Roc, the G-domain of the Parkinson's disease-associated protein LRRK2.

Mutation in leucine-rich repeat (LRR) kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD). Aberrant LRRK2 kinase activity is associated with disease pathogenesis and thus it is an attractive drug target for combating PD. Intense efforts in the past nearly two decades have focused on the development of small-molecule inhibitors of the kinase domain of LRRK2 and have identified potent kinase inhibitors. However, most LRRK2 kinase inhibitors have shown adverse effects; therefore, alternative-mechanism-based strategies are desperately needed. In this review, we discuss the new insights gleaned from recent cryoelectron microscope (cryo-EM) structures of LRRK2 towards understanding the mechanisms of actions of LRRK2 and explore the potential new therapeutic avenues.

Green space modified the association between air pollutants and hypertension in China.

Evidence regarding the combined effects of green space and air pollutants on hypertension remains limited and complex. This study aims to investigate the varying effects of greenness under different air pollution levels in China, using data from the wave 2018 China Health and Retirement Longitudinal Study (CHARLS) involving 17 468 adults (aged ≥ 45 years). As a result, the prevalence rate of hypertension was 42.04%. Logistic regression analyses revealed the positive associations between air pollution concentrations at the city level and prevalent hypertension and the negative associations between NDVI and prevalent hypertension, all of which were more prominent in the populations of the eastern and rural regions. Notably, the negative effect of green space was greater at the lowest quartiles of each air pollutant (OR for PM2.5 quartiles = 0.724, 0.792, 0.740, and 0.931) . Improving air quality and greenness could potentially reduce hypertension risk, and minimizing air pollution might optimize the protective effects of greenness.

Effects of ambient air pollution on cause-specific hospitalizations in Wuhan during 2017-2019.

BACKGROUND: Few studies have focused on the associations between air pollutants and multiple organ system diseases in the entire hospitalized population. The present study aims to explore the short-term effects of six routinely monitored air pollutants on the broad causes of hospital admissions and estimate the resulting hospital admission burdens. METHODS: Daily hospital admission records from 2017 to 2019 were obtained from the Wuhan Information center of Health and Family Planning. Generalized additive models (GAMs) were employed to evaluate the effects of air pollutants on the percent increase in the cause-specific daily number of hospital admissions. Increased hospital admission numbers, days, and expenses were also estimated. RESULTS: A total of 2636,026 hospital admissions were identified. We found that both PM2.5 and PM10 increased the risk of hospital admissions for most disease categories. Short-term exposure to PM2.5 was positively associated with hospitalizations of several rarely studied disease categories, such as diseases of the eye and adnexa (2.83%, 95%CI: 0.96-4.73%, P < 0.01) and diseases of the musculoskeletal system and connective tissue (2.17%, 95% CI: 0.88-3.47%, P < 0.001). NO2 was observed to have a robust effect on diseases of the respiratory system (1.36%, 95%CI: 0.74-1.98%, P < 0.001). CO was significantly associated with hospital admissions for six disease categories. Furthermore, each 10-µg/m3 increase in PM2.5 was associated with an annual increase of 13,444 hospital admissions (95% CI: 6239-20,649), 124,344 admission days (95% CI: 57,705-190,983), and 166-million-yuan admission expenses (95% CI: 77-255). CONCLUSION: Our study suggested that particulate matter (PM) had a short-term effect on hospital admissions of most major disease categories and resulted in a considerable hospital admission burden. In addition, the health effects of NO2 and CO emissions require more attention in megacities.

Effect of ambient fine particulates (PM2.5) on hospital admissions for respiratory and cardiovascular diseases in Wuhan, China.

