Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis.

Background: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins. Methods: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS. The plasma proteins were sourced from the UK Biobank Pharma Proteomics Project (UKB-PPP) database, encompassing GWAS data for 2,940 plasma proteins. Additionally, GWAS data for AS were extracted from the R9 version of the Finnish database, including 2,860 patients and 270,964 controls. The colocalization analysis was executed to identify shared causal variants between plasma proteins and AS. Finally, we examined the potential adverse effects of druggable proteins for AS therapy by conducting a phenome-wide association study (PheWAS) utilizing the extensive Finnish database in version R9, encompassing 2,272 phenotypes categorized into 46 groups. Results: The findings revealed a positive genetic association between the predicted plasma levels of six proteins and an elevated risk of AS, while two proteins exhibited an inverse association with AS risk (P fdr < 0.05). Among these eight plasma proteins, colocalization analysis identified AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13 as shared variation with AS(PPH3+PPH4>0.8), suggesting that they represent potential direct targets for AS intervention. Further phenotype-wide association studies have shown some potential side effects of these six targets (P fdr < 0.05). Conclusion: Our investigation examined the causal connections between six plasma proteins and AS, providing a comprehensive understanding of potential therapeutic targets.

ROS Balance Autoregulating Core-Shell CeO2@ZIF-8/Au Nanoplatform for Wound Repair.

Reactive oxygen species (ROS) plays important roles in living organisms. While ROS is a double-edged sword, which can eliminate drug-resistant bacteria, but excessive levels can cause oxidative damage to cells. A core-shell nanozyme, CeO2@ZIF-8/Au, has been crafted, spontaneously activating both ROS generating and scavenging functions, achieving the multi-faceted functions of eliminating bacteria, reducing inflammation, and promoting wound healing. The Au Nanoparticles (NPs) on the shell exhibit high-efficiency peroxidase-like activity, producing ROS to kill bacteria. Meanwhile, the encapsulation of CeO2 core within ZIF-8 provides a seal for temporarily limiting the superoxide dismutase and catalase-like activities of CeO2 nanoparticles. Subsequently, as the ZIF-8 structure decomposes in the acidic microenvironment, the CeO2 core is gradually released, exerting its ROS scavenging activity to eliminate excess ROS produced by the Au NPs. These two functions automatically and continuously regulate the balance of ROS levels, ultimately achieving the function of killing bacteria, reducing inflammation, and promoting wound healing. Such innovative ROS spontaneous regulators hold immense potential for revolutionizing the field of antibacterial agents and therapies.

Exploring causal correlations between inflammatory cytokines and ankylosing spondylitis: a bidirectional mendelian-randomization study.

Background: The impact of inflammatory factors on the development of Ankylosing Spondylitis (AS) is widely recognized, but the exact causal relationship remains unclear. Methods: The bidirectional mendelian-randomization study utilized genetic data from a genome-wide association study (GWAS) of 186 AS cases and 456,162 controls of European ancestry. Inflammatory cytokines were obtained from a GWAS summary of 8,293 healthy participants. Causal associations were primarily investigated using the inverse variance-weighted method, supplemented by MR Egger, weighted median and weighted mode analyses. Heterogeneity in the results was assessed using the Cochrane Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers (MR-PRESSO) test. Sensitivity analysis was conducted through leave-one-out analysis. Results: The results suggest a genetically predicted potential association between beta-nerve growth factor (ßNGF), Interleukin-1-beta (IL-1ß), and TNF-related apoptosis inducing ligand (TRAIL) with the risk of AS (OR: 2.17, 95% CI: 1.13-4.16; OR: 0.41, 95% CI: 0.18-0.95,; OR: 1.47, 95% CI: 1.02-2.13).Additionally, Interleukin-12p70 (IL-12p70), Interleukin-17 (IL-17), Interleukin-6 (IL-6), Interleukin-4 (IL-4), Stromal-cell-derived factor 1 alpha (SDF-1α), Macrophage inflammatory protein 1ß (MIP1ß), Monocyte chemoattractant protein-3 (MCP-3), Platelet-derived growth factor bb (PDGFbb), Granulocyte-colony stimulating factor (GCSF), Fibroblast growth factor basic (bFGF), TNF-related apoptosis inducing ligand (TRAIL), and Interferon-gamma (IFN -γ) are suggested as consequences of AS in genetically prediction.No evidence of horizontal pleiotropy or heterogeneity between the genetic variants was found (P>0.05), and a leave-one-out test confirmed the stability and robustness of this association. Conclusion: These findings suggest that ßNGF, IL-1ß, and TRAIL may play a crucial role in the pathogenesis of AS. Additionally, AS may impact the expression of cytokines such as IL-12p70, IL-17, IL-6, IL-4, SDF-1α, MIP1ß, MCP-3, PDGFbb,GCSF, bFGF,TRAIL,and IFN-γ. Further investigations are warranted to determine whether these biomarkers can be utilized for the prevention or treatment of AS.

Genotypic and Allelic Frequencies of GJB2 Variants and Features of Hearing Phenotypes in the Chinese Population of the Dongfeng-Tongji Cohort.

BACKGROUND: This study aimed to describe the distribution of the genotype and allele frequencies of GJB2 variants in the Chinese population of the Dongfeng Tongji cohort and to analyze the features of the hearing phenotype. METHODS: We used data from 9910 participants in the Dongfeng Tongji cohort in 2013 and selected nine GJB2 variants. Pure tone audiometry was employed to measure hearing. Differences in genotype and allele frequencies were analyzed via chi-squared test or Fisher's exact test. RESULTS: Of the 9910 participants, 5742 had hearing loss. The genotype frequency of the GJB2 variant c.109G>A was statistically significantly distributed between the normal and impaired hearing groups, but not for the variant c.235delC. A higher frequency of the c.109G>A homozygous genotype was found in the hearing loss group (0.5%) than in the normal hearing group (0.1%). Patients with c.109G>A and c.235delC homozygous mutations exhibited varying degrees of hearing loss, mainly presenting sloping and flat audiogram shapes. CONCLUSIONS: A significant difference was found in the genotype frequency of the GJB2 variant c.109G>A between the case and control groups, but not in that of the variant c.235delC. Different degrees of hearing loss and various audiogram shapes were observed in patients with c.109G>A and c.235delC homozygous mutations.

Overexpression of the First Peanut-Susceptible Gene, AhS5H1 or AhS5H2, Enhanced Susceptibility to Pst DC3000 in Arabidopsis.

Salicylic acid (SA) serves as a pivotal plant hormone involved in regulating plant defense mechanisms against biotic stresses, but the extent of its biological significance in relation to peanut resistance is currently lacking. This study elucidated the involvement of salicylic acid (SA) in conferring broad-spectrum disease resistance in peanuts through the experimental approach of inoculating SA-treated leaves. In several other plants, the salicylate hydroxylase genes are the typical susceptible genes (S genes). Here, we characterized two SA hydroxylase genes (AhS5H1 and AhS5H2) as the first S genes in peanut. Recombinant AhS5H proteins catalyzed SA in vitro, and showed SA 5-ydroxylase (S5H) activity. Overexpression of AhS5H1 or AhS5H2 decreased SA content and increased 2,5-DHBA levels in Arabidopsis, suggesting that both enzymes had a similar role in planta. Moreover, overexpression of each AhS5H gene increased susceptibility to Pst DC3000. Analysis of the transcript levels of defense-related genes indicated that the expression of AhS5H genes, AhNPR1 and AhPR10 was simultaneously induced by chitin. Overexpression of each AhS5H in Arabidopsis abolished the induction of AtPR1 or AtPR2 upon chitin treatment. Eventually, AhS5H2 expression levels were highly correlated with SA content in different tissues of peanut. Hence, the expression of AhS5H1 and AhS5H2 was tissue-specific.

Degradation of cochlear Connexin26 accelerate the development of age-related hearing loss.

The GJB2 gene, encoding Connexin26 (Cx26), is one of the most common causes of inherited deafness. Clinically, mutations in GJB2 cause congenital deafness or late-onset progressive hearing loss. Recently, it has been reported that Cx26 haploid deficiency accelerates the development of age-related hearing loss (ARHL). However, the roles of cochlear Cx26 in the hearing function of aged animals remain unclear. In this study, we revealed that the Cx26 expression was significantly reduced in the cochleae of aged mice, and further explored the underlying molecular mechanism for Cx26 degradation. Immunofluorescence co-localization results showed that Cx26 was internalized and degraded by lysosomes, which might be one of the important ways for Cx26 degradation in the cochlea of aged mice. Currently, whether the degradation of Cx26 in the cochlea leads directly to ARHL, as well as the mechanism of Cx26 degradation-related hearing loss are still unclear. To address these questions, we generated mice with Cx26 knockout in the adult cochlea as a model for the natural degradation of Cx26. Auditory brainstem response (ABR) results showed that Cx26 knockout mice exhibited high-frequency hearing loss, which gradually progressed over time. Pathological examination also revealed the degeneration of hair cells and spiral ganglions, which is similar to the phenotype of ARHL. In summary, our findings suggest that degradation of Cx26 in the cochlea accelerates the occurrence of ARHL, which may be a novel mechanism of ARHL.

Automatic Detection and Association Analysis of Multiple Surface Defects on Shield Subway Tunnels.

The surface defects on a shield subway tunnel can significantly affect the serviceability of the tunnel structure and may compromise operation safety. To effectively detect multiple surface defects, this study uses a tunnel inspection trolley (TIT) based on the mobile laser scanning technique. By conducting an inspection of the shield tunnel on a metro line section, various surface defects are identified with the TIT, including water leakage defects, dislocation, spalling, cross-section deformation, etc. To explore the root causes of the surface defects, association rules between different defects are calculated using an improved Apriori algorithm. The results show that: (i) there are significant differences in different association rules for various surface defects on the shield tunnel; (ii) the average confidence of the association rule "dislocation & spalling → water leakage" is as high as 57.78%, indicating that most of the water leakage defects are caused by dislocation and spalling of the shield tunnel in the sections being inspected; (iii) the weakest rule appears at "water leakage → spalling", with an average confidence of 13%. The association analysis can be used for predicting the critical defects influencing structural reliability and operation safety, such as water leakage, and optimizing the construction and maintenance work for a shield subway tunnel.

Investigation of the Mechanical Properties of Iron Tailings Concrete Subjected to Dry-Wet Cycle and Negative Temperature.

This research investigates the effects of iron tailings content on the mechanical properties and durability of concrete under dry-wet cycling and negative temperature conditions (-10 °C), where iron tailings replace river sand at rates of 0%, 10%, 20%, and 30%. A variety of tests were conducted on the iron tailings concrete, including compressive strength, flexural strength, splitting tensile strength, mass loss, and relative dynamic modulus, and its pore characteristics were analyzed using low-field nuclear magnetic resonance (NMR) experiments. The results reveal that when 20% of the river sand was replaced with iron tailings, the concrete achieved optimal splitting strength, compressive strength, and flexural strength at 28 days, improving by 0.46 MPa, 3.14 MPa, and 0.41 MPa, respectively, compared to conventional concrete. Furthermore, the concrete containing this proportion of iron tailings demonstrated superior mechanical properties and durability in both negative temperature conditions and dry-wet cycling experiments. Due to the excellent physical and chemical properties of iron tailings, they enhance the performance of concrete when incorporated in appropriate quantities. The fine granularity of iron tailings helps to compensate for the granularity defects in concrete aggregates by filling internal voids, optimizing the pore structure, and improving the concrete's density and integrity. This enhances the concrete's mechanical properties and its resistance to external solutions and harmful ion penetration. Additionally, the active substances in iron tailings promote the hydration reaction of cement, leading to the formation of an increased amount of C-S-H gel and other hydration products in the cement system.

Cytomembrane Trafficking Pathways of Connexin 26, 30, and 43.

The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6, respectively, are the most abundantly expressed connexins in the inner ear. Connexin 43, which is encoded by GJA1, appears to be widely expressed in various organs, including the heart, skin, the brain, and the inner ear. The mutations that arise in GJB2, GJB6, and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can properly operate. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of these connexins, the existing controversies in the trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness.

The Pathogenesis of Cytomegalovirus and Other Viruses Associated with Hearing Loss: Recent Updates.

Virus infection is one of the most common etiologies of hearing loss. Hearing loss associated with viral infection can be unilateral or bilateral, mild or severe, sudden or progressive, and permanent or recoverable. Many viruses cause hearing loss in adults and children; however, the pathogenesis of hearing loss caused by viral infection is not fully understood. This review describes cytomegalovirus, the most common virus causing hearing loss, and other reported hearing loss-related viruses. We hope to provide a detailed description of pathogenic characteristics and research progress on pathology, hearing phenotypes, possible associated mechanisms, treatment, and prevention measures. This review aims to provide diagnostic and treatment assistance to clinical workers.

Short-term environmental nitrogen dioxide exposure and neurology clinic visits for headaches, a time-series study in Wuhan, China.

BACKGROUND: Previous studies showed the adverse impacts of air pollution on headache attacks in developed countries. However, evidence is limited to the impact of exposure to air pollutants on headache attacks. In this study, we aimed to explore the impact of nitrogen dioxide (NO2) exposure on neurology clinic visits (NCVs) for headache onsets. METHODS: Records of NCVs for headaches, concentrations of ambient NO2, and meteorological variables were collected in Wuhan, China, from January 1st, 2017, to November 30th, 2019. A time-series study was conducted to investigate the short-term effects of NO2 exposure on daily NCVs for headaches. Stratified analyses were also computed according to season, age, and sex, and the exposure-response (E-R) curve was then plotted. RESULTS: A total of 11,436 records of NCVs for headaches were enrolled in our study during the period. A 10-µg/m3 increase of ambient NO2 corresponded to a 3.64% elevation of daily NCVs for headaches (95%CI: 1.02%, 6.32%, P = 0.006). Moreover, females aged less than 50 years of age were more susceptible compared to males (4.10% vs. 2.97%, P = 0.007). The short-term effects of NO2 exposure on daily NCVs for headaches were stronger in cool seasons than in warm seasons (6.31% vs. 0.79%, P = 0.0009). CONCLUSION: Our findings highlight that short-term exposure to ambient NO2 positively correlated with NCVs for headaches in Wuhan, China, and the adverse effects varied by season, age, and sex.

Non-invasive manipulation scheme of spherical particle in viscous fluids in a tube based on acoustic radiation force.

A theoretical solution of the acoustic radiation force (ARF) on spherical particles by an arbitrary beam in viscous fluids in a tube is proposed. Based on the parametric design with the purpose of promoting calculi in the urinary system, theoretical solutions and finite element simulations are carried out, which mutually confirm the accuracy and feasibility of the scheme. The variation law of the ARF with adjustable parameters, such as incident angle, frequency spectrum, particle radius, tube radius, and viscosity, is studied, and the mechanism of the variation law is explained. This solution lays a foundation for the application of non-contact and non-invasive in-tube manipulation based on ARF in medicine and life sciences.

Acute effects of ambient air pollution on daily neurology clinic visits for vertigo: a time-series study in Wuhan, China.

This study aimed to disclose the relationship between ambient air pollution and neurology clinic visits (NCVs) for vertigo. A time-series study was conducted to examine relationships between six different criteria air pollutants (SO2, NO2, PM2.5, PM10, CO, and O3) and daily NCVs for vertigo in Wuhan, China, from January 1st, 2017 to November 30th, 2019. Stratified analyses were computed according to gender, age, and season. A total of 14,749 records of NCVs for vertigo were enrolled in this study. Data showed that the increase in daily NCVs for vertigo corresponding to 10 µg/m3 increase of respective pollutants are: SO2 (- 7.60%; 95% CI: - 14.25 to - 0.44%), NO2 (3.14%; 95% CI: 0.23 to 6.13%), PM2.5 (0.53%; 95% CI: - 0.66 to 1.74%), PM10 (1.32%; 95% CI: - 0.36 to 3.06%), CO (0.00%; 95% CI: - 0.12 to 0.13%), and O3 (0.90%; 95% CI: - 0.01% to 1.83%). Males were more susceptible to acute exposure to SO2 and NO2, compared to females (SO2: - 11.91% vs. - 4.16%; NO2: 3.95% vs. 2.92%), whereas the acute effect of O3 exposure was more significantly obvious in females than males (0.94% vs. 0.87%). Moreover, correlations between daily NCVs for vertigo and acute exposure to SO2, NO2, and O3 were all stronger in individuals under 50 years old (SO2: - 12.75% vs. - 4.41%; NO2: 4.55% vs. 2.75%; O3: 1.27% vs. 0.70%). Short-term exposure to PM2.5 was more significantly associated with daily NCVs for vertigo in cool seasons (1.62% vs. - 0.68%), while the correlation between CO exposure and daily NCVs for vertigo was stronger in warm seasons (0.21% vs. - 0.03%). Our study demonstrated acute exposure to ambient NO2 and O3 positively associated with daily NCVs for vertigo. Acute effects of air pollution on daily NCVs for vertigo varied according to gender, age, and season.

Genome Resource of Streptomyces atratus PY-1, a Broad-Spectrum Antimicrobial Strain in Particular Antagonistic Against Plasmopara viticola.

Streptomyces atratus PY-1 exhibited promising antimicrobial properties; in particular, it is highly inhibitory to Plasmopara viticola, which causes downy mildew of grape. It is very necessary to carry out systematic and in-depth research on the PY-1 strain for the improvement, application, and promotion of biocontrol agents. The PY-1 genome was fully sequenced and assembled. We present the draft genome sequence of PY-1, with a size of 9, 254, and 781 bp. Preliminary analysis on the PY-1 genome sequence shows that at least 35 gene clusters are involved in the biosynthesis of polyketides, terpenes, and nonribosomally synthesized peptides.

Theoretical prediction of the scattering of spherical bubble clusters under ultrasonic excitation.

Due to the nonlinear vibration of ultrasound contrast agent bubbles, a nonlinear scattered sound field will be generated when bubbles are driven by ultrasound. A bubble cluster consists of numerous bubbles gathering in a spherical space. It has been noted that the forward scattering of a bubble cluster is larger than its backscattering, and some studies have experimentally found the angular dependence of a bubble cluster's scattering signal. In this paper, a theory is proposed to explain the difference of acoustic scattering at different directions of a bubble cluster when it is driven by ultrasound, and predicts the angular distribution of scattered acoustic pressure under different parameters. The theory is proved to be correct under circumstances of small clusters and weak interactions by comparing theoretical results with numerical simulations. This theory not only sheds light on the physics of bubble cluster scattering, but also may contribute to the improvement of ultrasound imaging technology, including ultrasonic harmonic imaging and contrast-enhanced ultrasonography.

Acoustic source localization based on acoustic leaky-wave antenna with heterogeneous structure.

In this study, an acoustic leaky-wave antenna (LWA) with heterogeneous structure is proposed and the functions of the spatial directional radiation and acoustic source localization are achieved via utilizing the presented antenna configuration. In the radiating mode, the designed antenna possesses peculiar frequency-scanning characteristics, which enable it to determine the directional radiation of sound waves with diverse incident frequencies. Considering the receiving mode, the antenna emerges with explicit directional frequency characteristics, which ensure its function of spatial acoustic source localization. Additionally, compared with the traditional acoustic LWA, the proposed antenna structure exhibits sharper directivity and has potential applications in high-precision acoustic source localization.

Spectrum of imaging findings in soft-tissue necrosis.

Soft tissue necrosis can occur at different tissue levels, with numerous underlying causes. In this pictorial review, we highlight myonecrosis, and its accompanying stages, fat necrosis, devitalized soft tissue seen with infection, and necrotizing soft tissue infections. Imaging examples are provided with each entity.

Cellular Processes Induced by HSV-1 Infections in Vestibular Neuritis.

Herpesvirus is a prevalent pathogen that primarily infects human epithelial cells and has the ability to reside in neurons. In the field of otolaryngology, herpesvirus infection primarily leads to hearing loss and vestibular neuritis and is considered the primary hypothesis regarding the pathogenesis of vestibular neuritis. In this review, we provide a summary of the effects of the herpes virus on cellular processes in both host cells and immune cells, with a focus on HSV-1 as illustrative examples.

Screening, and Optimization of Fermentation Medium to Produce Secondary Metabolites from Bacillus amyloliquefaciens, for the Biocontrol of Early Leaf Spot Disease, and Growth Promoting Effects on Peanut (Arachis hypogaea L.).

A novel Bacillus amyloliquefaciens BAM strain, with novel fermentation nutrient mediums and compositions, could produce potent antifungal secondary metabolites, as the existing strains face resistance from fungus pathogens. In the current study, we introduced two novel nutrient mediums for the fermentation process, semolina and peanut root extract, as carbon and nitrogen sources in order to maximize the antifungal effects of B. amyloliquefaciens against Cercaspora arachidichola to control early leaf spot disease in peanuts. Based on a single-factor test and the central composite design of response surface methodology, the optimum fermentation medium for Bacillus amyloliquefaciens antagonistic substance was determined, containing 15 gm/L of semolina flour, 12.5 gm/L of beef extract, and 0.5 gm/L of magnesium sulfate, which inhibited the fungal growth by 91%. In vitro, antagonistic activity showed that the fermentation broth of B. amyloliquefaciens BAM with the optimized medium formulation had an inhibition rate of (92.62 ± 2.07)% on the growth of C. arachidichola. Disease control effects in pot experiments show that the pre-infection spray of B. amyloliquefaciens BAM broth had significant efficiency of (92.00 ± 3.79)% in comparison to post-infection spray. B. amyloliquefaciens BAM broth significantly promoted peanut plant growth and physiological parameters and reduced the biotic stress of C. archidechola. Studies revealed that B. amyloliquefaciens BAM with a novel fermentation formulation could be an ideal biocontrol and biofertilizer agent and help in early disease management of early leaf spots in peanuts.

Analysis of the Results of Cytomegalovirus Testing Combined with Genetic Testing in Children with Congenital Hearing Loss.

To improve the etiological diagnosis of congenital hearing loss by combining whole-exome sequencing (WES) with cytomegalovirus (CMV) testing and to explore the potential benefits of adding CMV screening to newborn hearing screening, 80 children under 2 years of age with bilateral sensorineural hearing loss were recruited. Peripheral venous blood was extracted from the children for WES analysis. Saliva after mouthwash and the first urine in the morning were collected and used as samples to quantify CMV DNA copy number in urine and saliva by qPCR; among the 80 children with congenital deafness, 59 (74%) were found to have genetic variants that may cause congenital deafness, including 44 with GJB2 or SLC26A4 gene variant, 1 with STRC gene variant, and 14 with other genetic variants. A total of 12 children carried deafness gene variants associated with a syndrome; CMV test results showed that in two children, the CMV DNA copy number in saliva was >1000/mL, which indicates that they were CMV-positive, and their genetic test results were negative. A neonatal CMV test combined with genetic screening can improve the etiological diagnosis rate of congenital deafness, and the direct evidence of neonatal CMV infection deserves further verification.