Impacts of ship emissions and sea-land breeze on urban air quality using chemical characterization, source contribution and dispersion model simulation of PM2.5 at Asian seaport.

Fine particulate matter (PM2.5) emitted from marine transportation, bulk materials handling at the docks, and dust dispersion has garnered increased attention, particularly in the interface between port and urban areas. This study explored the inter-transport of PM2.5 between Kaohsiung Harbor and neighboring Metro Kaohsiung. Chemical analyses of PM2.5 samples from four sites include water-soluble ions, metallic elements, carbons, anhydrosugars, and organic acids to establish PM2.5's chemical fingerprints. The CALPUFF air dispersion model is employed to simulate the spatiotemporal distribution of PM2.5 in Kaohsiung Harbor and adjacent urban areas. A clear seasonal and diurnal variation of PM2.5 concentrations and chemical composition was observed in both harbor and urban areas. The high correlation of nighttime PM2.5 levels between the port and urban areas suggests inter-transport phenomena. Sea salt spray, ship emissions, secondary aerosols, and heavy fuel-oil boilers exhibit higher levels in the port area than in the urban area. In Metro Kaohsiung, mobile sources, fugitive dust, and waste incinerators emerge as major PM2.5 contributors. Furthermore, sea breeze significantly influences PM2.5 dispersion from Kaohsiung Harbor to Metro Kaohsiung, particularly in the afternoon. The average contribution of PM2.5 from ships' main engines in Kaohsiung Harbor ranges from 2.9% to 5.3%, while auxiliary engines contribute 3.8%-8.3% of PM2.5 in Metro Kaohsiung.

Epigenetic transgenerational effects of PM2.5 collected from southern Taiwan on sperm functions and DNA methylation in mouse offspring.

During respiration, particulate matter with a diameter of 2.5 µm or less (PM2.5) suspended in the atmosphere enters the terminal alveoli and blood. PM2.5 particles can attach to toxic substances, resulting in health problems. Limited information is available regarding the effects of prenatal exposure to water-soluble PM2.5 (WS-PM2.5) and water-insoluble PM2.5 (WI-PM2.5) on male reproduction. In addition, whether exposure to these particles has transgenerational effects remains unknown. We investigated whether prenatal exposure to WS-PM2.5 and WI-PM2.5 disrupts sperm function in generations F1, F2, and F3 of male mice. Pregnant BALB/c mice were treated using intratracheal instillation on gestation days 7, 11, and 15 with 10 mg of a water extract or insoluble PM2.5. On postnatal day 105, epididymal sperm count, motility, morphology, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, the sperm chromatin DNA fragmentation index (DFI), and testicular DNA methyltransferase (Dnmt) levels were evaluated in all generations. Whole-genome bisulfite sequencing was used to analyze the DNA methylation status of generation F3. According to the results, exposure to WS-PM2.5 affected sperm morphology, ROS production, and mean DFI in generation F1; ROS production and mean DFI in generation F2; and sperm morphology and MMP in generation F3. Similarly, exposure to WI-PM2.5 affected sperm morphology, ROS production, mean DFI, %DFI, and Dnmt1 expression in generation F1; sperm morphology, MMP, and ROS production in generation F2; and sperm morphology, ROS, and %DFI in generation F3. Two hypermethylated genes, PRR16 and TJP2, were observed in the WS-PM2.5 and WI-PM2.5 groups, two hypomethylated genes, NFATC1 and APOA5, were observed in the WS-PM2.5 group, and two hypomethylated genes, ZFP945 and GSE1, were observed in the WI-PM2.5 group. Hence, prenatal exposure to PM2.5 resulted in transgenerational epigenetic effects, which may explain certain phenotypic changes in male reproduction.

Spatiotemporal variation and inter-transport of atmospheric speciated mercury between Kaohsiung Harbor and neighboring urban areas.