BACKGROUND: Positive associations between ambient PM2.5 and cardiorespiratory disease have been well demonstrated during the past decade. However, few studies have examined the adverse effects of PM2.5 based on an entire population of a megalopolis. In addition, most studies in China have used averaged data, which results in variations between monitoring and personal exposure values, creating an inherent and unavoidable type of measurement error. METHODS: This study was conducted in Wuhan, a megacity in central China with about 10.9 million people. Daily hospital admission records, from October 2016 to December 2018, were obtained from the Wuhan Information center of Health and Family Planning, which administrates all hospitals in Wuhan. Daily air pollution concentrations and weather variables in Wuhan during the study period were collected. We developed a land use regression model (LUR) to assess individual PM2.5 exposure. Time-stratified case-crossover design and conditional logistic regression models were adopted to estimate cardiorespiratory hospitalization risks associated with short-term exposure to PM2.5. We also conducted stratification analyses by age, sex, and season. RESULTS: A total of 2,806,115 hospital admissions records were collected during the study period, from which we identified 332,090 cardiovascular disease admissions and 159,365 respiratory disease admissions. Short-term exposure to PM2.5 was associated with an increased risk of a cardiorespiratory hospital admission. A 10 µg/m3 increase in PM2.5 (lag0-2 days) was associated with an increase in hospital admissions of 1.23% (95% CI 1.01-1.45%) and 1.95% (95% CI 1.63-2.27%) for cardiovascular and respiratory diseases, respectively. The elderly were at higher PM-induced risk. The associations appeared to be more evident in the cold season than in the warm season. CONCLUSIONS: This study contributes evidence of short-term effects of PM2.5 on cardiorespiratory hospital admissions, which may be helpful for air pollution control and disease prevention in Wuhan.

Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics.

Mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). Recently, we showed that a disease-associated mutation R1441H rendered the GTPase domain of LRRK2 catalytically less active and thereby trapping it in a more persistently "on" conformation. However, the mechanism involved and characteristics of this on conformation remained unknown. Here, we report that the Ras of complex protein (ROC) domain of LRRK2 exists in a dynamic dimer-monomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the PD-associated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTP-bound-like monomeric conformation. Moreover, we show that residue Arg-1441 is critical for regulating the conformational dynamics of ROC. In summary, our results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomer-dimer dynamics and thereby trap its GTPase domain in an activated state.

The Parkinson's disease-associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2.

Parkinson disease-associated mutations within the GTPase domain Ras of complex proteins (ROC) of leucine rich repeat kinase 2 (LRRK2) result in an abnormal over-activation of its kinase domain. However, the mechanisms involved remain unclear. Recent study has shown that LRRK2 G-domain cycles between monomeric and dimeric conformations upon binding to GTP or guanosine diphosphate, and that the Parkinson's disease (PD)-associated R1441C/G/H mutations impair the G-domain monomer-dimer dynamics and trap the G-domain in a constitutive monomeric conformation. That led us to question whether other disease-associated mutations in G-domain would also affect its conformation. Here, we report that another PD-associated N1437H mutation also impairs its monomer-dimer conformational dynamics and GTPase activity. In contrast with mutations at R1441, ROCN1437H was found to be locked in a stable dimeric conformation in solution and its GTPase activity was ∼4-fold lower than that of the wild-type. Furthermore, the N1437H mutation reduced the GTP binding affinity by ∼2.5-fold when compared with other pathogenic G-domain mutations. Moreover, ROCN1437H was found to have a slower GTP dissociation rate, indicating that N1437H might interrupt the nucleotide exchange cycle. Taken together, our data support that conformational dynamics is important for LRRK2 GTPase activity and that the N1437H mutation impairs GTPase activity by locking the ROC domain in a persistently dimeric state.-Huang, X., Wu, C., Park, Y., Long, X., Hoang, Q. Q., Liao, J. The Parkinson's disease-associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2.

The association between ambient temperature and sperm quality in Wuhan, China.

BACKGROUND: Few epidemiological investigations have focused on the influence of environmental temperature on human sperm quality. Here, we evaluated the potential association between ambient temperature and human sperm quality in Wuhan, China, and examined the interactive effect of particulate matter (PM2.5) and temperature. METHODS: 1780 males who had been living in Wuhan for no less than three months and received semen analysis at the Department of Reproductive Medicine in Renmin Hospital of Wuhan University between April 8, 2013 and June 30, 2015 were recruited. Daily mean meteorological data and air pollution data (PM2.5, O3 and NO2) in Wuhan between 2013 and 2015 were collected. A generalized linear model was used to explore the associations between ambient temperature and sperm quality (including sperm concentration, percentage of normal sperm morphology, and progressive motility) at 0-9, 10-14, 15-69, 70-90, and 0-90 days before semen examination, and the interaction between temperature and PM2.5. RESULTS: The associations between ambient temperature and sperm quality were an inverted U-shape at five exposure windows, except for a lag of 0-9 days for sperm concentration. A 1 °C increase in ambient temperature above the thresholds was associated with a 2.038 (1.292 ~ 2.783), 1.814 (1.217 ~ 2.411), 1.458 (1.138 ~ 1.777), 0.934(0.617 ~ 1.251) and 1.604 (1.258 ~ 1.951) decrease in the percentage of normal sperm morphology at lag 0-9, lag 10-14, lag 15-69, lag 70-90, and lag 0-90 days, respectively. The interaction p-values of PM2.5 and temperature were mostly less than 0.05 at five exposure windows. When ambient temperature exposure levels were above the thresholds, a 0.979 (0.659-1.299) and 3.559 (0.251 ~ 6.867) decrease in percentage of normal sperm morphology per 1 °C increase in temperature at lag 0-90 days was observed in the PM2.5 ≤ P50 group and PM2.5 > P50 group, respectively. CONCLUSIONS: Our results indicate that exposure to ambient temperature has a threshold effect on sperm quality, and PM2.5 enhances the effect of temperature on sperm quality when temperatures are above the threshold.

