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Bin Peng,1,2 Xiaowei Yang,2 Yan Zhang,1 Jianghong Dai,3 Hao Liang,4 Yunfeng Zou,4 Jinkun Luo,5 Hongbin Peng,5 Xiaoni Zhong,1 Ailong Huang61School of Public Health, Chongqing Medical University, Chongqing, China; 2Division of Biostatistics, School of Medicine, University of California, Davis, CA, USA; 3School of Public Health, Xinjiang Medical University, Xinjiang, China; 4School of Public Health, Guangxi Medical University, Nanning, China; 5Shunqing Center for Disease Control and Prevention, Nanchong, Sichuan, China; 6Virus Hepatitis Research Institute of Chongqing Medical University, Chongqing, ChinaBackground: Pre-exposure prophylaxis (PrEP) is a strategy developed to prevent individuals who are human immunodeficiency virus (HIV)-negative from developing HIV infection. In China, while conducting a clinical trial to investigate the effectiveness and safety of PrEP, we performed this survey to assess the willingness of female sex workers to use PrEP, and identify predictors of this willingness.Methods: From July 2009 to April 2010, a cross-sectional study was carried out in four provinces of China. We recruited 1611 female sex workers who completed a self-administered survey to assess their awareness of and intention to use PrEP. The survey also canvassed demographic, behavioral, and psychosocial variables. Bivariate and multivariable logistic regression models were fitted to identify predictors of intent to use PrEP.Results: In total, 69% of the women (95% confidence interval [CI] 66.7–71.3) reported intent to use PrEP, and 12% (95% CI 10.5–13.7) had used drugs in the past to prevent a sexually transmitted infection. Further, 16.5% (95% CI 14.7–18.4) had previously heard of PrEP, and 1.4% (95% CI 0.9–2.1) had used PrEP previously to prevent HIV infection. Multivariate analysis indicated the following significant predictors of intent to use PrEP: Han ethnicity (adjusted odds ratio [AOR] 1.446; P = 0.011), urban residence (AOR 1.302; P = 0.027), knowledge about transmission of HIV/acquired immune deficiency virus syndrome (AIDS, AOR 1.817; P = 0.0007), a history of sexually transmitted infection (AOR 1.830; P < 0.0001), a history of using medication to prevent a sexually transmitted disease (AOR 2.547; P < 0.0001), and willingness to access knowledge about HIV/AIDS (AOR 2.153; P < 0.0001).Conclusion: The majority of female sex workers reported intent to use PrEP if it is safe and effective. Given that most of the participants had never heard of PrEP before, we strongly recommend that educational materials be developed with detailed introduction of PrEP. The risks and benefits of PrEP use should be fully explained to potential users when promoting PrEP in the future.Keywords: human immunodeficiency virus, infection, pre-exposure prophylaxis, PrEP, willingness, female sex workers

Background: Toxoplasma gondii, a globally distributed zoonotic obligate intracellular parasite, infects a wide array of mammals, including humans, sheep, and birds. As a unique sheep breed in southwestern China, Yunnan semi-fine wool sheep occupies an important position in animal husbandry in Zhaotong due to its strong adaptability, high reproductive rate, and excellent wool quality. Lambs infected with T. gondii are prone to neurological symptoms and growth retardation, while T. gondii infection in ewes can cause abortions, stillbirths, and deformities, thus affecting sheep reproduction and sheep product quality. Meanwhile, mutton and dairy products contaminated with T. gondii can become potential sources of human infection, potentially threatening public health and safety., Method: To understand the T. gondii infection in semi-fine wool sheep in Zhaotong, Yunnan Province, 586 blood samples were collected and subjected to indirect hemagglutination assay (IHA) for T. gondii antibodies, and the infection-related factors were analyzed through cross-sectional analysis. In the meantime, nested PCR was conducted on a total of 217 samples collected from 31 rodents caught in and around the sheep breeding ground to test the T. gondii B1 gene in rodent tissues., Results: A total of 94 sera tested positive for T. gondii antibodies, with a total positive rate of 16.04% (94/586) (95% CI: 14.77-20.89). Cross-sectional statistical analysis on factors related to semi-fine wool sheep infection rate, including sampling season, sex, age, and weight, suggested that age (< 6 months: 23.81%; 6-12 months: 11.74%; > 12 months: 15.83%) was a significant factor explaining the infection rate differences (P = 0.003 < 0.05, χ 2  = 11.62, df = 2). Thus, age was considered a key risk factor for T. gondii infection in this study (odds ratio, OR = 2.35, 95% CI: 1.42-3.87). Nested PCR analysis on 217 (heart, liver, spleen, lung, kidney, brain, and muscle) tissues from the 31 rodents indicated that 11 tested positive. The total infection rate of rodents in and around the breeding ground was 35.48% (11/31), and 14 samples tested positive, with a positive infection rate of 6.45% (14/217)., Conclusion: The T. gondii infection rates of semi-fine wool sheep and rodents from their breeding environment in Zhaotong, Yunnan Province, were high, necessitating enhanced prevention, control, and treatment measures to ensure the healthy breeding of semi-fine wool sheep and veterinary public health and safety., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ 40 and Aβ 42 ) peptides, Mdr1 and APP (amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40 weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ 40 , and Aβ 42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20 weeks old toward 40 weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain., (© 2024 John Wiley & Sons Ltd.)

