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Abstract Hip pain is a prevalent degenerative joint symptoms, imposing a significant global health burden. Hip pain is experiencing an increase in incidences in Korea due to its aging society, and the social burden of hip pain continues to rise as the hip joint is crucial for gait and balance. This study assessed the epidemiology of hip pain in Korea using data from the fifth version of Korea National Health and Nutrition Examination Survey (KNHANES V-5). The research analyzed data from 8,898,044 Koreans to evaluate the prevalence and characteristics of hip pain and abnormal hip X-ray. Variables encompassed medical, demographic, mental, social, and musculoskeletal factors. Descriptive analysis and propensity score matching analyses unveiled characteristics of Koreans experiencing hip pain or showing abnormal hip x-ray. The study provides insights into the epidemiology of hip pain in the entire Korean population, and further suggesting the effective management of hip pain.

The cytoplasmic FMR1-interacting protein 2 (CYFIP2) have diverse molecular functions in neurons, including the regulation of actin polymerization, mRNA translation, and mitochondrial morphology and function. Mutations in the CYFIP2 gene are associated with early-onset epilepsy and neurodevelopmental disorders, while decreases in its protein levels are linked to Alzheimer's disease (AD). Notably, previous research has revealed AD-like phenotypes, such as dendritic spine loss, in the hippocampal CA1 pyramidal neurons of 12-month-old Cyfip2 heterozygous mice but not of age-matched CA1 pyramidal neuron-specific Cyfip2 conditional knock-out (cKO) mice. This study aims to investigate whether dendritic spine loss in Cyfip2 cKO mice is merely delayed compared to Cyfip2 heterozygous mice, and to explore further neuronal phenotypes regulated by CYFIP2 in aged mice. We characterized dendrite and dendritic protrusion morphologies, along with excitatory/inhibitory synapse densities in CA1 pyramidal neurons of 17-month-old Cyfip2 cKO mice. Overall dendritic branching was normal, with a reduction in the length of basal, not apical, dendrites in CA1 pyramidal neurons of Cyfip2 cKO mice. Furthermore, while dendritic protrusion density remained normal, alterations were observed in the length of mushroom spines and the head volume of stubby spines in basal, not apical, dendrites of Cyfip2 cKO mice. Although excitatory synapse density remained unchanged, inhibitory synapse density increased in apical, not basal, dendrites of Cyfip2 cKO mice. Consequently, a cell-autonomous reduction of CYFIP2 appears insufficient to induce dendritic spine loss in CA1 pyramidal neurons of aged mice. However, CYFIP2 is required to maintain normal dendritic length, dendritic protrusion morphology, and inhibitory synapse density.

Abstract The main protease (Mpro) of SARS-CoV-2 is critical for viral function and a key drug target. Mpro is only active when reduced; turnover ceases upon oxidation but is restored by re-reduction. This suggests the system has evolved to survive periods in an oxidative environment, but the mechanism of this protection has not been confirmed. Here, we report a crystal structure of oxidized Mpro showing a disulfide bond between the active site cysteine, C145, and a distal cysteine, C117. Previous work proposed this disulfide provides the mechanism of protection from irreversible oxidation. Mpro forms an obligate homodimer, and the C117-C145 structure shows disruption of interactions bridging the dimer interface, implying a correlation between oxidation and dimerization. We confirm dimer stability is weakened in solution upon oxidation. Finally, we observe the protein’s crystallization behavior is linked to its redox state. Oxidized Mpro spontaneously forms a distinct, more loosely packed lattice. Seeding with crystals of this lattice yields a structure with an oxidation pattern incorporating one cysteine-lysine-cysteine (SONOS) and two lysine-cysteine (NOS) bridges. These structures further our understanding of the oxidative regulation of Mpro and the crystallization conditions necessary to study this structurally.

In this article, we present a comprehensive compilation of open access daily time-series datasets tailored to assess the temperature-mortality association. The data consists of daily mortality counts and average ambient temperature at various levels of geographic aggregation, including data from four cities, ten regions, and two counties, which have been utilised in previously published studies. These datasets are applicable for time-series regression analysis to estimate location-specific temperature-mortality associations. Additionally, the availability of data from multiple geographical locations enabled the exploration of geographical differences by pooling associations using meta-analysis. This compilation aims to serve as a valuable resource for researchers, educators, and students, facilitating their application of time-series regression modelling for research endeavours and training activities.

Abstract Background An accurate and easily accessible method for diagnosing malignancies in local veterinary clinics has not yet been established. Objectives To investigate the usefulness of serum thymidine kinase 1 (TK1) protein and its autoantibody as tumor biomarkers in dogs. Animals Serum samples from 1702 dogs were collected from local animal hospitals and referral animal medical centers in South Korea. Methods TK1 protein OD value and TK1 autoantibody ratio (TK1 autoantibody OD/total IgG OD) in serum samples of dogs classified into healthy controls, group with nontumor disease, group with benign and group with malignant tumors were measured using lateral flow immunochromatographic assay methods. Results TK1 autoantibody levels were significantly higher in malignant tumor group (median 0.71) than in healthy controls (median 0.34), group with nontumor disease (median 0.34), and group with benign tumor (median 0.32, Welch t test, P

Background: Temperature variability (TV) is associated with increased mortality risk. However, it is still unknown whether intra-day or inter-day TV has different effects. Objectives: We aimed to assess the association of intra-day TV and inter-day TV with all-cause, cardiovascular, and respiratory mortality. Methods: We collected data on total, cardiovascular, and respiratory mortality and meteorology from 758 locations in 47 countries or regions from 1972 to 2020. We defined inter-day TV as the standard deviation (SD) of daily mean temperatures across the lag interval, and intra-day TV as the average SD of minimum and maximum temperatures on each day. In the first stage, inter-day and intra-day TVs were modelled simultaneously in the quasi-Poisson time-series model for each location. In the second stage, a multi-level analysis was used to pool the location-specific estimates. Results: Overall, the mortality risk due to each interquartile range [IQR] increase was higher for intra-day TV than for inter-day TV. The risk increased by 0.59% (95% confidence interval [CI]: 0.53, 0.65) for all-cause mortality, 0.64% (95% CI: 0.56, 0.73) for cardiovascular mortality, and 0.65% (95% CI: 0.49, 0.80) for respiratory mortality per IQR increase in intra-day TV0–7 (0.9 °C). An IQR increase in inter-day TV0–7 (1.6 °C) was associated with 0.22% (95% CI: 0.18, 0.26) increase in all-cause mortality, 0.44% (95% CI: 0.37, 0.50) increase in cardiovascular mortality, and 0.31% (95% CI: 0.21, 0.41) increase in respiratory mortality. The proportion of all-cause deaths attributable to intra-day TV0–7 and inter-day TV0–7 was 1.45% and 0.35%, respectively. The mortality risks varied by lag interval, climate area, season, and climate type. Conclusions: Our results indicated that intra-day TV may explain the main part of the mortality risk related to TV and suggested that comprehensive evaluations should be proposed in more countries to help protect human health.