Roco Proteins and the Parkinson's Disease-Associated LRRK2.

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the 'on' state, and cycle to back to the monomeric conformation in the 'off' state. A new class of small G-proteins called "Roco" was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson's disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.

Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain.

Mutation in leucine-rich-repeat kinase 2 (LRRK2) is a common cause of Parkinson disease (PD). A disease-causing point mutation R1441H/G/C in the GTPase domain of LRRK2 leads to overactivation of its kinase domain. However, the mechanism by which this mutation alters the normal function of its GTPase domain [Ras of complex proteins (Roc)] remains unclear. Here, we report the effects of R1441H mutation (RocR1441H) on the structure and activity of Roc. We show that Roc forms a stable monomeric conformation in solution that is catalytically active, thus demonstrating that LRRK2 is a bona fide self-contained GTPase. We further show that the R1441H mutation causes a twofold reduction in GTPase activity without affecting the structure, thermal stability, and GDP-binding affinity of Roc. However, the mutation causes a twofold increase in GTP-binding affinity of Roc, thus suggesting that the PD-causing mutation R1441H traps Roc in a more persistently activated state by increasing its affinity for GTP and, at the same time, compromising its GTP hydrolysis.

Crystal structure of Bacillus subtilis GabR, an autorepressor and transcriptional activator of gabT.

Bacillus subtilis GabR is a transcription factor that regulates gamma-aminobutyric acid (GABA) metabolism. GabR is a member of the understudied MocR/GabR subfamily of the GntR family of transcription regulators. A typical MocR/GabR-type regulator is a chimeric protein containing a short N-terminal helix-turn-helix DNA-binding domain and a long C-terminal pyridoxal 5'-phosphate (PLP)-binding putative aminotransferase domain. In the presence of PLP and GABA, GabR activates the gabTD operon, which allows the bacterium to use GABA as nitrogen and carbon sources. GabR binds to its own promoter and represses gabR transcription in the absence of GABA. Here, we report two crystal structures of full-length GabR from B. subtilis: a 2.7-Å structure of GabR with PLP bound and the 2.55-Å apo structure of GabR without PLP. The quaternary structure of GabR is a head-to-tail domain-swap homodimer. Each monomer comprises two domains: an N-terminal winged-helix DNA-binding domain and a C-terminal PLP-binding type I aminotransferase-like domain. The winged-helix domain contains putative DNA-binding residues conserved in other GntR-type regulators. Together with sedimentation velocity and fluorescence polarization assays, the crystal structure of GabR provides insights into DNA binding by GabR at the gabR and gabT promoters. The absence of GabR-mediated aminotransferase activity in the presence of GABA and PLP, and the presence of an active site configuration that is incompatible with stabilization of the GABA external aldimine suggest that a GabR aminotransferase-like activity involving GABA and PLP is not essential to its primary function as a transcription regulator.

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.

Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras⋅GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras⋅GTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras⋅GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-Ras⋅GTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras⋅GTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target Ras⋅GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.

A soluble α-synuclein construct forms a dynamic tetramer.

A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of α-helices in the first 100 N-terminal residues of the 140-residue α-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated "hairpin" structure of α-synuclein.

Effects of green spaces on alleviating mortality attributable to PM2.5 in China.

Increasing research suggested that green spaces are associated with many health benefits, but evidence for the quantitative relationship between green spaces and mortality attributable to particulate matter with an aerodynamic diameter of 2.5 µm or less (PM2.5) is limited. We collected disease-specific mortality and PM2.5 data for a period of 4 years (2015-2018) along with green space data for an 8-year duration (2010-2017) in 31 provincial-level administrative regions of China. First, this study used the Integrated Exposure-Response model to estimate the mortality of four diseases attributable to PM2.5, including chronic obstructive pulmonary diseases (COPD), lung cancer (LC), ischemic heart disease (IHD), and cerebrovascular disease (CBVD). Then we performed linear regression and mixed-effects model to investigate the counteracting effect of green spaces on death caused by PM2.5 exposure. The differences in impacts among the Eastern, Central, and Western regions were explored using stratified analysis. The most significant results from linear regression analysis indicated that per 100 km2 of green spaces increase, there was a decreased total mortality (10-5) (COPD, LC, IHD, and CBVD) attributable to PM2.5 by - 4.012 [95% confidence interval (CI): - 5.535, - 2.488], while the reduction by mixed-linear regression analysis was - 2.702/105 (95% CI = - 3.645, - 1.759). Of all hysteresis analyses, the effect estimates (ß) at lag3 and lag4 were the largest. The effect of green spaces was more advantageous when targeting CBVD and the Eastern region. We found a negative correlation between green space exposure and mortality attributable to PM2.5, which can provide further support for city planners, government personnel, and others to build a healthier city and achieve national health goals.

Critical roles of interactions among switch I-preceding residues and between switch II and its neighboring alpha-helix in conformational dynamics of the GTP-bound Ras family small GTPases.

GTP-bound forms of Ras family small GTPases exhibit dynamic equilibrium between two interconverting conformations, "inactive" state 1 and "active" state 2. A great variation exists in their state distribution; H-Ras mainly adopts state 2, whereas M-Ras predominantly adopts state 1. Our previous studies based on comparison of crystal structures representing state 1 and state 2 revealed the importance of the hydrogen-bonding interactions of two flexible effector-interacting regions, switch I and switch II, with the γ-phosphate of GTP in establishing state 2 conformation. However, failure to obtain both state structures from a single protein hampered further analysis of state transition mechanisms. Here, we succeed in solving two crystal structures corresponding to state 1 and state 2 from a single Ras polypeptide, M-RasD41E, carrying an H-Ras-type substitution in residue 41, immediately preceding switch I, in complex with guanosine 5'-(ß,γ-imido)triphosphate. Comparison among the two structures and other state 1 and state 2 structures of H-Ras/M-Ras reveal two new structural features playing critical roles in state dynamics; interaction of residues 31/41 (H-Ras/M-Ras) with residues 29/39 and 30/40, which induces a conformational change of switch I favoring its interaction with the γ-phosphate, and the hydrogen-bonding interaction of switch II with its neighboring α-helix, α3-helix, which induces a conformational change of switch II favoring its interaction with the γ-phosphate. The importance of the latter interaction is proved by mutational analyses of the residues involved in hydrogen bonding. These results define the two novel functional regions playing critical roles during state transition.

Association between smoking and hypertension under different PM2.5 and green space exposure: A nationwide cross-sectional study.

Background: Smoking has been widely reported to have a significant relationship with hypertension, but the past description of this relationship has not been uniform. In addition, there has been a lack of research to discuss the impact of environmental exposure on the relationship between smoking and hypertension. Therefore, this study estimates the association between smoking and hypertension in middle aged and elderly people in China under different PM2.5 (fine particulate matter) concentrations and the green space exposure conditions. Methods: Individual sample data from the China Health and Retirement Longitudinal Study in 2018 and the long-term average exposure concentration of fine particles and green space exposure for all participants were used with a multilevel binary logistic mixed effects model. Adjustments were made for sociodemographic characteristics and other health behaviors including drinking, physical activity, and social activity. The normalized difference vegetation index (NDVI) and PM2.5 concentration stratification were assigned with the median of the population exposure concentration as the dividing line, and the dual environmental factor stratification was assigned in combination with the two types of environmental exposure. The analysis was also stratified using age groups. Results: A total of 10,600 participants over the age of 45 were included in the study. The effects of smoking on hypertension were diverse under different environmental exposure conditions. There was a significant relationship between smoking behavior and hypertension in the Low-NDVI group, and the effect value of this relationship was significantly different from that in the High-NDVI group. Furthermore, for respondents exposed to low green spaces and high PM2.5 environments at the same time (Low-NDVI/High-PM2.5 group), their smoking behavior may lead to an increase in the risk of hypertension. In addition, the risk of hypertension caused by smoking in the middle-aged (45-64) was significant under low green space exposure, but the effect difference between the different age groups was not significant. Conclusions: The relationship between smoking and hypertension was different under different environmental exposure conditions. Exposure to low green spaces may strengthen the association between smoking and hypertension risk. When participants were exposed to both low green spaces and high PM2.5 concentrations, the risk of hypertension caused by smoking was significantly higher than that of those who were exposed to high green spaces and low PM2.5 concentrations.

PM2.5-Associated Hospitalization Risk of Cardiovascular Diseases in Wuhan: Cases Alleviated by Residential Greenness.

PM2.5, a type of particulate matter with an aerodynamic diameter of less than 2.5 µm, is associated with the occurrence of cardiovascular diseases (CVDs), while greenness seems to be associated with better cardiovascular health. We identified 499,336 CVD cases in Wuhan's 74 municipal hospitals between 2017 and 2019. A high-resolution PM2.5 model and a normalized difference vegetation index (NDVI) map were established to estimate individual exposures. The time-stratified case-crossover design and conditional logistic regression models were applied to explore the associations between PM2.5 and CVDs under different levels of environmental factors. Greenness could alleviate PM2.5-induced hospitalization risks of cardiovascular diseases. Compared with patients in the low-greenness group (ER = 0.99%; 95% CI: 0.71%, 1.28%), patients in the high-greenness group (ER = 0.45%; 95% CI: 0.13%, 0.77%) showed a lower increase in total CVD hospitalizations. After dividing the greenness into quartiles and adding long-term PM2.5 exposure as a control factor, no significant PM2.5-associated hospitalization risks of CVD were identified in the greenest areas (quartile 4), whether the long-term PM2.5 exposure level was high or low. Intriguingly, in the least green areas (quartile 1), the PM2.5-induced excess risk of CVD hospitalization was 0.58% (95% CI: 0.04%, 1.11%) in the long-term high-level PM2.5 exposure group, and increased to 1.61% (95% CI: 0.95%, 2.27%) in the long-term low-level PM2.5 exposure group. In the subgroup analysis, males and participants aged 55-64 years showed more significant increases in the PM2.5-induced risk of contracting CVDs with a reduction in greenness and fine particle exposure conditions. High residential greenness can greatly alleviate the PM2.5-induced risk of cardiovascular admission. Living in the areas with long-term low-level PM2.5 may make people more sensitive to short-term increases in PM2.5, leading to CVD hospitalization.

Association Between Grip Strength and Cognitive Function in US Older Adults of NHANES 2011-2014.

BACKGROUND: The relationship between grip strength and cognitive function remains no consensus in the older adults. OBJECTIVE: To investigate the association of grip strength with cognitive function and cognitive performance in different domains. METHODS: Participants of the present cross-sectional study were from the National Health and Nutrition Examination Survey 2011-2014. Grip strength was measured by grip dynamometer, and combined handgrip strength was the sum of the largest reading from each hand. Four cognitive domains (immediate and delayed memory, language, and attention) were assessed by a set of neuropsychological tests. The subjective cognitive decline was determined via self-report. RESULTS: Among 2,618 participants, combined grip strength was positively associated with scores on global cognitive function and each cognitive domain after controlling for demographic characteristics, lifestyle factors, and history of disease. In addition, compared to those with grip strength < 46.7 kg, participants with grip strength≥75.3 kg had odds ratios of 0.36 (95% CI: 0.21 to 0.63) for poor global cognitive function, 0.66 (95% CI: 0.38 to 1.13) for poor immediate memory, 0.53 (95% CI: 0.30 to 0.93) for poor delayed memory, 0.48 (95% CI: 0.27 to 0.86) for poor language function, 0.20 (95% CI: 0.11 to 0.35) for poor attention, and 0.36 (95% CI: 0.18 to 0.73) for subjective cognitive decline in fully adjusted model. CONCLUSION: Older adults with higher grip strength were significantly associated with better performance on cognition function included global and various domains such as memory, language, attention, and subjective cognitive decline.

Association of NO2 with daily hospital admissions for mental disorders: Investigation of the modification effects of green spaces and long-term NO2 exposure.

Air pollution is a risk factor for increased hospital admissions due to mental disorders, while green spaces have been linked with better mental health. We linked daily hospital admission records from Wuhan's 74 municipal hospitals from 2017 to 2019 with modeled annual average NO2 concentrations and added data on the residential surrounding green spaces with 250 m and 500 m buffers based on the normalized difference vegetation index (NDVI) using a land use regression model (LUR). The conditional logistic regression model was used to estimate the acute effect of short-term NO2 exposure, and stratification analyses were applied to explore the modification effect of long-term NO2 exposure and green spaces by estimating the odds ratios in the single- and dual-environmental factor groups. A total of 42,705 hospital admissions for mental disorders were identified. Short-term exposure to NO2 was associated with an increased risk of hospital admission for mental disorders. A 10 µg/m3 increase in NO2 (lag01 day) was associated with an increase in hospital admissions of 2.86% (95% CI, 2.05-3.68) for the total mental disorders. Compared with patients in the "low-NDVI/low-NO2" group (ER = 2.27%, 95% CI, 0.27-4.31), patients in the "high-NDVI/low-NO2" group (ER = 1.93%, -0.10-3.99) showed a lower and insignificant increase in hospitalizations for the total mental disorders, while greenness had a slight moderating effect in the high-level long-term NO2 exposure areas. This study suggested that green spaces may moderate the acute effect of NO2 exposure for mental disorder hospitalizations, especially in low-level long-term NO2 exposure areas.

Short-term effects of air pollution on respiratory diseases among young children in Wuhan city, China.

BACKGROUND: The high risks for childhood respiratory diseases are associated with exposure to ambient air pollution. However, there are few studies that have explored the association between air pollution exposure and respiratory diseases among young children (particularly aged 0-2 years) based on the entire population in a megalopolis. METHODS: Daily hospital admission records were obtained from 54 municipal hospitals in Wuhan city, China. We included all children (aged 0-2 years) hospitalized with respiratory diseases between January 2017 and December 2018. Individual air pollution exposure assessment was used in Land Use Regression model and inverse distance weighted. Case-crossover design and conditional logistic regression models were adopted to estimate the hospitalization risk associated with air pollutants. RESULTS: We identified 62,425 hospitalizations due to respiratory diseases, of which 36,295 were pneumonia. Particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) and nitrogen dioxide (NO2) were significantly associated with respiratory diseases and pneumonia. ORs of pneumonia were 1.0179 (95% CI 1.0097-1.0260) for PM2.5 and 1.0131 (95% CI 1.0042-1.0220) for NO2 at lag 0-7 days. Subgroup analysis suggested that NO2, Ozone (O3) and sulfur dioxide (SO2) only showed effects on pneumonia hospitalizations on male patients, but PM2.5 had effects on patients of both genders. Except O3, all pollutants were strongly associated with pneumonia in cold season. In addition, children who aged elder months and who were in central urban areas had a higher hospitalization risk. CONCLUSIONS: Air pollution is associated with higher hospitalization risk for respiratory diseases, especially pneumonia, among young children, and the risk is related to gender, month age, season and residential location.

Structural basis for conformational dynamics of GTP-bound Ras protein.

Ras family small GTPases assume two interconverting conformations, "inactive" state 1 and "active" state 2, in their GTP-bound forms. Here, to clarify the mechanism of state transition, we have carried out x-ray crystal structure analyses of a series of mutant H-Ras and M-Ras in complex with guanosine 5'-(beta,gamma-imido)triphosphate (GppNHp), representing various intermediate states of the transition. Crystallization of H-RasT35S-GppNHp enables us to solve the first complete tertiary structure of H-Ras state 1 possessing two surface pockets unseen in the state 2 or H-Ras-GDP structure. Moreover, determination of the two distinct crystal structures of H-RasT35S-GppNHp, showing prominent polysterism in the switch I and switch II regions, reveals a pivotal role of the guanine nucleotide-mediated interaction between the two switch regions and its rearrangement by a nucleotide positional change in the state 2 to state 1 transition. Furthermore, the (31)P NMR spectra and crystal structures of the GppNHp-bound forms of M-Ras mutants, carrying various H-Ras-type amino acid substitutions, also reveal the existence of a surface pocket in state 1 and support a similar mechanism based on the nucleotide-mediated interaction and its rearrangement in the state 1 to state 2 transition. Intriguingly, the conformational changes accompanying the state transition mimic those that occurred upon GDP/GTP exchange, indicating a common mechanistic basis inherent in the high flexibility of the switch regions. Collectively, these results clarify the structural features distinguishing the two states and provide new insights into the molecular basis for the state transition of Ras protein.