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Background Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) is a novel indicator to evaluate the prognosis of acute critical illness in recent years. At present, AST/ALT has only been reported to evaluate the prognosis of hemophagocytic lymphohistiocytosis (HLH) in adults, while HLH in children has not been studied. Objective To explore the relationship between AST/ALT and clinical characteristics and its prognostic significance in children with HLH, so as to provide a theoretical basis for early clinical recognition and diagnosis of HLH in children. Methods A total of 128 hospitalized children diagnosed with HLH in the Affiliated Hospital of Zunyi Medical University from January 2013 to May 2022 were selected as the research objects, and the baseline data of children were collected through the electronic medical record system. The children were divided into the T1 group (AST/ALT≤1.57, n=43), T2 group (1.57

In this study, a compound filler consisting of zinc sulfide (ZnS) nanoparticles and reduced graphene oxide (RGO) was synthesized using the hydrothermal method and utilized to enhance the tribological properties of the polyimide (PI) film. The ZnS@RGO/PI composites displayed the lowest wear rate of 3.89 × 10−8 mm3 N−1 m−1 at a load of 200 N, which were significantly lower than that of both pure PI and RGO/PI films. Furthermore, the microstructure and chemical composition of the compound were characterized and analyzed, revealing that the ZnS nanoparticles were effectively attached to the surface of RGO through the chemical bonding between them. Finally, finite element analysis shows that the chemical bonding between ZnS and RGO have the effect to stop the crack expanding under pressure, and a wear mechanism is also given to demonstrate this 'Ball-on-plane' compound's enhancement to the tribological properties. [ABSTRACT FROM AUTHOR]

Accurately predicting actual evapotranspiration ( ET a ) at the regional scale is crucial for efficient water resource allocation and management. While previous studies mainly focused on predicting site-scale ET a , in-depth studies on regional-scale ET a are relatively scarce. This study aims to address this issue by proposing a MulSA-ConvLSTM model, which combines the multi-headed self-attention module with the Pyramidally Attended Feature Extraction (PAFE) method. By extracting feature information and spatial dependencies in various dimensions and scales, the model utilizes remote sensing data from ERA5-Land and TerraClimate to attain regional-scale ET a prediction in Shandong, China. The MulSA-ConvLSTM model enhances the efficiency of capturing the trend of ET a successfully, and the prediction results are more accurate than those of the other contrast models. The Pearson's correlation coefficient between observed and predicted values reaches 0.908. The study has demonstrated that MulSA-ConvLSTM yields superior performance in forecasting various ET a scenarios and is more responsive to climatic changes than other contrast models. By using a convolutional network feature extraction method, the PAFE method extracts global features via various convolutional kernels. The customized MulSAM module allows the model to concentrate on data from distinct subspaces, focusing on feature changes in multiple directions. The block-based training method is employed for the large-scale regional ET a prediction, proving to be effective in mitigating the constraints posed by limited hardware resources. This research provides a novel and effective method for accurately predicting regional-scale ET a . [ABSTRACT FROM AUTHOR]

N6 methyladenosine (m6A) is the most prevalent RNA epigenetic modification, regulated by methyltransferases and demethyltransferases and recognized by methylation-related reading proteins to impact mRNA splicing, translocation, stability, and translation efficiency. It significantly affects a variety of activities, including stem cell maintenance and differentiation, tumor formation, immune regulation, and metabolic disorders. Ubiquitination refers to the specific modification of target proteins by ubiquitin molecule in response to a series of enzymes. E3 ligases connect ubiquitin to target proteins and usually lead to protein degradation. On the contrary, deubiquitination induced by deubiquitinating enzymes (DUBs) can separate ubiquitin and regulate the stability of protein. Recent studies have emphasized the potential importance of ubiquitination and deubiquitination in controlling the function of m6A modification. In this review, we discuss the impact of ubiquitination and deubiquitination on m6A functional molecules in diseases, such as metabolism, cellular stress, and tumor growth. [ABSTRACT FROM AUTHOR]

