Regulation of glycolysis-derived L-lactate production in astrocytes rescues the memory deficits and Aß burden in early Alzheimer's disease models.

Aberrant energy metabolism in the brain is a common pathological feature in the preclinical Alzheimer's Disease (AD). Recent studies have reported the early elevations of glycolysis-involved enzymes in AD brain and cerebrospinal fluid according to a large-scale proteomic analysis. It's well-known that astrocytes exhibit strong glycolytic metabolic ability and play a key role in the regulation of brain homeostasis. However, its relationship with glycolytic changes and cognitive deficits in early AD patients is unclear. Here, we investigated the mechanisms by which astrocyte glycolysis is involved in early AD and its potential as a therapeutic target. Our results suggest that Aß-activated microglia can induce glycolytic-enhanced astrocytes in vitro, and that these processes are dependent on the activation of the AKT-mTOR-HIF-1α pathway. In early AD models, the increase in L-lactate produced by enhanced glycolysis of astrocytes leads to spatial cognitive impairment by disrupting synaptic plasticity and accelerating Aß aggregation. Furthermore, we find rapamycin, the mTOR inhibitor, can rescue the impaired spatial memory and Aß burden by inhibiting the glycolysis-derived L-lactate in the early AD models. In conclusion, we highlight that astrocytic glycolysis plays a critical role in the early onset of AD and that the modulation of glycolysis-derived L-lactate by rapamycin provides a new strategy for the treatment of AD.

Multimodal imaging diagnosis and analysis of prognostic factors in patients with adult-onset Coats disease.

AIM: To describe the multimodal imaging features, treatment, and outcomes of patients diagnosed with adult-onset Coats disease. METHODS: This retrospective study included patients first diagnosed with Coats disease at ≥18 years of age between September 2017 and September 2021. Some patients received anti-vascular endothelial growth factor (VEGF) therapy (conbercept, 0.5 mg) as the initial treatment, which was combined with laser photocoagulation as needed. All the patients underwent best corrected visual acuity (BCVA) and intraocular pressure examinations, fundus color photography, spontaneous fluorescence tests, fundus fluorescein angiography, optical coherence tomography (OCT), OCT angiography, and other examinations. BCVA alterations and multimodal image findings in the affected eyes following treatment were compared and the prognostic factors were analyzed. RESULTS: The study included 15 patients who were aged 24-72 (57.33±12.61)y at presentation. Systemic hypertension was the most common associated systemic condition, occurring in 13 (86.7%) patients. Baseline BCVA ranged from 2.0 to 5.0 (4.0±1.1), which showed improvement following treatment (4.2±1.0). Multimodal imaging revealed retinal telangiectasis in 13 patients (86.7%), patchy hemorrhage in 5 patients (33.3%), and stage 2B disease (Shield's staging criteria) in 11 patients (73.3%). OCT revealed that the baseline central macular thickness (CMT) ranged from 129 to 964 µm (473.0±230.1 µm), with 13 patients (86.7%) exhibiting a baseline CMT exceeding 250 µm. Furthermore, 8 patients (53.3%) presented with an epiretinal membrane at baseline or during follow-up. Hyper-reflective scars were observed on OCT in five patients (33.3%) with poor visual prognosis. Vision deteriorated in one patient who did not receive treatment. Final vision was stable in three patients who received laser treatment, whereas improvement was observed in one of two patients who received anti-VEGF therapy alone. In addition, 8 of 9 patients (88.9%) who received laser treatment and conbercept exhibited stable or improved BCVA. CONCLUSION: Multimodal imaging can help diagnose adult-onset Coats disease. Anti-VEGF treatment combined with laser therapy can be an option for improving or maintaining BCVA and resolving macular edema. The final visual outcome depends on macular involvement and the disease stage.

[Etiology, Clinical Characteristics and Prognosis of Secondary Hemophagocytic Syndrome].

