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With the rapid development of China’s economy, people are eager for an effective way to relieve work pressure and strengthen their health at the same time. Outdoor sport is one of the best choices for people. However, the amount of recommended data on the network is very large. As a result, when people understand outdoor sports through the network, they cannot effectively obtain the information they want. This is the problem of “information overload,” and personalized recommendation system can effectively alleviate this problem. In order to effectively recommend outdoor sports to users, a useful attempt was made in the personalized recommendation system for outdoor sports in this paper. The specific work of this paper is as follows: firstly, the current situation of outdoor sports in China was summarized, and the related technologies of the recommendation system were studied, including user modeling technology, recommendation target modeling technology, and recommendation algorithm. In order to obtain better recommendation effect, this paper proposes to mix user-based collaborative filtering recommendation algorithm, project-based collaborative filtering recommendation algorithm, and content-based recommendation algorithm. The hybrid algorithm adopts the way of feature expansion and weighted combination. Firstly, the hybrid model (model 1) of user-based collaborative filtering recommendation and content-based recommendation is obtained. Secondly, the hybrid model (model 2) based on project collaborative filtering recommendation and content-based recommendation was obtained. Finally, model 1 and model 2 were combined together to get a hybrid model with better final recommendation effect. For the common cold start problem in the recommendation system, the system adopts content-based recommendation algorithm to solve it.

Chromosomal translocations involving the mixed-lineage leukemia (MLL, KMT2A, MLL1) genes result in the production of MLL fusion proteins, which cause abnormal transcriptional regulation leading to acute leukemia (AL). Menin (MEN1) protein is essential for MLL to regulate the expression of related target genes. High-affinity interactions between the amino terminus of MLL proteins and Menin proteins are required to mediate the oncogenic transformation of MLL fusion proteins. Therefore, inhibition of Menin and MLL interaction is a potential therapeutic strategy for MLL rearrangement (MLL-r) leukemia and can provide a new choice for treatment of other diseases. Therefore, researchers have made great efforts to explore small-molecule Menin-MLL interaction inhibitors.This review is to provide an overview of the patented Menin-MLL protein-protein interaction inhibitors from 2014 to 2021.Menin-MLL interaction inhibitors have therapeutic potential in the treatment of acute leukemia, such as AML and ALL. SNDX-5613 and KO-539 have been granted orphan drug designation by the FDA for treatment of refractory/relapsed leukemia and AML, respectively. In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.

Malignant pleural effusion (MPE) is a functional 'cold' tumor microenvironment in which the antitumor activity of CD8

Mixed lineage leukemia (MLL) gene rearrangements are associated with acute leukemia. The protein menin is regarded as a critical oncogenic cofactor of the resulting MLL fusion proteins in acute leukemia. A direct interaction between menin and the MLL amino terminal sequences is necessary for MLL fusion protein-mediated leukemogenesis. Thus, inhibition of the interaction between menin and MLL has emerged as a novel therapeutic strategy. Recent improvements in structural biology and chemical reactivity have promoted the design and development of selective and potent menin-MLL interaction inhibitors. In this Perspective, different classes of menin-MLL interaction inhibitors are comprehensively summarized. Further research potential, challenges, and opportunities in the field are also discussed.

Background: Coronavirus disease 2019 (COVID-19) is primarily a respiratory disease that has become a global pandemic. Close contact plays an important role in infection spread, while fomite may also be a possible transmission route. Research during the COVID-19 pandemic has identified long-range airborne transmission as one of the important transmission routes although lack solid evidence. Methods: We examined video data related to a restaurant associated COVID-19 outbreak in Guangzhou. We observed more than 40,000 surface touches and 13,000 episodes of close contacts in the restaurant during the entire lunch duration. These data allowed us to analyse infection risk via both the fomite and close contact routes. Results: There is no significant correlation between the infection risk via both fomite and close contact routes among those who were not family members of the index case. We can thus rule out virus transmission via fomite contact and interpersonal close contact routes in the Guangzhou restaurant outbreak. The absence of a fomite route agrees with the COVID-19 literature. Conclusions: These results provide indirect evidence for the long-range airborne route dominating SARS-CoV-2 transmission in the restaurant. We note that the restaurant was poorly ventilated, allowing for increasing airborne SARS-CoV-2 concentration.

This study was designed to explore the effects of exosomal miR-421 secreted by cancer-associated fibroblasts (CAFs) on pancreatic cancer (PC) progression and the mechanisms involved. CAFs and exosomes (exos) were isolated and identified. PC cells were treated with CAF-derived exos (CAF-exos). Western blotting and quantitative polymerase chain reaction (qPCR) were used to measure miR-421, sirtuin-3 (SIRT3), and hypoxia duciblefactors-1 alpha (HIF-1α) levels. Cell counting kit-8 (CCK-8), wound-healing, and transwell migration assays were used to measure proliferation, migration, and invasion abilities of the cells. Dual-luciferase assay and RNA immunoprecipitation (RIP) experiment analyzed the relationship between miR-421 and SIRT3. Chromatin immunoprecipitation (f)-verified H3K9Ac enrichment in the HIF-1α promoter region. In vivo tumorigenesis experiments were performed to further explore the effects of exosomal miR-421 from CAFs on PC. CAFs and exos were successfully isolated. CAF-exo-treated PC cells highly expressed miR-421 and had increased cell proliferation, migration, and invasion abilities. Knocking down miR-421 increased the expression of SIRT3. SIRT3 is a target of miR-421, and inhibiting the expression of SIRT3 reversed the negative effects of miR-421 knockdown on PC cell. Knocking down miR-421 in CAF-exo inhibited the expression of HIF-1α in PC cells. Moreover, SIRT3-mediated HIF-1α expression by regulating H3K9Ac. HIF-1α overexpression reversed the inhibiting effects of SIRT3 overexpression on PC progression and counteracted the inhibiting effects of miR-421 knockdown on glycolysis. Moreover, in vivo tumorigenesis experiments showed that knocking down miR-421 attenuated CAF-exo induced tumor growth. Exosomal miR-421 from CAFs promoted PC progression by regulating the SIRT3/H3K9Ac/HIF-1α axis. This study provided insights into the molecular mechanism of PC.