Assessing the association between temperature frequency and mortality can provide insights into human adaptation to local ambient temperatures. We collected daily time-series data on mortality and temperature from 757 locations in 47 countries/regions during 1979–2020. We used a two-stage time series design to assess the association between temperature frequency and all-cause mortality. The results were pooled at the national, regional, and global levels. We observed a consistent decrease in the risk of mortality as the normalized frequency of temperature increases across the globe. The average increase in mortality risk comparing the 10th to 100th percentile of normalized frequency was 13.03% (95% CI: 12.17–13.91), with substantial regional differences (from 4.56% in Australia and New Zealand to 33.06% in South Europe). The highest increase in mortality was observed for high-income countries (13.58%, 95% CI: 12.56–14.61), followed by lower-middle-income countries (12.34%, 95% CI: 9.27–15.51). This study observed a declining risk of mortality associated with higher temperature frequency. Our findings suggest that populations can adapt to their local climate with frequent exposure, with the adapting ability varying geographically due to differences in climatic and socioeconomic characteristics.

Abstract Climatic factors influence malaria transmission via the effect on the Anopheles vector and Plasmodium parasite. Modelling and understanding the complex effects that climate has on malaria incidence can enable important early warning capabilities. Deep learning applications across fields are proving valuable, however the field of epidemiological forecasting is still in its infancy with a lack of applied deep learning studies for malaria in southern Africa which leverage quality datasets. Using a novel high resolution malaria incidence dataset containing 23 years of daily data from 1998 to 2021, a statistical model and XGBOOST machine learning model were compared to a deep learning Transformer model by assessing the accuracy of their numerical predictions. A novel loss function, used to account for the variable nature of the data yielded performance around + 20% compared to the standard MSE loss. When numerical predictions were converted to alert thresholds to mimic use in a real-world setting, the Transformer’s performance of 80% according to AUROC was 20–40% higher than the statistical and XGBOOST models and it had the highest overall accuracy of 98%. The Transformer performed consistently with increased accuracy as more climate variables were used, indicating further potential for this prediction framework to predict malaria incidence at a daily level using climate data for southern Africa.

ABSTRACTCytoplasmic FMR1-interacting protein 2 (CYFIP2) is an evolutionarily conserved multifunctional protein that regulates the neuronal actin cytoskeleton, mRNA translation and transport, and mitochondrial morphology and function. Supporting its critical roles in proper neuronal development and function, human genetic studies have repeatedly identified variants of the CYFIP2 gene in individuals diagnosed with neurodevelopmental disorders. Notably, a few recent studies have also suggested a mechanistic link between reduced CYFIP2 level and Alzheimer's disease (AD). Specifically, in the hippocampus of 12-month-old Cyfip2 heterozygous mice, several AD-like pathologies were identified, including increased levels of Tau phosphorylation and gliosis, and loss of dendritic spines in CA1 pyramidal neurons. However, detailed pathogenic mechanisms, such as cell types and their circuits where the pathologies originate, remain unknown for AD-like pathologies caused by CYFIP2 reduction. In this study, we aimed to address this issue by examining whether the cell-autonomous reduction of CYFIP2 in CA1 excitatory pyramidal neurons is sufficient to induce AD-like phenotypes in the hippocampus. We performed immunohistochemical, morphological, and biochemical analyses in 12-month-old Cyfip2 conditional knock-out mice, which have postnatally reduced CYFIP2 expression level in CA1, but not in CA3, excitatory pyramidal neurons of the hippocampus. Unexpectedly, we could not find any significant AD-like phenotype, suggesting that the CA1 excitatory neuron-specific reduction of CYFIP2 level is insufficient to lead to AD-like pathologies in the hippocampus. Therefore, we propose that CYFIP2 reduction in other neurons and/or their synaptic connections with CA1 pyramidal neurons may be critically involved in the hippocampal AD-like phenotypes of Cyfip2 heterozygous mice.

Abstract Background Dengue fever is a vector-borne disease of global public health concern, with an increasing number of cases and a widening area of endemicity in recent years. Meteorological factors influence dengue transmission. This study aimed to estimate the association between meteorological factors (i.e., temperature and rainfall) and dengue incidence and the effect of altitude on this association in the Lao People’s Democratic Republic (Lao PDR). Methods We used weekly dengue incidence and meteorological data, including temperature and rainfall, from 18 jurisdictions in Lao PDR from 2015 to 2019. A two-stage distributed lag nonlinear model with a quasi-Poisson distribution was used to account for the nonlinear and delayed associations between dengue incidence and meteorological variables, adjusting for long-term time trends and autocorrelation. Results A total of 55,561 cases were reported in Lao PDR from 2015 to 2019. The cumulative relative risk for the 90th percentile of weekly mean temperature (29 °C) over 22 weeks was estimated at 4.21 (95% confidence interval: 2.00–8.84), relative to the 25th percentile (24 °C). The cumulative relative risk for the weekly total rainfall over 12 weeks peaked at 82 mm (relative risk = 1.76, 95% confidence interval: 0.91–3.40) relative to no rain. However, the risk decreased significantly when heavy rain exceeded 200 mm. We found no evidence that altitude modified these associations. Conclusions We found a lagged nonlinear relationship between meteorological factors and dengue incidence in Lao PDR. These findings can be used to develop climate-based early warning systems and provide insights for improving vector control in the country.

Abstract Free-electron lasers (FEL) are revolutionizing X-ray-based structural biology methods. While protein crystallography is already routinely performed at FELs, Small Angle X-ray Scattering (SAXS) studies of biological macromolecules are not as prevalent. SAXS allows the study of the shape and overall structure of proteins and nucleic acids in solution, in a quasi-native environment. In solution, chemical and biophysical parameters that have an influence on the structure and dynamics of molecules can be varied and their effect on conformational changes can be monitored in time-resolved XFEL and SAXS experiments. We report here the collection of scattering form factors of proteins in solution using FEL X-rays. The form factors correspond to the scattering signal of the protein ensemble alone; the scattering contributions from the solvent and the instrument are separately measured and accurately subtracted. The experiment was done using a liquid jet for sample delivery. These results pave the way for time-resolved studies and measurements from dilute samples, capitalizing on the intense and short FEL X-ray pulses.

Background: Recent studies have reported that air pollution is related to kidney diseases. However, the global evidence on the risk of death from acute kidney injury (AKI) owing to air pollution is limited. Therefore, we investigated the association between short-term exposure to air pollution—particulate matter ≤ 2.5 μm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)—and AKI-related mortality using a multi-country dataset. Methods: This study included 41,379 AKI-related deaths in 136 locations in six countries during 1987–2018. A novel case time-series design was applied to each air pollutant during 0–28 lag days to estimate the association between air pollution and AKI-related deaths. Moreover, we calculated AKI deaths attributable to non-compliance with the World Health Organization (WHO) air quality guidelines. Results: The relative risks (95% confidence interval) of AKI-related deaths are 1.052 (1.003, 1.103), 1.022 (0.994, 1.050), and 1.022 (0.982, 1.063) for 5, 10, and 10 µg/m3 increase in lag 0–28 days of PM2.5, warm-season O3, and NO2, respectively. The lag-distributed association showed that the risk appeared immediately on the day of exposure to air pollution, gradually decreased, and then increased again reaching the peak approximately 20 days after exposure to PM2.5 and O3. We also found that 1.9%, 6.3%, and 5.2% of AKI deaths were attributed to PM2.5, warm-season O3, and NO2 concentrations above the WHO guidelines. Conclusions: This study provides evidence that public health policies to reduce air pollution may alleviate the burden of death from AKI and suggests the need to investigate the several pathways between air pollution and AKI death.