Evapotranspiration (ET) represents a significant component of the global water flux cycle, yet nocturnal evapotranspiration (ETn) is often neglected, leading to underestimation of global evapotranspiration. As for cropland, accurate modeling of ETn is essential for rational water management and is important for sustainable agriculture development. We used random forest (RF) to simulate ETn at 16 globally distributed cropland eddy covariance flux sites along with remote sensing and meteorological factors. The recursive feature elimination method was used to remove unimportant variables. We also simulated the ETn of C3 and C4 crops separately. The trained RF resulted in a determination coefficient (R2) (root mean square error (RMSE)) of 0.82 (7.30 W m−2) on the testing dataset. C3 and C4 crops on the testing dataset resulted in an R2 (RMSE) of 0.86 (5.59 W m−2) and 0.55 (4.86 W m−2) for the two types of crops. We also showed that net radiation is the dominant factor in regulating ETn, followed by 2 m horizontal wind speed and vapor pressure deficit (VPD), and these three meteorological factors showed a significant positive correlation with ETn. This research demonstrates that RF can simulate ETn from crops economically and accurately, providing a methodological basis for improving global ETn simulations. [ABSTRACT FROM AUTHOR]

Background: Low‐density lipoprotein cholesterol (LDL‐C) and diabetes mellitus are both modifiable risk factors for cardiovascular disease; however, whether elevated LDL‐C levels confer a risk for diabetes remains unclear. Objective: We aimed to examine the association between serum LDL‐C concentrations at baseline and the risk of developing diabetes at follow‐up in the general population of Chinese adults. Methods: This study included 5274 adults aged ≥ 40 years from a community cohort who were without diabetes and followed for a median of 4.4 years. A standard 75‐g oral glucose tolerance test was conducted at baseline and follow‐up visits to diagnose diabetes. Logistic regression models and a restricted cubic spline were used to examine the association between baseline serum LDL‐C levels and the risk of diabetes development. Subgroup analyses were conducted stratifying on age, sex, body mass index, hypertension, family history of diabetes, and LDL‐C levels. Results: A total of 652 participants (12%) developed diabetes during the follow‐up period. Compared to quartile 1 of serum LDL‐C, quartiles 2, 3, and 4 were associated with a 30%, 33%, and 30% significantly higher risk of diabetes, respectively after adjustment for confounders including homeostatic model assessment for insulin resistance. The linear relationship between baseline LDL‐C down to 30.1 mg/dL and incident diabetes was demonstrated by restricted cubic spline analysis, and each 1‐SD increase in LDL‐C concentration (28.5 mg/dL) was associated with a 12% increase in the risk of diabetes (odds ratio 1.12, 95% confidence interval 1.03–1.22). Conclusion: In this community‐based general population, higher serum LDL‐C levels were linearly associated with an elevated risk of incident diabetes. [ABSTRACT FROM AUTHOR]

This paper analyzes the influencing factors of carbon dioxide emissions from four aspects: Population, economy, industrial structure and energy, then from the carbon emissions, economic development, industrial structure, energy consumption structure to show the status quo of carbon emissions in Hubei Province. Based on the analysis of the influencing factors, the main influencing factors of carbon emission are population, regional gross product and coal consumption The multivariate linear regression model and the polynomial curve model are established and the error analysis is carried out. The combination weight coefficients of two single models are obtained through the linear programming model and the combination forecasting model is established, finally, the corresponding countermeasures to reduce carbon emissions are put forward.

Two apparatuses with lifting spherical source masses are built and used to verify the precision of gravimeters. The 333-kg source mass produces a maximum acceleration of 200 nm/s2 with an uncertainty of 0.31 nm/s2, which corresponds to a relative uncertainty of 0.16%. After evaluating the temperature effect, drift of the gravimeter, the atmospheric effect, and the tidal effect, a combined uncertainty of 1 nm/s2 is obtained. One CG6 gravimeter is tested using two apparatuses, the measured accelerations agree with the theoretical values within the error range. Differential measurement with two CG6 gravimeters on one apparatus is performed, which provides a common-mode rejection of the effects due to ambient noise, such as the gravity tide, atmospheric effect, and drift. The difference in acceleration measured by the two gravimeters is determined to be 199 ± 6 nm/s2, which agrees well with the value 200 ± 1 nm/s2 obtained by using apparatus II. Our apparatuses provide a verification of the precision of gravimeters with an uncertainty of 1 nm/s2, which is one of the lowest uncertainties reached so far. The determination of geometrical metrology and mass distribution and detailed error analysis are presented. The methods on error analysis as well as differential measurement used in our work are helpful for gravity measurement. [ABSTRACT FROM AUTHOR]