Meteorological factors and the increase in extreme weather events are closely related to the incidence rate of infectious diarrhea. However, few studies have explored whether the impact of the same meteorological factors on the incidence rate of infectious diarrhea in different climate regions has changed and quantified these changes. In this study, the time series fixed-effect Poisson regression model guided by climate was used to quantify the relationships between the incidence rate of various types of infectious diarrhea and meteorological factors in different climate regions of China from 2004 to 2018, with a lag of 0–2 months. In addition, six social factors, including per capita Gross Domestic Product (GDP), population density, number of doctors per 1000 people, proportion of urbanized population, proportion of children aged 0–14 years old, and proportion of elderly over 65 years old, were included in the model for confounding control. Additionally, the intercept of each province in each model was analyzed by a meta-analysis. Four climate regions were considered in this study: tropical monsoon areas, subtropical monsoon areas, temperate areas and alpine plateau areas. The results indicate that the influence of meteorological factors and extreme weather in different climate regions on diverse infectious diarrhea types is distinct. In general, temperature was positively correlated with all infectious diarrhea cases (0.2 ≤ r ≤ 0.6, p < 0.05). After extreme rainfall, the incidence rate of dysentery in alpine plateau area in one month would be reduced by 18.7% (95% confidence interval (CI): −27.8–−9.6%). Two months after the period of extreme sunshine duration happened, the incidence of dysentery in the alpine plateau area would increase by 21.9% (95% CI: 15.4–28.4%) in that month, and the incidence rate of typhoid and paratyphoid in the temperate region would increase by 17.2% (95% CI: 15.5–18.9%) in that month. The meta-analysis showed that there is no consistency between different provinces in the same climate region. Our study indicated that meteorological factors and extreme weather in different climate areas had different effects on various types of infectious diarrhea, particularly extreme rainfall and extreme sunshine duration, which will help the government develop disease-specific and location-specific interventions, especially after the occurrence of extreme weather.

OBJECTIVE: This study aimed to quantitatively assess the effectiveness of the Wuhan lockdown measure on controlling the spread of coronavirus diesase 2019 (COVID-19). METHOD: : Firstly，estimate the daily new infection rate in Wuhan before January 23 (rd)，2020 when the city went into lockdown by consulting the data of Wuhan population mobility and the number of cases imported from Wuhan in 217 cities of Mainland China. Then estimate what the daily new infection rate would have been in Wuhan from January 24 (th) to January 30th if the lockdown measure had been delayed for 7 days，assuming that the daily new infection in Wuhan after January 23 (rd) increased in a high，moderate and low trend respectively (using exponential, linear and logarithm growth models). Based on that，calculate the number of infection cases imported from Wuhan during this period. Finally，predict the possible impact of 7-day delayed lockdown in Wuhan on the epidemic situation in China using the susceptible-exposed-infectious-removed (SEIR) model. RESULTS: : The daily new infection rate in Wuhan was estimated to be 0.021%，0.026%，0.029%，0.033% and 0.070% respectively from January 19 (th) to January 23 (rd). And there were at least 20 066 infection cases in Wuhan by January 23 (rd)，2020. If Wuhan lockdown measure had been delayed for 7 days，the daily new infection rate on January 30 (th) would have been 0.335% in the exponential growth model，0.129% in the linear growth model，and 0.070% in the logarithm growth model. Correspondingly，there would have been 32 075，24 819 and 20 334 infection cases travelling from Wuhan to other areas of Mainland China，and the number of cumulative confirmed cases as of March 19 (th) in Mainland China would have been 3.3-3.9 times of the officially reported number. Conclusions: Timely taking city-level lockdown measure in Wuhan in the early stage of COVID-19 outbreak is essential in containing the spread of the disease in China.

Metabolic homoeostasis in adipose tissue plays a major role in obesity-related insulin resistance (IR). Regulatory T (Treg) cells have been recorded to regulate metabolic homoeostasis in adipose tissue. However, their specific mechanism is not yet known. This review aims to present the role of Treg cells and other immune cells in obesity-associated IR, focusing on the balance of numbers and functions of Treg cells and other immune cells as well as the crucial role of their interactions in maintaining adipose tissue homoeostasis. Th1 cells, Th17 cells, CD8+ T cells, and pro-inflammatory macrophages mediate the occurrence of obesity and IR by antagonizing Treg cells, while anti-inflammatory dendritic cells, eosinophils and type 2 innate lymphoid cells (ILC2s) regulate the metabolic homoeostasis of adipose tissue by promoting the proliferation and differentiation of Treg cells. γ δ T cells and invariant natural killer T (iNKT) cells have complex effects on Treg cells, and their roles in obesity-associated IR are controversial. The balance of Treg cells and other immune cells can help maintain the metabolic homoeostasis of adipose tissue. Further research needs to explore more specific molecular mechanisms, thus providing more precise directions for the treatment of obesity with IR.

Despite remarkable clinical achievements, camptothecin (CPT) still suffers from poor solubility and severe toxicity. Therefore, it is necessary to redevelop CPT derivatives as supplementary antitumor agents with good water solubility and small side effects. In this work, 27 camptothecin derivatives were synthesized and screened for their cytotoxicity against A549 (lung) and HCT-116 (colon) cancer cell lines. Among them, compound B7, 7-ethyl-10-(2-oxo-2-(4-methylpiperidin-1-yl)ethoxy)camptothecin,was demonstrated in vitro to be a more potent antitumor agent than SN-38 by comparison of their inhibitory activities against cell proliferation and colony formation and interference effect on process of cell cycle and cell apoptosis. Additionally, a molecular docking model revealed that B7 can interact with the topoisomerase I-DNA complex, and that the solubility of B7 reached 5.73 μg/mL in water. Moreover, B7 significantly inhibited tumor growth in an A549 xenograft model at dosages of 0.4 and 2.0 mg/kg, and exhibited minimum lethal doses comparable to those of irinotecan. These results indicated that B7, with improved solubility, enhanced activity and acceptable acute toxicity, can be used as a lead compound for the development of novel anticancer agents.

Texture analysis is an emerging field that allows mathematical detection of changes in MRI signals that are not visible among image pixels. Alzheimer's disease, a progressive neurodegenerative disease, is the most common cause of dementia. Recently, multiple texture analysis studies in patients with Alzheimer's disease have been performed. This review summarizes the main contributors to Alzheimer's disease-associated cognitive decline, presents a brief overview of texture analysis, followed by review of various MR imaging texture analysis applications in Alzheimer's disease. We also discuss the current challenges for widespread clinical utilization. MR texture analysis could potentially be applied to develop neuroimaging biomarkers for use in Alzheimer's disease clinical trials and diagnosis.

Many reports indicated that cigarette smoking was associated with internet gaming disorder (IGD). However, the underlying mechanism of comorbidity between smoking and IGD and whether they had interaction effects on topological organization of brain functional network are still unknown. Therefore, we investigated the interaction between smoking and IGD in resting-state brain functional networks for 60 healthy controls, 46 smokers, 38 IGD individuals and 34 IGD comorbid with smoking participants. The modular structures of functional networks were explored and participation coefficient (Pc) was used to characterize the importance of each brain region in the communication between modules. Significant main effect of IGD was found in the left superior frontal gyrus, bilateral medial part of superior frontal gyrus and bilateral posterior cingulate gyrus with lower Pc in IGD group than in non-IGD group. Significant interaction effects between smoking and IGD were found in the left posterior orbital gyrus, right lateral orbital gyrus, left supramarginal gyrus, left middle temporal gyrus and left inferior temporal gyrus. The interaction in these brain regions was characterized by no significant difference or significantly decreased Pc in smokers or IGD individuals while significantly increased Pc in IGD comorbid with smoking group under the influence of IGD or smoking. Our findings provide valuable information underlying the neurophysiological mechanisms of smoking and IGD, and also offer a potential target for future clinical treatment of smoking and IGD comorbidity.