Abstract Methylation patterns in cell-free DNA (cfDNA) have emerged as a promising genomic feature for detecting the presence of cancer and determining its origin. The purpose of this study was to evaluate the diagnostic performance of methylation-sensitive restriction enzyme digestion followed by sequencing (MRE-Seq) using cfDNA, and to investigate the cancer signal origin (CSO) of the cancer using a deep neural network (DNN) analyses for liquid biopsy of colorectal and lung cancer. We developed a selective MRE-Seq method with DNN learning-based prediction model using demethylated-sequence-depth patterns from 63,266 CpG sites using SacII enzyme digestion. A total of 191 patients with stage I–IV cancers (95 lung cancers and 96 colorectal cancers) and 126 noncancer participants were enrolled in this study. Our study showed an area under the receiver operating characteristic curve (AUC) of 0.978 with a sensitivity of 78.1% for colorectal cancer, and an AUC of 0.956 with a sensitivity of 66.3% for lung cancer, both at a specificity of 99.2%. For colorectal cancer, sensitivities for stages I–IV ranged from 76.2 to 83.3% while for lung cancer, sensitivities for stages I–IV ranged from 44.4 to 78.9%, both again at a specificity of 99.2%. The CSO model's true-positive rates were 94.4% and 89.9% for colorectal and lung cancers, respectively. The MRE-Seq was found to be a useful method for detecting global hypomethylation patterns in liquid biopsy samples and accurately diagnosing colorectal and lung cancers, as well as determining CSO of the cancer using DNN analysis. Trial registration: This trial was registered at ClinicalTrials.gov (registration number: NCT 04253509) for lung cancer on 5 February 2020, https://clinicaltrials.gov/ct2/show/NCT04253509 . Colorectal cancer samples were retrospectively registered at CRIS (Clinical Research Information Service, registration number: KCT0008037) on 23 December 2022, https://cris.nih.go.kr , https://who.init/ictrp . Healthy control samples were retrospectively registered.

Background Deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) are major complications of spinal cord disease. However, studies of their incidence in Korean patients are limited. Thus, this study investigated the incidence and risk factors of DVT and PTE in Korean patients with spinal cord disease. Methods We retrospectively analyzed the medical records of 271 patients with spinal cord disease who were admitted to a rehabilitation unit within 3 months of disease onset at a tertiary hospital. The presence of DVT and PTE was mainly determined using Doppler ultrasonography and chest embolism computed tomography. Risk factor analysis included variables such as sex, age, obesity, completeness of motor paralysis, neurological level of injury, cause of injury, lower extremity fracture, active cancer, and functional ambulation category (FAC) score. Results The incidences of DVT and PTE in the patients with spinal cord disease were both 6.3%. Risk factor analysis revealed that age of ≥65 years (p=0.031) and FAC score of ≤1 (p=0.023) were significantly associated with DVT development. Traumatic cause of injury (p=0.028) and DVT (p

Background: Air conditioning (AC) presents a viable means of tackling the ill-effects of heat on human health. However, AC releases additional anthropogenic heat outdoors, and this could be detrimental to human health, especially in urban communities. This study determined the excess heat-related mortality attributable to anthropogenic heat from AC use under various projected global warming scenarios in seven Japanese cities. The overall protection from AC use was also measured. Methods: Daily average 2-meter temperatures in the hottest month of August from 2000 to 2010 were modeled using the Weather Research and Forecasting (WRF) model with BEP+BEM (building effect parameterization and building energy model). Risk functions for heat–mortality associations were generated with and without AC use from a two-stage time series analysis. We coupled simulated August temperatures and heat–mortality risk functions to estimate averted deaths and unavoidable deaths from AC use. Results: Anthropogenic heat from AC use slightly augmented the daily urban temperatures by 0.046 °C in Augusts of 2000–2010 and up to 0.181 °C in a future with 3 °C urban warming. This temperature rise was attributable to 3.1–3.5 % of heat-related deaths in Augusts of 2000–2010 under various urban warming scenarios. About 36–47 % of heat-related deaths could be averted by air conditioning use under various urban warming scenarios. Discussion: AC has a valuable protective effect from heat despite some unavoidable mortality from anthropogenic heat release. Overall, the use of AC as a major adaptive strategy requires careful consideration.

The diversity of workloads drives studies to use GPU more effectively to overcome the limited memory of GPUs. Precisely, it is essential to understand and utilize data locality of workloads to utilize the memory and cache efficiently, which is relatively smaller than CPU ’ s. It is important to understand GPU memory hierarchy to efficiently use with multi-thread environment. Although there have been previous approaches to analyzing data locality on GPUs, these approaches focused on global memory and L2 cache levels with profiling at thread block levels. Data locality study in warp level in GPU has not been studied much. Especially, the concept of coalescing has been defined but the method of measuring the degree of coalescing has not been discussed. Our study focused on analyzing data locality in L1 cache levels, which is the smallest but fastest in cache level to analyze the impact of data locality. To achieve this analysis, our study profiles data locality in warp level, which is smallest segment in GPU thread groups. This paper introduces a novel perspective by introducing a quantitative measure for coalescing alongside static profiling of data locality. Furthermore, it offers a means of refining locality estimates by scrutinizing access patterns of L1 cache. To substantiate our approach, our study validates the estimated data locality against a range of real-world GPU benchmarks, including Rodina and Polybench. Through empirical experimentation, our results reveal a substantial correlation between the metrics of data locality and cache utilization, affirming the efficacy of our proposed method.

Background . Previous studies suggest that temperature may trigger suicide, with higher ambient temperatures associated with increased risk globally. However, quantification of the attributable suicide burden due to non-optimal temperatures, particularly across specific subgroups like sex, age, and method of suicide, is limited. This study aimed to quantify this attributable burden across Japan and assess variations in these subgroups to enhance understanding and identify high-risk populations. Methods . Data on daily suicide counts and mean temperatures were collected for all 47 prefectures in Japan (1973–2015) for a comprehensive, nationally representative analysis. Using time-stratified case-crossover analyses and a distributed lag non-linear model (DLNM), we estimated temperature-suicide associations, accounting for long-term trends, seasonality, and day-of-the-week effects, and capturing both nonlinear and delayed impacts of temperature. Overall attributable fractions and fractions attributable to cold (0th-10th percentile), cool (10th-50th), warm (50th-90th), and hot (90th-100th) temperatures were computed. Subgroup analyses were conducted by sex, age (0 – 64 years and ≥65 years), and method of suicide (violent or nonviolent). Results . Approximately 19.9% of suicides (95% empirical confidence interval (eCI): 18.8, 20.9) could be attributed to non-optimal temperatures, representing the proportion of cases that would not have occurred under optimal temperature conditions, identified at the temperature corresponding to the minimum risk of suicide. The highest fraction (9.9%, 95% eCI: 9.4, 10.4) was observed for warm temperatures (50th-90th percentile). Higher burdens were observed in females (23.7%), individuals aged ≥65 years (31.9%), and violent suicides (22.4%). Conclusions . Nearly 20% of suicides in Japan are associated with non-optimal temperatures, particularly during warmer conditions. These findings highlight the importance of integrating temperature considerations into suicide prevention strategies, particularly for vulnerable populations such as the elderly. While focused on Japan, these results advocate future research to explore similar burdens globally, enhancing our understanding of environmental impacts on suicide and informing targeted public health interventions.

