The Multi-domain Lifestyle Intervention for Cognitive Impairment in Community-Dwelling Older Adults in Hangzhou (The Heritage Study): Study Design and Protocol.

BACKGROUND: The globe has been working to promote a multi-domain lifestyle intervention for dementia prevention in older adults, referring to the Worldwide-FINGERS (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) initiative. In China, the multi-domain lifestyle intervention has been implemented in rural communities (MIND-China), yet the adaptability of such intervention based on the urban communities in China has not been verified. OBJECTIVE: To examine the effectiveness and feasibility of the multi-domain lifestyle intervention on dementia prevention in at-risk community-dwelling older adults in China. DESIGN, SETTING, PARTICIPANTS: The multi-domain lifestyle intervention study is a community-based 2-year cluster randomized controlled trial (RCT). A total of 1200 participants aged 60-80 years old will be recruited from twelve communities in Hangzhou, Zhejiang. Inclusion criteria were the Montreal Cognitive Assessment 5 minutes protocol (5 min MoCA) score of 6-9 or the Ascertain Dementia 8 (AD 8) score of ≥2, and having modifiable lifestyle factors. INTERVENTION, MEASUREMENTS, RESULTS: Participating communities will be randomized into either the structured multi-domain intervention (SMI) arm or the self-guided intervention (SGI, general health education) arm. The SMI consists of cognitive training, physical exercise, and nutritional and dietary instruction for the first 12 months; and vascular risks monitoring and control for 24 months. The primary outcome is the global cognitive performance, measured by the comprehensive Neuropsychological Test Battery (NTB). The secondary outcomes include domain-specific cognitive performances, physical function, mental health, physiological and biochemical indices, adherence to healthy lifestyles, and neuroimaging metrics. The feasibility of intervention will be evaluated around the five dimensions of the RE-AIM framework and in conjunction with quantitative data, operational data and results of focus group discussions. CONCLUSIONS: Following the Worldwide-FINGERS, this cluster RCT will verify the adaptability of the multi-domain lifestyle intervention in the urban community settings in China. This study will add evidence for global dementia prevention and management among older adults.

Chronically high stress hormone levels dysregulate sperm long noncoding RNAs and their embryonic microinjection alters development and affective behaviours.

Previous studies on paternal epigenetic inheritance have shown that sperm RNAs play a role in this type of inheritance. The microinjection of sperm small noncoding RNAs into fertilised mouse oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. While sperm long noncoding RNAs (lncRNAs) have also been investigated in a previous study, their microinjection into fertilised oocytes did not yield conclusive results regarding their role in modulating brain development and adult behavioural phenotypes. Therefore, in the current study we sought to investigate this further. We used our previously established paternal corticosterone (stress hormone) model to assess sperm lncRNA expression using CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable element transcripts. Although they have limited functional annotation, bioinformatic approaches indicated the potential of these lncRNAs in regulating brain development and function. We then separated and isolated the sperm lncRNAs and performed microinjections into fertilised oocytes, to generate embryos with modulated lncRNA populations. We observed that the resulting adult offspring had lower body weight and altered anxiety and affective behavioural responses, demonstrating roles for lncRNAs in modulating development and brain function. This study provides novel insights into the roles of lncRNAs in epigenetic inheritance, including impacts on brain development and behaviours of relevance to affective disorders.

Can We Miniaturize CT Technology for a Successful Mobile Stroke Unit Roll-Out?

Mortality from stroke remains high in Australia, especially for patients located outside the metropolitan cities. This is because they have limited access to specialized stroke facilities for optimal stroke treatment. Mobile stroke units have the capability to take CT scanners out to the patient however current CT commercial scanner designs are large and heavy. As such, this paper aims to design and develop a lightweight CT scanner for use in a mobile stroke unit (either road-based or air-based ambulance) to bring healthcare solution to patients in the rural and remote areas. We used the engineering design optimization approach to redesign and reduce the weight of the existing CT scanner with without compromised it structural performance. We managed to reduce the weight the CT scanner by three-fold while reducing design costs by allowing numerous simulations to be performed using computer software to achieve our design goals. The results are not only useful to optimize CT scanner structure to retrofit on a mobile stroke unit, but also bring the medical device solution to the market and support scalable solution to the larger community. Such an advance will allow for improved equity in healthcare whereby patients can be treated irrespective of location.

Is Online Video-Based Education an Effective Method to Teach Basic Surgical Skills to Students and Surgical Trainees? A Systematic Review and Meta-analysis.

