HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma.

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.

Utility of the triglyceride-glucose index for predicting restenosis following revascularization surgery for extracranial carotid artery stenosis: A retrospective cohort study.

BACKGROUND: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are effective interventions for treating extracranial carotid artery stenosis (ECAS), but long-term prognosis is limited by postoperative restenosis. Carotid restenosis is defined as carotid stenosis >50% by various examination methods in patients after carotid revascularization. This retrospective cohort study examined the value of the triglyceride-glucose (TyG) index for predicting vascular restenosis after carotid revascularization. METHODS: A total of 830 patients receiving CEA (408 cases, 49.2%) or CAS (422 cases, 50.8%) were included in this study. Patients were stratified into three subgroups according to TyG index tertile (high, intermediate, and low), and predictive value for restenosis was evaluated by constructing multivariate Cox proportional hazard regression models. RESULTS: Incidence of postoperative restenosis was significantly greater among patients with a high TyG index according to univariate analysis. Kaplan-Meier survival curve analysis revealed a progressive increase in restenosis prevalence with rising TyG index. Multivariate Cox regression models also identified TyG index as an independent predictor of restenosis, while receiver operating characteristic (ROC) curve analysis showed that TyG index predicted restenosis with moderate sensitivity (57.24%) and specificity (67.99%) (AUC: 0.619, 95% CI 0.585-0.652, z-statistic=4.745, p<0.001). Addition of the TyG index to an established risk factor model incrementally improved restenosis prediction (AUC: 0.684 (0.651-0.715) vs 0.661 (0.628-0.694), z-statistic =2.027, p = 0.043) with statistical differences. CONCLUSION: The TyG index is positively correlated with vascular restenosis risk after revascularization, which can be used for incremental prediction and has certain predictive value.

Aicardi-Goutières syndrome type 7 in a Chinese child: A case report.

BACKGROUND: IFIH1 is a protein-coding gene. Disorders associated with IFIH1 include Aicardi-Goutières syndrome (AGS) type 7 and Singleton-Merten syndrome type 1. Related pathways include RIG-I/MDA5-mediated induction of the interferon (IFN)-α/ß pathway and the innate immune system. AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment. In infancy, most patients present with psychomotor retardation, axial hypotonia, spasticity, and brain imaging changes Laboratory assessments showed increased IFN-α activity with upregulation of IFN signaling and IFN-stimulated gene expression. Some patients develop normally in the early stage, and then have episodic neurological deficits. CASE SUMMARY: The 5-year-old girl presented with postpartum height and weight growth retardation, language retardation, brain atrophy, convulsions, and growth hormone deficiency. DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation. Heterozygous mutations in the IFIH1 gene were found. Physical examination at admission found that language development was delayed, the reaction to name calling was average, there was no communication with people, but there was eye contact, no social smile, and no autonomous language. However, the child had rich gesture language and body language, could understand instructions, had bad temper. When she wants to achieve something, she starts crying or shouting. Cardiopulmonary examination showed no obvious abnormality, and abdominal examination was normal. Bilateral muscle strength and muscle tone were symmetrical and slightly decreased. Physiological reflexes exist, but pathological reflexes were not elicited. CONCLUSION: We reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7, which expanded the mutational spectrum of the IFIH1 gene.

Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma.

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.

Light-Enhanced Ion Migration in Two-Dimensional Perovskite Single Crystals Revealed in Carbon Nanotubes/Two-Dimensional Perovskite Heterostructure and Its Photomemory Application.

Two-dimensional (2D) hybrid perovskite sandwiched between two long-chain organic layers is an emerging class of low-cost semiconductor materials with unique optical properties and improved moisture stability. Unlike conventional semiconductors, ion migration in perovskite is a unique phenomenon possibly responsible for long carrier lifetime, current-voltage hysteresis, and low-frequency giant dielectric response. While there are many studies of ion migration in bulk hybrid perovskite, not much is known for its 2D counterparts, especially for ion migration induced by light excitation. Here, we construct an exfoliated 2D perovskite/carbon nanotube (CNT) heterostructure field effect transistor (FET), not only to demonstrate its potential in photomemory applications, but also to study the light induced ion migration mechanisms. We show that the FET I-V characteristic curve can be regulated by light and shows two opposite trends under different CNT oxygen doping conditions. Our temperature-dependent study indicates that the change in the I-V curve is probably caused by ion redistribution in the 2D hybrid perovskite. The first principle calculation shows the reduction of the migration barrier of I vacancy under light excitation. The device simulation shows that the increase of 2D hybrid perovskite dielectric constant (enabled by the increased ion migration) can change the I-V curve in the trends observed experimentally. Finally, the so synthesized FET shows the multilevel photomemory function. Our work shows that not only we could understand the unique ion migration behavior in 2D hybrid perovskite, it might also be used for many future memory function related applications not realizable in traditional semiconductors.