This study investigated the spatiotemporal variation, gas-particle partition, and source resolution of atmospheric speciation mercury (ASM) in Kaohsiung Harbor and neighboring Metro Kaohsiung. Four sampling sites were selected to determine the pollution characteristics and inter-transport of ASM between the port and urban areas. The yearly average GEM, GOM, and PBM concentrations were 7.13 ± 2.2 ng/m3, 331 ± 190 pg/m3, and 532 ± 301 pg/m3, respectively. Notably, GEM emerged as the predominant ASM species (85-94%), primarily originating from anthropogenic emissions from the harbor area and nearby industrial complex. The study revealed a distinct seasonal variation in ASM concentrations in the Kaohsiung Area in the following order: winter > fall > spring > summer. Concerning spatial distribution, ASM concentrations in the port areas were generally higher than those in the urban areas. This disparity was chiefly attributed to the influence of the prevailing winds, local sources, and atmospheric dispersion. Backward trajectory simulation revealed that polluted air masses blown from the northeast in winter and spring, moving along the western in-land part of Taiwan Island, were likely influenced by local sources and long-range transport (LRT). In summer, air pollutants originating from the south were likely transported from the coastal industrial sources. During fall, air masses blown from the western offshore waters transported air pollutants from Kaohsiung Harbor to neighboring Metro Kaohsiung. The results obtained from principle component analysis (PCA) indicated that primary sources in the port areas included ship emissions, vehicular exhausts, and nearby industrial complex, which align with the primary source factors identified by positive matrix factorization (PMF), which were mobile sources and coal-fired industrial boilers. Meanwhile, mobile sources and sulfur-containing fuel/waste combustion were identified as the primary sources in the urban areas.

Galectin-3 aggravates microglial activation and tau transmission in tauopathy.

Alzheimer's disease is characterized by the accumulation of amyloid-ß plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a ß-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.

Risk factors for anisometropia in schoolchildren: A population-based, longitudinal cohort study.

PURPOSE: To investigate the incidence rate and risk factors for anisometropia among young schoolchildren. METHODS: A population-based cohort study, the Myopia Investigation Study in Taipei, was conducted in primary schools in Taipei City. Children were recruited for biannual comprehensive eye examinations over 2 years. Cycloplegic autorefraction and slit lamp examinations were performed biannually. Data on demographic information, parental history, lifestyle and near-work activities were collected using parent-administered questionnaires at the first and final visits. Anisometropia was defined as ≥1 D difference in the spherical equivalent (SE) refractive error. RESULTS: A total of 7035 8-year-old children completed the 2-year follow-up evaluations. The average annual incidence of anisometropia was 3.8%. Multivariable logistic regression analysis revealed that baseline SE (odds ratio [OR]: 0.87 95% CI: 0.80-0.95) and female sex (OR: 1.24, 95% confidence interval [CI]: 1.02-1.50) were significantly associated with incident anisometropia. Among lifestyle risk factors, spending <1 h per day in after-school outdoor activities on weekdays (OR: 1.38, 95% CI: 1.08-1.76) and performing near work at a distance <30 cm (OR: 1.33, 95% CI: 1.08-1.64) were significantly associated with an increased risk of incident anisometropia. In the multiple linear regression analysis, the inter-eye difference in SE increased significantly in children performing near work at distances <30 cm (adjusted ß = 0.03; p = 0.02). CONCLUSIONS: This study indicated the annual incidence of anisometropia in Taiwanese schoolchildren. Less time spent outdoors and shorter eye-to-object distances during near work increased the risk of incident anisometropia.

Association of Preoperative Prognostic Nutritional Index with Risk of Postoperative Acute Kidney Injury: A Meta-Analysis of Observational Studies.

