Revisiting the four Hexapoda classes: Protura as the sister group to all other hexapods.

Insects represent the most diverse animal group, yet previous phylogenetic analyses based on morphological and molecular data have failed to agree on the evolutionary relationships of early insects and their six-legged relatives (together constituting the clade Hexapoda). In particular, the phylogenetic positions of the three early-diverging hexapod lineages-the coneheads (Protura), springtails (Collembola), and two-pronged bristletails (Diplura)-have been debated for over a century, with alternative topologies implying drastically different scenarios of the evolution of the insect body plan and hexapod terrestrialization. We addressed this issue by sampling all hexapod orders and experimenting with a broad range of across-site compositional heterogeneous models designed to tackle ancient divergences. Our analyses support Protura as the earliest-diverging hexapod lineage ("Protura-sister") and Collembola as a sister group to Diplura, a clade corresponding to the original composition of Entognatha, and characterized by the shared possession of internal muscles in the antennal flagellum. The previously recognized 'Elliplura' hypothesis is recovered only under the site-homogeneous substitution models with partial supermatrices. Our cross-validation analysis shows that the site-heterogeneous CAT-GTR model, which recovers "Protura-sister," fits significantly better than homogeneous models. Furthermore, the morphologically unusual Protura are also supported as the earliest-diverging hexapod lineage by other lines of evidence, such as mitogenomes, comparative embryology, and sperm morphology, which produced results similar to those in this study. Our backbone phylogeny of hexapods will facilitate the exploration of the underpinnings of hexapod terrestrialization and megadiversity.

Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair.

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.

Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension.

BACKGROUND & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a-knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a-knockout (Htr1aΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3',5'-cyclic monophosphate pathway-mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation-, and partial PV ligation-induced PH. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.

Human-Derived Induced GABAergic Progenitor Cells Improve Cognitive Function in Mice and Inhibit Astrocyte Activation with Anti-Inflammatory Exosomes.

OBJECTIVE: The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown. METHODS: Human-derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP). RESULTS: We showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin-1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD-related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti-inflammatory miRNA, inhibited astrocyte activation invitro and in vivo, and the mechanism was related to regulation of CD4+ Th1 cells mediated tumor necrosis factor (TNF) pathway. INTERPRETATION: Taken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti-inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024;96:488-507.

Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency.

OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024;96:758-773.

Trained immunity induced by high-salt diet impedes stroke recovery.

A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte-derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD-fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD-induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD-induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.

Metformin in elderly type 2 diabetes mellitus: dose-dependent dementia risk reduction.

This study aimed to investigate the controversial association between metformin use and diabetes-associated dementia in elderly patients with type 2 diabetes mellitus (T2DM) and evaluate the potential protective effects of metformin, as well as its intensity of use and dose-dependency, against dementia in this population. The study used a time-dependent Cox hazards model to evaluate the effect of metformin use on the incidence of dementia. The case group included elderly patients with T2DM (≥60 years old) who received metformin, while the control group consisted of elderly patients with T2DM who did not receive metformin during the follow-up period. Our analysis revealed a significant reduction in the risk of dementia among elderly individuals using metformin, with an adjusted hazard ratio of 0.34 (95% confidence interval: 0.33 to 0.36). Notably, metformin users with a daily intensity of 1 defined daily dose (DDD) or higher had a lower risk of dementia, with an adjusted hazard ratio (95% confidence interval) of 0.46 (0.22 to 0.6), compared to those with a daily intensity of <1 DDD. Additionally, the analysis of cumulative DDDs of metformin showed a dose-response relationship, with progressively lower adjusted hazard ratio across quartiles (0.15, 0.21, 0.28, and 0.53 for quartiles 4, 3, 2 and 1, respectively), compared to never metformin users (P for trend < 0.0001). Metformin use in elderly patients with T2DM is significantly associated with a substantial reduction in the risk of dementia. Notably, the protective effect of metformin demonstrates a dose-dependent relationship, with higher daily and cumulative dosages of metformin showing a greater risk reduction.

