Concerns about the application of resistance exercise with blood-flow restriction and thrombosis risk in hemodialysis patients

Background:Hemodialysis(HD) per se is a risk factor for thrombosis.Considering the growing body of evidence on blood-flow restriction(BFR) exercise in HD patients,identification of possible risk factors related to the prothrombotic agent D-dimer is required for the safety and feasibility of this training model.The aim of the present study was to identify risk factors associated with higher D-dimer levels and to determine the acute effect of resistance exercise(RE) with BFR on this molecule.Methods:Two hundred and six HD patients volunteered for this study(all with a glomerular filtration rate of <15 mL/min/1.73 m2).The RE+BFR session consisted of 50% arterial occlusion pressure during 50 min sessions of HD(intradialytic exercise).RE repetitions included concentric and eccentric lifting phases(each lasting 2 s) and were supervised by a strength and conditioning specialist.Results:Several variables were associated with elevated levels of D-dimer,including higher blood glucose,citrate use,recent cardiovascular events,recent intercurrents,higher inflammatory status,catheter as vascular access,older patients(>70 years old),and HD vintage.Furthermore,RE+BFR significantly increases D-dimer after 4 h.Patients with borderline baseline D-dimer levels(400-490 ng/mL) displayed increased risk of elevating D-dimer over the normal range(≥500 ng/mL).Conclusion:These results identified factors associated with a heightened prothrombotic state and may assist in the screening process for HD patients who wish to undergo RE+BFR.D-dimer and/or other fibrinolysis factors should be assessed at baseline and throughout the protocol as a precautionary measure to maximize safety during RE+BFR.

Effects of maternal methyl donor intake during pregnancy on ileum methylation and function in an intrauterine growth restriction pig model

Background Intrauterine growth retardation(IUGR)affects intestinal growth,morphology,and function,which leads to poor growth performance and high mortality.The present study explored whether maternal dietary methyl donor(MET)supplementation alleviates IUGR and enhances offspring’s growth performance by improving intestinal growth,function,and DNA methylation of the ileum in a porcine IUGR model.Methods Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery.After farrowing,8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum.Results The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets.Moreover,maternal MET supplementation significantly reduced the plasma concentrations of isoleucine,cysteine,urea,and total amino acids in sows and newborn pig-lets.It also increased lactase and sucrase activity in the jejunum of newborn piglets.MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets.DNA methylation analysis of the ileum showed that MET supplementation increased the methyla-tion level of DNA CpG sites in the ileum of newborn piglets.Down-regulated differentially methylated genes were enriched in folic acid binding,insulin receptor signaling pathway,and endothelial cell proliferation.In contrast,up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosyn-thetic process.Conclusions Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets,which may be associated with better intestinal function and methylation status.

Mechanisms underlying the role of endoplasmic reticulum stress in the placental injury and fetal growth restriction in an ovine gestation model

Background Exposure to bisphenol A(BPA),an environmental pollutant known for its endocrine-disrupting properties,during gestation has been reported to increase the risk of fetal growth restriction(FGR)in an ovine model of pregnancy.We hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta,oxidative stress,inflammatory responses,autophagy and endoplasmic reticulum stress(ERS).However,precise mechanisms underlying the BPA-induced placental dysfunction,and subsequently,FGR,as well as the potential involvement of placental ERS in these complications,remain to be investigated.Methods In vivo experiment,16 twin-pregnant(from d 40 to 130 of gestation)Hu ewes were randomly distributed into two groups(8 ewes each).One group served as a control and received corn oil once a day,whereas the other group received BPA(5 mg/kg/d as a subcutaneous injection).In vitro study,ovine trophoblast cells(OTCs)were exposed to 4 treatments,6 replicates each.The OTCs were treated with 400μmol/L BPA,400μmol/L BPA+0.5μg/m L tunicamycin(Tm;ERS activator),400μmol/L BPA+1μmol/L 4-phenyl butyric acid(4-PBA;ERS antagonist)and DMEM/F12 complete medium(control),for 24 h.Results In vivo experiments,pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency,progesterone(P4)level and fetal weight,and an increase in placental estrogen(E2)level,together with barrier dysfunctions,OS,inflammatory responses,autophagy and ERS in type A cotyledons.In vitro experiment,the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy,ERS,pro-apoptosis and inflammatory response,and a decrease in the P4 level and the related protein and gene expressions of antioxidant,anti-apoptosis and barrier function.Moreover,treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine(the increased E2 level and decreased P4 level),OS,inflammatory responses,autophagy,and ERS.However,treating the OTCs with 4-PBA reversed the counteracted effects of Tm mentioned above.Conclusions In general,the results reveal that BPA exposure can cause ERS in the ovine placenta and OTCs,and ERS induction might aggravate BPA-induced dysfunction of the placental barrier and endocrine,OS,inflammatory responses,and autophagy.These data offer novel mechanistic insights into whether ERS is involved in BPA-mediated placental dysfunction and fetal development.