Objectives Momentary solitude (the objective state of being alone) has a strong association with negative affective experiences in older people, but little is known about how the role of social relationship characteristics on relationship between momentary solitude and affect. We examined the momentary association between momentary solitude and negative affect (NA), and whether such association was moderated by the structural and functional aspects of social relationships. Methods A sample of 153 late-middle-aged and older adults were recruited and provided a total of 6,742 ecological momentary assessment surveys, of which momentary solitudes were reported for 1,885 (28%) surveys. Hierarchical linear model was used to examine how social networks and social support moderated the association of momentary solitude with NA experiences. Results The association of momentary solitude with NA experiences was significant among middle-aged and older adults (b = 0.025, SE = 0.008, p <.01). Family networks had the main effect on NA. Perceived social support buffered against increased NA in momentary solitude: Individuals with a higher level of perceived support reported fewer increases in NA during momentary solitude than those perceiving a lower level of support. Discussion Momentary solitude was experienced less negatively for middle-aged and older persons embedded in a context of higher levels of perceived social support. Practitioners need to pay more attention to the promotion of social resources when delivering programs to improve the subjective well-being of late-middle-aged and older adults. [ABSTRACT FROM AUTHOR]

Background Recently, a newly proposed data-driven approach for classifying diabetes has challenged the status quo of the classification of adult-onset patients with diabetes. This study investigated the association between liver injury and diabetes, classified by data-driven cluster analysis, as liver injury is a significant risk factor for diabetes. Methods We enrolled 822 adult patients with newly diagnosed diabetes. Two-step cluster analysis was performed using six parameters, including age at diagnosis, body mass index, hemoglobin A1C, homoeostatic assessment model 2 estimates about insulin resistance (HOAM2-IR) and beta-cell function (HOMA2-B), and glutamic acid decarboxylase antibodies (GADA) positivity. Patients were allocated into five clusters. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were compared as indicators of liver injury among clusters. Results Serum ALT and AST activities were significantly different among clusters (P =0.002), even among those without GADA positivity (P =0.004). Patients with severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) had a more severe liver injury. Gender dimorphism was also found for serum ALT and AST activities among subgroups. Female patients had better liver function than males with SIRD and MOD. Conclusions We verified the feasibility of a newly proposed diabetes classification system and found robust and significant relationship and gender differences between serum ALT and AST activities and diabetes in some specific subgroups. Our findings indicate that more attention should be paid to diabetes subgroups when studying risk factors, indicators, or treatment in diabetic research. [ABSTRACT FROM AUTHOR]

Frailty is a pervasive symptom among the older population, and social participation is a beneficial factor of late‐life well‐being. However, studies on the bidirectional association between social participation and frailty are limited. This study examined the cross‐sectional and lagged associations of social participation and frailty. The analytic sample contained 6865 community‐dwelling older adults, with 21,141 observations, from the first four waves (2011–2018) China Health and Retirement Longitudinal Study (CHARLS). Frailty was measured by the Frailty Index (FI). Social participation was measured by the accumulation of the frequencies of six social activities. Random intercept two‐level models were used to analyse the concurrent and lagged association between social participation and frailty. The results showed significantly cross‐sectional associations between higher levels of frailty and lower levels of social participation in the same wave. Moreover, there was a lagged association of social participation in the prior wave with the current frailty (b = −0.001, SE = 0.001, p = 0.028), and frailty in the prior wave with the current social participation (b = −0.634, SE = 0.088, p < 0.001) even after adjusting for sociodemographic characteristics, and frailty or social participation in the prior wave. The bidirectional associations between social participation and frailty imply the necessity of enhancing social participation to prevent or slow the frailty progression, and improving the physical and social environment to reduce social participation restrictions imposed by frailty status. [ABSTRACT FROM AUTHOR]

Background: The study aimed to explore the associations of nonalcoholic fatty liver disease (NAFLD) with the remission and progression along the glycemic continuum. Methods: This prospective cohort study was performed among the general population in 2010–2015. NAFLD was defined as ultrasound‐detected hepatic steatosis with absence of excessive alcohol consumption and other hepatic diseases. Remission of type 2 diabetes referred to glycated hemoglobin <6.5% without hypoglycemic agents for ≥3 months. Prediabetes remission referred to normalization of blood glucose. Multivariable logistic analysis was applied to identify the risk of glycemic metabolic transition. Results: During a median follow‐up of 4.3 years, participants with NAFLD had a significantly higher risk of progressing from normal glucose tolerance to diabetes (3.36 [1.60–7.07]) and lower likelihood of diabetes remission (0.48 [0.30–0.78]). Associations in participants with overweight or obesity and higher probability of hepatic fibrosis remained consistent. Results related to the effect of NAFLD on the specific glucose parameters were generally in line with the changes of glycemic status. NAFLD improvement decreased the risk of prediabetes progressing to diabetes (0.50 [0.32–0.80]) and increased the probability of prediabetes remission (2.67 [1.49–4.79]). NAFLD tended to show the most significant association with glycemic progression and decreased the likelihood in remission of prediabetes and diabetes. Conclusions: Presence of NAFLD increased risk of glycemic progression and decreased likelihood of remission. NAFLD improvement mitigated glycemic deterioration, whereas NAFLD progression impeded the chance of remission. The results emphasized joint management of NAFLD and diabetes and further focused on liver‐specific subgroups of diabetes to tailor early intervention. [ABSTRACT FROM AUTHOR]

