Neurodevelopmental disorder-associated CYFIP2 regulates membraneless organelles and eIF2α phosphorylation via protein interactors and actin cytoskeleton.

De novo variants in the Cytoplasmic FMR1-interacting protein 2 (CYFIP2) have been repeatedly associated with neurodevelopmental disorders and epilepsy, underscoring its critical role in brain development and function. While CYFIP2's role in regulating actin polymerization as part of the WAVE regulatory complex (WRC) is well-established, its additional molecular functions remain relatively unexplored. In this study, we performed unbiased quantitative proteomic analysis, revealing 278 differentially expressed proteins (DEPs) in the forebrain of Cyfip2 knock-out embryonic mice compared to wild-type mice. Unexpectedly, these DEPs, in conjunction with previously identified CYFIP2 brain interactors, included not only other WRC components but also numerous proteins associated with membraneless organelles (MLOs) involved in mRNA processing and translation within cells, including the nucleolus, stress granules, and processing bodies. Additionally, single-cell transcriptomic analysis of the Cyfip2 knock-out forebrain revealed gene expression changes linked to cellular stress responses and MLOs. We also observed morphological changes in MLOs in Cyfip2 knock-out brains and CYFIP2 knock-down cells under basal and stress conditions. Lastly, we demonstrated that CYFIP2 knock-down in cells, potentially through WRC-dependent actin regulation, suppressed the phosphorylation levels of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), thereby enhancing protein synthesis. These results suggest a physical and functional connection between CYFIP2 and various MLO proteins and also extend CYFIP2's role within the WRC from actin regulation to influencing eIF2α phosphorylation and protein synthesis. With these dual functions, CYFIP2 may fine-tune the balance between MLO formation/dynamics and protein synthesis, a crucial aspect of proper mRNA processing and translation.

A single-component, light-assisted uncaging switch for endoproteolytic release.

Proteases function as pivotal molecular switches, initiating numerous biological events. Notably, potyviral protease, derived from plant viruses, has emerged as a trusted proteolytic switch in synthetic biological circuits. To harness their capabilities, we have developed a single-component photocleavable switch, termed LAUNCHER (Light-Assisted UNcaging switCH for Endoproteolytic Release), by employing a circularly permutated tobacco etch virus protease and a blue-light-gated substrate, which are connected by fine-tuned intermodular linkers. As a single-component system, LAUNCHER exhibits a superior signal-to-noise ratio compared with multi-component systems, enabling precise and user-controllable release of payloads. This characteristic renders LAUNCHER highly suitable for diverse cellular applications, including transgene expression, tailored subcellular translocation and optochemogenetics. Additionally, the plug-and-play integration of LAUNCHER into existing synthetic circuits facilitates the enhancement of circuit performance. The demonstrated efficacy of LAUNCHER in improving existing circuitry underscores its significant potential for expanding its utilization in various applications.

Selective Flocculation and H2O2-Free Oxidative Etching-Based Synthesis of Highly Monodisperse Ag Nanospheres for Uniform Quantum Dot Photoluminescence-Enhancing Plasmonic Cavity Applications.

Ag nanoparticles have garnered significant attention for their excellent plasmonic properties and potential use as plasmonic cavities, primarily because of their intrinsically low ohmic losses and optical properties in the visible range. These are particularly crucial in systems involving quantum dots that absorb light at low wavelengths, where the need for a high threshold energy of interband transitions necessitates the incorporation of Ag nanostructures. However, the synthesis of Ag nanoparticles still encounters challenges in achieving structural uniformity and monodispersity, along with chemical stability, consequentially inducing inconsistent and poorly reliable optical responses. Here, we present a two-step approach for synthesizing highly uniform spherical Ag nanoparticles involving depletion-induced flocculation and Cu(II)-mediated oxidative etching. We found that the selective flocculation of multitwinned Ag nanocrystals significantly enhances the uniformity of the resulting Ag nanostructures, leaving behind only single-crystalline and single-twinned nanostructures. Subsequent oxidative etching, in which cupric ions are directly involved in the reaction, was designed based on Pourbaix diagrams to proceed following thermodynamically favorable states and circumvent the generation of reactive chemical species such as H2O2. This leads to perfectly spherical shapes of final Ag nanoparticles with a synthetic yield of 99.5% and additionally reduces the overall reaction time. Furthermore, we explore the potential applications of these monodisperse Ag nanospheres as uniform plasmonic cavities. The fabricated Ag nanosphere films uniformly enhanced the photoluminescence of InP/ZnSe/ZnS quantum dots, showcasing their capabilities in exhibiting consistent plasmonic responses across a large area.