Associations of serum D-dimer and glycosylated hemoglobin levels with third-trimester fetal growth restriction in gestational diabetes mellitus

BACKGROUND Gestational diabetes mellitus(GDM)is a special type of diabetes that commonly occurs in women during pregnancy and involves impaired glucose tolerance and abnormal glucose metabolism;GDM is diagnosed for the first time during pregnancy and can affect fetal growth and development.AIM To investigate the associations of serum D-dimer(D-D)and glycosylated hemoglobin(HbA1c)levels with third-trimester fetal growth restriction(FGR)in GDM patients.METHODS The clinical data of 164 pregnant women who were diagnosed with GDM and delivered at the Obstetrics and Gynecology Hospital of Fudan University from January 2021 to January 2023 were analyzed retrospectively.Among these women,63 whose fetuses had FGR were included in the FGR group,and 101 women whose fetuses had normal body weights were included in the normal body weight group(normal group).Fasting venous blood samples were collected from the elbow at 28-30 wk gestation and 1-3 d before delivery to measure serum D-D and HbA1c levels for comparative analysis.The diagnostic value of serum D-D and HbA1c levels for FGR was evaluated by receiver operating characteristic analysis,and the influencing factors of third-trimester FGR in GDM patients were analyzed by logistic regression.RESULTS Serum fasting blood glucose,fasting insulin,D-D and HbA1c levels were significantly greater in the FGR group than in the normal group,while the homeostasis model assessment of insulin resistance values were lower(P<0.05).Regarding the diagnosis of FGR based on serum D-D and HbA1c levels,the areas under the curves(AUCs)were 0.826 and 0.848,the cutoff values were 3.04 mg/L and 5.80%,the sensitivities were 81.0%and 79.4%,and the specificities were 88.1%and 87.1%,respectively.The AUC of serum D-D plus HbA1c levels for diagnosing FGR was 0.928,and the sensitivity and specificity were 84.1%and 91.1%,respectively.High D-D and HbA1c levels were risk factors for third-trimester FGR in GDM patients(P<0.05).CONCLUSION D-D and HbA1c levels can indicate the occurrence of FGR in GDM patients in the third trimester of pregnancy to some extent,and their combination can be used as an important index for the early prediction of FGR.

The Effect of Macronutrient Restrictions on Gut Microbiome and Biochemical Parameters of Wistar Albino Rats