This meta-analysis aimed to assess the clinical association of the preoperative prognostic nutritional index (pre-PNI) with the risk of postoperative acute kidney injury. Four databases (e.g., Medline) were searched from inception to December 2022 to investigate the association between pre-PNI (i.e., low vs. high) and PO-PNI as well as the correlation between pre-PNI and other postoperative prognostic indices. Overall, 13 observational studies, including 9185 patients, were eligible for analysis. A low PNI was related to increased risks of PO-AKI [odd ratio (OR) = 1.65, p = 0.001, 3811 patients], postoperative infection (OR = 2.1, p < 0.00001, 2291 patients), and mortality (OR = 1.93, p < 0.0001, 2159 patients). Albeit statistically nonsignificant, a trend was noted, linking a low PNI to higher risks of postoperative bleeding (OR = 2.5, p = 0.12, 1157 patients) and stroke (OR = 1.62, p = 0.07, 2036 patients). Pooled results revealed a prolonged intensive care unit (ICU) stay in patients with low PNIs compared to those with high PNIs (MD: 0.98 days, p = 0.02, 2209 patients) without a difference in hospital stay between the two groups (MD: 1.58 days, p = 0.35, 2249 patients). This meta-analysis demonstrated an inverse correlation between PNI and the risks of PO-AKI, postoperative infection, and mortality, as well as the length of ICU stay, which warrants further investigations for verification.

The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification.

Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.

Augmented Reality Surgical Navigation System Integrated with Deep Learning.

Most current surgical navigation methods rely on optical navigators with images displayed on an external screen. However, minimizing distractions during surgery is critical and the spatial information displayed in this arrangement is non-intuitive. Previous studies have proposed combining optical navigation systems with augmented reality (AR) to provide surgeons with intuitive imaging during surgery, through the use of planar and three-dimensional imagery. However, these studies have mainly focused on visual aids and have paid relatively little attention to real surgical guidance aids. Moreover, the use of augmented reality reduces system stability and accuracy, and optical navigation systems are costly. Therefore, this paper proposed an augmented reality surgical navigation system based on image positioning that achieves the desired system advantages with low cost, high stability, and high accuracy. This system also provides intuitive guidance for the surgical target point, entry point, and trajectory. Once the surgeon uses the navigation stick to indicate the position of the surgical entry point, the connection between the surgical target and the surgical entry point is immediately displayed on the AR device (tablet or HoloLens glasses), and a dynamic auxiliary line is shown to assist with incision angle and depth. Clinical trials were conducted for EVD (extra-ventricular drainage) surgery, and surgeons confirmed the system's overall benefit. A "virtual object automatic scanning" method is proposed to achieve a high accuracy of 1 ± 0.1 mm for the AR-based system. Furthermore, a deep learning-based U-Net segmentation network is incorporated to enable automatic identification of the hydrocephalus location by the system. The system achieves improved recognition accuracy, sensitivity, and specificity of 99.93%, 93.85%, and 95.73%, respectively, representing a significant improvement from previous studies.

Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.

Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1's fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors.

Chemical characteristics and spatiotemporal variation of marine fine particles for clustered channels of air masses transporting toward remote background sites in East Asia.

This study investigated the chemical characteristics, spatiotemporal distribution, and source apportionment of marine fine particles (PM2.5) for clustered transport channels/routes of air masses moving toward three remote sites in East Asia. Six transport routes in three channels were clustered based on backward trajectory simulation (BTS) in the order of: West Channel > East Channel > South Channel. Air masses transported toward Dongsha Island (DS) came mainly from the West Channel, while those transported toward Green Island (GR) and Kenting Peninsula (KT) came mostly from the East Channel. High PM2.5 commonly occurred from late fall to early spring during the periods of Asian Northeastern Monsoons (ANMs). Marine PM2.5 was dominated by water-soluble ions (WSIs) which were predominated by secondary inorganic aerosols (SIAs). Although the metallic content of PM2.5 was predominated by crustal elements (Ca, K, Mg, Fe, and Al), enrichment factor clearly showed that trace metals (Ti, Cr, Mn, Ni, Cu, and Zn) came mainly from anthropogenic sources. Organic carbon (OC) was superior to elemental carbon (EC), while OC/EC and SOC/OC ratios in winter and spring were higher than those in other two seasons. Similar trends were observed for levoglucosan and organic acids. The mass ratio of malonic acid and succinic acid (M/S) was commonly higher than unity, showing the influences of biomass burning (BB) and secondary organic aerosols (SOAs) on marine PM2.5. We resolved that the main sources of PM2.5 were sea salts, fugitive dust, boiler combustion, and SIAs. Boiler combustion and fishing boat emissions at the site DS had higher contribution than those at the sites GR and KT. The highest/lowest contribution ratios of cross-boundary transport (CBT) were 84.9/29.6% in winter and summer, respectively.

