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The formation of linolenic (Ln) and linoleic (L) acyl oxidation products during storage of flaxseed oil (FO)-in-water emulsions was monitored using proton nuclear magnetic resonance (

Recent advances in genetic diagnosis identified variants in genes encoding GABAAreceptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABAAreceptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding and assembly and reduce the degradation of GABAAvariants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAAreceptor-specific manner.

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurodegenerative, neurological, and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is not well understood. Previous proteomics studies identified Hsp47 (Gene:SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric type A (GABAA) receptors. Here, we show that Hsp47 enhances neuronal GABAAreceptor functional surface expression, acting after Binding immunoglobulin Protein (BiP) to preferentially bind the folded conformation of GABAAreceptors. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAAreceptors. These Hsp47 properties are also extended to other Cys-loop receptors, including nicotinic acetylcholine receptors. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 also plays a critical and general role in the maturation of multi-subunit neuroreceptors.HighlightsHsp47 positively regulates the functional surface expression of endogenous GABAAreceptors.Hsp47 acts after BiP and preferentially binds the folded conformation of GABAAreceptors.Hsp47 promotes the subunit-subunit assembly of GABAAreceptors.Hsp47 plays a critical and general role in the maturation of multi-subunit neuroreceptors.

Background Newly graduated RNs leaving the nursing profession in the early stages of their career have enormous financial and time implications for nursing organizations and affect the quality of nursing care. Methods An electronic search was conducted for English articles to identify research studies published between 2011–2021 using the following database of PubMed, MEDLINE, CINAHL, PsycINFO, and Scopus. Eligible publications were critically reviewed and scored using standardized critical appraisal instruments from the Joanna Briggs Institute. Results Twenty-one studies were analyzed. The main factors affecting newly graduated registered nurses’ intention to leave the nursing profession included demographic factors, supervisor and peer support, challenges in the workplace, cognitive and affective response to work, work environment, gender stereotypes, autonomous motivation, role models, and resilience. Conclusions The factors affecting newly graduated registered nurses’ intention to leave the nursing profession are multifaceted and should receive continuous attention from nurse managers. The results provide a baseline of data for nurse administrators to develop intervention strategies to mitigate newly graduated registered nurses’ turnover intention.

Objective. Colorectal cancer (CRC) is globally one of the most often diagnosed cancers with high mortality rates. This study aimed to explore novel biomarkers for the diagnosis and prognosis of CRC. Methods. We collected 4 datasets about CRC in GEO and sought differentially expressed genes (DEGs) with GEO2R. Leucine-rich repeat-containing protein 19 (LRRC19) expression was assessed through the Oncomine and TIMER database analyses, which was further confirmed by qRT-PCR of CRC samples. We used online survival analysis tools (GEPIA, PrognoScan, and Kaplan–Meier plotter) to examine the prognostic value of LRRC19 in CRC and other malignancies. GO and KEGG enrichment analyses were employed to explore the biological functions of LRRC19. Finally, we conducted network prediction by STRING and further validation on the GEPIA to discover other molecules that might interact with LRRC19. Results. A total of 21 upregulated and 46 downregulated DEGs were identified from the 4 datasets. The TIMER and Oncomine online analyses showed lower mRNA of LRRC19 in CRC tissues compared with adjacent normal tissues, which was validated by qRT-PCR in CRC patient samples. The survival analysis through the GEPIA and PrognoScan websites revealed that low LRRC19 expression was significantly correlated with poor prognosis in CRC patients. The Kaplan–Meier plotter survival analysis indicated that low LRRC19 expression was significantly associated with the disease progression of patients with ovarian cancer, gastric cancer, breast cancer, and lung cancer. The enrichment analysis suggested that low expression of LRRC19 could be involved in the retinol metabolism and the zymogen granule membrane. Through STRING and GEPIA, it was found that LRRC19 is clearly associated with ZCCHC10, MOB3B, IMMP2L, and TRMT11. Conclusion. LRRC19 mRNA was prominently decreased in human CRC tissues and was significantly associated with shorter survival in CRC patients. LRRC19 might serve as a possible target for early diagnosis and prognosis assessment in CRC.