Suicide, a leading cause of death among the youth, has shown a positive association with high temperatures. However, few studies have explored the association between tropical nights and suicide and the potential role of greenness on this association. We investigated the association between suicide and two hot night indices: hot night duration (HNd) and hot night excess (HNe), representing heat duration and excess heat during night-time. We also explored whether the association was modified by urban greenspace, measured by satellite-derived normalized difference vegetation index (NDVI), across 25 districts in Seoul, South Korea from 2000 to 2020. Based on the multi-district daily time-series data, we performed a space-time-stratified case-crossover analysis with a distributed lag linear model with lags of up to 7 d for HNd and HNe, adjusting for daily mean temperature and relative humidity. We added an interaction term between the hot night index and NDVI to assess the effect modification of greenness. In total, 14 693 suicides were included in this study. The relative risk (RR) of suicide per a 10% increase in HNd was 1.059 (95% CI: 1.017–1.103) in low NDVI areas and 1.031 (95% CI: 0.988–1.075) in high NDVI areas. The RR per a 1 °C increase in HNe was 1.011 (95% CI: 0.998–1.024) and 1.005 (95% CI: 0.992–1.018) in low and high NDVI areas, respectively. Greenspaces have expanded over time in all districts of Seoul, and the risk of suicide for night-time heat decreased over time in both low and high NDVI areas. Our findings suggest that exposure to night-time heat is associated with an increased risk of suicide, but this risk may be mitigated by greater greenspaces in urban areas. Prioritizing development and maintenance of urban greenspaces will be a critical co-benefit strategy for promoting public mental health in changing climates.

Pump–probe experiments at X-ray free-electron laser (XFEL) facilities are a powerful tool for studying dynamics at ultrafast and longer timescales. Observing the dynamics in diverse scientific cases requires optical laser systems with a wide range of wavelength, flexible pulse sequences and different pulse durations, especially in the pump source. Here, the pump–probe instrumentation available for measurements at the Single Particles, Clusters, and Biomolecules and Serial Femtosecond Crystallography (SPB/SFX) instrument of the European XFEL is reported. The temporal and spatial stability of this instrumentation is also presented.

Free-electron lasers are capable of high repetition rates and it is assumed that protein crystals often do not survive the first X-ray pulse. Here the authors address these issues with a demonstration of multi-hit serial crystallography in which multiple FEL pulses interact with the sample without destroying it.

Shank3 is a member of the Shank family proteins (Shank1–3), which are abundantly present in the postsynaptic density (PSD) of neuronal excitatory synapses. As a core scaffold in the PSD, Shank3 plays a critical role in organizing the macromolecular complex, ensuring proper synaptic development and function. Clinically, various mutations of the SHANK3 gene are causally associated with brain disorders such as autism spectrum disorders and schizophrenia. However, recent in vitro and in vivo functional studies and expression profiling in various tissues and cell types suggest that Shank3 also plays a role in cardiac function and dysfunction. For example, Shank3 interacts with phospholipase Cβ1b (PLCβ1b) in cardiomyocytes, regulating its localization to the sarcolemma and its role in mediating Gq-induced signaling. In addition, changes in cardiac morphology and function associated with myocardial infarction and aging have been investigated in a few Shank3 mutant mouse models. This review highlights these results and potential underlying mechanisms, and predicts additional molecular functions of Shank3 based on its protein interactors in the PSD, which are also highly expressed and function in the heart. Finally, we provide perspectives and possible directions for future studies to better understand the roles of Shank3 in the heart.

Copy number variation (CNV) is a primary source of structural variation in the human genome, leading to several disorders. Therefore, analyzing neonatal CNVs is crucial for managing CNV-related chromosomal disabilities. However, genomic waves can hinder accurate CNV analysis. To mitigate the influences of the waves, we adopted a machine learning approach and developed a new method that uses a modified log R ratio instead of the commonly used log R ratio. Validation results using samples with known CNVs demonstrated the superior performance of our method. We analyzed a total of 16,046 Korean newborn samples using the new method and identified CNVs related to 39 genetic disorders were identified in 342 cases. The most frequently detected CNV-related disorder was Joubert syndrome 4. The accuracy of our method was further confirmed by analyzing a subset of the detected results using NGS and comparing them with our results. The utilization of a genome-wide single nucleotide polymorphism array with wave offset was shown to be a powerful method for identifying CNVs in neonatal cases. The accurate screening and the ability to identify various disease susceptibilities offered by our new method could facilitate the identification of CNV-associated chromosomal disease etiologies.

Measurement(s) lysozyme measurement Technology Type(s) X-ray crystallography

Abstract Background The recently developed Screening Tool of Older Persons' Prescriptions in Frail adults with a limited life expectancy (STOPPFrail) criteria can be helpful for screening medications (PIMs), but it is yet to be widely used in clinical practice. Herein, we aimed to investigate the prevalence of PIMs based on the STOPPFrail criteria (STOPPFrail-PIM) among frail older adults with limited life expectancy admitted to the geriatric center. Methods This was a retrospective cross-sectional study conducted in the geriatric center at an academic tertiary care hospital in Korea. We evaluated frail older adults with limited life expectancy who received comprehensive geriatric assessment (CGA) admitted between 1 January, 2019 and 30 June, 2020. Frail older adults with limited life expectancy were identified by geriatricians with retrospective records and the prevalence of STOPPFrail-PIMs was analysed by trained pharmacists. Descriptive analysis, t-test, and chi-square test were conducted using IBM SPSS software version 25.0. Results Among 504 older adults who underwent CGA after admission, 171 frail older adults with limited life expectancy were identified by geriatricians and included in the study. An average of 11.3 ± 4.7 medications were administered regularly to each patient before admission. Overall, 97.1% (166/171) had at least one STOPPFrail-PIM, and the mean number of STOPPFrail-PIM was 4.2 ± 2.8. Drugs without clear clinical indication (A2) were the most frequent pre-admission STOPPFrail-PIM, followed by lipid-lowering therapies (B1) and neuroleptic antipsychotics (D1). The number of STOPPFrail-PIM was significantly lower at discharge than that at admission, with the decrease being the highest for A2 at 94.7%. Conclusions Most frail older adults with limited life expectancy had at least one STOPPFrail-PIM at admission, and the rate of STOPPFrail-PIM decreased significantly at discharge after the geriatric multidisciplinary team care. Further studies are needed to investigate the association between the use of STOPPFrail-PIM and adverse consequences in frail older adults.

