Constraining the Excessive Aggregation of Non-Fullerene Acceptor Molecules Enables Organic Solar Modules with the Efficiency >16.

Translating high-performance organic solar cell (OSC) materials from spin-coating to scalable processing is imperative for advancing organic photovoltaics. For bridging the gap between laboratory research and industrialization, it is essential to understand the structural formation dynamics within the photoactive layer during printing processes. In this study, two typical printing-compatible solvents in the doctor-blading process are employed to explore the intricate mechanisms governing the thin-film formation in the state-of-the-art photovoltaic system PM6:L8-BO. Our findings highlight the synergistic influence of both the donor polymer PM6 and the solvent with a high boiling point on the structural dynamics of L8-BO within the photoactive layer, significantly influencing its morphological properties. The optimized processing strategy effectively suppresses the excessive aggregation of L8-BO during the slow drying process in doctor-blading, enhancing thin-film crystallization with preferential molecular orientation. These improvements facilitate more efficient charge transport, suppress thin-film defects and charge recombination, and finally enhance the upscaling potential. Consequently, the optimized PM6:L8-BO OSCs demonstrate power conversion efficiencies of 18.42% in small-area devices (0.064 cm2) and 16.02% in modules (11.70 cm2), respectively. Overall, this research provides valuable insights into the interplay among thin-film formation kinetics, structure dynamics, and device performance in scalable processing.

The role of RNA modifications in hepatocellular carcinoma: functional mechanism and potential applications.

Hepatocellular carcinoma (HCC) is a highly aggressive cancer with a poor prognosis. The molecular mechanisms underlying its development remain unclear. Recent studies have highlighted the crucial role of RNA modifications in HCC progression, which indicates their potential as therapeutic targets and biomarkers for managing HCC. In this review, we discuss the functional role and molecular mechanisms of RNA modifications in HCC through a review and summary of relevant literature, to explore the potential therapeutic agents and biomarkers for diagnostic and prognostic of HCC. This review indicates that specific RNA modification pathways, such as N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N1-methyladenosine, are erroneously regulated and are involved in the proliferation, autophagy, innate immunity, invasion, metastasis, immune cell infiltration, and drug resistance of HCC. These findings provide a new perspective for understanding the molecular mechanisms of HCC, as well as potential targets for the diagnosis and treatment of HCC by targeting specific RNA-modifying enzymes or recognition proteins. More than ten RNA-modifying regulators showed the potential for use for the diagnosis, prognosis and treatment decision utility biomarkers of HCC. Their application value for HCC biomarkers necessitates extensive multi-center sample validation in the future. A growing number of RNA modifier inhibitors are being developed, but the lack of preclinical experiments and clinical studies targeting RNA modification in HCC poses a significant obstacle, and further research is needed to evaluate their application value in HCC treatment. In conclusion, this review provides an in-depth understanding of the complex interplay between RNA modifications and HCC while emphasizing the promising potential of RNA modifications as therapeutic targets and biomarkers for managing HCC.

Design, Synthesis, Anti-TMV Activity, and Structure-Activity Relationships of Seco-pregnane C21 Steroids and Their Derivatives.

seco-pregnane C21 steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of seco-pregnane C21 steroids and the structure-activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural seco-pregnane C21 steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, 5g, 5j, and 5l with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of NtHsp70-1 and NtHsp70-061. Computational simulations indicated that 5l displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (ΔGbind = -56.2 kcal/mol) compared with Ribavirin (ΔGbind = -47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.

Validation of a single specimen pneumatic tube system in the clinical laboratory.

The single-specimen pneumatic tube (PTS) is a commonly used rapid specimen delivery system in modern clinical laboratories. However, its impact on sample integrity and laboratory test results remains controversial. The installation and configuration of single-specimen PTS are unique to their institution. We sought to validate our single-specimen PTS by comparing routine chemistry, immunology, and hematology results with a repeat sample integrity index for manual transport. In 2023, 30 employees were randomly selected from the company medical examination, and three tubes of procoagulant serum samples and three tubes of EDTA anticoagulant blood samples were collected from each of them. Group A uses a single specimen PTS at 8 m/s, Group B uses a single specimen PTS at 15 m/s, and Group C uses manual transfer. Specimens from all three groups were simultaneously analysed for ALT, AST, TG, TC, LDL, K, NA, CI, TSH, hs-cTnT, NSE, Cyfra21-1 and haematological analysis. The differences between the three groups of NSE and Cyfra21-1 were statistically significant (P < 0.05). The differences of the rest of the items were not statistically significant. The difference in NSE was not statistically significant between groups A and B (P = 0.401), B and C, and C and A (P < 0.05). The difference in Cyfra21-1 was not statistically significant between groups A and B (P = 0.897), B and C (P = 0.052), and C and A (P = 0.145). Individual sample PTS should be validated for testing prior to use to ensure the results' accuracy.

Utilizing artificial intelligence for precision exploration of N protein targeting phenanthridine sars-cov-2 inhibitors: A novel approach.

The persistent mutation of the novel coronavirus presents a continual threat of infections and associated illnesses. While considerable research efforts have concentrated on the functional proteins of SARS-CoV-2 in the development of anti-COVID-19 therapeutics, the structural proteins, particularly the N protein, have received comparatively less attention. This study focuses on the N protein, a critical structural component of the virus, and employs advanced deep learning models, including EMPIRE and DeepFrag, to optimize the structures of phenanthridine-based compounds. More than 10,000 small molecules, derived through deep learning, underwent high-throughput virtual screening, resulting in the synthesis of 44 compounds. Compound 38 showed a binding potential energy of -8.2 kcal/mol in molecular docking. Surface Plasmon Resonance (SPR) and Microscale Thermophoresis (MST) validation yielded dissociation constants of 353 nM and 726 nM, confirming strong binding to the N protein. Compound 38 demonstrated antiviral activity in vitro and exhibited anti-COVID-19 effects by interfering with the binding of N proteins to RNA. This research underscores the potential of targeting the SARS-CoV-2 N protein for therapeutic intervention and illustrates the efficacy of deep learning model in the design of lead compounds. The application of these deep learning models represents a promising approach for accelerating the discovery and development of antiviral agents.

Anemia, blood cell indices, genetic correlations, and brain structures: A comprehensive analysis of roles in Parkinson's disease risk.

INTRODUCTION: Anemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study. METHODS: We used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume. RESULTS: During a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81-2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk. CONCLUSION: In summary, we consider there to be a substantial correlation between anemia and increased PD risk.

A natural acylphloroglucinol exerts anti-erythroleukemia effects via targeting STAT3 and p38-MAPK, and inhibiting PI3K/AKT/mTOR signaling pathway.

Erythroleukemia, a subtype of acute myeloid leukemia (AML), is a life-threatening malignancy that affects the blood and bone marrow. Despite the availability of clinical treatments, the complex pathogenesis of the disease and the severe side effects of chemotherapy continue to impede therapeutic progress in leukemia. In this study, we investigated the antitumor activity of L76, an acylphloroglucinol compound derived from Callistemon salignus DC., against erythroleukemia, along with its underlying mechanisms. MTT assays were performed to evaluate the inhibitory effects of L76 on cancer cell viability, while flow cytometry was used to analyze apoptosis and cell cycle arrest in HEL cells. The molecular mechanisms of L76 were further explored using Western blotting, microscopic analysis, and cellular thermal shift assays (CETSA). Our in vitro experiments demonstrated that L76 inhibits proliferation, induces G1/S cell cycle arrest, and promotes apoptosis in human leukemia cells. Mechanistically, L76 exerts its effects by targeting STAT3 and p38-MAPK, and by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, this study highlights the potential of L76 as an anti-erythroleukemia agent, demonstrating its ability to target STAT3 and p38-MAPK, and to inhibit the PI3K/AKT/mTOR signaling pathway. These findings suggest that L76 could be a promising candidate for the treatment of erythroleukemia.

[Causal relationship between relative abundance of gut microbiota and teratozoospermia: A two-sample Mendelian randomization analysis].

OBJECTIVE: To explore the potential causal relationship between gut microbiota and teratozoospermia. METHODS: We searched the database of Genome-Wide Association Study (GWAS) for gut microbiota- and teratozoospermia-related data. We used gut microbiota as an exposure factor, determined the instrumental variables according to the GWAS data on 18 340 participants released by the MiBioGen Alliance, and derived the outcome variables from the European data on teratozoospermia, with a sample size of 85 716, including 915 cases and 209 006 controls. Using inverse-variance weighting (IVW), MR-Egger regression and the weighted median estimator (WME), we performed two-sample Mendelian randomization (MR) analysis on the retrieved data, and estimated the causal relationship between gut microbiota and teratozoospermia based on the ß value. RESULTS: Two-sample MR analysis indicated that the class Erysipelotrichia, family Erysipelotrichaceae, family Streptococcaceae, genus Coprococcusl, genus Ruminococcaceae UCG009, genus Streptococcus, order Clostridialesm and order Erysipelotrichales were causally related with the increased risk, while the family Porphyromonadaceae with the decreased risk of teratozoospermia. CONCLUSION: The class Erysipelotrichia, family Erysipelotrichaceae, family Streptococcaceae, genus Coprococcusl, genus Ruminococcaceae UCG009, genus Streptococcus, order Clostridialesm and order Erysipelotrichales are one of the causes of teratozoospermia, related to the increased risk of the condition, while the family Porphyromonadaceae has a protective effect on sperm morphology, reducing the risk of teratozoospermia.

Reduction of eEF2 kinase alleviates the learning and memory impairment caused by acrylamide.

BACKGROUND: The impact of acrylamide (ACR) on learning and memory has garnered considerable attention. However, the targets and mechanisms are still unclear. RESULTS: Elongation factor 2 (eEF2) was significantly upregulated in the results of serum proteomics. Results from in vitro and in vivo experiments indicated a notable upregulation of Eukaryotic elongation factor 2 kinase (eEF2K), the sole kinase responsible for eEF2 phosphorylation, following exposure to ACR (P < 0.05). Subsequent in vitro experiments using eEF2K siRNA and in vivo experiments with eEF2K-knockout mice demonstrated significant improvements in abnormal indicators related to ACR-induced learning and memory deficits (P < 0.05). Proteomic analysis of the hippocampus revealed Lpcat1 as a crucial downstream protein regulated by eEF2K. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that eEF2K may play a role in the process of ACR-induced learning and memory impairment by affecting ether lipid metabolism. CONCLUSIONS: In summary, eEF2K as a pivotal treatment target in the mechanisms underlying ACR-induced learning and memory impairment, and studies have shown that it provides robust evidence for potential clinical interventions targeting ACR-induced impairments.

Diterpenoids target SARS-CoV-2 RdRp from the roots of Euphorbia fischeriana Steud.

Introduction: Currently, the development of new antiviral drugs against COVID-19 remains of significant importance. In traditional Chinese medicine, the herb Euphorbia fischeriana Steud is often used for antiviral treatment, yet its therapeutic effect against the COVID-19 has been scarcely studied. Therefore, this study focuses on the roots of E. fischeriana Steud, exploring its chemical composition, antiviral activity against COVID-19, and the underlying basis of its antiviral activity. Methods: Isolation and purification of phytochemicals from E. fischeriana Steud. The elucidation of their configurations was achieved through a comprehensive suite of 1D and 2D NMR spectroscopic analyses as well as X-ray diffraction. Performed cytopathic effect assays of SARS-CoV-2 using Vero E6 cells. Used molecular docking to screen for small molecule ligands with binding to SARS-CoV-2 RdRp. Microscale thermophoresis (MST) was used to determine the dissociation constant Kd. Results: Ultimately, nine new ent-atisane-type diterpenoid compounds were isolated from E. fischeriana Steud, named Eupfisenoids A-I (compounds 1-9). The compound of 1 was established as a C-19-degraded ent-atisane-type diterpenoid. During the evaluation of these compounds for their antiviral activity against COVID-19, compound 1 exhibited significant antiviral activity. Furthermore, with the aid of computer virtual screening and microscale thermophoresis (MST) technology, it was found that this compound could directly bind to the RNA-dependent RNA polymerase (RdRp, NSP12) of the COVID-19, a key enzyme in virus replication. This suggests that the compound inhibits virus replication by targeting RdRp. Discussion: Through this research, not only has our understanding of the antiviral components and material basis of E. fischeriana Steud been enriched, but also the potential of atisane-type diterpenoid compounds as antiviral agents against COVID-19 has been discovered. The findings mentioned above will provide valuable insights for the development of drugs against COVID-19.

LDHA-induced histone lactylation mediates the development of osteoarthritis through regulating the transcription activity of TPI1 gene.

Osteoarthritis (OA) is a worldwide joint disease, leading to the physical pain, stiffness, and even disability. Lactate dehydrogenase A (LDHA) is known as a lactylation mediator that can regulate histone lactylation of its target genes. However, the role of LDHA-mediated histone H3 lysine 18 lactylation (H3K18la) in OA progression is yet to be clarified. Our study aims at revealing the role and mechanism of LDHA-mediated histone lactylation in the glycolysis of chondrocytes. In this study, we determined at first that the H3K18la level was enhanced in OA. Energy metabolism such as glycolysis is often altered in OA progress. Therefore, we further explored the mechanism mediating glycolysis and thus promoting OA progress. Moreover, glycolysis was enhanced in LPS-induced OA cell model, as evidenced by the increased glucose consumption and lactate production. Furthermore, we silenced LDHA for loss-of-function assays. The results showed that knockdown of LDHA suppressed glycolysis of LPS-induced chondrocytes. In vivo animal study demonstrated that knockout of LDHA recovered cartilage injury of OA mice. Mechanistically, we uncovered that LDHA-mediated H3K18la in TPI1 promoter enhanced the transcription activity of TPI1. Mutation of K69 site was found to ameliorate LPS-induced glycolysis in OA cell model. In conclusion, our study reveals the role of LDHA-mediated H3K18la of TPI1 promoter in OA progress.

[Effects of 40 Years of Fertilizer Application on the Characteristics of Soil Enzymatic Stoichiometry in Black Soil].

Microorganisms produce extracellular enzymes to meet elemental requirements and cope with stoichiometric imbalances of resources. To gain insights into the cycling of C, N, and P, the activities of the C∶N∶P acquisition enzymes have been extensively investigated. To detect the effects of long-term fertilization practices on soil nutrient balance and characteristics of soil enzymatic stoichiometry in black soil, four different fertilization treatments were selected： no fertilization （CK）, nitrogen fertilizer （N）, phosphorus fertilizer （P）, and combination of nitrogen and phosphorus fertilizers （NP）. Soil samples were collected in both April 2021 and April 2022 to determine soil enzyme activities and their stoichiometric characteristics. The results showed that soil acid phosphatase and ß-D-glucosidase activities were significantly higher in the N and NP treatments than in CK by 68%-158% and 26%-222%, respectively. Soil ß-N-acetylaminoglucosidase activities were significantly higher in the P and NP treatments, with the highest around 75.48 nmol·ï¼ˆg·h）-1 and 106.81 nmol·ï¼ˆg·h）-1, respectively. Two-way ANOVA analysis showed that N and P inputs had a great impact on soil enzyme activities. Redundancy analysis showed that the main factors controlling enzyme activities were soil pH, microbial biomass phosphorus, and soil available P content. It was found that N inputs significantly increased enzyme vector length, which was ranged from 1.32 to 1.52, and the enzyme vector angles were all larger than 45°, suggesting C and P co-limited in the black soils. These findings suggest that 40 years of fertilization have had a great impact on soil enzymes and the related resource use strategy, which provides great implications for assessing soil nutrients balance and soil sustainability.

Past and present: a bibliometric study on the treatment of recurrent ovarian cancer.

Background: Ovarian cancer (OC) is a gynecological malignancy with a high mortality rate worldwide. The unfavorable prognosis of OC is mainly attributed to the recurrent propensity. Recently, mortality from OC has exhibited a downward trend. These favorable patterns are likely to be driven by advancements in novel therapeutic regimens. However, there is a lack of visualize analysis of the application of these new drugs on women with recurrent OC (ROC). Therefore, we aimed to provide a bibliometric analysis of the evolving paradigms in the ROC treatment. Methods: Documents on ROC treatment were systematically collected from the MEDLINE database and Web of Science Core Collection (WOSCC). The retrieved documents were exported in the plain text file format, and files were named and saved to the paths specified by the Java application. Microsoft Excel (version 2010), Citespace (6.2.R4) and VOSviewer (1.6.19) were used for data analysis, and included the following: 1) annual publication trend; 2) contributions of countries, institutions and authors; 3) co-citation of journals and references; and 4) co-occurrence of keywords. Results: A total of 914 documents published in the MEDLINE and 9,980 ones in WOSCC were retrieved. There has been an upward trend in the productivity of publications on ROC treatment on by years. The United States was the leading contributor in this field, and the University of Texas System stood out as the most productive institution. Giovanni Scambia and Maurie Markman were the research leaders in the field of ROC treatment. The journal Gynecologic Oncology had the highest citation frequency. The reference entitled with "Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer" got highest centrality of 0.14 in the co-citation network. Keyword analysis revealed that the focus of current ROC treatment was on platinum-based anticancer drugs, paclitaxel, angiogenesis inhibitors (AIs), immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase inhibitors (PARPis). Conclusion: Scholars from a multitude of countries have been instrumental in the advancement of ROC treatment. The research hotspots and trend in the field of predominantly originated from leading international journals and specialized periodicals focused on gynecologic oncology. Maintenance therapy using AIs or (and) PARPis has emerged as a significant complement to platinum-based chemotherapy for patients with ROC.

Moxibustion improves motor function by down-regulating SNX5 and inhibiting ferroptosis in neurons of corpus striatum in mice with Parkinson's disease. / 艾灸调控SNX5å¯¹å¸•é‡‘æ£®ç— æ¨¡åž‹å°é¼ ç¥žç»å ƒé“æ­»äº¡çš„å½±å“.

OBJECTIVES: To explore the effect of moxibustion on the expression of sorting nexin 5 (SNX5), glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1) in the corpus striatum in mice with Parkinson's disease (PD), so as to explore its mechanisms underlying improvement of PD by ameliorating ferroptosis in the substantia nigra striatum. METHODS: C57BL/6J mice were randomly divided into normal, sham operation, model, and moxibustion groups, with 10 mice in each group. The PD model was established by unilateral injection of 6-hydroxydopamine (3.5 µL) into the right medial forebrain bundle (AP=-1.2 mm, ML=-1.3 mm, DV=-4.75 mm). The mice in the moxibustion group received moxibustion at "Baihui"(GV20) and "Sishencong"(EX-HN1) for 20 min each time, once a day, 6 times a week for 4 weeks. After the intervention, mice received apomorphine rotation behavior detection and pole climbing test. The expression of tyrosine hydroxylase (TH) in the substantia nigra was detected by immunofluorescence, the contents of Fe2+, malondialdehyde (MDA), the ratio of glutathione/oxidized glutathione (GSH/GSSG) in the corpus striatum were detected by using photocolorimetric method, and the expression levels of SNX5 (endocytosomal protein), GPX4 (one of the key targets for inhibiting ferroptosis) and FTH1 proteins and mRNAs in the corpus striatum were detected by Western blot and qPCR, respectively. RESULTS: Behavior tests showed that the pole climbing time and number of body rotation were significantly increased in the model group relevant to the sham operation group (P<0.01), and strikingly decreased in the moxibustion group relevant to the model group (P<0.01). The immunofluorescence intensity of TH in the substantia nigra, the ratio of GSH/GSSG, and the expression levels of GPX4 and FTH1 mRNAs and proteins in the corpus striatum were markedly decreased (P<0.01, P<0.05), while the contents of Fe2+ and MDA and the expression levels of SNX5 mRNA and protein in the corpus striatum significantly increased in the model group relevant to the sham operation group (P<0.01, P<0.05). Compared with the model group, the decreased immunofluorescence intensity of TH, GSH/GSSH, and the expression levels of GPX4 and FTH1 mRNAs and proteins, and the increased contents of Fe2+ and MDA and the expression levels of SNX5 mRNA and protein were reversed in the moxibustion group relevant to the model group (P<0.01, P<0.05). CONCLUSIONS: Moxibustion may improve motor dysfunction in PD mice, which may be related to its effects in down-regulating the expression of SNX5, promoting the synthesis of GSH, decreasing the contents of Fe2+ and MDA, up-regulating the ratio of GSH/GSSG and the expression of GPX4 and FTH1 mRNAs and proteins in the corpus striatum, and inhibiting the occurrence of ferroptosis.

Distribution characteristics of sulfonamide antibiotics between water and extracellular polymeric substances in municipal sludge.

The interaction between extracellular polymeric substances (EPS) in municipal sludge and antibiotics in wastewater is critical in wastewater treatment, resource recovery, and sludge management. Therefore, it is increasingly urgent to investigate the distribution coefficient (Log K) of sulfonamide antibiotics (SAs) in EPS, particularly in sludge-derived dissolved organic carbon (DOC) and aqueous phase systems. Herein, through balance experiments, the concentrations of SAs were determined using alkaline extraction EPS (AEPS) and alginate-like extracellular polymer (ALE) systems, and the Log KDOC values were determined. The results showed that the Log KDOC of AEPS was higher than that of ALE, which exhibited a negative KDOC value, indicating an inhibitory effect on dissolution. For the three SAs studied, the Log KDOC values were in the following order: sulfamethoxazole > sulfapyridine > sulfadiazine. This order can be attributed to the differing physicochemical properties, such as polarity, of the SAs. Three-dimensional excitation-emission matrix fluorescence spectra and fitting results indicated a lack of aromatic proteins dominated by tryptophan and humus-like substances in ALE. Meanwhile, the hydrophobic interaction of aromatic proteins dominated by tryptophan was the main driving force in the binding process between AEPS and SAs.

Potential SARS-CoV-2 Mpro steroid inhibitors from Aphanamixis polystachya (Wall.) R. N. Parker.

Herein, six previously undescribed steroids (1-6), were isolated from leaves and twigs of Aphanamixis polystachya (Wall.) R. N. Parker (Meliaceae). Their structures were elucidated by comprehensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR, UV, and IR. Antiviral activity of these compounds were evaluated. Compounds 1-6 showed varying degrees of inhibitory activity against the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) at 200 µM.

Analysis of Phenotypes Associated with Deficiency of PAX6 Haplotypes in Chinese Aniridia Families.

OBJECTIVE: To examine the clinical phenotype and genetic deficiencies present in Chinese aniridia families with PAX6 haplotype deficiency. METHODS: A comprehensive questionnaire and ophthalmological assessments were administered to both affected patients and unaffected relatives. The clinical feature analysis included the evaluation of visual acuity, intraocular pressure, slit-lamp anterior segment examination, fundus photography, and spectral domain optical coherence tomography. To identify the mutation responsible for aniridia, targeted next-generation sequencing was used as a beneficial technique. RESULTS: A total of 4 mutations were identified, consisting of two novel frameshift mutations (c.314delA, p.K105Sfs*33 and c.838_845dup AACACACC, p.S283Tfs*85), along with two recurring nonsense mutations (c.307C>T, p.R103X and c.619A>T, p.K207*). Complete iris absence, macular foveal hypoplasia, and nystagmus were consistent in these PAX6 haplotype-deficient Chinese aniridia families, while corneal lesions, cataracts, and glaucoma exhibited heterogeneity both among the families and within the same family. CONCLUSION: In our study, two novel PAX6 mutations associated with aniridia were identified in Chinese families, which expanded the phenotypic and genotypic spectrum of PAX6 mutations. We also analyzed the clinical characteristics of PAX6 haplotype deficiency in Chinese aniridia families.

The potential protective role of peripheral immunophenotypes in Alzheimer's disease: a Mendelian randomization study.

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous. Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes. Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs). Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD.

Single-cell transcriptomics of blood identified IFIT1+ neutrophil subcluster expansion in NTM-PD patients.

OBJECTIVE: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is caused by an imbalance between pathogens and impaired host immune responses. Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are the two major pathogens that cause NTM-PD. In this study, we sought to dissect the transcriptomes of peripheral blood immune cells at the single-cell resolution in NTM-PD patients and explore potential clinical markers for NTM-PD diagnosis and treatment. METHODS: Peripheral blood samples were collected from six NTM-PD patients, including three MAB-PD patients, three MAC-PD patients, and two healthy controls. We employed single-cell RNA sequencing (scRNA-seq) to define the transcriptomic landscape at a single-cell resolution. A comprehensive scRNA-seq analysis was performed, and flow cytometry was conducted to validate the results of scRNA-seq. RESULTS: A total of 27,898 cells were analyzed. Nine T-cells, six mononuclear phagocytes (MPs), and four neutrophil subclusters were defined. During NTM infection, naïve T-cells were reduced, and effector T-cells increased. High cytotoxic activities were shown in T-cells of NTM-PD patients. The proportion of inflammatory and activated MPs subclusters was enriched in NTM-PD patients. Among neutrophil subclusters, an IFIT1+ neutrophil subcluster was expanded in NTM-PD compared to healthy controls. This suggests that IFIT1+ neutrophil subcluster might play an important role in host defense against NTM. