N 2-Alkyl-dG lesions elicit R-loop accumulation in the genome.

Humans are exposed to DNA alkylating agents through endogenous metabolism, environmental exposure and cancer chemotherapy. The resulting alkylated DNA adducts may elicit genome instability by perturbing DNA replication and transcription. R-loops regulate various cellular processes, including transcription, DNA repair, and telomere maintenance. However, unscheduled R-loops are also recognized as potential sources of DNA damage and genome instability. In this study, by employing fluorescence microscopy and R-loop sequencing approaches, we uncovered, for the first time, that minor-groove N2-alkyl-dG lesions elicit elevated R-loop accumulation in chromatin and in plasmid DNA in cells. We also demonstrated that the N2-alkyl-dG-induced R-loops impede transcription elongation and compromise genome integrity. Moreover, genetic depletion of DDX23, a R-loop helicase, renders cells more sensitive toward benzo[a]pyrene diolepoxide, a carcinogen that induces mainly the minor-groove N2-dG adduct. Together, our work unveiled that unrepaired minor-groove N2-alkyl-dG lesions may perturb genome integrity through augmenting R-loop levels in chromatin. Our findings suggest a potential therapeutic strategy involving the combination of R-loop helicase inhibitors with DNA alkylating drugs.

TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization.

The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery.

A Green Host-Guest Protocol to Improve Water Solubility of Fluorescent Dyes.

Improving fluorescence emission efficiency is essential to develop novel luminescent materials. However, the low water solubility of conventional fluorescent dyes is a serious obstacle to broadening the application scope. Herein, a green protocol have been proposed: Two poorly water-soluble naphthalimide derivatives MONI and MANI with high fluorescent quantum yields (larger than 0.95 in toluene solution) were loaded in three different sizes of cyclodextrin (CD; α, ß, γ-CD) with high water solubility. To further check the feasibility of the proposal, density functional theory (DFT) and time dependent-DFT (TD-DFT) methods combining the Own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM) model with dispersion correction were employed to investigate the geometric and electronic structures of complexes CD·MXNI (X = N, O) in the excited-state process. TD-DFT calculations predict that the fantastic emission behavior of MXNI can be reserved after binding with CD, even improving fluorescent intensity in aqueous solution. Basis set superposition error (BSSE) correction and symmetry adapted perturbation theory (SAPT) were adopted to estimate the complexation energies and weak noncovalent interactions. The middle-sized ß-CD is the perfect candidate to allow fluorescent molecules to settle into its cavity, forming an inclusion complex. Energy decomposition analysis (EDA) indicates that dispersion is superior to electrostatics interaction in embedding-type ß-CD·MXNI, while it is contrary in α,γ-CD·MXNI. NMR calculations further prove the existence of a strong intermolecular hydrogen bond interaction between host and guest. Weak interactions that limited molecular vibration and hampered the nonradiative inactivation channel are conducive to the enhanced emission intensity.

Designed Polar Cosolvent-Prepared Zinc Oxide Film for Efficient and Stable Inverted Organic Solar Cells.

Here, a simple method of applying dimethylformamide (DMF) as cosolvent in the sol-gel technology is used to improve the quality of ZnO bulk films. First-principles calculations show that with the addition of polar solvent DMF, the adsorption energy (Eads) between the solvent and Zn(OH)2 increases from -1.42 to -1.74 eV, which can stabilize the existence of Zn(OH)2, thereby promoting the ZnO synthesis. Besides, the elimination of amine residues in the DMF-ZnO film significantly suppress the photocatalytic activity induced by amine-induced coordination or redox reactions. Inverted organic solar cells (OSCs) based on PM6:Y6 and PM6:BTP-eC9 achieves impressive power conversion efficiencies (PCE) of 17.58 and 18.14%, respectively. Furthermore, benefiting from the reduced defects of bulk ZnO, pseudo-bilayer bulk heterojunction (PBHJ) devices based on the optimized ZnO film exhibited superior stability, the PM6:Y6 devices based on DMF-ZnO ETLs can maintain 90.28% of their initial PCE after 1000 h of thermal aging at 85 °C, and 80.98% of their initial PCE after 168 h of UV aging. This simple solvent optimization strategy can significantly improve the charge transport of ZnO bulk films, making it a reliable strategy for the preparation of electron transport layers in OSCs.