BackgroundMalnutrition is prevalent among hospitalized older patients. Therefore, this study aimed to investigate the association between nutritional status [assessed using the Mini Nutritional Assessment (MNA) and serum albumin levels] and adverse outcomes in hospitalized older patients. We also aimed to compare the predictive utility of our findings.MethodsThis retrospective cohort study was conducted between January 2016 and June 2020. In total, 808 older patients (aged ≥ 65 years, mean age 82.8 ± 6.70 years, 45.9% male) admitted to the acute geriatric unit were included in our sample. Comprehensive geriatric assessments, including the MNA, were performed. Malnutrition and risk of malnutrition were defined as MNA < 17, albumin < 3.5 g/dL and 17 ≤ MNA ≤ 24, 3.5 g/dL ≤ albumin < 3.9 g/dL, respectively. The primary outcome was that patients could not be discharged to their own homes. The secondary outcomes were overall all-cause mortality, 3-month all-cause mortality, and incidence of geriatric syndrome, including delirium, falls, and newly developed or worsening pressure sores during hospitalization.ResultsPoor nutritional status was associated with older age; female sex; admission from the emergency room; high risk of pressure sores and falls; lower physical and cognitive function; higher depressive score; and lower serum albumin, protein, cholesterol, and hemoglobin levels. In the fully adjusted model, malnutrition assessed using the MNA predicted discharge to nursing homes or long-term care hospitals [odds ratio (OR) 5.822, 95% confidence interval (CI): 2.092–16.199, P = 0.001], geriatric syndrome (OR 2.069, 95% CI: 1.007–4.249, P = 0.048), and 3-month mortality (OR 3.519, 95% CI: 1.254–9.872, P = 0.017). However, malnutrition assessed using albumin levels could only predict 3-month mortality (OR 3.848, 95% CI: 1.465–10.105, P = 0.006). The MNA predicted 3-month mortality with higher precision than serum albumin levels (P = 0.034) when comparing the areas under the receiver operating characteristic curve.ConclusionNutritional risk measured by the MNA was an independent predictor of various negative outcomes in hospitalized older patients. Poor nutritional status assessed by serum albumin levels, the most widely used biochemical marker, could predict mortality, but not the development of geriatric syndrome or discharge location reflecting functional status.

One of the outstanding analytical problems in X-ray single-particle imaging (SPI) is the classification of structural heterogeneity, which is especially difficult given the low signal-to-noise ratios of individual patterns and the fact that even identical objects can yield patterns that vary greatly when orientation is taken into consideration. Proposed here are two methods which explicitly account for this orientation-induced variation and can robustly determine the structural landscape of a sample ensemble. The first, termed common-line principal component analysis (PCA), provides a rough classification which is essentially parameter free and can be run automatically on any SPI dataset. The second method, utilizing variation auto-encoders (VAEs), can generate 3D structures of the objects at any point in the structural landscape. Both these methods are implemented in combination with the noise-tolerant expand–maximize–compress (EMC) algorithm and its utility is demonstrated by applying it to an experimental dataset from gold nanoparticles with only a few thousand photons per pattern. Both discrete structural classes and continuous deformations are recovered. These developments diverge from previous approaches of extracting reproducible subsets of patterns from a dataset and open up the possibility of moving beyond the study of homogeneous sample sets to addressing open questions on topics such as nanocrystal growth and dynamics, as well as phase transitions which have not been externally triggered.

The Sample Environment and Characterization (SEC) group of the European X-ray Free-Electron Laser (EuXFEL) develops sample delivery systems for the various scientific instruments, including systems for the injection of liquid samples that enable serial femtosecond X-ray crystallography (SFX) and single-particle imaging (SPI) experiments, among others. For rapid prototyping of various device types and materials, sub-micrometre precision 3D printers are used to address the specific experimental conditions of SFX and SPI by providing a large number of devices with reliable performance. This work presents the current pool of 3D printed liquid sample delivery devices, based on the two-photon polymerization (2PP) technique. These devices encompass gas dynamic virtual nozzles (GDVNs), mixing-GDVNs, high-viscosity extruders (HVEs) and electrospray conical capillary tips (CCTs) with highly reproducible geometric features that are suitable for time-resolved SFX and SPI experiments at XFEL facilities. Liquid sample injection setups and infrastructure on the Single Particles, Clusters, and Biomolecules and Serial Femtosecond Crystallography (SPB/SFX) instrument are described, this being the instrument which is designated for biological structure determination at the EuXFEL.

Highlights Using the satellite-detected tropospheric NO2 concentrations, we observed an association between individual exposure to NO2 and symptoms of Acute Respiratory Infections (ARIs) among children under 5 years old in Senegal. This is the first population-based epidemiological study conducted in Senegal that investigated the adverse health effect of early childhood exposure to ambient concentrations of NO2 on ARIs in children.

Abstract Background The differential effects of PM2.5 fractions on children’s lung function remain inconclusive. This study aimed to examine whether lung function in asthmatic children was associated with increased PM2.5 fractions in urban areas in Nagasaki prefecture, Japan, where the air pollution level is relatively low but influenced by transboundary air pollution. Methods We conducted a multiyear panel study of 73 asthmatic children (boys, 60.3%; mean age, 8.2 years) spanning spring 2014–2016 in two cities. We collected self-measured peak expiratory flow (PEF) twice a day and daily time-series data for PM2.5 total mass and its chemical species. We fitted a linear mixed effects model to examine short-term associations between PEF and PM2.5, adjusting for individual and time-varying confounders. A generalized linear mixed effects model was also used to estimate the association for worsening asthma defined by severe PEF decline. Back-trajectory and cluster analyses were used to investigate the long-range transboundary PM2.5 in the study areas. Results We found that morning PEFs were adversely associated with higher levels of sulfate (− 1.61 L/min; 95% CI: − 3.07, − 0.15) in Nagasaki city and organic carbon (OC) (− 1.02 L/min; 95% CI: − 1.94, − 0.09) in Isahaya city, per interquartile range (IQR) increase at lag1. In addition, we observed consistent findings for worsening asthma, with higher odds of severe PEF decline in the morning for sulfate (odds ratio (OR) = 2.31; 95% CI: 1.12, 4.77) and ammonium (OR = 1.73; 95% CI: 1.06, 2.84) in Nagasaki city and OC (OR = 1.51; 95% CI: 1.06, 2.15) in Isahaya city, per IQR increase at lag1. The significant chemical species were higher on days that could be largely attributed to the path of Northeast China origin (for sulfate and ammonium) or both the same path and local sources (for OC) than by other clusters. Conclusions This study provides evidence of the differential effects of PM2.5 fractions on lung function among asthmatic children in urban areas, where the Japanese national standards of air quality have been nearly met. Continuous efforts to promote mitigation actions and public awareness of hazardous transboundary air pollution are needed to protect susceptible children with asthma.

