A developmental mechanism to regulate alternative polyadenylation in an adult stem cell lineage.

Alternative cleavage and polyadenylation (APA) often results in production of mRNA isoforms with either longer or shorter 3' UTRs from the same genetic locus, potentially impacting mRNA translation, localization, and stability. Developmentally regulated APA can thus make major contributions to cell type-specific gene expression programs as cells differentiate. During Drosophila spermatogenesis, ∼500 genes undergo APA when proliferating spermatogonia differentiate into spermatocytes, producing transcripts with shortened 3' UTRs, leading to profound stage-specific changes in the proteins expressed. The molecular mechanisms that specify usage of upstream polyadenylation sites in spermatocytes are thus key to understanding the changes in cell state. Here, we show that upregulation of PCF11 and Cbc, the two components of cleavage factor II (CFII), orchestrates APA during Drosophila spermatogenesis. Knockdown of PCF11 or cbc in spermatocytes caused dysregulation of APA, with many transcripts normally cleaved at a proximal site in spermatocytes now cleaved at their distal site, as in spermatogonia. Forced overexpression of CFII components in spermatogonia switched cleavage of some transcripts to the proximal site normally used in spermatocytes. Our findings reveal a developmental mechanism where changes in expression of specific cleavage factors can direct cell type-specific APA at selected genes.

Set2 regulates Ccp1 and Swc2 to ensure centromeric stability by retargeting CENP-A.

Precise positioning of the histone-H3 variant, CENP-A, ensures centromere stability and faithful chromosomal segregation. Mislocalization of CENP-A to extra-centromeric loci results in aneuploidy and compromised cell viability associated with formation of ectopic kinetochores. The mechanism that retargets mislocalized CENP-A back to the centromere is unclarified. We show here that the downregulation of the histone H3 lysine 36 (H3K36) methyltransferase Set2 can preserve centromere localization of a temperature-sensitive mutant cnp1-1 Schizosaccharomyces pombe CENP-A (SpCENP-A) protein and reverse aneuploidy by redirecting mislocalized SpCENP-A back to centromere from ribosomal DNA (rDNA) loci, which serves as a sink for the delocalized SpCENP-A. Downregulation of set2 augments Swc2 (SWR1 complex DNA-binding module) expression and releases histone chaperone Ccp1 from the centromeric reservoir. Swc2 and Ccp1 are directed to the rDNA locus to excavate the SpCENP-Acnp1-1, which is relocalized to the centromere in a manner dependent on canonical SpCENP-A loaders, including Mis16, Mis17 and Mis18, thereby conferring cell survival and safeguarding chromosome segregation fidelity. Chromosome missegregation is a severe genetic instability event that compromises cell viability. This mechanism thus promotes CENP-A presence at the centromere to maintain genomic stability.

Machine learning enables pan-cancer identification of mutational hotspots at persistent CTCF binding sites.

CCCTC-binding factor (CTCF) is an insulator protein that binds to a highly conserved DNA motif and facilitates regulation of three-dimensional (3D) nuclear architecture and transcription. CTCF binding sites (CTCF-BSs) reside in non-coding DNA and are frequently mutated in cancer. Our previous study identified a small subclass of CTCF-BSs that are resistant to CTCF knock down, termed persistent CTCF binding sites (P-CTCF-BSs). P-CTCF-BSs show high binding conservation and potentially regulate cell-type constitutive 3D chromatin architecture. Here, using ICGC sequencing data we made the striking observation that P-CTCF-BSs display a highly elevated mutation rate in breast and prostate cancer when compared to all CTCF-BSs. To address whether P-CTCF-BS mutations are also enriched in other cell-types, we developed CTCF-INSITE-a tool utilising machine learning to predict persistence based on genetic and epigenetic features of experimentally-determined P-CTCF-BSs. Notably, predicted P-CTCF-BSs also show a significantly elevated mutational burden in all 12 cancer-types tested. Enrichment was even stronger for P-CTCF-BS mutations with predicted functional impact to CTCF binding and chromatin looping. Using in vitro binding assays we validated that P-CTCF-BS cancer mutations, predicted to be disruptive, indeed reduced CTCF binding. Together this study reveals a new subclass of cancer specific CTCF-BS DNA mutations and provides insights into their importance in genome organization in a pan-cancer setting.