Impact of Bmal1 Rescue and Time-Restricted Feeding on Liver and Muscle Proteomes During the Active Phase in Mice.

Molecular clocks and daily feeding cycles support metabolism in peripheral tissues. Although the roles of local clocks and feeding are well defined at the transcriptional level, their impact on governing protein abundance in peripheral tissues is unclear. Here, we determine the relative contributions of local molecular clocks and daily feeding cycles on liver and muscle proteomes during the active phase in mice. LC-MS/MS was performed on liver and gastrocnemius muscle harvested 4 h into the dark phase from WT, Bmal1 KO, and dual liver- and muscle-Bmal1-rescued mice under either ad libitum feeding or time-restricted feeding during the dark phase. Feeding-fasting cycles had only minimal effects on levels of liver proteins and few, if any, on the muscle proteome. In contrast, Bmal1 KO altered the abundance of 674 proteins in liver and 80 proteins in muscle. Local rescue of liver and muscle Bmal1 restored ∼50% of proteins in liver and ∼25% in muscle. These included proteins involved in fatty acid oxidation in liver and carbohydrate metabolism in muscle. For liver, proteins involved in de novo lipogenesis were largely dependent on Bmal1 function in other tissues (i.e., the wider clock system). Proteins regulated by BMAL1 in liver and muscle were enriched for secreted proteins. We found that the abundance of fibroblast growth factor 1, a liver secreted protein, requires BMAL1 and that autocrine fibroblast growth factor 1 signaling modulates mitochondrial respiration in hepatocytes. In liver and muscle, BMAL1 is a more potent regulator of dark phase proteomes than daily feeding cycles, highlighting the need to assess protein levels in addition to mRNA when investigating clock mechanisms. The proteome is more extensively regulated by BMAL1 in liver than in muscle, and many metabolic pathways in peripheral tissues are reliant on the function of the clock system as a whole.

Altered corticalfunctional networks in Wilson's disease: A resting-state electroencephalogram study.

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD.

Collectin 11 has a pivotal role in host defense against kidney and bladder infection in mice.

The urinary tract is constantly exposed to microorganisms. Host defense mechanisms in protection from microbial colonization and development of urinary tract infections require better understanding to control kidney infection. Here we report that the lectin collectin 11 (CL-11), particularly kidney produced, has a pivotal role in host defense against uropathogen infection. CL-11 was found in mouse urine under normal and pathological conditions. Mice with global gene ablation of Colec11 had increased susceptibility to and severity of kidney and to an extent, bladder infection. Mice with kidney-specific Colec11 ablation exhibited a similar disease phenotype to that observed in global Colec11 deficient mice, indicating the importance of kidney produced CL-11 for protection against kidney and bladder infection. Conversely, intravesical or systemic administration of recombinant CL-11 reduced susceptibility to and severity of kidney and bladder infection. Mechanism analysis revealed that CL-11 can mediate several key innate defense mechanisms (agglutination, anti- adhesion, opsonophagocytosis), and limit local inflammatory responses to pathogens. Furthermore, CL-11-mediated innate defense mechanisms can act on clinically relevant microorganisms including multiple antibiotic resistant strains. CL-11 was detectable in eight of 24 urine samples from patients with urinary tract infections but not detectable in urine samples from ten healthy individuals. Thus, our findings demonstrate that CL-11 is a key factor of host defense mechanisms in kidney and bladder infection with therapeutic potential for human application.

Molecular Insights into MpAGO1 and Its Regulatory miRNA, miR11707, in the High-Temperature Acclimation of Marchantia polymorpha.