Understanding species distribution patterns and what determines them is critical for effective conservation planning and management. In the case of shorebirds migrating along the East Asian-Australasian Flyway (EAAF), the loss of stopover habitat in the Yellow Sea region is thought to be the primary reason for the precipitous population declines. However, the rates of decline vary considerably among species, and it remains unclear how such differences could arise within a group of closely related species using apparently similar habitats at the same locales. We mapped the spatial distributions of foraging shorebirds, as well as biotic (benthic invertebrates consumed by migrating shorebirds) and abiotic (sediment characteristics) environmental factors, at a key stopover site in eastern China. Five of the six sediment characteristics showed significant spatial variation with respect to distance along the shoreline or distance from the seawall in the same tidal flat. The biomasses of four of the six most abundant benthic invertebrates were concentrated in the upper or middle zones of the tidal flat. The distribution patterns of all three focal shorebird species on the tidal flat were best explained jointly by this heterogeneity of sediment characteristics and invertebrate prey. These results suggest that the loss of tidal flats along the Yellow Sea, which is typically concentrated at the upper and middle zones, may not only reduce the overall amount of staging habitat, but also disproportionately affect the most resource-rich portions for the birds. Effective conservation of shorebird staging areas along the EAAF and likely elsewhere must consider the subtle habitat heterogeneity that characterizes these tidal flats, prioritizing the protection of those portions richest in food resources, most frequently used by focal bird species, and most vulnerable to anthropogenic threats. Article impact statement: Heterogeneity of tidal flats with respect to biotic and abiotic factors must be considered in shorebird conservation planning., (© 2023 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in several tumor types, one among them is the lncRNA H19. The paternally imprinted oncofetal gene is expressed in the embryo, downregulated at birth, and reappears in tumors. H19 aids in CRC cell growth, proliferation, invasion, and metastasis via various mechanisms of action, significantly through the lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network, where H19 behaves as a miRNA sponge. The RNA transcript of H19 obtained from the first exon of the H19 gene, miRNA-675 also promotes CRC carcinogenesis. Overexpression of H19 in malignant tissues compared to adjacent non-malignant tissues marks H19 as an independent prognostic marker in CRC. Besides its prognostic value, H19 serves as a promising target for therapy in CRC treatment., (Copyright ©2023, Yale Journal of Biology and Medicine.)

Background: Group living animals, such as shorebirds foraging on intertidal mudflats, may use social information about where to find hidden food items. However, flocking also increases intraspecific competition for resources, which may be exacerbated by food scarcity. Therefore, although aggregation may bring benefits, it may also increase the intensity of intraspecific competition., Methods: We examined this trade-off in adult great knots Calidris tenuirostris, a molluscivorous long-distance migrating shorebird species, using interannual variation based on 2 years with different levels of food availability during their northward migratory staging in the northern Yellow Sea, China. We estimated individual home ranges and the extent of spatial overlap of home ranges of individually tagged birds in 2012 and 2015, whilst discounting for possible differences in body size, body mass, sex and migration schedule between years., Results: We found that home range size was not associated with body mass, arrival date, body size, or sex of the individual. Despite a significant difference in food availability between the two study years, there was no significant change in the 50% and 95% home range size of great knots in the contrasting situations. However, there was a significantly smaller spatial overlap between individuals in the year when food was less available, suggesting that great knots operated more independently when food was scarce than when it was abundant., Conclusions: These results suggest that minimizing intraspecific competition became more important when food was scarce. Where it is impossible to monitor all habitats en route, monitoring the local movements of shorebirds may offer a way to detect changes in habitat quality in real time., (© 2023. The Author(s).)

Loss and/or deterioration of refuelling habitats have caused population declines in many migratory bird species but whether this results from unequal mortality among individuals varying in migration traits remains to be shown. Based on 13 years of body mass and size data of great knots (Calidris tenuirostris) at a stopover site of the Yellow Sea, combined with resightings of individuals marked at this stopover site along the East Asian-Australasian Flyway, we assessed year to year changes in annual apparent survival rates, and how apparent survival differed between migration phenotypes (i.e. migration timing and fuel stores). The measurements occurred over a period of habitat loss and/or deterioration in this flyway. We found that the annual apparent survival rates of great knots rapidly declined from 2006 to 2018, late-arriving individuals with small fuel stores exhibiting the lowest apparent survival rate. There was an advancement in mean arrival date and an increase in the mean fuel load of stopping birds over the study period. Our results suggest that late-arriving individuals with small fuel loads were selected against. Thus, habitat loss and/or deterioration at staging sites may cause changes in the composition of migratory phenotypes at the population-level., (© 2023 The Authors. Journal of Animal Ecology © 2023 British Ecological Society.)

Objective: This study aimed to evaluate the predictive performance of end-tidal carbon monoxide corrected to ambient carbon monoxide (ETCOc) values phototherapy in neonates with significant hyperbilirubinemia., Methods: A prospective study was conducted on neonates with significant hyperbilirubinemia who received phototherapy between 3 and 7 days of life. The breath ETCOc and serum total bilirubin of the recruited infants were measured on admission., Results: The mean ETCOc at admission in 103 neonates with significant hyperbilirubinemia was 1.70 ppm. The neonates were categorized into two groups: phototherapy duration ≤72 h ( n  = 87) and >72 h ( n  = 16) groups. Infants who received phototherapy for >72 h had significantly higher ETCOc (2.45 vs. 1.60, P  = 0.001). The cutoff value of ETCOc on admission for predicting longer phototherapy duration was 2.4 ppm, with a sensitivity of 62.5% and specificity of 88.5%, yielding a 50% positive predictive value and a 92.7% negative predictive value., Conclusion: ETCOc on admission can help predict the duration of phototherapy in neonates with hyperbilirubinemia, facilitate clinicians to judge disease severity, and make clinical communication easier and more efficient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zhan, Peng, Jin, Su, Tan, Zhao and Zhang.)