To mitigate SARS-CoV-2 transmission, vaccines have been urgently approved. With their limited availability, it is critical to distribute the vaccines reasonably. We simulated the SARS-CoV-2 transmission for 365 days over four intervention periods: free transmission, structural mitigation, personal mitigation, and vaccination. Sensitivity analyses were performed to obtain robust results. We further evaluated two proposed vaccination allocations, including one-dose-high-coverage and two-doses-low-coverage, when the supply was low. 33.35% (infection rate, 2.68 in 10 million people) and 40.54% (2.36) of confirmed cases could be avoided as the nonpharmaceutical interventions (NPIs) adherence rate rose from 50% to 70%. As the vaccination coverage reached 60% and 80%, the total infections could be reduced by 32.72% and 41.19%, compared to the number without vaccination. When the durations of immunity were 90 and 120 days, the infection rates were 2.67 and 2.38. As the asymptomatic infection rate rose from 30% to 50%, the infection rate increased 0.92 (SD, 0.16) times. Conditioned on 70% adherence rate, with the same amount of limited available vaccines, the 20% and 40% vaccination coverage of one-dose-high-coverage, the infection rates were 2.70 and 2.35; corresponding to the two-doses-low-coverage with 10% and 20% vaccination coverage, the infection rates were 3.22 and 2.92. Our results indicated as the duration of immunity prolonged, the second wave of SARS-CoV-2 would be delayed and the scale would be declined. On average, the total infections in two-doses-low-coverage was 1.48 times (SD, 0.24) as high as that in one-dose-high-coverage. It is crucial to encourage people in order to improve vaccination coverage and establish immune barriers. Particularly when the supply is limited, a wiser strategy to prevent SARS-CoV-2 is equally distributing doses to the same number of individuals. Besides vaccination, NPIs are equally critical to the prevention of widespread of SARS-CoV-2.

Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has largely limited the clinical use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer (NSCLC). Herein, to overcome the intractable problem of drug resistance, proteolysis targeting chimeras (PROTACs) targeting EGFR mutants were developed by optimizing covalent EGFR ligands. Covalent or reversible covalent pyrimidine- or purine-containing PROTACs were designed, synthesized, and evaluated. As a consequence, covalent PROTAC

Purpose: To seek optimal keV settings for imaging carpal tunnel in adults by dual-energy computed tomography (DECT) monoenergetic technique; to describe anatomic characteristics of carpal tunnel and to observe correlation between carpal bony and soft tissue structures. Methods: DECT images of 20 wrists (11 left and 9 right wrists; 14 men, mean age 26.93 ± 1.38 years, range 23 to 28, and 6 women, mean age 24.17 ± 0.98 years, range 23 to 26) were evaluated. Monoenergetic images were reconstructed at 42, 62, 82, 102, 122, and 142 keV. Image quality was assessed along a 5-point Likert scale, and the highest-quality images were chosen for quantitative analysis. Two musculoskeletal radiologists performed both analyses independently. Results: The optimal energy spectrum with the best contrast-to-noise ratio (CNR) for monoenergetic images were at 62 keV (19 wrists, 95%) and 61 keV (1 wrist, 5%). There was substantial interobserver agreement between the readers in the 5-point Likert scale analysis of image quality (? = 0.793). Bland-Altman plots also indicated good agreement between observers in quantitative analysis. Intra-category 1 and 2 correlation was mostly discovered at hamate hook level and middle level of pisiform (P < 0.05), while bony and soft tissue structures partly reached correlation (P < 0.05). Conclusion: The optimal energy spectrum for monoenergetic DECT imaging of carpal tunnel structures was 62 keV. DECT monoenergetic imaging could predict changes in soft tissue structures and demonstrate carpal tunnel anatomic structures. Keywords: DECT, monoenergetic, keV, carpal tunnel, Continuous...

Background Out-of-hospital cardiac arrest (OHCA) is a leading cause of sudden cardiac death worldwide. Researchers have found significant pathophysiological differences between females and males and clinically significant sex differences related to medical services. However, conflicting results exist and there is no uniform agreement regarding sex differences in survival and prognosis after OHCA. Therefore, we investigated the relationship between the prognosis of OHCA and sex factors. Methods We comprehensively searched the PubMed, Embase, and Cochrane databases and obtained a total of 1042 articles, from which 33 studies were selected for inclusion. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effects model. Results The meta-analysis included 1,268,664 patients. Compared with males, females were older (69.7 years vs. 65.4 years, p p Conclusions Our results indicate that the overall discharge survival rate of females is lower than that of males, and females face a poor prognosis of the nervous system. This is likely related to the pathophysiological characteristics of females, more conservative treatment measures compared with males, and different post-resuscitation care. However, these findings should be interpreted with caution due to the presence of several confounding factors.

To suppress the ongoing COVID-19 pandemic, the Chinese government has implemented nonpharmaceutical interventions (NPIs). Because COVID-19 and influenza have similar means of transmission, NPIs targeting COVID-19 may also affect influenza transmission. In this study, the extent to which NPIs targeting COVID-19 have affected seasonal influenza transmission was explored. Indicators of seasonal influenza activity in the epidemiological year 2019–2020 were compared with those in 2017–2018 and 2018–2019. The incidence rate of seasonal influenza reduced by 64% in 2019–2020 (P < .001). These findings suggest that NPIs aimed at controlling COVID-19 significantly reduced seasonal influenza transmission in China.

Cardiac hypertrophy is a significant risk factor for cardiovascular disease, including heart failure, arrhythmia, and sudden death. Cardiac hypertrophy involves both embryonic gene expression and transcriptional reprogramming, which are tightly regulated by epigenetic mechanisms. An increasing number of studies have demonstrated that epigenetics plays an influential role in the occurrence and development of cardiac hypertrophy. Here, we summarize the latest research progress on epigenetics in cardiac hypertrophy involving DNA methylation, histone modification, and non-coding RNA, to help understand the mechanism of epigenetics in cardiac hypertrophy. The expression of both embryonic and functional genes can be precisely regulated by epigenetic mechanisms during cardiac hypertrophy, providing a substantial number of therapeutic targets. Thus, epigenetic treatment is expected to become a novel therapeutic strategy for cardiac hypertrophy. According to the research performed to date, epigenetic mechanisms associated with cardiac hypertrophy remain far from completely understood. Therefore, epigenetic mechanisms require further exploration to improve the prevention, diagnosis, and treatment of cardiac hypertrophy.