Impact of intravenous vitamin C as a monotherapy on mortality risk in critically ill patients: A meta-analysis of randomized controlled trials with trial sequential analysis.

Background: This meta-analysis aimed at investigating the pooled evidence regarding the effects of intravenous vitamin C (IVVC) on mortality rate in critically ill patients. Methods: Databases including Medline, Embase, and Cochrane Library were searched from inception to October, 2022 to identify RCTs. The primary outcome was the risk of overall mortality. Subgroup analyses were performed based on IVVC dosage (i.e., cut-off value: 100 mg/kg/day or 10000 mg/day). Trial sequential analysis (TSA) was used to examine the robustness of evidence. Results: A total of 12 trials including 1,712 patients were analyzed. Although meta-analysis demonstrated a lower risk of mortality in patients with IVVC treatment compared to those without [risk ratio (RR): 0.76, 95% CI: 0.6 to 0.97, p = 0.02, I 2 = 36%, 1,711 patients), TSA suggested the need for more studies for verification. Moreover, subgroup analyses revealed a reduced mortality risk associated with a low IVVC dosage (RR = 0.72, p = 0.03, 546 patients), while no beneficial effect was noted with high IVVC dosage (RR = 0.74, p = 0.13, I 2 = 60%, 1,165 patients). The durations of vasopressor [mean difference (MD): -37.75 h, 404 patients) and mechanical ventilation (MD: -47.29 h, 388 patients) use were shorter in the IVVC group than those in the controls, while there was no significant difference in other prognostic outcomes (e.g., length of stay in intensive care unit/hospital) between the two groups. Conclusion: Although intravenous vitamin C as a monotherapy reduced pooled mortality, durations of vasopressor use and mechanical ventilation, further research is required to support our findings and to identify the optimal dosage of vitamin C in the critical care setting. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022371090.

A 3D culture system for evaluating the combined effects of cisplatin and anti-fibrotic drugs on the growth and invasion of lung cancer cells co-cultured with fibroblasts.

Fibrosis and fibroblast activation usually occur in the tissues surrounding a malignant tumor; therefore, anti-fibrotic drugs are used in addition to chemotherapy. A reliable technique for evaluating the combined effects of anti-fibrotic drugs and anticancer drugs would be beneficial for the development of an appropriate treatment strategy. In this study, we manufactured a three-dimensional (3D) co-culture system of fibroblasts and lung cancer cell spheroids in Matrigel supplemented with fibrin (fibrin/Matrigel) that simulated the tissue microenvironment around a solid tumor. We compared the efficacy of an anticancer drug (cisplatin) with or without pretreatments of two anti-fibrotic drugs, nintedanib and pirfenidone, on the growth and invasion of cancer cells co-cultured with fibroblasts. The results showed that the addition of nintedanib improved cisplatin's effects on suppressing the growth of cancer cell spheroids and the invasion of cancer cells. In contrast, pirfenidone did not enhance the anticancer activity of cisplatin. Nintedanib also showed higher efficacy than pirfenidone in reducing the expression of four genes in fibroblasts associated with cell adhesion, invasion, and extracellular matrix degradation. This study demonstrated that the 3D co-cultures in fibrin/Matrigel would be useful for assessing the effects of drug combinations on tumor growth and invasion.