Triggered drug delivery strategies have been shown to enhance drug accumulation at target diseased sites in comparison to administration of free drug. In particular, many studies have demonstrated improved targetability of chemotherapeutics when delivered via thermosensitive liposomes. However, most studies continue to focus on encapsulating doxorubicin while many other drugs would benefit from this targeted and localized delivery approach. The proposed study explores the therapeutic potential of a thermosensitive liposome formulation of the commonly used chemotherapy drug vinorelbine in combination with mild hyperthermia (39-43 °C) in a murine model of rhabdomyosarcoma. Rhabdomyosarcoma, the most common soft tissue sarcoma in children, is largely treated using conventional chemotherapy which is associated with significant adverse long-term sequelae. In this study, mild hyperthermia was pursued as a non-invasive, non-toxic means to improve the efficacy and safety profiles of vinorelbine. Thorough assessment of the pharmacokinetics, biodistribution, efficacy and toxicity of vinorelbine administered in the thermosensitive liposome formulation was compared to administration in a traditional, non-thermosensitive liposome formulation. This study shows the potential of an advanced formulation technology in combination with mild hyperthermia as a means to target an untargeted therapeutic agent and result in a significant improvement in its therapeutic index., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: There are limited studies on the use of bronchodilators for the treatment of bronchiectasis. This study investigated the efficacy of tiotropium in patients with bronchiectasis and airflow limitation., Methods: This study was a prospective cohort study, including 169 patients with bronchiectasis and airflow limitation from 2015 to 2019. The clinical outcomes observed in our study were the effect of tiotropium on the frequency of moderate exacerbations, the time to the first severe exacerbation, and the annual decline in FEV 1 ., Results: After 12 months, the annual decline in the FEV 1 after bronchodilator use was 27.08 ml or 42.9 ml per year in the group with or without tiotropium, respectively. Treatment with tiotropium was associated with a decreased risk of moderate exacerbation of bronchiectasis (Adjusted RR 0.618 95% CI 0.493-0.774; P < 0.005). The time to the first severe acute exacerbation of bronchiectasis in the tiotropium group was longer than the non-tiotropium group (Adjusted HR 0.333 95% CI 0.219-0.506; P < 0.001)., Conclusion: In conclusion, prospective cohort study showed that tiotropium effectively ameliorated the annual decline in the FEV 1, with a lower-risk rate of moderate exacerbations and prolonging the time to the first-time severe exacerbation in patients with bronchiectasis and airflow limitation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this work, a ratiometric fluorescence system was designed for the detection of trace UO 2 2+ in water based on the inner filter effect (IFE) between gold nanoparticles (AuNPs) and gold nanoclusters (AuNCs). IFE-induced fluorescence quenching was achieved due to the enhanced complementary overlap between the absorption spectra of AuNPs and the emission spectrum of AuNCs after the addition of UO 2 2+ . Blue carbon dots (B-CDs) were added to serve as reference fluorophores to expand the color tonality and make human eye recognition easier. The ratiometric fluorescent sensor demonstrated a unique fluorescence color change from red to blue when different doses of UO 2 2+ were added, with a detection limit of 8.4 nM. Furthermore, the ratiometric fluorescent sensor was effectively used for UO 2 2+ determination in real-world water samples, with acceptable recoveries.

The amyloid-β (Aβ) peptides of 40 and 42 amino acids that are implicated in Alzheimer's disease may potentially aggregate into toxic oligomers and form neuritic plaques. The enzyme-linked immunosorbent assay (ELISA) is a facile method used for the determination of Aβ concentrations in biological matrices, namely plasma, cerebrospinal fluid, and brain. The method is mostly used for the measurement of Aβ concentrations in transgenic mice, but it is unknown whether the ELISA method is suitable for measuring low, endogenous levels of Aβ in the brains of wild-type mice. The Aβ ELISA kit manufacturer recommends use of 5 M guanidine hydrochloride (GuHCl), a protein-denaturing agent, for homogenization of the brain tissue, followed by dilution back down to 0.1 M to avoid quenching by GuHCl. Components of brain matrices and GuHCl that could interfere with the quantitation have not been investigated. In this article, we describe an improved method involving homogenization of mouse brain with 1 M instead of 5 M GuHCl, reducing the dilution factor by 5× to provide a higher sensitivity. The modified ELISA assay is improved for the quantitation of brain Aβ peptides in wild-type mice, where Aβ peptide levels are much lower than those in transgenic mouse models. © 2021 Wiley Periodicals LLC., (© 2021 Wiley Periodicals LLC.)