Aim: To explore the clinical outcomes among preadmission insulin-treated type 2 diabetes mellitus (T2DM) in intensive care units (ICU). Patients and Methods: In this retrospective observational study, 578 T2DM patients admitted to ICU were recruited from March 2011 to February 2021, which were composed of 528 patients treated with insulin after ICU admission (including 300 preadmission non-insulin-treated and 228 preadmission insulin-treated patients) and 50 patients treated without insulin before and after ICU admission. Clinical outcomes were compared between the groups. Variables of age (± 10 years), gender, blood glucose > 10 mmol/l on ICU admission, and original comorbidities were used for matching to get the 1:1 matched cohort. The Kaplan–Meier survival curves were graphed to describe the survival trend and Cox regression analysis was performed to get adjusted hazard ratio (HR). Results: Compared with the preadmission non-insulin-treated T2DM patients, preadmission insulin-treated T2DM patients had higher incidence of hypoglycemia [14.5% (33/228) vs 8.7% (26/300); p = 0.036]. In the 1:1 matched cohort, the preadmission insulin-treated T2DM patients had significantly increased mortality rate [30.0% (45/150) vs (16.0% (24/150)); adjusted HR, 1.68 (1.01– 2.80)] than preadmission non-insulin-treated T2DM patients. Compared with T2DM patients treated without insulin before and after ICU admission, preadmission insulin-treated T2DM patients had higher mortality and longer length of ICU stay (all p < 0.05). Conclusion: Preadmission insulin treatment was associated with increased mortality rate and longer length of ICU stay among T2DM patients in ICU. Preadmission insulin-treated T2DM patients might have worse clinical outcomes when they are critically ill. [ABSTRACT FROM AUTHOR]

Background: Previous studies showed altered angiopoietin-like protein-8 (ANGPTL-8) and resistin circulating levels in type 2 diabetes mellitus (T2DM). Whether or not the alteration in ANGPTL-8 and resistin level can be a predictive maker for increased diabetic nephropathy risk remains unclear. Aim: To Investigate the possible association of ANGPTL-8 and resistin with DN, and whether this association is affected by NAFLD status. Methods: A total of 278 T2DM patients were enrolled. Serum levels of ANGPTL8, resistin, BMI, blood pressure, duration of diabetes, glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), hypersensitive C-reactive protein (hs-CRP), lipid profile, liver, and kidney function tests were assessed. The relationship between DN with ANGPTL8 and resistin was analyzed in the unadjusted and multiple-adjusted regression models. Results: Serum levels of ANGPTL8 and resistin were significantly higher in DN compared with T2DM subjects without DN (respectively; P <0.001), especially in non-NAFLD populations. ANGPTL8 and resistin showed positive correlation with hs-CRP (respectively; P <0.01), and negative correlation with estimated GFR (eGFR) (respectively; P =<0.001) but no significant correlation to HOMA-IR(respectively; P>0.05). Analysis showed ANGPTL8 levels were positively associated with resistin but only in T2DM patients with DN(r=0.1867; P <0.05), and this significant correlation disappeared in T2DM patients without DN. After adjusting for confounding factors, both ANGPTL8(OR=2.095, 95%CI 1.253-3.502 P=0.005) and resistin (OR=2.499, 95%CI 1.484-4.208 P=0.001) were risk factors for DN. Data in non-NAFLD population increased the relationship between ANGPTL8 (OR=2.713, 95% CI 1.494-4.926 P=0.001), resistin (OR=4.248, 95% CI 2.260-7.987 P<0.001)and DN. The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and resistin was 0.703, and the specificity was 70.4%. These data were also increased in non-NAFLD population, as the AUC (95%CI) was 0.756, and the specificity was 91.2%. Conclusion: This study highlights a close association between ANGPTL8, resistin and DN, especially in non-NAFLD populations. These results suggest that ANGPTL-8 and resistin may be risk predictors of DN. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to compare HOMA-IR, leptin, and resistin as the risk factors for diabetic nephropathy in the type 2 diabetes mellitus (T2DM) patients with different BMI classifications. Materials and Methods: A total of 309 patients with T2DM were enrolled in this cross-sectional study. All participants were divided into three groups according to BMI: the normal weight group (18.5 kg/m2≤BMI< 24 kg/m2), the overweight group (24kg/m2≤BMI< 28 kg/m2) and the obesity group (BMI≥ 28 kg/m2). The clinical information and laboratory examinations were recorded in detail. Leptin and resistin levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: Higher HOMA-IR, leptin and resistin levels were found to be the risk factors for diabetic nephropathy when we made comparisons in the total population (P< 0.05). In the normal weight group, logistic regression analysis showed that T2DM patients with higher HOMA-IR (OR=4.210, P=0.001), leptin (OR=2.474, P=0.031) and resistin levels (OR=8.299, P< 0.001) had nearly 4-fold, 2-fold and 8-fold risk for diabetic nephropathy, respectively, after adjustments. The receiver operating characteristic (ROC) curves indicated that the area under the curves (AUCs) of HOMA-IR and resistin were 0.699 (95% CI 0.617– 0.772) and 0.790 (95% CI 0.715– 0.854), respectively, which were significantly larger than the AUC of 0.5 (all P< 0.001). However, no significant association was observed between HOMA-IR, leptin, and resistin and renal complications (all P> 0.05) in the overweight and obesity groups in both logistic regression and AUC analysis. Conclusion: Higher insulin resistance, leptin and resistin levels were observed as risk factors for diabetic nephropathy in T2DM patients with lower BMI. These were not obvious in the overweight and obese patients. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to explore the new role of telomere length (TL) in the novel classification of type 2 diabetes mellitus (T2DM) patients driven by cluster analysis. Materials and Methods: A total of 541 T2DM patients were divided into 4 subgroups by k-means analysis: mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), and mild age-related diabetes (MARD). After patients with insufficient data were excluded, further analysis was conducted on 246 T2DM patients. The TL was detected using telomere restriction fragment, and the related diabetic indexes were also measured by clinical standard procedures. Results: The MARD group had significantly shorter TLs than the MOD and SIDD groups. Then, we subdivided all T2DM patients into the MARD and NONMARD groups, which included the MOD, SIDD, and SIRD groups. The TLs of the MARD group, associated with age, were discovered to be significantly shorter than those of the NONMARD group (p = 0.0012), and this difference in TL disappeared after metformin (p = 0.880) and acarbose treatment (p = 0.058). The linear analysis showed that metformin can more obviously reduce telomere shortening in the MARD group (r = 0.030, 95% CI 0.010–0.051, p = 0.004), and acarbose can more apparently promote telomere attrition in the SIRD group (r = –0.069, 95% CI –0.100 to –0.039, p< 0.001) compared with other T2DM patients after adjusting for age and gender. Conclusions: The MARD group was found to have shorter TLs and benefit more from the antiaging effect of metformin than other T2DM. Shorter TLs were observed in the SIRD group after acarbose use. [ABSTRACT FROM AUTHOR]

A biomimetic fluorescent nanosensor based on molecularly imprinted polymers modified with carbon dots (CDs@MIPs) has been prepared for rapid, selective and sensitive detection of alpha-fetoprotein (AFP) in clinical samples. The nanosensor was produced using vinyl-functionalized CDs (V-CDs) as transducer elements and support materials, AFP as the template protein, N-isopropylacrylamide (NIPAM) and 4-vinylphenylbronic acid (VPBA) as the thermo-responsive and pH-responsive monomer, respectively, and ammonium peroxodisulphate (APS) and N,N′-methylene bisacrylamide (MBA) as the initiator and cross-linker, respectively. The newly synthesized nanosensor was characterized by FT-IR, TEM, XRD and elemental analysis, which unambiguously confirmed the successful formation of the nanosensor. The fluorescence quenching degree of CDs@MIPs exhibited a good linear response to AFP in a concentration range of 10 to 100 ng mL−1, the limit of detection (LOD) of 0.474 ng mL−1, and high recoveries at three spiking levels of AFP ranging from 97.05% to 102.00%, with relative standard deviations (RSDs) below 4.2% being obtained. Moreover, the proposed CDs@MIPs were successfully exploited to detect AFP in human serum samples. This study successfully established a novel method for rapid, convenient, and highly sensitive and selective detection of AFP, which provides new ideas for the detection of tumor markers. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that a low pluripotency of donor nuclei might lead to abnormal development of cloned embryos and underlie the inefficiency of mammalian somatic cell nuclear transfer (SCNT). To improve the pluripotency of SCNT embryo, RepSox, a defined small-molecule compound that functions in inhibiting the transforming growth factor β signaling pathway, was used to treat nuclear-transferred porcine oocytes after activation. We found that the developmental ability of porcine SCNT embryos (defined as the blastocyst rate) was significantly increased (13.5% vs. 21.8%) when 25 μm RepSox was added to the porcine embryo culturing system for 14–16 hours after activation. Of note, RepSox treatment significantly increased the transcriptional expression of the pluripotency gene NANOG at the four- and eight-cell stages. Furthermore, according to the TUNEL (TdT-mediated dUTP nick end labeling) staining and expression levels of the apoptosis-regulated gene Caspase 3 and proapoptotic gene Bax, the percentage of apoptotic cells in blastocyst cells was not affected after RepSox treatment. These results indicated that treatment with RepSox enhanced the developmental competence of porcine SCNT embryos through improvements in nuclear pluripotency. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a common disease in which pancreatic β cells are impaired due to auto-immunity, pregnancy in women with it is associated with increased risk of neonatal morbidity, mortality. However, the effects of gestational diabetes on the reproduction of newborn offspring are still poorly understood. Here, we determined the cyst breakdown and primordial follicle formation in neonatal offspring born by streptozotocin (STZ)-induced diabetic or non-diabetic female mice, and found that the germ cell cyst breakdown was promoted in neonatal offspring of STZ -induced diabetic mice at postnatal Day 1, which sequentially accelerated the primordial follicle formation. Further investigation revealed that, the expression level of PI3K and p-AKT were significantly increased in ovaries of offspring born by T1D mice. These results indicated that STZ -induced gestational diabetes promotes germ cell cyst breakdown and primordial follicle formation by regulating the PI3K/AKT signaling pathway in the newborn offspring. In addition, this effect can be rescued by an insulin supplement. Taken together, our results uncover the intergenerational effects of gestational diabetes on neonatal offspring folliculogenesis, and provide an experimental model for treating gestational diabetes and its complications in neonatal offspring. [ABSTRACT FROM AUTHOR]

Recently, clustered regularly interspaced short palindromic repeats (CRISPR) based genomic editing technologies have armed researchers with powerful new tools to biological and biomedical investigations. To further improve and expand its functionality, natural, and engineered CRISPR associated nine proteins (Cas9s) have been investigated, various CRISPR delivery strategies have been tested and optimized, and multiple schemes have been developed to ensure precise mammalian genome editing. Benefiting from those in‐depth understanding and further development of CRISPR, versatile CRISPR‐based platforms for genome editing have been rapidly developed to advance investigations in biology and biomedicine. In biological research area, CRISPR has been widely adopted in both fundamental and applied research fields, such as accurate base editing, transcriptional regulation, and genome‐wide screening. In biomedical research area, CRISPR has also shown its extensive applicability in the establishment of animal models for genetic disorders especially those large animals and non‐human primates models, and gene therapy to combat virus infectious diseases, to correct monogenic disorders in vivo or in pluripotent cells. In this prospect article, after highlighting recent developments of CRISPR systems, we outline different applications and current limitations of CRISPR use in biological and biomedical investigation. Finally, we provide a perspective for future development and potential risks of this multifunctional technology. [ABSTRACT FROM AUTHOR]

In the search for novel efficient nNOS–PSD-95 (nitric oxide synthase–postsynaptic density protein-95) uncouplers from natural products for stroke treatment, highly selective surface molecular imprinted polymers based on sandwich structured magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@MIPs, MMS@MIPs) were designed and optimized as artificial antibodies. The resultant polymers exhibited satisfactory adsorption performance and excellent recyclability, and were successfully utilized as sorbents to capture candidate uncouplers from natural products. Furthermore, the biological activity and the functional mechanism of the obtained candidates were investigated in vivo and in vitro. Consequently, coptisine, chelerythrine and nitidine chloride presented both potent neuroprotective effects on glutamate-injured PC12 cells and uncoupling activity targeting nNOS–PSD-95 in vitro. Simultaneously, they effectively ameliorated neurological deficit and reduced infarct volume of MCAO/R (middle cerebral artery occlusion and reperfusion) rats. Therefore, coptisine, chelerythrine and nitidine chloride were considered the most promising nNOS–PSD-95 uncouplers for further preclinical studies of ischemic stroke treatment. [ABSTRACT FROM AUTHOR]

In the scope of stroke treatment, new neuronal nitric oxide synthase-postsynaptic density protein-95 uncouplers from herbal medicines were discovered and captured. To do so, highly selective magnetic molecularly imprinted polymers with a core-shell structure were prepared as artificial antibodies. According to the results of computational simulations, we designed and synthesized various polymers with varying amounts and types of template, functional monomer, cross-linker, and solvent. Characterization and performance tests revealed that the most appropriate artificial antibodies showed uniform spherical morphologies, large adsorption capacities, fast-binding kinetics, high selectivity, and quick separation. These artificial antibodies were then used as sorbents for dispersive magnetic solid-phase extraction coupled with high-performance liquid chromatography and mass spectrometry to capture and identify structural analogs to ZL006 from extracts of Scutellariae radix, Psoraleae fructus, and Trifolium pratense. Furthermore, according to the neuroprotective effect and coimmunoprecipitation test, Baicalein, Neobavaisoflavone, Corylifol A, and Biochanin A can be the potential uncouplers of neuronal nitric oxide synthase-postsynaptic density protein-95. Therefore, this present study contributes valuable information for the discovery of neuronal nitric oxide synthase-postsynaptic density protein-95 uncouplers from herbal medicines. [ABSTRACT FROM AUTHOR]

Pigs have anatomical, physiological and genomic characteristics that make them highly suitable for modeling human diseases. Genetically modified (GM) pig models of human diseases are critical for studying pathogenesis, treatment, and prevention. The emergence of nuclease-mediated genome editing technology has been successfully employed for engineering of the pig genome, which has revolutionize the creation of GM pig models with highly complex pathophysiologies and comorbidities. In this review, we summarize the progress of recently developed genome editing technologies, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9), which enable highly efficient and precise introduction of genome modifications into pigs, and tailored disease models that have been generated in various disciplines via genome editing technology. We also summarize the GM pig models that have been generated by conventional transgenic strategies. Additionally, perspectives regarding the application of GM pigs in biomedical research are discussed. [ABSTRACT FROM AUTHOR]

A novel molecularly imprinted polymer (MIP) was synthesized by precipitation polymerization with baicalein (BAI) as the template and used as solid-phase extraction (SPE) adsorbent, aiming at the affinity isolation and selective knockout of BAI from Scutellaria baicalensis Georgi (SB). We used computational simulation to predict the optimal functional monomer, polymerization solvent and molar ratio of template to functional monomer. Characterization and performance tests revealed that MIP exhibited uniform spherical morphology, rapid binding kinetics, and higher adsorption capacity for BAI compared with nonimprinted polymer (NIP). The application of MIP in SPE coupled with high-performance liquid chromatography to extract BAI from SB showed excellent recovery (94.3%) and purity (97.0%). Not only the single BAI compound, but also the BAI-removed SB extract was obtained by one-step process. This new method is useful for isolation and knockout of key bioactive compounds from herbal medicines. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Metagenome of gut microbes has been implicated in metabolism, immunity, and health maintenance of its host. However, in most of previous studies, the microbiota was sampled from feces instead of gastrointestinal (GI) tract. In this study, we compared the microbial populations from feces at four different developmental stages and contents of four intestinal segments at maturity to examine the dynamic shift of microbiota in pigs and investigated whether adult porcine fecal samples could be used to represent samples of the GI tract. Analysis results revealed that the ratio of Firmicutes to Bacteroidetes from the feces of the older pigs (2-, 3-, 6- month) were 10 times higher compared to those from piglets (1-month). As the pigs matured, so did it seem that the composition of microbiome became more stable in feces. In adult pigs, there were significant differences in microbial profiles between the contents of the small intestine and large intestine. The dominant genera in the small intestine belonged to aerobe or facultative anaerobe categories, whereas the main genera in the large intestine were all anaerobes. Compared to the GI tract, the composition of microbiome was quite different in feces. The microbial profile in large intestine was more similar to feces than those in the small intestine, with the similarity of 0.75 and 0.38 on average, respectively. Microbial functions, predicted by metagenome profiles, showed the enrichment associated with metabolism pathway and metabolic disease in large intestine and feces while higher abundance of infectious disease, immune function disease, and cancer in small intestine. Fecal microbes also showed enriched function in metabolic pathways compared to microbes from pooled gut contents. Our study extended the understanding of dynamic shift of gut microbes during pig growth and also characterized the profiles of bacterial communities across GI tracts of mature pigs. [ABSTRACT FROM AUTHOR]

Almost all plants and animals exhibit inherent 24-hour oscillations to adapt the Earth's rotation. The main function of circadian rhythm was to prepare an organism for the potential outer opportunities and challenges. Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is more popular in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disorder on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability and AD-related pathophysiology. Our results indicated housing in these conditions had disrupted diurnal circadian rhythms in hippocampus and contributed to weight gain. In the brain, circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in Aβ deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under 6:18 light/dark cycle. In conclusion, circadian alterations could promote the development of AD in the patients of T2DM. Disclosure: J. Huang: None. Funding: National Natural Science Foundation of China (81670754, 81800686, 81974114) [ABSTRACT FROM AUTHOR]

Background: Growing evidence supported that type 2 diabetes mellitus (T2DM) patients had a greater risk of developing Alzheimer's disease (AD). Insulin secreted by "β cells" in brain played a critical role in T2DM patients and in AD patients. GLP-1 could improve cognition in AD patients via enhancing brain insulin signaling. We hypothesize the therapeutic effect of GLP-1 in T2DM might be due to promoting the insulin secretion of "β cells" in the nervous system. However, the molecular mechanism is unclear. Methods: The hippocampus cell- HT-22 cell line and T2DM rats were used in this study. The genes of insulin syntheses, animals' cognitive function and the phosphorylation of tau protein in hippocampus of T2DM brain were examined. Results: Firstly, HT22 cell line was intervened by GLP-1 or high glucose or GLP-1+ high glucose. When stimulated by GLP-1 combined with high glucose, IRS1/PI3K/AKT located in insulin signal pathway could be activated and the expression of neurod-1 and ngn3 (insulin synthesis genes) were notably increased. These results indicated that neuronal cell could secrete insulin under a certain condition. Secondly, RAAV-sh- neurod-1 and RAAV-sh-ngn3 were icv to the T2DM rats to prevent the production of brain insulin. The Barnes Maze test indicated the T2DM rats with peripheral GLP-1 and icv RAAV-sh-nc injection had a more intelligence than those with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3. Thirdly, the T2DM rats with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3 had a significantly hyperphsphorylation of tau protein than those rats with peripheral GLP-1 and icv RAAV-sh-nc injection. This result showed that brain insulin could improve cognition by GLP-1 in T2DM rats. Conclusions: These results suggested that neuronal cells might synthesis and secrete insulin under the condition of high glucose and GLP-1. And GLP-1 could not improve cognitive ability in T2DM when brain insulin synthesized was prevented. Disclosure: J. Huang: None. Y. Yang: None. Funding: National Natural Science Foundation of China (81670754) [ABSTRACT FROM AUTHOR]

Porcine‐derived xenogeneic sources for transplantation are a promising alternative strategy for providing organs for treatment of end‐stage organ failure in human patients because of the shortage of human donor organs. The recently developed blastocyst or pluripotent stem cell (PSC) complementation strategy opens a new route for regenerating allogenic organs in miniature pigs. Since the eye is a complicated organ with highly specialized constituent tissues derived from different primordial cell lineages, the development of an intact eye from allogenic cells is a challenging task. Here, combining somatic cell nuclear transfer technology (SCNT) and an anophthalmic pig model (MITFL247S/L247S), allogenic retinal pigmented epithelium cells (RPEs) were retrieved from an E60 chimeric fetus using blastocyst complementation. Furthermore, all structures were successfully regenerated in the intact eye from the injected donor blastomeres. These results clearly demonstrate that not only differentiated functional somatic cells but also a disabled organ with highly specialized constituent tissues can be generated from exogenous blastomeres when delivered to pig embryos with an empty organ niche. This system may also provide novel insights into ocular organogenesis. Synopsis: Blastocyst complementation is a new route for regenerating allogeneic organs in pigs for xenotransplantation, but reconstituting complicated organs, like a whole eye, was never done up to now. This strategy offers potentials for generating personalized human patient‐specific organs in large animals. Intact allogenic eyes can be regenerated using exogenous blastocyst complementation in an anophthalmic pig model.Porcine RPEs are isolated and cultured in vitro from 60‐day chimeric foetuses.The chimeric pig with regenerated eyes was derived from the somatic cloned blastocyst complementation and developed to full term. Blastocyst complementation is a new route for regenerating allogeneic organs in pigs for xenotransplantation, but reconstituting complicated organs, like a whole eye, was never done up to now. This strategy offers potentials for generating personalized human patient‐specific organs in large animals. [ABSTRACT FROM AUTHOR]