A Small Lattice Change Induces Significant Dynamic Changes of CH3NH3+ Caged in Hybrid Perovskite Crystals: Toward Understanding the Interplay between Host Lattices and Guest Molecules.

Two perovskite-type compounds, (MA)2[B'Co(CN)6] (MA = methylammonium, B' = K(I) and Na(I)), have very similar structures, but exhibit marked differences in the phase and dielectric transitions. Solid state 2H NMR studies reveal the detailed dynamic changes of the caged methylammonium (MA) cations before and after the phase transitions, which are correlated with the different dielectric states of the compounds. Using solid state 59Co NMR, the dynamic changes of the host lattices before and after the transitions, which accompany the changes in the dynamics of the caged MA cations, are unveiled, demonstrating the intriguing interplay between the MA cations and the host lattices. On the basis of these observations, the molecular origins of the dielectric transitions are discussed in detail.

The association between hantavirus infection and selenium deficiency in mainland China.

Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses and transmitted by rodents is a significant public health problem in China, and occurs more frequently in selenium-deficient regions. To study the role of selenium concentration in HFRS incidence we used a multidisciplinary approach combining ecological analysis with preliminary experimental data. The incidence of HFRS in humans was about six times higher in severe selenium-deficient and double in moderate deficient areas compared to non-deficient areas. This association became statistically stronger after correction for other significant environment-related factors (low elevation, few grasslands, or an abundance of forests) and was independent of geographical scale by separate analyses for different climate regions. A case-control study of HFRS patients admitted to the hospital revealed increased activity and plasma levels of selenium binding proteins while selenium supplementation in vitro decreased viral replication in an endothelial cell model after infection with a low multiplicity of infection (MOI). Viral replication with a higher MOI was not affected by selenium supplementation. Our findings indicate that selenium deficiency may contribute to an increased prevalence of hantavirus infections in both humans and rodents. Future studies are needed to further examine the exact mechanism behind this observation before selenium supplementation in deficient areas could be implemented for HFRS prevention.

7,7-[Ethane-1,2-diylbis(oxy)]-2-[hydroxy(phenyl)methyl]bicyclo[3.3.1]nonan-3-one.

In the title compound, C18H22O4, the cyclo-hexane and cyclo-hexa-none rings adopt normal chair and half-chair conformations, respectively. The dioxolane ring is almost planar, with an r.m.s. deviation of 0.094 (3) Å. In the crystal, mol-ecules are connected by O-H⋯O hydrogen bonds, forming 21 helical chains along the a-axis direction. The chains are further connected by C-H⋯O hydrogen bonds.

Using interrupted time series design to analyze changes in hand, foot, and mouth disease incidence during the declining incidence periods of 2008-2010 in China.

OBJECTIVE: To identify patterns of hand, foot and mouth disease (HFMD) incidence in China during declining incidence periods of 2008, 2009, and 2010. METHODS: Reported HFMD cases over a period of 25 months were extracted from the National Disease Reporting System (NDRS) and analyzed. An interrupted time series (ITS) technique was used to detect changes in HFMD incidence rates in terms of level and slope between declining incidence periods of the three years. RESULTS: Over 3.58 million HFMD cases younger than 5 years were reported to the NDRS between May 1, 2008, and May 31, 2011. Males comprised 63.4% of the cases. ITS analyses demonstrated a significant increase in incidence rate level (P<0.0001) when comparing the current period with the previous period. There were significant changes in declining slopes when comparing 2010 to 2009, and 2010 to 2008 (all P<0.005), but not 2009 to 2008. CONCLUSION: Incremental changes in incidence rate level during the declining incidence periods of 2009 and 2010 can potentially be attributed to a few factors. The more steeply declining slope in 2010 compared with previous years could be ascribed to the implementation of more effective interventions and preventive strategies in 2010. Further investigation is required to examine this possibility.