Age, hypercholesterolemia, and vitamin D deficiency are risk factors that increase the brain accumulation of pathogenic β-amyloid peptides (40 and 42), precursors leading to Alzheimer's disease (AD) in humans. The relative changes accompanying aging, high cholesterol, and/or treatment of calcitriol, active vitamin D receptor (VDR) ligand, under normal physiology are unknown. We examined these relative changes in C57BL/6 mice of ages 2, 4-8, and more than 10 months old, which were fed a normal or high fat / high cholesterol diet and treated with calcitriol, active ligand of the vitamin D receptor (0 or 2.5 μg/kg ×4, intraperitoneally, every other day to elicit cholesterol lowering in liver). Aβ 40 but not Aβ 42 accumulation in brain and lower P-glycoprotein (P-gp) and neprilysin protein expressions for Aβ efflux and degradation, respectively, were found to be associated with aging. But there was no trend for BACE1 (β-secretase 1, a cholesterol-sensitive enzyme) toward Aβ synthesis with age. In response to calcitriol treatment, P-gp was elevated, mitigating partially the age-related changes. Although age-dependent decreasing trends in mRNA expression levels existed for Cyp46a1, the brain cholesterol processing enzyme, whose inhibition increases BACE1 and ApoE to facilitate microglia Aβ degradation, mRNA changes for other cholesterol transporters: Acat1 and Abca1, and brain cholesterol levels remained unchanged. There was no observable change in the mRNA expression of amyloid precursor protein (APP) and the influx (RAGE) and efflux (LRP1) transporters with respect to age, diet, or calcitriol treatment. Overall, aging poses as a risk factor contributing to Aβ accumulation in brain, and VDR-mediated P-gp activation partially alleviates the outcome., (© 2021 John Wiley & Sons Ltd.)

Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer disease. The kinetics of human amyloid-β (hAβ) 40 were examined in the rat pursuant to intravenous and intracerebroventricular administration after pretreatment with calcitriol, the active vitamin D receptor ligand (6.4 nmol·kg -1 in 0.3 ml corn oil every other day for four intraperitoneal doses) to induce P-glycoprotein (P-gp) and enhance hAβ 40 brain efflux. The interference of hAβ 40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ 40 plasma and cerebrospinal fluid (CSF) data after intravenous and intracerebroventricular administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one to four CSF compartments. The model with only one CSF compartment (model I) best fitted the intravenous data that showed a faster plasma decay t 1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased the brain efflux rate constant, k 41 (1.8-fold), at the blood-brain barrier when compared with the control group, as confirmed by the 2-fold ( P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT: An accurate description of the kinetic behavior of human amyloid-β (hAβ) 40 is needed in defining the toxic peptide as a biomarker of Alzheimer disease. Modeling of hAβ 40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflected faster peripheral distribution but slower equilibration between plasma and brain/cerebrospinal fluid even with calcitriol pretreatment that increased P-glycoprotein protein expression and enhanced efflux clearance from brain., Competing Interests: The authors declare no conflicts., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

The formation of acetylcholine receptor (AChR) clusters at the postsynaptic muscle membrane in response to motor innervation is a key event in the development of the neuromuscular junction. The synaptic AChR clustering process is initiated by motor axon-released agrin, which activates a tyrosine kinase-based signaling pathway to cause AChR aggregation. In cultured muscle cells, AChR clustering is elicited by diverse nonneural signals, and this process is also mediated by tyrosine kinases. Conversely, the formation of new AChR clusters induced by innervation or nonneural stimuli is unfailingly associated with the dispersal of pre-existing AChR clusters, and this process is mediated by tyrosine phosphatases. In this review, we address how local kinase activation leads to global phosphatase action in muscle. More specifically, we discuss the roles of Src kinase and the SH2 domain-containing tyrosine phosphatase Shp-2 in establishing a regenerative mechanism to propagate the AChR cluster dispersing signal extrasynaptically and in defining the boundary of cluster formation subsynaptically., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We have carried out a comparative study of the lateral motion of ganglioside GM1, which is a glycosphingolipid residing on the outer leaflet of the plasma membrane, and acetylcholine receptor (AChR), which is a well-characterized ion channel. Both the lipid molecules and the transmembrane proteins reside on the plasma membranes of live Xenopus muscle cells. From a thorough analysis of a large volume of individual molecular trajectories obtained from more than 300 live cells over a wide range of sampling rates and long durations, we find that the GM1s and AChRs share the same dynamic heterogeneity and non-Gaussian statistics. Our measurements with the ATP-depleted cells reveal that the diffusion dynamics of the GM1s and AChRs is uniformly affected by the intracellular ATP level of the living muscle cells, further demonstrating that membrane diffusion is strongly coupled to the dynamics of the underlying cortical actin network, as predicted by the dynamic picket-fence model.

Objective: To investigate the current status of antibiotic use for very and extremely low birth weight (VLBW/ELBW) infants in neonatal intensive care units (NICUs) of Hunan Province., Methods: The use of antibiotics was investigated in multiple level 3 NICUs of Hunan Province for VLBW and ELBW infants born between January, 2017 and December, 2017., Results: The clinical data of 1 442 VLBW/ELBW infants were collected from 24 NICUs in 2017. The median antibiotic use duration was 17 days (range: 0-86 days), accounting for 53.0% of the total length of hospital stay. The highest duration of antibiotic use was up to 91.4% of the total length of hospital stay, with the lowest at 14.6%. In 16 out of 24 NICUs, the antibiotic use duration was accounted for more than 50.0% of the hospitalization days. There were 113 cases with positive bacterial culture grown in blood or cerebrospinal fluid, making the positive rate of overall bacterial culture as 7.84%. The positive rate of bacterial culture in different NICUs was significantly different from 0% to 14.9%. The common isolated bacterial pathogens Klebsiella pneumoniae was 29 cases (25.7%); Escherichia coli 12 cases (10.6%); Staphylococcus aureus 3 cases (2.7%). The most commonly used antibiotics were third-generation of cephalosporins, accounting for 41.00% of the total antibiotics, followed by penicillins, accounting for 32.10%, and followed by carbapenems, accounting for 13.15%. The proportion of antibiotic use time was negatively correlated with birth weight Z-score and the change in weight Z-score between birth and hospital discharge (r s =-0.095, -0.151 respectively, P<0.01), positively correlated with death/withdrawal of care (r s =0.196, P<0.01)., Conclusions: Antibiotics used for VLBW/ELBW infants in NICUs of Hunan Province are obviously prolonged in many NICUs. The proportion of routine use of third-generation of cephalosporins and carbapenems antibiotics is high among the NICUs.

The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (F I ) and liver (F H ) and the route of drug administration. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. A similar pattern exists for drug-drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro-in vivo extrapolations (IVIVE).

The Aspongopus chinensis is an insect of the genus Hemiptera, which can be used both as a medicinal and as a gourmet in the folk. It has a long history as a drug, which has the effect of regulating Qi and relieving pain, and warming the Yang. It is mainly used to treat stomach cold and pain, liver and stomach pain, kidney deficiency and impotence, and waist and knee pain. Modern pharmacological studies have shown that A. chinensis has a variety of pharmacological activities. For example, it can be used to fight tumors, improve reproductive damage, and antibacterial, anti-oxidation, anti-coagulation, anti-ulcer, anti-fatigue and so on. The chemical constituents of A. chinensis currently reported mainly include odorous components, vitamins, fatty acids and proteins, amino acids, and other nutrients, as well as nucleosides and dopamines. This study summarizes and analyzes the related research literatures of A. chinensis in China and abroad, and provides a reference for its further development and research from the aspects of chemical composition, pharmacological action and clinical application.

Background: To optimize and apply an approach suitable for large-scale neonatal thalassemia genetic screening in China, thalassemia genotypes were determined by polymerase chain reaction-reverse dot blot using DNA extracted from dried blood spots (DBS) obtained from newborn screening programs., Methods: Firstly, the most suitable commercial DNA extraction kit for DBS was screened. Then, the appropriate amount of DBS required for the automated high-throughput DNA extraction system was evaluated. Finally, the thalassemia prevalence and genotype spectrum in Shenzhen were investigated in 2028 newborns using the optimized screening procedure., Results: The Magentec extraction kit was best suited for the automated DBS DNA extraction system using eight 3-mm DBS discs. The neonatal thalassemia prevalence in Shenzhen was 9.12%; 6.31% α-thalassemia, 2.37% β-thalassemia, and 0.44% α-/β-thalassemia., Conclusions: Genetic screening based on DBS can precisely identify the thalassemia genotypes. Both α- and β-thalassemia are widely distributed in Shenzhen newborns. Newborn genetic screening is important for establishing a comprehensive thalassemia prevention program and for public education.

Organisms cope with environmental stressors by behavioral, morphological, and physiological adjustments. Documentation of such adjustments in the wild provides information on the response space in nature and the extent to which behavioral and bodily adjustments lead to appropriate performance effects. Here we studied the morphological and digestive adjustments in a staging population of migrating Great Knots Calidris tenuirostris in response to stark declines in food abundance and quality at the Yalu Jiang estuarine wetland (northern Yellow Sea, China). At Yalu Jiang, from 2011 to 2017 the densities of intertidal mollusks, the food of Great Knots, declined 15-fold. The staple prey of Great Knots shifted from the relatively soft-shelled bivalve Potamocorbula laevis in 2011-2012 to harder-shelled mollusks such as the gastropod Umbonium thomasi in 2016-2017. The crushing of the mollusks in the gizzard would require a threefold to 11-fold increase in break force. This was partially resolved by a 15% increase in gizzard mass which would yield a 32% increase in shell processing capacity. The consumption of harder-shelled mollusks was also accompanied by reliance on regurgitates to excrete unbreakable parts of prey, rather than the usual intestinal voidance of shell fragments as feces. Despite the changes in digestive morphology and strategy, there was still an 85% reduction in intake rate in 2016-2017 compared with 2011-2012. With these morphological and digestive adjustments, the Great Knots remaining faithful to the staging site to a certain extent buffered the disadvantageous effects of dramatic food declines. However, compensation was not complete. Locally, birds will have had to extend foraging time and use a greater daily foraging range. This study offers a perspective on how individual animals may mitigate the effects of environmental change by morphological and digestive strategies and the limits to the response space of long-distance migrating shorebirds in the wild., Competing Interests: None declared.

