Potential mechanisms of hexaconazole resistance in Fusarium graminearum.

The Fusarium head blight (FHB) caused by Fusarium graminearum is a serious fungal disease that can dramatically impact wheat production. At present, control is mainly achieved by the use of chemical fungicides. Hexaconazole (IUPAC name: 2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)hexan-2-ol) is a widely used triazole fungicide, but the sensitivity of F. graminearum to this compound has yet to be established. The current study found that the EC50 values of 83 field isolates of F. graminearum ranged between 0.06 and 4.33 µg/mL, with an average EC50 of 0.78 µg/mL. Assessment of four hexaconazole-resistant laboratory mutants of F. graminearum revealed that their mycelial growth, and pathogenicity were reduced compared to their parental isolates, and that asexual reproduction was reduced by resistance to hexaconazole. Meanwhile, the mutants appeared to be more sensitive to abiotic stress associated with SDS, and H2O2, while their tolerance of high concentration of Congo red, and Na+ and K+ increased. Molecular analysis revealed numerous point mutations in the FgCYP51 target genes that resulted in amino acid substitutions, including L92P and N123S in FgCYP51A, as well as M331V, F62L, Q252R, A412V, and V488A in FgCYP51B, and S28L, S256A, V307A, D287G and R515I in FgCYP51C, three of which (S28L, S256A, and V307A) were conserved in all of the resistant mutants. Furthermore, the expression of the FgCYP51 genes in resistant strains was found to be significantly (p < 0.05) reduced compared to their sensitive parental isolates. Positive cross-resistance was found between hexaconazole and metconazole and flutriafol, as well as with the diarylamine fungicide fluazinam, but not with propiconazole, and the phenylpyrrole fungicide fludioxonil, or with tebuconazole, which actually exhibited negative cross-resistance. These results provide valuable insight into resistant mechanisms to triazole fungicides in F. graminearum, as well as the appropriate selection of fungicide combinations for the control of FHB to ensure optimal wheat production.

Effects of Timing and Types of Protein Supplementation on Improving Muscle Mass, Strength, and Physical Performance in Adults Undergoing Resistance Training: A Network Meta-Analysis.

Precise protein supplementation strategies for muscle improvement are still lacking. The timing or type of protein supplementation has been debated as a window of opportunity to improve muscle mass, strength, and physical performance. We conducted a network meta-analysis of randomized controlled trials with protein supplements and resistance training. PubMed, Web of Science, Cochrane Library, and SPORTDiscus databases were searched until May 1, 2023. We included 116 eligible trials with 4,711 participants that reported on 11 timing and 14 types of protein supplementation. Compared with placebo, protein supplementation after exercise (mean difference [MD]: 0.54 kg [95% confidence intervals 0.10, 0.99] for fat-free mass, MD: 0.34 kg [95% confidence intervals 0.10, 0.58] for skeletal muscle mass) and at night (MD: 2.85 kg [0.49, 5.22] for handgrip strength, MD: 12.12 kg [3.26, 20.99] for leg press strength) was most effective in improving muscle mass and strength, respectively (moderate certainty). Milk proteins (milk, whey protein, yogurt, casein, and bovine colostrum), red meat, and mixed protein were effective for gains in both muscle mass and strength (moderate certainty). No timing or type of protein showed a significant enhancement in physical performance (timed up-to-go test, 6-min walk test, and gait speed). Pre/postexercise and Night are key recommended times of protein intake to increase muscle mass and strength, respectively. Milk proteins are the preferred types of protein supplements for improving muscle mass and strength. Future randomized controlled trials that directly compare the effects of protein timing or types are needed. This trial was registered at International Prospective Register of Systematic Reviews as CRD42022358766.

Effect of flavonoid intake on circulating levels of adiponectin and leptin: A systematic review and meta-analysis of randomized controlled clinical trials.

This meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effects of flavonoid intake on adiponectin and leptin levels. The PubMed, EMBASE, and Cochrane Library databases were searched on March 1, 2021. Random-effects, subgroup, sensitivity, and meta-regression analyses were conducted on 40 publications. Flavonoid intake significantly increased circulating adiponectin (0.54 µg/ml, 95% CI [0.20, 0.88], p = .002; I2  = 86.4%) and significantly reduced leptin levels (weighted mean difference: -0.79 ng/ml, 95% CI [-1.33, -0.25], p = .004; I2  = 87.7%). Subgroup analysis demonstrated that flavonoid intervention produced a significant elevation in adiponectin levels only in studies that lasted more than 12 weeks, conducted in Asian regions, were parallel-designed, involved obese or overweight participants and participants with type 2 diabetes mellitus (T2DM) or cardiovascular diseases, used tea catechins, and used a dietary supplement intervention. A significantly negative effect on leptin levels was observed in studies conducted in Asian countries, with healthy participants and participants with T2DM, used whole food interventions, and involved participants with lower baseline leptin levels. In conclusion, flavonoid intake significantly increased circulating adiponectin and decreased leptin levels; however, study heterogeneity was very high. Future well-designed trials are required to address heterogeneous study designs and clarify the efficacy of plants in regulating adiponectin and leptin levels.

Occurrence and potentially zoonotic genotypes of Enterocytozoon bieneusi in wild rhesus macaques (Macaca mulatta) living in Nanwan Monkey Island, Hainan, China: a public health concern.

BACKGROUND: Enterocytozoon bieneusi, a microsporidian species, is a zoonotic pathogen found in both humans and animals. Here, we determined the prevalence, explored the different genotypes of E. bieneusi in wild rhesus macaques (Macaca mulatta) (Hainan Island of China), and assessed their zoonotic potential. METHODS: We collected 173 fecal specimens from wild rhesus macaques living in Nanwan Monkey Island, Hainan, China. Subsequently, we identified and genotyped E. bieneusi using nested PCR analysis amplification of the internal transcribed spacer region (ITS) of the rRNA gene. Lastly, a neighbor-joining tree was built based on gene sequences from the ITS region of E. bieneusi. RESULTS: Of the 173 specimens from wild rhesus macaques, 26 (15%) were infected with E. bieneusi. We identified six genotypes of E. bieneusi, of which five were known: PigEBITS7 (n = 20), D (n = 2), Type IV (n = 1), Peru6 (n = 1), Henan-III (n = 1), and a novel genotype: HNM-IX (n = 1). From the phylogenetic analysis, the six genotypes identified here were all clustered into zoonotic group 1. CONCLUSION: This study is the first report to detect E. bieneusi infection in wild rhesus macaques from Hainan, China. Human-pathogenic genotypes D, Henan-III, Peru6, PigEbITS7, and Type IV in the wild rhesus macaques support these animals infected with E. bieneusi have a public health significance.

The effect of hormone replacement therapy on cognitive function in healthy postmenopausal women: a meta-analysis of 23 randomized controlled trials.

To investigate how hormone replacement therapy (HRT) intervention affects cognitive function in randomized controlled trials of healthy postmenopausal women, the PubMed and Web of Science databases were searched for relevant publications up to 1 May 2020. Random-effects, subgroup analysis, sensitivity analysis and meta-regression analyses were conducted with 23 selected publications. HRT had a significant negative effect on global cognition (standardized mean difference (SMD): -0.04, 95% confidence interval (CI): -0.08 to -0.01). Via subgroup analysis, for those older than 60 years and with more than 6 months' intervention duration, HRT aggravated global cognition (SMD: -0.05, 95% CI: -0.08 to -0.01; SMD: -0.05, 95% CI: -0.08 to -0.01). The results of meta-regression demonstrated no significant association between HRT intervention and global cognition after adjusting for participants' age or intervention duration. In conclusion, HRT had a significant negative effect on global cognition, and this effect might be especially more visible for those aged more than 60 years and with more than 6 months' intervention. Further randomized controlled trials for postmenopausal women with a younger age and short-term HRT exposure are necessary to clarify the effects of HRT on global and domain-specific cognitive functions.

Prevalence and genotypic identification of Cryptosporidium spp. and Enterocytozoon bieneusi in captive Asiatic black bears (Ursus thibetanus) in Heilongjiang and Fujian provinces of China.