[Spatial clustering and changing trend of hand-foot-mouth disease during 2008-2011 in China].

OBJECTIVE: The purpose of this study was to explore the spatial clustering, specific clustering areas, as well as changing trend of clustering areas of hand-foot-mouth disease (HFMD). METHODS: Exploratory spatial data analysis (ESDA) was used to conduct spatial statistical analyses for the HFMD using 2008 - 2011 data at both provincial and county/district levels. RESULTS: The Global Moran's I coefficients appeared to be 0.3336, 0.6074, 0.3372, 0.4620 and 0.4367 for 2008 - 2011 and for the combined 4 years, respectively. The corresponding P-values were 0.002, 0.001, 0.004, 0.001 and 0.001 respectively, when using the Monte Carlo tests with all the P-values less than 0.05. Moran's I coefficients ranged between 0.3 and 0.7, showing the appearance of moderate or higher clustering nature. Based on the results from nationwide analyses on clustering areas at the county/district levels between 2008 and 2011 (Moran's I = 0.5198, P = 0.001), it appeared a moderate clustering nature. When local autocorrelation analysis was applied at the provincial level, 3 hot spot areas in Beijing, Tianjin and Shanghai cities in 2008; 7 hot spot areas in Beijing, Tianjin, Hebei, Shanxi, Shanghai, Jiangsu and Shandong in 2009; four hot spot areas: Beijing, Tianjin, Guangdong and Guangxi; five hot spot areas: Fujian, Jiangxi, Hunan, Guangdong and Guangxi in 2011, were discovered. 390 hot-spot counties/districts were found through local autocorrelation analyses using the three-year data of 2008 to 2010. CONCLUSION: Spatial clustering nature of HFMD incidence between 2008 and 2011 in China appeared to be moderate or high, with the clustered areas a north to south shifting trend. However, further investigation was in need to address this changing trend.

Change in rainfall drives malaria re-emergence in Anhui Province, China.

Malaria is re-emerging in Anhui Province, China after a decade long' low level of endemicity. The number of human cases has increased rapidly since 2000 and reached its peak in 2006. That year, the malaria cases accounted for 54.5% of total cases in mainland China. However, the spatial and temporal patterns of human cases and factors underlying the re-emergence remain unclear. We established a database containing 20 years' (1990-2009) records of monthly reported malaria cases and meteorological parameters. Spearman correlations were used to assess the crude association between malaria incidence and meteorological variables, and a polynomial distributed lag (PDL) time-series regression was performed to examine contribution of meteorological factors to malaria transmission in three geographic regions (northern, mid and southern Anhui Province), respectively. Then, a two-year (2008-2009) prediction was performed to validate the PDL model that was created by using the data collected from 1990 to 2007. We found that malaria incidence decreased in Anhui Province in 1990s. However, the incidence has dramatically increased in the north since 2000, while the transmission has remained at a relatively low level in the mid and south. Spearman correlation analyses showed that the monthly incidences of malaria were significantly associated with temperature, rainfall, relative humidity, and the multivariate El Niño/Southern Oscillation index with lags of 0-2 months in all three regions. The PDL model revealed that only rainfall with a 1-2 month lag was significantly associated with malaria incidence in all three regions. The model validation showed a high accuracy for the prediction of monthly incidence over a 2-year predictive period. Malaria epidemics showed a high spatial heterogeneity in Anhui Province during the 1990-2009 study periods. The change in rainfall drives the reemergence of malaria in the northern Anhui Province.

Distribution and risk factors of 2009 pandemic influenza A (H1N1) in mainland China.

