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Abstract Background Aging is a major risk factor for type 2 diabetes (T2D), but individuals of the same chronological age may vary in their biological aging rate. The associations of Phenotypic Age Acceleration (PhenoAgeAccel), a new accelerated biological aging indicator based on clinical chemistry biomarkers, with the risk of dynamic progression remain unclear. We aimed to assess these associations and examine whether these associations varied by genetic risk and lifestyle. Methods We conducted a prospective cohort study that included 376,083 adults free of T2D and diabetes-related events at baseline in UK Biobank. PhenoAgeAccel > 0 and ≤ 0 were defined as biologically older and younger than chronological age. The outcomes of interest were incident T2D, diabetic complications, and mortality. Hazard ratios (HRs) with 95% confidence intervals (CIs) and population attributable fractions (PAFs) for these associations were calculated using multi-state model. Results During a median follow-up of 13.7 years, 17,615 participants developed T2D, of whom, 4,524 subsequently developed complications, and 28,373 died. Being biologically older was associated with increased risks of transitions from baseline to T2D (HR 1.77, 95% CI 1.71–1.82; PAF 24.8 [95% CI 23.5–26.2]), from T2D to diabetic complications (1.10, 1.04–1.17; 4.4 [1.4–7.4]), from baseline to all-cause death (1.53, 1.49–1.57; 17.6 [16.6–18.6]), from T2D to all-cause death (1.14, 1.03–1.26; 7.4 [1.8–13.0]), and from diabetic complications to all-cause death (1.32, 1.15–1.51; 15.4 [7.5–23.2]) than being biologically younger. Additionally, participants with older biological age and high genetic risk had a higher risk of incident T2D (4.76,4.43–5.12;18.2 [17.5–19.0]) than those with younger biological age and low genetic risk. Compared with participants with younger biological age and healthy lifestyle, those with older biological age and unhealthy lifestyle had higher risks of transitions in the T2D trajectory, with HRs and PAFs ranging from 1.34 (1.16–1.55; 3.7 [1.8–5.6]) to 5.39 (5.01–5.79; 13.0 [12.4–13.6]). Conclusions PhenoAgeAccel was consistently associated with an increased risk of all transitions in T2D progression. It has the potential to be combined with genetic risk to identify early T2D incidence risk and may guide interventions throughout T2D progression while tracking their effectiveness.

Transfer learning aims to integrate useful information from multi-source datasets to improve the learning performance of target data. This can be effectively applied in genomics when we learn the gene associations in a target tissue, and data from other tissues can be integrated. However, heavy-tail distribution and outliers are common in genomics data, which poses challenges to the effectiveness of current transfer learning approaches. In this paper, we study the transfer learning problem under high-dimensional linear models with t-distributed error (Trans-PtLR), which aims to improve the estimation and prediction of target data by borrowing information from useful source data and offering robustness to accommodate complex data with heavy tails and outliers. In the oracle case with known transferable source datasets, a transfer learning algorithm based on penalized maximum likelihood and expectation-maximization algorithm is established. To avoid including non-informative sources, we propose to select the transferable sources based on cross-validation. Extensive simulation experiments as well as an application demonstrate that Trans-PtLR demonstrates robustness and better performance of estimation and prediction when heavy-tail and outliers exist compared to transfer learning for linear regression model with normal error distribution. Data integration, Variable selection, T distribution, Expectation maximization algorithm, Genotype-Tissue Expression, Cross validation.