OBJECTIVE: To understand the etiology, clinical characteristics and prognosis of secondary hemophagocytic syndrome (HLH), so as to improve the understanding of HLH and reduce the rates of misdiagnosis and missed diagnosis of HLH. METHODS: A retrospective study was conducted to analyze the cause, clinical characteristics, laboratory findings, therapy and outcomes of 75 adult patients with secondary HLH admitted to our hospital from January 2015 to December 2021. Follow-up continued until the last discharge time. RESULTS: Among 75 patients, infection-related HLH was the most common (45.33%), followed by lymphoma-related HLH (17.33%). Fever was the most common clinical manifestation (97.67%). Laboratory indicators such as NK cell activity (98.31% low or absent), sCD25 (93.22% increased), and serum ferritin (94.44% elevated) had higher sensitivity in diagnosis. By comparing the clinical manifestations and laboratory indicators of HLH patients with different causes, sex, lymph node enlargement and bone marrow morphology were more valuable for the diagnosis of primary disease (all P <0.05). By comparing the treatment and clinical outcomes of HLH patients with different causes, the highest clinical remission rate (83.3%) was achieved in patients with autoimmune disease-related HLH treated with hormone+cyclosporine (P <0.05). The overall 12-month survival rate of all patients was 26.7%, in which the infection-related HLH was the lowest (14.7%) while autoimmune disease-related HLH was the highest (63.6%). CONCLUSION: The causes and clinical characteristics of adult secondary HLH are varied, with poor prognosis and heterogeneity in disease severity. It is important to identify HLH cause early for diagnosis and needed to further understand HLH.

Harnessing the plant microbiome for environmental sustainability: From ecological foundations to novel applications.

In plant environments, there exist heterogeneous microbial communities, referred to as the plant microbiota, which are recruited by plants and play crucial roles in promoting plant growth, aiding in resistance against pathogens and environmental stresses, thereby maintaining plant health. These microorganisms, along with their genomes, collectively form the plant microbiome. Research on the plant microbiome can help unravel the intricate interactions between plants and microbes, providing a theoretical foundation to reduce pesticide use, enhance agricultural productivity, and promote environmental sustainability. Despite significant progress in the field of research, unresolved challenges persist due to ongoing technological limitations and the complexities inherent in studying microorganisms at small scales. Recently, synthetic community (SynCom) has emerged as a novel technique for microbiome research, showing promising prospects for applications in the plant microbiome field. This article systematically introduces the origin and distribution of plant microbiota, the processes of their recruitment and colonization, and the mechanisms underlying their beneficial functions for plants, from the aspects of composition, assembly, and function. Furthermore, we discuss the principles, applications, challenges, and prospects of SynCom for promoting plant health.

A review of Legionella transmission risk in built environments: sources, regulations, sampling, and detection.

The risk of Legionella transmission in built environments remains a significant concern. Legionella can spread within buildings through aerosol transmission, prompting the exploration of airborne transmission pathways and proposing corresponding prevention and control measures based on building characteristics. To this end, a comprehensive literature review on the transmission risk of Legionella in built environments was performed. Four electronic databases (PubMed, Web of Science, Google Scholar, and CNKI) were searched from inception to March 2024 for publications reporting the risk of Legionella transmission in built environments. Relevant articles and gray literature reports were hand-searched, and 96 studies were finally included. Legionella pollution comes from various sources, mainly originates in a variety of built environments in which human beings remain for extended periods. The sources, outbreaks, national standards, regulations, and monitoring techniques for Legionella in buildings are reviewed, in addition to increases in Legionella transmission risk due to poor maintenance of water systems and long-distance transmission events caused by aerosol characteristics. Air and water sampling using various analytical methods helps identify Legionella in the environment, recognize sources in the built environments, and control outbreaks. By comparing the standard regulations of national organizations globally, the authors further highlight gaps and deficiencies in Legionella surveillance in China. Such advancements offer essential insights and references for understanding and addressing Legionella transmission risk in the built environment, with the potential to contribute to safeguarding public health and building environment safety.