Data from all reported cases of 2009 pandemic influenza A (H1N1) were obtained from the China Information System for Disease Control and Prevention. The spatiotemporal distribution patterns of cases were characterized through spatial analysis. The impact of travel-related risk factors on invasion of the disease was analyzed using survival analysis, and climatic factors related to local transmission were identified using multilevel Poisson regression, both at the county level. The results showed that the epidemic spanned a large geographic area, with the most affected areas being in western China. Significant differences in incidence were found among age groups, with incidences peaking in school-age children. Overall, the epidemic spread from southeast to northwest. Proximity to airports and being intersected by national highways or freeways but not railways were variables associated with the presence of the disease in a county. Lower temperature and lower relative humidity were the climatic factors facilitating local transmission after correction for the effects of school summer vacation and public holidays, as well as population density and the density of medical facilities. These findings indicate that interventions focused on domestic travel, population density, and climatic factors could play a role in mitigating the public health impact of future influenza pandemics.

Sex differences in the incidence and case fatality rates from hemorrhagic fever with renal syndrome in China, 2004-2008.

BACKGROUND: Differences between male and female individuals in response to infectious diseases are an overlooked global health problem. METHODS: The relationship between sex and disease outcome was examined in populations of patients with hemorrhagic fever with renal syndrome (HFRS) in mainland China, where most cases of hantavirus exposure occur. HFRS in China is diagnosed on the basis of symptoms and is confirmed with serological testing. The geographical distribution, incidence, and case fatality rates (CFRs) of HFRS in China were estimated and compared by patient sex and age. In a subset of patients with HFRS, clinical manifestations of HFRS were assessed using latent class analysis and compared by sex. RESULTS: There were 80,671 HFRS cases reported during the period 2004-2008, with a majority of HFRS cases (39.2%) occurring among individuals 20-39 years of age. The incidence of HFRS was higher among male patients than among female patients for all individuals >10 years of age. There were 945 deaths (CFR, 1.17%) due to HFRS in China during the period 2004-2008. CFRs were higher among women than among men between the ages of 20-39 and ≥ 50 years of age. There were no sex differences in the geographical distribution of HFRS cases or deaths. Although the prevalence of each clinical marker did not differ by sex, 2 profiles of clinical markers were identified that were related to both severity of disease and sex. CONCLUSIONS: These data illustrate a paradox in which the incidence of disease is greater for males, but the severity of disease outcome is worse for females. Several behavioral, societal, and biological factors are hypothesized to be involved.

[Comparison on the performance of both temporal and temporal-spatial models for outbreak detection through China Infectious Diseases Automated-alert and Response System (CIDARS)].

OBJECTIVE: To analyze the pilot results of both temporal and temporal-spatial models in outbreaks detection in China Infectious Diseases Automated-alert and Response System (CIDARS) to further improve the system. METHODS: The amount of signal, sensitivity, false alarm rate and time to detection regarding these two models of CIDARS, were analyzed from December 6, 2009 to December 5, 2010 in 221 pilot counties of 20 provinces. RESULTS: The sensitivity of these two models was equal (both 98.15%). However, when comparing to the temporal model, the temporal-spatial model had a 59.86% reduction on the signals (15 702) while the false alarm rate of the temporal-spatial model (0.73%) was lower than the temporal model (1.79%), and the time to detection of the temporal-spatial model (0 day) was also 1 day shorter than the temporal model. CONCLUSION: Comparing to the temporal model, the temporal-spatial model of CIDARS seemed to be better performed on outbreak detection.

[Preliminary application on China Infectious Diseases Automated-alert and Response System (CIDARS), between 2008 and 2010].

OBJECTIVE: To analyze the results of application on China Infectious Diseases Automated-alert and Response System (CIDARS) and for further improving the system. METHODS: Amount of signal, proportion of signal responded, time to signal response, manner of signal verification and the outcome of each signal in CIDARS were descriptively analyzed from July 1, 2008 to June 30, 2010. RESULTS: A total of 533 829 signals were generated nationwide on 28 kinds of infectious diseases in the system. 97.13% of the signals had been responded and the median time to response was 1.1 hours. Among them, 2472 signals were generated by the fixed-value detection method which involved 9 kinds of diseases after the preliminary verification, field investigation and laboratory tests. 2202 signals were excluded, and finally 246 cholera cases, 15 plague cases and 9 H5N1 cases as well as 39 outbreaks of cholera were confirmed. 531 357 signals were generated by the other method - the 'moving percentile method' which involved 19 kinds of diseases. The average amount of signal per county per week was 1.65, with 6603 signals (1.24%) preliminarily verified as suspected outbreaks and 1594 outbreaks were finally confirmed by further field investigation. For diseases in CIDARS, the proportion of signals related to suspected outbreaks to all triggered signals showed a positive correlation with the proportion of cases related to outbreaks of all the reported cases (r = 0.963, P < 0.01). CONCLUSION: The signals of CIDARS were responded timely, and the signal could act as a clue for potential outbreaks, which helped enhancing the ability on outbreaks detection for local public health departments.