BACKGROUND: Online education has been increasingly utilized over the past decades. The COVID-19 pandemic accelerated the transition of conventional face-to-face curricula to online platforms, with limited evidence for its teaching efficacy. This systematic review aims to assess the effectiveness of online video-based education compared with standard conventional education in teaching basic surgical skills to surgical trainees and students undergoing medical training. METHODS: We performed a literature search in Embase, Medline, Cochrane CENTRAL and Scopus from inception until February 2022. Studies included were randomised controlled trials (RCTs) and observational studies. We included randomised controlled trials only for meta-analysis. The primary outcome was surgical skill proficiency. The secondary outcomes were participant perception, confidence and satisfaction. Two authors independently assessed the search results for eligibility, extracted the data and assessed the risk of bias using the Cochrane Risk of Bias tool 2. Where appropriate, we performed random effects meta-analyses of the pooled study data to calculate a standardized mean difference. RESULTS: A total of 11 studies met the inclusion criteria totaling 715 participants; 603 were included in qualitative analysis and 380 in meta-analysis. All included studies were assessed as having a low risk of bias. The majority of studies found no significant difference between conventional and video-based education in teaching basic surgical skills, three studies found video-based education was superior and one study found conventional education was superior. There was no statistically significant difference in skill proficiency between the two groups (standardized mean difference of -0.02 (95% CI: -0.34, 0.30); p=0.90). Video-based education results in an equivalent improvement in confidence and satisfaction rates. Additional benefits of video-based education include convenience, accessibility and efficiency. CONCLUSIONS: Basic surgical skills can be taught as effectively through online video-based education as conventional teaching methods. Online education should be utilized as an adjunct to medical curricula beyond the COVID-19 era.

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety.

Independent studies have observed that a paternal history of stress or trauma is associated with his children having a greater likelihood of developing psychopathologies such as anxiety disorders. This father-to-child effect is reproduced in several mouse models of stress, which have been crucial in developing a greater understanding of intergenerational epigenetic inheritance. We previously reported that treatment of C57Bl/6J male breeders with low-dose corticosterone (CORT) for 28 days prior to mating yielded increased anxiety-related behaviours in their male F1 offspring. The present study aimed to determine whether subchronic 7-day CORT treatment of male mice just prior to mating would be sufficient to induce intergenerational modifications of anxiety-related behaviours in offspring. We report that subchronic CORT treatment of male breeders reduced their week-on-week body weight gain and altered NR3C1 and CRH gene expression in the hypothalamus. There were no effects on sperm count and glucocorticoid receptor protein levels within the epididymal tissue of male breeders. Regarding the F1 offspring, screening for anxiety-related behaviours using the elevated-plus maze, light-dark box, and novelty-suppressed feeding test revealed no differences between the offspring of CORT-treated breeders compared to controls. Thus, it is crucial that future studies take into consideration the duration of exposure when assessing the intergenerational impacts of paternal health.

Propofol suppresses migration, invasion, and epithelial-mesenchymal transition in papillary thyroid carcinoma cells by regulating miR-122 expression.

OBJECTIVE: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and PTC patients with invasion and metastases features have a poor prognosis. Propofol is an intravenous anesthetic which has been reported to be involved in cancer progression. However, the roles of propofol and the exact molecular mechanisms in PTC remain largely unknown. MATERIALS AND METHODS: Cells viability was detected using the CCK-8 (Cell Counting Kit-8) assay. The expressions of microRNA-122 (miR-122) were measured by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Cells migration and invasion abilities were investigated by transwell. Western blot was used to demonstrate the expression of metastasis-and EMT-related proteins. RESULTS: We found a significant inhibition of cells viability in TPC-1 and IHH-4 cells compared to Nthy-ori 3-1 cell line after exposed to propofol. The functional experiment showed propofol could suppress cells migration, invasion, and EMT in PTC. Subsequently, a decreased expression of miR-122 was detected in TPC-1 and IHH-4 cells, while a promotion of propofol on miR-122 expression was identified. Furthermore, we found miR-122 could inhibit cells migration, invasion, and EMT in PTC. Next, the rescue study indicated that miR-122 inhibitor transfection could attenuate propofol-induced suppression on TPC-1 and IHH-4 cells metastasis. CONCLUSIONS: Propofol suppresses migration, invasion, and EMT in papillary thyroid carcinoma cells by regulating miR-122 expression. The findings may indicate significant clinical implications for anesthetic agents to prevent metastasis and improve outcomes in papillary thyroid carcinoma.

