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BackgroundClozapine is widely regarded as a highly efficacious psychotropic drug that is largely underused worldwide. Recent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is not well-established due to the absence of analytic cohort studies. The clinical significance of such a potential risk remains unclear.Methods and findingsWe extracted data from a territory-wide public healthcare database from January 2001 to August 2022 in Hong Kong to conduct a retrospective cohort study of anonymized patients aged 18+ years with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least 2 prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment (IPTW) based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated. In total, 9,965 patients with a median follow-up period of 6.99 years (25th to 75th percentile: 4.45 to 10.32 years) were included, among which 834 were clozapine users. After IPTW, the demographic and clinical characteristics of clozapine users were comparable to those of olanzapine users. Clozapine users had a significant weighted IRR of 2.22 (95% confidence interval (CI) [1.52, 3.34]; p < 0.001) for HM compared to olanzapine users. The absolute rate difference was estimated at 57.40 (95% CI [33.24, 81.55]) per 100,000 person-years. Findings were consistent across subgroups by age and sex. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers. The main limitation of this observational study is the potential residual confounding effects that could have arisen from the lack of randomization in clozapine or olanzapine use.ConclusionsAbsolute rate difference in HM incidence associated with clozapine is small despite a 2-fold elevated rate. Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary.

Abstract Purpose The relationship between delayed ambulation (DA) and postoperative adverse events (AEs) following transforaminal lumbar interbody fusion (TLIF) in elderly patients remains elusive. The aim of our study was to evaluate the effects of DA on the postoperative AEs including complications, readmission and prolonged length of hospital stay (LOS). Methods This was a retrospective analysis of a prospectively established database of elderly patients (aged 65 years and older) who underwent TLIF surgery. The early ambulation (EA) group was defined as patients ambulated within 48 h after surgery, whereas the delayed ambulation (DA) group was patients ambulated at a minimum of 48 h postoperatively. The DA patients were 1:1 propensity-score matched to the EA patients based on age, gender and the number of fused segments. Univariate analysis was used to compare postoperative outcomes between the two groups, and multivariate logistic regression analysis was used to identify risk factors for adverse events and DA. Results After excluding 125 patients for various reasons, 1025 patients (≤ 48 h: N = 659 and > 48 h: N = 366) were included in the final analysis. After propensity score matching, there were 326 matched patients in each group. There were no significant differences in the baseline data and the surgery-related variables between the two groups (p > 0.05). The patients in the DA group had a significant higher incidence of postoperative AEs (46.0% vs. 34.0%, p = 0.002) and longer LOS (p = 0.001). Multivariate logistic regression identified that age, operative time, diabetes, and DA were independently associated with postoperative AEs, whereas greater age, higher international normalized ratio, and intraoperative estimated blood loss were identified as independent risk factors for DA. Conclusions Delayed ambulation was an independent risk factor for postoperative AEs after TLIF in elderly patients. Older age, increased intraoperative blood loss and worse coagulation function were associated with delayed ambulation.

Abstract Wounding initiates intricate responses crucial for tissue repair and regeneration. Yet, the gene regulatory networks governing wound healing remain poorly understood. Here, employing single-worm RNA sequencing (swRNA-seq) across 12 time-points, we delineated a three-stage wound repair process in C. elegans: response, repair, and remodeling. Integrating diverse datasets, we constructed a dynamic regulatory network comprising 241 transcription regulators and their inferred targets. We identified potentially seven autoregulatory TFs and five cross-autoregulatory loops involving pqm-1 and jun-1. We revealed that TFs might interact with chromatin factors and form TF-TF combinatory modules via intrinsically disordered regions to enhance response robustness. We experimentally validated six regulators functioning in transcriptional and translocation-dependent manners. Notably, nhr-76, daf-16, nhr-84, and oef-1 are potentially required for efficient repair, while elt-2 may act as an inhibitor. These findings elucidate transcriptional responses and hierarchical regulatory networks during C. elegans wound repair, shedding light on mechanisms underlying tissue repair and regeneration.

