The effect of stretching exercises before orthotic treatment on the immediate in-orthosis correction of the patients with adolescent idiopathic scoliosis: A pilot study.

BACKGROUND: Stretching exercise is generally used for improving flexibility. However, its application to promote orthotic treatment for patients with adolescent idiopathic scoliosis (AIS) remains unknown. OBJECTIVE: This study was to explore the effect of pre-orthosis stretching exercises on spinal flexibility and initial in-orthosis correction for the patients with AIS. STUDY DESIGN: A pilot-controlled study. METHODS: An experimental group (EG) of 13 subjects (10 girls and 3 boys) with AIS allocating to self-stretching exercises and a control group (CG) of 19 AIS subjects (14 girls and 5 boys) with no stretching before orthosis fitting were recruited. The spinal flexibility of the EG was evaluated with an ultrasound imaging system and physical measurements. The initial in-orthosis correction rates between the 2 groups were compared with the independent t test, and the correlation analysis between the spinal flexibility measured from ultrasound images and physical measurement was performed with the Pearson correlation test. RESULTS: The initial Cobb angle of EG and CG were 25.70° ± 7.30° and 28.09° ± 5.58°, respectively. No significant difference was observed between the initial in-orthosis Cobb angle of EG (11.13° ± 6.80°) and CG (15.65° ± 9.10°) (p = 0.06). However, the spinal flexibility after stretching exercises was improved (p < 0.001), and the spinal flexibility changes measured with ultrasound and physical forward-bending method were significantly correlated (r = 0.57, p < 0.05). CONCLUSION: Stretching exercises before orthotic treatment could improve the spinal flexibility but did not cause a better in-orthosis correction. A study with a larger sample size and longer follow-up period should be conducted to investigate the long-term effect of stretching exercises.

Enhanced Biosynthesis of d-Allulose from a d-Xylose-Methanol Mixture and Its Self-Inductive Detoxification by Using Antisense RNAs in Escherichia coli.

d-Allulose, a C-3 epimer of d-fructose, has great market potential in food, healthcare, and medicine due to its excellent biochemical and physiological properties. Microbial fermentation for d-allulose production is being developed, which contributes to cost savings and environmental protection. A novel metabolic pathway for the biosynthesis of d-allulose from a d-xylose-methanol mixture has shown potential for industrial application. In this study, an artificial antisense RNA (asRNA) was introduced into engineered Escherichia coli to diminish the flow of pentose phosphate (PP) pathway, while the UDP-glucose-4-epimerase (GalE) was knocked out to prevent the synthesis of byproducts. As a result, the d-allulose yield on d-xylose was increased by 35.1%. Then, we designed a d-xylose-sensitive translation control system to regulate the expression of the formaldehyde detoxification operon (FrmRAB), achieving self-inductive detoxification by cells. Finally, fed-batch fermentation was carried out to improve the productivity of the cell factory. The d-allulose titer reached 98.6 mM, with a yield of 0.615 mM/mM on d-xylose and a productivity of 0.969 mM/h.

Identification of key sensory and chemical factors determining flavor quality of Xinyu mandarin during ripening and storage.

Xinyu mandarin is popular for its good flavor, but its flavor deteriorates during postharvest storage. To better understand the underlying basis of this change, the dynamics of the sensory profiles were investigated throughout fruit ripening and storage. Sweetness and sourness, determined especially by sucrose and citric acid content, were identified as the key sensory factors in flavor establishment during ripening, but not in flavor deterioration during storage. Postharvest flavor deterioration is mainly attributed to the reduction of retronasal aroma and the development of off-flavor. Furthermore, sugars, acids and volatile compounds were analyzed. Among the 101 detected volatile compounds, 10 changed significantly during the ripening process. The concentrations of 15 volatile components decreased during late postharvest storage, among which α-pinene and d-limonene were likely to play key roles in the reduction of aroma. Three volatile compounds were found to increase during storage, associated with off-flavor development.

Multi-strain probiotics ameliorate Alzheimer's-like cognitive impairment and pathological changes through the AKT/GSK-3ß pathway in senescence-accelerated mouse prone 8 mice.

BACKGROUND: Alzheimer's disease (AD), the most prevalent type of dementia, still lacks disease-modifying treatment strategies. Recent evidence indicates that maintaining gut microbiota homeostasis plays a crucial role in AD. Targeted regulation of gut microbiota, including probiotics, is anticipated to emerge as a potential approach for AD treatment. However, the efficacy and mechanism of multi-strain probiotics treatment in AD remain unclear. METHODS: In this study, 6-month-old senescence-accelerated-mouse-prone 8 (SAMP8) and senescence-accelerated-mouse-resistant 1 (SAMR1) were utilized. The SAMP8 mice were treated with probiotic-2 (P2, a probiotic mixture of Bifidobacterium lactis and Lactobacillus rhamnosus) and probiotic-3 (P3, a probiotic mixture of Bifidobacterium lactis, Lactobacillus acidophilus, and Lactobacillus rhamnosus) (1 × 109 colony-forming units) once daily for 8 weeks. Morris water maze (MWM) and novel object recognition (NOR) tests were employed to assess the memory ability. 16S sequencing was applied to determine the composition of gut microbiota, along with detecting serum short-chain fatty acids (SCFAs) concentrations. Neural injury, Aß and Tau pathology, and neuroinflammation level were assessed through western blot and immunofluorescence. Finally, potential molecular mechanisms was explored through transcriptomic analysis and western blotting. RESULTS: The MWM and NOR test results indicated a significant improvement in the cognitive level of SAMP8 mice treated with P2 and P3 probiotics compared to the SAMP8 control group. Fecal 16S sequencing revealed an evident difference in the α diversity index between SAMP8 and SAMR1 mice, while the α diversity of SAMP8 mice remained unchanged after P2 and P3 treatment. At the genus level, the relative abundance of ten bacteria differed significantly among the four groups. Multi-strain probiotics treatment could modulate serum SCFAs (valeric acid, isovaleric acid, and hexanoic acid) concentration. Neuropathological results demonstrated a substantial decrease in neural injury, Aß and Tau pathology and neuroinflammation in the brain of SAMP8 mice treated with P3 and P2. Transcriptomic analysis identified the chemokine signaling pathway as the most significantly enriched signaling pathway between SAMP8 and SAMR1 mice. Western blot test indicated a significant change in the phosphorylation level of downstream AKT/GSK-3ß between the SAMP8 and SAMR1 groups, which could be reversed through P2 and P3 treatment. CONCLUSIONS: Multi-strain probiotics treatment can ameliorate cognitive impairment and pathological change in SAMP8 mice, including neural damage, Aß and Tau pathology, and neuroinflammation. This effect is associated with the regulation of the phosphorylation of the AKT/GSK-3ß pathway.

High throughput screening of pure silica zeolites for CF4 capture from electronics industry gas.

The capture and separation of CF4 from CF4/N2 mixture gas is a crucial issue in the electronics industry, as CF4 is a commonly used etching gas and the ratio of CF4 to N2 directly affects process efficiency. Utilizing high-throughput computational screening techniques and grand canonical Monte Carlo (GCMC) simulations, we comprehensively screened and assessed 247 types of pure silicon zeolite materials to determine their adsorption and separation performance for CF4/N2 mixtures. Based on screening, the relationships between the structural parameters and adsorption and separation properties were meticulously investigated. Four indicators including adsorption selectivity, working capacity, adsorbent performance score (APS), and regenerability (R%) were used to evaluate the performance of adsorbents. Based on the evaluation, we selected the top three best-performing zeolite structures for vacuum swing adsorption (LEV, AWW and ESV) and pressure swing adsorption (AVL, ZON, and ERI) processes respectively. Also, we studied the preferable adsorption sites of CF4 and N2 in the selected zeolite structures through centroid density distributions at the molecule level. We expect the study may provide some valuable guidance for subsequent experimental investigations on adsorption and separation of CF4/N2.

Endophytic Fungi-Mediated Defense Signaling in Maize: Unraveling the Role of WRKY36 in Regulating Immunity against Spodoptera frugiperda.

Seed priming with beneficial endophytic fungi is an emerging sustainable strategy for enhancing plant resistance against insect pests. This study examined the effects of Beauvaria bassiana Bb20091317 and Metarhizium rileyi MrCDTLJ1 fungal colonization on maize growth, defence signalling, benzoxazinoid levels and gene expression. The colonization did not adversely affect plant growth but reduced larval weights of Spodoptera frugiperda. Maize leaves treated with M. rileyi exhibited higher levels of jasmonic acid, jasmonoyl-Isoleucine, salicylic acid, and indole acetic acid compared to control. B. bassiana and M. rileyi accelerated phytohormone increase upon S. frugiperda herbivory. Gene expression analysis revealed modulation of benzoxazinoid biosynthesis genes. We further elucidated the immune regulatory role of the transcription factor zmWRKY36 using virus-induced gene silencing (VIGS) in maize. zmWRKY36 positively regulates maize immunity against S. frugiperda, likely by interacting with defense-related proteins. Transient overexpression of zmWRKY36 in tobacco-induced cell death, while silencing in maize reduced chitin-triggered reactive oxygen species burst, confirming its immune function. Overall, B. bassiana and M. rileyi successfully colonized maize, impacting larval growth, defense signalling, and zmWRKY36-mediated resistance. This sheds light on maize-endophyte-insect interactions for sustainable plant protection.

The BTB/TAZ domain-containing protein CmBT1-mediated CmANR1 ubiquitination negatively regulates root development in chrysanthemum.

Roots are fundamental for plants to adapt to variable environmental conditions. The development of a robust root system is orchestrated by numerous genetic determinants and, among them, the MADS-box gene ANR1 has garnered substantial attention. Prior research has demonstrated that, in chrysanthemum, CmANR1 positively regulates root system development. Nevertheless, the upstream regulators involved in the CmANR1-mediated regulation of root development remain unidentified. In this study, we successfully identified bric-a-brac, tramtrack and broad (BTB) and transcription adapter putative zinc finger (TAZ) domain protein CmBT1 as the interacting partner of CmANR1 through a yeast-two-hybrid (Y2H) screening library. Furthermore, we validated this physical interaction through bimolecular fluorescence complementation and pull-down assays. Functional assays revealed that CmBT1 exerted a negative influence on root development in chrysanthemum. In both in vitro and in vivo assays, it was evident that CmBT1 mediated the ubiquitination of CmANR1 through the ubiquitin/26S proteasome pathway. This ubiquitination subsequently led to the degradation of the CmANR1 protein and a reduction in the transcription of CmANR1-targeted gene CmPIN2, which was crucial for root development in chrysanthemum. Genetic analysis suggested that CmBT1 modulated root development, at least in part, by regulating the level of CmANR1 protein. Collectively, these findings shed new light on the regulatory role of CmBT1 in degrading CmANR1 through ubiquitination, thereby repressing the expression of its targeted gene and inhibiting root development in chrysanthemum.

Integrating TSPO PET imaging and transcriptomics to unveil the role of neuroinflammation and amyloid-ß deposition in Alzheimer's disease.

PURPOSE: Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-ß (Aß) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aß PET imaging in clinical AD cohort. METHODS: We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [18F]DPA-714) and Aß ([18F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aß PET imaging. RESULTS: TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with Aß deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aß deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003). CONCLUSION: By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aß deposition and cognitive dysfunction.

Transporter mining and metabolic engineering of Escherichia coli for high-level D-allulose production from D-fructose by thermo-swing fermentation.

D-Allulose is an ultra-low-calorie sweetener with broad market prospects in the fields of food, beverage, health care, and medicine. The fermentative synthesis of D-allulose is still under development and considered as an ideal route to replace enzymatic approaches for large-scale production of D-allulose in the future. Generally, D-allulose is synthesized from D-fructose through Izumoring epimerization. This biological reaction is reversible, and a high temperature is beneficial to the conversion of D-fructose. Mild cell growth conditions seriously limit the efficiency of producing D-allulose through fermentation. FryABC permease was identified to be responsible for the transport of D-allulose in Escherichia coli by comparative transcriptomic analysis. A cell factory was then developed by expression of ptsG-F, dpe, and deletion of fryA, fruA, manXYZ, mak, and galE. The results show that the newly engineered E. coli was able to produce 32.33 ± 1.33 g L-1 of D-allulose through a unique thermo-swing fermentation process, with a yield of 0.94 ± 0.01 g g-1 on D-fructose.

The structural and electronic properties of (001) surface of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) with first-principles calculations.

CONTEXT: 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) is a typical insensitive energetic material. It can be used in explosive formulations, such as PBX-9502 and LX-17-0. TATB is an intriguing and unusual explosive for another reason: it crystallizes into a wide array of planar hydrogen bonds, forming a graphite-like layered structure. Therefore, TATB is one of the important research objects, and its surface structure needs to be deeply understood. In this research work, the electronic and energetic properties of TATB (001) surface are explored. METHODS: In this paper, the structural, electronic, energetic properties and impact sensitivity of TATB (001) surface structure at 0 and -3 GPa along with x-axis were calculated in this study using the first-principles calculations. The calculations in this paper are performed in the CASTEP code, which is based on the density functional theory with the first-principles calculation method using the plan-wave pseudopotential approach. The exchange-correlation interaction was adopted by the generalized gradient approximation (GGA) with the Perdew-Burke-Ernzerhof (PBE) functional. The DFT-D method with the Grimme correction accurately models van der Waals interactions. To model the surface structures of TATB, the planar slab method was employed. We constructed TATB (001) periodic slabs including three layers with a 15-Å vacuum layer.

Successful management of camrelizumab-induced immune-checkpoint-inhibitors-related myocarditis.

INTRODUCTION: Immune checkpoint inhibitors can cause immune-related toxicity in various systems, with myocarditis being the most severe and life-threatening manifestation. This report presents a case in which myocarditis developed following administration of programmed cell death protein-1 (PD-1) inhibitors therapy. We describe the diagnosis and treatment of this patient in detail. CASE REPORT: We present the case of a 59-year-old female diagnosed with post-operative esophageal cancer and hepatic metastases. The patient underwent second-line treatment with domestically-made PD-1 inhibitor, camrelizumab, in combination with paclitaxel (albumin-bound) and carboplatin for two cycles. During the course of treatment, an electrocardiogram (ECG) revealed ST segment elevation in leads II, III, aVF, V2, V3, and V4, along with T wave changes in leads I and aVL. Laboratory examinations showed abnormal levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). Despite the absence of clinical symptoms, the patient was routinely hospitalized three weeks later. Based on the findings from the ECG, cardiac biomarkers, echocardiography, echocardiogram, cardiac magnetic resonance, and angiography, she was diagnosed with immune-checkpoint-inhibitors-related myocarditis. MANAGEMENT AND OUTCOME: The patient received immunoglobulin (0.5 g/kg/day) and was initially given methylprednisolone (1000 mg/day). Methylprednisolone was gradually reduced to 40 mg/day in 2 weeks. During this time, the levels of biomarkers indicative of myocardial injury also exhibited a simultaneous decline. DISCUSSION: This case highlights the importance of early detection and prompt intervention, including initiating appropriate steroid therapy and discontinuing of immune checkpoint inhibitors. Such measures can effectively prevent morbidity and mortality, ultimately leading to an improved prognosis.

[Degradation of Ciprofloxacin by CuNiFe LDHs/BiO2-x Heterojunction-activated Peroxymonosulfate Under Visible Light Irradiation].

Herein, a CuNiFe LDHs/BiO2-x composite photocatalyst was successfully synthesized using a hydrothermal method and applied to activate peroxymonosulfate to degrade ciprofloxacin under visible light irradiation. Owing to the synergistic effect of photocatalysis and PMS activation, a high removal efficiency of CIP up to 88.3% was achieved. The prepared photocatalysts were characterized using XRD, FT-IR, SEM, XPS, UV-Vis DRS, and other methods. The optimal loading amount of CuNiFe LDHs was determined, and the effects of PMS dosage, initial pH value, and inorganic anions (Cl-, CO32-, and NO3-) on the degradation were investigated. Electron paramagnetic resonance and free radical trapping experiments demonstrated that·OH and h+ were the main active species for degrading CIP, and the possible degradation mechanism of the system was proposed.

[Effects of Straw Biochar on Carbon Footprint of Maize Farmland Ecosystem Under Mulched Drip Irrigation in Hetao Irrigation District].

To explore the effect of biochar on greenhouse gas emissions and the carbon footprint of a corn farmland ecosystem under drip irrigation with film in an arid region, biochar treatments with different application rates[0 (CK), 15 (C15), 30 (C30), and 45 t·hm-2 (C45)] were established. The seasonal changes in soil greenhouse gases (CO2, N2O, and CH4) and their comprehensive warming potential in the maize farmland ecosystem were monitored for two consecutive years after a one-time application of biochar. The carbon emissions caused by agricultural production activities and their carbon footprint were estimated using the life cycle assessment method. Compared with that in CK, the cumulative CO2 emissions in the crop growing season decreased by 17.6%-24.7%, the cumulative N2O emissions decreased by 71.1%-110.4%, and the global warming potential decreased by 19.5%-25.9%. In the second year of the crop growing season after biochar application, the cumulative CO2 emissions were reduced by 19.2%-40.6%, the cumulative N2O emissions were reduced by 38.7-46.7%, and the comprehensive warming potential was reduced by 19.7%-40.5%. For two consecutive years, the treatment of C15 and C30 increased the cumulative absorption of CH4 to different degrees, whereas the treatment of C45 significantly decreased the cumulative absorption of CH4. C15 and C45 were the treatments with the least carbon footprint per unit yield in the current and the succeeding year of biochar application, and their carbon footprint per unit yield was 10.1% and 26.2% lower than that of CK, respectively. Soil greenhouse gas emissions showed the most contribution to the carbon footprint of the maize farmland ecosystem (38.1%-59.2%), followed by nitrogen fertilizer production (19.8%-33.4%), electric energy production (6.7%-8.8%), and plastic film mulching (4.4%-7.4%). Biochar contributed 5.7%-13.8% to the ecosystem's carbon footprint. The application of 30 t·hm-2 biochar had a better effect on carbon reduction, carbon fixation, and yield increase in the farmland ecosystem. Improving the biochar production process and transportation route, increasing nitrogen use efficiency, and developing water-saving and energy-saving irrigation technology are important ways to reduce the carbon footprint of farmland ecosystems in arid regions.

ABCA7-Associated Clinical Features and Molecular Mechanisms in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of neurodegenerative disease and its pathogenesis is still unclear. Genetic factors are thought to account for a large proportion of the overall AD phenotypes. ATP-binding cassette transporter A7 (ABCA7) is one of the most important risk gene for AD. Multiple forms of ABCA7 variants significantly increase the risk of AD, such as single-nucleotide polymorphisms, premature termination codon variants, missense variants, variable number tandem repeat, mutations, and alternative splicing. AD patients with ABCA7 variants usually exhibit typical clinical and pathological features of traditional AD with a wide age of onset range. ABCA7 variants can alter ABCA7 protein expression levels and protein structure to affect protein functions such as abnormal lipid metabolism, amyloid precursor protein (APP) processing, and immune cell function. Specifically, ABCA7 deficiency can cause neuronal apoptosis by inducing endoplasmic reticulum stress through the PERK/eIF2α pathway. Second, ABCA7 deficiency can increase Aß production by upregulating the SREBP2/BACE1 pathway and promoting APP endocytosis. In addition, the ability of microglia to phagocytose and degrade Aß is destroyed by ABCA7 deficiency, leading to reduced clearance of Aß. Finally, disturbance of lipid metabolism may also be an important method by which ABCA7 variants influence the incidence rate of AD. In the future, more attention should be given to different ABCA7 variants and ABCA7 targeted therapies for AD.

Reliability and validity of assessing lower-limb muscle architecture of patients with cerebral palsy (CP) using ultrasound: A systematic review.

AIMS: To investigate the reliability, validity, and level of evidence of applying ultrasound in assessing the lower-limb muscles of patients with cerebral palsy (CP). METHOD: Publications in Medline, PubMed, Web of Science, and Embase were searched on May 10, 2023, to identify and examine relevant studies investigating the reliability/validity of ultrasound in evaluating the architecture of CP lower-limb muscles systematically, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines. RESULTS: Out of 897 records, 9 publications with 111 CP participants aged 3.8-17.0 years were included (8 focused on intra-rater and inter-rater reliability, 2 focused on validity, and 4 were with high quality). The ultrasound-based measurements of muscle thickness (intra-rater only), muscle length, cross-sectional area, muscle volume, fascicle length, and pennation angle showed high reliability, with the majority of intraclass correlation coefficient (ICC) values being larger than 0.9. Moderate-to-good correlations between ultrasound and magnetic resonance imaging measurements existed in muscle thickness and cross-sectional area (0.62 ≤ ICC ≤ 0.82). INTERPRETATION: Generally, ultrasound has high reliability and validity in evaluating the CP muscle architecture, but this is mainly supported by moderate and limited levels of evidence. More high-quality future studies are needed.

Influence of the casing layer on the specific volatile compounds and microorganisms by Agaricus bisporus.

One of the major variables affecting yield of the mushroom Agaricus bisporus is the casing layer, which directly affects the productivity and mass. Here, volatile organic compounds were extracted by headspace solid-phase microextraction and high-throughput sequencing was used to analyze the microbial community diversity. The relationship between mushroom yield at different cropping stages and the contents of volatile organic compounds and microorganisms in three different casing layers: peat, peat + soil and soil were systematically evaluated. The result shows that Benzaldehyde and (E)-2-octenal which stimulate yield, obviously increased as mushrooms grew, while 3-octanone, which inhibits yield, decreased over time in all three casing layers. However, there was not a strong correlation between the concentration of volatile compounds and yield. In addition, more than 3,000 bacterial operational taxonomic units (OTUs) by performing high throughput sequencing of the microbes were obtained in the three casing layers. Interestingly, the microbial community compositions were very similar between the three casing layers at a later cropping stage, but the community richness varied significantly in different casing layers and at different cropping stages. At the phylum level, the communities had similar structures but were quantitively very different, and this was even more obvious at the genus level. Principal component analysis revealed significant alterations in microbial community structure in different casing layers. Sphingomonas, Dongia and Achromobacter were the dominant genera at cropping stage 1, and the stage 3 were abundant in Saccharibacteria_norank, Pseudomonas, Flavobacterium and Brevundimonas, which was positively correlated with yield, while the abundance of Pseudomonas at stage 1 and Lactococcus and Bacillus at stage 3 was negatively correlated with yield. These results provide a guide for the development and agricultural application of microbial agents for yield improvement in the production of A. bisporus.

Investigating the causal association between branched-chain amino acids and Alzheimer's disease: A bidirectional Mendelian randomized study.

Background: There are many metabolic pathway abnormalities in Alzheimer's disease (AD). Several studies have linked branched-chain amino acid (BCAA) metabolism disorders with AD but have not obtained consistent results. The purpose of this study is to explore the causal association between BCAA concentration and the risk of AD. Methods: A bidirectional Mendelian randomized (MR) study was applied to explore the causal effect between BCAA level and the risk of AD. Genetic instrumental variables from the genome-wide association study (GWAS) of serum BCAA levels [total BCAAs (115,047 participants), valine (115,048 participants), leucine (115,074 participants), and isoleucine (115,075 participants)] from the UK Biobank and AD (21,982 AD cases and 41,944 controls) from the International Genomics of Alzheimer's Project were applied to explore the causal effect through the inverse variance-weighted (IVW) method, MR-Egger, and weighted median, accompanied by multiple pluripotency and heterogeneity tests. Results: The forward MR analysis showed that there was no causal effect of total BCAAs (OR: 1.067, 95% CI: 0.838-1.358; p = 0.838), valine (OR: 1.106, 95% CI: 0.917-1.333; p = 0.292), leucine (OR: 1.096, 95% CI: 0.861-1.396; p = 0.659), and isoleucine (OR: 1.457, 95% CI: 1.024-2.742; p = 0.037) levels on the risk of AD. The reverse analysis showed that AD was related to reduced levels of total BCAAs (OR: 0.979, 95% CI: 0.989-0.990; p < 0.001), valine (OR: 0.977, 95% CI: 0.963-0.991; p = 0.001), leucine (OR: 0.983, 95% CI: 0.973-0.994; p = 0.002), and isoleucine (OR: 0.982, 95% CI: 0.971-0.992; p = 0.001). Conclusion: We provide robust evidence that AD was associated with a decreased level of BCAAs, which can serve as a marker for early diagnosis of AD.

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome.

BACKGROUND: Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. METHODS: We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. RESULTS: One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. CONCLUSIONS: We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

Switching the memory behaviour from binary to ternary by triggering S62- relaxation in polysulfide-bearing zinc-organic complex molecular memories.

The use of crystalline metal-organic complexes with definite structures as multilevel memories can enable explicit structure-property correlations, which is significant for designing the next generation of memories. Here, four Zn-polysulfide complexes with different degrees of conjugation have been fabricated as memory devices. ZnS6(L)2-based memories (L = pyridine and 3-methylpyridine) can exhibit only bipolar binary memory performances, but ZnS6(L)-based memories (L = 2,2'-bipyridine and 1,10-phenanthroline) illustrate non-volatile ternary memory performances with high ON2/ON1/OFF ratios (104.22/102.27/1 and 104.85/102.58/1) and ternary yields (74% and 78%). Their ON1 states stem from the packing adjustments of organic ligands upon the injection of carriers, and the ON2 states are a result of the ring-to-chain relaxation of S62- anions. The lower conjugated degrees in ZnS6(L)2 result in less compact packing; consequently, the adjacent S62- rings are too long to trigger the S62- relaxation. The deep structure-property correlation in this work provides a new strategy for implementing multilevel memory by triggering polysulfide relaxation based on the conjugated degree regulation of organic ligands.