[Analysis of the effects and influencing factors of thymectomy for myasthenia gravis].

Objective: To explore the effects of surgical treatment for myasthenia gravis as well as its influencing factors. Methods: A total of 180 patients with myasthenia gravis who underwent thymectomy from August 2012 to September 2018 were enrolled. Clinical data such as age, gender, disease classification, preoperative AChR-Ab, preoperative course, operation time, intraoperative blood loss, and pathological type was retrospectively reviewed. Univariate analysis and Cox regression model were used to analyze possible influencing factors of surgical effects. Results: A total of 145 patients were finally enrolled and the follow-up period was from 4 to 78 months, with a median follow-up time of 34 months. Thirty-four patients (23.4%) achieved complete stable remission (CSR). The total clinical remission and effective rate reached 75.1% (109 cases) and 89.6% (130 cases), respectively. Correlation analysis showed that age below 45 years old, preoperative course within 12 months, positive AChR-Ab and thymic hyperplasia were clinical influencing factors for better surgical results (P=0.030, 0.048, 0.019 and 0.042, respectively). Conclusions: It is safe and effective to undergo thymectomy for myasthenia gravis. Age, preoperative course, AChR-Ab level and pathological type were the influencing factors of surgical effects.

Sevoflurane inhibits the progression of PTC by downregulating miR-155.

OBJECTIVE: Surgery resection is the primary treatment for papillary thyroid carcinoma (PTC) patients with the risk of tumor cell invasion and distant metastasis. Sevoflurane is a volatile anesthetic agent widely used in clinical applications. However, the effect of sevoflurane on PTC cells and its precise mechanism remain largely unknown. MATERIALS AND METHODS: Cell viability was assessed by MTT assay. The migrative and invasive abilities of the cells were measured by transwell assay. The protein expression level of Bax, Bcl-2, MMP 9, and MMP 2 were detected by Western blot. Cell apoptosis was analyzed by flow cytometry. The qRT-PCR analysis was used to determine miR-155 expressions. RESULTS: Sevoflurane greatly decreased the viability of PTC cells in a dose-dependent manner. Moreover, sevoflurane significantly inhibited migration and invasion, but increased the apoptosis in PTC cells, which could be reversed by the addition of miR-155. Besides, sevoflurane evidently increased the Bax protein level and inhibited the protein level of Bcl-2, MMP9, and MPP2 in PTC cells. In addition, miR-155 was upregulated in PTC cells; however, the amount of miR-155 would be decreased in PTC cells treated with sevoflurane. Furthermore, abrogation of miR-155 promoted cell apoptosis and inhibited cell migration and invasion in PTC cells. CONCLUSIONS: Sevoflurane inhibited migration and invasion, while enhanced cell apoptosis by downregulating miR-155 in PTC cells, suggesting important clinical implications for anesthetic agents to prevent the metastasis in PTC.

Identification of susceptibility SNPs in CTLA-4 and PTPN22 for scleritis in Han Chinese.

The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ2 test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc) = 0·02, odds ratio (OR) = 1·475, 95% confidence interval (CI) = 1·175-1·851; Pc = 0·04, OR = 1·546, 95% CI = 1·190-2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc = 4·26 × 10-3 , OR = 0·618, 95% CI = 0·540-0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc = 2·83 × 10-4 , OR = 1·457, 95% CI = 1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.

A multicentre, UK, retrospective, observational study to assess the effectiveness of insulin glargine 300 units/ml in treating people with Type 1 diabetes mellitus in routine clinical practice (SPARTA).

AIM: To conduct an open-label study to provide UK real-world evidence regarding the use of insulin glargine 300 units/ml (U300) in people with Type 1 diabetes mellitus. METHODS: People with Type 1 diabetes who had been prescribed U300 ≥6 months before data collection and had HbA1c levels recorded within 3 months prior to U300 (baseline) were included. The primary endpoint was change in HbA1c from baseline to month 6 after U300 initiation. Other endpoints included number of documented hypoglycaemic and diabetic ketoacidosis episodes, and change in daily basal insulin dose. RESULTS: A total of 298 people with Type 1 diabetes were included [mean age 42.1 years, mean HbA1c 79 mmol/mol (9.4%)]. After U300 initiation, the mean reduction in HbA1c from baseline to month 6 was -4 mmol/mol (-0.4%; P<0.001; n=188). The total daily basal insulin dose at 6 months was 1.3 units higher than at the time of U300 initiation (P<0.001; n=275) but was not significantly different from the prior basal insulin dose. There was no clinically significant difference in weight between baseline and month 6 [mean difference +0.7 kg, 95% CI -0.1, 1.5; P=0.084; n=115). During the 6 months before and after U300 initiation, severe hypoglycaemic episodes were documented for 6/298 and 4/298 participants. Diabetic ketoacidosis episodes requiring Accident and Emergency department visits or hospitalization were documented for 4/298 and 6/298 participants, before and after U300 initiation, respectively. CONCLUSIONS: In people with Type 1 diabetes, a change in basal insulin to U300 was associated with clinically and statistically significant HbA1c improvements, without significant changes in basal insulin dose and weight. Documented severe hypoglycaemia episodes and diabetic ketoacidosis requiring Accident and Emergency department visits or hospitalization were low and similar before and after U300 initiation.