Theoretical study on multi-perspective interaction analysis of ADN and ADN-H2O-CH3OH solutions.

CONTEXT: Revealing the mechanism of intermolecular interactions in dinitroamine ammonium (ADN)-based liquid propellants and exploring the reasons for their performance changes, multi-perspective interaction analyses of ADN and ADN-water (H2O)-methanol (CH3OH) solutions have been conducted via theoretical methods. The band structure, density of states (DOS), surface electrostatic potential (ESP), Hirshfeld surface, reduced density gradient (RDG), AIM topological analysis, and detonation performance were studied and the results showed that both the ADN and ADN-H2O-CH3OH solutions had hydrogen bonds and van der Waals interactions. By introducing the small molecules H2O and CH3OH, the detonation performance of the ADN-H2O-CH3OH solution slightly decreased, but its sensitivity also decreased. Overall, the comprehensive performance of the ADN-H2O-CH3OH solution has improved, and the application range has expanded. These results are helpful for obtaining a deeper understanding of ADN-based liquid propellants at the atomic level and contribute to the development of new liquid propellants. METHODS: The ADN and ADN-H2O-CH3OH solutions were constructed by Amorphous cell module and optimized via GGA with PBE methods in the Dmol3 module of the Materials Studio, and their electronic properties were calculated. Hirshfeld surfaces were generated with CrystalExplorer 3.0. A topological analysis of a variety of molecular clusters was performed via QTAIM. The QTAIM and RDG analyses in this work were generated by Multiwfn 3.0.

Exploring the optimal chain length of modification module in disulfide bond bridged paclitaxel prodrug nanoassemblies for breast tumor treatment.

In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a "fatty alcoholization" strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC12, AC16, AC20, AC24) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC12 to AC20), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC24, the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC20 PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies.

Microvesicles derived from mesenchymal stem cells inhibit acute respiratory distress syndrome-related pulmonary fibrosis in mouse partly through hepatocyte growth factor.

BACKGROUND: Pulmonary fibrosis is one of the main reasons for the high mortality rate among acute respiratory distress syndrome (ARDS) patients. Mesenchymal stromal cell-derived microvesicles (MSC-MVs) have been shown to exert antifibrotic effects in lung diseases. AIM: To investigate the effects and mechanisms of MSC-MVs on pulmonary fibrosis in ARDS mouse models. METHODS: MSC-MVs with low hepatocyte growth factor (HGF) expression (siHGF-MSC-MVs) were obtained via lentivirus transfection and used to establish the ARDS pulmonary fibrosis mouse model. Following intubation, respiratory mechanics-related indicators were measured via an experimental small animal lung function tester. Homing of MSC-MVs in lung tissues was investigated by near-infrared live imaging. Immunohistochemical, western blotting, ELISA and other methods were used to detect expression of pulmonary fibrosis-related proteins and to compare effects on pulmonary fibrosis and fibrosis-related indicators. RESULTS: The MSC-MVs gradually migrated and homed to damaged lung tissues in the ARDS model mice. Treatment with MSC-MVs significantly reduced lung injury and pulmonary fibrosis scores. However, low expression of HGF (siHGF-MSC-MVs) significantly inhibited the effects of MSC-MVs (P < 0.05). Compared with the ARDS pulmonary fibrosis group, the MSC-MVs group exhibited suppressed expression of type I collagen antigen, type III collagen antigen, and the proteins transforming growth factor-ß and α-smooth muscle actin, whereas the siHGF-MVs group exhibited significantly increased expression of these proteins. In addition, pulmonary compliance and the pressure of oxygen/oxygen inhalation ratio were significantly lower in the MSC-MVs group, and the effects of the MSC-MVs were significantly inhibited by low HGF expression (all P < 0.05). CONCLUSION: MSC-MVs improved lung ventilation functions and inhibited pulmonary fibrosis in ARDS mice partly via HGF mRNA transfer.

Identification and validation of coagulation and fibrinolytic-related diagnostic biomarkers for ulcerative colitis by bioinformatics analysis.