Objectives: Diabetes was associated with increased serum urate levels and a higher risk of dementia. However, current evidence regarding the association between serum urate and dementia is controversial.The research gap on how to effectively control urate levels in the population with diabetes still remains. We aim to examine the association of diabetes status and serum urate with dementia incidence, and the differences in this association among participants with different diabetes statuses. Methods: A total of 321,896 participants was recruited from the UK Biobank and followed up until 2022. Diabetes status was classified into diabetes, prediabetes and normoglycaemia according to the American Diabetes Association 2023 guideline. Serum urate levels were stratified using gender-specific quartiles of concentrations. All-cause dementia, Alzheimer’s disease and vascular dementia were ascertained using the International Classification of Diseases-10th revision (ICD-10). Cox proportional hazards regression models were used to examine the association between serum urate, diabetes status, and dementia incidence. Results: Of the 321,896 participants (mean age, 57 years old; 43.5% males), 7,087 (2.20%) individuals were diagnosed with dementia during the follow-up period. Diabetes was associated with a 70% 58%, and 134% increased risk for all-cause dementia, Alzheimer’s disease, and vascular dementia respectively. Elevated serum urate levels were associated with a lower risk of all-cause and cause-specific dementia regardless of the status of diabetes. Each standard deviation increase in urate concentration was related to a 11% reduced risk for all-cause dementia (HR, 0.89; 95% CI, 0.86 to 0.91), 7% for Alzheimer’s disease (HR, 0.93; 95% CI, 0.88 to 0.98), and 12% for vascular dementia (HR, 0.88; 95% CI, 0.81 to 0.95). Conclusion: : Appropriately higher urate levels within the threshold of hyperuricemia can reduce the adverse health effects of excessively high urate levels and better protect the cognitive health of people with varying diabetes status.

Abstract Background Obesity may increase perioperative mortality of acute Stanford type A aortic dissection (ATAAD). However, the available evidence was limited. This study aimed to systematically review published literatures about body mass index (BMI) and perioperative mortality of ATAAD. Methods Electronic literature search was conducted in PubMed, Medline, Embase and Cochrane Library databases. All observational studies that investigated BMI and perioperative mortality of ATAAD were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model. Meta-regression analysis was performed to assess the effects of different clinical variables on BMI and perioperative mortality of ATAAD. Sensitivity analysis was performed to determine the sources of heterogeneity. Egger’s linear regression method and funnel plot were used to determine the publication bias. Results A total of 12 studies with 5,522 patients were eligible and included in this meta-analysis. Pooled analysis showed that perioperative mortality of ATAAD increased by 22% for each 1 kg/m2 increase in BMI (OR = 1.22, 95% CI: 1.10–1.35). Univariable meta-regression analysis indicated that age and female gender significantly modified the association between BMI and perioperative mortality of ATAAD in a positive manner (meta-regression on age: coefficient = 0.04, P = 0.04; meta-regression on female gender: coefficient = 0.02, P = 0.03). Neither significant heterogeneity nor publication bias were found among included studies. Conclusions BMI is closely associated with perioperative mortality of ATAAD. Optimal perioperative management needs to be further explored and individualized for obese patient with ATAAD, especially in elderly and female populations. Trial registration PROSPERO (CRD42022358619). Graphical Abstract BMI and perioperative mortality of ATAAD.

Abstract Magnetization promoted activity of magnetic catalysts towards the oxygen evolution reaction (OER) has attracted great attention, but remains a puzzle where the increment comes from. Magnetization of a ferromagnetic material only changes its magnetic domain structure. It does not directly change the spin orientation of unpaired electrons in the material. The confusion is that each magnetic domain is a small magnet and theoretically the spin-polarization promoted OER already occurs on these magnetic domains, and thus the enhancement should have been achieved without magnetization. Here, we demonstrate that the enhancement comes from the disappeared domain wall upon magnetization. Magnetization leads to the evolution of the magnetic domain structure, from a multi-domain one to a single domain one, in which the domain wall disappears. The surface occupied by the domain wall is reformatted into one by a single domain, on which the OER follows the spin-facilitated pathways and thus the overall increment on the electrode occurs. This study fills the missing gap for understanding the spin-polarized OER and it further explains the type of ferromagnetic catalysts which can give increment by magnetization.