Geo-spatial hotspots of hemorrhagic fever with renal syndrome and genetic characterization of Seoul variants in Beijing, China.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China, and has extended from rural areas to cities recently. Beijing metropolis is a novel affected region, where the HFRS incidence seems to be diverse from place to place. METHODOLOGY/PRINCIPAL FINDINGS: The spatial scan analysis based on geographical information system (GIS) identified three geo-spatial "hotspots" of HFRS in Beijing when the passive surveillance data from 2004 to 2006 were used. The Relative Risk (RR) of the three "hotspots" was 5.45, 3.57 and 3.30, respectively. The Phylogenetic analysis based on entire coding region sequence of S segment and partial L segment sequence of Seoul virus (SEOV) revealed that the SEOV strains circulating in Beijing could be classified into at least three lineages regardless of their host origins. Two potential recombination events that happened in lineage #1 were detected and supported by comparative phylogenetic analysis. The SEOV strains in different lineages and strains with distinct special amino acid substitutions for N protein were partially associated with different spatial clustered areas of HFRS. CONCLUSION/SIGNIFICANCE: Hotspots of HFRS were found in Beijing, a novel endemic region, where intervention should be enhanced. Our data suggested that the genetic variation and recombination of SEOV strains was related to the high risk areas of HFRS, which merited further investigation.

[Using exploratory spatial data analysis (ESDA) on the regional distribution of human brucellosis in six provinces of north China: 2004 - 2007].

Based on data related to human brucellosis which was collected from the national notifiable infectious disease reporting system in the 6 provinces (Inner Mongolia, Shanxi, Heilongjiang, Shaanxi, Jilin and Liaoning) of north China from 2004 to 2007, at the county scale. Data would include age and gender standardized mortality ratios (SMRs) while ESDA was including histograms, box plots and box maps, global and local Moran's I statistics, etc. The global Moran's I values from 2004 to 2007 were 0.2581, 0.4574, 0.4457, 0.4841, respectively and all with statistically significant differences. Most of local Moran's I values were significant positive statistically. High-high counties were mainly in the northeast, most of which were pastoral areas, but the farming-pastoral areas and agricultural areas/town had an increasing trend over time. Low-low counties were mainly in the western and southern areas and most of which were agricultural areas/towns. Low-high counties appeared to be rare, mainly around the counties with high incidence, mainly belonged to agricultural areas/towns. The incidence rates of brucellosis in the six provinces of north China had a trend of increase from 2004 to 2007, namely spreading from east to west, from south to north, and from pastoral areas to farming-pastoral areas and agricultural areas/towns. ESDA could be used to develop effective measures for prevention and control of brucellosis.

[Application of exponential smoothing method in prediction and warning of epidemic mumps].

OBJECTIVE: To analyze the daily data of epidemic Mumps in a province from 2004 to 2008 and set up exponential smoothing model for the prediction. METHODS: To predict and warn the epidemic mumps in 2008 through calculating 7-day moving summation and removing the effect of weekends to the data of daily reported mumps cases during 2005-2008 and exponential summation to the data from 2005 to 2007. RESULTS: The performance of Holt-Winters exponential smoothing is good. The result of warning sensitivity was 76.92%, specificity was 83.33%, and timely rate was 80%. CONCLUSIONS: It is practicable to use exponential smoothing method to warn against epidemic Mumps.

Spatiotemporal dynamics of hemorrhagic fever with renal syndrome, Beijing, People's Republic of China.

We used geographic information systems to characterize the dynamic change in spatial distribution of hemorrhagic fever with renal syndrome (HFRS) in Beijing, People's Republic of China. The seasonal variation in its incidence was observed by creating an epidemic curve. HFRS was associated with developed land, orchards, and rice paddies.