BACKGROUND: Cryptosporidium and Enterocytozoon bieneusi are two important pathogens with zoonotic potential that cause enteric infections in a wide range of hosts, including humans. Both are transmitted from animals to humans by direct contact or through contaminated equipment. Bears are frequently found in Chinese zoos as ornamental animals as well as farmed as commercial animals, and are therefore in close contact with zoo- or farm-keepers, but the prevalence and zoonotic potential of Cryptosporidium and E. bieneusi in bears is poorly understood. In this study, we aimed to provide data on the occurrence and genetic diversity of Cryptosporidium and E. bieneusi in Asiatic black bears from Heilongjiang and Fujian, China. From May 2015 to December 2017, 218 fresh fecal specimens were collected from captive Asiatic black bears in Heilongjiang (n = 36) and Fujian (n = 182), China. Cryptosporidium and E. bieneusi were examined by PCR amplification of the partial small subunit of ribosomal DNA (SSU rDNA) and the internal transcribed spacer (ITS) region of rDNA, respectively. C. andersoni-positive isolates were subtyped through PCR analysis of the four minisatellite/microsatellite (MS1, MS2, MS3 and MS16) loci. RESULTS: The overall prevalence of Cryptosporidium and E. bieneusi were 2.4% (4/218) and 6.4% (14/218), respectively, with 2.8% (1/36) and 22.2% (8/36) in the Heilongjiang Province, and 1.6% (3/182) and 3.3% (6/182) in the Fujian Province. Sequence analysis confirmed the presence of Cryptosporidium species: C. andersoni (n = 3) and a genotype termed Cryptosporidium rat genotype IV (n = 1). All three identified C. andersoni belonged to the MLST subtype A4, A4, A4, A1. Two known E. bieneusi genotypes D (n = 4) and SC02 (n = 10) were identified, both of which belong to zoonotic Group 1. CONCLUSIONS: This is the first report of C. andersoni and Cryptosporidium rat genotype IV in bears. The discovery of the zoonotic potential of E. bieneusi genotype D in bears highlights its significant zoonotic potential and potential threat to human health.

PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.

Associations of Various Physical Activities with Mortality and Life Expectancy are Mediated by Telomere Length.

OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56 years) from the UK Biobank were analyzed. METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy. RESULTS: During a median follow-up of 13.8 years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720 minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6 years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300 minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150 minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61 years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375 minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300 minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (≈1% mediation proportion, both P < .001). CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720 minutes/wk of walking, 75 to 375 minutes/wk of MPA, and 75 to 300 minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.

Long-term exercise training and inflammatory biomarkers in healthy subjects: a meta-analysis of randomized controlled trials.

Objective: This meta-analysis investigated the effect of long-term exercise training (ET) including aerobic, resistance, and multicomponent ET on the levels of inflammatory biomarkers in randomized controlled trials (RCTs) involving healthy subjects. Methods: We searched seven databases for articles until May 1st, 2023. A random-effect meta-analysis, subgroup analysis, meta-regressions as well as trim and fill method were conducted using STATA 16.0. Result: Thirty-eight studies were included in the meta-analysis, involving 2,557 healthy subjects (mean age varies from 21 to 86 years). Long-term ET induced significantly decreased in the levels of interleukin-6 (IL-6) (SMD -0.16, 95% CI -0.30 to -0.03, p = 0.017), C-reactive protein (CRP) (SMD -0.18, 95% CI -0.31 to -0.06, p = 0.005), as well as tumor necrosis factor alpha (TNFα) (SMD -0.43, 95% CI -0.62 to -0.24, p < 0.001). Subgroup analysis revealed that Long-term ET conducted for more than 12 weeks and exercise of moderate intensity had greater anti-inflammatory effects. Meta-regression analysis showed that the reduction in CRP level induced by long-term ET was weakened by increasing exercise intensity. Conclusion: Long-term ET induced significant anti-inflammatory effects in healthy subjects. Long-term ET-induced anti-inflammatory effects were associated with exercise of moderate intensity and training conducted for more than 12 weeks.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/# myprospero, PROSPERO, identifier CRD42022346693.

Association of muscle wasting with mortality risk among adults: A systematic review and meta-analysis of prospective studies.