As a model plant for bryophytes, Marchantia polymorpha offers insights into the role of RNA silencing in aiding early land plants navigate the challenges posed by high-temperature environments. Genomic analysis revealed unique ARGONAUTE1 ortholog gene (MpAGO1) in M. polymorpha, which is regulated by two species-specific microRNAs (miRNAs), miR11707.1 and miR11707.2. Comparative studies of small RNA profiles from M. polymorpha cellular and MpAGO1 immunoprecipitation (MpAGO1-IP) profiles at various temperatures, along with analyses of Arabidopsis AGO1 (AtAGO1), revealed that MpAGO1 has a low selectivity for a diverse range of small RNA species than AtAGO1. Protein structural comparisons revealed no discernible differences in the guide strand small RNA recognition middle domain, MID domain, of MpAGO1 and AtAGO1, suggesting the complexity of miRNA species specificity and necessitating further exploration. Small RNA profiling and size exclusion chromatography have pinpointed a subset of M. polymorpha miRNAs, notably miR11707, that remain in free form within the cell at 22°C but are loaded into MpAGO1 at 28°C to engage in RNA silencing. Investigations into the mir11707 gene editing (mir11707ge) mutants provided evidence of the regulation of miR11707 in MpAGO1. Notably, while MpAGO1 mRNA expression decreases at 28°C, the stability of the MpAGO1 protein and its associated miRNAs is essential for enhancing the RNA-inducing silencing complex (RISC) activity, revealing the importance of RNA silencing in enabling M. polymorpha to survive thermal stress. This study advances our understanding of RNA silencing in bryophytes and provides groundbreaking insights into the evolutionary resilience of land plants to climatic adversities.

Prognostic factors for survival in unresectable stage III EGFR mutation-positive lung adenocarcinoma: impact of pre-CCRT PET-CT.

PURPOSE: To assess the survival impact of pre-concurrent chemoradiotherapy (CCRT) staging with positron emission tomography-CT (PET-CT) in patients with unresectable epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma. METHODS: Patients with unresectable stage IIIA-IIIC EGFR mutation-positive adenocarcinoma undergoing definitive CCRT were divided into two groups: those who received PET-CT staging prior to CCRT and those with other staging methods. Survival outcomes were compared after propensity score matching. RESULTS: Analysis of 11 856 patients (5928 in each group) showed that PET-CT staging was associated with improved survival (adjusted HR of all-cause mortality: 0.74, 95% CI 0.71 to 0.79). Other prognostic factors included male sex, age group, clinical stage, adjuvant treatment, smoking status, Charlson Comorbidity Index score and treatment setting. CONCLUSION: Pre-CCRT staging with PET-CT in patients with unresectable EGFR mutation-positive adenocarcinoma of clinical stage IIIA-IIIC was associated with enhanced survival. Independent prognostic factors were also identified.

dmTGS: Precise Targeted Enrichment Long-Read Sequencing Panel for Tandem Repeat Detection.

BACKGROUND: Tandem repeats (TRs) are abundant in the human genome and associated with repeat expansion disorders. Our study aimed to develop a tandem repeat panel utilizing targeted long-read sequencing to evaluate known TRs associated with these disorders and assess its clinical utility. METHODS: We developed a targeted long-read sequencing panel for 70 TR loci, termed dynamic mutation third-generation sequencing (dmTGS), using the PacBio Sequel II platform. We tested 108 samples with suspected repeat expansion disorders and compared the results with conventional molecular methods. RESULTS: For 108 samples, dmTGS achieved an average of 8000 high-fidelity reads per sample, with a mean read length of 4.7 kb and read quality of 99.9%. dmTGS outperformed repeat-primed-PCR and fluorescence amplicon length analysis-PCR in distinguishing expanded from normal alleles and accurately quantifying repeat counts. The method demonstrated high concordance with confirmatory methods (rlinear = 0.991, P < 0.01), and detected mosaicism with sensitivities of 1% for FMR1 CGG premutation and 5% for full mutations. dmTGS successfully identified interruptive motifs in genes that conventional methods had missed. For variable number TRs in the PLIN4 gene, dmTGS identified precise repeat counts and sequence motifs. Screening 57 patients with suspected genetic muscular diseases, dmTGS confirmed repeat expansions in genes such as GIPC1, NOTCH2NLC, NUTM2B-AS1/LOC642361, and DMPK. Additionally, dmTGS detected CCG interruptions in CTG repeats in 8 myotonic dystrophy type 1 patients with detailed characterization. CONCLUSIONS: dmTGS accurately detects repeat sizes and interruption motifs associated with repeat expansion disorders and demonstrates superior performance compared to conventional molecular methods.

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.

Stepwise changes in flavonoids in spores/pollen contributed to terrestrial adaptation of plants.

Protecting haploid pollen and spores against UV-B light and high temperature, 2 major stresses inherent to the terrestrial environment, is critical for plant reproduction and dispersal. Here, we show flavonoids play an indispensable role in this process. First, we identified the flavanone naringenin, which serves to defend against UV-B damage, in the sporopollenin wall of all vascular plants tested. Second, we found that flavonols are present in the spore/pollen protoplasm of all euphyllophyte plants tested and that these flavonols scavenge reactive oxygen species to protect against environmental stresses, particularly heat. Genetic and biochemical analyses showed that these flavonoids are sequentially synthesized in both the tapetum and microspores during pollen ontogeny in Arabidopsis (Arabidopsis thaliana). We show that stepwise increases in the complexity of flavonoids in spores/pollen during plant evolution mirror their progressive adaptation to terrestrial environments. The close relationship between flavonoid complexity and phylogeny and its strong association with pollen survival phenotypes suggest that flavonoids played a central role in the progression of plants from aquatic environments into progressively dry land habitats.

Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. RESULTS: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

The association between TyG and all-cause/non-cardiovascular mortality in general patients with type 2 diabetes mellitus is modified by age: results from the cohort study of NHANES 1999-2018.

BACKGROUND: The prognostic value of triglyceride-glucose (TyG) index in general type 2 diabetes mellitus (T2DM) patients is still unclear. Therefore, we aimed to determine the associations between TyG and all-cause/cause-specific death in a T2DM cohort and explore whether such associations would be modified by age. METHODS: A total of 3,376 patients with T2DM from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were selected and divided into the younger group (< 65 yrs) and the older group (≥ 65 yrs). Baseline TyG was calculated and cause-specific mortality status [cardiovascular (CV), cancer, and non-CV] was determined by the NHANES Public-Use Linked Mortality Files through 31 December 2019. Multivariate Cox and restricted cubic spline (RCS) regression models were used to evaluate the association between TyG and all-cause/cause-specific mortality. Interaction between TyG and age to mortality was also evaluated. Sensitivity analyses were performed in patients without cardiovascular disease, chronic kidney disease, or insulin treatment. RESULTS: During a median follow-up of 107 months, 805 all-cause deaths occurred, of which 250 and 144 were attributed to CV and cancer deaths. There was a significant age interaction to the association between TyG and all-cause/non-CV mortality. After fully adjusting for potential confounding factors, higher TyG was associated with an increased risk of all-cause [TyG per unit increase Hazard Ratio (HR) 1.33, 95% Confidence Interval (CI) 1.06-1.66, p = 0.014] and non-CV mortality (TyG per unit increase HR 1.54, 95% CI 1.18-2.01, p = 0.002) only in the younger group, but not in the older group. There was no significant association between TyG and CV/cancer death in the total cohort and two age subgroups. Similar results were found in RCS and sensitivity analyses. CONCLUSION: In a national sample of patients with T2DM in the United States, we found that the association between TyG and all-cause/non-CV death was modified by age. Higher TyG was only associated with an increased risk of all-cause/non-CV only in T2DM patients younger than 65 years old, but not in older patients.

Design of an optically transparent and broadband absorber based on a multi-objective optimization algorithm.