Abnormalities in coagulation and fibrinolytic status have been demonstrated to be relevant to inflammatory bowel disease. Nevertheless, there is no study to methodically examine the role of the coagulation and fibrinolysis-related genes in the diagnosis of ulcerative colitis (UC). UC-related datasets (GSE169568 and GSE94648) were originated from the Gene Expression Omnibus database. The biomarkers related to coagulation and fibrinolysis were identified through combining differentially expressed analysis and machine learning algorithms. Moreover, Gene Set Enrichment Analysis and immune analysis were carried out. A total of 4 biomarkers (MAP2K1, CREBBP, TAF1, and HP) were identified, and biomarkers were markedly enriched in pathways related to immunity, such as T-cell receptor signaling pathway, primary immunodeficiency, chemokine signaling pathway, etc. In total, the infiltrating abundance of 4 immune cells between UC and control was markedly different, namely eosinophils, macrophage M0, resting mast cells, and regulatory T cells. And all biomarkers were significantly relevant to eosinophils. Our findings detected 4 coagulation and fibrinolysis-related biomarkers (MAP2K1, CREBBP, TAF1, and HP) for UC, which contributed to the advancement of UC for further clinical investigation.

Longitudinal Study and Predictive Modeling of Urinary Pesticide Metabolite Concentrations in Residents of Guangzhou, China.

Continuous human biomonitoring and predictive modelling of urinary pesticide metabolites are critical for evaluating pesticide exposure trends and associated health risks. We conducted repeat cross-sectional surveys to determine the urinary concentrations of eight pesticide metabolites in the residents of Guangzhou, China, from 2018 to 2022. We longitudinally analyzed the changes in these metabolite concentrations over the years and assessed the potential non-carcinogenic risks by calculating the hazard quotient and hazard index. No significant differences were observed in the total urinary pesticide metabolite concentrations over the 5 years (9.16 to 12.99 µg/L). The urinary concentrations of 3,5,6-trichloro-2-pyridinol and 2,4-dichlorophenoxyacetic acid reached their lowest levels in 2020 (1.47 and 0.11 µg/L). Conversely, urinary para-nitrophenol concentrations exhibited an inverse trend, peaking in 2020 (6.16 µg/L). The composition profiles of urinary pesticide metabolites showed that para-nitrophenol consistently constituted the largest proportion each year. Males consistently showed higher median concentrations of total urinary pesticide metabolites and individual metabolites of 3,5,6-trichloro-2-pyridinol, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid, and para-nitrophenol than females. The concentrations of cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid in adults' urine were significantly higher than those in minors' urine each year. The total pesticide metabolite concentrations in adults' urine were significantly higher than those in minors' urine in 2018 and 2020, whereas no significant differences were observed in other years. No significant differences in urinary pesticide metabolite concentrations were observed among different BMI groups. Results showed that 14.17% of the population had hazard index values above 1, indicating a higher risk of health hazards. Three predictive models were employed to predict urinary pesticide metabolite concentrations for 2023-2024, revealing an increasing trend in 3,5,6-trichloro-2-pyridinol concentrations while other metabolites are expected to decrease. The study showed the concentration of para-nitrophenol peaked in 2020 while 3,5,6-trichloro-2-pyridinol and 2,4-dichlorophenoxyacetic acid reached their lowest levels, suggests that the COVID-19 pandemic may have influenced pesticide exposure patterns.

Causality between Celiac disease and kidney disease: A Mendelian Randomization Study.

Celiac disease, characterized as an autoimmune disorder, possesses the capacity to affect multiple organs and systems. Earlier research has indicated an increased risk of kidney diseases associated with celiac disease. However, the potential causal relationship between genetic susceptibility to celiac disease and the risk of kidney diseases remains uncertain. We conducted Mendelian randomization analysis using nonoverlapping European population data, examining the link between celiac disease and 10 kidney traits in whole-genome association studies. We employed the inverse variance-weighted method to enhance statistical robustness, and results' reliability was reinforced through rigorous sensitivity analysis. Mendelian randomization analysis revealed a genetic susceptibility of celiac disease to an increased risk of immunoglobulin A nephropathy (OR = 1.44; 95% confidence interval [CI] = 1.17-1.78; P = 5.7 × 10-4), chronic glomerulonephritis (OR = 1.15; 95% CI = 1.08-1.22; P = 2.58 × 10-5), and a decline in estimated glomerular filtration rate (beta = -0.001; P = 2.99 × 10-4). Additionally, a potential positive trend in the causal relationship between celiac disease and membranous nephropathy (OR = 1.37; 95% CI = 1.08-1.74; P = 0.01) was observed. Sensitivity analysis indicated the absence of pleiotropy. This study contributes novel evidence establishing a causal link between celiac disease and kidney traits, indicating a potential association between celiac disease and an elevated risk of kidney diseases. The findings provide fresh perspectives for advancing mechanistic and clinical research into kidney diseases associated with celiac disease.

Age-related changes in mitral annular disjunction: A retrospective analysis using enhanced cardiac CT.

AIMS: The current recognition of mitral annular disjunction (MAD) as an anatomical abnormality potentially associated with ventricular arrhythmias has sparked controversy regarding its prevalence and clinical implications. This study aimed to investigate the prevalence and extent of MAD in individuals with no significant structural abnormalities involving the left heart using enhanced cardiac CT, while also exploring potential factors, such as age, that may be associated with MAD. METHODS: Systolic datasets of cardiac CT from 742 subjects were retrospectively included. MAD was determined by rotating orthogonal multiplanar reconstruction images around the central axis of the mitral annulus. The maximal distance of disjunction (DMAD) and segments involved (SI, 0 to 5 basal segments at left ventricular wall) was quantified to evaluate the extent of separation. RESULTS: In total, 449 (60.5%) had MAD. Subjects with MAD were significantly older (51.3 ± 19.9 years vs. 29.6 ± 20.3 years, P < 0.001). Age was found to be an independent relevant factor for MAD (OR = 1.059; 95%CI: 1.033, 1.085; P < 0.001). Subjects with MAD were then divided into 4 subgroups (G1: ≤20 years, G2: 21-40 years, G3: 41-60 years, G4: ≥61 years). DMAD and SI of each age subgroup were 1.9 ± 0.2 mm, 2.0 ± 1.2 (G1, n = 36), 2.7 ± 0.8 mm, 2.9 ± 1.3 (G2, n = 51), 3.0 ± 0.8 mm, 3.0 ± 1.3 (G3, n = 183), and 3.0 ± 1.0 mm, 3.7 ± 1.1 (G4, n = 179). Age was an independent relevant factor associated with DMAD (R2 = 0.132; ß = 0.014; 95%CI: 0.004, 0.024; P = 0.007) and SI (OR = 1.030; 95%CI: 1.005, 1.055; P = 0.016). CONCLUSIONS: MAD is a common finding on cardiac CT. Its prevalence and extent increase with age.

Convenient Size Analysis of Polystyrene Nanoplastics via Regulating the Radiative Transition Efficiency.

Developing a convenient method to efficiently determine the size of nanoplastics in the environment is urgent in terms of ecological or human health protection. In this work, a novel strategy for discriminating the size of polystyrene (PS)-based nanoplastics was reported via regulating the radiative transition efficiency of NH2-UIO-66 (NU) with benzoic acid (BA) as the auxiliary ligand. The elaborately doped BA capped the defect sites and triggered nonradiative transition efficiency of NU. As a result, the formed composite (denoted as BA-NU) was more sensitive to interaction among neighboring NU and nanoplastics. The interaction between particles limited the rotation and vibration of the benzene ring within the BA-NU molecule, thus increasing the BA-NU fluorescence. The sensitivity of BA-NU on nanoplastics was well controlled by manipulating the doping contents of BA, leading to precisely tunable physicochemical properties for this structure. Deriving from the exquisitely designed nanostructures, the composite of BA-NU was successfully used to discriminate different size PS as an ultrasensitive turn-on probe. This work highlights the possibility of boosting the detection performance by regulating the main structure with guest molecules at the molecular level.

Genetic and pathophysiological insights from autopsied patient with primary familial brain calcification: novel MYORG variants and astrocytic implications.

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.

Unlocking multi-photon excited luminescence in pyrazolate trinuclear gold clusters for dynamic cell imaging.

