Correction: Structural variation underlies functional diversity at methyl salicylate loci in tomato.

[This corrects the article DOI: 10.1371/journal.pgen.1010751.].

Highly extensile approach for comminuted ulna coronoid process fractures with mini-plate fixation: a case series of 31 patients.

BACKGROUND: For the treatment of coronoid process fractures, medial, lateral, anterior, anteromedial, and posterior approaches have been increasingly reported; however, there is no general consensus on the method of fixation of coronal fractures. Here, we present a highly-extensile minimally invasive approach to treat coronoid process fractures using a mini-plate that can achieve anatomic reduction, stable fixation, and anterior capsular repair. Further, the study aimed to determine the complication rate of the anterior minimally invasive approach and to evaluate functional and clinical patient-reported outcomes during follow-up. METHODS: Thirty-one patients diagnosed with coronoid fractures accompanied with a "terrible triad" or posteromedial rotational instability between April 2012 and October 2018 were included in the analysis. Anatomical reduction and mini-plate fixation of coronoid fractures were performed using an anterior minimally invasive approach. Patient-reported outcomes were evaluated using the Mayo Elbow Performance Index (MEPI) score, range of motion (ROM), and the visual analog score (VAS). The time of fracture healing and complications were recorded. RESULTS: The mean follow-up time was 26.7 months (range, 14-60 months). The average time to radiological union was 3.6 ± 1.3 months. During the follow-up period, the average elbow extension was 6.8 ± 2.9° while the average flexion was 129.6 ± 4.6°. According to Morrey's criteria, 26 (81%) elbows achieved a normal desired ROM. At the last follow-up, the mean MEPI score was 98 ± 3.3 points. There were no instances of elbow instability, elbow joint stiffness, subluxation or dislocation, infection, blood vessel complications, or nerve palsy. Overall, 10 elbows (31%) experienced heterotopic ossification. CONCLUSION: An anterior minimally invasive approach allows satisfactory fixation of coronoid fractures while reducing incision complications due to over-dissection of soft tissue injuries. In addition, this incision does not compromise the soft tissue stability of the elbow joint and allows the patient a more rapid return to rehabilitation exercises.

Linking Disulfide Levels and NAD+ Metabolism with Alzheimer's Disease for Diagnostic Modeling and Target Drug Analysis.

BACKGROUND: Alzheimer's disease (AD) is a condition that affects the nervous system and that requires considerably more in-depth study. Abnormal Nicotinamide Adenine Dinucleotide (NAD+) metabolism and disulfide levels have been demonstrated in AD. This study investigated novel hub genes for disulfide levels and NAD+ metabolism in relation to the diagnosis and therapy of AD. METHODS: Data from the gene expression omnibus (GEO) database were analyzed. Hub genes related to disulfide levels, NAD+ metabolism, and AD were identified from overlapping genes for differentially expressed genes (DEGs), genes in the NAD+ metabolism or disulfide gene sets, and module genes obtained by weighted gene co-expression network analysis (WGCNA). Pathway analysis of these hub genes was performed by Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was constructed based on the expression level of hub genes in brain samples. CIBERSORT was used to evaluate immune cell infiltration and immune factors correlating with hub gene expression. The DrugBank database was also used to identify drugs that target the hub genes. RESULTS: We identified 3 hub genes related to disulfide levels in AD and 9 related to NAD+ metabolism in AD. Pathway analysis indicated these 12 genes were correlated with AD. Stepwise regression analysis revealed the area under the curve (AUC) for the predictive model based on the expression of these 12 hub genes in brain tissue was 0.935, indicating good diagnostic performance. Additionally, analysis of immune cell infiltration showed the hub genes played an important role in AD immunity. Finally, 33 drugs targeting 10 hub genes were identified using the DrugBank database. Some of these have been clinically approved and may be useful for AD therapy. CONCLUSION: Hub genes related to disulfide levels and NAD+ metabolism are promising biomarkers for the diagnosis of AD. These genes may contribute to a better understanding of the pathogenesis of AD, as well as to improved drug therapy.

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data.

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Identification of a lncRNA/circRNA-miRNA-mRNA ceRNA Network in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) occurs in the elderly and pre-elderly, characterized by decline of memory, cognitive dysfunction, impairment of learning capacity, and motor dysfunction. Recently a competitive endogenous RNA (ceRNA) network has been found to be related to AD progression, but there is still little understanding of the ceRNA regulatory network in AD. This study aims to explore the important regulatory mechanisms of ceRNA regulatory networks containing long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in AD. METHODS: Data from the gene expression omnibus (GEO) database were used for the analysis. To study enrichment function for the upregulated and downregulated mRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Metascape database, respectively. Based on the STRING database and Cytoscape software 3.9.1, a protein-protein interaction (PPI) network was constructed. The hub genes in this network were identified utilizing the CytoHubba plugin in Cytoscape. The TargetScan, miRWalk, and miRDB were selected to calculate the regulatory interaction between miRNAs and the hub genes. LncRNAs were predicted using RNA22. Additionally, circRNA prediction was executed using the circBank database. RESULTS: 711 downregulated and 670 upregulated overlapping mRNAs were identified between AD and control samples. 32 downregulated and 340 upregulated miRNAs were obtained from AD samples compared with control samples. 78 upregulated and 205 downregulated circRNAs were screened. 275 upregulated lncRNAs and 209 downregulated lncRNAs were found between AD samples and control samples. The PPI network constructed consists of 1016 nodes and 13,946 edges. Ten hub genes were selected to identify target miRNAs and ceRNAs. On the basis of the ceRNA hypothesis, a circRNA/lncRNA-miRNA-mRNA network was established. It included five lncRNAs (TRHDE-AS1, SNHG10, OIP5-AS, LINC00926 and LINC00662), 26 circRNAs, five miRNAs (hsa-miR-3158-3p, hsa-miR-4435, hsa-let-7d-3p, hsa-miR-330-5p and hsa-miR-3605-3p), and ten mRNAs (RPL11, RPL34, RPL21, RPL22, RPL6, RPL32, RPL24, RPL35, RPL31, and RPL35A). RPL35 and RPL35A were found to be significantly associated with AD pathology in tau and Aß line AD models by the AlzData database. The study discovered the significance of several lncRNA-miRNA-mRNA axes and circRNA-miRNA-mRNA axes that included RPL35A and RPL35. CONCLUSIONS: ceRNAs were found to be important regulators in the development of AD and provide potential biological therapy targets for AD management.

SAGN: Sparse Adaptive Gated Graph Neural Network With Graph Regularization for Identifying Dual-View Brain Networks.

Due to the absence of a gold standard for threshold selection, brain networks constructed with inappropriate thresholds risk topological degradation or contain noise connections. Therefore, graph neural networks (GNNs) exhibit weak robustness and overfitting problems when identifying brain networks. Furthermore, existing studies have predominantly focused on strongly coupled connections, neglecting substantial evidence from other intricate systems that highlight the value of weakly coupled connections. Consequently, the potential of weakly coupled brain networks remains untapped. In this study, we pioneeringly construct weakly coupled brain networks and validate their values in emotion identification tasks. Subsequently, we propose a sparse adaptive gated GNN (SAGN) that can simultaneously perceive the valuable topology of dual-view (i.e., strongly coupled and weakly coupled) brain networks. The SAGN contains a sparse adaptive global receptive field. Moreover, SAGN employs a gated mechanism with feature enhancement and adaptive noise suppression capabilities. To address the lack of inductive bias and the large capacity of SAGN, a graph regularization term built with prior topology of dual-view brain networks is introduced to enhance generalization. Besides a public dataset (SEED), we also built a custom dataset (MuSer) with 60 subjects to evaluate weakly coupled brain networks' value and validate the SAGN's performance. Experiments demonstrate that brain physiological patterns associated with different emotional states are separable and rooted in weakly coupled brain networks. In addition, SAGN exhibits excellent generalization and robustness in identifying brain networks.

Trends in the global burden of vision loss among the older adults from 1990 to 2019.

Purpose: To quantify the global impact of vision impairment in individuals aged 65 years and older between 1990 and 2019, segmented by disease, age, and sociodemographic index (SDI). Methods: Using the Global Burden of Diseases 2019 (GBD 2019) dataset, a retrospective demographic evaluation was undertaken to ascertain the magnitude of vision loss over this period. Metrics evaluated included case numbers, prevalence rates per 100,000 individuals, and shifts in prevalence rates via average annual percentage changes (AAPCs) and years lived with disability (YLDs). Results: From 1990 to 2019, vision impairment rates for individuals aged 65 years and older increased from 40,027.0 (95% UI: 32,232.9-49,945.1) to 40,965.8 (95% UI: 32,911-51,358.3, AAPC: 0.11). YLDs associated with vision loss saw a significant decrease, moving from 1713.5 (95% UI: 1216.2-2339.7) to 1579.1 (95% UI: 1108.3-2168.9, AAPC: -0.12). Gender-based evaluation showed males had lower global prevalence and YLD rates compared to females. Cataracts and near vision impairment were the major factors, raising prevalence by 6.95 and 2.11%, respectively. Cataract prevalence in high-middle SDI regions and near vision deficits in high SDI regions significantly influenced YLDs variation between 1990 and 2019. Conclusion: Over the past three decades, there has been a significant decrease in the vision impairment burden in individuals aged 65 and older worldwide. However, disparities continue, based on disease type, regional SDI, and age brackets. Enhancing eye care services, both in scope and quality, is crucial for reducing the global vision impairment burden among the older adults.

The prognostic value of serum α-klotho in age-related diseases among the US population: A prospective population-based cohort study.

Objective: α-Klotho is a potential biological marker of aging with satisfactory clinical applicability. However, its prognostic significance in age-related diseases has largely been undermined. Therefore, we aimed to report the prognostic value of serum α-klotho levels in age-related diseases. Methods: Participants with available serum α-klotho data from the National Health and Nutrition Examination Survey (2007-2016) were included. Their survival status was collected at 7.62 ± 2.99 years after serum α-klotho data was collected, and the endpoint was all-cause and cardiovascular mortality. A Cox regression model was established to examine the association between serum α-klotho levels and all-cause and cardiovascular mortality. Results: The present study included 13,746 U.S. adults with a survey-weighted mean age of 56.19 ± 10.42 years old. Of these, 52.2 % were female and 72.9 % were non-Hispanic whites. The optimal cutoff value of serum α-klotho for predicting all-cause mortality risk in the general population was 603.5 pg/ml. Individuals with low serum α-klotho (<603.5 pg/ml) had a significantly higher risk of all-cause (adjusted HR: 1.34(1.18-1.52), P < 0.001) and cardiovascular mortality (adjusted HR: 1.63(1.27-2.10), P < 0.001). Subgroup analysis showed that low serum α-klotho level was an independent risk factor for all-cause and cardiovascular mortality in people with hypertension, congestive heart failure, diabetes mellitus, and emphysema, while it was an independent risk factor for all-cause mortality in patients with renal insufficiency. Conclusion: A low serum α-klotho concentration (<603.5 pg/ml) could serve as a marker of all-cause and cardiovascular mortality in the general population and in people with age-related diseases, including hypertension, congestive heart failure, diabetes mellitus, and emphysema.

Optimizing commercial Arabica coffee quality by integrating flavor precursors with anaerobic germination strategy.

This study attempted to improve commercial Arabica coffee quality by integrating flavor precursors with anaerobic germination. Using raw coffee beans as materials, anaerobic germination was conducted with 5 g/100 g of flavor precursors (sucrose, glucose, fructose). The chemical composition and sensory quality of roasted coffee beans were analyzed. Results showed that adding flavor precursors facilitated the harmonization of water-soluble chemical components and altered aroma characteristics. Specifically, the inclusion of flavor precursors significantly increased the levels of 5-Hydroxymethylfurfural and volatile aldehydes. Principal component analysis (PCA) on chemical composition dataset revealed 48.7% variability. Sensory analysis, employing the Specialty Coffee Association (SCA) cupping protocol, demonstrated that combining flavor precursors with anaerobic germination transformed coffee flavor properties, enhanced quality, and substantially increased sensory scores (p < 0.05). Sucrose supplementation produced the highest sensory score and intensified fruity flavor attributes. Therefore, adding different flavor precursors forms distinct flavor characteristics, conducive to further improving the quality of germinated coffee.

Identification of New Diterpenoids from the Pulp of Coffea arabica and Their α-Glucosidase Inhibition Activity.

Six new (1, 2, 3, 5, 6, and 8) and seven known (4, 7, 9, 10, 11, 12, and 13) diterpenoids have been identified in the pulp of Coffea arabica. The structures of new diterpenoids were elucidated by extensive spectroscopic analysis, including 1D, 2D NMR (HSQC, HMBC, 1H-1H COSY, and ROESY), HRESIMS, IR, DP4+, electronic circular dichroism, and X-ray crystallography analysis. Compound 1 is ent-labdane-type diterpenoid, whereas compounds (2-13) are ent-kaurane diterpenoids. The result of α-glucosidase inhibitory assay demonstrated that compounds (1, 3, 5, 7, and 10) have moderate inhibitory activity with IC50 values of 55.23 ± 0.84, 74.02 ± 0.89, 66.46 ± 1.05, 49.70 ± 1.02, and 76.34 ± 0.46 µM, respectively, compared to the positive control (acarbose, 51.62 ± 0.21 µM). Furthermore, molecular docking analysis has been conducted to investigate the interaction between the compounds and the receptors of α-glucosidase to interpret their mechanism of activity. This study is the first investigation that successfully discovered the presence of diterpenoids within the coffee pulp.

Dual-functional thermosensitive hydrogel for reducing infection and enhancing bone regeneration in infected bone defects.

The contamination of bone defects is a serious therapeutic problem. The treatment of infected bone defects involves rigorous infection control followed by bone reconstruction. Considering these two processes, the development of biomaterials possessing antibacterial and osteogenic properties offers a promising approach for the treatment of infected bone defects. In this study, a dual-functional, thermosensitive, and injectable hydrogel composed of chitosan (CS), quaternized CS (QCS), and nano-hydroxyapatite (nHA) was designed, and the ratio of CS to QCS in the hydrogel was optimized to enhance the antibacterial efficacy of CS while reducing the cytotoxicity of QCS. In vitro studies demonstrated that the hydrogel with an 85 %:15 % ratio of CS to QCS exhibited excellent biocompatibility and antibacterial properties while also possessing suitable mechanical characteristics and degradability. The incorporation of nHA into the hydrogel enhanced MC3T3-E1 proliferation and osteogenic differentiation. Moreover, this hydrogel demonstrated superior in vivo therapeutic effectiveness in a rabbit model of infected bone defect. In summary, this study provides a promising material design and a comprehensive one-step treatment strategy for infected bone defects.

Dual-functional 3D-printed porous bioactive scaffold enhanced bone repair by promoting osteogenesis and angiogenesis.

The treatment of bone defects is a difficult problem in orthopedics. The excessive destruction of local bone tissue at defect sites destroys blood supply and renders bone regeneration insufficient, which further leads to delayed union or even nonunion. To solve this problem, in this study, we incorporated icariin into alginate/mineralized collagen (AMC) hydrogel and then placed the drug-loaded hydrogel into the pores of a 3D-printed porous titanium alloy (AMCI/PTi) scaffold to prepare a bioactive scaffold with the dual functions of promoting angiogenesis and bone regeneration. The experimental results showed that the ACMI/PTi scaffold had suitable mechanical properties, sustained drug release function, and excellent biocompatibility. The released icariin and mineralized collagen (MC) synergistically promoted angiogenesis and osteogenic differentiation in vitro. After implantation into a rabbit radius defect, the composite scaffold showed a satisfactory effect in promoting bone repair. Therefore, this composite dual-functional scaffold could meet the requirements of bone defect treatment and provide a promising strategy for the repair of large segmental bone defects in clinic.

Sound as a bell: a deep learning approach for health status classification through speech acoustic biomarkers.

BACKGROUND: Human health is a complex, dynamic concept encompassing a spectrum of states influenced by genetic, environmental, physiological, and psychological factors. Traditional Chinese Medicine categorizes health into nine body constitutional types, each reflecting unique balances or imbalances in vital energies, influencing physical, mental, and emotional states. Advances in machine learning models offer promising avenues for diagnosing conditions like Alzheimer's, dementia, and respiratory diseases by analyzing speech patterns, enabling complementary non-invasive disease diagnosis. The study aims to use speech audio to identify subhealth populations characterized by unbalanced constitution types. METHODS: Participants, aged 18-45, were selected from the Acoustic Study of Health. Audio recordings were collected using ATR2500X-USB microphones and Praat software. Exclusion criteria included recent illness, dental issues, and specific medical histories. The audio data were preprocessed to Mel-frequency cepstral coefficients (MFCCs) for model training. Three deep learning models-1-Dimensional Convolution Network (Conv1D), 2-Dimensional Convolution Network (Conv2D), and Long Short-Term Memory (LSTM)-were implemented using Python to classify health status. Saliency maps were generated to provide model explainability. RESULTS: The study used 1,378 recordings from balanced (healthy) and 1,413 from unbalanced (subhealth) types. The Conv1D model achieved a training accuracy of 91.91% and validation accuracy of 84.19%. The Conv2D model had 96.19% training accuracy and 84.93% validation accuracy. The LSTM model showed 92.79% training accuracy and 87.13% validation accuracy, with early signs of overfitting. AUC scores were 0.92 and 0.94 (Conv1D), 0.99 (Conv2D), and 0.97 (LSTM). All models demonstrated robust performance, with Conv2D excelling in discrimination accuracy. CONCLUSIONS: The deep learning classification of human speech audio for health status using body constitution types showed promising results with Conv1D, Conv2D, and LSTM models. Analysis of ROC curves, training accuracy, and validation accuracy showed all models robustly distinguished between balanced and unbalanced constitution types. Conv2D excelled with good accuracy, while Conv1D and LSTM also performed well, affirming their reliability. The study integrates constitution theory and deep learning technologies to classify subhealth populations using noninvasive approach, thereby promoting personalized medicine and early intervention strategies.

Optogenetic Stimulation of the Cardiac Vagus Nerve to Promote Heart Regenerative Repair after Myocardial Infarction.

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.