Many soft-matter systems are composed of macromolecules or nanoparticles suspended in water. The characteristic times at intrinsic length scales of a few nanometres fall therefore in the microsecond and sub-microsecond time regimes. With the development of free-electron lasers (FELs) and fourth-generation synchrotron light-sources, time-resolved experiments in such time and length ranges will become routinely accessible in the near future. In the present work we report our findings on prototypical soft-matter systems, composed of charge-stabilized silica nanoparticles dispersed in water, with radii between 12 and 15 nm and volume fractions between 0.005 and 0.2. The sample dynamics were probed by means of X-ray photon correlation spectroscopy, employing the megahertz pulse repetition rate of the European XFEL and the Adaptive Gain Integrating Pixel Detector. We show that it is possible to correctly identify the dynamical properties that determine the diffusion constant, both for stationary samples and for systems driven by XFEL pulses. Remarkably, despite the high photon density the only observable induced effect is the heating of the scattering volume, meaning that all other X-ray induced effects do not influence the structure and the dynamics on the probed timescales. This work also illustrates the potential to control such induced heating and it can be predicted with thermodynamic models.

Prion diseases are fatal infectious diseases caused by conformational changes of a prion protein (PrPSc) derived from a normal prion protein (PrPC). Prion diseases have been reported in several mammalian hosts but not in any birds, including the most popular poultry species, of which chickens showed some resistance to experimental prion infection. To identify the genetic polymorphisms in the quail prion protein gene (PRNP), polymerase chain reaction and DNA sequencing were performed with gene-specific primers in 164 quails. Four in silico programs, including PROVEAN, PANTHER, SIFT, and AMYCO, were used to investigate the effect of non-synonymous single nucleotide polymorphisms (SNPs) on quail PrP. Furthermore, to investigate the genetic relationship of avian PrPs, phylogenetic analysis and multiple sequence alignments were performed using MEGA X program. Finally, the secondary and tertiary structures of avian PrPs were analyzed by SWISS-MODEL. We identified 33 novel SNPs in the quail PRNP gene, including three non-synonymous SNPs, c.56C>T (T19I), c.60C>T (V21I), and c.61G>A (A22S). Although V21I was predicted to have deleterious effects by SIFT, the substitutions of all three amino acids did not affect the amyloid propensity, 3D structure, or hydrogen bonds of quail PrP. Quail PrP showed a close evolutionary relationship and similar secondary and tertiary structures to chicken PrP compared to duck PrP. To our knowledge, this is the first report on the genetic and structural properties of the quail PRNP gene.

Abstract Photochemical thrombosis is a method for the induction of ischemic stroke in the cerebral cortex. It can generate localized ischemic infarcts in the desired region; therefore, it has been actively employed in establishing an ischemic stroke animal model and in vivo assays of diagnostic and therapeutic techniques for stroke. To establish a rabbit ischemic stroke model and overcome the shortcoming of previous studies that were difficult to build a standardized photothrombotic rabbit model, we developed a photochemical thrombosis induction system that can produce consistent brain damage on a specific area. To verify the generation of photothrombotic brain damage using the system, longitudinal magnetic resonance imaging, 2,3,5-triphenyltetrazolium chloride staining, and histological staining were applied. These analytical methods have a high correlation for ischemic infarction and are appropriate for analyzing photothrombotic brain damage in the rabbit brain. The results indicated that the photothrombosis induction system has a main advantage of being accurately controlled a targeted region of photothrombosis and can produce cerebral hemisphere lesions on the target region of the rabbit brain. In conjugation with brain atlas, it can induce photochemical ischemic stroke locally in the part of the brain that is responsible for a particular brain function and the system can be used to develop animal models with degraded specific functions. Also, the photochemical thrombosis induction system and a standardized rabbit ischemic stroke model that uses this system have the potential to be used for verifications of biomedical techniques for ischemic stroke at a preclinical stage in parallel with further performance improvements.

Abstract The SH3 and multiple ankyrin repeat domains 3 (Shank3) protein is a core organizer of the macromolecular complex in excitatory postsynapses, and its defects cause numerous synaptopathies, including autism spectrum disorders. Although the function of Shank3 as a postsynaptic scaffold is adequately established, other potential mechanisms through which Shank3 broadly modulates the postsynaptic proteome remain relatively unexplored. In our previous quantitative proteomic analysis, six up-regulated ribosomal proteins were identified in the striatal synaptosome of Shank3-overexpressing transgenic (TG) mice. In the present study, we validated the increased levels of RPLP1 and RPL36A in synaptosome, but not in whole lysate, of the TG striatum. Moreover, protein synthesis and extracellular signaling-regulated kinase (ERK) activity were enhanced in the TG striatal synaptosome. To understand the potential contribution of increased protein synthesis to the proteomic change in the TG striatal synaptosome, we performed RNA-sequencing analyses on both whole synaptosomal and synaptic polysome-enriched fractions. Comparative analyses showed a positive correlation only between the polysome-associated transcriptome and up-regulated proteome in the TG striatal synaptosome. Our findings suggest a novel mechanism through which Shank3 may remodel the postsynaptic proteome by regulating synaptic protein synthesis, whose dysfunction can be implicated in SHANK3-associated synaptopathies.

Due to the pulsed nature of X-ray free electron laser (XFEL) instruments the majority of protein crystals, which are injected using continuous jet injection techniques are wasted. Here, the authors present a microfluidic device to deliver aqueous protein crystal laden droplets segmented with an immiscible oil and demonstrate that with this device an approx. 60% reduction in sample waste was achieved for data collection of 3-deoxy-D-manno-octulosonate 8-phosphate synthase crystals at the EuXFEL.

Abstract Variants of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are associated with numerous neurodevelopmental and neuropsychiatric disorders. According to several studies, CYFIP1 regulates the development and function of both pre- and post-synapses in neurons. Furthermore, various studies have evaluated CYFIP2 functions in the postsynaptic compartment, such as regulating dendritic spine morphology; however, no study has evaluated whether and how CYFIP2 affects presynaptic functions. To address this issue, in this study, we have focused on the presynapses of layer 5 neurons of the medial prefrontal cortex (mPFC) in adult Cyfip2 heterozygous (Cyfip2 +/− ) mice. Electrophysiological analyses revealed an enhancement in the presynaptic short-term plasticity induced by high-frequency stimuli in Cyfip2 +/− neurons compared with wild-type neurons. Since presynaptic mitochondria play an important role in buffering presynaptic Ca2+, which is directly associated with the short-term plasticity, we analyzed presynaptic mitochondria using electron microscopic images of the mPFC. Compared with wild-type mice, the number, but not the volume or cristae density, of mitochondria in both presynaptic boutons and axonal processes in the mPFC layer 5 of Cyfip2 +/− mice was reduced. Consistent with an identification of mitochondrial proteins in a previously established CYFIP2 interactome, CYFIP2 was detected in a biochemically enriched mitochondrial fraction of the mouse mPFC. Collectively, these results suggest roles for CYFIP2 in regulating presynaptic functions, which may involve presynaptic mitochondrial changes.