Macronutrients serve as a source of energy for both gut microbiota and its host. An increase or decrease in macronutrients can either increase or decrease the composition of gut microbiota, leading to gut dysbiosis which has been implicated in many diseases state including non-communicable diseases. To achieve this, seven diets were formulated by restricting 60% of each macronutrient. These diets were fed on 42 albino rats (Wistar), divided into 7 groups of 6 rats each. Group 1 was fed on a normal laboratory chow diet (ND), group 2 received a fat-restricted diet (FRD), group 3 received a protein-restricted diet, (PFD), group 4 received a carbohydrate-restricted diet (CRD), group 5 received a protein and fat-restricted diet (PFRD), group 6 re-ceived a carbohydrate and fat-restricted diet (CFRD) and group 7 received a carbohydrate and protein-restricted diet (CPRD). Feed and water intake were given ad libitum and daily weight and food intake were recorded. The experiment went on for 4 weeks after which animals were sacrificed and intestinal content and blood were collected for analysis (gut microbial composition, glucose, insulin levels, serum lipid, and enzyme). Compared to the control group results showed a decrease in Bacteroides (40.50 - 14.00 CFU), HDL (68.20 - 40.40 mg/dl), and AST (66.62 - 64.74 U/L) in FRD. An increase in AST (66.6 - 69.43 U/L), Bifidobacterial (59.50 - 92.00 CFU) and decreased Bacteroides (40.5 - 19.5 CFU) for PRD was also recorded. CRD reduced Lactobacillus (73 - 33.5 CFU), total bacterial count (129 - 48 CFU), HDL (68.2 - 30.8 mg/dl), and cholesterol (121.44 - 88.65 mg/dl) whereas intestinal composition of E. coli (30.5 - 51.5 CFU) increased. PFRD increased Lactobacillus (73.00 - 102.5 CFU), Bifidobacterial (59.5 - 100 CFU), HDL (68.2 - 74.7 mg/dl), and Triglyceride (111.67 - 146.67 mg/dl) concentration. Meanwhile, a reduction in Bifidobacterial (59.5 - 41.5 CFU), and an increasing of AST (66.62 - 70.30 U/l) were recorded for CFRD. However, Bacteroides (40.5 69.5 CFU), LDL (30.95 - 41.98 mg/dl) increased and Bifidobacterial (59.5 - 38.00 CFU) and HDL (68.2 - 53.5 mg/dl) decreased for CPRD. This work, therefore, concludes that macronutrient restriction causes significant changes in serum marker and enzyme profile, and gut microbial composition which can cause gut dysbiosis and later on could expose the host to inflammatory diseases in the long run.

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis:a retrospective observational study

Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.

Restriction of Intramolecular Motion(RIM):Investigating AIE Mechanism from Experimental and Theoretical Studies

Mechanistic studies promote scientific development from phenomena to theories.Aggregation-induced emission(AIE),as an unusual photophysical phenomenon,builds the bridge between molecular science and aggregate mesoscience.With the twenty-year development of AIE,restriction of intramolecular motion(RIM)has been verified as the working mechanism of AIE effect.In this review,these mechanistic works about RIM are summarized from experimental and theoretical perspectives.Thereinto,the experimental studies are introduced from three parts:external rigidification,structural modification and structural characterization.In the theoretical part,calculations on the low-frequency motion of AIEgens have been performed to prove the RIM mechanism.By virtue of the theoretical calculations,some new mechanisms are proposed to supplement the RIM,such as restriction of access to conical intersection,suppression of Kasha transition,restriction of access to dark state,etc.It is foreseeable that the RIM mechanism will unify the photophysical theories for both molecules and aggregates,and inspire more progress in aggregate science.

Effects of Intrauterine Growth Restriction on Gene Expression in Small Intestine of Piglets