Recent studies have demonstrated sex-specific differences in etiology, course and brain dysfunction that are associated with cigarette smoking. However, little is known about sex-specific differences in subcortical structure and function. In this study, structural and resting-state functional magnetic resonance imaging (fMRI) data were collected from 60 cigarette smokers (25 females) and 67 nonsmokers (28 females). The structural MRI was applied to identify deficits in sex-specific subcortical volume. Using resting-state fMRI, sex-related alterations in resting-state functional connectivity (rsFC) were investigated in subcortical nuclei with volume deficits as seed regions. Compared to nonsmokers, male but not female smokers demonstrated a significantly smaller volume in the left caudate, while female but not male smokers showed a smaller volume in the right amygdala. Resting-state FC analysis revealed that male but not female smokers had increased rsFC between the left caudate and the left prefrontal cortex but decreased rsFC within the bilateral caudate and between the right amygdala and right orbitofrontal cortex (OFC). Furthermore, the right amygdala volume was negatively correlated with the impulsivity score in female but not male smokers. The rsFC of the right amygdala-OFC circuit was negatively associated with the craving score in male but not female smokers. These findings indicate that cigarette smoking may have differential effects on the caudate and amygdala volumes as well as rsFC between men and women, contributing to our knowledge of sex-specific effects of nicotine addiction. Such sex-specific differences in subcortical structure and function may provide a methodological framework for the development of sex-specific relapse prevention therapies.

Background An efficient surface cleaning strategy would first target cleaning to surfaces that make large contributions to the risk of infections. Methods In this study, we used data from the literature about methicillin-resistant Staphylococcus aureus (MRSA) and developed an ordinary differential equations based mathematical model to quantify the impact of contact heterogeneity on MRSA transmission in a hypothetical 6-bed intensive care unit (ICU). The susceptible patients are divided into two types, these who are cared by the same nurse as the MRSA infected patient (Type 1) and these who are not (Type 2). Results The results showed that the mean MRSA concentration on three kinds of susceptible patient nearby surfaces was significantly linearly associated with the hand-touch frequency (p Conclusions This study provided a framework to study the pathogen concentration dynamics on environmental surfaces and quantitatively showed the importance of cleaning patient nearby HTSs on controlling the nosocomial infection transmission via contact route.

A series of multi-substituted isatin derivatives were synthesized using the powerful Sandmeyer reaction. The structures of these derivatives were confirmed by 1H-NMR, 13C-NMR, and HR-MS. Inhibition of proliferation activities of these derivatives against human leukemia cells (K562), human hepatocellular carcinoma cells (HepG2) and human colon carcinoma cells (HT-29) were evaluated in vitro using the MTT assay. Among the series, compound 4l exhibited strong antiproliferatory activities against K562, HepG2 and HT-29 cells with IC50 values of 1.75, 3.20, and 4.17 &mu, M, respectively. The morphological, growth inhibitory and apoptosic effects of compound 4l in K562 cells, wound healing effect in HepG2 cells, and tube formating effect in matrix gel of HUVEC cells were evaluated consequently. All results indicated that compound 4l could be used as a potential antitumor agent in further investigations.

Personal protective behaviors of healthcare workers (HCWs) and dynamic changes in them are known to play a major role in the hospital transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, 1,499 HCWs in Chinese hospitals completed an online survey about their knowledge on SARS-CoV-2 transmission and their personal protective behaviors before and after coronavirus disease 2019 (COVID-19) vaccination. Of all the respondents, 89% were vaccinated at the time of the survey and 96% believed that the vaccine was effective or highly effective. Further, 88% of the vaccinated HCWs expressed that they would get revaccinated if the vaccination failed. Compared with HCWs with a lower education level, those with a higher education level had less fear of being infected with SARS-CoV-2 and reported a lower negative impact of the pandemic on how they treated patients. Physicians and nurses were willing to believe that short-range airborne and long-range fomite are possible transmission routes. HCWs with a higher education level had a better knowledge of COVID-19 but worse personal protective behaviors. The fact that HCWs with a longer work experience had worse personal protective behaviors showed that HCWs gradually relax their personal protective behaviors over time. Moreover, vaccination reduced the negative effects of the COVID-19 pandemic on how the HCWs treated patients. Importantly, the survey revealed that after vaccination, HCWs in China did not relax their personal protective behaviors, and it may bring a low potential risk for following waves of variant virus (e.g., delta).

Background Understanding the transmission source, pattern, and mechanism of infectious diseases is essential for targeted prevention and control. Though it has been studied for many years, the detailed transmission patterns and drivers for the seasonal influenza epidemics in China remain elusive. Methods In this study, utilizing a suite of epidemiological and genetic approaches, we analyzed the updated province-level weekly influenza surveillance, sequence, climate, and demographic data between 1 April 2010 and 31 March 2018 from continental China, to characterize detailed transmission patterns and explore the potential initiating region and drivers of the seasonal influenza epidemics in China. Results An annual cycle for influenza A(H1N1)pdm09 and B and a semi-annual cycle for influenza A(H3N2) were confirmed. Overall, the seasonal influenza A(H3N2) virus caused more infection in China and dominated the summer season in the south. The summer season epidemics in southern China were likely initiated in the “Lingnan” region, which includes the three most southern provinces of Hainan, Guangxi, and Guangdong. Additionally, the regions in the south play more important seeding roles in maintaining the circulation of seasonal influenza in China. Though intense human mobility plays a role in the province-level transmission of influenza epidemics on a temporal scale, climate factors drive the spread of influenza epidemics on both the spatial and temporal scales. Conclusion The surveillance of seasonal influenza in the south, especially the “Lingnan” region in the summer, should be strengthened. More broadly, both the socioeconomic and climate factors contribute to the transmission of seasonal influenza in China. The patterns and mechanisms revealed in this study shed light on the precise forecasting, prevention, and control of seasonal influenza in China and worldwide.

Background School closure is a common mitigation strategy during severe influenza epidemics and pandemics. However, the effectiveness of this strategy remains controversial. In this study, we aimed to explore the effectiveness of school closure on seasonal influenza epidemics in provincial-level administrative divisions (PLADs) with varying urbanization rates in China. Methods This study analyzed influenza surveillance data between 2010 and 2019 provided by the Chinese National Influenza Center. Taking into consideration the climate, this study included a region with 3 adjacent PLADs in Northern China and another region with 4 adjacent PLADs in Southern China. The effect of school closure on influenza transmission was evaluated by the reduction of the effective reproductive number of seasonal influenza during school winter breaks compared with that before school winter breaks. An age-structured Susceptible-Infected-Recovered-Susceptible (SIRS) model was built to model influenza transmission in different levels of urbanization. Parameters were determined using the surveillance data via robust Bayesian method. Results Between 2010 and 2019, in the less urbanized provinces: Hebei, Zhejiang, Jiangsu and Anhui, during school winter breaks, the effective reproductive number of seasonal influenza epidemics reduced 14.6% [95% confidential interval (CI): 6.2–22.9%], 9.6% (95% CI: 2.5–16.6%), 7.3% (95% CI: 0.1–14.4%) and 8.2% (95% CI: 1.1–15.3%) respectively. However, in the highly urbanized cities: Beijing, Tianjin and Shanghai, it reduced only 5.2% (95% CI: -0.7–11.2%), 4.1% (95% CI: -0.9–9.1%) and 3.9% (95% CI: -1.6–9.4%) respectively. In China, urbanization is associated with decreased proportion of children and increased social contact. According to the SIRS model, both factors could reduce the impact of school closure on seasonal influenza epidemics, and the proportion of children in the population is thought to be the dominant influencing factor. Conclusions Effectiveness of school closure on the epidemics varies with the age structure in the population and social contact patterns. School closure should be recommended in the low urbanized regions in China in the influenza seasons. Graphical abstract

