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Objectives Prognoses for nasopharyngeal carcinoma (NPC) between categories T2 and T3 in the Eighth American Joint Committee on Cancer (AJCC) staging system were overlapped. We explored the value of skull base invasion (SBI) subclassification in prognostic stratification and use of induction chemotherapy (IC) to optimize T2/T3 categorization for NPC patients. Methods We retrospectively reviewed 1752 NPC patients from two hospitals. Eight skull base bone structures were evaluated. Survival differences were compared between slight SBI (T3 patients with pterygoid process and/or base of the sphenoid bone invasion only) and severe SBI (T3 patients with other SBIs) with or without IC using random matched-pair analysis. We calculated the prognosis and Harrel concordance index (C-index) for the revised T category and compared IC outcomes for the revised tumor stages. Results Compared to severe SBI, slight SBI showed better 5-year overall survival (OS) (81.5% vs. 92.3%, p = 0.001) and progression-free survival (PFS) (71.5% vs. 83.0%, p = 0.002). Additional IC therapy did not significantly improve OS and PFS in slight SBI. The proposed T category separated OS, PFS, and locoregional recurrence-free survival in T2 and T3 categories with statistical significance. An improved C-index for OS prediction was observed in the proposed T category with combined confounding factors, compared to the AJCC T staging system (0.725 vs. 0.713, p = 0.046). The survival benefits of IC were more obvious in the advanced stage. Conclusions NPC patients with slight SBI were recommended to downstage to T2 category. The adjustment for T category enabled better prognostic stratification and guidance for IC use. Key Points • For nasopharyngeal carcinoma (NPC) patients in T3 category, slight skull base invasion was a significant positive predictor for OS and PFS. • NPC patients with slight SBI might not gain significant survival benefits from induction chemotherapy. • Downstaging slight SBI NPC patients to T2 category would make a more accurate risk stratification, improve the predicting performance in OS, and have a better guidance in the use of IC for patients in advanced stage.

Gastric cancer (GC) is one of the most common malignant tumors globally. About 20–30% of patients with gastric cancer show peritoneal implantation metastasis at the first diagnosis. Peritoneal metastasis is responsible for 70% of deaths of patients with advanced gastric cancer. Although there are many ways to treat advanced gastric cancer, the prognosis of patients with recurrence is unsatisfactory. An auxiliary treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), is an internationally recognized recommended treatment for advanced gastric cancer. A series of clinical trials have shown that HIPEC significantly improves the overall survival of patients with cancer. Compared with the cytoreductive surgery (CRS) alone, HIPEC combined with CRS markedly reduced the rate of peritoneal metastasis in patients with ovarian cancer and colorectal cancer. It has been demonstrated that HIPEC alters transcription of many genes by affecting non-coding RNAs, which may contribute to the suppressive effect of HIPEC on the synthesis of nucleic acids and proteins in cancer cells. This paper reviews the recent advances in understanding the role of non-coding RNAs in tumor invasion and metastasis of advanced gastric cancer. We also consider changes in noncoding RNA levels and other molecules in advanced gastric cancer cases treated with HIPEC. We hope that our review will provide a reference for future research on molecular epidemiology and etiology of advanced gastric cancer and promote precise treatment of this malignancy using HIPEC.

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a newly developed technique involves stimulating the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear, with resulting activation of vagal connections to central and peripheral nervous systems. Increasing evidence indicates that maladaptive neural plasticity may underlie the pathology of several pediatric neurodevelopmental and psychiatric disorders, such as autism spectrum disorder, attention deficit hyperactivity disorder, disruptive behavioral disorder and stress-related disorder. Vagal stimulation may therefore provide a useful intervention for treating maladaptive neural plasticity. In the current review we summarize the current literature primarily on therapeutic use in adults and discuss the prospects of applying taVNS as a therapeutic intervention in specific pediatric neurodevelopmental and other psychiatric disorders. Furthermore, we also briefly discuss factors that would help optimize taVNS protocols in future clinical applications. We conclude from these initial findings that taVNS may be a promising alternative treatment for pediatric disorders which do not respond to other interventions.

Background In China, numerous people still rely on solid fuel for household use. To date, the association between household solid fuel use and functional disability, and what benefit reducing household solid fuel usage could bring at the population level to China remain unclear.Method Data were from the China Health and Retirement Longitudinal Study. Household fuel was classified as clean or solid for cooking or heating. Functional disability was defined as difficulties in any item of activities of daily living (ADL) or instrumental activities of daily living (IADL). The associations of household fuel use in 2011 and its transitions between 2011 and 2013 with subsequent ADL or IADL disability were assessed with Cox proportional-hazards models. The number of events prevented in a population (NEPP) was generated to estimate how many functionally disabled patients could be rescued by reducing solid fuel usage. Results A total of 6226 and 9730 participants without prior ADL or IADL disability in 2011 were included. Solid (vs. clean) fuel users were more likely to develop ADL and IADL disability, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.37 (1.29~1.46) and 1.38 (1.31~1.46) for using both solid cooking and heating fuel. Furthermore, participants that switched heating fuel from solid to clean (vs. keep solid) were about 20% less likely to develop functional disability. Cooking fuel use switching from solid to clean (vs. keep solid) was also negatively associated with IADL disability (HR=0.84, 95% CI 0.74~0.95). Over the next 7 years, raising clean fuel usage to 80% could rescue about 11 million ADL disability and 5 million IADL disability among Chinese aged 45 and older.Conclusion Household solid fuel use was a risk factor for functional disability. Reducing solid fuel usage could help reduce the burden of functional disability in the current aging society of China.

