PKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer.

Phosphoglycerate mutase 1 (PGAM1) is a key node enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, monomeric and dimeric but not tetrameric PKM2 are efficient to phosphorylate and activate PGAM1. In response to epidermal growth factor signaling, Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent PGAM1 H11 phosphorylation, which constitutes a discrepancy between tumor and normal cells. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupts the interaction of PGAM1 with PKM2 and PGAM1 H11 phosphorylation, dampening the glycolysis shunts and tumor growth. Together, these results identify a function of PKM2 as a histidine kinase, and illustrate the importance of enzyme crosstalk as a regulatory mode during metabolic reprogramming and tumorigenesis.

From sub-Saharan Africa to China: Evolutionary history and adaptation of Drosophila melanogaster revealed by population genomics.

Drosophila melanogaster is a widely used model organism for studying environmental adaptation. However, the genetic diversity of populations in Asia is poorly understood, leaving a notable gap in our knowledge of the global evolution and adaptation of this species. We sequenced genomes of 292 D. melanogaster strains from various ecological settings in China and analyzed them along with previously published genome sequences. We have identified six global genetic ancestry groups, despite the presence of widespread genetic admixture. The strains from China represent a unique ancestry group, although detectable differentiation exists among populations within China. We deciphered the global migration and demography of D. melanogaster, and identified widespread signals of adaptation, including genetic changes in response to insecticides. We validated the effects of insecticide resistance variants using population cage trials and deep sequencing. This work highlights the importance of population genomics in understanding the genetic underpinnings of adaptation, an effort that is particularly relevant given the deterioration of ecosystems.

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications.

(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

Conditional chemoconnectomics (cCCTomics) as a strategy for efficient and conditional targeting of chemical transmission.

Dissection of neural circuitry underlying behaviors is a central theme in neurobiology. We have previously proposed the concept of chemoconnectome (CCT) to cover the entire chemical transmission between neurons and target cells in an organism and created tools for studying it (CCTomics) by targeting all genes related to the CCT in Drosophila. Here we have created lines targeting the CCT in a conditional manner after modifying GFP RNA interference, Flp-out, and CRISPR/Cas9 technologies. All three strategies have been validated to be highly effective, with the best using chromatin-peptide fused Cas9 variants and scaffold optimized sgRNAs. As a proof of principle, we conducted a comprehensive intersection analysis of CCT genes expression profiles in the clock neurons, uncovering 43 CCT genes present in clock neurons. Specific elimination of each from clock neurons revealed that loss of the neuropeptide CNMa in two posterior dorsal clock neurons (DN1ps) or its receptor (CNMaR) caused advanced morning activity, indicating a suppressive role of CNMa-CNMaR on morning anticipation, opposite to the promoting role of PDF-PDFR on morning anticipation. These results demonstrate the effectiveness of conditional CCTomics and its tools created here and establish an antagonistic relationship between CNMa-CNMaR and PDF-PDFR signaling in regulating morning anticipation.

Study on the inhibition activity and mechanism of Tanreqing against Klebsiella pneumoniae biofilm formation in vitro and in vivo.