[ Objective] To profile the differentially expressed genes in small intestine between piglets with intrauterine growth restriction （IUGR）, describe the relationships between growth performance and gene expression in IUGR piglets, and thus provide a theoretical basis for further research. [Metbed] Eight suckling piglets at the age of 21 d Efour with normal body weight （NBW） of （1 503 ± 310） g and four with low BW of （806 ±35） g] were killed, and the intestinal samples were collected. Gene expression was detected by Affymetrix Porcine GeneChip and further confirmed by quantitative real-time PCR. [ ReseltJ Microarray analysis showed that there were 156 differentially expressed genes in the small intestine between the IUGR piglets and the age-matched NBW piglets, including 61 down-regulated genes and 95 up-regulated genes, The up-regulated genes included protein tyrosine phosphatase, myosin, troponin, heat shock protein, metallothionein, arginine vasopressin-induced 1, ribosomal protein L6, apoptosls antagonizing transcription factor, muscle creatine kinase, mannosidase, lysozyme, folliculin, urate transporterchannel protein, pyrroline-5-carboxylate reductese-like, and adenine phosphor-dbosyltransferase. The down-regulated genes included protein kinase, arachidohate 12-1ipoxygenase, transcription factor A, GTP-GDP dissociation stimulator 1, serine （or cysteine） proteinase inhibitor, fetuin, dolichol-phosphate-mannose synthase, apolipoprotein H, argininosuccinate synthetase 1, iron-regulated transporter, alpha-2-macroglobulin, immunoglobulin superfamily, thioltransferase, and guanylate binding protein 2. The gene expression profile changed in the small intestine of piglets with intrauterine growth restriction, providing a theoretical basis for eady intervention in growth restriction.

Intermittent energy restriction in type 2 diabetes: A short discussion of medication management

AIM To discuss type 2 diabetes mellitus(T2DM) medication changes required during the popular 5:2 intermittent energy restriction(IER) diet. METHODS A search was conducted in MEDLINE, EMBASE, AMED, CINAHL and Cochrane library for original research articles investigating the use of very low calorie diets(VLCD) in people with T2 DM. The search terms used included "VLCD" or "very low energy diet" or "very low energy restriction" or "IER" or "intermittent fasting" or "calorie restriction" or "diabetes mellitus type 2" and "type 2 diabetes". Reference lists of selected articles were also screened for relevant publications. Only research articles written in English, which also included an explanation of medication changes were included. A recent pilot trial using the 5:2 IER method, conducted by our research group, will also be summarized.RESULTS A total of 8 studies were found that investigated the use of VLCD in T2 DM and discussed medication management. Overall these studies indicate that the use of a VLCD for people with T2 DM usually require the cessation of medication to prevent hypoglycemia. Therefore, the 5:2 IER method will also require medication changes, but as seen in our pilot trial, may not require total cessation of medication, rather a cessation on the 2 IER days only. CONCLUSION Guidelines outlined here can be used in the initial stages of a 2-d IER diet, but extensive blood glucose monitoring is still required to make the necessary individual reductions to medications in response to weight loss.

Application of restriction display PCR technique in the preparation of cDNA microarray probes

AIM: To develop a simplified and efficient method for the preparation of hepatitis C virus (HCV) cDNA microarray probes.METHODS: With the technique of restriction display PCR (RD-PCR), restriction enzyme Sau3A I was chosen to digest the full-length HCV cDNAs. The products were classified and re-amplified by RD-PCR. We separated the differential genes by polyacrylamide gel electrophoresis and silver staining. Single bands cut out from the polyacrylamide gel were isolated. The third-round PCR was performed using the single bands as PCR template.The RD-PCR fragments were purified and cloned into the pMD18-T vector. The recombinant plasmids were extracted from positive clones, and the target gene fragments were sequenced. The cDNA microarray was prepared by spotting RD-PCR products to the surface of amino-modified glass slides using a robot. We validated the detection of microarray by hybridization and sequence analysis.RESULTS: A total of 24 different cDNA fragments ranging from 200 to 800 bp were isolated and sequenced,which were the specific gene fragments of HCV. These fragments could be further used as probes in microarray preparation. The diagnostic capability of the microarray was evaluated after the washing and scanning steps. The results of hybridization and sequence analysis showed that the specificity, sensitivity, accuracy, reproducibility,and linearity in detecting HCV RNA were satisfactory.CONCLUSION: The RD-PCR technique is of great value in obtaining a large number of size-comparable gene probes, which provides a speedy protocol in generating probes for the preparation of microarrays. Microarray prepared as such could be further optimized and applied in the clinical diagnosis of HCV.