Techniques to Ameliorate the Impact of Second Warm Ischemic Time on Kidney Transplantation Outcomes.

Anastomosing the renal artery and vein in transplant recipients without a cooling mechanism exposes the kidney to temperatures exceeding the metabolic threshold (15°C to 18°C), at which the protective effects of renal hypothermia are lost. This anastomotic time, or second warm ischemic time, can be deleterious to graft outcomes, especially if it is prolonged. Techniques to ameliorate organ warming prior to reperfusion have been designed, and range from simpler surface cooling techniques, to organ immersion in bags of ice slush, and the application of 'jackets' that incorporate their own internal cooling mechanism. The efficacy of these methods with respect to the minimization of kidney temperature prior to reperfusion and subsequent effects on graft outcomes are discussed using clinical and experimental data, in the setting of open, laparoscopic, and robotic kidney transplantation.

[Clinical observation of continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B].

Objective: To observe continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B. Methods: Data of patients with active stage of chronic hepatitis B over the past 6 years were collected and analyzed retrospectively. The incidence of drug resistance mutation and related factors between patients taking LAM or ETV continuously and intermittently were compared with those taking LAM or ETV. Data comparison was performed using χ(2) test. Results: Patients with HBV DNA≥10(5) copies / ml at the time of initial treatment had higher resistance mutation rates than those with HBV DNA < 10(5) copies / ml at either continuous or intermittent treatment, and patients with intermittent treatment had higher resistance mutation rates than those with continuous treatment. Simultaneously, the incidence of drug resistance mutation in LAM and ETV in the first, second and third years were significantly higher in intermittent treatment than that of continuous treatment (P < 0.05). There was a positive correlation between the frequency of drug withdrawal and the rate of drug resistance mutation. There were no individual difference and drug difference between LAM and ETV. Conclusion: In the treatment of chronic hepatitis B with oral nucleoside analogues, drug resistance may occur in either continuous or intermittent treatment. When comparing continuous with intermittent treatment, it suggests that intermittent is more likely to cause viral resistance mutation.

LncRNA H19 contributes to Rh2-mediated MC3T3-E1cell proliferation by regulation of osteopontin.

20(R)-ginsenoside Rh2 (Rh2) is one of the most active components of red ginseng, possessing the beneficial effects in cancer prevention and metabolic diseases. However, the detailed mechanisms that contribute to Rh2-mediated bone formation remain largely unknown. In this study, we assessed the expression of 17 long non-coding RNAs (lncRNAs) in cultured MC3T3-E1 cells under Rh2 treatments. We found that lncRNA H19 was significantly increased in Rh2-treated MC3T3-E1 cells. Expression of lncRNA H19 was promoted in a dose- and time-dependent manner after Rh2 treatments. Increased expression of lncRNA H19 resulted in osteopontin (OPN) overexpression in Rh2-treated MC3T3-E1 cells. Furthermore, knockdown of lncRNA H19 by specific siRNAs significantly abolished the Rh2-mediated cell proliferation effects. Knockdown of lncRNA H19 also decreased both mRNA and protein levels of OPN in the Rh2-treated cells, which was accomplished by inhibiting histones H3 and H4 acetylation of OPN promoter. Importantly, OPN knockdown fully blocked Rh2 induced MC3T3-E1 cell proliferation. Our results suggest that lncRNA H19 is an important contributor to Rh2-mediated MC3T3-E1 proliferation by regulation of OPN.

Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety.