The relationship between muscle wasting and mortality risk in the general population remains unclear. Our study was conducted to examine and quantify the associations between muscle wasting and all-cause and cause-specific mortality risks. PubMed, Web of Science and Cochrane Library were searched until 22 March 2023 for main data sources and references of retrieved relevant articles. Prospective studies investigating the associations of muscle wasting with risks of all-cause and cause-specific mortality in the general population were eligible. A random-effect model was used to calculate the pooled relative risk (RR) and 95% confidence intervals (CIs) for the lowest versus normal categories of muscle mass. Subgroup analyses and meta-regression were performed to investigate the potential sources of heterogeneities among studies. Dose-response analyses were conducted to evaluate the relationship between muscle mass and mortality risk. Forty-nine prospective studies were included in the meta-analysis. A total of 61 055 deaths were ascertained among 878 349 participants during the 2.5- to 32-year follow-up. Muscle wasting was associated with higher mortality risks of all causes (RR = 1.36, 95% CI, 1.28 to 1.44, I2  = 94.9%, 49 studies), cardiovascular disease (CVD) (RR = 1.29, 95% CI, 1.05 to 1.58, I2  = 88.1%, 8 studies), cancer (RR = 1.14, 95% CI, 1.02 to 1.27, I2  = 38.7%, 3 studies) and respiratory disease (RR = 1.36, 95% CI, 1.11 to 1.67, I2  = 62.8%, 3 studies). Subgroup analyses revealed that muscle wasting, regardless of muscle strength, was significantly associated with a higher all-cause mortality risk. Meta-regression showed that risks of muscle wasting-related all-cause mortality (P = 0.06) and CVD mortality (P = 0.09) were lower in studies with longer follow-ups. An approximately inverse linear dose-response relationship was observed between mid-arm muscle circumference and all-cause mortality risk (P < 0.01 for non-linearity). Muscle wasting was associated with higher mortality risks of all causes, CVD, cancer and respiratory disease in the general population. Early detection and treatment for muscle wasting might be crucial for reducing mortality risk and promoting healthy longevity.

The effect of physical exercise on circulating brain-derived neurotrophic factor in healthy subjects: A meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate how physical exercise (PE) would affect brain-derived neurotrophic factor (BDNF) in randomized controlled trials (RCTs) of healthy subjects. METHODS: Seven databases (PubMed, Web of Science, Cochrane, Embase, PsycINFO, CINAHL, SPORTDiscus) were searched for RCTs assessing the effects of PE on serum and/or plasma BDNF until December 18, 2021. Meta-analysis was performed by random-effects method with standardized mean difference (SMD) and 95% confidence intervals (CIs). Subgroup analysis and meta-regression analysis were conducted to investigate the potential source of heterogeneity. Trim and fill method, and leave-one-out cross-validation were conducted. RESULTS: Eventually, 21 articles, involving 809 participants, were included in the meta-analysis. Overall, both acute (5 trials, SMD: 1.20, 95% CI: 0.36 to 2.04, p = .005) and long-term (17 trials, SMD: 0.68, 95% CI: 0.27 to 1.08, p = .001) PE had significant positive effects on BDNF levels. Via subgroup analysis, studies of long-term PE with larger sample sizes, female participants, participants older than 60 years, and aerobic exercise contributed to a more pronounced improvement on BDNF levels than that found when all studies were combined. CONCLUSION: Both acute and long-term PE had significant positive effects on circulating BDNF in healthy subjects. This review suggests that acute exercise and long-term aerobic exercise are powerful forms of PE to enhance neurotrophic effect, especially for female subjects or subjects over 60 years.

Lifestyle intervention during pregnancy in patients with gestational diabetes mellitus and the risk of neonatal hypoglycemia: A systematic review and meta-analysis.

Objective: Neonatal hypoglycemia is a severe adverse consequence of infants born to mothers with gestational diabetes mellitus (GDM), which can lead to neonatal mortality, permanent neurological consequences, and epilepsy. This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effect of lifestyle intervention during pregnancy in women with GDM on the risk of neonatal hypoglycemia. Methods: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus databases were searched by 1st April 2022. Data were pooled as the risk ratio (RR) with 95% CIs of neonatal hypoglycemia. Random-effects, subgroup analyses, meta-regression analysis, and leave-one-out analysis were conducted, involving 18 RCTs. Results: Prenatal lifestyle intervention could significantly reduce the risk of neonatal hypoglycemia (RR: 0.73, 95% CI: 0.54-0.98, P = 0.037). Subgroup analysis further demonstrated that the reduced risk of neonatal hypoglycemia was observed only when subjects were younger than 30 years, initiated before the third trimester, and with dietary intervention. Meta-regression analysis revealed that the risk of neonatal hypoglycemia post lifestyle intervention was lower in mothers with lower fasting glucose levels at trial entry. Conclusion: We found that prenatal lifestyle intervention in women with GDM significantly reduced the risk of neonatal hypoglycemia. Only lifestyle intervention before the third trimester of pregnancy, or dietary intervention only could effectively reduce the risk of neonatal hypoglycemia. Future studies are required to explore the best pattern of lifestyle intervention and to determine the proper diagnostic criteria of GDM in the first/second trimester of pregnancy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprospero, PROSPERO, identifier: CRD42021272985.