Investigating the associations between organophosphate flame retardants (OPFRs) and fine particles in paired indoor and outdoor air: A probabilistic prediction model for deriving OPFRs in indoor environments.

Contaminants of emerging concern such as organophosphate flame retardants (OPFRs) are associated with atmospheric fine particles (PM2.5), which pose the greatest health risk in the world. However, few surveys have explored the interaction between PM2.5 and OPFRs in residential paired indoor/outdoor environments. 11 priority OPFRs and PM2.5 were investigated across 178 paired indoor and outdoor air samples taken from 89 children's households in southern Taiwan, across cold and warm seasons. This involved exploring their associations with building characteristics, interior materials, and human activities. We developed a probabilistic predictive model for indoor OPFRs based on the indoor/outdoor (I/O) ratio of contaminants and an air quality index. The significant associations of paired indoor/outdoor OPFRs and PM2.5 were explored. The indoor level of OPFRs was greater than that of outdoor households, contrasting with PM2.5. The I/O OPFRs ratio was higher than 1 (except for TEHP, EHDPP, and TCP), which suggests that the sources of OPFRs were primarily emitted from indoors. Indoor TCEP was significantly positively associated with indoor and outdoor PM2.5. The OPFR level detected in apartments was higher than in houses due to the greater decoration, furniture and electronic devices. However, this was not the case for PM2.5. TCIPP was the dominant compound in paired indoor and outdoor air. The indoor OPFR predictive model obtained a high accuracy with an R2 value of 0.87. The material used in mattresses, the use of purifiers and heaters, and the total material area were the main influencing factors for indoor OPFRs in households. These findings could provide important evidence of the interaction between paired indoor/outdoor OPFRs and PM2.5 and interior equipment in different building types. In addition, it could prevent the potential risks posed by indoor/outdoor air pollutants and eliminate OPFR emissions through the selection of better construction and building materials.

Tissue Characteristics of Endometrial Carcinoma Analyzed by Quantitative Synthetic MRI and Diffusion-Weighted Imaging.

BACKGROUND: This study investigates the association of T1, T2, proton density (PD) and the apparent diffusion coefficient (ADC) with histopathologic features of endometrial carcinoma (EC). METHODS: One hundred and nine EC patients were prospectively enrolled from August 2019 to December 2020. Synthetic magnetic resonance imaging (MRI) was acquired through one acquisition, in addition to diffusion-weighted imaging (DWI) and other conventional sequences using 1.5T MRI. T1, T2, PD derived from synthetic MRI and ADC derived from DWI were compared among different histopathologic features, namely the depth of myometrial invasion (MI), tumor grade, cervical stromal invasion (CSI) and lymphovascular invasion (LVSI) of EC by the Mann-Whitney U test. Classification models based on the significant MRI metrics were constructed with their respective receiver operating characteristic (ROC) curves, and their micro-averaged ROC was used to evaluate the overall performance of these significant MRI metrics in determining aggressive histopathologic features of EC. RESULTS: EC with MI had significantly lower T2, PD and ADC than those without MI (p = 0.007, 0.006 and 0.043, respectively). Grade 2-3 EC and EC with LVSI had significantly lower ADC than grade 1 EC and EC without LVSI, respectively (p = 0.005, p = 0.020). There were no differences in the MRI metrics in EC with or without CSI. Micro-averaged ROC of the three models had an area under the curve of 0.83. CONCLUSIONS: Synthetic MRI provided quantitative metrics to characterize EC with one single acquisition. Low T2, PD and ADC were associated with aggressive histopathologic features of EC, offering excellent performance in determining aggressive histopathologic features of EC.

Impact of parental rheumatoid arthritis on risk of autism spectrum disorders in offspring: A systematic review and meta-analysis.