Many species depend on multiple habitats at different points in space and time. Their effective conservation requires an understanding of how and when each habitat is used, coupled with adequate protection. Migratory shorebirds use intertidal and supratidal wetlands, both of which are affected by coastal landscape change. Yet the extent to which shorebirds use artificial supratidal habitats, particularly at highly developed stopover sites, remains poorly understood leading to potential deficiencies in habitat management. We surveyed shorebirds on their southward migration in southern Jiangsu, a critical stopover region in the East Asian Australasian Flyway (EAAF), to measure their use of artificial supratidal habitats and assess linkages between intertidal and supratidal habitat use. To inform management, we examined how biophysical features influenced occupancy of supratidal habitats, and whether these habitats were used for roosting or foraging. We found that shorebirds at four of five sites were limited to artificial supratidal habitats at high tide for ~11-25 days per month because natural intertidal flats were completely covered by seawater. Within the supratidal landscape, at least 37 shorebird species aggregated on artificial wetlands, and shorebirds were more abundant on larger ponds with less water cover, less vegetation, at least one unvegetated bund, and fewer built structures nearby. Artificial supratidal habitats were rarely used for foraging and rarely occupied when intertidal flats were available, underscoring the complementarity between supratidal roosting habitat and intertidal foraging habitat. Joined-up artificial supratidal management and natural intertidal habitat conservation are clearly required at our study site given the simultaneous dependence by over 35,000 migrating shorebirds on both habitats. Guided by observed patterns of habitat use, there is a clear opportunity to improve habitat condition by working with local land custodians to consider shorebird habitat requirements when managing supratidal ponds. This approach is likely applicable to shorebird sites throughout the EAAF., Competing Interests: None declared.

N‑acetyl‑seryl‑aspartyl‑lysyl‑proline (Ac‑SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin‑angiotensin system, angiotensin‑converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac‑SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac‑SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac‑SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac‑SDKP decreased. Ac‑SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac‑SDKP treatment had an anti‑fibrotic effect in vivo. Compared with the silicosis group, the expression of α‑smooth muscle actin (α‑SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase‑1 (MMP‑1) expression and the MMP‑1/tissue inhibitor of metalloproteinases‑1 (TIMP‑1) ratio was increased in the Ac‑SDKP treatment group. In vitro, pre‑treatment with Ac‑SDKP or valsartan attenuated the expression of α‑SMA, Col I, Fn and AT1 in Ang II‑induced fibroblasts. In addition, MMP‑1 expression and the MMP‑1/TIMP‑1 ratio were significantly higher in Ac‑SDKP and valsartan pre‑treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac‑SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac‑SDKP protects against silicotic fibrosis by inhibiting Ang II‑induced myofibroblast differentiation and extracellular matrix production.

Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to have several benefits and medicinal properties. However, its protective effects against silica‑induced lung injury and fibrosis remain to be elucidated. The aim of the present study was to investigate the effects of OA on oxidative stress, and the expression of cytokines and collagen in silicotic rats. Male rats were induced by intratracheal instillation of silicosis (250 mg/kg), with the exception of the control group (NS). The rats in the OA group were intragastrically administered with OA (60 mg/kg/d). The rats in the solvent control group were gavaged daily with 0.6% sodium carboxymethyl cellulose (10 ml/kg) solution for 56 consecutive days. The data showed that OA significantly attenuated the extent of silicosis fibrosis by histopathologic analysis of the lung tissues. In addition, oxidative stress activated by silica exposure, as evidenced by increasing of malondialdehyde content, and activities of superoxide dismutase and glutathione peroxidase in the lung, was regulated by treatment with OA. Furthermore, enzyme‑linked immunosorbent assay analysis showed that OA significantly decreased the levels of tumor necrosis factor‑α and transforming growth factor‑β1. Immunohistochemistry analysis showed that OA significantly decreased collagen types I and III. In investigating the mechanisms underlying the action of OA, it was found that OA decreased the level of phosphorylated AKT1, which in turn inactivated the transcriptional of nuclear factor (NF)‑κB in the development and progress of silicosis. In conclusion, these results suggested that the protective effects of OA were due, at least in part, to its anti‑oxidant activity and its ability to decrease the expression of cytokines and collagen by modulating the AKT/NF‑κB pathway.

Objective: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the gene ataxin-2 (ATXN2). ATXN2 intermediate-length CAG expansions were identified as a risk factor for amyotrophic lateral sclerosis (ALS). The ATXN2 CAG repeat is translated into polyglutamine, and SCA2 pathogenesis has been thought to derive from ATXN2 protein containing an expanded polyglutamine tract. However, recent evidence of bidirectional transcription at multiple CAG/CTG disease loci has led us to test whether additional mechanisms of pathogenesis may contribute to SCA2., Methods: In this work, using human postmortem tissue, various cell models, and animal models, we provide the first evidence that an antisense transcript at the SCA2 locus contributes to SCA2 pathogenesis., Results: We demonstrate the expression of a transcript, containing the repeat as a CUG tract, derived from a gene (ATXN2-AS) directly antisense to ATXN2. ATXN2-AS transcripts with normal and expanded CUG repeats are expressed in human postmortem SCA2 brains, human SCA2 fibroblasts, induced SCA2 pluripotent stem cells, SCA2 neural stem cells, and lymphoblastoid lines containing an expanded ATXN2 allele associated with ALS. ATXN2-AS transcripts with a CUG repeat expansion are toxic in an SCA2 cell model and form RNA foci in SCA2 cerebellar Purkinje cells. Finally, we detected missplicing of amyloid beta precursor protein and N-methyl-D-aspartate receptor 1 in SCA2 brains, consistent with findings in other diseases characterized by RNA-mediated pathogenesis., Interpretation: These results suggest that ATXN2-AS has a role in SCA2 and possibly ALS pathogenesis, and may therefore provide a novel therapeutic target for these diseases. Ann Neurol 2016;80:600-615., (© 2016 American Neurological Association.)

