Isolation and Biological Characteristics of a Novel Phage and Its Application to Control Vibrio Parahaemolyticus in Shellfish Meat.

Vibrio parahaemolyticus is a common foodborne pathogenic bacterium. With the overuse of antibiotics, an increasing proportion of drug-resistant strains are emerging, which puts enormous pressure on public health. In this study, a V. parahaemolyticus-specific phage, VP41s3, was isolated. The head length, width, and tail length of the phage were 77.7 nm, 72.2 nm, and 17.5 nm, respectively. It remained active in the temperature range of 30-50°C and pH range of 4-11. The lytic curve of phage VP41s3 showed that the host bacteria did not grow until 11 h under phage treatment at MOI of 1000, indicating that the phage had good bacteriostatic ability. When it was added to shellfish contaminated with V. parahaemolyticus (15°C, 48 h), the number of bacteria in the experimental group was 2.11 log10 CFU/mL lower than that in the control group at 24 h. Furthermore, genomic characterization and phylogenetic analysis indicated that phage VP41s3 was a new member of the Podoviridae family. The genome contained 50 open reading frames (ORFs), in which the ORF19 (thymidine kinase) was an enzyme involved in the pyrimidine salvage pathway, which might lead to the accelerated DNA synthesis efficiency after phage entered into host cells. This study not only contributed to the improvement of phage database and the development of beneficial phage resources but also revealed the potential application of phage VP41s3 in food hygiene and safety.

Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment.

The potassium (K+) ion channel KCNK13 is specifically expressed in human microglia with elevated expression observed in post-mortem human brain tissue from patients with Alzheimer's disease. Modulation of KCNK13 activity by a small-molecule inhibitor is proposed as a potential treatment for neurodegenerative diseases. Herein, we describe the evolution of a series of KCNK13 inhibitors derived from a high-throughput screening campaign, resulting in CVN293, a potent, selective, and brain permeable clinical candidate molecule. CVN293 demonstrated a concentration-dependent inhibition of the NLRP3-inflammasome mediated production of IL-1ß from LPS-primed murine microglia. Cross-species pharmacokinetic data of CVN293 are also disclosed. These findings support the advancement of CVN293 in clinical trials.

[Clinical experience of Shao's nu-needle manipulation method for post-stroke depression].

The clinical experience of Shao's needling technique for post-stroke depression is introduced. Professor SHAO Jingming proposes that the main pathogenesis of this condition lies in the "imbalance of body and spirit," with its onset closely related to the heart, liver, spleen, and kidney. In clinical practice, based on the principle of "treating both the body and spirit", "three acupoints for treating the spirit" including Dazhui (GV 14), Fengchi (GB 20), and Baihui (GV 20) are selected, combined with back-shu points such as Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20), and Shenshu (BL 23). The nu-needle manipulation method is applied. The treatment focuses on both physical and mental aspects, achieving remarkable therapeutic effects.

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity.

BACKGROUND: Inflammatory bowel disease (IBD) and Parkinson's disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. METHODS: We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. RESULTS: The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein-protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. CONCLUSIONS: Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization.

Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

miR-2940-1 is involved in the circadian regulation of oviposition in Aedes albopictus.

The vast majority of all global species have circadian rhythm cycles that allow them to adapt to natural environments. These regular rhythms are regulated by core clock genes and recent studies have also implicated roles for microRNAs in this regulation. Oviposition is an important circadian behavior in the reproductive cycle of insect vectors of diseases, and little is known about the rhythm or its regulation in mosquitoes. Aedes albopictus is a diurnal mosquito that transmits arboviruses and is the major cause of outbreaks of dengue fever in China. We analyzed the oviposition rhythm patterns of A. albopictus under different light/dark conditions and show that the mosquitoes have an oviposition peak between zeitgeber time 9 (ZT 9) and ZT 12. Furthermore, the antagomir-mediated knockdown of expression of the microRNA miR-2940-1 affected the oviposition rhythm of A. albopictus. These data support the conclusion that miR-2940-1 is involved in the regulation of oviposition rhythm in A. albopictus and provide a foundation for using oviposition rhythms as a new target for vector mosquito control.

Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

Tandem Sulfonylative Annulation/Halogenation of 1,7-Enynes with Sodium Sulfinate and TBAX for the Assembly of 4-Methylenechromanes.

An effective and stereoselective synthesis of halogenated (E)-4-methylenechromanes with a sulfonyl group was developed via the copper-catalyzed sulfonylative annulation/halogenation of 1,7-enynes, in which sodium sulfinates were used as the sulfonyl reagents and tetrabutylammonium halide provided the halogen sources. The formed alkenyl C-X bonds were valuable and can efficiently undergo the subsequent hydrolysis, alkenylation, alkynylation, arylation, alkylthiolation, and alkoxylation to furnish a series of highly functionalized 4-methylenechromanes.

Colony-stimulating factor-1 receptor inhibition combined with paclitaxel exerts effective antitumor effects in the treatment of ovarian cancer.

Ovarian cancer is the tumor with the highest mortality among gynecological malignancies. Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages (TAMs) in the microenvironment. Colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) plays a key role in regulating the number and differentiation of macrophages in certain solid tumors. There are few reports on the effects of targeted inhibition of CSF-1R in combination with chemotherapy on ovarian cancer and the tumor microenvironment. Here, we explored the antitumor efficacy and possible mechanisms of the CSF - 1R inhibitor pexidartinib (PLX3397) when combined with the first-line chemotherapeutic agent paclitaxel in the treatment of ovarian cancer. We found that CSF-1R is highly expressed in ovarian cancer cells and correlates with poor prognosis. Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo. Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.

Sclerotherapy with intralesional bleomycin injection under guidance of multi-slice CT for retrobulbar orbital low-flow vascular lesions-single-center experience.

OBJECTIVE: This study investigated the safety and efficacy of sclerotherapy with intralesional bleomycin injection (IBI) for retrobulbar orbital low-flow vascular lesions under multi-slice computed tomography (CT) guidance. METHODS: Between January 2010 and September 2021, consecutive patients with retrobulbar orbital low-flow vascular lesions who underwent CT-guided IBI at a tertiary centre in Taiwan were enrolled. Their medical records and imaging data were retrospectively collected. RESULTS: This study enrolled 13 patients (7 male and 6 female patients; age range: 1-57 years; mean age: 25.9 years) with lymphatic malformation (LM, n = 4), venolymphatic malformation (n = 1), and venous malformation (VM, n = 8). The overall radiological response rate was 76.9% (10 of 13); the radiological response rate was 75.0% in the VM group (6 of 8) and 75.0% in the LM group (3 of 4). Moreover, 3 patients (23.1%) had minor complications and 1 (7.7%) had a major complication. The mean clinical and radiological follow-up was 8.3 months and no recurrence or progression was reported. CONCLUSION: CT-guided IBI is an effective and relatively safe minimally invasive treatment for retrobulbar orbital low-flow vascular lesions, with an overall radiological response rate of 76.9% in a mean of 1.5 sessions and a low complication rate. ADVANCES IN KNOWLEDGE: CT-guided sclerotherapy with IBI is a relatively safe, effective, and feasible alternative treatment option for retrobulbar orbital low-flow vascular lesions.

Maternal serum polyols and its link to gestational diabetes mellitus: A population-based nested case-control study.

CONTEXT: Sugar alcohols (also called polyols) confer a"healthy"sugar substitute. One of possible reasons to support the safe use in pregnant women is their natural origin and the presence of polyols in maternal and fetal samples during normal human gestation. But little is known about the association between circulating sugar alcohols levels and maternal metabolic disorders during pregnancy. OBJECTIVE: We aimed to detect the concentration of the polyols in participants with and without GDM, and to investigate the association between maternal serum levels of polyols and gestational diabetes mellitus (GDM), as well as newborn outcomes. DESIGN: A nested population-based case-control study was conducted in 109 women with and without GDM. Maternal concentrations of serum erythritol, sorbitol, and xylitol at fasting state were quantified using a time-of-flight mass spectrometry system. RESULT: In women with GDM, serum concentrations of erythritol and sorbitol were higher, but serum concentrations of xylitol were lower, compared with those in women without GDM. Per 1-SD increment of Box-Cox transformed concentrations of erythritol and sorbitol were associated with the increased odds of GDM by 43% and 155% (95% CI 1.07-1.92 and 95 CI%: 1.77-3.69), while a decreased odd was found for xylitol by 25% (95 CI%: 0.57-1.00). Additionally, per 1-SD increase of Box-Cox transformed concentrations of serum sorbitol was associated with a 52% increased odd of large-for-gestational-age newborns controlling for possible confounders (95% CI 1.00-2.30). CONCLUSIONS: Maternal circulating sugar alcohols levels during pregnancy were significantly associated with GDM. These findings provide the potential roles of polyols on maternal metabolic health during pregnancy.

Exploring salt tolerance and indicator traits across four temperate lineages of the common wetland plant, Phragmites australis.

Common reed (Phragmites australis) is a widely utilized plant for wetland restoration and construction, facing challenges posed by high salinity as a stressor. Among the diverse P. australis lineages, functional traits variation provides a valuable genetic resource for identifying salt-tolerant individuals. However, previous investigations on P. australis salt tolerance have been restricted to regional scales, hindering the identification of key functional traits associated with salt tolerance in natural habitats. To address this gap, we conducted a greenhouse experiment to assess and compare the salt tolerance of four major temperate P. australis lineages worldwide. We utilized the maximum quantum yield of photosystem II (Fv/Fm) as a health indicator, while final biomass and wilt status served as indicators of salt tolerance across lineages. Our findings revealed significant differentiation in plant functional traits among different lineages, but no significant effect of interaction between salinity and lineage on most traits. Correlation analyses between salt-tolerance indicators and functional traits in the control group indicated that biomass, leaf width, and relative leaf water content are potential predictors of salt tolerance. However, ecological strategies, physiological traits, and latitudinal origin did not exhibit significant correlations with salt tolerance. Our study provides valuable indicator traits for effectively screening salinity-tolerant genotypes of P. australis in field settings, and holds significant potential for enhancing wetland construction and biomass production in marginal lands.

Identifying Genetic Factors of Polycystic Ovary Syndrome in Women with Epilepsy: A Whole-Genome Sequencing Study.

INTRODUCTION: Women with epilepsy (WWE) are more likely to develop reproductive endocrine disorders, especially polycystic ovary syndrome (PCOS). This study aimed to explore the genetic factors of PCOS in WWE in hope of improving individual precision diagnosis and treatment. METHODS: WWE registered at West China Hospital between January 2022 and October 2022 were enrolled in this study. Demographic and epilepsy-related characteristics were recorded, and blood samples were collected for hormones, glucose metabolism testing, and whole-genome sequencing. RESULTS: After sample sequencing, quality control, and variants selection, association analyses were performed. Pathway analysis was performed to identify involved biological pathways. The overall and PCOS "burden score" of each individual were calculated to count the deleterious variants. A total of 95 WWE were included in this study and 19 patients were diagnosed with PCOS. WWE with PCOS showed a significantly different hormone profiles and a tendency of impaired glucose metabolism. The most commonly associated genes were ZFYVE28, COL19A1, SIK3, ANKK1, PPIG, and REPIN1. The top 3 canonical pathways are adipogenesis pathway, epoxysqualene biosynthesis signaling, and glutamate degradation signaling. The most significant common variant was rs11914038 located in gene CELSR1 and rs651748 located in gene ZBTB16. In human gene connectome prioritizations, ITGA9, PNPLA2, and DAB2 are the top 3 genes having the shortest distance to known PCOS genes. CONCLUSION: Genetic factors involved in the abnormal regulation of glucose and insulin metabolism are likely to be associated with the comorbidity of PCOS in WWE. Interventions targeting these processes should be given more priority in clinical practice.

A Synergistic Therapy With Antioxidant and Anti-VEGF: Toward its Safe and Effective Elimination for Corneal Neovascularization.

Corneal neovascularization (CNV) is one of the leading causes of blindness in the world. In clinical practice; however, it remains a challenge to achieve a noninvasive and safe treatment. Herein, a biocompatible shell with excellent antioxidant and antivascularity is prepared by co-assembly of epigallocatechin gallate/gallic acid and Cu (II). After loading glucose oxidase (GOx) inside, the shell is modified with dimeric DPA-Zn for codelivering vascular endothelial growth factor (VEGF) small interfering RNA (VEGF-siRNA). Meanwhile, the Arg-Gly-Asp peptide (RGD) peptide-engineered cell membranes coating improves angiogenesis-targeting and is biocompatible for the multifunctional nanomedicine (CEGs/RGD). After eye drops administration, CEGs/RGD targets enrichment in neovascularization and CEGs NPs enter cells. Then, the inner GOx consumes glucose with a decrease in local pH, which in turn leads to the release of EGCE and VEGF-siRNA. As a result, the nanomedicines significantly reduce angiogenesis and inhibit CNV formation through synergistic effect of antioxidant and antivascular via down-regulation of cluster of differentiation 31 and VEGF. The nanomedicine represents a safe and efficient CNV treatment through the combined effect of antioxidant/gene, which provides important theoretical and clinical significance.

Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set.

Gain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, whilst available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, a machine learning method for predicting pathogenic GOF, pathogenic LOF, and neutral genetic variants, trained on a broad range of gene-, protein-, and variant-level features describing diverse biological characteristics. LoGoFunc outperforms other tools trained solely to predict pathogenicity for identifying pathogenic GOF and LOF variants and is available at https://itanlab.shinyapps.io/goflof/ .

Topology-Mediated Molecule Nucleation Anchoring Enables Inkjet Printing of Organic Semiconducting Single Crystals for High-Performance Printed Electronics.

Printable organic semiconducting single crystals (OSSCs) offer tantalizing opportunities for next-generation wearable electronics, but their development has been plagued by a long-standing yet inherent problem─spatially uncontrolled and stochastic nucleation events─which usually causes the formation of polycrystalline films and hence limited performance. Here, we report a convenient approach to precisely manipulate the elusive molecule nucleation process for high-throughput inkjet printing of OSSCs with record-high mobility. By engineering curvature of the contact line with a teardrop-shaped micropattern, molecule nucleation is elegantly anchored at the vertex of the topological structure, enabling formation of a single nucleus for the subsequent growth of OSSCs. Using this approach, we achieve patterned growth of 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene single crystals, yielding a breakthrough for an organic field-effect transistor array with a high average mobility of 12.5 cm2 V-1 s-1. These findings not only provide keen insights into controlling molecule nucleation kinetics but also offer opportunities for high-performance printed electronics.

ICG-based laser treatments for ophthalmic diseases: Toward their safe and rapid strategy.

The eye is a very important organ, and keratitis, corneal neovascularization, floaters, age-related macular degeneration, and other vision problems have seriously affected people's quality of life. Among the ophthalmic treatments, laser photocoagulations have been proposed and have shown therapeutic effects in clinical settings. However, corneal thinning and bleeding lesions induced by laser damage have led to limit its applications. To treat the issues of traditional hyperthermia treatments, photosensitizers [e.g., indocyanine green (ICG)] have been investigated to increase the therapeutic effects of corneal neovascularization and choroidal neovascularization. In the recent study, with the help of ICG, laser-induced nanobubble was proposed to treat vitreous opacities. The developed strategies could enlarge the effect of laser irradiation and reduce the side effects, so as to expand the scope of laser treatments in clinical ophthalmic diseases.

Acid-Responsive Aggregation of Gold Nanoparticles for the Photothermal Treatment of Bacterial Infections.

Photothermal therapy (PTT) is considered to be one of the promising methods to combat pathogenic bacteria. However, traditional PTT is prone to generate undesired temperature increase to surrounding normal tissues, which limits the application of PTT. Herein, an acid-responsive PTT system (Au nanoparticles system: AuNPs-S) was constructed based on the photothermal feature of spherical gold nanoparticles (AuNPs) and the low pH of the bacterial infected site. AuNPs-S is composed of two kinds of AuNPs: AuNPs modified with Asp-Asp-Asp-Asp-Asp-Cys (peptide A) were denoted as AuNPs-A; AuNPs modified with 2,3-dimethylmaleic anhydride (DA) grafted Lys-Gly-Gly-Lys-Gly-Gly-Lys-Cys (peptide B) were denoted as AuNPs-B/DA. AuNPs-B/DA with an acid-responsive moiety showed a charge-convertible feature. The negatively charged AuNPs-B/DA became positively charged AuNPs-B at low pH, aggregating with the negatively charged AuNPs-A via an electrostatic interaction, reaching the threshold to the interparticle plasmonic coupling effect among AuNPs, thereby killing bacteria precisely under the irradiation of near-infrared (NIR) light through the elevated temperature at the targeted area. This acid-responsive PTT strategy supplies an excellent mode for combating bacterial infections with no vital damage to normal tissues.