A Chemist's View on Electronic and Steric Effects of Surface Ligands on Plasmonic Metal Nanostructures.

ConspectusPlasmonic metal nanostructures have been extensively developed over the past few decades because of their ability to confine light within the surfaces and manipulate strong light-matter interactions. The light energy stored by plasmonic nanomaterials in the form of surface plasmons can be utilized to initiate chemical reactions, so-called plasmon-induced catalysis, which stresses the importance of understanding the surface chemistry of the plasmonic materials. Nevertheless, only physical interpretation of plasmonic behaviors has been a dominant theme, largely excluding chemical intuitions that facilitate understanding of plasmonic systems from molecular perspectives. To overcome and address the lack of this complementary understanding based on molecular viewpoints, in this Account we provide a new concept encompassing the well-developed physics of plasmonics and the corresponding surface chemistry while reviewing and discussing related references. Inspired by Roald Hoffmann's descriptions of solid-state surfaces based on the molecular orbital picture, we treat molecular interfaces of plasmonic metal nanostructures as a series of metal-ligand complexes. Accordingly, the effects of the surface ligands can be described by bisecting them into electronic and steric contributions to the systems. By exploration of the quality of orbital overlaps and the symmetry of the plasmonic systems, electronic effects of surface ligands on localized surface plasmon resonances (LSPRs), surface diffusion rates, and hot-carrier transfer mechanisms are investigated. Specifically, the propensity of ligands to donate electrons in a σ-bonding manner can change the LSPR by shifting the density of states near the Fermi level, whereas other types of ligands donating or accepting electrons in a π-bonding manner modulate surface diffusion rates by affecting the metal-metal bond strength. In addition, the formation of metal-ligand bonds facilitates direct hot-carrier transfer by forming a sort of molecular orbital between a plasmonic structure and ligands. Furthermore, effects of steric environments are discussed in terms of ligand-ligand and ligand-surface nonbonding interactions. The steric hindrance allows for controlling the accessibility of the surrounding chemical species toward the metal surface by modulating the packing density of ligands and generating repulsive interactions with the surface atoms. This unconventional approach of considering the plasmonic system as a delocalized molecular entity could establish a basis for integrating chemical intuition with physical phenomena. Our chemist's outlook on a molecular interface of the plasmonic surface can provide insights and avenues for the design and development of more exquisite plasmonic catalysts with regio- and enantioselectivities as well as advanced sensors with unprecedented chemical controllability and specificity.

CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.

Here, we report the generation and comprehensive characterization of a knockin mouse model for the hotspot p.Arg87Cys variant of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) gene, which was recently identified in individuals diagnosed with West syndrome, a developmental and epileptic encephalopathy. The Cyfip2+/R87C mice recapitulated many neurological and neurobehavioral phenotypes of the patients, including spasmlike movements, microcephaly, and impaired social communication. Age-progressive cytoarchitectural disorganization and gliosis were also identified in the hippocampus of Cyfip2+/R87C mice. Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains, we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2. ANN NEUROL 2023;93:155-163.

Associations of meteorological factors and dynamics of scrub typhus incidence in South Korea: A nationwide time-series study.