Objective: To evaluate the antibacterial effect of Tanreqing (TRQ) against K. pneumoniae and its inhibition activity on bacterial biofilm formation in vitro and in vivo, and to explore the mechanism of the inhibitory effects of TRQ on K. pneumoniae biofilm formation. Methods: An in vitro biofilm model of K. pneumoniae was established, and the impact of TRQ on biofilm formation was evaluated using crystal violet staining and scanning electron microscopy (SEM). Furthermore, the clearance effect of TRQ against K. pneumoniae in the biofilm was assessed using the viable plate counting method; q-RT PCR was used to evaluate the inhibitory effect of different concentrations of TRQ on the expression of biofilm-related genes in Klebsiella pneumoniae; The activity of quorum sensing signal molecule AI-2 was detected by Vibrio harveyi bioluminescence assay; Meanwhile, a guinea pig lung infection model of Klebsiella pneumoniae was constructed, and after treated with drugs, pathological analysis of lung tissue and determination of bacterial load in lung tissue were performed. The treatment groups included TRQ group, imipenem(IPM) group, TRQ+IPM group, and sterile saline group as the control. Results: The formation of K. pneumoniae biofilm was significantly inhibited by TRQ in vitro experiments. Furthermore, when combined with IPM, the clearance of K. pneumoniae in the biofilm was notably increased compared to the TRQ group and IPM group alone. q-RT PCR analysis revealed that TRQ down-regulated the expression of genes related to biofilm formation in K. pneumoniae, specifically luxS, wbbm, wzm, and lsrK, and also inhibited the activity of AI-2 molecules in the bacterium. In vivo experiments demonstrated that TRQ effectively treated guinea pig lung infections, resulting in reduced lung inflammation. Additionally, when combined with IPM, there was a significant reduction in the bacterial load in lung tissue. Conclusion: TRQ as a potential therapeutic agent plays a great role in the treatment of K. pneumoniae infections, particularly in combination with conventional antibiotics. And TRQ can enhanced the clearance effect on the bacterium by inhibiting the K. pneumoniae biofilm formation, which provided experimental evidence in support of clinical treatment of TRQ against K. pneumoniae infections.

Human genetics of face recognition: discovery of MCTP2 mutations in humans with face blindness (Congenital Prosopagnosia).

Face recognition is important for both visual and social cognition. While prosopagnosia or face blindness has been known for seven decades and face specific neurons for half a century, the molecular genetic mechanism is not clear. Here we report results after 17 years of research with classic genetics and modern genomics. From a large family with 18 congenital prosopagnosia (CP) members with obvious difficulties in face recognition in daily life, we uncovered a fully cosegregating private mutation in the MCTP2 gene which encodes a calcium binding transmembrane protein expressed in the brain. After screening through cohorts of 6589, we found more CPs and their families, allowing detection of more CP associated mutations in MCTP2. Face recognition differences were detected between 14 carriers with the frameshift mutation S80fs in MCTP2 and 19 non-carrying volunteers. 6 families including one with 10 members showed the S80fs-CP correlation. Functional magnetic resonance imaging found association of impaired recognition of individual faces by MCTP2 mutant CPs with reduced repetition suppression to repeated facial identities in the right fusiform face area. Our results have revealed genetic predisposition of MCTP2 mutations in CP, 76 years after the initial report of prosopagnosia and 47 years after the report of the first CP. This is the first time a gene required for a higher form of visual social cognition was found in humans.

Characterization of the biological and transcriptomic landscapes of bone marrow-derived mesenchymal stem cells in patients with multiple myeloma.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) have been acknowledged as the most important stromal cells in the bone marrow (BM) microenvironment for physiologic hematopoiesis and the concomitant hematologic malignancies. However, the systematic and detailed dissection of the biological and transcriptomic signatures of BM-MSCs in multiple myeloma (MM) are largely unknown. METHODS: In this study, we isolated and identified BM-MSCs from 10 primary MM patients and 10 healthy donors (HD). On the one hand, we compared the multifaceted biological characteristics of the indicated two BM-MSCs, including biomarker expression pattern, multilineage differentiation potential, stemness and karyotyping, together with the cellular vitality and immunosuppressive property. On the other hand, we took advantage of RNA-SEQ and bioinformatics analysis to verify the similarities and differences at the transcriptomic level between MM-MSCs and HD-MSCs. RESULTS: As to biological phenotypes and biofunctions, MM-MSCs revealed conservation in immunophenotype, stemness and differentiation towards adipocytes and chondrocytes with HD-MSCs, whereas with impaired osteogenic differentiation potential, cellular vitality and immunosuppressive property. As to transcriptomic properties, MM-MSCs revealed multidimensional alterations in gene expression profiling and genetic variations. CONCLUSIONS: Overall, our date systematic and detailed reflected the multifaceted similarities and variations between MM-MSCs and HD-MSCs both at the cellular and molecular levels, and in particular, the alterations of immunomodulation and cellular viability of MM-MSCs, which wound benefit the further exploration of the pathogenesis and new drug application (NDA) of multiple myeloma from the view of BM-MSCs.