The family of coinage-metal-based cyclic trinuclear complexes exhibits abundant photophysical properties, promising for diverse applications. However, their utility in biochemistry is often hindered by large particle size and strong hydrophobicity. Meanwhile, the investigation into multi-photon excited luminescence within this family remained undocumented, limiting their potential in bio-imaging. Herein, we unveil the multi-photon excited luminescent properties of pyrazolate-based trinuclear gold(I) clusters, facilitated by excimeric gold(I)···gold(I) interactions, revealing a nonlinear optical phenomenon within this family. Furthermore, to address issues of poor biocompatibility, we employ electrospinning coupled with hydroxypropyl-beta-cyclodextrin as the matrix to fabricate a flexible, durable, transparent, and red emissive film with a photoluminescence quantum yield as high as 88.3%. This strategy not only produces the film with sufficient hydrophilicity and stability, but also achieves the downsizing of trinuclear gold(I) clusters from microscale to nanoscale. Following the instantaneous dissolution of the film in the media, the released trinuclear gold(I) nanoparticles have illuminated cells and bacteria through a real-time, non-toxic, multi-photon bio-imaging approach. This achievement offers a fresh approach for utilizing coinage-metal-based cyclic trinuclear complexes in biochemical fields.

The TaWAK2-TaNAL1-TaDST pathway regulates leaf width via cytokinin signaling in wheat.

Leaves play a crucial role in photosynthesis and respiration, ultimately affecting the final grain yield of crops, including wheat (Triticum aestivum L.); however, the molecular mechanisms underlying wheat leaf development remain largely unknown. Here, we isolated a narrow-leaf gene, TaWAK2-A, through a map-based cloning strategy. TaWAK2-A encodes a wall-associated kinase (WAK), for which a single Ala-to-Val amino acid substitution reduces the protein stability, leading to a narrow-leaf phenotype in wheat. Further investigation suggests that TaWAK2 directly interacts with and phosphorylates TaNAL1, a trypsin-like serine/cysteine protease. The phosphorylated TaNAL1 is then involved in the degradation of the zinc finger transcription factor TaDST, which acts as a repressor of leaf expansion by activating the expression of the cytokinin oxidase gene TaCKX9 and triggering in vivo cytokinin degradation. Therefore, our findings elucidate a signaling cascade involving TaWAK2-TaNAL1-TaDST that sheds light on the regulation of wheat leaf development.

Lower Visceral Fat is Related to Diabetic Peripheral Neuropathy.

Objective: Visceral fat area (VFA) levels have been found to exhibit a strong association with various conditions such as insulin resistance (IR), inflammation, oxidative stress, metabolic syndrome (MetS), hyperlipidemia, diabetes, and its vascular complications. These complications include hypertension, cardiovascular disease, diabetic retinopathy (DR), albuminuria, and cardiovascular autonomic dysfunction, which is considered one of the main types of diabetic neuropathy. This study aimed to investigate the correlation between visceral fat and peripheral neuropathy in patients with type 2 diabetes (T2DM). Methods: A retrospective analysis of clinical data of patients diagnosed with type 2 diabetes admitted to our hospital was conducted. After excluding 28 cases, a total of 488 patients were included, divided into the group with peripheral neuropathy (207 cases) and the control group without peripheral neuropathy (281 cases). The correlation between VFA and the presence of DPN was assessed using correlation and multiple logistic regression analyses. Results: In terms of general information, the group with peripheral neuropathy had lower BMI but longer duration of diabetes compared to the control group. Regarding biochemical indicators, VFA were lower in the group with peripheral neuropathy, while FPG and HbA1c levels were higher (all P<0.05). Spearman correlation analysis showed a negative correlation between VFA, and the presence of peripheral neuropathy in patients with type 2 diabetes (P<0.05). Logistic regression analysis indicated that VFA, duration of diabetes, and HbA1c level were influencing factors for the occurrence of peripheral neuropathy in patients with type 2 diabetes (P<0.05). Conclusion: This study revealed a correlation between visceral fat and peripheral neuropathy in patients with type 2 diabetes, highlighting the importance of monitoring visceral fat in such patients. In addition to lower levels of VFA, factors such as duration of diabetes and glycated hemoglobin (HbA1c) level were also associated with peripheral neuropathy in patients with T2DM.

YWHAB is regulated by IRX5 and inhibits the migration and invasion of breast cancer cells.

Highly metastatic and heterogeneous breast cancer affects the health of women worldwide. Abnormal expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein ß (YWHAB), also known as 14-3-3ß, is associated with the tumorigenesis and progression of bladder cancer, lung cancer and hepatocellular carcinoma; however, to the best of our knowledge, the role of YWHAB in breast cancer remains unknown. In the present study, a dual luciferase assay demonstrated that the transcription factor iroquois homeobox 5 may regulate YWHAB expression by affecting the promoter sequence upstream of its transcription start site. Subsequently, it was demonstrated that overexpression of YWHAB did not affect proliferation, but did reduce the migration and invasion of MDA-MB-231 cells. Furthermore, knockdown of YWHAB promoted the migration and invasion of MCF7 cells. Transcriptomics analysis demonstrated that when YWHAB was overexpressed, 61 genes were differentially expressed, of which 43 genes were upregulated and 18 genes were downregulated. These differentially expressed genes (DEGs) were enriched in cancer-related pathways, such as 'TNF signaling pathway' [Kyoto Encyclopedia of Genes and Genomes (KEGG): map04688]. The pathway with the largest number of DEGs was 'Rheumatoid arthritis' (KEGG: map05323). Notably, YWHAB downregulated vimentin, which is a mesenchymal marker, thus suggesting that it may weaken the mesenchymal properties of cells. These findings indicate that YWHAB may be a potential therapeutic target in breast cancer and further work should be performed to assess its actions as a potential tumor suppressor.

Relationship between preoperative psychological stress and short-term prognosis in elderly patients with femoral neck fracture.

BACKGROUND: Older adults are at high risk of femoral neck fractures (FNFs). Elderly patients face and adapt to significant psychological burdens, resulting in different degrees of psychological stress response. Total hip replacement is the preferred treatment for FNF in elderly patients; however, some patients have poor postoperative prognoses, and the underlying mechanism is unknown. We speculated that the postoperative prognosis of elderly patients with FNF may be related to preoperative psychological stress. AIM: To explore the relationship between preoperative psychological stress and the short-term prognosis of elderly patients with FNF. METHODS: In this retrospective analysis, the baseline data, preoperative 90-item Symptom Checklist score, and Harris score within 6 months of surgery of 120 elderly patients with FNF who underwent total hip arthroplasty were collected. We analyzed the indicators of poor short-term postoperative prognosis and the ability of the indicators to predict poor prognosis and compared the correlation between the indicators and the Harris score. RESULTS: Anxiety, depression, garden classification of FNF, cause of fracture, FNF reduction quality, and length of hospital stay were independent influencing factors for poor short-term postoperative prognoses in elderly patients with FNF (P < 0.05). The areas under the curve for anxiety, depression, and length of hospital stay were 0.742, 0.854, and 0.749, respectively. The sensitivities of anxiety, depression, garden classification of FNF, and prediction of the cause of fracture were 0.857, 0.786, 0.821, and 0.821, respectively. The specificities of depression, FNF quality reduction, and length of hospital stay were the highest at 0.880, 0.783, and 0.761, respectively. Anxiety, depression, and somatization scores correlated moderately with Harris scores (r = -0.523, -0.625, and -0.554; all P < 0.001). CONCLUSION: Preoperative anxiety, depression, and somatization are correlated with poor short-term prognosis in elderly patients with FNF and warrant consideration.

Long-term warming and decreased precipitation regulated microbial community structure and potential function through enhanced predator-prey relationships in the Tibetan Plateau.

Global climate change can shape the interactions among soil microbes and, in turn, mediate ecosystem functions. However, how these interactions were regulated remains to be investigated. This study utilized 16S rRNA, ITS, and 18S rRNA high-throughput sequencing to investigate the effects of simulated warming and precipitation changes on the major components of soil micro-food webs in the Qinghai-Tibetan Plateau through a field experiment. Adonis and non-metric multidimensional scaling (NMDS) analyses showed that compositions of bacteria, fungi and protists were all affected by changes in temperature and precipitation. Correlation and cross-trophic network analyses revealed that warming and decreased precipitation, both separately and together, enhanced the relationships between bacteria and protists, especially protistan predators. We found that the modified stochasticity ratio of the bacterial community assembly was best predicted by protists. The potential functional structures of bacteria were positively correlated with protistan predators under warming and decreased precipitation condition, suggesting enhanced predator-prey relationships between protists and bacteria might further influence the potential functional characteristics of bacterial communities. Our study indicated that climate change altered bacterial compositional and functional structure via enhanced predator-prey interactions. Therefore, in the context of global climate change, broader and more comprehensive studies on protist-regulated soil bacterial and fungal communities are imperative.

Linking LRP12 CGG repeat expansion to inherited peripheral neuropathy.

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.