Mechanism of Pydiflumetofen Resistance in Fusarium graminearum in China.

Fusarium head blight (FHB), which is primarily caused by Fusarium graminearum, is a widespread and devastating disease of wheat. In the absence of resistant varieties, the control of FHB relies heavily on the application of fungicides, and the new generation SDHI fungicide, pydiflumetofen, has recently been registered in China for the control of FHB in wheat. The current study explored three genetically stable, highly resistant laboratory mutants (S2-4-2R, S27-3R, and S28-2R, with EC50 values of 25.10, 28.57, and 19.22 µg/mL, respectively) to investigate the potential risks associated with pydiflumetofen resistance. Although the mycelial growth of the mutants differed little compared to their parental isolates, the study found that the resistant mutants exhibited significantly reduced (p < 0.05) levels of sporulation and pathogenicity, which suggests a significant fitness cost associated with pydiflumetofen resistance in F. graminearum. Sequence analysis of the Sdh target protein identified numerous amino acid substitutions in the predicted sequences of the four subunits: FgSdhA, FgSdhB, FgSdhC, and FgSdhD. Indeed, the mutants were found to have a series of substitution in multiple subunits such that all three exhibited five identical changes, including Y182F in the FgSdhA subunit; H53Q, C90S, and A94V in FgSdhB; and S31F in FgSdhC. In addition, gene expression analysis revealed that all of the FgSdh genes had significantly altered expression (p < 0.05), particularly FgSdhA and FgdhC, which exhibited remarkably low levels of expression. However, the study found no evidence of cross-resistance between pydiflumetofen and tebuconazole, fludioxonil, prochloraz, fluazinam, carbendazim, pyraclostrobin, or difenoconazole, which indicates that these fungicides, either in rotation or combination with pydiflumetofen, could mitigate the risk of resistance emerging and provide ongoing control of FHB to ensure high and stable wheat yields.

Exploring Potential Mechanisms of Fludioxonil Resistance in Fusarium oxysporum f. sp. melonis.

Melon Fusarium wilt (MFW), which is caused by Fusarium oxysporum f. sp. melonis (FOM), is a soil-borne disease that commonly impacts melon cultivation worldwide. In the absence of any disease-resistant melon cultivars, the control of MFW relies heavily on the application of chemical fungicides. Fludioxonil, a phenylpyrrole fungicide, has been shown to have broad-spectrum activity against many crop pathogens. Sensitivity analysis experiments suggest that fludioxonil has a strong inhibitory effect on the mycelial growth of FOM isolates. Five fludioxonil-resistant FOM mutants were successfully generated by repeated exposure to fludioxonil under laboratory conditions. Although the mutants exhibited significantly reduced mycelial growth in the presence of the fungicide, there initially appeared to be little fitness cost, with no significant difference (p < 0.05) in the growth rates of the mutants and wild-type isolates. However, further investigation revealed that the sporulation of the fludioxonil-resistant mutants was affected, and mutants exhibited significantly (p < 0.05) reduced growth rates in response to KCl, NaCl, glucose, and mannitol. Meanwhile, molecular analysis of the mutants strongly suggested that the observed fludioxonil resistance was related to changes in the sequence and expression of the FoOs1 gene. In addition, the current study found no evidence of cross-resistance between fludioxonil and any of the other fungicides tested. These results indicate that fludioxonil has great potential as an alternative method of control for FOM in melon crops.

Cardiac Safety in Breast Cancer Patients Receiving Pegylated Liposome Doxorubicin Sequential Anti-HER2 Monoclonal Antibody Therapy.