Pan-cancer strategy, an integrative analysis of different cancer types, can be used to explain oncogenesis and identify biomarkers using a larger statistical power and robustness. Fine-mapping defines the casual loci, whereas genome-wide association studies (GWASs) typically identify thousands of cancer-related loci and not necessarily have a fine-mapping component. In this study, we develop a novel strategy to identify the causal loci using a pan-cancer and fine-mapping assumption, constructing the CAusal Pan-cancER gene (CAPER) score and validating its performance using internal and external validation on 1,287 individuals and 985 cell lines. Summary statistics of 15 cancer types were used to define 54 causal loci in 15 potential genes. Using the Cancer Genome Atlas (TCGA) training set, we constructed the CAPER score and divided cancer patients into two groups. Using the three validation sets, we found that 19 cancer-related variables were statistically significant between the two CAPER score groups and that 81 drugs had significantly different drug sensitivity between the two CAPER score groups. We hope that our strategies for selecting causal genes and for constructing CAPER score would provide valuable clues for guiding the management of different types of cancers.

In this paper, in order to settle the problem of unintentional interference between communication devices and obtain effective information quickly and accurately in cognitive radio (CR), and an intelligent modulation pattern recognition method based on wavelet approximate coefficient entropy (WACE) is proposed. Based on the traditional wavelet entropy, an improved wavelet entropy, WACE, is presented, which can characterize the modulated signal pattern and suppress the noise effectively. Furthermore, in order to solve the problem of high complexity for linear weighting calculation, the deep neural network (DNN) is adopted, and the vector of the WACE is used as the input of the DNN to realize intelligent recognition of a variety of typical communication signal modulation patterns. Simulation results verify the correctness of the theoretical analysis, and show that the proposed intelligent recognition method can effectively realize the modulation pattern recognition of multiple signals at low signal-to-noise ratio (SNR), with relative low computational complexity.

Abstract The family of exponential pseudo-splines is the non-stationary counterpart of the pseudo-splines and includes the exponential B-spline functions as special members. Among the family of the exponential pseudo-splines, there also exists the subclass consisting of interpolatory cardinal functions, which can be obtained as the limits of the exponentials reproducing subdivision. In this paper, we mainly focus on this subclass of exponential pseudo-splines and propose their dual refinable functions with explicit form of symbols. Based on this result, we obtain the corresponding biorthogonal wavelets using the non-stationary Multiresolution Analysis (MRA). We verify the stability of the refinable and wavelet functions and show that both of them have exponential vanishing moments, a generalization of the usual vanishing moments. Thus, these refinable and wavelet functions can form a non-stationary generalization of the Coifman biorthogonal wavelet systems constructed using the masks of the D–D interpolatory subdivision.

Optic atrophy1 (OPA1) is crucial for inner mitochondrial membrane (IMM) fusion and essential for maintaining crista structure and mitochondrial morphology. Optic atrophy and hearing impairment are the most prevalent clinical features associated with mutations in the OPA1 gene, but the function of OPA1 in hearing is still unknown. In this study, we examined the ability of Opa1 to protect against cisplatin-induced cochlear cell death in vitro and in vivo. Our results revealed that knockdown of Opa1 affects mitochondrial function in HEI-OC1 and Neuro 2a cells, as evidenced by an elevated reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. The dysfunctional mitochondria release cytochrome c, which triggers apoptosis. Opa1 expression was found to be significantly reduced after cell exposed to cisplatin in HEI-OC1 and Neuro 2a cells. Loss of Opa1 aggravated the apoptosis and mitochondrial dysfunction induced by cisplatin treatment, whereas overexpression of Opa1 alleviated cisplatin-induced cochlear cell death in vitro and in explant. Our results demonstrate that overexpression of Opa1 prevented cisplatin-induced ototoxicity, suggesting that Opa1 may play a vital role in ototoxicity and/or mitochondria-associated cochlear damage.

Summary: In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations’ specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (BRD4) bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio could be a common mechanism regulating the bromodomain factors’ functional genomic distribution.