Unveiling Sb3+ Doping and Tricolor Luminescence from Intrinsic Self-Trapped Excitons in Cs2ZnCl4 Crystals.

Zero-dimensional (0D) lead-free halide perovskites have lately received significant interest owing to their captivating broadband emissions. An in-depth understanding of the luminescence mechanism of self-trapped excitons (STEs) and realization of effective regulation of luminescence properties have become a major challenge in the research of lead-free metal halides. Herein, we have synthesized the Cs2ZnCl4 and Sb3+-doped Cs2ZnCl4 crystals and conducted a comprehensive investigation into their distinct electronic structures and optical characteristics. The findings from both experimental and theoretical investigations indicate that the tricolor luminescence in Cs2ZnCl4 and blue emission in Sb3+-doped Cs2ZnCl4 stem from intrinsic STEs, and the near-infrared emission originates from extrinsic STEs associated with the Sb3+ ion in Sb3+-doped Cs2ZnCl4. Sb3+ doping increases the quantum yield of Cs2ZnCl4 to a large extent. In addition, intersystem crossing, exciton self-trapping, and lattice relaxation are the main reasons for the large Stokes shift. The present study is expected to provide a novel perspective for researchers in comprehending the luminescent mechanism of STEs and advancing the utilization of 0D lead-free metal halides in optoelectronic applications.

Knowledge Graph for Breast Cancer Prevention and Treatment: Literature-Based Data Analysis Study.

Background: The incidence of breast cancer has remained high and continues to rise since the 21st century. Consequently, there has been a significant increase in research efforts focused on breast cancer prevention and treatment. Despite the extensive body of literature available on this subject, systematic integration is lacking. To address this issue, knowledge graphs have emerged as a valuable tool. By harnessing their powerful knowledge integration capabilities, knowledge graphs offer a comprehensive and structured approach to understanding breast cancer prevention and treatment. Objective: We aim to integrate literature data on breast cancer treatment and prevention, build a knowledge graph, and provide support for clinical decision-making. Methods: We used Medical Subject Headings terms to search for clinical trial literature on breast cancer prevention and treatment published on PubMed between 2018 and 2022. We downloaded triplet data from the Semantic MEDLINE Database (SemMedDB) and matched them with the retrieved literature to obtain triplet data for the target articles. We visualized the triplet information using NetworkX for knowledge discovery. Results: Within the scope of literature research in the past 5 years, malignant neoplasms appeared most frequently (587/1387, 42.3%). Pharmacotherapy (267/1387, 19.3%) was the primary treatment method, with trastuzumab (209/1805, 11.6%) being the most commonly used therapeutic drug. Through the analysis of the knowledge graph, we have discovered a complex network of relationships between treatment methods, therapeutic drugs, and preventive measures for different types of breast cancer. Conclusions: This study constructed a knowledge graph for breast cancer prevention and treatment, which enabled the integration and knowledge discovery of relevant literature in the past 5 years. Researchers can gain insights into treatment methods, drugs, preventive knowledge regarding adverse reactions to treatment, and the associations between different knowledge domains from the graph.

Regulatory focus as a mediator in the relationship between nurses' organizational silence and professional identity.

AIMS: This work aims to analyse the current state of the professional identity of Chinese nurses; examine the relationship amongst regulatory focus, organizational silence and professional identity and determine how regulatory focus affects the relationship between professional identity and organizational silence. DESIGN: This study conducted a cross-sectional survey. METHODS: From June to August 2023, 420 nurses from six hospitals in Hunan Province, China, were selected through convenience sampling and surveyed by using a general information questionnaire, the regulatory focus scale, the organizational silence scale and the professional identity scale. The relationship amongst the regulatory focus, organizational silence and professional identity of nurses was examined by utilizing SPSS 25.0 and the mediating role of regulatory focus between organizational silence and nurses' professional identity was examined by applying AMOS 24.0. RESULTS: Nurses had a moderate level of professional identity. Professional identity was positively correlated with regulatory focus and negatively correlated with organizational silence. Regulatory focus was negatively correlated with organizational silence. Mediation effect studies revealed that organizational silence and professional identity were partially mediated by regulatory focus. CONCLUSION: In accordance with research showing that nurses' organizational silence can indirectly affect professional identity via regulatory focus, clinical nursing managers should concentrate on the interaction amongst these three variables to strengthen professional identity. IMPACT: The results of this study serve as a reminder to nurses to select a preventive or promotive focus based on their career objectives and to effectively express their views to enhance their professional identity. This also reminds nursing managers assess nurse-led regulatory focus, identify their underlying qualities and understand their professional aspirations and career orientation, create a good atmosphere for advice and encourage nurses to express their views, so as to improve nurses 'professional identity. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Light-Mediated Multilevel Flexible High-Efficiency Perovskite Resistive Switching Memory Based on Mn:CsPbCl3 Nanocrystals.