Background: As an important part of the promotion of immunization programs and the suppression of infectious diseases, paid vaccines can prevent a variety of diseases and meet the needs of different populations. However, few studies focus on the public’s intention to pay for vaccination. Methods: The survey was conducted from 10 July to 15 September 2021, adopting a cross-sectional survey in China. We used a multi-stage sampling strategy to recruit participators from 120 cities. Participants filled out questions which assessed their intentions to pay for vaccination. A linear regression analysis was given to identify the predictors associated with the subjects’ attitudes. Results: There were 11,031 residents who finished our questionnaire. Chinese residents’ intention to receive paid vaccines scored 74.5 points. Residents who were male (β = −0.03) and older (30–44 (β = −0.03) or 45–59 (β = −0.06) or ≥60 (β = −0.08)), living alone (β = −0.03), who had moderate to severe anxiety (β = −0.03) or severe anxiety (β = −0.03) were more likely to refuse vaccination, while those who lived in Western China (β = 0.03) who had higher PSSS scores and HLS-SF12 index might acquire the intention to pay for vaccination. Conclusions: The study found that gender, age, region, living alone, anxiety, social support, and health literacy were the main influencing factors of residents’ attitudes. Governments and health institutions should take targeted measures to improve the health literacy and mental health of the population in order to facilitate the implementation of vaccination withdrawal and immunization policies.

Background The prevalence of infectious diseases remains one of the major challenges faced by the Chinese health sector. Policymakers have a tremendous interest in investigating the spatiotemporal epidemiology of infectious diseases. We aimed to review the small-scale (city level, county level, or below) spatiotemporal epidemiology of notifiable infectious diseases in China through a systematic review, thus summarizing the evidence to facilitate more effective prevention and control of the diseases. Methods We searched four English language databases (PubMed, EMBASE, Cochrane Library, and Web of Science) and three Chinese databases (CNKI, WanFang, and SinoMed), for studies published between January 1, 2004 (the year in which China’s Internet-based disease reporting system was established) and December 31, 2021. Eligible works were small-scale spatial or spatiotemporal studies focusing on at least one notifiable infectious disease, with the entire territory of mainland China as the study area. Two independent reviewers completed the review process based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results A total of 18,195 articles were identified, with 71 eligible for inclusion, focusing on 22 diseases. Thirty-one studies (43.66%) were analyzed using city-level data, 34 (47.89%) were analyzed using county-level data, and six (8.45%) used community or individual data. Approximately four-fifths (80.28%) of the studies visualized incidence using rate maps. Of these, 76.06% employed various spatial clustering methods to explore the spatial variations in the burden, with Moran’s I statistic being the most common. Of the studies, 40.85% explored risk factors, in which the geographically weighted regression model was the most commonly used method. Climate, socioeconomic factors, and population density were the three most considered factors. Conclusions Small-scale spatiotemporal epidemiology has been applied in studies on notifiable infectious diseases in China, involving spatiotemporal distribution and risk factors. Health authorities should improve prevention strategies and clarify the direction of future work in the field of infectious disease research in China.

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique with promising therapeutic potential in the context of epilepsy, pain, and depression and which may also have beneficial effects on social cognition. However, the underlying mechanisms of taVNS are unclear and evidence regarding its role in social cognition improvement is limited.ObjectiveIn order to investigate the impact of taVNS on social cognition we have studied its effects on gaze towards emotional faces using an eye-tracking task and also on release of the neuropeptide oxytocin which plays a key role in influencing social cognition and motivation.MethodsA total of fifty-four subjects were enrolled in a sham-controlled, participant-blind crossover experiment, consisting of two treatment sessions, separated by one week. In one session participants received 30-min taVNS (tragus), and in the other, they received 30-min sham (earlobe) stimulation with the treatment order counterbalanced across participants. Gaze duration towards the faces and facial features (eyes, nose, and mouth) were measured together with resting pupil size. Additionally, saliva samples were taken for the measurement of oxytocin concentrations by enzyme-linked immunoassay.ResultsSaliva oxytocin concentrations increased significantly after taVNS compared to sham stimulation, while resting pupil size did not. In addition, taVNS increased fixation time on the nose region irrespective of face emotion, and this was positively correlated with increased saliva oxytocin concentrations.ConclusionOur findings suggest that taVNS biases visual attention towards socially salient facial features across different emotions and this is associated with its effects on increasing endogenous oxytocin release.

No consensus has yet been reached on the associations of lipid variability (LV) with cardiovascular diseases (CVDs) and all-cause mortality. We aimed to quantify the associations of different types and metrics of LV with CVDs and all-cause mortality. PubMed, Medline, and Embase databases were searched for eligible cohort studies published until 14 December 2021. Lipids included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Metrics of variability included standard deviation (SD), coefficient of variation (CV), and variation independent of the mean (VIM). The primary outcomes were CVDs and all-cause mortality. Random-effects meta-analysis was used to generate a summary of the relative risks (SRRs). Sources of heterogeneity were explored by subgroup analysis and meta-regression. A total of 11 articles based on seven cohorts were included. Participants in the top quartile of TC variability had an increased risk of CVDs (vs. bottom quartile: TC-CV: SRR 1.29, 95% CI 1.15-1.45; TC-SD: 1.28, 1.15–1.43; TC-VIM: 1.26, 1.13–1.41, respectively) and all-cause mortality (vs. bottom quartile: TC-CV: 1.28, 1.15–1.42; TC-SD: 1.32, 1.22–1.44; TC-VIM: 1.32, 1.25–1.40, respectively). Participants in the top quartile of HDL-C variability had an increased risk of CVDs (vs. bottom quartile: HDL-C-CV: 1.11, 1.07–1.15; HDL-C-SD: 1.18, 1.02–1.38; HDL-C-VIM: 1.18, 1.09–1.27, respectively) and all-cause mortality (vs. bottom quartile: HDL-C-CV: 1.29, 1.27–1.31; HDL-C-SD: 1.24, 1.09–1.41; HDL-C-VIM: 1.25, 1.22–1.27, respectively). LDL-C variability was also associated with an increased risk of CVDs (for top vs. bottom quartile; LDL-C-SD: 1.09, 1.02–1.17; LDL-C-VIM: 1.16, 1.02–1.32, respectively) and all-cause mortality (for top vs. bottom quartile; LDL-C-CV: 1.19, 1.04–1.36; LDL-C-SD: 1.17, 1.09–1.26, respectively). The relationships of TG variability with the risk of CVDs and all-cause mortality were inconclusive across different metrics. The effects of SRR became stronger when analyses were restricted to studies that adjusted for lipid-lowering medication and unadjusted for mean lipid levels. These findings indicate that the measurement and surveillance of lipid variability might have important clinical implications for risk assessment of CVDs and all-cause mortality.

Introduction: There are currently no approved drug interventions for social behavior dysfunction in autism spectrum disorder (ASD). Previous trials investigating effects of daily intranasal oxytocin treatment have reported inconsistent results and have not combined it with positive social interaction. However, in two preclinical studies we established that treatment every other day rather than daily is more efficacious in maintaining neural and behavioral effects by reducing receptor desensitization. Objective: We aimed to establish whether a 6-week intranasal oxytocin compared with placebo treatment, followed by a period of positive social interaction, would produce reliable symptom improvements in children with ASD. Methods: A pilot double-blind, randomized, crossover design trial was completed including 41 children with ASD aged 3–8 years. Primary outcomes were the Autism Diagnostic Observation Schedule-2 (ADOS-2) and social responsivity scale-2 (SRS-2). Secondary measures included cognitive, autism- and caregiver-related questionnaires, and social attention assessed using eye-tracking. Results: Significant improvements were found for oxytocin relative to placebo in primary outcome measures (total ADOS-2 and SRS-2 scores, ps < 0.001) and in behavioral adaptability and repetitive behavior secondary measures. Altered SRS-2 scores were associated with increased saliva oxytocin concentrations. Additionally, oxytocin significantly increased time spent viewing dynamic social compared to geometric stimuli and the eyes of angry, happy, and neutral expression faces. There were no adverse side effects of oxytocin treatment. Conclusions: Overall, results demonstrate that a 6-week intranasal oxytocin treatment administered every other day and followed by positive social interactions can improve clinical, eye tracking, and questionnaire-based assessments of symptoms in young autistic children.

Di-2-ethylhexyl phthalate (DEHP) and Dioctyl phthalate (DnOP) are widely used as plasticizers in various industries for which the consequent health problems are of great concern. In this context, we treated HepG2 cells with DEHP or DnOP for 48 h. The results showed that DEHP and DnOP caused increase in oxygen species (ROS), malondialdehyde (MDA), Alanine aminotransferase (ALT) and Aspartate transaminase (AST). The proteins NF⁃E2-related factor 2 (Nrf2) and haemeoxygenase-1 (HO-1), were significantly down-regulated. Subsequently, the mitochondrial structure was disrupted, and the ATP content, the mitochondrial copy number as well as the expression of the corresponding mitochondrial genes were also reduced. The expression of sirtuin 1(SIRT1), PPAR gamma co-activator 1 alpha (PGC-1α), Nuclear respiratory factor 1(Nrf1), Mitochondrial transcription factor A (TFAM) on the SIRT1/PGC-1α pathway were significantly reduced. Finally, neither DEHP nor DnOP was found to induce apoptosis, but could significantly up-regulate Light chain 3 II (LC3II) levels. In conclusion, DEHP and DnOP could induce HepG2 cell damage via mitochondria, probably by causing oxidative stress, inhibiting the Nrf2 pathway and inhibiting the mitochondrial biogenesis pathway, which leads to excessive autophagy and cell death. DEHP and DnOP differ in the Nrf2 pathway, autophagic pathway and MAPK pathway, which may be structurally related.

Atherogenic Index of Plasma (AIP) has been proposed as a novel marker of plasma atherogenicity, but its longitudinal predictive value in type 2 diabetes mellitus (T2DM) remains unclear. We aimed to assess the associations of AIP and its longitudinal transition with T2DM among middle-aged and older Chinese. Data were extracted from four rounds of the China Health and Retirement Longitudinal Study (2011, 2013, 2015, and 2018). AIP was calculated as log10 (triglyceride/high-density lipoprotein cholesterol). Participants were classified into high and low AIP groups at baseline, and subsequently into four transition patterns during follow-up: maintained-high, maintained-low, high-to-low, and low-to-high AIP. Multivariable Cox frailty models were applied to explore the longitudinal transition patterns of AIP on the development of T2DM. A total of 8760 subjects without T2DM were selected in 2011, of which 981 developed T2DM until 2018. When compared with people with maintained-low AIP patterns, those with transition patterns of maintained-high AIP, high-to-low AIP, and low-to-high AIP were at around 1.5 times higher risk of T2DM (HRadj = 1.69, 1.32, and 1.47, respectively, all P

Dimethoxyethyl phthalate (DMEP) is an environmental endocrine disruptor. However, research into the underlying mechanisms of DMEP mitochondrial toxicity is still in its infancy. We therefore expect to understand whether DMEP induced mitochondrial damage in HepG2 cells and the associated signaling pathways. DMEP (0.125, 0.25, 0.5, 1 and 2 mM) exposure for 48 h induced a notable increment in reactive oxygen species (ROS), malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate transaminase (AST) and 8-hydroxydeoxyguanosine (8-OHdG) in hepG2 cells, resulting in cellular oxidative stress. Low doses of DMEP upregulated nuclear factor E2-related factor 2 (Nrf2) and downstream protein haeme oxygenase-1 (HO-1) levels and high doses down-regulated their levels. Nrf2 levels increased after ROS scavenging by N-acetyl- L -cysteine (NAC), which indicated that the Nrf2 pathway may be affected by oxidative stress. We also found that DMEP decreased ATP content, mitochondrial copy number (mtDNA), translocase of the outer membrane subunit 20 (TOM20) expression, mitochondria-encoded genes CO1, CO2, CO3, ATP6, ATP8 expression, inhibited mitochondrial biogenesis pathway, down-regulated sirtuin 1(SIRT1), PPAR gamma co-activator 1 alpha (PGC-1α), Nuclear respiratory factor 1(Nrf1), Mitochondrial transcription factor A (TFAM) content and activated PINK1/Parkin autophagy pathway. DMEP also activated the mitochondrial apoptotic pathway, causing cytochrome c cytoplasmic translocation and caspase 3 cleavage. What’s more, DMEP activated the Nuclear factor-κB (NF-κB) pathway and levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were significantly upregulated, causing an inflammatory response. In summary, DMEP can cause inflammatory response and oxidative stress in HepG2 cells, inhibited the Nrf2 pathway and mitochondrial biogenesis, and induced autophagy and apoptosis. And oxidative stress at least partially affected the Nrf2 pathway and mitochondrial biogenesis SIRT1/PGC-1α pathway.

The recent changes in the compositions of polychlorinated biphenyls (PCBs) after their restriction for 40 years may have various effects on human health. In order to characterize the congener-specific compositions of PCBs in the soil-air process and assess the associated human health risks, soil and air samples were simultaneously collected in winter and summer at two different functional locations. Homologue patterns suggest that long-range atmospheric transport might be the major source of soil and air residues of PCBs. The net deposition from air to soil was overwhelming for most PCB congeners. Variations in the occurrence and the homologue patterns of PCBs between the soil and air interface depended on chemical volatility, soil organic matter (OM) content, ambient temperature, topographical condition and atmospheric transport. Dioxin-like PCBs accounted for 11.0–70.3% and 2.31–54.8% of total PCB residues in soil and air, respectively. Non-carcinogenic and carcinogenic risks associated with exposure to soil and air PCBs were also estimated. Different PCB congeners showed different health effects, with the highest contribution from PCB-26. Additionally, the non-carcinogenic risk levels of PCBs were enhanced, while the carcinogenic risk levels decreased during the soil-air exchange process of PCBs with time. Our results highlight the soil-air interaction of PCBs in predicting their potential human exposure health risks.

Human milk (HM) is the primary source of nutrients and bioactive components that supports the growth and development of infants. However, the proteins present in human milk may change depending on the period of lactation. In this light, the objective of the present study was to evaluate the effect of lactation period on HM utilizing a data-independent acquisition (DIA) approach to identify the differences in HM whey protein proteomes. As part of the study, whey proteins of January, February, and June in human milk were studied. The results identified a total of 1563 proteins in HM whey proteins of which 114 groups were subunits of differentially expressed proteins as revealed by cluster analysis. Protein expression was observed to be affected by the period of lactation with expression levels of plasminogen, thrombospondin-1, and tenascin higher during January, keratin, type I cytoskeletal 9 highest in February, and transcobalamin-1 highest in June. The results of this study contribute to expand our understanding of the human whey proteome but also provide strong evidence for the nutritional difference of HM during different lactation periods.

G protein-coupled receptors (GPCRs) comprise the most important superfamily of protein targets in current ligand discovery and drug development. GPCRs are integral membrane proteins that play key roles in various cellular signaling processes. Therefore, GPCR signaling pathways are closely associated with numerous diseases, including cancer and several neurological, immunological, and hematological disorders. Computer-aided drug design (CADD) can expedite the process of GPCR drug discovery and potentially reduce the actual cost of research and development. Increasing knowledge of biological structures, as well as improvements on computer power and algorithms, have led to unprecedented use of CADD for the discovery of novel GPCR modulators. Similarly, machine learning approaches are now widely applied in various fields of drug target research. This review briefly summarizes the application of rising CADD methodologies, as well as novel machine learning techniques, in GPCR structural studies and bioligand discovery in the past few years. Recent novel computational strategies and feasible workflows are updated, and representative cases addressing challenging issues on olfactory receptors, biased agonism, and drug-induced cardiotoxic effects are highlighted to provide insights into future GPCR drug discovery.

Because of economic reform, dietary pattern in China changed rapidly during the past two decades. Meanwhile, the changes of income and nutrients intake had the same trend. This study aims to measure the income-related inequality in daily nutrients intake and its health-related income mobility over time. Data was sourced from four waves of China Health and Nutrition Survey. Concentration indexes and health-related income mobility indexes were employed to measure the income-related inequality of nutrients intake and its change over time. This study found that the daily protein intake, daily fat intake, daily energy intake, and proportion of energy from fat over 30% were more concentrated on the rich, whereas daily carbohydrates intake among the poor. The income-related inequalities were more severe than the cross-sectional perspective in the long run. The dynamic change of urbanisation indexes has resulted that over 30% of energy from fat was more concentrated among the rich and carbohydrates intake among the poor. The nutrition transition may bring about more severe disease economic burden to the poor in the future. This study recommends an approach to minimize gaps between rural and city areas by promoting rural revitalization to reduce the income-related inequality in daily nutrient intake.

Lack of adequate dietary knowledge may result in poor health conditions. This study aims to measure income-related inequality in dietary knowledge, and to explain the sources of the inequality. Data were from the China Health and Nutrition Survey (CHNS) conducted in 2015. A summary of the dietary knowledge score and dietary guideline awareness was used to measure the dietary knowledge of respondents. The concentration index was employed as a measure of socioeconomic inequality and was decomposed into its determining factors. The study found that the proportion of respondents who correctly answered questions on dietary knowledge was significantly low for some questions. Compared to rural residents, urban residents had a higher proportion of correctly answered dietary knowledge questions. In addition, there are pro-rich inequalities in dietary knowledge. This observed inequality is determined not only by individual factors but also high-level area factors. Our study recommends that future dietary education programs could take different strategies for individuals with different educational levels and focus more on disadvantaged people. It would be beneficial to consider local dietary habits in developing education materials.

Even though the application of dichlorodiphenyltrichloroethanes (DDTs) has been restricted for over 30 years, their ubiquitous existence still poses profound adverse impacts on ecosystem and human health. In this study, simultaneous soil and air sampling campaigns at different functional areas were conducted in warm and cold seasons. Based on the residue levels and enantiomeric signatures of DDT and its metabolites in soils and air, the parameters influencing ecological and human health risks were explored. ΣDDT concentrations in soils correlated positively with organic matter (OM) and negatively with pH, whereas atmospheric DDT levels were primarily facilitated by increased temperature. High temperature and low soil pH were also favorable for the transformation of DDT into its metabolites. The inhabitants living in agricultural regions or in areas with higher soil OM or pH 7 were exposed to higher existing and potential health risks of soil DDTs. In addition, at lower temperatures, the existing and potential carcinogenic risks of DDTs from soil exposure were higher, whereas risks from air inhalation were lower. Health risks would be increased when considering the enantioselective toxicity of o,p'-DDT and o,p'-DDD. The results from this study could provide baseline support for risk control and avoidance of DDTs.

Global warming is one of the major threats to human survival and social development. Agriculture, as an important source of greenhouse gas (GHG) emissions, cannot be ignored. China is the world's largest carbon emitter, and if it does not actively participate, other countries in the world will not be able to achieve the 1.5 degree temperature control target. Hence, the issue of China's agricultural emissions reduction is worthy of attention. As part of this study a framework for estimating agricultural GHG emissions was constructed. A directional distance function was then used to estimate the cost of emission reduction from the perspective of economic output. Furthermore, through the economic elasticity of shadow prices, agricultural economic development and emission reduction were included in the same framework to study the regional gap of agricultural emission reduction models. Finally, reducing agricultural emission reduction costs was discussed from the perspective of economy, technology, and policy. We found that (1) Agricultural emission reduction costs have phased characteristics and regional differences, and differentiated emission reduction cost improvement measures can help with efficient emission reduction. (2) The emission reduction cost in developed regions is more likely to be affected by technological progress and the strength of environmental governance by government. The emission reduction cost in regions dominated by planting is affected by the industrial structure and energy consumption structure. The emission reduction cost in underdeveloped regions is affected by the economic level. (3) We must give full play to the leading role of benchmarking regions in reducing emissions.

Relief of cancer-related pain remains challenging despite the availability of a range of opioid and nonopioid medications. Animal models demonstrate that T lymphocytes may mediate analgesia by producing endogenous opioids, but definitive clinical data are limited. Transfer of ex vivo adoptive cellular therapy (ACT) is being tested as an anticancer therapy. We retrospectively reviewed the medical charts of 357 patients with various malignancies who received 3 intravenous infusions of autologous cytokine-activated T-cell-enriched products. Among these were 55 patients who required opioids for moderate or severe cancer-related pain. Opioid dosage and cancer pain score were recorded daily for 2 consecutive weeks before and 2 weeks after the ACT infusions. The average oral morphine equivalent doses and cancer pain scores were significantly decreased after the ACT infusions. The proportion of patients with breakthrough pain also declined. Moreover, higher frequencies of expanded CD3, CD3/CD4, and CD3/CD8 T cells within the ACT product were associated with favorable analgesic effects. Transient elevations in CD3 and CD3/CD8T-cell subpopulations and decreases in CD4CD25 Treg were observed in patients' blood after the ACT. In conclusion, ACT was capable of reducing cancer pain severity and opioid consumption and favorably modulating peripheral blood T-cell populations.

CXC-type chemokine receptor 4 (CXCR4) is well known as a co-receptor for cellular entry and infection of human immunodeficiency virus type 1 (HIV-1). As an important member of the G protein-coupled receptor (GPCR) family, CXCR4 also mediates a variety of cellular processes and functions, such as cell chemotaxis, proliferation, and calcium signal transductions. Identification and characterization of molecular ligands or probes of CXCR4 have been an intensive area of investigations as such ligands or probes are of significant clinical values for the studies and treatments of HIV-1 infection and other human diseases mediated by the receptor. The crystal structures of CXCR4 in complex with different ligands have revealed two distinctive binding regions or subpockets. Thus, understanding the interactions of diverse ligands with these distinctive CXCR4 binding regions has become vital for elucidating the relationship between binding modes and biological mechanisms of ligand actions. Peptidic CVX15 is the only ligand that has been validated to bind one of these distinctive binding regions (or so called the major subpocket) of CXCR4. Therefore, in this study, we developed an efficient probe system including two high-affinity peptidic fluorescent probes, designated as FITC-CVX15 and FITC-DV1, with the aim of targeting distinctive CXCR4 subpockets. We conducted rational design and chemical characterization of the two CXCR4-specific probes and examined their application in biological experiments including competitive binding assays, flow cytometry analysis, and confocal imaging. Especially these two probes were applied in parallel CXCR4 competitive binding assays to detect and analyze potential binding modes of diverse CXCR4 ligands, together with molecular docking and simulations. Our results have indicated that these peptidic fluorescent probe systems provide novel ligand detecting tools, as well as present a new approach for analyzing distinctive binding modes of diverse CXCR4 ligands.

G-protein coupled receptors (GPCRs) are implicated in many diseases and attractive targets for drug discovery. Peptide fragments derived from protein ligands of GPCRs are commonly used as probes of GPCR function and as leads for drug development. However, these peptide fragments lack the structural integrity of their parent full-length protein ligands and often show low receptor affinity, which limits their research and therapeutic values. It remains a challenge to efficiently generate high affinity peptide inhibitors of GPCRs. We have investigated a combinational approach involving the synthetic covalent linkage of two low affinity peptide fragments to determine if the strategy can yield high affinity GPCR inhibitors. We examined this design approach using the chemokine receptor CXCR4 as a model of GPCR system. Here, we provide a proof of concept demonstration by designing and synthesizing two peptides, AR5 and AR6, that combine a peptide fragment derived from two viral ligands of CXCR4, vMIP-II and HIV-1 envelope glycoprotein gp120. AR5 and AR6 display nanomolar binding affinity, in contrast to the weak micromolar CXCR4 binding of each peptide fragment alone, and inhibit HIV-1 entry via CXCR4. Further studies were carried out for the representative peptide AR6 using western blotting and site-directed mutagenesis in conjunction with molecular dynamic simulation and binding free energy calculation to determine how the peptide interacts with CXCR4 and inhibits its downstream signaling. These results demonstrate that this combinational approach is effective for generating nanomolar active inhibitors of CXCR4 and may be applicable to other GPCRs.

Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain&ndash, Barr&eacute, syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 &mu, M and 15.2 &mu, M, respectively). Binding mode analysis, absolute binding free energy calculation, and structure&ndash, activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

People with the genetic disease cystic fibrosis (CF) often carry a deletion mutation ΔF508 on the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) Cl‒ channel. This mutation greatly reduces the CFTR maturation process and slows the channel opening rate. Here, we investigate whether residues near F508 contribute to these defects in ΔF508-CFTR. Most deletion mutations, but not alanine substitutions, of individual residues from position 503 to 513 impaired CFTR maturation. Interestingly, only protein processing of ΔY512-CFTR, like that of ΔF508-CFTR, was greatly improved by low-temperature culture at 27 °C or small molecule corrector C18. The two mutant Cl‒ channels were equally slow to open, suggesting that they may share common structural flaws. Studies on the H3-H4 loop that links residues F508 and Y512 demonstrate that G509A/V510G mutations, moving G509 one position backward in the loop, markedly enhanced ΔF508-CFTR maturation and opening rate, while promoting protein stability and persistence of the H3 helix in ΔF508 NBD1.Moreover, V510A/S511A mutations noticeably increased ΔY512-CFTR maturation at 27 °C and its opening rate. Thus, loop abnormalities may contribute to ΔF508- and ΔY512-CFTR defects. Importantly, correctingdefects from G509 displacement in ΔF508-CFTR may offer a new avenue for drug discovery and CF treatments.

Human immunodeficiency virus type 1 (HIV-1) is responsible for the majority of HIV infections worldwide, and we still lack a cure for this infection. Blocking the interaction of HIV-1 and its primary receptor CD4 is one strategy for identifying new anti-HIV-1 entry inhibitors. Here we report the discovery of a novel ligand that can inhibit HIV-1 entry and infection via CD4. Biological and computational analyses of this inhibitor and its analogs, using bioactivity evaluation, Rule of Five (RO5), comparative molecular field analysis (CoMFA)/comparative molecular similarity index analysis (CoMSIA) models, and three-dimensional quantitative structure-activity relationship (3D-QSAR), singled out compound 3 as a promising lead molecule for the further development of therapeutics targeting HIV-1 entry. Our study demonstrates an effective approach for employing structure-based, rational drug design techniques to identify novel antiviral compounds with interesting biological activities.

CXCR4, a well-studied coreceptor of human immunodeficiency virus type 1 (HIV-1) entry, recognizes its cognate ligand SDF-1α (also named CXCL12) which plays many important roles, including regulating immune cells, controlling hematopoietic stem cells, and directing cancer cells migration. These pleiotropic roles make CXCR4 an attractive target to mitigate human disorders. Here a new class of symmetrical polyamines was designed and synthesized as potential small molecule CXCR4 antagonists. Among them, a representative compound 21 (namely HF50731) showed strong CXCR4 binding affinity (mean IC50 = 19.8 nM) in the CXCR4 competitive binding assay. Furthermore, compound 21 significantly inhibited SDF-1α-induced calcium mobilization and cell migration, and blocked HIV-1 infection via antagonizing CXCR4 coreceptor function. The structure-activity relationship analysis, site-directed mutagenesis, and molecular docking were conducted to further elucidate the binding mode of compound 21, suggesting that compound 21 could primarily occupy the minor subpocket of CXCR4 and partially bind in the major subpocket by interacting with residues W94, D97, D171, and E288. Our studies provide not only new insights for the fragment-based design of small molecule CXCR4 antagonists for clinical applications, but also a new and effective molecular probe for CXCR4-targeting biological studies.

Stimuli that have been frequently used to induce self-relevant processing are highly familiar to individuals (e.g., self-name [SN] and self-face). One’s surname is an important form of collective self-concept; it represents the line of ancestry, and is psychologically salient. According to this concept, a stranger with the same surname may also elicit salient self-relevant processing, despite unfamiliarity; however, this has not yet been directly investigated. The present study adopted a three-stimulus oddball paradigm and multimodal electroencephalography to study the potential self-relevant processing of such stimuli. Behavioral results indicated that same-surname unfamiliar (SSU) names were rated more self-relevant than different-surname unfamiliar (DSU) names, although they were rated equally unfamiliar to subjects. Analysis of EEG data showed similar P2 enhancement in response to SN and SSU when compared to DSU. In contrast, the self-relevant effect on P3 amplitudes and theta synchronization decreased linearly from SN, SSU, to DSU conditions. Thus, both the behavioral and electrophysiological data indicate that unfamiliar names with the same surname can evoke reliable self-relevant processing.

Pollution of agricultural soils by pesticides, such as organochlorine pesticides (OCPs), can be a significant issue since high detection rates of these compounds were reported in our previous studies. However, more uncertain kinds, quantities and density of pollutants remained in soil samples were unidentified. In this study, the total hormonal activities of complex mixtures of both known and unknown contaminants in agricultural soils in mainland China were measured by applying highly sensitive reporter gene assays for detecting agonists/antagonists for estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). High detection rates of estrogenic activities and anti-progestogenic activities were observed among the 123 soil samples, reaching 79% and 73%, respectively. More than half of the soil samples showed obvious antagonistic effects against AR and GR. Approximately a third of tested samples exhibited androgenic, progestogenic and glucocorticoidic effects. A total of 72% and 78% soil extracts had mineralocorticoid-like and anti-mineralocorticoid activities, respectively. Significant positive correlations were observed between estrogenic activity and the concentrations of Σdichlorodiphenyltrichloroethanes (DDTs), Σendosulfans, Σchlordanes, heptachlor and Σdrins, respectively, but not other receptors. As a rapid and convenient pre-caution method, determination of endocrine-disrupting potencies of contaminated soils via bioassay could help to identify and define sites that required further attention for ecological risk assessments.

One emerging and exciting topic in robotics research is the design of micro-/nanoscale robots for biomedical operations. Unlike industrial robots that are developed primarily to automate routine and dangerous tasks, biomedical nanorobots are designed for complex, physiologically relevant environments, and tasks that involve unanticipated biological events. Here, a biologically interfaced nanorobot is reported, made of magnetic helical nanomotors cloaked with the plasma membrane of human platelets. The resulting biomimetic nanorobots possess a biological membrane coating consisting of diverse functional proteins associated with human platelets. Compared to uncoated nanomotors which experience severe biofouling effects and hence hindered propulsion in whole blood, the platelet-membrane-cloaked nanomotors disguise as human platelets and display efficient propulsion in blood over long time periods. The biointerfaced nanorobots display platelet-mimicking properties, including adhesion and binding to toxins and platelet-adhering pathogens, such as Shiga toxin and Staphylococcus aureus bacteria. The locomotion capacity and platelet-mimicking biological function of the biomimetic nanomotors offer efficient binding and isolation of these biological threats. The dynamic biointerfacing platform enabled by platelet-membrane cloaked nanorobots thus holds considerable promise for diverse biomedical and biodefense applications.

Organochlorine pesticides (OCPs) with different usage states, such as currently, historically or never used, may show different behaviors and potential risks in the environment. It is essential to identify their distribution patterns and fates and to assess their associated health risks to humans. In this study, based on a nationwide sampling campaign across China, we determined the concentrations of currently (endosulfan), historically (chlordane and heptachlor) and never-used (aldrin, dieldrin and endrin) OCPs in agricultural soils. The total residue inventories of ∑Endosulfans, ∑Chlordanes, heptachlor and ∑Drins in soils were 260, 64.3, 54.2 and 88.6 t, respectively. The residues of endosulfan were influenced by current usage, showing a latitude transect trend. Drins were mainly from long-range transport, but the illegal usage in China still affected their residues. This finding indicates that endosulfan and drins in Chinese agricultural soils mainly follow the primary and secondary distribution pattern, respectively. Both primary and secondary distribution have a great impact on the distribution pattern of chlordane, which had been banned for only 4 years at the time we sampled. The health risks of these OCPs were estimated based on their concentrations. There were 0.813% and 1.63% of samples that exceeded the target values for chlordane and endrin according to the Netherlands guideline for unpolluted soil. Their residues in most of the samples posed no or few non-carcinogenic and carcinogenic risks to human beings. The results from this study will provide powerful support for pollution control and management.

Arsenic (As) has been proven to be highly toxic to humans, but limited attention has focused on exposure levels and potential risks to mother-neonate pairs of coastal populations. This study was conducted by examining the As concentration in colostrum and umbilical cord serum collected from 106 mother-neonate pairs living on Shengsi Island, facing the Yangtze River estuary and Hangzhou Bay in China. Average concentrations of total As in colostrum and cord serum were 18.51 ± 7.00 and 19.83 ± 10.50 μg L−1. One-way ANOVA analysis showed delivered ages and source of drinking water played significant roles in influencing the maternal exposure patterns. Correlation analysis indicated a significantly positive association between As concentrations in colostrum and cord serum. Multivariable linear regression models adjusted for other confounders clarified the dose-response relationship with a coefficient value of 0.23 and a 95 % confidence interval of (0.006, 0.492); p