Lung squamous cell carcinoma (LUSC) is one of the leading causes of tumor-driven deaths in the world. To date, studies on the tumor heterogeneity of LUSC at genomic level have only revealed limited therapeutic benefits. Therefore, system-wide research of LUSC at proteomic level may further improve precision medicine strategies on individual demands. To this end, we performed proteomic and phosphoproteomic study for LUSC samples of 25 Chinese patients. From our results, two subgroups (Cluster I and II) based on proteomic data were identified, which were associated with distinct molecular characteristics and clinicopathologic features. Combined with phosphoproteomic data, our result showed that spliceosome pathway was enriched in Cluster I, while focal adhesion pathway, immune-related pathways and Ras signaling pathway were enriched in Cluster II. In addition, we found that lymph node metastasis (LNM) was associated with our proteomic subgroups and cell cycle pathway was enriched in patients with LNM. Further analysis showed that MCM2, a DNA replication licensing factor involved in cell cycle pathway, was highly expressed in patients with poor prognosis, which was further proved by immunohistochemistry (IHC) analysis. In summary, our study provided a resource of the proteomic and phosphoproteomic features of LUSC in Chinese patients.

Current therapeutics options for viral myocarditis are unsatisfactory. Melatonin (MLT), a hormone secreted by the pineal gland and other organs, has protective effects on ischemic heart injury. However, the potential therapeutic effect of MLT on viral myocarditis is unknown. In this study, we investigated the protective effect of MLT on viral myocarditis in a mouse model of myocarditis infected with coxsackievirus B3 (CVB3) and explored the probable mechanisms. Mice with CVB3-induced myocarditis displayed inflammatory cell infiltration and interstitial edema. MLT treatment significantly ameliorated the myocardial injuries. In addition, the rate of autophagy changed, although apoptosis was inhibited in mouse hearts following treatment with MLT. These results suggest that MLT has a strong therapeutic effect on acute viral myocarditis, which is associated with changes in autophagy and apoptosis in the heart. Thus, MLT could be a promising novel therapeutic approach against viral myocarditis.

Abdominal aortic aneurysm (AAA) is a fatal disease, and exposure to 3,4-benzopyrene (Bap) is closely related to the development of AAA. We have found that Bap could impair the biological function of endothelial progenitor cells (EPCs), which are associated with the occurrence of AAA. We have also demonstrated that macrophage activation plays a key role in Bap-induced AAA, but the mechanism is unknown. Here, we used a mouse lncRNA array to investigate the expression signatures of lncRNAs and mRNAs in Bap-activated macrophage. A total of 457 lncRNAs and 219 mRNAs were found to be differentially expressed. The function of differential mRNAs was determined by pathway and Gene Ontology analysis. Eight pathways associated with inflammation were upregulated, and seven pathways including cell apoptosis were downregulated. It was worth noting that AGE-RAGE pathway, which was involved in Bap-induced EPC dysfunction, was significantly upregulated in Bap-activated macrophage and may contribute to AAA formation. Thus, lncRNAs may exert a key role in activated macrophages and intervene the core lncRNAs and may inhibit the occurrence of a series of cascade reactions in the macrophages, which may provide potential targets for AAA caused by smoking.

Background: A recent study indicates that the incidence of smoking cessation varies with age. Although nicotine dependence (ND) has been regarded as one of the most significant barriers of successful smoking cessation, few researches have focused on the relationship between nicotine dependence and age. Methods: A cross-sectional study (conducted in 2013) with 596 Chinese rural male current smokers was performed to study the relationship between ND and age. The ND level was assessed using the Fagerström Test for Nicotine Dependence (FTND) scale. The univariate two-degree fractional polynomials (FPs) regression was used to explore the relation of ND to age. Results: The mean of FTND scores in the middle-aged group (45-64 yr old) was higher than that in the younger (

Abstract Background Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency syndrome, manifested as recurrent infections and inflammatory complications. Although prophylactic treatment with antibiotics and antifungals improved the outcome of CGD patients, infections remain the major cause of mortality. Case presentation A boy aged 3 years and 8 months was admitted to hospital complaining of lip swelling with fever for half a month and neck abscess for 11 days. After a thorough examination, severe pneumonia, respiratory failure, oral and maxillofacial space infection, and perianal abscess were confirmed. However, his condition didn’t improve after initial comprehensive therapy. Subsequently, overlapping infections of Nocardia farcinica and Aspergillus fumigatus were identified by metagenomic next-generation sequencing. He was treated with imipenem, linezolid, and voriconazole intravenously, plus taking oral compound sulfamethoxazole. Later, his condition improved. Through whole-exome sequencing, the child was ultimately diagnosed as X-linked chronic granulomatous disease (X-CGD) caused by CYBB gene mutation. Allogeneic hematopoietic stem cell transplantation was the potential sanative approach but there were no available human leukocyte antigen compatible donors for the child. The family requested to transfer to a superior hospital for further treatment. Two months later, we followed up the child’s family. Unfortunately, the child had expired due to severe infection. Conclusion To our knowledge, this is the first case of overlapping infection of Nocardia farcinica and Aspergillus fumigatus identified by metagenomic next-generation sequencing in a child with X-CGD from China. For infectious pathogens that are hard to diagnosis by traditional detection methods, metagenomic next-generation sequencing is recommended as an adminicle or indispensable approach for microbial identification. Patients with X-CGD have poor prognosis, early diagnosis and intervention of X-CGD may reduce the mortality.

Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor-α caused by PTSD. Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1A receptor. Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration, as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs. Overall, nasal CBD TSGs are safe and effective and have controlled release. There are a novel promising option for the clinical treatment of PTSD.

Systemic chemotherapy of breast cancer is commonly delivered as a large dose and has toxic side effects. Local chemotherapy would overcome the shortcomings of systemic reconstruction and could play an important role in breast cancer surgery according to personalized demand. The application of three-dimensional (3D) printing technology makes personalized customization possible. We designed and prepared a prosthesis containing paclitaxel (PTX) and doxorubicin (DOX) microspheres (PPDM) based on 3D printing to prevent tumor recurrence and metastasis after breast conserving surgery. Polydimethysiloxane has good biocompatibility and was used as a drug carrier in this study. The average particle size of the PTX and DOX microspheres were approximately 3.1 µm and 2.2 µm, respectively. The drug loading of PTX and DOX microspheres was 4.2% and 2.1%, respectively. In vitro drug release studies demonstrated that the 3D-printed prosthesis loaded with PTX and DOX microspheres could release the drugs continuously for more than 3 weeks and thereby suppress cancer recurrence with reduced side effects. The PTX and DOX microspheres not only exerted a synergistic effect, but also achieved a good sustained release effect. In vivo evaluation showed that the PPDM could effectively inhibit breast cancer recurrence and metastasis in mice with breast cancer. PPDM are expected to achieve postoperative chemotherapy for breast cancer and be highly efficient to prevent local breast cancer recurrence and metastasis.

Background: Blepharospasm (BSP) and dry eye disease (DED) are clinically common diseases characterized by an increased blinking rate. A sustained eyelid muscle activity may alter the cortical sensorimotor concordance and lead to secondary functional changes. This study aimed to explore the central mechanism of BSP by assessing brain functional differences between the two groups and comparing them with healthy controls.Methods: In this study, 25 patients with BSP, 22 patients with DED, and 23 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The amplitude of low-frequency fluctuations (ALFF) was applied to analyze the imaging data.Results: Analysis of covariance (ANCOVA) revealed widespread differences in ALFF across the three groups. In comparison with healthy controls, patients with BSP showed abnormal ALFF in the sensorimotor integration related-brain regions, including the bilateral supplementary motor area (SMA), left cerebellar Crus I, left fusiform gyrus, bilateral superior medial prefrontal cortex (MPFC), and right superior frontal gyrus (SFG). In comparison with patients with DED, patients with BSP exhibited a significantly increased ALFF in the left cerebellar Crus I and left SMA. ALFF in the left fusiform gyrus/cerebellar Crus I was positively correlated with symptomatic severity of BSP.Conclusions: Our results reveal that the distinctive changes in the brain function in patients with BSP are different from those in patients with DED and healthy controls. The results further emphasize the primary role of sensorimotor integration in the pathophysiology of BSP.