Herein, the electrical characteristics, photoelectric properties, resistive switching (RS) mechanism, and flexible storage application of Ag/PMMA&Mn:CsPbCl3/ITO (PMMA = poly(methyl methacrylate)) devices are studied by using the photoelectric material Mn:CsPbCl3 nanocrystals (NCs) embedded in PMMA as the RS layer. The devices exhibit bipolar RS behavior with low operating voltage, excellent cycling endurance (>1000 times), long retention time (≥104 s), high ON/OFF ratio (≈104), and good environmental stability. The flexible memory devices have demonstrated reliable mechanical stability of consecutive 1000 bending cycles. In addition, multilevel data storage is realized by introducing the UV light, and the adjustive resistive switching characteristics is achieved through photoelectric synergistic work. The resistive switching mechanism under the excitation of light has been studied comprehensively. This work may pave a new way for developing the next generation of high-density data storage and photoelectric memristor.

Evaluation of the effects of three different processing methods of aconite on rat metabolites based on high-coverage pseudotargeted metabolomics.

Aconite is the processed product of the seed root of Aconitum carmichaelii Debx. Aconite is a commonly used traditional Chinese medicine, which is generally used after processing. Black aconite, light aconite, and salted aconite are three different processed aconite products. They have the effects of restoring yang and saving energy enemy, dispersing cold, and relieving pain. However, clinical aconite poisoning cases have frequently been reported. In our study, we investigated the effects of three different processed aconite products on the changes of metabolites in vivo. A total of 42 rats were randomly divided into seven groups with six rats in each group. After three consecutive days of intragastric administration of 2.7 g/kg of the aconite-processed product, rat serums were obtained. The rat metabolites were detected using liquid chromatography-tandem mass spectrometry. The altered metabolites related to aconite-processed products were discovered by statistical analysis using metaboanalyst software. Our study is the first time to comprehensively evaluate the effects of three different processed aconite products on rat metabolites based on pseudotargeted metabolomics.

Cysteine and homocysteine can be exploited by GPX4 in ferroptosis inhibition independent of GSH synthesis.

Ferroptosis is inhibited by glutathione peroxidase 4 (GPX4), an antioxidant enzyme that uses reduced glutathione (GSH) as a cofactor to detoxify lipid hydroperoxides. As a selenoprotein, the core function of GPX4 is the thiol-dependent redox reaction. In addition to GSH, other small molecules such as cysteine and homocysteine also contain thiols; yet, whether GPX4 can exploit cysteine and homocysteine to directly detoxify lipid hydroperoxides and inhibit ferroptosis has not been addressed. In this study, we found that cysteine and homocysteine inhibit ferroptosis in a GPX4-dependent manner. However, cysteine inhibits ferroptosis independent of GSH synthesis, and homocysteine inhibits ferroptosis through non-cysteine and non-GSH pathway. Furthermore, we used molecular docking and GPX4 activity analysis to study the binding patterns and affinity between GPX4 and GSH, cysteine, and homocysteine. We found that besides GSH, cysteine and homocysteine are also able to serve as substrates for GPX4 though the affinities of GPX4 with cysteine and homocysteine are lower than that with GSH. Importantly, GPX family and the GSH synthetase pathway might be asynchronously evolved. When GSH synthetase is absent, for example in Flexibacter, the fGPX exhibits higher affinity with cysteine and homocysteine than GSH. Taken together, the present study provided the understanding of the role of thiol-dependent redox systems in protecting cells from ferroptosis and propose that GSH might be a substitute for cysteine or homocysteine to be used as a cofactor for GPX4 during the evolution of aerobic metabolism.