Scrub typhus, also known as Tsutsugamushi disease, is a climate-sensitive vector-borne disease that poses a growing public health threat. However, studies on the association between scrub typhus epidemics and meteorological factors in South Korea need to be complemented. Therefore, we aimed to analyze the association among ambient temperature, precipitation, and the incidence of scrub typhus in South Korea. First, we obtained data on the weekly number of scrub typhus cases and concurrent meteorological variables at the city-county level (Si-Gun) in South Korea between 2001 and 2019. Subsequently, a two-stage meta-regression analysis was conducted. In the first stage, we conducted time-series regression analyses using a distributed lag nonlinear model (DLNM) to investigate the association between temperature, precipitation, and scrub typhus incidence at each location. In the second stage, we employed a multivariate meta-regression model to combine the association estimates from all municipalities, considering regional indicators, such as mite species distribution, Normalized Difference Vegetation Index (NDVI), and urban-rural classification. Weekly mean temperature and weekly total precipitation exhibited a reversed U-shaped nonlinear association with the incidence of scrub typhus. The overall cumulative association with scrub typhus incidence peaked at 18.7 C° (with RRs of 9.73, 95% CI: 5.54-17.10) of ambient temperature (reference 9.7 C°) and 162.0 mm (with RRs of 1.87, 95% CI: 1.02-3.83) of precipitation (reference 2.8 mm), respectively. These findings suggest that meteorological factors contribute to scrub typhus epidemics by interacting with vectors, reservoir hosts, and human behaviors. This information serves as a reference for future public health policies and epidemiological research aimed at controlling scrub typhus infections.

High-Throughput Synthesis of Nanogap-Rich Gold Nanoshells Using Dual-Channel Infusion System.

Gold nanoshells have been actively applied in industries beyond the research stage because of their unique optical properties. Although numerous methods have been reported for gold nanoshell synthesis, the labor-intensive and time-consuming production process is an issue that must be overcome to meet industrial demands. To resolve this, we report a high-throughput synthesis method for nanogap-rich gold nanoshells based on a core silica support (denoted as SiO2@Au NS), affording a 50-fold increase in scale by combining it with a dual-channel infusion pump system. By continuously dropping the reactant solution through the pump, nanoshells with closely packed Au nanoparticles were prepared without interparticle aggregation. The thickness of the gold nanoshells was precisely controlled at 2.3-17.2 nm by regulating the volume of the reactant solution added dropwise. Depending on the shell thickness, the plasmonic characteristics of SiO2@Au NS prepared by the proposed method could be tuned. Moreover, SiO2@Au NS exhibited surface-enhanced Raman scattering activity comparable to that of gold nanoshells prepared by a previously reported low-throughput method at the same reactant ratio. The results indicate that the proposed high-throughput synthesis method involving the use of a dual-channel infusion system will contribute to improving the productivity of SiO2@Au NS with tunable plasmonic characteristics.

Continuous cardiac output estimation using a new modified Fick method during off-pump coronary artery bypass graft surgery: a retrospective observational study.

PURPOSE: Several technical aspects of the Fick method limit its use intraoperatively. A data-driven modification of the Fick method may enable its use in intraoperative settings. METHODS: This two-center retrospective observational study included 57 (28 and 29 in each center) patients who underwent off-pump coronary artery bypass graft (OPCAB) surgery. Intraoperative recordings of physiological data were obtained and divided into training and test datasets. The Fick equation was used to calculate cardiac output (CO-Fick) using ventilator-determined variables, intraoperative hemoglobin level, and SvO2, with continuous thermodilution cardiac output (CCO) used as a reference. A modification CO-Fick was derived and validated: CO-Fick-AD, which adjusts the denominator of the original equation. RESULTS: Increased deviation between CO-Fick and CCO was observed when oxygen extraction was low. The root mean square error of CO-Fick was decreased from 6.07 L/min to 0.70 L/min after the modification. CO-Fick-AD showed a mean bias of 0.17 (95% CI 0.00-0.34) L/min, with a 36.4% (95% CI 30.6-44.4%) error. The concordance rates of CO-Fick-AD ranged from 73.3 to 87.1% depending on the time interval and exclusion zone. CONCLUSIONS: The original Fick method is not reliable when oxygen extraction is low, but a modification using data-driven approach could enable continuous estimation of cardiac output during the dynamic intraoperative period with minimal bias. However, further improvements in precision and trending ability are needed.