The European X-ray free-electron laser (EuXFEL) in Hamburg is the first XFEL with a megahertz repetition rate. Here the authors present the 2.9 Å structure of the large membrane protein complex Photosystem I from T. elongatus that was determined at the EuXFEL.

Recently, research has been conducted to assist in the processing and analysis of histopathological images using machine learning algorithms. In this study, we established machine learning-based algorithms to detect photothrombotic lesions in histological images of photothrombosis-induced rabbit brains. Six machine learning-based algorithms for binary classification were applied, and the accuracies were compared to classify normal tissues and photothrombotic lesions. The lesion classification model consisting of a 3-layered neural network with a rectified linear unit (ReLU) activation function, Xavier initialization, and Adam optimization using datasets with a unit size of 128×128 pixels yielded the highest accuracy (0.975). In the validation using the tested histological images, it was confirmed that the model could identify regions where brain damage occurred due to photochemical ischemic stroke. Through the development of machine learning-based photothrombotic lesion classification models and performance comparisons, we confirmed that machine learning algorithms have the potential to be utilized in histopathology and various medical diagnostic techniques.

Background: Previous studies have reported that high ambient temperature is associated with increased risk of suicide; however, the association has not been extensively investigated with drug overdose which is the most common method of unsuccessful suicidal behavior in Japan. Therefore, this study aims to examine the short-term association between daily mean temperature and the incidence of self-harm attempts by drug overdose in Tokyo, Japan. Methods: We collected the emergency ambulance dispatch data and daily meteorological data in Tokyo from 2010 to 2014. A quasi-Poisson regression model incorporating a distributed lag non-linear function was applied to estimate the non-linear and delayed association between temperature and drug overdose, adjusting for relative humidity, seasonal and long-term trends, and days of the week. Sex, age and location-specific associations of ambient temperature with drug overdose was also estimated. Results: 12,937 drug overdose cases were recorded during the study period, 73.9% of which were female. We observed a non-linear association between temperature and drug overdose, with the highest risk observed at 21 °C. The highest relative risk (RR) was 1.30 (95% Confidence Interval (CI): 1.10–1.67) compared with the risk at the first percentile of daily mean temperature (2.9 °C) over 0–4 days lag period. In subgroup analyses, the RR of a drug overdose at 21 °C was 1.36 (95% CI: 1.02–1.81) for females and 1.07 (95% CI: 0.66–1.75) for males. Also, we observed that the risk was highest among those aged ≥65 years (RR = 2.54; 95% CI: 0.94–6.90), followed by those aged 15–34 years (RR = 1.25; 95% CI: 0.89–1.77) and those aged 35–64 years (RR = 1.15; 95% CI: 0.78–1.68). There was no evidence for the difference in RRs between urban (23 special wards) and sub-urban areas in Tokyo. Conclusions: An increase in daily mean temperature was associated with increased drug overdose risk. This study indicated the positive non-linear association between temperature and incomplete attempts by drug overdose. The findings of this study may add further evidence of the association of temperature on suicidal behavior and suggests increasing more research and investigation of other modifying factors.

Both deletions and duplications of the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene, encoding excitatory postsynaptic scaffolds, are causally associated with various brain disorders, suggesting that proper Shank3 dosage is critical for normal brain development and function. In addition to its well-established synaptic functions, recent studies have suggested that Shank3 can also affect gene expression in the nucleus. However, it has not been investigated whether there are a group of genes whose directional expression is regulated in a Shank3 dosage-dependent manner (i.e. showing opposite changes in expression following Shank3 reduction and overexpression). This is an important issue to be examined for better understanding why neuronal development and function are sensitive to Shank3 dosage, and how much transcriptional changes contribute to neuronal phenotypes affected by Shank3 dosage. To examine this, we performed transcriptome analyses on the striatum of Shank3 heterozygous and knock-out mice, which identified three and 17 differentially expressed genes, respectively. We then compared the results to those of our previous striatal transcriptome analysis of Shank3 overexpressing mice and identified 31 candidate genes showing directional expression changes in a Shank3 dosage-dependent manner. However, overall, their Shank3 dosage-dependent fold changes were very subtle (average of absolute log2(fold change) was 0.139). Meanwhile, the gene set enrichment analyses of the striatal transcriptome suggested that Shank3 dosage may affect anchoring junction-related functions. Taken together, these results suggest that Shank3 dosage minimally affects directional gene expression changes in the mouse striatum.

Laser-matter interaction has been intensively studied in equilibrium states, but irreversible processes in a highly nonequilibrium state at nanoscales remains elusive due to experimental challenges. Here, Ihm et al. image heterogeneous melting of gold nanoparticles with nanometer and picosecond resolution.

Abstract Various mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene are associated with neurodevelopmental and neuropsychiatric disorders. Thus far, synaptic abnormalities in multiple brain regions, including the hippocampus, prefrontal cortex, striatum, and ventral tegmental area, have been investigated in several lines of Shank3 mutant mice. However, although some reports have shown loss and gain of body weight in Shank3 knock-out and overexpressing transgenic (TG) mice, respectively, the potential functions of Shank3 in the hypothalamus, a brain region critically involved in energy intake and expenditure, are unknown. Hence, we first characterized endogenous Shank3 mRNA and protein expression in the hypothalamus of adult wild-type mice. Thereafter, we performed transcriptome analysis (RNA-sequencing) in the hypothalamus of adult Shank3 TG mice which mildly overexpress Shank3 proteins. By comparing the 174 differentially expressed genes in the hypothalamus with those previously reported in the striatum and medial prefrontal cortex (mPFC) of Shank3 TG mice, we found that 159 were hypothalamus-specific while only 15 were also observed in either the striatum or mPFC. Furthermore, gene set enrichment analysis of the RNA-sequencing analysis revealed that ribosome-related genes were enriched especially in the up-regulated genes of Shank3 TG hypothalamus, which is in contrast to the results of the Shank3 TG striatum and mPFC analyses, where ribosome-related genes were enriched in the down-regulated genes. Beyond revealing endogenous Shank3 mRNA and protein expression in the hypothalamus, our results suggest unique molecular changes in the hypothalamus of Shank3 TG mice compared with those in the striatum and mPFC.

The new European X-Ray Free-Electron Laser (EuXFEL) is the first XFEL that generates X-ray pulses with a megahertz inter-pulse spacing. Here the authors demonstrate that high-quality and damage-free protein structures can be obtained with the currently available 1.1 MHz repetition rate pulses using lysozyme as a test case and furthermore present a β-lactamase structure.