Gamma-aminobutyric acid type A (GABA

Gamma-aminobutyric acid type A (GABAA) receptors, the primary inhibitory neurotransmitter-gated ion channels in the mammalian central nervous system, inhibit neuronal firing to preserve balanced neuronal activity. Maintenance of GABAA receptor protein homeostasis (proteostasis) in the cell utilizing its interacting proteins is essential for the function of GABAA receptors. However, how the proteostasis network orchestrates GABAA receptor biogenesis in the endoplasmic reticulum (ER) is not well understood. To address this question systematically, we employed a proteomics-based approach to identify the interactomes of GABAA receptors by carrying out a quantitative immunoprecipitation-tandem mass spectrometry (IP-MS/MS) analysis utilizing stable isotope labeling by amino acids in cell culture (SILAC). To enhance the coverage and reliability of the identified proteins, we performed comparative proteomics by using both wild type α1 subunit and a misfolding-prone α1 subunit carrying the A322D variant as the bait proteins. The wild type α1 interactome contains 125 proteins, the α1(A322D) interactome contains 105 proteins, and 54 proteins overlap within two interactomes. Bioinformatics analysis identified potential GABAA receptor proteostasis network components, including chaperones, folding enzymes, trafficking factors, and degradation factors. Further, their potential involvement is modelled in the cellular folding, degradation and trafficking pathways for GABAA receptors. In addition, we verified endogenous interactions between α1 subunit and their selected interactors by carrying out co-immunoprecipitation assay in mouse brain homogenates. This study paves the way for understanding the molecular mechanisms as well as fine-tuning of GABAA receptor proteostasis to ameliorate related neurological diseases such as epilepsy.

The endoplasmic reticulum membrane complex (EMC) plays a critical role in the biogenesis of tail-anchored and a subset of multi-pass membrane proteins in the endoplasmic reticulum. However, due to the nearly exclusive expression of neurotransmitter-gated ion channels in the central nervous system, the role of the EMC in their biogenesis is not well understood. In this study, we demonstrated that the EMC positively regulates the surface trafficking and thus function of endogenous γ-aminobutyric acid (GABAA) receptors, the primary inhibitory ion channels in the mammalian brain. Further, among ten EMC subunits, EMC3 and EMC6 have the most prominent effects, indicating a subunit-specific contribution. EMC3 and EMC6 show endogenous interactions with major neuroreceptors, which depends on their transmembrane domains. Overexpression of EMC3 and EMC6 is sufficient to restore the function of epilepsy-associated GABAA receptor variants, suggesting that operating EMC has the potential to ameliorate neurological diseases associated with protein conformational defects.In briefThe multi-subunit EMC serves as an insertase for a subset of membrane proteins and enables their biogenesis in the endoplasmic reticulum. However, the subunit-specific effect of the EMC on multi-pass neuroreceptors is not well understood. Whittsette et al. demonstrate that EMC3 and EMC6 interact with GABAA receptors and positively regulate their trafficking and function.HighlightsEMC3 and EMC6 positively regulate the function of endogenous GABAA receptors.The EMC interacts with major endogenous neuroreceptors.The interaction between EMC and GABAA receptors depends on the EMC transmembrane domains.Overexpressing the EMC is sufficient to restore the function of pathogenic GABAA receptor variants.

A growing consensus worldwide has indicated the need to protect the ecological environment and achieve sustainable development. Ensuring ecological protection and high-quality development of the Yellow River basin have become China's major national strategy. We reviewed extant literature, summarised government reports and guidance documents on the Yellow River basin, and proposed introducing a strong sustainable development theory into the study of total factor productivity (TFP). The spatial–temporal evolution and influencing factors of urban ecological TFP in the Yellow River basin are of great practical significance. We proposed a new ecological TFP indicator: the modified input-oriented Luenberger productivity indicator (MIL). Using panel data from 78 cities in the Yellow River basin during 2003–2019, we measured the urban ecological TFP. We adopted the geographic information system tool and kernel density estimation to analyse the temporal and spatial evolution of the indicator, as well as its spatial effects and influencing factors, using the global Moran's I index and dynamic spatial Durbin model (SDM). Our results show that, during the sample period, our indicator increased in cities in the region with an average annual growth rate of 0.627%, driven by technological progress. The average annual growth rate in urban areas showed a decreasing distribution of ‘downstream-midstream-upstream’. Fiscal decentralisation (FD), industrial structure (IND), financial development (FIN), urbanisation level (URB) and research and development (RD) investment improved growth rates in this and the adjacent regions through direct and indirect effects. However, environmental regulation (ER), opening level (OPEN) of cities and population density (POP) were obstacles to TFP growth.

Eighty-nine agricultural surface soil samples from different types of land of Yinchuan were collected and detected for sixteen phthalate acid ester (PAE) compounds; the pollution characteristics and pollution distribution were analyzed. In addition, the potential health risk exposures to local resident of six priority control phthalates by the US EPA were assessed. All soil samples were contaminated with PAEs, the total concentrations of Σ16PAEs were between 0.391 and 11.924 mg kg−1, and the mean concentrations were 4.427 mg kg−1 in soil. Among the sixteen PAE congeners, DMP was the most abundant component, which accounted for average 44.64% of the total PAEs, then DnBP and DEHP, which accounted for the average contribution rate, were 21.25% and 23.34%, respectively, and DpHP was not detected in all soil samples. Risk assessment indicated that the risk of non-carcinogenesis in this study was within the acceptable range; however, the carcinogenic risk of DEHP through intake dietary significantly exceeded the carcinogenic level recommended by the US EPA (1 × 10−6) and therefore presented a potential carcinogenic risk. More considerable attention should be given to the PAEs contamination status in soils and potential effects on local resident health.

A total of 43 surface soil samples were collected from Yinchuan farmland and high performance liquid chromatography(HPLC) was used to measure the concentrations of oxytetracycline(OTC), tetracycline(TC), chlortetracycline(CTC), and doxycycline(DOC). The pollution characteristics and spatial distribution of TC were further analyzed using spatial Kriging interpolation, and the ecological risks of OTC, TC, CTC, and DOC in farmland soils were also assessed. Tetracycline antibiotics were detected in all the soil samples at concentrations ranging from 40.68 to 1074.42 μg·kg

OBJECTIVE: To investigate the incidence of maternal group B Streptococcus (GBS) colonization and neonatal early-onset GBS disease (GBS-EOD), and to study the factors associated with the development of GBS-EOD in the offspring of pregnant women with GBS colonization. METHODS: A total of 16 384 pregnant women and 16 634 neonates delivered by them were enrolled prospectively who had medical records in Xiamen Maternal and Child Care Hospital, Beijing Obstetrics and Gynecology Hospital of Capital Medical University, and Zhangzhou Zhengxing Hospital from May 1, 2019 to April 30, 2020. Unified GBS screening time, culture method, and indication for intrapartum antibiotic prophylaxis (IAP) were adopted in the three hospitals. The incidence rates of maternal GBS colonization and neonatal GBS-EOD were investigated. A multivariate logistic regression analysis was used to identify the factors associated with the development of GBS-EOD in the offspring of pregnant women with GBS colonization. RESULTS: In these three hospitals, the positive rate of GBS culture among the pregnant women in late pregnancy was 11.29% (1 850/16 384), and the incidence rate of neonatal GBS-EOD was 0.96‰ (16/16 634). The admission rate of live infants born to the GBS-positive pregnant women was higher than that of those born to the GBS-negative ones (P

BackgroundThis meta-analysis of prospective observational studies and randomized controlled trials (RCTs) was carried out to explore the association between selenium and the risk of cardiovascular disease (CVD) and all-cause mortality.Methods and Study DesignWe searched the PubMed, EMBASE and Web of Science database for eligible studies which included the relationship between selenium and the outcomes of interest. 25 prospective observational studies and 9 RCTs were included in our meta-analysis.ResultsThe observational studies showed that there was a significant inverse association between serum selenium and the risk of CVD (RR: 0.78; 95% CI: 0.68–0.89), coronary heart disease (CHD) (RR: 0.75; 95% CI: 0.58–0.95) and all-cause mortality (RR: 0.77; 95% CI: 0.71–0.84). We also found a significant inverse association between selenium supplements and the risk of total CVD (RR: 0.78; 95% CI: 0.62–0.98) and all-cause mortality (RR: 0.81; 95% CI: 0.65-1.00) in RCTs studies.ConclusionsOur meta-analysis found a significant inverse association between selenium and CVD, CHD, and all-cause mortality in prospective observational studies and RCTs, which indicate the selenium has protective effect in cardiovascular disease and all-cause mortality.

Background Postnatal care and growth in extremely low birth weight (ELBW) infants are being increasingly focused on worldwide. However, few data from China have been reported, expecially multicenters. This multicenter study was designed to investigate the problems existing in postnatal care, weight gain and the related risk factors in in-patient ELBW infants. Methods Eligible ELBW infants admitted to involved neonatal intensive care units (NICUs) in 2017 in Beijing were studied retrospectively. Except for general early outcomes, Weight Z score and feeding practice related information was caculated, and collected. Growth retardation (GR) was diagnosed if body weight Z score at discharge dropped more than one standard deviation (SD) compared with birth. Results Of our cohort of 137 ELBW infants, 92 infants discharged with medical advice were analyzed. Full enteral feeding reached at 37.0 (27.0, 51.8)days. Exclusive breast milk feeding rate was 30.4% at discharge. All infants had decreased weight Z score, and its change was similar in different weight subgroups. The incidence of GR was 66.3%. Multiple-factor analysis showed the risk factors for GR were small for gestational age(OR 34.768, 95%CI 1.652-731.728), average weight gain rate 28days(OR 6.867, 95%CI 1.211–38.957), P༜0.05. Keeping ELBW infants staying in hospital longer was beneficial to their weight gain (OR = 0.950, 95% CI 0.909–0.993, P

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P-gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax ), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2-fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug-drug interaction (DDI) with increasing RI severity, a similar 3.1-fold to 4.4-fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1-fold to 4.7-fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P-gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst-case scenario for clinically derisking P-gp and BCRP substrates in the setting of RI.

Background Recent studies have shown that amyloid-β (Aβ) burden influenced white matter (WM) integrity before the onset of dementia. Objective To assess whether the effects of Aβ burden on WM integrity in cognitively normal (CN) individuals were regionally specific. Methods Our cohort consisted of 71 CNs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who underwent both AV45 amyloid-PET and diffusion tensor imaging. Standardized uptake value ratio (SUVR) was computed across four bilateral regions of interest (ROIs) corresponding to four stages of in vivo amyloid staging model (Amyloid stages I-IV). Linear regression models were conducted in entire CN group and between APOEɛ4 carriers and non-carriers. Results Our results indicated that higher global Aβ-SUVR was associated with higher mean diffusivity (MD) in the entire CN group (p = 0.023), and with both higher MD (p = 0.015) and lower fractional anisotropy (FA) (p = 0.026) in APOEɛ4 carriers. Subregion analysis showed that higher Amyloid stage I-II Aβ-SUVRs were associated with higher MD (Stage-1: p = 0.030; Stage-2: p = 0.016) in the entire CN group, and with both higher MD (Stage-1: p = 0.004; Stage-2: p = 0.010) and lower FA (Stage-1: p = 0.022; Stage-2: p = 0.014) in APOEɛ4 carriers. No associations were found in APOEɛ4 non-carriers and in Amyloid stage III-IV ROIs. Conclusions Our results indicated that the effects of Aβ burden on WM integrity in CNs might be regionally specific, particularly in Amyloid stage I-II ROIs, and modulated by APOEɛ4 status.

Using a sandwich-type immunoassay, a novel electrochemical immunosensor based on the successful preparation of a hexestrol (HEX) monoclonal antibody was successfully constructed to detect four phenolic oestrogens: HEX, diethylstilboestrol (DES), dienestrol (DE) and bisphenol A (BPA). An innovative strategy to design the HEX monoclonal antibody/mercapto acetic acid (MACA)/nanogold immunosensor was developed by combining a nanosized effect, self-assembly and specific immune technology. The differential pulse voltammetry (DPV) response for four phenolic oestrogens was in the order BPA > DE > HEX > DES with detection limits of 0.037, 0.047, 0.052 and 0.060 ng mL−1, respectively (S/N = 3). This immunosensor exhibits superior electrochemical properties with a wide linear range, low detection limit, excellent reproducibility and high selectivity. Compared with a high-performance liquid chromatography method, a high accuracy of DES detection in beef, duck and milk powder samples was achieved by the immunosensor proposed, which exhibits great potential for the detection of phenolic oestrogens in applications in environmental and food safety.

Recent years have witnessed more and more enterprises outsource transportation business, which saves the transportation cost of the enterprise and promotes the development of the core business, but also increases the complexity of the transportation service market environment, resulting in insufficient utilization of transportation resources. This paper designs a novel multi-agent cross matching (MCM) continuous double auction mechanism to maximize the overall benefit of the transportation market and improve resource utilization. We first establish the probability function of quotation according to the historical effective information of the transportation service market, and transform the discrete probability function into a continuous function by the cubic spline interpolation method to solve the more accurate optimal quotation. Then we find the optimal matching scheme according to the price advantage principle and establish a mathematical model for calculating the total market benefits. Finally, we conclude that the novel mechanism not only improves the overall benefit of the market but also riches market efficiency through an example.

Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD., Mitochondria defects caused by mutant huntingtin (mtHtt) have been implicated in Huntington's disease. Here authors show that VCP binds to mtHtt on the mitochondria, and that treatment with a peptide that disrupts this interaction reduces the cellular and behavioural deficits in mouse models of HD.

In 2007, Andrews and Paule introduced the notion of broken k-diamond partitions. Let \(\Delta _k(n)\) denote the number of broken k-diamond partitions of n for a fixed positive integer k. Recently, Paule and Radu presented some conjectures on congruences modulo 7 for \(\Delta _3(n)\) which were proved by Jameson and Xiong based on the theory of modular forms. Very recently, Xia proved several infinite families of congruences modulo 7 for \(\Delta _3(n)\) using theta function identities. In this paper, many new infinite families of congruences modulo 7 for \(\Delta _3(n)\) are derived based on an identity of Newman and the (p; k)-parametrization of theta functions due to Alaca, Alaca and Williams. In particular, some non-standard congruences modulo 7 for \(\Delta _3(n)\) are deduced. For example, we prove that for \(\alpha \ge 0\), \(\Delta _3\left( \frac{14\times 757^{\alpha }+1}{3}\right) \equiv 6 -\alpha \ (\mathrm{mod}\ 7)\).

In order to reduce the pollution of the waste material, the waste leather powder tanned with vegetable tannin was used in this work, and vinyitrimethoxy silane was chosen as coupling agent. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to investigate the thermal properties of the powder sample. Both thermal decomposition temperature and denaturation temperature of the modified sample were higher than those of the raw samples due to the interaction between leather powder and silane, which can be demonstrated by Scanning Electron Microscopy-Energy Dispersive Spectrometer (SEM-EDS) and Fourier Transform Infrared Spectroscopy (FT-IR). Additionally, the flowing property, hydrophilicity and water absorption rate of the powder samples was also examined. The results showed that the hydrophilicity and moisture absorption of the leather powder sample modified with silane was lower than the raw materials. And the flowing properties of the modified samples also decreased because of the coupling reaction of the flexible vinyitrimethoxy silane.

Chronic hepatitis B virus (HBV) infection (CHB) is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Although the availability of HBV vaccines effectively reduces the incidence of HBV infection, the healthcare burden from CHB remains high. Several antiviral agents, such as (pegylated-) interferon-α and nucleos(t)ide analogs are approved by US FDA for chronic HBV infection management. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been recommended as the first-line anti-HBV drugs for excellent viral suppression with a low risk of antiviral resistance, but the cost and need for essentially life-long treatment are considerable challenges. And none of these current treatments can eradicate the intracellular virus. Given these issues, there is still an unmet medical need for an efficient HBV cure. We summarize here the key developments of antivirals against hepatitis B virus, including HBV replication cycle inhibitors and host immune regulators.

Since December 2019, there has been an outbreak of novel coronavirus (2019-nCoV) infection in China. Two cases of neonates with positive 2019-nCoV tests have been reported. Due to the immature immune system and the possibility of vertical transmission from mother to infant, neonates have become a high-risk group susceptible to 2019-nCoV, which emphasize a close cooperation from both perinatal and neonatal pediatrics. In neonatal intensive care unit (NICU), to prevent and control infection, there should be practical measures to ensure the optimal management of children potentially to be infected. According to the latest 2019-nCoV national management plan and the actual situation, the Chinese Neonatal 2019-nCoV expert working Group has put forward measures on the prevention and control of neonatal 2019-nCoV infection.