Time-resolved serial femtosecond crystallography at the European XFEL.

The European XFEL (EuXFEL) is a 3.4-km long X-ray source, which produces femtosecond, ultrabrilliant and spatially coherent X-ray pulses at megahertz (MHz) repetition rates. This X-ray source has been designed to enable the observation of ultrafast processes with near-atomic spatial resolution. Time-resolved crystallographic investigations on biological macromolecules belong to an important class of experiments that explore fundamental and functional structural displacements in these molecules. Due to the unusual MHz X-ray pulse structure at the EuXFEL, these experiments are challenging. Here, we demonstrate how a biological reaction can be followed on ultrafast timescales at the EuXFEL. We investigate the picosecond time range in the photocycle of photoactive yellow protein (PYP) with MHz X-ray pulse rates. We show that difference electron density maps of excellent quality can be obtained. The results connect the previously explored femtosecond PYP dynamics to timescales accessible at synchrotrons. This opens the door to a wide range of time-resolved studies at the EuXFEL.

Association between ambient temperature and cause-specific cardiovascular disease admissions in Japan: A nationwide study.

BACKGROUND: Substantial evidence suggests that non-optimal temperatures can increase the risk of cardiovascular disease (CVD) mortality and morbidity; however, limited studies have reported inconsistent results for hospital admissions depending on study locations, which also lack national-level investigations on cause-specific CVDs. METHODS: We performed a two-stage meta-regression analysis to examine the short-term associations between temperature and acute CVD hospital admissions by specific categories [i.e., ischemic heart disease (IHD), heart failure (HF), and stroke] in 47 prefectures of Japan from 2011 to 2018. First, we estimated the prefecture-specific associations using a time-stratified case-crossover design with a distributed lag nonlinear model. We then used a multivariate meta-regression model to obtain national average associations. RESULTS: During the study period, a total of 4,611,984 CVD admissions were reported. We found cold temperatures significantly increased the risk of total CVD admissions and cause-specific categories. Compared with the minimum hospitalization temperature (MHT) at the 98th percentile of temperature (29.9 °C), the cumulative relative risks (RRs) for cold (5th percentile, 1.7 °C) and heat (99th percentile, 30.5 °C) on total CVD were 1.226 [95% confidence interval (CI): 1.195, 1.258] and 1.000 (95% CI: 0.998, 1.002), respectively. The RR for cold on HF [RR = 1.571 (95% CI: 1.487, 1.660)] was higher than those of IHD [RR = 1.119 (95% CI: 1.040, 1.204)] and stroke [RR = 1.107 (95% CI: 1.062, 1.155)], comparing to their cause-specific MHTs. We also observed that extreme heat increased the risk of HF with RR of 1.030 (95% CI: 1.007, 1.054). Subgroup analysis showed that the age group ≥85 years was more vulnerable to these non-optimal temperature risks. CONCLUSIONS: This study indicated that cold and heat exposure could increase the risk of hospital admissions for CVD, varying depending on the cause-specific categories, which may provide new evidence to reduce the burden of CVD.

Daily temperature effects on under-five mortality in a tropical climate country and the role of local characteristics.

BACKGROUND: Climate change and its subsequent effects on temperature have raised global public health concerns. Although numerous epidemiological studies have shown the adverse health effects of temperature, the association remains unclear for children aged below five years old and those in tropical climate regions. METHODS: We conducted a two-stage time-stratified case-crossover study to examine the association between temperature and under-five mortality, spanning the period from 2014 to 2018 across all six regions in Malaysia. In the first stage, we estimated region-specific temperature-mortality associations using a conditional Poisson regression and distributed lag nonlinear models. We used a multivariate meta-regression model to pool the region-specific estimates and examine the potential role of local characteristics in the association, which includes geographical information, demographics, socioeconomic status, long-term temperature metrics, and healthcare access by region. RESULTS: Temperature in Malaysia ranged from 22 °C to 31 °C, with a mean of 27.6 °C. No clear seasonality was observed in under-five mortality. We found no strong evidence of the association between temperature and under-five mortality, with an "M-" shaped exposure-response curve. The minimum mortality temperature (MMT) was identified at 27.1 °C. Among several local characteristics, only education level and hospital bed rates reduced the residual heterogeneity in the association. However, effect modification by these variables were not significant. CONCLUSION: This study suggests a null association between temperature and under-five mortality in Malaysia, which has a tropical climate. The "M-" shaped pattern suggests that under-fives may be vulnerable to temperature changes, even with a small temperature change in reference to the MMT. However, the weak risks with a large uncertainty at extreme temperatures remained inconclusive. Potential roles of education level and hospital bed rate were statistically inconclusive.

