections were identified. Through path and module exploring in the network, the bridges were found from pathways of cellular response to calcium ion, SMAD protein signal transduction, regulation of transcription from RNA polymerase II promoter in response to stress and muscle stretch that were significantly enriched by the up-regulated mRNAs, to the cascades of cAMP metabolic processes and positive regulation of cyclase activities by the down-regulated ones. This link is mainly dependent on Fos/Jun - Vip connection. Our data, for the first time, report the PPI network analysis of differentially expressed mRNAs in the uterus of PD syndrome rats, to give insight into screening drugs and find new therapeutic strategies to relieve PD.

Sucrose preference test for measurement of stress-induced anhedonia in mice.

Anhedonia is the inability to experience pleasure from rewarding or enjoyable activities and is a core symptom of depression in humans. Here, we describe a protocol for the measurement of anhedonia in mice, in which anhedonia is measured by a sucrose preference test (SPT) based on a two-bottle choice paradigm. A reduction in the sucrose preference ratio in experimental relative to control mice is indicative of anhedonia. To date, inconsistent and variable results have been reported following the use of the SPT by different groups, probably due to the use of different protocols and equipment. In this protocol, we describe how to set up a clearly defined apparatus for SPT and provide a detailed protocol to ensure greater consistency when carrying out SPT. This optimized protocol is highly sensitive, reliable, and adaptable for evaluation of chronic stress-related anhedonia, as well as morphine-induced dependence. The whole SPT, including adaptation, baseline measurement, and testing, takes 8 d.

Nuclear and membrane estrogen receptor antagonists induce similar mTORC2 activation-reversible changes in synaptic protein expression and actin polymerization in the mouse hippocampus.

AIMS: Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERß) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. METHODS: We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2. Then, we examined the changes in hippocampal SRC-1 expression, mTORC2 signaling (rictor and phospho-AKTSer473), actin polymerization (phospho-cofilin and profilin-1), synaptic protein expression (GluR1, PSD95, spinophilin, and synaptophysin), CA1 spine density, and synapse density. RESULTS: All of the examined parameters except synaptophysin expression were significantly decreased by MPP/PHTPP and G15 treatment. MPP/PHTPP and G15 induced a similar decrease in most parameters except p-cofilin, GluR1, and spinophilin expression. The ER antagonist-induced decreases in these parameters were significantly reversed by mTORC2 activation, except for the change in SRC-1, rictor, and synaptophysin expression. CONCLUSIONS: nERs and mER contribute similarly to the changes in proteins and structures associated with synaptic plasticity, and mTORC2 may be a novel target of hippocampal-dependent dementia such as Alzheimer's disease as proposed by previous studies.

Correlation between Tissue Characterization and Dynamic Expression of Matrix Metalloproteinase-2 and Its Tissue Inhibitor in Conjunctival Filtering Bleb of Rats.

PURPOSE: Using rat conjunctival bleb model, we correlated changes morphology and histology in the bleb with changes in MMP-2 and TIMP-2 levels. METHODS: Filtering surgeries were performed on rats. Dynamic changes in morphology and histopathology were observed using HE staining. Expression of MMP-2 and TIMP-2 was determined by immunofluorescence microscopy and western blotting. RESULTS: Well-elevated filtering blebs formed and persisted for an average of 12 days. Histological examination showed that inflammatory was dominant in postoperative days 1-3, and proliferating manifestation became the main sign 5 days later. Western blot showed that MMP-2 was downregulated 1 day after surgery, upregulated at 3 days, and observed with a peak at 7 days; then it persisted until 28 days. The difference was statistically significant (F = 280.18, p < 0.01).TIMP-2 was upregulated 1 day after surgery and observed with a peak at 5 days; then it persisted until 28 days. The difference was statistically significant (F = 145.34, p < 0.01). CONCLUSIONS: During the processes of conjunctival filtering bleb and scar formation in rats, the changes in MMP-2 and TIMP-2 levels in the filtering area, together with a corresponding proliferation of fibroblasts and the accumulation of collagen fibres, resulted in scarring of filtering blebs.

Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development.

The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert-/-) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.

Values of hemodynamic variation in response to passive leg raising in predicting exercise capacity of heart failure with preserved ejection fraction.

In heart failure patients with preserved ejection fraction, their hemodynamic parameters usually change when they are from recumbent to passive leg raising. The authors designed this study to investigate the relationship between hemodynamic parameters measured by impedance cardiography (ICG) and 6-minute walk distance (6MWD) of heart failure with preserved ejection fraction (HFPEF). We recruited 49 subjects with HFPEF in the study, and all the subjects were separated into 2 groups: the patients whose hemodynamic parameters rose after passive leg raising were in group 1 (n = 26) and the patients whose hemodynamic parameters did not rise after passive leg raising were in group 2 (n = 23). Our study then compared the 6MWD, left ventricular ejection fraction, and plasma NT-pro-brain natriuretic peptide between the 2 groups. Group 1 had significantly longer 6MWD than group 2 (515.38 ±â€Š24.97 vs 306.39 ±â€Š20.20 m; P = 0.043). Hemodynamic parameters measured by ICG significantly correlated with 6MWD in both groups. Patients whose hemodynamic parameters rose in response to passive leg raising were more likely to have better exercise capacity. Hemodynamic variation in response to passive leg raising measured by ICG may be more sensitive in predicting exercise capacity of patients with HFPEF.