Background: Cardiotoxicity associated with the sequential use of anthracyclines followed by trastuzumab is common in adjuvant therapy of patients with HER2-positive early breast cancer (eBC). However, the cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) is relatively less studied. Method: Clinical data of patients with HER2-positive eBC treated with PLD and cyclophosphamide (PLD-C) followed by taxanes plus trastuzumab ± pertuzumab (TH or TPH) who then completed standard anti-HER2 treatment for 12 months from June 2012 to August 2021 were retrospectively collected. The primary endpoints were clinical and subclinical cardiotoxicity. Result: In total, 70 eligible patients were enrolled. Among them, 55 patients (78.6%) received PLD-C → TH and 15 patients (21.4%) received PLD-C → TPH. The median follow-up time was 41.8 months. Until August 2021, only two patients had recurrent or metastatic diseases, with 2-year and 5-year disease-free survivals of 98.6% and 96.8%, respectively. Clinical cardiotoxicity occurred in six patients (8.6%), and all of them had an absolute decline of ≥16% from baseline left ventricular ejection fraction (LVEF) but not below the lower limit of normal (LLN = 50%). Subclinical cardiotoxicity events occurred in 17 patients (24.3%), and all of them had absolute declines of ≥10% and <16% from baseline LVEF but not below the LLN. No patients were interrupted from treatment, and all patients completed anti-HER2 treatment for 12 months. The sharpest decrease in LVEF was observed at 18 months after the start of PLD treatment. The cumulative incidences of clinical and subclinical cardiotoxicity were 9.8% and 28.3%, respectively. In the univariate analysis, body mass index, age, left chest wall radiotherapy, and ongoing cardiovascular risk factors were not significantly associated with clinical or subclinical cardiotoxicity (p > 0.05). No patients had congestive heart failure or death caused by PLD or anti-HER2 treatment. Conclusion: The sequential use of PLD and trastuzumab showed a lower incidence of clinical cardiotoxicity, presented as asymptomatic decreased LVEF, compared with the results obtained in previous clinical studies using conventional anthracycline, taxanes and trastuzumab. The study regimen demonstrated good cardiac tolerance and is an alternative strategy for cardioprotection in patients with HER2-positive eBC.

Sex-Specific Neurotoxicity of Dietary Advanced Glycation End Products in APP/PS1 Mice and Protective Roles of Trehalose by Inhibiting Tau Phosphorylation via GSK-3ß-TFEB.

SCOPE: It remains unclear whether dietary advanced glycation end products (dAGEs)-induced cognitive impairment is sex-dependent. Trehalose may antagonize dAGEs-induced neurotoxicity via glycogen synthase kinase-3 beta (GSK3ß)-transcription factor EB (TFEB) signaling. METHODS AND RESULTS: The sex-specific neurotoxicity of dAGEs and the protective role of trehalose are investigated both in vivo and in vitro. Both sexes of APP/PS1 mice are divided into three groups: that is, control, dAGEs, and dAGEs supplemented with trehalose. SHSY-5Y cells incubated with AGE-BSA and trehalose are also utilized. Dietary AGEs impair cognitive function only in female mice, which is restored by trehalose. Trehalose upregulates phosphorylated-GSK3ß serine9 (p-GSK3ß ser9), TFEB and transient receptor potential mucolipin 1, ADAM10, oligosaccharyl transferase-48, estrogen receptor α and induces TFEB nuclear translocation in hippocampus, elevates IDE and ERß in cortex, while reduces p-tau ser396&404, CDK5, cathepsin B, and glial fibrillary acidic protein in hippocampus. Trehalose elevates p-GSK3ß ser9, induces TFEB nuclear translocation, consequently reverses AGE-BSA-induced tau phosphorylation in vitro. CONCLUSIONS: Female mice are more susceptible to the deleterious effects of dAGEs on cognitive function, which may be owing to its regulation on ERß. Trehalose can strongly reverse dAGEs-induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK-3ß.

Dietary lactoferrin has differential effects on gut microbiota in young versus middle-aged APPswe/PS1dE9 transgenic mice but no effects on cognitive function.