The adipocytokine, apelin-13, is an abundantly expressed peptide in the nervous system. Apelin-13 protects the brain against ischemia/reperfusion injury and attenuates traumatic brain injury by suppressing autophagy. However, secondary apelin-13 effects on traumatic brain injury-induced neural cell death and blood-brain barrier integrity are still not clear. Here, we found that apelin-13 significantly decreases cerebral water content, mitigates blood-brain barrier destruction, reduces aquaporin-4 expression, diminishes caspase-3 and Bax expression in the cerebral cortex and hippocampus, and reduces apoptosis. These results show that apelin-13 attenuates secondary injury after traumatic brain injury and exerts a neuroprotective effect., Competing Interests: Conflicts of Interest: None declared.

The Brownian motion of molecules at thermal equilibrium usually has a finite correlation time and will eventually be randomized after a long delay time, so that their displacement follows the Gaussian statistics. This is true even when the molecules have experienced a complex environment with a finite correlation time. Here, we report that the lateral motion of the acetylcholine receptors on live muscle cell membranes does not follow the Gaussian statistics for normal Brownian diffusion. From a careful analysis of a large volume of the protein trajectories obtained over a wide range of sampling rates and long durations, we find that the normalized histogram of the protein displacements shows an exponential tail, which is robust and universal for cells under different conditions. The experiment indicates that the observed non-Gaussian statistics and dynamic heterogeneity are inherently linked to the slow-active remodelling of the underlying cortical actin network.

Oil palm breeding has been progressing very well in Southeast Asia, especially in Malaysia and Indonesia. Despite this progress, there are still problems due to the difficulty of controlled crossing in oil palm. Contaminated/illegitimate progeny has appeared in some breeding programs; late and failure of detection by the traditional method causes a waste of time and labor. The use of molecular markers improves the integrity of breeding programs in perennial crops such as oil palm. Four half-sib families with a total of 200 progeny were used in this study. Thirty polymorphic single locus DNA microsatellites markers were typed to identify the illegitimate individuals and to obtain the correct parental and progeny assignments by using the CERVUS and COLONY programs. Three illegitimate palms (1.5%) were found, and 16 loci proved to be sufficient for sibship assignments without parental genotypes by using the COLONY program. The pairwise-likelihood score (PLS) method was better for half-sib family assignments than the full likelihood (FL) method.

Shape memory alloys are a unique class of materials that can recover their original shape upon heating after a large deformation. Ti-Ni alloys with a large recovery strain are expensive, while low-cost conventional processed Fe-Mn-Si-based steels suffer from a low recovery strain (<3%). Here we show that the low recovery strain results from interactions between stress-induced martensite and a high density of annealing twin boundaries. Reducing the density of twin boundaries is thus a critical factor for obtaining a large recovery strain in these steels. By significantly suppressing the formation of twin boundaries, we attain a tensile recovery strain of 7.6% in an annealed cast polycrystalline Fe-20.2Mn-5.6Si-8.9Cr-5.0Ni steel (weight%). Further attractiveness of this material lies in its low-cost alloying components and simple synthesis-processing cycle consisting only of casting plus annealing. This enables these steels to be used at a large scale as structural materials with advanced functional properties.

Copy number variation (CNV) has been recognized as a major contributor to human genome diversity. It plays an important role in determining phenotypes and has been associated with a number of common and complex diseases. However CNV data from diverse populations is still limited. Here we report the first investigation of CNV in the indigenous populations from Peninsular Malaysia. We genotyped 34 Negrito genomes from Peninsular Malaysia using the Affymetrix SNP 6.0 microarray and identified 48 putative novel CNVs, consisting of 24 gains and 24 losses, of which 5 were identified in at least 2 unrelated samples. These CNVs appear unique to the Negrito population and were absent in the DGV, HapMap3 and Singapore Genome Variation Project (SGVP) datasets. Analysis of gene ontology revealed that genes within these CNVs were enriched in the immune system (GO:0002376), response to stimulus mechanisms (GO:0050896), the metabolic pathways (GO:0001852), as well as regulation of transcription (GO:0006355). Copy number gains in CNV regions (CNVRs) enriched with genes were significantly higher than the losses (P value <0.001). In view of the small population size, relative isolation and semi-nomadic lifestyles of this community, we speculate that these CNVs may be attributed to recent local adaptation of Negritos from Peninsular Malaysia.

In a majority of patients with myasthenia gravis (MG), anti-acetylcholine receptor (AChR) antibodies target postsynaptic AChR clusters and thus compromise the membrane integrity of neuromuscular junctions (NMJs) and lead to muscle weakness. Antibody-induced endocytosis of AChRs in the postsynaptic membrane represents the initial step in the pathogenesis of MG; however, the molecular mechanisms underlying AChR endocytosis remain largely unknown. Here, we developed an approach to mimic the pathogenic antibodies for inducing the crosslinking and internalization of AChRs from the postsynaptic membrane. Using biotin-α-bungarotoxin and quantum dot (QD)-streptavidin, cell-surface and internalized AChRs could be readily distinguished by comparing the size, fluorescence intensity, trajectory, and subcellular localization of the QD signals. QD-induced AChR endocytosis was mediated by clathrin-dependent and caveolin-independent mechanisms, and the trafficking of internalized AChRs in the early endosomes required the integrity of microtubule structures. Furthermore, activation of the agrin/MuSK (muscle-specific kinase) signaling pathway strongly suppressed QD-induced internalization of AChRs. Lastly, QD-induced AChR crosslinking potentiated the dispersal of aneural AChR clusters upon synaptic induction. Taken together, our results identify a novel approach to study the mechanisms of AChR trafficking upon receptor crosslinking and endocytosis, and demonstrate that agrin-MuSK signaling pathways protect against crosslinking-induced endocytosis of AChRs.