Environmental greenspace, subjective well-being, and all-cause mortality in elderly Chinese: Association and mediation study in a prospective cohort.

BACKGROUND: Subjective well-being (SWB) measures mental health and happiness. Greenspace can have a positive impact on mental health, and higher SWB is associated with lower all-cause mortality. We conducted a mediation analysis on greenspace and all-cause mortality through improving SWB, in a prospective cohort of Chinese older adults. METHODS: We included older adults over 65 from the 2008-2014 Chinese Longitudinal Healthy Longevity Survey (CLHLS). We used satellite-derived normalized difference vegetation index (NDVI) to measure greenspaces and calculated SWB measured by eight items. Three main statistical approaches were used. First, we used generalized estimating equations (GEE) and Cox proportional hazard models to examine NDVI-SWB and SWB-mortality relationships. Second, we conducted a causal mediation analysis to investigate the mediating effect of greenspace on all-cause mortality through SWB. Third, we conducted subgroup analyses to discover effect modification. FINDINGS: Among 13,133 participants, the mean SWB score and NDVI in 2008 were 28·9 (SD 4·34) and 0·41 (SD 0·14), respectively. We found SWB partially mediated the relationship between residential greenspace and mortality in the adjusted model (average causal mediation effect = 0·11, p = 0·04; average direct effect = 1·96, p < 0·001; total effect = 2·07, p < 0·001) with varying proportions in subgroups. The protective influence was more evident for people with impaired cognitive function, living in rural areas and towns, and with lower income. INTERPRETATION: We found a positive association between greenspace, SWB, and mortality. Greenness in the living environment confers better mental health and promotes longevity in the elderly population.

Long-term trends in mortality risk associated with short-term exposure to air pollution in 10 Japanese cities between 1977 and 2015.

BACKGROUND AND AIM: Short-term associations between air pollution and mortality have been well reported in Japan, but the historical changes in mortality risk remain unknown. We examined temporal changes in the mortality risks associated with short-term exposure to four criteria air pollutants in selected Japanese cities. METHODS: We collected daily mortality data for non-accidental causes (n = 5,748,206), cardiovascular (n = 1,938,743) and respiratory diseases (n = 777,266), and air pollutants (sulfur dioxide [SO2], nitrogen dioxide [NO2], suspended particulate matter [SPM], and oxidants [Ox]) in 10 cities from 1977 to 2015. We performed two-stage analysis with 5-year stratification to estimate the relative risk (RR) of mortality per 10-unit increase in the 2-day moving average of air pollutant concentrations. In the first stage, city-specific associations were assessed using a quasi-Poisson generalized linear regression model. In the second stage, city-specific estimates were pooled using a random-effects meta-analysis. Linear trend and ratio of relative risks (RRR) were computed to examine temporal changes. RESULTS: When stratifying the analysis by every 5 years, average concentrations in each sub-period decreased for SO2, NO2, and SPM (14.2-2.3 ppb, 29.4-17.5 ppb, 52.1-20.6 µg/m3, respectively) but increased for Ox (29.1-39.1 ppb) over the study period. We found evidence of a negative linear trend in the risk of cardiovascular mortality associated with SPM across sub-periods. However, the risks of non-accidental and respiratory mortality per 10-unit increase in SPM concentration were significantly higher in the most recent period than in the earliest period. Other gaseous pollutants did not show such temporal risk change. The risks posed by these pollutants were slightly to moderately heterogeneous in the different cities. CONCLUSIONS: The mortality risks associated with short-term exposure to SPM changed, with different trends by cause of death, in 10 cities over 39 years whereas the risks for other gaseous pollutants were relatively stable.

Association between environmental factors and dengue incidence in Lao People's Democratic Republic: a nationwide time-series study.

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.

Errors in pressure measurements due to changes in pressure transducer levels during adult cardiac surgery: a prospective observational study.

BACKGROUND: Blood pressure measurement is an essential element during intraoperative patient management. However, errors caused by changes in transducer levels can occur during surgery. METHODS: This single center, prospective, observational study enrolled 25 consecutive patients scheduled for elective cardiac surgery with invasive arterial and central venous pressure (CVP) monitoring. Hydrostatic pressures caused by level differences (leveling pressure) between a reference point (on the center of the left biceps brachii muscle) and the transducers (fixed on the right side of the operating table) for arterial and central lines were continuously measured using a leveling transducer. Adjusted pressures were calculated as measured pressure - leveling pressure. Hypotension (mean arterial pressure < 80, <70, and < 60 mmHg), and CVP (< 6, ≥6 and < 15, or ≥ 15 mmHg) and pulmonary artery pressure (PAP, mean > 20 mmHg) levels were determined using unadjusted and adjusted pressures. RESULTS: Twenty-two patients were included in the analysis. Leveling pressure ≥ 3 mmHg and ≥ 5 mmHg observed at 46.0 and 18.7% of pooled data points, respectively. Determinations of hypotension using unadjusted and adjusted pressures showed disagreements ranging from 3.3 to 9.4% depending on the cutoffs. Disagreements in defined levels of CVP and PAP were observed at 23.0 and 17.2% of the data points, respectively. CONCLUSIONS: The errors in pressure measurement due to changes in transducer level were not trivial and caused variable disagreements in the determination of MAP, CVP, and PAP levels. To prevent distortions in intraoperative hemodynamic management, strategies should be sought to minimize or adjust for these errors in clinical practice. TRIAL REGISTRATION: cris.nih.go.kr (KCT0006510).

Emergence of anomalous dynamics in soft matter probed at the European XFEL.

Dynamics and kinetics in soft matter physics, biology, and nanoscience frequently occur on fast (sub)microsecond but not ultrafast timescales which are difficult to probe experimentally. The European X-ray Free-Electron Laser (European XFEL), a megahertz hard X-ray Free-Electron Laser source, enables such experiments via taking series of diffraction patterns at repetition rates of up to 4.5 MHz. Here, we demonstrate X-ray photon correlation spectroscopy (XPCS) with submicrosecond time resolution of soft matter samples at the European XFEL. We show that the XFEL driven by a superconducting accelerator provides unprecedented beam stability within a pulse train. We performed microsecond sequential XPCS experiments probing equilibrium and nonequilibrium diffusion dynamics in water. We find nonlinear heating on microsecond timescales with dynamics beyond hot Brownian motion and superheated water states persisting up to 100 µs at high fluences. At short times up to 20 µs we observe that the dynamics do not obey the Stokes-Einstein predictions.

Injury to the Left Sciatic and Right Common Peroneal Nerves Combined With Multifocal Rhabdomyolysis in a Survivor of the Itaewon Crowd Crush: A Case Report.

We report the case of a 27-year-old survivor of the Halloween crowd crush in Itaewon, Seoul, Korea who was diagnosed with left sciatic neuropathy and right common peroneal neuropathy accompanied by multifocal rhabdomyolysis. The patient presented to the emergency room complaining of pain from her lower back to her whole lower extremities with paraparesis and paresthesia. Her blood test showed the marked elevation of creatine kinase and liver enzymes. Magnetic resonance imaging revealed multifocal signal changes in the abdominalis and pelvic girdle muscles suggestive of rhabdomyolysis. Magnetic resonance neurography demonstrated injury to the left sciatic and right peroneal nerves. Electrophysiologic studies also revealed lesions in the left sciatic and right peroneal nerves. After comprehensive rehabilitation and conservative treatment for three months, her muscle strength improved, and she could walk independently. Although several previous studies have reported peripheral neuropathy in immobilized patients, to the best of our knowledge, no case associated with a crowd crush has been reported. Therefore, we report the case of multifocal neuropathy combined with rhabdomyolysis in a victim of a crowd crush incident with good recovery.

Statistical methods for handling missing data to align with treatment policy strategy.

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received. The estimand using the treatment policy strategy, which collects and analyzes data regardless of the occurrence of intercurrent events, is usually utilized. In this article, we explain how missing data can be handled using the treatment policy strategy from the authors' viewpoint in connection with antihyperglycemic product development programs. The article discusses five statistical methods to impute missing data occurring after intercurrent events. All five methods are applied within the framework of the treatment policy strategy. The article compares the five methods via Markov Chain Monte Carlo simulations and showcases how three of these five methods have been applied to estimate the treatment effects published in the labels for three antihyperglycemic agents currently on the market.

Positive Association of Aggression with Ambient Temperature.

Background: Relatively little attention has been paid to the potential effects of rising temperatures on changes in human behavior that lead to health and social consequences, including aggression. This study investigated the association between ambient temperature and aggression using assault death data from Seoul, South Korea (1991-2020). Methods: We conducted a time-stratified case-crossover analysis based on conditional logistic regression to control for relevant covariates. The exposure-response curve was explored, and stratified analyses were conducted by season and sociodemographic characteristics. Results: The overall risk of assault deaths significantly increased by 1.4% per 1°C increase in ambient temperature. A positive curvilinear relationship was observed between ambient temperature and assault deaths, which flattened out at 23.6°C during the warm season. Furthermore, risk increases were higher in males, teenagers, and those with the least education. Conclusion: This study highlighted the importance of understanding the impact of rising temperatures on aggression in the context of climate change and public health.

Protein interactome and cell-type expression analyses reveal that cytoplasmic FMR1-interacting protein 1 (CYFIP1), but not CYFIP2, associates with astrocytic focal adhesion.

The two members of the cytoplasmic FMR1-interacting protein family, CYFIP1 and CYFIP2, are evolutionarily conserved multifunctional proteins whose defects are associated with distinct types of brain disorders. Even with high sequence homology between CYFIP1 and CYFIP2, several lines of evidence indicate their different functions in the brain; however, the underlying mechanisms remain largely unknown. Here, we performed reciprocal immunoprecipitation experiments using CYFIP1-2 × Myc and CYFIP2-3 × Flag knock-in mice and found that CYFIP1 and CYFIP2 are not significantly co-immunoprecipitated with each other in the knock-in brains compared with negative control wild-type (WT) brains. Moreover, CYFIP1 and CYFIP2 showed different size distributions by size-exclusion chromatography of WT mouse brains. Specifically, mass spectrometry-based analysis of CYFIP1-2 × Myc knock-in brains identified 131 proteins in the CYFIP1 interactome. Comparison of the CYFIP1 interactome with the previously identified brain region- and age-matched CYFIP2 interactome, consisting of 140 proteins, revealed only eight common proteins. Investigations using single-cell RNA-sequencing databases suggested non-neuronal cell- and neuron-enriched expression of Cyfip1 and Cyfip2, respectively. At the protein level, CYFIP1 was detected in both neurons and astrocytes, while CYFIP2 was detected only in neurons, suggesting the predominant expression of CYFIP1 in astrocytes. Bioinformatic characterization of the CYFIP1 interactome, and co-expression analysis of Cyfip1 with astrocytic genes, commonly linked CYFIP1 with focal adhesion proteins. Immunocytochemical analysis and proximity ligation assay suggested partial co-localization of CYFIP1 and focal adhesion proteins in cultured astrocytes. Together, these results suggest a CYFIP1-specific association with astrocytic focal adhesion, which may contribute to the different brain functions and dysfunctions of CYFIP1 and CYFIP2. Cover Image for this issue: https://doi.org/10.1111/jnc.15410.