Background: To investigate the association of risk of offspring autism spectrum disorder (ASD) with both maternal and paternal rheumatoid arthritis (RA). Methods: The Embase, Medline, Cochrane Library databases were searched for studies that investigated the association of parental RA with risk of offspring ASD. The primary outcome was the associations of maternal/paternal RA with the risk of offspring ASD. Subgroup analyses were conducted based on the timing of maternal RA diagnosis (i.e., before/after childbirth) and geographical location (i.e., Western vs. Asian countries) of studies. Results: Ten studies published between 2005 and 2022 involving 6,177,650 participants were analyzed. Pooled results revealed a significant association between maternal RA and the risk of ASD (OR = 1.246, p < 0.001, 10 studies), while there was no association of paternal RA with the risk of offspring ASD (OR = 1.104, p = 0.253, four studies). Subgroup analysis demonstrated no correlation between diagnosis of maternal RA before childbirth and the risk of offspring ASD (OR = 1.449, p = 0.192, four studies), while there was a significant association of maternal RA regardless of the timing of diagnosis with the risk of offspring ASD (OR = 1.227, p = 0.001, six studies). Subgroup analysis on geographical location showed a significant association of maternal RA with the risk of offspring ASD regardless of the study location (all p < 0.05). Conclusion: Our findings supported an association between maternal RA and an elevated risk of ASD in offspring. However, given the limited numbers of studies investigating the risk of offspring ASD in mothers diagnosed with RA before childbirth, further studies are warranted to elucidate this issue. Systematic review registration: [www.crd.york.ac.uk/prospero/], identifier [CRD42022358470].

Hybrid modes in gold nanoslit arrays on Bragg nanostructures and their application for sensitive biosensors.

In this work, we present high-performance surface plasmonic sensors using gold nanostructures and Bragg photonic structures. The gold film on the Bragg structure provides Tamm plasmon states (TPs). The Fano coupling between higher order TPs and Bloch-wave surface plasmon polariton (BW-SPP) on the gold nanoslit array results in a new hybrid Tamm-plasmon mode. Using finite-difference time-domain calculations, we demonstrate that the hybrid mode has the advantages of high surface sensitivity of BW-SPP mode and high resonant quality of Tamm state. The calculated plasmonic field distribution shows that the hybrid mode has a similar evanescent distribution with BW-SPP mode on gold surface and TPs field in the Bragg structure. The experimental results verify that the hybrid mode has one hundred times higher wavelength sensitivity than the Tamm state. The figure of merit of the hybrid mode is five times better than the BW-SPP mode in conventional nanoslit arrays. The real-time sensorgram further confirms that the hybrid mode has a much higher sensitivity and better signal to noise ratios in the biomolecular interaction measurement.

Efficacy of methylphenidate for the treatment of apathy in patients with Alzheimer's disease: a systematic review and meta-analysis of randomized controlled studies.

RATIONALE: Despite the reported efficacy of methylphenidate (MET) against Alzheimer's disease (AD)-associated apathy, a recent larger clinical trial was not included in pooled analysis. OBJECTIVES: This study aimed at investigating the efficacy of MET for attenuating apathy in patients diagnosed with AD. METHODS: The PubMed, Cochrane Library, and EMBASE databases were searched from inception until March, 2022 to identify randomized controlled trials (RCTs). The primary outcome was apathy improvement assessed with the Neuropsychiatric Inventory (NPI) apathy subscale, Apathy Evaluation Scale (AES), or Clinical Global Impressions of Change scale (CGI-C apathy). RESULTS: Meta-analysis of four RCTs revealed an improvement in apathy among patients receiving MET compared to placebo (MD = - 5.12, p = 0.04, three trials, 144 participants) at follow-ups of 1-3 months assessed with AES score. Despite the absence of improvement on NPI-apathy subscale at follow-ups of 1-2 months (MD = - 0.74, p = 0.37, three trials, 265 participants), significant improvement was noted at follow-ups of 6 months (MD = - 1.4, p = 0.02, one trial, 180 participants). Assessment with CGI-C apathy revealed no significant association between improvement in apathy with MET use (RR = 1.38, p = 0.05, three trials, 265 participants). No significant differences in global cognitive function (using the Mini Mental State Exam) or adverse events were noted between the two groups. CONCLUSION: While AES score suggested an early attenuation effect of MET on apathy in different domains, the NPI-apathy subscale did not show early improvement in apathy until the 6-month follow-up. Further studies with longer follow-ups are needed to elucidate the efficacy of MET for relieving caregiver burden and improving global functional performance.