NOP14-mediated ribosome biogenesis is required for mTORC2 activation and predicts rapamycin sensitivity.

The mechanistic target of rapamycin (mTOR) forms two distinct complexes: rapamycin-sensitive mTOR complex 1 (mTORC1) and rapamycin-insensitive mTORC2. mTORC2 primarily regulates cell survival by phosphorylating Akt, though the upstream regulation of mTORC2 remains less well-defined than that of mTORC1. In this study, we show that NOP14, a 40S ribosome biogenesis factor and a target of the mTORC1-S6K axis, plays an essential role in mTORC2 signaling. Knockdown of NOP14 led to mTORC2 inactivation and Akt destabilization. Conversely, overexpression of NOP14 stimulated mTORC2-Akt activation and enhanced cell proliferation. Fractionation and coimmunoprecipitation assays demonstrated that the mTORC2 complex was recruited to the rough endoplasmic reticulum through association with endoplasmic reticulum-bound ribosomes. In vivo, high levels of NOP14 correlated with poor prognosis in multiple cancer types. Notably, cancer cells with NOP14 high expression exhibit increased sensitivity to mTOR inhibitors, because the feedback activation of the PI3K-PDK1-Akt axis by mTORC1 inhibition was compensated by mTORC2 inhibition partly through NOP14 downregulation. In conclusion, our findings reveal a spatial regulation of mTORC2-Akt signaling and identify ribosome biogenesis as a potential biomarker for assessing rapalog response in cancer therapy.

Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes.

Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study.

BACKGROUND AND AIMS: Emerging evidence has raised an obesity paradox in observational studies of body mass index (BMI) and health among the oldest-old (aged ≥80 years), as an inverse relationship of BMI with mortality was reported. This study was to investigate the causal associations of BMI, waist circumference (WC), or both with mortality in the oldest-old people in China. METHODS: A total of 5306 community-based oldest-old (mean age 90.6 years) were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 1998 and 2018. Genetic risk scores were constructed from 58 single-nucleotide polymorphisms (SNPs) associated with BMI and 49 SNPs associated with WC to subsequently derive causal estimates for Mendelian randomization (MR) models. One-sample linear MR along with non-linear MR analyses were performed to explore the associations of genetically predicted BMI, WC, and their joint effect with all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. RESULTS: During 24 337 person-years of follow-up, 3766 deaths were documented. In observational analyses, higher BMI and WC were both associated with decreased mortality risk [hazard ratio (HR) 0.963, 95% confidence interval (CI) 0.955-0.971 for a 1-kg/m2 increment of BMI and HR 0.971 (95% CI 0.950-0.993) for each 5 cm increase of WC]. Linear MR models indicated that each 1 kg/m2 increase in genetically predicted BMI was monotonically associated with a 4.5% decrease in all-cause mortality risk [HR 0.955 (95% CI 0.928-0.983)]. Non-linear curves showed the lowest mortality risk at the BMI of around 28.0 kg/m2, suggesting that optimal BMI for the oldest-old may be around overweight or mild obesity. Positive monotonic causal associations were observed between WC and all-cause mortality [HR 1.108 (95% CI 1.036-1.185) per 5 cm increase], CVD mortality [HR 1.193 (95% CI 1.064-1.337)], and non-CVD mortality [HR 1.110 (95% CI 1.016-1.212)]. The joint effect analyses indicated that the lowest risk was observed among those with higher BMI and lower WC. CONCLUSIONS: Among the oldest-old, opposite causal associations of BMI and WC with mortality were observed, and a body figure with higher BMI and lower WC could substantially decrease the mortality risk. Guidelines for the weight management should be cautiously designed and implemented among the oldest-old people, considering distinct roles of BMI and WC.

Apoptosis and NETotic cell death affect diabetic nephropathy independently: An study integrative study encompassing bioinformatics, machine learning, and experimental validation.

OBJECTIVE: Although programmed cell death (PCD) and diabetic nephropathy (DN) are intrinsically conneted, the interplay among various PCD forms remains elusive. In this study, We aimed at identifying independently DN-associated PCD pathways and biomarkers relevant to the related pathogenesis. METHODS: We acquired DN-related datasets from the GEO database and identified PCDs independently correlated with DN (DN-PCDs) through single-sample Gene Set Enrichment Analysis (ssGSEA) as well as, univariate and multivariate logistic regression analyses. Subsequently, applying differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Mfuzz cluster analysis, we filtered the DN-PCDs pertinent to DN onset and progression. The convergence of various machine learning techniques ultimately spotlighted hub genes, substantiated through dataset meta-analyses and experimental validations, thereby confirming hub genes and related pathways expression consistencies. RESULTS: We harmonized four DN-related datasets (GSE1009, GSE142025, GSE30528, and GSE30529) post-batch-effect removal for subsequent analyses. Our differential expression analysis yielded 709 differentially expressed genes (DEGs), comprising 446 upregulated and 263 downregulated DEGs. Based on our ssGSEA as well as univariate and multivariate logistic regressions, apoptosis and NETotic cell death were appraised as independent risk factors for DN (Odds Ratio > 1, p < 0.05). Next, we further refined 588 apoptosis- and NETotic cell death-associated genes through WGCNA and Mfuzz analysis, resulting in the identification of 17 DN-PCDs. Integrating protein-protein interaction (PPI) network analyses, network topology, and machine learning, we pinpointed hub genes (e.g., IL33, RPL11, and CX3CR1) as significant DN risk factors with expression corroborating in subsequent meta-analyses and experimental validations. Our GSEA enrichment analysis discerned differential enrichments between DN and control samples within pathways such as IL2/STAT5, IL6/JAK/STAT3, TNF-α via NF-κB, apoptosis, and oxidative phosphorylation, with related proteins such as IL2, IL6, and TNFα, which we subsequently submitted to experimental verification. CONCLUSION: Innovatively stemming from from PCD interactions, in this study, we discerned PCDs with an independent impact on DN: apoptosis and NETotic cell death. We further screened DN evolution- and progression-related biomarkers, i.e. IL33, RPL11, and CX3CR1, all of which we empirically validated. This study not only poroposes a PCD-centric perspective for DN studies but also provides evidence for PCD-mediated immune cell infiltration exploration in DN regulation. Our results could motivate further exploration of DN pathogenesis, such as how the inflammatory microenvironment mediates NETotic cell death in DN regulation, representing a promising direction for future research.

Two Key Descriptors for Designing Second Near-Infrared Dyes and Experimental Validation.

Second near-infrared (NIR-II) optical imaging technology has emerged as a powerful tool for diagnostic and image-guided surgery due to its higher imaging contrast. However, a general strategy for efficiently designing NIR-II organic molecules is still lacking, because NIR-II dyes are usually difficult to synthesize, which has impeded the rapid development of NIR-II bioprobes. Herein, based on the theoretical calculations on 62 multiaryl-pyrrole (MAP) systems with spectra ranging from the visible to the NIR-II region, a continuous red shift of the spectra toward the NIR-II region could be achieved by adjusting the type and site of substituents on the MAPs. Two descriptors (ΔEgs and µgs) were identified as exhibiting strong correlations with the maximum absorption/emission wavelengths, and the descriptors could be used to predict the emission spectrum in the NIR-II region only if ΔEgs ≤ 2.5 eV and µgs ≤ 22.55 D. The experimental absorption and emission spectra of ten MAPs fully confirmed the theoretical predictions, and biological imaging in vivo of newly designed MAP23-BBT showed high spatial resolution in the NIR-II region in deep tissue angiography. More importantly, both descriptors of ΔEgs and µgs have shown general applicability to most of the reported donor-acceptor-donor-type non-MAP NIR-II dyes. These results have broad implications for the efficient design of NIR-II dyes.

PARP-2 mediates cardiomyocyte aging and damage induced by doxorubicin through SIRT1 Inhibition.

Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.

Genome-wide identification, expression analysis of WRKY transcription factors in Citrus ichangensis and functional validation of CiWRKY31 in response to cold stress.

BACKGROUND: Ichang papeda (Citrus ichangensis), a wild perennial plant of the Rutaceae family, is a cold-hardy plant. WRKY transcription factors are crucial regulators of plant growth and development as well as abiotic stress responses. However, the WRKY genes in C. ichangensis (CiWRKY) and their expression patterns under cold stress have not been thoroughly investigated, hindering our understanding of their role in cold tolerance. RESULTS: In this study, a total of 52 CiWRKY genes identified in the genome of C. ichangensis were classified into three main groups and five subgroups based on phylogenetic analysis. Comprehensive analyses of motif features, conserved domains, and gene structures were performed. Segmental duplication plays a significant role in the CiWRKY gene family expansion. Cis-acting element analysis revealed the presence of various stress-responsive elements in the promoters of the majority of CiWRKYs. Gene ontology (GO) analysis and protein-protein interaction predictions indicate that the CiWRKYs exhibit crucial roles in regulation of both development and stress response. Expression profiling analysis demonstrates that 14 CiWRKYs were substantially induced under cold stress. Virus-induced gene silencing (VIGS) assay confirmed that CiWRKY31, one of the cold-induced WRKYs, functions positively in regulation of cold tolerance. CONCLUSION: Sequence and protein properties of CiWRKYs were systematically analyzed. Among the 52 CiWRKY genes 14 members exhibited cold-responsive expression patterns, and CiWRKY31 was verified to be a positive regulator of cold tolerance. These findings pave way for future investigations to understand the molecular functions of CiWRKYs in cold tolerance and contribute to unravelling WRKYs that may be used for engineering cold tolerance in citrus.

3D Printing Photonic Crystals: A Review.

Living organisms in nature possess diverse and vibrant structural colors generated from their intrinsic surface micro/nanostructures. These intricate micro/nanostructures can be harnessed to develop a new generation of colorful materials for various fields such as photonics, information storage, display, and sensing. Recent advancements in the fabrication of photonic crystals have enabled the preparation of structurally colored materials with customized geometries using 3D printing technologies. Here, a comprehensive review of the historical development of fabrication methods for photonic crystals is provided. Diverse 3D printing approaches along with the underlying mechanisms, as well as the regulation methods adopted to generate photonic crystals with structural color, are discussed. This review aims to offer the readers an overview of the state-of-the-art 3D printing techniques for photonic crystals, present a guide and considerations to fabricate photonic crystals leveraging different 3D printing methods.

Allosteric Effects of EF-G Domain I Mutations Inducing Ribosome Frameshifting Revealed by Multiplexed Force Spectroscopy.

Ribosome translocation catalyzed by elongation factor G (EF-G) is a critical step in protein synthesis where the ribosome typically moves along the mRNA by three nucleotides at each step. To investigate the mechanism of EF-G catalysis, it is essential to precisely resolve the ribosome motion at both ends of the mRNA, which, to our best knowledge, is only achieved with the magnetic-based force spectroscopy developed by our groups. Here, we introduce a novel multiplexed force spectroscopy technique that, for the first time, offers single-nucleotide resolution for multiple samples. This technique combines multiple acoustic force generators with the smallest atomic magnetometer designed for biological research. Utilizing this technique, we demonstrate that mutating EF-G at the GTP binding pocket results in the ribosome moving only two nucleotides on both ends of the mRNA, thereby compromising ribosome translocation. This finding suggests a direct link between GTP hydrolysis and ribosome translocation. Our results not only provide mechanistic insights into the role of GTP binding pocket but also illuminate how allosteric mutations can manipulate translocation. We anticipate broader applications of our technique in the ribosome field, leveraging its high efficiency and single-nucleotide resolution.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Micro/nanoplastics pollution poses a potential threat to soil health.

Micro/nanoplastic (MNP) pollution in soil ecosystems has become a growing environmental concern globally. However, the comprehensive impacts of MNPs on soil health have not yet been explored. We conducted a hierarchical meta-analysis of over 5000 observations from 228 articles to assess the broad impacts of MNPs on soil health parameters (represented by 20 indicators relevant to crop growth, animal health, greenhouse gas emissions, microbial diversity, and pollutant transfer) and whether the impacts depended on MNP properties. We found that MNP exposure significantly inhibited crop biomass and germination, and reduced earthworm growth and survival rate. Under MNP exposure, the emissions of soil greenhouse gases (CO2, N2O, and CH4) were significantly increased. MNP exposure caused a decrease in soil bacteria diversity. Importantly, the magnitude of impact of the soil-based parameters was dependent on MNP dose and size; however, there is no significant difference in MNP type (biodegradable and conventional MNPs). Moreover, MNPs significantly reduced As uptake by plants, but promoted plant Cd accumulation. Using an analytical hierarchy process, we quantified the negative impacts of MNP exposure on soil health as a mean value of -10.2% (-17.5% to -2.57%). Overall, this analysis provides new insights for assessing potential risks of MNP pollution to soil ecosystem functions.

Multibranch Elastic Bound States in the Continuum.

Constructing a highly localized wave field by means of bound states in the continuum (BICs) promotes enhanced wave-matter interaction and offers approaches to high-sensitivity devices. Elastic waves can carry complex polarizations and thus differ from electromagnetic waves and other scalar mechanical waves in the formation of BICs, which is yet to be fully explored and exploited. Here, we report the investigation of local resonance modes supported by a Lamb waveguide side-branched with two pairs of resonant pillars and show the emergence of two groups of elastic BICs with different polarizations or symmetries. Particularly, the two groups of BICs exhibit distinct responses to external perturbations, based on which a label-free sensing scheme with enhanced-sensitivity is proposed. Our study reveals the rich properties of BICs arising from the complex wave dynamics in elastic media and demonstrates their unique functionality for sensing and detection.

Host-guest interaction induced room-temperature phosphorescence enhancement of organic dyes: a computational study.

To achieve the effective regulation of organic room temperature phosphorescence (RTP) in supramolecular systems, the elucidation of host-guest interactions in RTP is of vital importance. Herein, we employed two organic dyes (PYCl and PYBr) and their four host-guest complexes with CB[6] and CB[7] and explored the mechanism of host-guest interaction induced RTP enhancement using quantum mechanics/molecular mechanics (QM/MM) approach. For the two organic dyes, we found that the better RTP performance of PYBr than PYCl is attributed to intersystem crossing (ISC) augmentation induced by the heavy atom effect. Binding to CB[6] through host-guest interactions can simultaneously accelerate the radiative decay process by increasing the transition dipole moment of T1 → S0 (µT1→S0), block the nonradiative decay process, and promote the ISC process, eventually leading to a remarkably boosted RTP. Upon complexation, the conversion of S1 from 1(n, π*) to 1(π, π*) is key to µT1→S0 enhancement; reduced reorganization energies reflect the suppression of the nonradiative decay process by restricting the rotation of rings A and B in organic dyes. In addition, the promoted ISC process is due to the activation of more ISC channels between S1 and high-lying triplet states with large spin-orbital coupling constants and small energy gap. The case of CB[7]-type complexes is much different, because of the extremely large cavity size of CB[7] for encapsulation. This work proposes the mechanism of host-guest interaction-induced RTP enhancement of organic dyes, thus laying a solid foundation for the rational design of advanced RTP materials based on supramolecular assemblies.

Pressure effects on both fluorescent emission and charge transport properties of organic semiconductors: a computational study.