BACKGROUND: Existing evidence suggest that lactoferrin might be beneficial for Alzheimer's disease, while precise mechanisms are not fully elucidated. OBJECTIVE: To determine the effects of lactoferrin intervention on cognitive function from APPswe/PS1dE9 (APP/PS1) mice, and potential mechanisms involved. DESIGN: Both the young and middle-aged male APP/PS1 mice were divided into the control and lactoferrin intervention groups with 16 weeks' intervention. RESULTS: Lactoferrin had no effects on cognitive function for both the young and middle-aged mice, and no key markers involved in Aß, tau pathology, neuro-inflammation and synaptic plasticity were altered after lactoferrin intervention. With regards to gut microbiota profiles, in the young APP/PS1 mice, lactoferrin elevated the α diversity index including ACE and Chao 1, and reduced the relative abundance of the genera Bacteroides and Alistipes and elevated Oscillibacter; in addition, Oscillibacter, Anaerotruncus, EF096579_g, EU454405_g, Mollicutes_RF39, EU474361_g, EU774448_g, and EF096976_g were specifically abundant via linear discriminant analysis with effect size (LEfSe) analysis. In the middle-aged APP/PS1 mice, the relative abundance of the phylum Proteobacteria, as well as the genera Oscillospira, Coprococcus, and Ruminococcus was significantly reduced post lactoferrin; additionally, S24_7, Bacteroidia, Bacteroidetes, and Methylobacterium were specific via LEfSe analysis in the lactoferrin group. CONCLUSIONS: Dietary lactoferrin might be beneficial for gut microbiota homeostasis although it might have no effects on cognition.

Voluntary wheel running is capable of improving cognitive function only in the young but not the middle-aged male APPSwe/PS1De9 mice.

To determine whether voluntary wheel running could improve cognitive function from both the young and middle-aged APP/PS1 mice and the underlying mechanisms involved in. Young (9-weeks old) and middle-aged (24-weeks old) APP/PS1 mice were randomly assigned into control and exercise groups, respectively. Mice from exercise group had free and unlimited access to the running wheel for a total of 16 weeks. Voluntary exercise only improved cognitive function from young but not the middle-aged APP/PS1 mice. This might be owing to that in young APP/PS1 mice voluntary exercise reduced tau phosphorylation via inhibiting p-GSK3ß activity, as well as reduced neuro-inflammation and elevated key proteins involved in synaptic plasticity. Additionally, exercise also elevated circulating L-Valine, Glucosamine, Formylanthranilic acid, Myristic acid level and improved gut microbiota profiles (i.e. elevated Oscillibacter, EF097061_g, EU454870_g, EU504554_g, EU505046_g and EF096172_g and reduced Alistipes). Improved circulating metabolites and intestinal microbiome might also contribute to improved learning and memory abilities post exercise. For the middle-aged APP/PS1 mice, exercise reduced ADAM10 and GFAP protein expression in hippocampus, with no notable alterations in circulating metabolites; additionally, mice from exercise group had markedly reduced abundance of the phyla Proteobacteria and Tenericutes, genera Bacteroides and Faecalibacterium, and elevated abundance of the genera Allobaculum. It is suggested that voluntary exercise should be initiated at an early adulthood period rather than at late stage in order to prevent cognitive decline or Alzheimer's disease.

Molecular detection of Enterocytozoon bieneusi in farm-raised pigs in Hainan Province, China: infection rates, genotype distributions, and zoonotic potential.

Enterocytozoon bieneusi is a zoonotic fungal pathogen with a high degree of host diversity that can parasitize many animals, including humans. Pigs may play an important role in the epidemiology of E. bieneusi as reservoir hosts. Nevertheless, the genotypes of E. bieneusi in pigs in China remain poorly understood. The aim of this study was to determine the prevalence of E. bieneusi infection amongst pigs raised on farms from four cities of Hainan Province, using nested polymerase chain reaction (PCR) of the partial small subunit of the ribosomal RNA gene, and to identify genotypes of E. bieneusi isolates based on sequence analysis of the ribosomal internal transcribed spacer (ITS) region. Among 188 stool samples, E. bieneusi was detected in 46.8% (88/188). Eight genotypes including four known (EbpA, CS-4, MJ14, and CHG19) and four novel (HNP-I - HNP-IV) genotypes were identified. Using phylogenetic analysis, genotypes EbpA, CS4, CHG19, HNP-III, and HNP-IV were clustered into zoonotic Group 1, while the remaining three genotypes (MJ14, HNP-I, and HNP-II) clustered into Group 10. The high prevalence of zoonotic genotypes of E. bieneusi among pigs suggests that pig farming is a potential source of human infection. Additionally, this is the first identification of genotypes in Group 10 in pigs indicating unique epidemic features of E. bieneusi in pigs in Hainan Province, the southernmost part of China.