OBJECTIVE: :To evaluate the impact of socioeconomic status，population mobility，prevention and control measures on the early-stage coronavirus disease 2019 (COVID-19) development in major cities of China. METHODS: : The rate of daily new confirmed COVID-19 cases in the 51 cities with the largest number of cumulative confirmed cases as of February 19，2020 (except those in Hubei province) were collected and analyzed using the time series cluster analysis. It was then assessed according to three aspects，that is, socioeconomic status，population mobility，and control measures for the pandemic. RESULTS: : According to the analysis on the 51 cities，4 development patterns of COVID-19 were obtained，including a high-incidence pattern (in Xinyu)，a late high-incidence pattern (in Ganzi)，a moderate incidence pattern (in Wenzhou and other 12 cities)，and a low and stable incidence pattern (in Hangzhou and other 35 cities). Cities with different types and within the same type both had different scores on the three aspects. CONCLUSION: : There were relatively large difference on the COVID-19 development among different cities in China，possibly affected by socioeconomic status，population mobility and prevention and control measures that were taken. Therefore，a timely public health emergency response and travel restriction measures inside the city can interfere the development of the pandemic. Population flow from high risk area can largely affect the number of cumulative confirmed cases.

Touching contaminated surfaces might lead to the spread of pathogens, that is, the fomite transmission route. Although hand- and surface-hygiene practices are potentially important non-pharmaceutical interventions for the fomite route, the two interventions have been mostly studied separately in the literature. In this study, we develop a new conceptual model based on the law of mass action, analyze the temporal diffusion of contaminated surfaces and hands, and verify the model with simulations in an assumed norovirus outbreak in a buffet restaurant. A quantitative hygiene criterion is developed for the required frequency of surface disinfection and hand hygiene to control the fomite transmission in indoor environments. To eliminate surface contaminations, the product of pathogen-removal rates (including hygiene and natural death) on hands and surfaces must be no smaller than that of the human hand and surface contact frequency (ie, the net removal product must be non-negative). When the net removal product is negative, the number of contaminated surfaces and hands would show a logistic growth trend and finally approach the equilibrium. Our approach sheds light into how to optimize the combined use of hand hygiene and environmental decontamination for the best effectiveness under different settings.

This cross-temporal meta-analysis involved 86 studies (N = 71,397) on aggression among Chinese college students conducted from 2003 to 2017. We collected articles investigating college students' aggression using the Aggression Questionnaire. The results showed that college students' aggression generally decreased steadily over 15 years. Compared to 2003, aggression in 2017 decreased by 1.030 standard deviations. The decline in physical aggression, verbal aggression, and hostility among college students were more rapid than anger. College students from the Eastern region of China demonstrated this decline more than those from the Center and Western regions. Both male and female college students showed decreasing aggression, and the decline was larger in males compared to females.

// Wei Zhao 1, * , Hao Lei 1, 2, * , Xiaodong Zhu 1 , Ling Li 1 , Song Qu 1 , Xia Liang 1 1 Department of Radiation Oncology, Cancer Hospital of Guangxi Medical University, Nanning, 530021, China 2 Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, 430079, China * Wei Zhao and Hao Lei are co-first authors Correspondence to: Xiaodong Zhu, email: zhuxidonggxmu@126.com Keywords: failure pattern, intensity-modulated radiotherapy, long-term outcome, nasopharyngeal carcinoma, retrospective analysis Received: August 16, 2016 Accepted: November 07, 2016 Published: November 24, 2016 ABSTRACT Intensity-modulated radiotherapy (IMRT) has replaced the conventional radiotherapy (2D-RT) and improved clinical efficacy in Nasopharyngeal Carcinoma (NPC) patients. In the present study, we retrospectively analyzed the clinical characteristics of patients with NPC treated with IMRT to assess the long-term survival outcomes and failure patterns. Of the 527 patients, One hundred and twenty-one patients experienced treatment failure, 86 patients developed distant metastases, and 12 patients developed a second primary tumor. The local and regional recurrence rates were 31.4% and 14.0%, respectively. The 5-year overall survival (OS), progression-free survival (PFS), local recurrence-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastatic relapse-free survival (DMFS) rates were 80.9%, 75.6%, 91.7%, 96.2%, and 83.0%, respectively. The 5-year LRFS rates of Stage T1-4 patients were 100.0%, 93.1%, 92.0%, and 85.8%, respectively. The 5-year DMFS rates of Stage N0-3 patients were 95.0%, 86.1%, 79.5%, and 67.2%, respectively. Multivariate analysis showed age and T-stage were independent predictors of OS, T-stage was an independent predictor of LRFS, and age and N-stage were independent predictors of PFS and DMFS. In summary, the improved treatment results with IMRT are primarily due to the achievement of a higher local tumor control rate and OS in NPC patients. However, distant metastasis was the most commonly observed failure pattern after treatment. These results provide deep insights about the value of IMRT in the treatment and prognosis of NPC patients.

Among the diverse medical education systems in China, the 8-year program is dedicated to cultivating physician scientists. Although the research ability of senior students in 8-year medical programs is a pivotal quality, it remains unclear. This study aimed to clarify the current status and challenges of students' research experience, abilities, and outputs.A multicenter cross-sectional study was conducted in 5 medical schools in northern China. Electronic questionnaires were sent to 235 randomly chosen fifth-grade or sixth-grade 8-year-program medical students. A total of 211 responses were collected and analyzed using SPSS 22.0.Only 13.3% of participants chose research as their future career goal. Students generally felt that conducting research was stressful and difficult. The greatest obstacle was a lack of time due to heavy workloads. The 2 major motivations for research were graduation and/or future employment (75.8%) and research interest (24.2%). More than half of the students (142, 67.3%) had research experience by the time of the survey, among whom 84 students already had research outputs. A higher proportion of students with outputs was motivated by the requirements for graduation or employment compared to students without outputs (71.4% vs 55.2%, P = .046).Senior 8-year-program medical students in China generally had high pressure to conduct research and devoted their efforts to overcome these challenges. More guidance and novel encouragement to enhance students' initiative and interest in research could be provided by medical schools and educators in the future.

Background Coronavirus disease 2019 (COVID-19) continues to threaten human life worldwide. We explored how human behaviors have been influenced by the COVID-19 pandemic in Hong Kong, and how the transmission of other respiratory diseases (eg, influenza) has been influenced by human behavior. Methods We focused on the spread of COVID-19 and influenza infections based on the reported COVID-19 cases and influenza surveillance data and investigated the changes in human behavior due to COVID-19 based on mass transit railway data and the data from a telephone survey. We did the simulation based on a susceptible-exposed-infected-recovered (SEIR) model to assess the risk reduction of influenza transmission caused by the changes in human behavior. Results During the COVID-19 pandemic, the number of passengers fell by 52.0% compared with the same period in 2019. Residents spent 32.2% more time at home. Each person, on average, came into close contact with 17.6 and 7.1 people per day during the normal and pandemic periods, respectively. Students, workers, and older people reduced their daily number of close contacts by 83.0%, 48.1%, and 40.3%, respectively. The close contact rates in residences, workplaces, places of study, restaurants, shopping centers, markets, and public transport decreased by 8.3%, 30.8%, 66.0%, 38.5%, 48.6%, 41.0%, and 36.1%, respectively. Based on the simulation, these changes in human behavior reduced the effective reproduction number of influenza by 63.1%. Conclusions Human behaviors were significantly influenced by the COVID-19 pandemic in Hong Kong. Close contact control contributed more than 47% to the reduction in infection risk of COVID-19.

Background Nonpharmaceutical interventions (NPIs) against coronavirus disease 2019 (COVID-19) are vital to reducing transmission risks. However, the relative efficiency of social distancing against COVID-19 remains controversial, since social distancing and isolation/quarantine were implemented almost at the same time in China. Methods In this study, surveillance data of COVID-19 and seasonal influenza in 2018–2020 were used to quantify the relative efficiency of NPIs against COVID-19 in China, since isolation/quarantine was not used for the influenza epidemics. Given that the relative age-dependent susceptibility to influenza and COVID-19 may vary, an age-structured susceptible/infected/recovered model was built to explore the efficiency of social distancing against COVID-19 under different population susceptibility scenarios. Results The mean effective reproductive number, Rt, of COVID-19 before NPIs was 2.12 (95% confidence interval [CI], 2.02–2.21). By 11 March 2020, the overall reduction in Rt of COVID-19 was 66.1% (95% CI, 60.1–71.2%). In the epidemiological year 2019–20, influenza transmissibility was reduced by 34.6% (95% CI, 31.3–38.2%) compared with transmissibility in epidemiological year 2018–19. Under the observed contact pattern changes in China, social distancing had similar efficiency against COVID-19 in 3 different scenarios. By assuming the same efficiency of social distancing against seasonal influenza and COVID-19 transmission, isolation/quarantine and social distancing could lead to 48.1% (95% CI, 35.4–58.1%) and 34.6% (95% CI, 31.3–38.2%) reductions of the transmissibility of COVID-19, respectively. Conclusions Though isolation/quarantine is more effective than social distancing, given that the typical basic reproductive number of COVID-19 is 2–3, isolation/quarantine alone could not contain the COVID-19 pandemic effectively in China.

Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC50 of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.

A series of tetracyclic oxindole derivatives was synthesized by asymmetric 1, 3-dipole reaction in 2–4 steps in 57–86% overall yields. These compounds were evaluated for α-glucosidase inhibitory and glucose consumption-promoting activity in vitro. Compound 4l competitively and reversibly inhibited α-glucosidase (IC50 = 3.64 μM) with activity 14-fold higher than that of acarbose. Docking analysis substantiated these findings. In addition, compound 4l exhibited significant glucose consumption promoting activity at 1 μM.

Background: Since Dec 2019, Wuhan and other cities in China have experienced an outbreak caused by a novel coronavirus, 2019-nCoV. Even worse, this outbreak overlapped with the traditional Chinese Spring Festival, a time when billions of people travel across the country. The government has implemented a number of policies and interventions, including a travel ban from and to Wuhan since Jan 23, 2020, an extension of the Spring Festival holiday, etc. However, a considerable volume of population movement had already occurred before the travel ban, potentially causing the spread of cases to other cities in China. As people return to their place of work, this reflux of population movement is also likely to facilitate transmission of 2019-nCoV. Thus, it is urgent to evaluate the impact of existing population movement and future population reflux on the spread of 2019-nCoV, to provide evidence for precise control of the epidemic. Methods: We used domestic human mobility data from January to February (2019-20) to infer the population movement network between cities in China. We obtained data on confirmed cases from the daily official reports of the health commission of 34 provincial-level administrative units and 341 city-level units, from the time of the outbreak to Feb 14, 2020. We used a linear regression model to simulate the relationship between population flow and imported cases, and evaluate the deduction and risk of imported cases in different scenarios of human movement. Findings: There is a statistically significant positive correlation between population influx from Wuhan and confirmed cases in other cities across China (R2=0×85, P

Identifying the exact transmission route(s) of infectious diseases in indoor environments is a crucial step in developing effective intervention strategies. In this study, we proposed a comparative analysis approach and built a model to simulate outbreaks of 3 different in-flight infections in a similar cabin environment, that is, influenza A H1N1, severe acute respiratory syndrome (SARS) coronavirus (CoV), and norovirus. The simulation results seemed to suggest that the close contact route was probably the most significant route (contributes 70%, 95% confidence interval [CI]: 67%-72%) in the in-flight transmission of influenza A H1N1 transmission; as a result, passengers within 2 rows of the index case had a significantly higher infection risk than others in the outbreak (relative risk [RR]: 13.4, 95% CI: 1.5-121.2, P = .019). For SARS CoV, the airborne, close contact, and fomite routes contributed 21% (95% CI: 19%-23%), 29% (95% CI: 27%-31%), and 50% (95% CI: 48%-53%), respectively. For norovirus, the simulation results suggested that the fomite route played the dominant role (contributes 85%, 95% CI: 83%-87%) in most cases; as a result, passengers in aisle seats had a significantly higher infection risk than others (RR: 9.5, 95% CI: 1.2-77.4, P = .022). This work highlighted a method for using observed outbreak data to analyze the roles of different infection transmission routes.

Objective: The aim of this study was to evaluate the safety and efficiency of enucleation (EU) for proximal pancreatic non-invasive neoplasms. Methods: Patients with solitary non-invasive neoplasms in the proximal pancreas from January 1998 to April 2014 at the Second Affiliated Hospital of Zhejiang University, Hangzhou, China were included. Different operations and outcomes were analyzed. Results: A total of 123 patients were enrolled. Forty patients (32.5%) underwent EU including 18 patients who had tumors close to the main pancreatic duct (MPD). Sixty-one patients (49.6%) had pancreaticoduodenectomy (PD) performed and 22 (17.9%) underwent central pancreatectomy (CP). Pathological outcomes included neuroendocrine tumors, cystic lesions, and solid pseudopapillary tumors. Operation time, intra-operative blood loss, and duration of hospital stay were significantly reduced in the EU group. PD was associated with the greatest complication rate (55.7%), followed by EU (50%) and CP (40.9%), though the pancreatic fistula rate after EU was the highest (50%), especially in patients with tumors larger than 3 cm and tumors close to the MPD. EU had advantages in the preservation of pancreatic parenchyma and endocrine and exocrine function. Conclusions: EU can be carried out safely and effectively for tumors in the proximal pancreas with improved outcomes compared with standard resections, even if the tumor is larger than 3 cm and close to the MPD.

Targeting L858R/T790M/C797S mutant EGFR is a major challenge in the new-generation EGFR tyrosine kinase inhibitors development for conquering drug resistant NSCLC. In this study, a series of novel 9-heterocyclyl substituted 9H-purine derivatives were designed as EGFRL858 R/T790 M/C797S tyrosine kinase inhibitors. Among these compounds, D4, D9, D11 and D12 showed significantly potent anti-proliferation and EGFRL858 R/T790 M/C797S inhibition activity. In particular, the most potent compound D9 showed anti-proliferation against HCC827 and H1975 cell lines with the IC50 values of 0.00088 and 0.20 μM, respectively. And D9 inhibited the EGFRL858R/T790M/C797S with an IC50 value of 18 nM. Furtherly, D9 could significantly suppress the EGFR phosphorylation, induce the apoptosis, arrest cell cycle at G0/G1, and inhibit colony formation in HCC827 cell line by a concentration-dependent manner. Molecular docking indicated that the introduction of a cyclopropylsulfonamide group in D9 led to the formation of additional two hydrogen bonds with mutant Ser797 which played key roles in generating efficient EGFRL858 R/T790 M/C797S inhibitory activity. These findings strongly indicated that 9-heterocyclyl substituted 9H-purine derivatives were promising L858R/T790M/C797S mutant EGFR-TKIs. The introduction of extra hydrogen bond interaction with mutant Ser797 is efficient method for the design of the fourth-generation EGFR-TKIs.

Epidermal growth factor receptor (EGFR) is an important therapeutic target for the treatment of non-small cell lung cancer. A number of efficacious EGFR tyrosine kinase inhibitors have been developed. However, acquired drug resistance largely encumbered their clinical practicability. Therefore, there is an urgent need to develop new therapeutic regime. Herein, we designed and synthesized a set of EGFR-targeting small molecule PROTACs which showed promising efficacy. In particular, VHL-recruiting compound P3 showed potent anti-proliferative activity against HCC827 and H1975 cell lines with IC50 values of 0.83 and 203.01 nM, respectively. Furthermore, both EGFRdel19 and EGFRL858R/T790M could be significantly induced to be degraded under treatment of P3 with DC50 values of 0.51 and 126.2 nM, respectively. Compound P3 was able to dramatically suppress EGFR pathway signal transduction. Moreover, compound P3 could significantly induce cell apoptosis, arrest cell cycle and suppress cell colony formation. In addition, we identified that ubiquitination was indispensable in the degradation process, and found that the degradation was related to autophagy. Our work would provide an alternative approach for development of potentially effective EGFR degraders and give a new clue for investigation of PROTAC-induced protein degradation.

Background/Aims: Hirschsprung's disease (HSCR), known as aganglionosis, is an infrequent congenital gut motility disorder characterized by absence of enteric neurons. In this study, we focus on the role of the intronic miR-215 and its host gene isoleucyl-tRNA synthetase 2 (IARS2) in the pathogenesis of HSCR. Methods: Quantitative real time PCR and Western blot were used to detect the miRNA, mRNAs, and proteins levels. The dual-luciferase reporter gene assay confirmed the direct regulation of the specific mRNA and miRNAs in cell lines. Transwell assays, CCK8 assay, and flow cytometry were used to measure cell function of the human 293T and SH-SY5Y cells. Results: Expression levels of miR-215 in HSCR patient colon tissues were outstandingly lower than controls, which was positively correlated with expression of the host gene IARS2 and negatively correlated with predicted target gene: sialic acid binding Ig-like lectin 8 (SIGLEC-8). The loss of miR-215 inhibited cell migration and proliferation, which was consistent with the reduction of IARS2. The dual-luciferase reporter gene assay confirmed that miR-215 resulted in the inhibition of SIGLEC-8 by directly binding to the 3'-UTR of SIGLEC-8. Moreover, knocking-down SIGLEC-8 rescued the extent of suppressed cell migration and proliferation that resulted from the diminishment of miR-215. Conclusions: Our findings indicate that miR-215 acts in concert with the host gene IARS2 to affect neuron migration and proliferation through the target gene SIGLEC-8. We infer that the IARS2-miR-215-SIGLEC-8 pathway may play a crucial role in the pathogenesis of HSCR.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and important risk factor for cardiac diseases, diabetes and extrahepatic cancers. Natural 3′-geranylchalconaringenin (GC) and desmethylxanthohumol (DX) from hop were synthesized using a regio-selective iodination and the Suzuki coupling reaction as key steps. GC and DX, along with their aglycone naringenin chalcone (NC) were investigated their decreasing the accumulation of cellular lipids. GC reduced lipid content and activated the AMP-activated protein kinase (AMPK) pathway in HepG2 and 3T3-L1 cells. In addition, GC had an obvious therapeutic effect on alleviating NAFLD and metabolic syndrome by activating the AMPK pathway in vivo. In conclusion, GC may be potentially used as a candidate drug and functional food for treating NAFLD and metabolic syndrome.

Knowledge about the infection transmission routes is significant for developing effective intervention strategies. We searched the PubMed databases and identified 10 studies with 14 possible inflight influenza A(H1N1)pdm09 outbreaks. Considering the different mechanisms of the large-droplet and airborne routes, a meta-analysis of the outbreak data was carried out to study the difference in attack rates for passengers within and beyond two rows of the index case(s). We also explored the relationship between the attack rates and the flight duration and/or total infectivity of the index case(s). The risk ratios for passengers seated within and beyond the two rows of the index cases were 1.7 (95% confidence interval (CI) 0.98–2.84) for syndromic secondary cases and 4.3 (95% CI 1.25–14.54) for laboratory-confirmed secondary cases. Furthermore, with an increase of the product of the flight duration and the total infectivity of the index cases, the overall attack rate increased linearly. The study indicates that influenza A(H1N1)pdm09 may mainly be transmitted via the airborne route during air travel. A standardised approach for the reporting of such inflight outbreak investigations would help to provide more convincing evidence for such inflight transmission events.

In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025 μM and 0.49 μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50 = 1.7 nM) and EGFRL858R/T790M (IC50 = 23.3 nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50 mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.

Human immunodeficiency virus (HIV) infection significantly affect neurodevelopmental and behavioral outcomes. We investigated whether alterations of gray matter organization and structural covariance networks with vertical HIV infection adolescents exist, by using the GAT toolbox. MRI data were analysed from 25 HIV vertically infected adolescents and 33 HIV-exposed-uninfected control participants. The gray matter volume (GMV) was calculated, and structural brain networks were reconstructed from gray matter co-variance. Gray matter losses were pronounced in anterior cingulate cortex (ACC), right pallidum, right occipital lobe, inferior parietal lobe, and bilateral cerebellum crus. The global brain network measures were not significantly different between the groups; however, the nodal alterations were most pronounced in frontal, temporal, basal ganglia, cerebellum, and temporal lobes. Brain hubs in the HIV-infected subjects increased in number and tended to shift to sensorimotor and temporal areas. In the HIV-infected subjects, decreased GMVs in ACC and bilateral cerebellum were related to lower Mini-Mental State Examination scores; the CD4 counts were positively related to the GMVs in ACC and sensorimotor areas. These findings suggest that focally reduced gray matter, disrupted nodal profiles of structural wirings, and a shift in hub distribution may represent neuroanatomical biomarkers of HIV infection on the developing brain.

Although numerous studies have demonstrated that social support affects a range of life experiences, few have examined its moderating and mediating effects. In the current study, 479 Chinese parents of children with ASD (aged 3–18 years) completed the surveys assessing parenting stress, social support and life satisfaction. Results indicated that parenting stress, social support and life satisfaction were significantly related. Moreover, social support both mediated and moderated the influence of parenting stress on life satisfaction. These findings imply that parenting stress and social support are critical indicators of life satisfaction and can serve as basic intervention strategies that promote life satisfaction among Chinese parents of children with ASD.

In this paper, we reviewed the long-term survival outcomes, safety, and quality-of-life of androgen-deprivation therapy (ADT) alone versus combined with radiation therapy (RT) or chemotherapy for locally advanced and metastatic prostate cancer (PCa). A literature search was performed using OvidSP. Randomized controlled trials (RCTs) that met the following criteria were included: including locally advanced or metastatic PCa, comparing ADT alone versus combined with any treatment method and reporting quantitative data of disease control or survival outcomes. Finally, eight RCTs met the inclusion criteria. Among these, three compared ADT versus ADT plus RT (n = 2344) and one compared ADT versus ADT plus docetaxel-estramustine (n = 413) in locally advanced PCa; two compared ADT versus ADT plus docetaxel (n = 1175) and two compared ADT versus ADT plus estramustine (n = 114) in metastatic PCa. For locally advanced PCa, the addition of RT to long-term ADT can improve the outcomes of survival and tumor control with fully acceptable adverse effects. Specially, the pooled odds ratio (OR) of overall survival (OS) was 1.43 (95% confidence interval 1.20-1.71) when compared ADT plus RT with ADT alone (P < 0.0001). For metastatic hormonally sensitive PCa, the concurrent use of docetaxel plus ADT was effective and safe (pooled OR of OS: 1.29 [1.01-1.65]: P = 0.04). In all, long-term ADT plus RT and long-term ADT plus docetaxel should be considered as proper treatment option in locally advanced and metastatic hormonally sensitive PCa, respectively. The major limitation for the paper was that only eight RCTs were available.

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making critical binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compound acts as a competitive inhibitor with an IC50 of 6 μM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 μM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addition, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).

Surfaces and objects surround us, and touching them is integral to everyday life. Pathogen contaminated surfaces (fomites) are known to transmit diseases. However, little is known about the ways and speed at which surfaces become contaminated. We found that under certain conditions, the number of contaminated surfaces grows logistically, corresponding to possible rapid transmission of infection. In such a surface network, pathogen can be transmitted great distances quickly—as far as people move. We found that the surface contamination network in aircraft cabins exhibits a community structure, with small communities connected by the aisle seatback surfaces and toilets, which are high-touch surfaces. In less than two to three hours, most high-touch surfaces in the cabin are contaminated, and within five to six hours nearly all touchable surfaces are contaminated. During short haul flight, aisle passengers have higher fomite exposure. This closely matches the spatial infection pattern of one reported inflight norovirus outbreaks. Our model is generally applicable to other crowded settings. The commonly repeated advice to “wash hands frequently” may be replaced in future by more strategic advice such as “clean surfaces right now”, or advice based on who should wash their hands, and when.

Background Cleaning of environmental surfaces in hospitals is important for the control of methicillin-resistant Staphylococcus aureus (MRSA) and other hospital-acquired infections transmitted by the contact route. Guidance regarding the best approaches for cleaning, however, is limited. Methods In this study, a mathematical model based on ordinary differential equations was constructed to study MRSA concentration dynamics on high-touch and low-touch surfaces, and on the hands and noses of two patients (in two hospitals rooms) and a health care worker in a hypothetical hospital environment. Two cleaning interventions – whole room cleaning and wipe cleaning of touched surfaces – were considered. The performance of the cleaning interventions was indicated by a reduction in MRSA on the nose of a susceptible patient, relative to no intervention. Results Whole room cleaning just before first patient care activities of the day was more effective than whole room cleaning at other times, but even with 100% efficiency, whole room cleaning only reduced the number of MRSA transmitted to the susceptible patient by 54%. Frequent wipe cleaning of touched surfaces was shown to be more effective that whole room cleaning because surfaces are rapidly re-contaminated with MRSA after cleaning. Wipe cleaning high-touch surfaces was more effective than wipe cleaning low-touch surfaces for the same frequency of cleaning. For low wipe cleaning frequency (≤3 times per hour), high-touch surfaces should be targeted, but for high wipe cleaning frequency (>3 times per hour), cleaning should target high- and low-touch surfaces in proportion to the surface touch frequency. This study reproduces the observations from a field study of room cleaning, which provides support for the validity of our findings. Conclusions Daily whole room cleaning, even with 100% cleaning efficiency, provides limited reduction in the number of MRSA transmitted to susceptible patients via the contact route; and should be supplemented with frequent targeted cleaning of high-touch surfaces, such as by a wipe or cloth containing disinfectant.

Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4-SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4-SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.

Abnormal macrostructural brain abnormalities in both gray matter and white matter have been reported in cigarette smokers. However, less is known about white matter microstructure in heavy cigarette smokers. In this study, we used diffusion tensor imaging (DTI) to investigate the integrity of the white matter microstructure in heavy smokers.Thirty-four heavy smokers and 34 non-smokers participated in this study. Whole brain analysis of fractional anisotropy (FA) was performed using tract-based spatial statistics (TBSS) to detect abnormal white matter regions between groups. Volume-of-interest (VOI) analysis was used to investigate changes in diffusivity indices in the regions showing FA abnormalities. Multiple regression analysis was applied to assess the relationships between diffusion indices and smoking-related variables in heavy smokers.Compared with non-smokers, heavy smokers had lower FA in the left anterior (i.e., the genu and rostral body) corpus callosum while exhibiting no areas of higher FA. In the affected region, FA reduction was accompanied by a significantly decreased axial diffusivity and increased radial diffusivity, which suggests that axonal damage and disrupted myelin integrity may be associated with the degraded white matter integrity in heavy smokers. Moreover, significant positive correlations were found between both radial diffusivity and mean diffusivity and the duration of regular smoking.Our findings suggest that heavy smokers demonstrate abnormal integrity of the white matter microstructure in the anterior corpus callosum, which is related to the duration of regular smoking. In addition, our study may increase the understanding of the neurobiological basis of chronic cigarette smoking.