External pressure can regulate the photophysical property and charge transport performance of organic semiconductors, however, the underlying mechanism at the microscopic level is still elusive. Using thermal vibrational correlation function coupled quantum mechanics/molecular mechanics and full quantum charge transfer rate theory, we systematically explore the influence of pressure on fluorescence emission and charge transport behaviours of representative cyclooctatetrathiophene (COTh). It is found that, upon pressurization, the intramolecular configurations of COTh became more twisted, leading to the blue-shifted emission. The fluorescence quantum efficiency (FQE) of COTh crystals decreases monotonically in a wide pressure range of 0-4.38 GPa, because the increase of intermolecular electronic energy transfer rate constant (keet) is larger than the decrease of internal conversion rate constant (kic), and the variation of keet is dominant. The decrease in kic is attributed to the decreasing reorganization energy, reflecting the suppression of the low-frequency flipping vibrations of four thiophene rings and the high-frequency stretching vibrations of central cyclooctatetraene, while the keet increase is due to the simultaneous increase in exciton coupling and spectra overlap. Moreover, we predicted that the hole mobility of COTh increases monotonically by nearly an order of magnitude from 0.39 to 3.00 cm2 V-1 s-1 upon compression, because of the increase in transfer integral and the decrease of charged reorganization energy. Furthermore, its hole mobility exhibits obvious anisotropy. Our work systematically builds the external pressure, molecular packing, luminescence and transport properties relationships of organic semiconductors and provides theoretical guidance for the rational design of pressure responsive organic semiconductors with excellent photoelectric performance.

Bi-directional association between outdoor or social activities and cognitive function: do the PM2.5 exposure catalyze the detrimental inactivity-poor cognition cycle?

BACKGROUND: Previous research has shown that lack of leisure activities, either outdoor or social activities, impedes cognitive function. However, the interrelationship between poor cognition and deficient activities is understudied. In addition, whether exposure to air pollution, such as PM2.5, can accelerate the detrimental 'inactivity-poor cognition' cycle, is worthy of investigation. METHODS: We used data from the 2008, 2011, 2014, and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). We assessed the frequency of outdoor or social activities at each wave. The cognitive function was examined using a China-Modified Mini-mental State Examination. We estimated the residential exposure to fine particular matter (PM2.5) via a satellite-based model. We applied cross-lagged panel (CLP) model to examine the bi-directional relationship between outdoor or social activities and cognitive function. We then examined the effect of PM2.5 exposure with sequent cognitive function and activities using generalized estimation equation (GEE) model. FINDINGS: Overall, we observed significant bi-directional associations between outdoor or social activities and cognitive function. Participants with better cognitive function in the last wave were more likely to engage in outdoor or social activities in the following wave (outdoor activities: ß = 0.37, 95% CI [0.27,0.48], P < 0.01; social activities: ß = 0.05, 95% CI [0.02,0.09] P < 0.01). Meanwhile, higher engagement in outdoor or social activities in the last wave was associated with more favorable cognitive function in the following wave (outdoor activities: ß = 0.06, 95% CI [0.03,0.09], P < 0.01; social activities: ß = 0.10, 95% CI [0.03,0.18], P < 0.01). Notably, an increase in PM2.5 exposure during the preceding year was significantly associated with a declining cognitive function (ß = -0.05, 95% CI [-0.08,-0.03], P < 0.01), outdoor activities (ß = -0.02, 95% CI [-0.04, -0.01], P < 0.01) and social activities (ß = -0.02, 95% CI [-0.02, -0.01], P < 0.01) in the current year; the lagged effects of the PM2.5 exposure in the past year of the last wave on activities and cognitive function of the following wave were also observed. INTERPRETATION: Our findings not only indicate the bi-directional links between the frequency of outdoor or social activities and cognitive function, but also report that PM2.5 exposure plays a role in catalyzing the detrimental inactivity-poor cognition cycle. Future research should investigate whether the policy-driven interventions, such as clean air policies, can break the unfavorable activity-cognition cycle, and thereby promoting health from the dual gains in leisure activities and cognition.

The clinical outcome of emergency superficial temporal artery-to-middle cerebral artery bypass in acute ischemic stroke with large vessel occlusion.

The role of superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in acute ischemic stroke (AIS) is contentious, with no evidence in patients with AIS and large vessel occlusion (AIS-LVO). We conducted a cohort study to assess emergency STA-MCA outcomes in AIS-LVO and a meta-analysis to evaluate STA-MCA outcomes in early AIS treatment. From January 2018 to March 2021, we consecutively recruited newly diagnosed AIS-LVO patients, dividing them into STA-MCA and non-STA-MCA groups. To evaluate the neurological status and outcomes, we employed the National Institutes of Health Stroke Scale (NIHSS) during the acute phase and the modified Rankin Scale (mRS) during the follow-up period. Additionally, we conducted a meta-analysis encompassing all available clinical studies to assess the impact of STA-MCA on patients with AIS. In the cohort study (56 patients), we observed more significant neurological improvement in the STA-MCA group at two weeks (p = 0.030). However, there was no difference in the clinical outcomes between the two groups. Multivariable logistic regression identified the NIHSS at two weeks (OR: 0.840; 95% CI: 0.754-0.936, p = 0.002) as the most critical predictor of a good outcome. Our meta-analysis of seven studies indicated a 67% rate for achieving a good outcome (mRS < 3) at follow-up points (95% CI: 57%-77%, I2 = 44.1%). In summary, while the meta-analysis suggested the potential role of STA-MCA bypass in mild to moderate AIS, our single-center cohort study indicated that STA-MCA bypass does not seem to improve the prognosis of patients who suffer from AIS-LVO.

Excess deaths and loss of life expectancy attributed to long-term NO2 exposure in the Chinese elderly.

BACKGROUND: Evidence linking nitrogen dioxide (NO2) air pollution to life span of high-vulnerability older adults is extensively scarce in low- and middle-income countries. This study seeks to quantify mortality risk, excess deaths, and loss of life expectancy (LLE) associated with long-term exposure to NO2 among elderly individuals in China. METHODS: A nationwide dynamic cohort of 20352 respondents ≥65 years old were enrolled from the China Longitudinal Health and Longevity Survey during 2005-2018. Residential exposures to NO2 and co-pollutants were assessed by well-validated spatiotemporal prediction models. A Cox regression model with time-dependent covariates was utilized to quantify the association of all-cause mortality with NO2 exposure, controlling for confounders such as demographics, lifestyle, health status, and ambient temperature. NO2-attributable deaths and LLE were evaluated for the years 2010 and 2020 based on the pooled NO2-mortality relation derived from multi-national cohort investigations. Decomposition analyses were conducted to dissociate net shift in NO2-related deaths between 2010 and 2020 into four primary contributing factors. RESULTS: A total of 14313 deaths were recorded during follow-up of approximately 100 hundred person-years (median 3.6 years). We observed an approximately linear relationship (nonlinear P = 0.882) of NO2 exposure with all-cause death across a broad range from 6.6 to 95.7 µg/m3. Every 10-µg/m3 rise in yearly average NO2 concentration was linked to a hazard ratio (HR) of 1.045 (95% confidence interval [CI]: 1.031-1.059). In the updated meta-analysis of this study and 9 existing cohorts, we estimated a pooled HR of 1.043 (95% CI: 1.023-1.063) for each 10-µg/m3 growth in NO2. Reaching a 10-µg/m3 counterfactual target of NO2 concentration in China could avoid 0.33 (95% empirical CI: 0.19-0.49) million premature deaths and an LLE of 0.40 (95% empirical CI: 0.23-0.59) years in 2010, which greatly dropped to 0.24 (95% empirical CI: 0.14-0.36) million deaths and 0.21 (95% empirical CI: 0.12-0.31) years of LLE in 2020. The net fall in NO2-attributable deaths (-26.8%) between 2010 and 2020 was primarily driven by the declines in both NO2 concentration (-41.6%) and mortality rate (-27.1%) under population growth (+41.0%) and age structure transition (+0.9%). CONCLUSIONS: Our findings provide national evidence for increased risk of premature death and loss of life expectancy attributed to later-life NO2 exposure among the elderly in China. In an accelerated aging society, strengthened clean air actions should be formulated to minimize the health burden and regional inequality in NO2-attributable mortality.