General anesthesia but not conscious sedation improves functional outcome in patients receiving endovascular thrombectomy for acute ischemic stroke: A meta-analysis of randomized clinical trials and trial sequence analysis.

Background: This study aimed at comparing the difference in prognostic outcomes between patients receiving general anesthesia (GA) and conscious sedation (CS) for endovascular thrombectomy after acute ischemic stroke. Methods: Databases from Medline, Embase, Google scholar, and Cochrane library were searched for randomized controlled studies (RCTs) comparing patients undergoing GA and CS for endovascular thrombectomy following anterior circulation ischemic stroke. The primary outcome was frequency of 90-day good functional outcome [defined as modified Rankin Scale score of ≤ 2], while secondary outcomes included successful recanalization rate (SRR) [i.e., modified thrombolysis in cerebral infarction = 2b or 3], mortality risk, symptomatic intracranial hemorrhage (ICH), procedure-related complications, hypotension, pneumonia, neurological outcome at post-procedure 24-48 h, and puncture-to-recanalization time. Results: Six RCTs including 883 patients published between 2016 and 2022 were included. Merged results revealed a higher SRR [risk ratio (RR) = 1.11, 95% CI: 1.03-1.2, p = 0.007; I 2 = 29%] and favorable neurological outcomes at 3-months (RR = 1.2, 95% CI: 1.01-1.41, p = 0.04; I 2 = 8%) in the GA group compared to CS group, without difference in the risk of mortality (RR = 0.88), symptomatic ICH (RR = 0.91), procedure-related complications (RR = 1.05), and pneumonia (RR = 1.9) as well as post-procedure neurological outcome (MD = -0.21) and successful recanalization time (MD = 3.33 min). However, GA was associated with a higher risk of hypotension compared with that of CS. Conclusion: Patients with acute anterior circulation ischemic stroke receiving GA were associated with a higher successful recanalization rate as well as a better 3-month neurological outcome compared to the use of CS. Further investigations are warranted to verify our findings. Systematic review registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022342483, identifier: CRD42022342483.

Identification of two pathways mediating protein targeting from ER to lipid droplets.

Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD-ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.

In situ structural analysis reveals membrane shape transitions during autophagosome formation.

Autophagosomes are unique organelles that form de novo as double-membrane vesicles engulfing cytosolic material for destruction. Their biogenesis involves membrane transformations of distinctly shaped intermediates whose ultrastructure is poorly understood. Here, we combine cell biology, correlative cryo-electron tomography (cryo-ET), and extensive data analysis to reveal the step-by-step structural progression of autophagosome biogenesis at high resolution directly within yeast cells. The analysis uncovers an unexpectedly thin intermembrane distance that is dilated at the phagophore rim. Mapping of individual autophagic structures onto a timeline based on geometric features reveals a dynamical change of membrane shape and curvature in growing phagophores. Moreover, our tomograms show the organelle interactome of growing autophagosomes, highlighting a polar organization of contact sites between the phagophore and organelles, such as the vacuole and the endoplasmic reticulum (ER). Collectively, these findings have important implications for the contribution of different membrane sources during autophagy and for the forces shaping and driving phagophores toward closure without a templating cargo.