There is growing evidence that the preconceptual lifestyle and other environmental exposures of a father can significantly alter the physiological and behavioral phenotypes of their children. We and others have shown that paternal preconception stress, regardless of whether the stress was experienced during early-life or adulthood, results in offspring with altered anxiety and depression-related behaviors, attributed to hypothalamic-pituitary-adrenal axis dysregulation. The transgenerational response to paternal preconceptual stress is believed to be mediated by sperm-borne small noncoding RNAs, specifically microRNAs. As physical activity confers physical and mental health benefits for the individual, we used a model of voluntary wheel-running and investigated the transgenerational response to paternal exercise. We found that male offspring of runners had suppressed reinstatement of juvenile fear memory, and reduced anxiety in the light-dark apparatus during adulthood. No changes in these affective behaviors were observed in female offspring. We were surprised to find that running had a limited impact on sperm-borne microRNAs. The levels of three unique microRNAs (miR-19b, miR-455 and miR-133a) were found to be altered in the sperm of runners. In addition, we discovered that the levels of two species of tRNA-derived RNAs (tDRs)-tRNA-Gly and tRNA-Pro-were also altered by running. Taken together, we believe this is the first evidence that paternal exercise is associated with an anxiolytic behavioral phenotype of male offspring and altered levels of small noncoding RNAs in sperm. These small noncoding RNAs are known to have an impact on post-transcriptional gene regulation and can thus change the developmental trajectory of offspring brains and associated affective behaviors.

[Outcomes of pregnancy among women with alpha-thalassemia minor: A retrospective study of Pingguo county in Guangxi Zhuang Autonomous Region].

Objective: To investigate the association between the value of α-thalassemia minor and the outcomes in pregnant women. Methods: A total of 445 pregnant women with α-thalassemia minor were selected as thalassemia group in the Pingguo County Maternal and Child Health Hospital of Guangxi from January 2011 to December 2015, with ratio of 1∶4 healthy pregnant women was randomly recruited as non-thalassemia group. Clinical characteristics and pregnancy outcomes of the two groups were retrospectively analyzed using methods including t test, χ(2) test, and logistic regression model and ROC curve. Results: There were no significant differences noticed in factors as age, BMI, gestational age and educational level of the two groups. Hemoglobin of the thalassemia group was significantly lower than that of the non-thalassemia group (P<0.001). Differences on parity, ethnicities or occupation were statistically significant. Results from univariate analysis showed that the proportions of low birth weight, small for date infant and 1 min Apgar score<7 were higher in the thalassemia group, but the ratio of adverse pregnancy outcomes was comparable on parameters as preterm birth, stillbirth, macrosomia. Findings from the unconditional logistic regression showed that pregnancy complicated with α-thalassemia minor appeared a risk for both newborns with low birth weight (aOR=2.29, 95%CI: 1.32-3.95) and small for date infant (aOR= 2.11, 95%CI: 1.16-3.84). The ROC curve showed that α-thalassemia minor combined with multiple indicators presented a certain predictive value on neonatal birth weight. Conclusion: Pregnancy complicated with α-thalassemia minor was likely to increase the risk of birth weight loss in newborns, suggesting that prenatal care for pregnant women with thalassemia be strengthened, in order to reduce the incidence of adverse pregnancy outcomes.

A pre-operative clinical model to predict microvascular invasion and long-term outcome after resection of hepatocellular cancer: The Australian experience.

BACKGROUND: Hepatocellular cancer (HCC) is a leading cause of mortality worldwide. Liver resection or transplantation offer the best chance of long-term survival. The aim of this study was to perform a survival and prognostic factor analysis on patients who underwent resection of HCC at two major tertiary referral hospitals, and to investigate a pre-operative prediction model for microvascular invasion (MVI). METHODS: Clinico-pathological and survival data were collected from all patients who underwent liver resection for HCC at two tertiary referral centres (Royal North Shore/North Shore Private Hospitals and Westmead Hospital) from 1998 to 2012. An overall and disease-free survival analysis was performed and a predictive model for MVI identified. RESULTS: The total number of patients in this series was 125 and the 5-year overall and disease-free survival rates were 56% and 37%, respectively. MVI was the only factor to be independently associated with a poor prognosis on both overall and disease-free survival. Age ≥64 years, a serum alpha-fetoprotein (AFP) ≥400 ng/ml (×40 above normal) and tumor size ≥50 mm were independently associated with MVI. An MVI prediction model using these three pre-operative factors provides a good assessment of the risk of MVI. CONCLUSION: MVI in the resected specimen of patients with HCC is associated with a poor prognosis. A preoperative MVI prediction model offers a useful way to identify patients at risk of relapse. However, more precise predictive models using molecular and genetic variables are needed to improve selection of patients most suitable for radical surgical treatment.

Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring.

Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic-pituitary-adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light-dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.

Dissociating the therapeutic effects of environmental enrichment and exercise in a mouse model of anxiety with cognitive impairment.

Clinical evidence indicates that serotonin-1A receptor (5-HT1AR) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise (Ex) and environmental enrichment (EE) can change emotionality-related behaviours, as well as enhance some aspects of cognition and hippocampal neurogenesis. We investigated the effects of Ex and EE (which does not include running wheels) on cognition and anxiety-like behaviours in wild-type (WT) and 5-HT1AR knock-out (KO) mice. Using an algorithm-based classification of search strategies in the Morris water maze, we report for we believe the first time that Ex increased the odds for mice to select more hippocampal-dependent strategies. In the retention probe test, Ex (but not EE) corrected long-term spatial memory deficits displayed by KO mice. In agreement with these findings, only Ex increased hippocampal cell survival and BDNF protein levels. However, only EE (but not Ex) modified anxiety-like behaviours, demonstrating dissociation between improvements in cognition and innate anxiety. EE enhanced hippocampal cell proliferation in WT mice only, suggesting a crucial role for intact serotonergic signalling in mediating this effect. Together, these results demonstrate differential effects of Ex vs EE in a mouse model of anxiety with cognitive impairment. Overall, the 5-HT1AR does not seem to be critical for those behavioural effects to occur. These findings will have implications for our understanding of how Ex and EE enhance experience-dependent plasticity, as well as their differential impacts on anxiety and cognition.

A cultured endophyte community is associated with the plant Clerodendrum inerme and antifungal activity.

Fungal endophytes live in the inner tissues of Clerodendrum inerme and may be significant resources for new chemicals in drug discovery. A total of 242 endophytic fungi were recovered from 602 sample segments of C. inerme; 66 were purified. The 66 fungi belonging to 16 taxa and 11 genera (Alternaria, Nigrospora, Bartalinia, Pestalotiopsis, Fusarium, Mycoleptodiscus, Trichoderma, Phomopsis, Diaporthe, Lasiodiplodia, and Curvularia) were identified by morphological characteristics and fungal internal transcribed spacer sequences. The most abundant genera were Alternaria and Lasiodiplodia. Some of the endophytes exhibited tissue specificity. The colonization frequencies of endophytes in the stems were evidently higher than those in the roots and leaves. The crude ethyl acetate extracts were tested against 6 endophytes isolated from C. inerme. Three of 10 (33.3%) endophytes, which were identified as Phomopsis sp, Curvularia sp, and Mycoleptodiscus sp, displayed distinct antifungal activity against ≥3 tested fungi. To our knowledge, this is the first report of an endophytic community associated with C. inerme in China and its antifungal activity in vitro.

The influence of the HPG axis on stress response and depressive-like behaviour in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, neurodegenerative disease caused by a CAG tandem repeat mutation encoding a polyglutamine tract expansion in the huntingtin protein. Depression is among the most common affective symptoms in HD but the pathophysiology is unclear. We have previously discovered sexually dimorphic depressive-like behaviours in the R6/1 transgenic mouse model of HD at a pre-motor symptomatic age. Interestingly, only female R6/1 mice display this phenotype. Sexual dimorphism has not been explored in the human HD population despite the well-established knowledge that the clinical depression rate in females is almost twice that of males. Female susceptibility suggests a role of sex hormones, which have been shown to modulate stress response. There is evidence suggesting that the gonads are adversely affected in HD patients, which could alter sex hormone levels. The present study examined the role sex hormones play on stress response in the R6/1 mouse model of HD, in particular, its modulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis and depression-like behaviour. We found that the gonads of female R6/1 mice show atrophy at an early age. Expression levels of gonadotropin-releasing hormone (GnRH) were decreased in the hypothalamus of female HD mice, relative to wild-type female littermates, as were serum testosterone levels. Female serum estradiol levels were not significantly changed. Gonadectomy surgery reduced HPA-axis activity in female mice but had no effect on behavioural phenotypes. Furthermore, expression of the oestrogen receptor (ER) α gene was found to be higher in the adrenal cells of female HD mice. Finally, administration of an ERß agonist diarylpropionitrile (DPN) rescued depressive-like behaviour in the female HD mice. Our findings provide new insight into the pathogenesis of sexually dimorphic neuroendocrine, physiological and behavioural endophenotypes in HD, and suggest a new avenue for therapeutic intervention.