AI-assisted discovery of high-temperature dielectrics for energy storage.

Electrostatic capacitors play a crucial role as energy storage devices in modern electrical systems. Energy density, the figure of merit for electrostatic capacitors, is primarily determined by the choice of dielectric material. Most industry-grade polymer dielectrics are flexible polyolefins or rigid aromatics, possessing high energy density or high thermal stability, but not both. Here, we employ artificial intelligence (AI), established polymer chemistry, and molecular engineering to discover a suite of dielectrics in the polynorbornene and polyimide families. Many of the discovered dielectrics exhibit high thermal stability and high energy density over a broad temperature range. One such dielectric displays an energy density of 8.3 J cc-1 at 200 °C, a value 11 × that of any commercially available polymer dielectric at this temperature. We also evaluate pathways to further enhance the polynorbornene and polyimide families, enabling these capacitors to perform well in demanding applications (e.g., aerospace) while being environmentally sustainable. These findings expand the potential applications of electrostatic capacitors within the 85-200 °C temperature range, at which there is presently no good commercial solution. More broadly, this research demonstrates the impact of AI on chemical structure generation and property prediction, highlighting the potential for materials design advancement beyond electrostatic capacitors.

Evaluating China's primary healthcare services' efficiency and spatial correlation: a three-stage DEA-Malmquist model.

Introduction: Enhancing the efficiency of primary healthcare services is essential for a populous and developing nation like China. This study offers a systematic analysis of the efficiency and spatial distribution of primary healthcare services in China. It elucidates the fundamental landscape and regional variances in efficiency, thereby furnishing a scientific foundation for enhancing service efficiency and fostering coordinated regional development. Methods: Employs a three-stage DEA-Malmquist model to assess the efficiency of primary healthcare services across 31 provincial units in mainland China from 2012 to 2020. Additionally, it examines the spatial correlation of efficiency distribution using the Moran Index. Results: The efficiency of primary healthcare services in China is generally suboptimal with a noticeable declining trend, highlighting significant potential for improvement in both pure technical efficiency and scale efficiency. There is a pronounced efficiency gap among provinces, yet a positive spatial correlation is evident. Regionally, efficiency ranks in the order of East > Central > West. Factors such as GDP per capita and population density positively influence efficiency enhancements, while urbanization levels and government health expenditures appear to have a detrimental impact. Discussion: The application of the three-stage DEA-Malmquist model and the Moran Index not only expands the methodological framework for researching primary healthcare service efficiency but also provides scientifically valuable insights for enhancing the efficiency of primary healthcare services in China and other developing nations.

Language-aware multiple datasets detection pretraining for DETRs.

Pretraining on large-scale datasets can boost the performance of object detectors while the annotated datasets for object detection are hard to scale up due to the high labor cost. What we possess are numerous isolated filed-specific datasets, thus, it is appealing to jointly pretrain models across aggregation of datasets to enhance data volume and diversity. In this paper, we propose a strong framework for utilizing Multiple datasets to pretrain DETR-like detectors, termed METR, without the need for manual label spaces integration. It converts the typical multi-classification in object detection into binary classification by introducing a pre-trained language model. Specifically, we design a category extraction module for extracting potential categories involved in an image and assign these categories into different queries by language embeddings. Each query is only responsible for predicting a class-specific object. Besides, to adapt our novel detection paradigm, we propose a Class-wise Bipartite Matching strategy that limits the ground truths to match queries assigned to the same category. Extensive experiments demonstrate that METR achieves extraordinary results on either multi-task joint training or the pretrain & finetune paradigm. Notably, our pre-trained models have high flexible transferability and increase the performance upon various DETR-like detectors on COCO val2017 benchmark. Our code is publicly available at: https://github.com/isbrycee/METR.