TITLE: Détection moléculaire d'Enterocytozoon bieneusi chez les porcs d'élevage dans la province de Hainan en Chine : taux d'infection, répartition des génotypes et potentiel zoonotique. ABSTRACT: Enterocytozoon bieneusi est un pathogène fongique zoonotique avec une grande diversité d'hôte qui peut parasiter de nombreux animaux, y compris les humains. Les porcs peuvent jouer un rôle important dans l'épidémiologie d'E. bieneusi en tant qu'hôtes réservoirs. Néanmoins, les génotypes d'E. bieneusi chez le porc en Chine restent mal connus. Le but de cette étude était de déterminer la prévalence de l'infection par E. bieneusi chez les porcs élevés dans des fermes de quatre villes de la province de Hainan, en utilisant la réaction en chaîne par polymérase emboîtée (PCR) de la petite sous-unité partielle du gène de l'ARN ribosomal et de identifier les génotypes des isolats d'E. bieneusi sur la base d'une analyse de séquence de la région des espaceurs internes transcrits ribosomiques (ITS). Sur 188 échantillons de selles, E. bieneusi a été détecté dans 46,8 % (88/188). Huit génotypes, dont quatre génotypes connus (EbpA, CS-4, MJ14 et CHG19) et quatre génotypes nouveaux (HNP-I à IV), ont été identifiés. Dans une analyse phylogénétique, les génotypes EbpA, CS4, CHG19, HNP-III et HNP-IV étaient regroupés dans le groupe zoonotique 1, tandis que les trois génotypes restants (MJ14, HNP-I et HNP-II) étaient regroupés dans le groupe 10. La prévalence élevée des génotypes zoonotiques d'E. bieneusi chez les porcs suggère que l'élevage porcin est une source potentielle d'infection humaine. De plus, il s'agit de la première identification de génotypes du groupe 10 chez les porcs, indiquant des caractéristiques épidémiques uniques d'E. bieneusi chez les porcs dans la province de Hainan, la partie la plus méridionale de la Chine.

Genotyping and zoonotic potential of Enterocytozoon bieneusi in cattle farmed in Hainan Province, the southernmost region of China.

Enterocytozoon bieneusi is an intestinal pathogen that infects a wide range of species, including humans. Cattle constitute an important host for E. bieneusi; however, there is a scarcity of information on the prevalence and genotyping of E. bieneusi in cattle in the Hainan Province of China. In this study, PCR analysis of 314 fecal samples from cattle in six cities of Hainan was performed for genotype identification. The average prevalence of E. bieneusi in these animals was 9.9% (31/314), and ranged from 0.0% (0/12) to 20.5% (8/39). Five known genotypes - EbpC (n = 14), BEB4 (n = 12), J (n = 2), I (n = 1), and CHG5 (n = 1) - and a novel genotype: HNC-I (n = 1) - were identified. Genotypes EbpC and HNC-I were placed in zoonotic Group 1, and the remaining four genotypes (BEB4, J, I, and CHG5) were placed in Group 2. Since 93.5% of the genotypes found in the cattle (29/31) (EbpC, BEB4, J, and I) have previously been found in humans, these genotypes are probably involved in the transmission of microsporidiosis to humans.

TITLE: Génotypage et potentiel zoonotique d'Enterocytozoon bieneusi chez les bovins élevés dans la province de Hainan, la région la plus au sud de la Chine. ABSTRACT: Enterocytozoon bieneusi est un pathogène intestinal qui infecte un large éventail d'espèces, y compris les humains. Le bétail constitue un hôte important pour E. bieneusi, mais les informations sur la prévalence et le génotypage d'E. bieneusi chez les bovins de la province de Hainan en Chine sont rares. Dans cette étude, une analyse PCR de 314 échantillons fécaux provenant de bovins dans six villes de Hainan a été réalisée pour l'identification du génotype. La prévalence moyenne d'E. bieneusi chez ces animaux était de 9,9 % (31/314), et variait de 0,0 % (0/12) à 20,5 % (8/39). Cinq génotypes connus, EbpC (n = 14), BEB4 (n = 12), J (n = 2), I (n = 1) et CHG5 (n = 1), et un nouveau génotype, HNC-I (n = 1), ont été identifiés. Les génotypes EbpC et HNC-I sont placés dans le groupe zoonotique 1, et les quatre génotypes restants (BEB4, J, I et CHG5) sont placés dans le groupe 2. Puisque 93,5 % (29/31) (EbpC, BEB4, J et I) des génotypes trouvés chez les bovins ont déjà été trouvés chez l'homme, ces génotypes sont probablement impliqués dans la transmission de la microsporidiose à l'homme.