Variants of the SH3 and multiple ankyrin repeat domains 3 (SHANK3), which encodes postsynaptic scaffolds, are associated with brain disorders. The targeted alleles in a few Shank3 knock-out (KO) lines contain a neomycin resistance (Neo) cassette, which may perturb the normal expression of neighboring genes; however, this has not been investigated in detail. We previously reported an unexpected increase in the mRNA expression of Shank3 exons 1–12 in the brains of Shank3B KO mice generated by replacing Shank3 exons 13–16 with the Neo cassette. In this study, we confirmed that the increased Shank3 mRNA in Shank3B KO brains produced an unusual ∼60 kDa Shank3 isoform (Shank3-N), which did not properly localize to the synaptic compartment. Functionally, Shank3-N overexpression altered the dendritic spine morphology in cultured neurons. Importantly, Shank3-N expression in Shank3B KO mice was not a compensatory response to a reduction of full-length Shank3 because expression was still detected in the brain after normalizing the level of full-length Shank3. Moreover, in another Shank3 KO line (Shank3 gKO) with a similar Shank3 exonal deletion as that in Shank3B KO mice but without a Neo cassette, the mRNA expression levels of Shank3 exons 1–12 were lower than those of wild-type mice and Shank3-N was not detected in the brain. In addition, the expression levels of genes neighboring Shank3 on chromosome 15 were altered in the striatum of Shank3B KO but not Shank3 gKO mice. These results suggest that the Neo cassette has potential off-target effects in Shank3B KO mice.

Summary: Background: Various retrospective studies have reported on the increase of mortality risk due to higher diurnal temperature range (DTR). This study projects the effect of DTR on future mortality across 445 communities in 20 countries and regions. Methods: DTR-related mortality risk was estimated on the basis of the historical daily time-series of mortality and weather factors from Jan 1, 1985, to Dec 31, 2015, with data for 445 communities across 20 countries and regions, from the Multi-Country Multi-City Collaborative Research Network. We obtained daily projected temperature series associated with four climate change scenarios, using the four representative concentration pathways (RCPs) described by the Intergovernmental Panel on Climate Change, from the lowest to the highest emission scenarios (RCP 2.6, RCP 4.5, RCP 6.0, and RCP 8.5). Excess deaths attributable to the DTR during the current (1985–2015) and future (2020–99) periods were projected using daily DTR series under the four scenarios. Future excess deaths were calculated on the basis of assumptions that warmer long-term average temperatures affect or do not affect the DTR-related mortality risk. Findings: The time-series analyses results showed that DTR was associated with excess mortality. Under the unmitigated climate change scenario (RCP 8.5), the future average DTR is projected to increase in most countries and regions (by −0·4 to 1·6°C), particularly in the USA, south-central Europe, Mexico, and South Africa. The excess deaths currently attributable to DTR were estimated to be 0·2–7·4%. Furthermore, the DTR-related mortality risk increased as the long-term average temperature increased; in the linear mixed model with the assumption of an interactive effect with long-term average temperature, we estimated 0·05% additional DTR mortality risk per 1°C increase in average temperature. Based on the interaction with long-term average temperature, the DTR-related excess deaths are projected to increase in all countries or regions by 1·4–10·3% in 2090–99. Interpretation: This study suggests that globally, DTR-related excess mortality might increase under climate change, and this increasing pattern is likely to vary between countries and regions. Considering climatic changes, our findings could contribute to public health interventions aimed at reducing the impact of DTR on human health. Funding: Korea Ministry of Environment.

The cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) gene is associated with epilepsy, intellectual disability (ID), and developmental delay, suggesting its critical role in proper neuronal development and function. CYFIP2 is involved in regulating cellular actin dynamics and also interacts with RNA-binding proteins. However, the adult brain function of CYFIP2 remains unclear because investigations thus far are limited to Cyfip2 heterozygous (Cyfip2+/−) mice owing to the perinatal lethality of Cyfip2-null mice. Therefore, we generated Cyfip2 conditional knock-out (cKO) mice with reduced CYFIP2 expression in postnatal forebrain excitatory neurons (CaMKIIα-Cre). We found that in the medial prefrontal cortex (mPFC) of adult Cyfip2 cKO mice, CYFIP2 expression was decreased in both layer 2/3 (L2/3) and layer 5 (L5) neurons, unlike the L5-specific CYFIP2 reduction observed in adult Cyfip2+/− mice. Nevertheless, filamentous actin (F-actin) levels were increased only in L5 of Cyfip2 cKO mPFC possibly because of a compensatory increase in CYFIP1, the other member of CYFIP family, in L2/3 neurons. Abnormal dendritic spines on basal, but not on apical, dendrites were consistently observed in L5 neurons of Cyfip2 cKO mPFC. Meanwhile, neuronal excitability and activity were enhanced in both L2/3 and L5 neurons of Cyfip2 cKO mPFC, suggesting that CYFIP2 functions of regulating F-actin and excitability/activity may be mediated through independent mechanisms. Unexpectedly, adult Cyfip2 cKO mice did not display locomotor hyperactivity or reduced anxiety observed in Cyfip2+/− mice. Instead, both exhibited enhanced social dominance accessed by the tube test. Together, these results provide additional insights into the functions of CYFIP2 in the adult brain.

Stroke is the second most common cause of death and third most common cause of disability worldwide. Therefore, it is an important disease from a medical standpoint. For this reason, various studies have developed diagnostic and therapeutic techniques for stroke. Among them, developments and applications of optical modalities are being extensively studied. In this article, we explored three important optical modalities for research, diagnostic, and therapeutics for stroke and the brain injuries related to it: (1) photochemical thrombosis to investigate stroke animal models; (2) optical imaging techniques for in vivo preclinical studies on stroke; and (3) optical neurostimulation based therapy for stroke. We believe that an exploration and an analysis of previous studies will help us proceed from research to clinical applications of optical modalities for research, diagnosis, and treatment of stroke.

It has been reported that suicide is associated with ambient temperature; however, the heterogeneity in this association and its underlying factors have not been extensively investigated. Therefore, we investigated the spatial and temporal variation in the temperature–suicide association and examined climatic, demographic, and socioeconomic factors that may underlie such heterogeneity. We analyzed the daily time-series data for the suicide counts and ambient temperature, which were collected for the 47 prefectures of Japan from 1972 to 2015, using a two-stage analysis. In the first stage, the prefecture-specific temperature–suicide association was estimated by using a generalized linear model. In the second stage, the prefecture-specific associations were pooled, and key factors explaining the spatial and temporal variation were identified by using mixed effects meta-regression. Results showed that there is an inverted J-shape nonlinear association between temperature and suicide; the suicide risk increased with temperature but leveled off above 24.4 °C. The nationwide relative risk (RR) for the maximum suicide temperature versus 5th temperature percentile (2.9 °C) was estimated as 1.26 (95% CI: 1.22, 1.29). The RRs were larger for females than for males (1.32 vs. 1.22) and larger for elderly people (≥65 y) than for the non-elderly (15–64 y) (1.51 vs. 1.18). The RRs were larger for rural prefectures, which are characterized by smaller population, higher proportions of females and elderly people, and lower levels of financial capability and the proportion of highly educated people. The RRs were also larger in colder and less humid prefectures. These findings may help in understanding the potential mechanism of the temperature–suicide association and projecting the future risk of suicide under climate change.

The European X-ray free-electron laser (EuXFEL) in Hamburg is the first megahertz (MHz) repetition rate XFEL. Here the authors use lysozyme crystals and microcrystals from jack bean proteins and demonstrate that damage-free high quality data can be collected at a MHz repetition rate.