Objective: To study changes in T lymphocyte subsets in preterm infants with intrauterine growth retardation (IUGR)., Methods: The study enrolled 29 IUGR preterm infants, 38 preterm infants born appropriate for gestational age (AGA), and 20 healthy full-term infants. Peripheral blood was sampled during the first 24 hours of life, and again at a corrected age of 38 weeks of the preterm infants. T lymphocyte subsets were analyzed by flow cytometry, and absolute counts of leukocytes, total lymphocytes, and T lymphocytes were determined with an automated hematology analyzer., Results: Within the first 24 hours of life, percentages of CD3(+) and CD4(+) were lower in IUGR preterm infants than in AGA preterm infants and full-term infants (P<0.05), percentages of CD8(+) and CD4(+)/CD8(+) ratio were lower in IUGR preterm infants than in full-term infants (P<0.05), and percentages of CD3(+), CD4(+) and CD4(+)/CD8(+) ratio were lower in AGA preterm infants than in full-term infants (P<0.05). Moreover, the absolute counts of total lymphocytes were lower in IUGR preterm infants than in full-term infants (P<0.05); the absolute counts of T lymphocytes were lower in preterm infants, regardless of IUGR, than in full-term infants (P<0.05), and lower in IUGR infants than in AGA infants (P<0.05). At the corrected age of 38 weeks, percentages of CD3(+), CD4(+) and CD4(+)/CD8(+) ratio were increased in both IUGR and AGA infants as compared to the measurements within the first 24 hours of life (P<0.05), and percentages of CD3(+), CD4(+), CD8(+) and CD4(+)/CD8(+) ratio were lower in IUGR infants than in AGA infants (P<0.05), whereas there were no significant differences in counts of leukocytes, total lymphocytes and T lymphocytes between IUGR and AGA infants (P>0.05)., Conclusions: There may be a certain degree of compromise in cell-mediated immunity in preterm infants with IUGR and this compromise may last to 38 weeks after birth.

Background: During vertebrate neuromuscular junction (NMJ) development, contact between motor axons and muscle fibers is followed by pre- and post-synaptic specialization. Using Xenopus nerve-muscle cocultures, we recently showed that spinal neurons initially contacted muscle cells by means of filopodial processes, and that muscle-derived basic fibroblast growth factor induced axonal filopodia and slowed axonal advance to promote nerve-muscle interaction and NMJ establishment. In contrast, neurotrophins enhanced axonal growth but suppressed the extension of axonal filopodia and blocked NMJ formation., Results: Here we report that hepatocyte growth factor (HGF), which also supports motor neuron survival, was expressed by Xenopus muscle cells, and that forced expression of HGF in Xenopus spinal neurons inhibited the extension of axonal filopodia. Overexpression of the HGF-receptor c-Met in neurons also blocked the formation of axonal filopodia and furthermore sped up axonal growth, but a kinase-dead form of c-Met was unable to effect these changes. Importantly, treatment of nerve-muscle cocultures with recombinant HGF or the expression of HGF or active c-Met in neurons, or that of excess HGF in muscle, inhibited nerve-induced AChR clustering in muscle., Conclusions: Our results suggest that HGF/c-Met signaling in neurons promotes axonal growth but suppresses filopodial assembly in neurons and hinders NMJ establishment., (Copyright © 2012 Wiley Periodicals, Inc.)

During the development of the vertebrate neuromuscular junction (NMJ), motor axon tips stop growing after contacting muscle and transform into presynaptic terminals that secrete the neurotransmitter acetylcholine and activate postsynaptic ACh receptors (AChRs) to trigger muscle contraction. The neuron-intrinsic signaling that retards axonal growth to facilitate stable nerve-muscle interaction and synaptogenesis is poorly understood. In this paper, we report a novel function of presynaptic signaling by phosphatase and tensin homologue (PTEN) in mediating a growth-to-synaptogenesis transition in neurons. In Xenopus nerve-muscle cocultures, axonal growth speed was halved after contact with muscle, when compared with before contact, but when cultures were exposed to the PTEN blocker bisperoxo (1,10-phenanthroline) oxovanadate, axons touching muscle grew ~50% faster than their counterparts in control cultures. Suppression of neuronal PTEN expression using morpholinos or the forced expression of catalytically inactive PTEN in neurons also resulted in faster than normal axonal advance after contact with muscle cells. Significantly, interference with PTEN by each of these methods also led to reduced AChR clustering at innervation sites in muscle, indicating that disruption of neuronal PTEN signaling inhibited NMJ assembly. We thus propose that PTEN-dependent slowing of axonal growth enables the establishment of stable nerve-muscle contacts that develop into NMJs.