Abstract Background Most studies on the impact of the COVID-19 pandemic on depression burden focused on the earlier pandemic phase specific to lockdowns, but the longer-term impact of the pandemic is less well-studied. In this population-based cohort study, we examined the short-term and long-term impacts of COVID-19 on depression incidence and healthcare service use among patients with depression. Methods Using the territory-wide electronic medical records in Hong Kong, we identified all patients aged ≥ 10 years with new diagnoses of depression from 2014 to 2022. We performed an interrupted time-series (ITS) analysis to examine changes in incidence of medically attended depression before and during the pandemic. We then divided all patients into nine cohorts based on year of depression incidence and studied their initial and ongoing service use patterns until the end of 2022. We applied generalized linear modeling to compare the rates of healthcare service use in the year of diagnosis between patients newly diagnosed before and during the pandemic. A separate ITS analysis explored the pandemic impact on the ongoing service use among prevalent patients with depression. Results We found an immediate increase in depression incidence (RR = 1.21, 95% CI: 1.10–1.33, p

Magnesium chelatase (MgCh) plays a pivotal role in photosynthesis, catalyzing the insertion of magnesium into protoporphyrin IX (Proto IX), a key intermediate in chlorophyll (Chl) biosynthesis. MgCh is a heteromeric complex composed of the MgCh D subunit (CHLD), the MgCh H subunit (CHLH), and the MgCh I subunit (CHLI). The bright yellow leaves (byl) mutant was obtained through ethyl methanesulfonate (EMS) mutagenesis of the ‘FT’ Chinese cabbage (Brassica rapa L. ssp. pekinensis) doubled haploid line, whose Chl content, net photosynthetic rate (Pn), and non-photochemical quenching coefficient (NPQ) were decreased, and whose chloroplast development was incomplete. byl recovered to a light green phenotype under weak light conditions. Genetic analysis revealed that the bright yellow leaves phenotype of byl was caused by a single recessive nuclear gene. Using Mutmap sequencing and Kompetitive allele-specific PCR (KASP) identification, BraA01g010040.3.5C, encoding the CHLI subunit of MgCh, was identified as the candidate gene and named Brchli1. A nonsynonymous G-to-A mutation in the Brchli1 exon resulted in the substitution of aspartic acid with asparagine. Brchli1-silenced Chinese cabbage displayed bright yellow leaves with decreased Brchli1 expression. Transiently overexpressed Brchli1 in the byl mutant restored the green leaf phenotype and significantly increased relative Brchli1 expression levels. Both BrCHLI1 and its mutated variant were localized in chloroplasts. Yeast two-hybrid and luciferase complementation imaging assays demonstrated that BrCHLI1 interacted with both BrCHLD and itself. BrCHLI1 mutations did not affect its interaction with BrCHLD. Together, Brchli1 mutations impaired the function of MgCh, providing insights into the molecular mechanism of leaf coloration.

The poor lighting environment in the underground coal mine is easy to cause the miners to have psychological irritability, which leads to the occurrence of accidents. In order to reduce the incidence of accidents and ensure the personal safety of miners. In this paper, different illumination levels are used as control variables. With the help of cognitive ability tests commonly used in psychology, accuracy(AC), reaction time(RT)and performance indicators(PI) are selected to describe how different illumination levels affect the psychological state of miners. The results show that: (1) In the two selected cognitive ability test tasks, when the illumination level is very low, the AC is not high and the RT is longer. As the illumination increases, the AC in the cognitive test task becomes higher and the RT becomes faster. The optimal value is reached at 200lux–300lux.At this time, the illumination level increases again, the AC value decreases, and the RT value increases. When the illuminance is lower than 200Lux, the results of the two tasks are not the same, but when 200Lux∼300Lux, the PI values are larger, and then increase the illuminance, the PI value decreases. (2)The regression analysis of three indicators and illuminance level was carried out, and the binary linear regression equation of different illuminance levels and PI/RT was established to monitor the influence of illuminance on the psychological state of miners. (3) Reasonable control of lighting environment can effectively promote the cognitive ability of miners in the work, and minimize the risk of coal mine accidents.

Observations at (sub-)millimeter wavelengths offer a complementary perspective on our Sun and other stars, offering significant insights into both the thermal and magnetic composition of their chromospheres. Despite the fundamental progress in (sub-)millimeter observations of the Sun, some important aspects require diagnostic capabilities that are not offered by existing observatories. In particular, simultaneously observations of the radiation continuum across an extended frequency range would facilitate the mapping of different layers and thus ultimately the 3D structure of the solar atmosphere. Mapping large regions on the Sun or even the whole solar disk at a very high temporal cadence would be crucial for systematically detecting and following the temporal evolution of flares, while synoptic observations, i.e., daily maps, over periods of years would provide an unprecedented view of the solar activity cycle in this wavelength regime. As our Sun is a fundamental reference for studying the atmospheres of active main sequence stars, observing the Sun and other stars with the same instrument would unlock the enormous diagnostic potential for understanding stellar activity and its impact on exoplanets. The Atacama Large Aperture Submillimeter Telescope (AtLAST), a single-dish telescope with 50m aperture proposed to be built in the Atacama desert in Chile, would be able to provide these observational capabilities. Equipped with a large number of detector elements for probing the radiation continuum across a wide frequency range, AtLAST would address a wide range of scientific topics including the thermal structure and heating of the solar chromosphere, flares and prominences, and the solar activity cycle. In this white paper, the key science cases and their technical requirements for AtLAST are discussed.

In order to establish the internal relationship between the composition and crystallization characteristics of fat and the product quality and whipping properties, the fat composition and crystallization characteristics, emulsion quality, whipped product quality and whipping properties of dairy, non-dairy and mixed creams were analyzed in this study. The results showed that the crystal network formed by mixed animal and vegetable fats had a dense structure and high susceptibility to shear-induced partial aggregation, the resulting emulsion had high viscosity and low overrun, while the whipped product had high hardness and moderate conformal capacity. However, the crystallization properties of vegetable fat were opposite to those of mixed animal and vegetable fats, and the susceptibility to shear-induced partial aggregation was low. The vegetable cream emulsion had low viscosity and high overrun, whereas the whipped product has low hardness and the best conformal capacity. Animal fat had the lowest solid fat content, resulting in the weakest crystal network structure; the rate of partial aggregation, viscosity and overrun of the resulting emulsion were the lowest, and the whipped product had the lowest hardness and conformal capacity. Therefore, the product quality and whipping performance can be controlled by regulating the fat composition and crystallization characteristics. This study can provide theoretical guidance for the development of high-quality whipped cream.

As an essential application of unmanned aerial vehicle (UAV) systems, payload transportation has garnered significant attention in recent years. Collaborative payload transportation utilizing multiple UAVs can effectively increase the payload capacity of the transportation system. Nevertheless, the incorporation of multiple UAVs makes the dynamic model of the transportation system more complex due to the coupled UAV and payload states. In the immediate disaster relief response, the collaborative system is often required to promptly deliver supplies to the target site while avoiding obstacles to ensure the system’s safety. Consequently, devising fast delivery trajectories that avoid collisions for such complicated systems poses a considerable challenge. To this end, a novel trajectory planning method is presented for collaborative transportation systems. Specifically, the dynamic model of the collaborative transportation system is derived by utilizing the Euler–Lagrange method. Then, the trajectory planning problem is formulated as an optimization problem with considerations of dynamics, actuation, safety, and formation constraints. To expedite the optimization process, the collision avoidance safety constraint is constructed using dual variables. The efficacy of this trajectory planning approach is confirmed through multiple real-world flight experiments involving collaborative aerial transportation systems of two and three UAVs.

Phosphorus (P) plays a vital role in fish life and its application in aquatic feed deserves thoroughly study. To evaluate the effects of dietary P on growth performance, serum biochemical parameters and intestinal microbiota of the juvenile hybrid of A. baerii♀ × A. schrenckii♂, five diets containing 3.7, 6.5, 9.6, 12.2 and 14.8 g/kg of available phosphorus (AP) were assigned to feed fish at initial weight of 10.06 ± 0.39 g for 8 weeks. The results showed that weight gain (WG) of juvenile hybrid sturgeon was improved significantly with dietary AP level up to 9.6 g/kg. Feed efficiency (FE) and P digestibility of fish were significantly enhanced by P supplementation, but were dropped when dietary AP level further increased to 12.2 and 14.8 g/kg. Alkaline phosphatase (ALP) activity increased firstly and then slightly decreased at a stable level in the high dietary AP groups (12.2 and 14.8 g/kg). With dietary AP level increasing, significantly decrease of the content of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in serum were observed. Serum antioxidant indicators including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) exhibited the improved activity by addition P in diet. Intestinal microbiota analysis indicated that the supplementation of P in diet increased the richness and diversity of bacteria communities. Cyanobacteria was the dominant phyla in the intestine of hybrid sturgeon, and was significantly increased in P addition group. Compared with the basal diet group, abundant genera in dietary P supplementation group exhibited a higher diversity and were composed of Clostridium, Cetobacterium, Bacteroides, Empedobacter, Ruminococcus, Faecalibacterium, Rhodococcus and Candidatus Arthromitus. In conclusion, appropriate dietary P supplementation could positively affect the growth, biological processes and intestinal microbial communities of fish, and a level of 8.5 g/kg of AP in diet is suggested for juvenile hybrid sturgeon.

Enhancing regional ecosystem stability and managing land resources effectively requires identifying ecological function zones and understanding the factors that influence them. However, most current studies have primarily focused on ecosystem service bundles, paying less attention to the trade-offs, synergies, and ecological sensitivity, leading to a more uniform approach to functional zoning. This study aimed to analyze and describe the spatial and temporal patterns of four essential ecosystem services, including water yield (WY), net primary productivity (NPP), soil conservation (SC), and habitat quality (HQ), in the Sichuan-Yunnan ecological buffer area over the period from 2005 to 2019. Spatial overlay analysis was used to assess ecological sensitivity, trade-offs, synergies, and ecosystem service bundles to define ecological functional zones. Geographic detectors were then applied to identify the primary drivers of spatial variation in these zones. The findings showed a progressive improvement in ecosystem service functions within the Sichuan-Yunnan ecological buffer zone. Between 2005 and 2019, NPP, soil conservation, and water yield all demonstrated positive trends, while HQ displayed a declining trend. There was significant spatial heterogeneity and distinct regional patterns in ecosystem service functions, with a general decrease from southwest to northeast, particularly in NPP and HQ. Trade-offs were evident in most ecosystem services, with the most significant between WY and HQ and most in the northeast and east regions. Ecological sensitivity decreased from southwest to northeast. Regions with a higher ecological sensitivity were primarily situated in the southwestern region, and their spatial distribution pattern was comparable to that of high habitat quality. The spatial overlay analysis categorized areas into various types, including human production and settlement zones, ecologically vulnerable zones, ecological transition zones, and ecological conservation zones, accounting for 17.28%, 22.30%, 7.41%, and 53.01% of the total area, respectively. The primary environmental factor affecting ecological function zoning was identified as precipitation, while the main social variables were human activity and population density. This study enhances the understanding of ecological functions and supports sustainable development in the Sichuan-Yunnan ecological buffer area, offering important guidance for ecological zoning.

Abstract Background Preclinical evidence suggests that certain antipsychotic medications may inhibit the development of lung cancer. This study aims to investigate the association between incident lung cancer and different cumulative exposure periods of flupentixol or any antipsychotics. Methods Using electronic health records from the Hospital Authority in Hong Kong, this nested case-control study included case participants aged 18 years or older with newly diagnosed lung cancer after initiating antipsychotics between January 1, 2003, and August 31, 2022. Each case was matched to up to ten controls of the same sex and age, who were also antipsychotic users. Multivariable conditional logistic regression models were conducted to quantify the association between lung cancer and different cumulative exposure times of flupentixol (0–365 days [ref]; 366–1825 days; 1826+ days) and any antipsychotics (1–365 days [ref]; 366–1825 days; 1826+ days), separately. Results Here we show that among 6435 cases and 64,348 matched controls, 64.06% are males, and 52.98% are aged 65–84 years. Compared to patients with less than 365 days of exposure, those with 366–1825 days of exposure to flupentixol (OR = 0.65 [95% CI, 0.47–0.91]) and any antipsychotics (0.42 [0.38–0.45]) have a lower risk of lung cancer. A decreased risk is observed in patients who have 1826+ days of cumulative use of any antipsychotics (0.54 [0.47–0.60]). Conclusions A reduced risk of lung cancer is observed in patients with more than one year of exposure to flupentixol or any antipsychotics. Further research on the association between lung cancer and other antipsychotic agents is warranted.

Microbial natural products have been one of the most important sources for drug development. In the current postgenomic era, sequence-driven approaches for natural product discovery are becoming increasingly popular. Here, we develop an effective genome mining strategy for the targeted discovery of microbial metabolites with antitumor activities. Our method employs uvrA-like genes as genetic markers, which have been identified in the biosynthetic gene clusters (BGCs) of several chemotherapeutic drugs of microbial origin and confer self-resistance to the corresponding producers. Through systematic genomic analysis of gifted actinobacteria genera, identification of uvrA-like gene-containing BGCs, and targeted isolation of products from a BGC prioritized for metabolic analysis, we identified a new tetracycline-type DNA intercalator timmycins. Our results thus provide a new genome mining strategy for the efficient discovery of antitumor agents acting through DNA intercalation.

Abstract Aims Population-wide restrictions during the COVID-19 pandemic may create barriers to mental health diagnosis. This study aims to examine changes in the number of incident cases and the incidence rates of mental health diagnoses during the COVID-19 pandemic. Methods By using electronic health records from France, Germany, Italy, South Korea and the UK and claims data from the US, this study conducted interrupted time-series analyses to compare the monthly incident cases and the incidence of depressive disorders, anxiety disorders, alcohol misuse or dependence, substance misuse or dependence, bipolar disorders, personality disorders and psychoses diagnoses before (January 2017 to February 2020) and after (April 2020 to the latest available date of each database [up to November 2021]) the introduction of COVID-related restrictions. Results A total of 629,712,954 individuals were enrolled across nine databases. Following the introduction of restrictions, an immediate decline was observed in the number of incident cases of all mental health diagnoses in the US (rate ratios (RRs) ranged from 0.005 to 0.677) and in the incidence of all conditions in France, Germany, Italy and the US (RRs ranged from 0.002 to 0.422). In the UK, significant reductions were only observed in common mental illnesses. The number of incident cases and the incidence began to return to or exceed pre-pandemic levels in most countries from mid-2020 through 2021. Conclusions Healthcare providers should be prepared to deliver service adaptations to mitigate burdens directly or indirectly caused by delays in the diagnosis and treatment of mental health conditions.

We investigated the effects of dietary tannic acid (TA) supplementation of a high-carbohydrate diet on growth, feed utilization, whole-body proximate composition, serum biochemical indicators, antioxidant capacity, digestive enzyme activity, and liver and intestinal health of juvenile largemouth bass, Micropterus salmoides (initial mean weight: 8.08 ± 0.08 g). Five diets were prepared, including a positive control (dietary carbohydrate level, 16%, LC0), a negative control (dietary carbohydrate level, 21%, HC0), and three TA-supplementation diets based on the negative control diet with TA addition at 200, 400, and 800 mg/kg, respectively. After 8 weeks of feeding, the results showed that compared with the LC0 diet, 400–800 mg/kg dietary TA significantly improved the survival rate of largemouth bass (P

The Tibetan Plateau is a region where the Indian and Asian-European plates collide. A high-precision Moho topography model is important for the study of plate motion and internal tectonics of the Tibetan Plateau. However, previous gravity-based models failed in representing adequately the Moho topography because crustal effects and biases in the inversion parameters were not fully considered. To address these issues, we extracted the gravity effect caused by the crust using wavelet multi-scale analysis, and used an adaptive linear inversion method with available gravity and seismic data to estimate more accurate inversion parameters. With these two improvements, we inverted for a high-precision Moho topography model of the Tibetan Plateau. The results show that the majority of the Tibetan Plateau has a Moho depth of 60–70 km. The Moho depth in the center of the Qaidam Basin is about 50 km, and the Moho topography between the east and west of the basin has obvious undulations. The Moho depth of the Tarim Basin ranges from 38–50 km. While the undulation of Moho is limited in the center of the basin, obvious uplifts are shown in northern and southern basin. The plate driving force between the Tibetan Plateau and the Tarim Basin may be the primary cause of this phenomenon. By comparing the difference with the seismic data, we found that the RMS of our model is 2.8 km smaller than that of the CRUST 1.0 model, which shows that our model is more accurate.