Growth Properties and Metabolomic Analysis Provide Insight into Drought Tolerance in Barley (Hordeum vulgare L.).

Drought stress is a major meteorological threat to crop growth and yield. Barley (Hordeum vulgare L.) is a vital cereal crop with strong drought tolerance worldwide. However, the underlying growth properties and metabolomic regulatory module of drought tolerance remains less known. Here, we investigated the plant height, spike length, effective tiller, biomass, average spikelets, 1000-grain weight, number of seeds per plant, grain weight per plant, ash content, protein content, starch content, cellulose content, and metabolomic regulation mechanisms of drought stress in barley. Our results revealed that the growth properties were different between ZDM5430 and IL-12 under drought stress at different growth stages. We found that a total of 12,235 metabolites were identified in two barley genotype root samples with drought treatment. More than 50% of these metabolites showed significant differences between the ZDM5430 and IL-12 roots. The Kyoto Encyclopedia of Genes and Genomes pathway analysis identified 368 differential metabolites mainly involved in starch and sucrose metabolism, the pentose phosphate pathway, pyrimidine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis in ZDM5430 under drought stress, whereas the different metabolites of IL-12 under drought stress related to starch and sucrose metabolism, the pentose phosphate pathway, 2-oxocarboxylic acid metabolism, cutin, suberine and wax biosynthesis, carbon metabolism, fatty acid biosynthesis, and C5-branched dibasic acid metabolism. These metabolites have application in the tricarboxylic cycle, the urea cycle, the met salvage pathway, amino acid metabolism, unsaturated fatty acid biosynthesis, phenolic metabolism, and glycolysis. On the other hand, the expression patterns of 13 genes related to the abovementioned bioprocesses in different barley genotypes roots were proposed. These findings afford an overview for the understanding of barley roots' metabolic changes in the drought defense mechanism by revealing the differently accumulated compounds.

Impact of dairy supplementation on bone acquisition in children's limbs: a 12-month cluster-randomized controlled trial and meta-analysis.

The impact of milk on bone health in rural preschoolers is under-researched. This study, through a clinical trial and a meta-analysis, finds that milk supplementation enhances forearm and calcaneus bone acquisition in children, supporting the benefits of daily milk consumption. PURPOSE: This study evaluated the impact of dairy supplementation on bone acquisition in children's limbs through a cluster-randomized controlled trial and a meta-analysis. METHODS: The trial involved 315 children (4-6 year) from Northwest China, randomized to receive either 390 ml of milk daily (n = 215) or 20-30 g of bread (n = 100) over 12 months. We primarily assessed bone mineral density (BMD) and content (BMC) changes at the limbs, alongside bone-related biomarkers, measured at baseline, the 6th and 12th months. The meta-analysis aggregated BMD or BMC changes in the forearm/legs/calcaneus from published randomized trials involving children aged 3-18 years supplemented with dairy foods (vs. control group). RESULTS: Of 278 completed the trial, intention-to-treat analysis revealed significant increases in BMD (4.05% and 7.31%) and BMC (4.69% and 7.34%) in the left forearm at the 6th and 12th months in the milk group compared to controls (P < 0.001). The calcaneus showed notable improvements in BMD (2.01%) and BMC (1.87%) at 6 months but not at 12 months. Additionally, milk supplementation was associated with beneficial changes in bone resorption markers, parathyroid hormone (- 12.70%), insulin-like growth factor 1 (6.69%), and the calcium-to-phosphorus ratio (2.22%) (all P < 0.05). The meta-analysis, encompassing 894 children, indicated that dairy supplementation significantly increased BMD (SMD, 0.629; 95%CI: 0.275, 0.983) and BMC (SMD, 0.616; 95%CI: 0.380, 0.851) (P < 0.05) in the arms, but not in the legs (P > 0.05). CONCLUSION: Milk supplementation significantly improves bone health in children's forearms, underscoring its potential as a strategic dietary intervention for bone development. Trial registration NCT05074836.

Therapeutic effects of exendin-4 on spinal cord injury via restoring autophagy function and decreasing necroptosis in neuron.

AIMS: Necroptosis is one of programmed death that may aggravate spinal cord injury (SCI). We aimed to investigate the effect and mechanism of exendin-4 (EX-4) on the recovery of motor function and necroptosis after SCI. METHODS: The SD rats with left hemisection in the T10 spinal cord as SCI model were used. The behavior tests were measured within 4 weeks. The effects of EX-4 on necroptosis-associated proteins and autophagy flux were explored. In addition, the SHSY5Y cell model was introduced to explore the direct effect of EX-4 on neurons. The effect of lysosome was explored using mTOR activator and AO staining. RESULTS: EX-4 could improve motor function and limb strength, promote the recovery of autophagy flux, and accelerate the degradation of necroptosis-related protein at 3 d after injury in rats. EX-4 reduced lysosome membrane permeability, promoted the recovery of lysosome function and autophagy flux, and accelerated the degradation of necroptosis-related proteins by inhibiting the phosphorylation level of mTOR in the SHSY5Y cell model. CONCLUSION: Our results demonstrated that EX-4 may improve motor function after SCI via inhibiting mTOR phosphorylation level and accelerating the degradation of necroptosis-related proteins in neurons. Our findings may provide new therapeutic targets for clinical treatment after SCI.

Endodontic Treatment of a Dilacerated Maxillary Second Premolar With a Severely Curved Root Canal: A Case Report and Literature Review.

Dilaceration is a developmental anomaly characterized by a sharp change in the axial inclination between the crown and the root of a tooth. Severe root curvature in a dilacerated tooth can greatly complicate root canal treatment. This case report details the successful endodontic treatment of a dilacerated maxillary second premolar with significant root curvature. It highlights the importance of a thorough understanding of root canal anatomy and demonstrates the effectiveness of using pre-curved hand files along with heat-treated nickel-titanium rotary instruments in navigating complex root structures to achieve successful treatment outcomes.

Up-regulating GABA transporter-3 in the zona incerta prevents surgery-induced memory impairment in mice.

Clinical surgery can lead to severe neuroinflammation and cognitive dysfunctions. It has been reported that astrocytes mediate memory formation and postoperative cognitive dysfunction (POCD), however, the thalamic mechanism of astrocytes in mediating POCD remains unknown. Here, we report that reactive astrocytes in zona incerta (ZI) mediate surgery-induced recognition memory impairment in male mice. Immunostaining results showed that astrocytes are activated with GABA transporter-3 (GAT-3) being down-expressed, and neurons were suppressed in the ZI. Besides, our work revealed that reactive astrocytes caused increased tonic current in ZI neurons. Up-regulating the expression of GAT-3 in astrocytes ameliorates surgery-induced recognition memory impairment. Together, our work demonstrates that the reactive astrocytes in the ZI play a crucial role in surgery-induced memory impairment, which provides a new target for the treatment of surgery-induced neural dysfunctions.

NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment.

CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.

Honghua Xiaoyao tablet combined with estradiol improves ovarian function in D-galactose-induced aging mice by reducing apoptosis and affecting the release of reproductive hormones: an in vivo study.

Context: It is very necessary to delay ovarian aging and prevent age-related health problems. The active ingredient in Honghua Xiaoyao tablet (HHXYT) has the effects of anti-oxidation, anti-inflammation, immune regulation and so on. Objective: To explore the effect and mechanism of Honghua Xiaoyao tablet on aging model mice. Materials and methods: The aging model was established by intraperitoneal injection of D-galactose in model mice. The mice in the HHXYT-L,M,H group were given 0.3 g/kg, 0.6 g/kg and 1.2 g/kg Honghua Xiaoyao tablet suspension respectively, and the HHXYT-M + E2 group was given 0.6 g/kg HHXYT +0.13 mg/kg estradiol valerate for 30 days. In this study, ELISA, HE, Western blot, IH and TUNEL were used. Results: HHXYT + E2 can improve the gonadal index, estrous cycle of aging mice. In HHXYT-M + E2 group, the level of FSH and LH decreased, while E2 and AMH increased significantly. The number of growing follicles in HHXYT-M + E2 group increased, which was better than that of HHXYT alone. Western blot results showed that HHXYT-M + E2 group decreased the expression of Bax, cleaved-Parp, cleaved-Casp-3 and CytC molecules and increased the expression of Bcl-2 in ovarian tissue. FSHR expression decreased in model group and increased in HHXYT group. TUNEL staining showed that the number of apoptotic cells in HHXYT group was reduced, and the HHXYT-M + E2 group was the most significantly. Discussion and conclusion: HHXYT can improve the level of sex hormones and increase the number of growing follicles in aging mice. HHXYT-M + E2 group has the best effect, and its mechanism may be related to reducing ovarian granulosa cell apoptosis.

Comparative analysis of plastid genomes reveals rearrangements, repetitive sequence features, and phylogeny in the Annonaceae.

The Annonaceae stands as the most species rich family in the Magnoliales, a basal group of angiosperms. Widely distributed in tropical and subtropical regions, it holds significant ecological and economic value. The plastid genome (plastome) is often employed in studies related to plant phylogenetics, comparative genomics, evolutionary biology, and genetic engineering. Nonetheless, research progress on plastid genomics in the Annonaceae has been relatively slow. In this study, we analyzed the structure and repetitive sequence features of plastomes from 28 Annonaceae species. Among them, Mitrephora tomentosa and Desmos chinensis were newly sequenced, with sizes of 160,157 bp and 192,167 bp, and GC contents of 38.3% and 38.4%, respectively. The plastome size in the Annonaceae ranged from 158,837 bp to 202,703 bp, with inverted repeat (IR) region sizes ranging from 64,621 bp to 25,861 bp. Species exhibiting expansion in the IR region showed an increase in plastome size and gene number, frequent boundary changes, different expansion modes (bidirectional or unidirectional), and an increase in repetitive sequences. Specifically, a large number of dispersed repetitive sequences lead to an increase in the size of the LSC region in Goniothalamus tamirensis. Phylogenetic analysis revealed Annonoideae and Malmeoideae as monophyletic groups and sister clades, with Cananga odorata outside of them, followed by Anaxagorea javanica. This research uncovers the structural variation characteristics of plastomes in the Annonaceae, providing valuable information for understanding the phylogeny and plastome evolution of Annonaceae.

Dimensional and Doping Engineering of Chiral Perovskites with Enhanced Spin Selectivity for Green Emissive Spin Light-Emitting Diodes.

Chiral perovskites play a pivotal role in spintronics and optoelectronic systems attributed to their chiral-induced spin selectivity (CISS) effect. Specifically, they allow for spin-polarized charge transport in spin light-emitting diodes (LEDs), yielding circularly polarized electroluminescence at room temperature without external magnetic fields. However, chiral lead bromide-based perovskites have yet to achieve high-performance green emissive spin-LEDs, owing to limited CISS effects and charge transport. Herein, we employ dimensional regulation and Sn2+-doping to optimize chiral bromide-based perovskite architecture for green emissive spin-LEDs. The optimized (PEA)x(S/R-PRDA)2-xSn0.1Pb0.9Br4 chiral perovskite film exhibits an enhanced CISS effect, higher hole mobility, and better energy level alignment with the emissive layer. These improvements allow us to fabricate green emissive spin-LEDs with an external quantum efficiency (EQE) of 5.7% and an asymmetry factor |gCP-EL| of 1.1 × 10-3. This work highlights the importance of tailored perovskite architectures and doping strategies in advancing spintronics for optoelectronic applications.