Effects of quantitative feed restriction and sex on carcass traits,meat quality and meat lipid profile of Morada Nova lambs

Background: An experiment was conducted to evaluate the effects of feed restriction(FR) and sex on the quantitative and qualitative carcass traits of Morada Nova lambs. Thirty-five animals with an initial body weight of 14.5 ± 0.89 kg and age of 120 d were used in a completely randomized study with a 3 × 3 factorial scheme consisting of three sexes(11 entire males, 12 castrated males and 12 females) and three levels of feeding(ad libitum – AL and 30% and 60% FR).Results: Entire males presented greater hot and cold carcass weights(P < 0.05), followed by castrated males and females. However, the hot carcass yield was higher for females and castrated males than for entire males. Luminosity values were influenced(P < 0.05) by sex, with entire males presenting higher values than castrated males and females.Females showed higher(P < 0.05) concentrations of linoleic acid and arachidonic acid in the meat of the longissimus thoracis muscle. The meat of animals submitted to AL intake and 30% FR showed similar(P > 0.05) concentrations, and the concentrations of palmitic acid, palmitoleic acid, stearic acid, oleic acid and conjugated linoleic acid were higher(P < 0.05) than those of animals with 60% FR. The meat of females had a higher ω6/ω3 ratio and lower h/H ratio, and females had greater levels of feeding. The meat of animals on the 60% FR diet had a greater ω6/ω3 ratio, lower h/H ratio and lower concentration of desirable fatty acids in addition to a greater atherogenicity index(AI) and thrombogenicity index(TI).Conclusion: Lambs of different sexes had carcasses with different quantitative traits without total influence on the chemical and physical meat characteristics. The lipid profile of the meat was less favorable to consumer health when the animals were female or submitted to 60% feed restriction.

Protective effects of estrogens and caloric restriction during aging on various rat testis parameters

Aim： To investigate the effects of 17β-estradiol （E2）, Peganum harmala extract （PHE） and caloric restriction （CR） on various testis parameters during aging. Methods： Twelve-month-old male rats were treated for 6 months with either E2 or PHE, or submitted to CR （40%）. Results： Our results show that estrogens and CR are able to protect the male gonad by preventing the decrease of testosterone and E2 levels as well as the decrease of aromatase and estrogen receptor gene expressions. Indeed, E2, PHE and CR treatments induced an increase in the superoxide dismutase activities and decreased the activity of testicular enzymes： gamma-glutamyl transferase, alkaline phosphatase, lactate deshydrogenase as well as the aspartate and lactate transaminases in aged animals. In addition, the testicular catalase and gluthatione peroxidase activities were enhanced in E2, PHE and CR-treated rats compared to untreated animals at 18 months of age. Moreover, the positive effects of estradiol, PHE and CR were further supported by a lower level of lipid peroxidation. Recovery of spermatogenesis was recorded in treated rats. Conclusion： Besides a low caloric diet which is beneficial for spermatogenesis, a protective antioxydant role of estrogens is suggested. Estrogens delay testicular cell damage, which leads to functional senescence and, therefore, estrogens are helpful in protecting the reproductive functions from the adverse effects exerted by reactive oxygen species （ROS） produced in large quanti- ties in the aged testis.

Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences

The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease(CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction(CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas:(1) mechanisms underlying age-related cardiac remodeling;(2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women;(3) we select a few polyphenol or polyamine rich compounds as the CRmimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.

Effects of restrictions on maternal feed intake on the immune indexes of umbilical cord blood and liver Toll-like receptor signaling pathways in fetal goats during pregnancy

Background: Liver has important immune function during fetal development and after birth.However,the effect of maternal malnutrition on immune function of the fetal liver is rarely reported.In this study,twelve pregnant goats(Xiangdong black goat,at d 45 of gestation) were assigned to the control group(fed 100% of nutritional requirements) and the restriction group(fed 60% of the intake of the control group) during gestation from d 55 to100.Fetal goats were harvested at d 100 of gestation and immune indexes and amino acid profiles of the umbilical cord blood and liver Toll-like receptors(TLRs) signaling pathways were measured.Results: Maternal body weight in the restriction group was lower than the control group(P < 0.05).Maternal feed intake restriction decreased(P < 0.05) heart weight,heart index,alkaline phosphatase and serum amyloid protein A in the umbilical cord blood(UCB).Moreover,only histidine was decreased in the restricted group(P = 0.084),and there were no differences in other amino acids contents in the UCB between the two groups(P > 0.05).The TLR2 and TLR4 mRNA expression in the fetal liver in the restriction group was greater(P < 0.05) than that in the control group.Furthermore,the mRNA expression levels of myeloid differentiation primary response 88(MyD88),TNF receptor associated factor 6,nuclear factor kappa B subunit 1,NFKB inhibitor alpha,IFN-β,TGF-β,TNF-α and IL-1β in the restricted group were upregulated(P < 0.05),and the expression of TLR3(P = 0.099) tended to be higher in the restricted group.However,protein levels of TLR2,TLR4,IκBα,phosphorylated IκBα,phosphorylated IκBα/total IκBα,TRIF and MyD88 were not affected(P > 0.05) by maternal intake restriction.Conclusions: These results revealed that the restriction of maternal feed intake influenced the development of heart and hepatic protein synthesis at the acute phase of fetal goats and upregulated the mRNA expression of genes involved in MyD88-dependent signaling pathways and of target cytokines.

Assessing the Effect of Global Travel and Contact Restrictions on Mitigating the COVID-19 Pandemic

Travel restrictions and physical distancing have been implemented across the world to mitigate the coronavirus disease 2019(COVID-19)pandemic,but studies are needed to understand their effectiveness across regions and time.Based on the population mobility metrics derived from mobile phone geolocation data across 135 countries or territories during the first wave of the pandemic in 2020,we built a metapopulation epidemiological model to measure the effect of travel and contact restrictions on containing COVID-19 outbreaks across regions.We found that if these interventions had not been deployed,the cumulative number of cases could have shown a 97-fold(interquartile range 79–116)increase,as of May 31,2020.However,their effectiveness depended upon the timing,duration,and intensity of the interventions,with variations in case severity seen across populations,regions,and seasons.Additionally,before effective vaccines are widely available and herd immunity is achieved,our results emphasize that a certain degree of physical distancing at the relaxation of the intervention stage will likely be needed to avoid rapid resurgences and subsequent lockdowns.

Effect of Bushen Yiqi Huoxue Recipe on Placental Vasculature in Pregnant Rats with Fetal Growth Restriction Induced by Passive Smoking

Interactions of vascular endothelial growth factor （VEGF） with receptors VEGFR1/Fltl and VEGFR2/Flk1, and those of angiopoietins （Ang-1, Ang-2） with receptor Tie2 play important roles in placental angiogenesis. This study investigated vascular morphology and expression of these angiogenic factors in rat placenta on the day 15, 18, 21 of gestation （D 15, D 18 and D21）. The rats were randomly assigned into 3 groups： normal group, model group [fetal growth restriction （FGR） model], and Bushen Tqi Huoxue （BYHR） recipe treatment group （BYHR group, the pregnant rats with FGR were treated with BYHR recipe）. Morphological analysis indicated that during initial villous formation, fetal nucle- ated erythrocytes （FNEs） appeared in maternal blood sinus （MBS）. Subsequently, FNEs were sur- rounded by endothelial cells to form fetal capillary （FC） and then by trophoblast cells to form villi. As pregnancy proceeded, FC density increased progressively with increasing endothelial identification staining （EIS） in normal and BYHR groups. Whereas, villous formation was suppressed, normal in- crease in FC density was impaired and EIS was weakened in model group. Quantitative PCR analysis showed that VEGF and Flkl mRNA increased over gestation in all groups, indicating that VEGF might play a pivotal role in FC growth during late gestation. VEGF mRNA was increased on D15, while de- creased on D21 in model group as compared with normal group and BYHR group. Immunohistochemi- cally, Ang-2 protein was highly expressed in FNEs, gradually disappeared as villi matured, and decreased over gestation in all groups, indicating that Ang-2 might play a pivotal role in villous formation, which was further supported by decreased Ang-2 mRNA and protein expression in model group on D 15. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio increased from D15 to D18 in all groups as placenta matured. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio were decreased on D18 in model group as compared with normal and BYHR groups, indicating delayed maturity of FGR placenta. Alterations in angiogenic factors may result in altered placental vasculature and cause placental insufficiency. BYHR recipe could balance the angiogenic factors to promote the formation and maturation of FGR placental vasculature.

Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus(HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein(GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A(VAP-A) in competition with the HCV NS5 A, causing an interruption of the complex formation between VAP-A and HCV NS5 A. As the formation of VAP-A/NS5 A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5 A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents(DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.

Expression of soluble vascular endothelial growth factor receptor-1 and placental growth factor in fetal growth restriction cases and intervention effect of tetramethylpyrazine

Objective:To investigate the expression of soluble vascular endothelial growth factor receptor-1(sFlt-1) and placental growth factor(PLGF) in the fetal growth restriction(FGR) cases and the intervention mechanism of tetramelhylpyrazine.Methods:A total of 60 fetal growth restriction cases that admitted lo our hospital were randomly divided into ligustrazine intervention group(group A) and nutritional support group(group B).A total of 50 healthy pregnant women were also enrolled as control group(group C).Expression level of maternal serum sFlt1,FLGF and fetal growth parameters including HC,AC,FL,BPD,EFW as well as placenta PLGF,sFlt-1 mRNA expression were recorded and compared among the three groups.A total of 15 SD rats were selected and were divided into lliree groups.TMP group,alcohol and tobacco group and blank control group.Three groups of rats were dissected on the twentieth day of gestation.Result:Expression level of sFlt-1 and PLGF in group A was not significantly different from that of group C(P>0.05):but significant difference in SFlt1 and PLGF expression level was observed between group C and group B(P<0.05).Before treatment.HC,AC,FL,BPD and EFW of group A and group B were significant lower than those of group C.hut after treatment,those parameters in group A were significantly improved(P<0.05).In the animal experiment there was no significant difference in sFlt-1 between treatment group and FGR group without treatment or control group(P>0.05).There was significant difference in PLGF between FGR group with treatment and FGR group without treatment or control group(P<0.01).Conclusions:PLGF level is decreased and sFlt-1 increased in patients suffered from fetal growth restriction,and FGR rats show increased sFlt-1 and decreased PLGF.thus they can be indicator of the fetal growth restriction.Ligustrazinc can effectively improve sFlt-1,PLGF expression level in fetal growth restriction cases,which can be used as treatment for FGR.

Insertion Mutagenesis of Trichoderma atroviride by Restriction Enzyme-mediated DNA integration

Restriction enzyme-mediated integration(REMI) of DNA has been recently received attention as a new technique for the generation of mutants by transformation in fungi. Trichoderma atroviride strain T23 was transformed with linearized plasmid pV2, conferring resistance to hygromycin B, in the presence of restriction enzyme used to linearize the plasmid. A total of 172 regeneration transformants were detected by successive inoculation for seven times subcultivation on fresh PDA plate containing hygromycin B. The plasmid was integrated stably into the chromosome DNA, which was confirmed by PCR and southern analysis. The difference between 172 transformants and the parent strain was confirmed in colonial color, sporulation and growth rate. The results showed that the significant difference appeared in above mentioned characters between transformants and parent strain is sporulation capability. Transformants TC6, TD5, TE7, TF1 and TK1 produced higher amounts of conidia than the parent strain T23. In addition, transformants TK1and TC6 showed stronger inhibition to the growth rate of the cucumber wilt pathogen (Fusarium oxyporum) in vitro.