In this Letter, an optically transparent and broadband absorber designed using a multi-objective genetic algorithm (MOGA) is proposed. The absorption of the multilayer lossy frequency selective surface-based absorber is calculated by multilayer absorption equations and equivalent circuit models. To solve the problem of the unbalanced structure absorption bandwidth and thickness, an algorithm is used for optimizing the geometric and sheet resistance parameters of the structure. A multilayer and optically transparent absorber with 90% absorption bandwidth covering a frequency range of 2-18 GHz (S-band to Ku-band) is developed based on the MOGA design method with optical transmittance of 60%. Its total thickness consists of a wavelength of only 0.095, and it has high oblique incidence stability, which makes it useful in the stealth technology and transparent electromagnetic shielding applications.

Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization.

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurologic disorders characterized by progressive lower-extremity spasticity. Despite the identification of several HSP-related genes, many patients lack a genetic diagnosis. OBJECTIVES: The aims were to confirm the pathogenic role of biallelic COQ4 mutations in HSP and elucidate the clinical, genetic, and functional molecular features of COQ4-associated HSP. METHODS: Whole exome sequences of 310 index patients with HSP of unknown cause from three distinct populations were analyzed to identify potential HSP causal genes. Clinical data obtained from patients harboring candidate causal mutations were examined. Functional characterization of COQ4 variants was performed using bioinformatic tools, single-cell RNA sequencing, biochemical assays in cell lines, primary fibroblasts, induced pluripotent stem cell-derived pyramidal neurons, and zebrafish. RESULTS: Compound heterozygous variants in COQ4, which cosegregated with HSP in pedigrees, were identified in 7 patients from six unrelated families. Patients from four of the six families presented with pure HSP, whereas probands of the other two families exhibited complicated HSP with epilepsy or with cerebellar ataxia. In patient-derived fibroblasts and COQ4 knockout complementation lines, stable expression of these missense variants exerted loss-of-function effects, including mitochondrial reactive oxygen species accumulation, decreased mitochondrial membrane potential, and lower ubiquinone biosynthesis. Whereas differentiated pyramidal neurons expressed high COQ4 levels, coq4 knockdown zebrafish displayed severe motor dysfunction, reflecting motor neuron dysregulation. CONCLUSIONS: Our study confirms that loss-of-function, compound heterozygous, pathogenic COQ4 variants are causal for autosomal recessive pure and complicated HSP. Moreover, reduced COQ4 levels attributable to variants correspond with decreased ubiquinone biosynthesis, impaired mitochondrial function, and higher phenotypic disease severity. © 2023 International Parkinson and Movement Disorder Society.

Early childhood general anesthesia and risk of Attention Deficit Hyperactivity Disorder.

BACKGROUND: The relationship between early childhood exposure to general anesthesia (GA) and the risk of developing Attention Deficit Hyperactivity Disorder (ADHD) is still uncertain and previous studies have presented conflicting results. This population-based cohort study aimed to investigate the potential relationship between GA exposure and ADHD risk using propensity score matching (PSM) in a large sample size. METHODS: The study included 15,072 children aged 0-3 years who received GA and were hospitalized for more than 1 day in Taiwan from 2004 to 2014. The nonexposed group was randomly selected through 1:1 PSM from the Taiwan Maternal and Child Health Database (TMCHD). The primary objectives of this study were to determine the incidence rates (IR) and incidence rate ratios (IRR) of ADHD in the two cohorts, employing Poisson regression models. RESULTS: The GA group and non-GA group each comprised 7,536 patients. The IR of ADHD was higher in the GA group (122.45 per 10,000 person-years) than in the non-GA group (64.15 per 10,000 person-years), and the IRR of ADHD in the GA group was 1.39 (95% CI: 1.26, 1.55). The study found that the number of times of exposure to GA, duration of exposure, male gender, and central nervous system surgery were significant risk factors for ADHD in the future. CONCLUSIONS: This study's findings suggest that there is a significant correlation between early childhood exposure to GA and the risk of developing ADHD, and GA may be an important risk factor for ADHD in children undergoing surgery. The study also identified several risk factors for ADHD, including the number of times of exposure to GA, duration of exposure, male gender, and central nervous system surgery.