Impact of perioperative red blood cell transfusion on the prognosis of patients with epithelial ovarian cancer.

Background: Surgery for advanced ovarian cancer tends to be extensive. We performed an analysis to determine whether perioperative red blood cell transfusion (PRBCT) is associated with a poor prognosis in women with epithelial ovarian cancer (EOC). Methods: Our retrospective analysis included 314 women. The Mann-Whitney rank-sum test and chi-square test were used to analyze the clinical characteristics of the PRBCT and non-PRBCT groups, and Cox proportional hazard models were used for the multivariate analysis. Results: PRBCT was associated with higher relapse and mortality rates in 121 (38.54 %) patients. After multivariate analysis, transfused patients were 1.59 times at risk of death (hazard ratio [HR] = 1.59; 95%CI, 1.12-2.25) and 1.63 times at risk of recurrence (HR = 1.63; 95%CI, 1.22-2.18) than non-transfused patients. Conclusions: PRBCT could prolong hospital stay, and increased hospital costs were significantly associated with increased cancer recurrence and overall mortality in patients with EOC.

Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology.

The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in Slc6a8 and Agat mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.

Population Exposure Changes to Mean and Extreme Climate Events Over Pakistan and Associated Mechanisms.

The increasing prevalence of warmer trends and climate extremes exacerbate the population's exposure to urban settlements. This work investigated population exposure changes to mean and extreme climate events in different Agro-Ecological Zones (AEZs) of Pakistan and associated mechanisms (1979-2020). Spatiotemporal trends in mean and extreme temperatures revealed significant warming mainly over northern, northeastern, and southern AEZs. In contrast, mean-to-extreme precipitation changes showed non-uniform patterns with a significant increase in the northeast AEZs. Population exposure to mean (extreme) temperature and precipitation events increased two-fold during 2000-2020. The AEZs in urban settlements (i.e., Indus Delta, Northern Irrigated Plain, and Barani/Rainfall) show a maximum exposure to extreme temperatures of about 70-100 × 106 (person-days) in the reference period (1979-1999), which increases to 140-200 × 106 person-days in the recent period (2000-2020). In addition, the highest exposure to extreme precipitation days also increases to 40-200 × 106 person-days during 2000-2020 than 1979-1999 (20-100 × 106) person-days. Relative changes in exposure are large (60%-90%) for the AEZs across northeast Pakistan, justifying the spatial population patterns over these zones. Overall, the observed changes in exposure are primarily attributed to the climate effect (50%) over most AEZs except Northern Irrigated Plain for R10 and R20 events, where the interaction effect takes the lead. The population exposure rapidly increased over major AEZs of Pakistan, which could be more vulnerable to extreme events due to rapid urbanization and population growth in the near future.

Comparison of different predictive biomarker testing assays for PD-1/PD-L1 checkpoint inhibitors response: a systematic review and network meta-analysis.

Background: Accurate prediction of efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors is of critical importance. To address this issue, a network meta-analysis (NMA) comparing existing common measurements for curative effect of PD-1/PD-L1 monotherapy was conducted. Methods: We searched PubMed, Embase, the Cochrane Library database, and relevant clinical trials to find out studies published before Feb 22, 2023 that use PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), microsatellite instability (MSI), multiplex IHC/immunofluorescence (mIHC/IF), other immunohistochemistry and hematoxylin-eosin staining (other IHC&HE) and combined assays to determine objective response rates to anti-PD-1/PD-L1 monotherapy. Study-level data were extracted from the published studies. The primary goal of this study was to evaluate the predictive efficacy and rank these assays mainly by NMA, and the second objective was to compare them in subgroup analyses. Heterogeneity, quality assessment, and result validation were also conducted by meta-analysis. Findings: 144 diagnostic index tests in 49 studies covering 5322 patients were eligible for inclusion. mIHC/IF exhibited highest sensitivity (0.76, 95% CI: 0.57-0.89), the second diagnostic odds ratio (DOR) (5.09, 95% CI: 1.35-13.90), and the second superiority index (2.86). MSI had highest specificity (0.90, 95% CI: 0.85-0.94), and DOR (6.79, 95% CI: 3.48-11.91), especially in gastrointestinal tumors. Subgroup analyses by tumor types found that mIHC/IF, and other IHC&HE demonstrated high predictive efficacy for non-small cell lung cancer (NSCLC), while PD-L1 IHC and MSI were highly efficacious in predicting the effectiveness in gastrointestinal tumors. When PD-L1 IHC was combined with TMB, the sensitivity (0.89, 95% CI: 0.82-0.94) was noticeably improved revealed by meta-analysis in all studies. Interpretation: Considering statistical results of NMA and clinical applicability, mIHC/IF appeared to have superior performance in predicting response to anti PD-1/PD-L1 therapy. Combined assays could further improve the predictive efficacy. Prospective clinical trials involving a wider range of tumor types are needed to establish a definitive gold standard in future.

Precipitation regime changes in High Mountain Asia driven by cleaner air.

High Mountain Asia (HMA) has experienced a spatial imbalance in water resources in recent decades, partly because of a dipolar pattern of precipitation changes known as South Drying-North Wetting1. These changes can be influenced by both human activities and internal climate variability2,3. Although climate projections indicate a future widespread wetting trend over HMA1,4, the timing and mechanism of the transition from a dipolar to a monopolar pattern remain unknown. Here we demonstrate that the observed dipolar precipitation change in HMA during summer is primarily driven by westerly- and monsoon-associated precipitation patterns. The weakening of the Asian westerly jet, caused by the uneven emission of anthropogenic aerosols, favoured a dipolar precipitation trend from 1951 to 2020. Moreover, the phase transition of the Interdecadal Pacific Oscillation induces an out-of-phase precipitation change between the core region of the South Asian monsoon and southeastern HMA. Under medium- or high-emission scenarios, corresponding to a global warming of 0.6-1.1 °C compared with the present, the dipolar pattern is projected to shift to a monopolar wetting trend in the 2040s. This shift in precipitation patterns is mainly attributed to the intensified jet stream resulting from reduced emissions of anthropogenic aerosols. These findings underscore the importance of considering the impact of aerosol emission reduction in future social planning by policymakers.

Aqueous-Based Inorganic Colloidal Halide Perovskites Customizing Liquid Scintillators.

Compared to solid scintillators and organic liquid scintillators, aqueous-based liquid scintillators (AbLS) have more superiority in highly flexible scalability, yet are now limited by their low light yield (≈100 photons MeV-1 ). Here, aqueous-based inorganic colloidal halide perovskites with high photoluminescence quantum yield (PLQY) of three primary color luminescence up to 88.1% (red), 96% (green), and 81.8% (blue) are respectively synthesized, and a new generation of colloidal perovskite-mediated AbLS (PAbLS) with light yield increased in comparison with the commercial scintillator AbLS is fabricated. This paper exhibits that the excellent PLQY and colloidal dispersion of halide perovskites benefit from poly(ethylene glycol) modification and this modification ensures the vacancy inhibition and formation of defect-free surfaces in an aqueous solution. Moreover, their high luminescent emission can be maintained for 100 days at low temperatures, and such modification also promises the heat-to-cold customization of operating temperature even in ice below 0 °C. Finally, depending on the light yield of around 3058 and 8037 photons MeV-1 at room temperature and low temperature, PAbLS with shape/size scalability exhibit their robust radiation hardness (dose rate as high as 23 mGy s-1 ) and conceptual application potential in high-energy ray radiation detection from every angle of 360°.

Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability.

Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of SLC6A17-based-ID were both unclear. Here, we report learning deficits in Slc6a17 knockout and point mutant mice. Biochemistry, proteomic, and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of Slc6a17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with seven types of genetically modified mice have shown Gln as an endogenous substrate of SLC6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID.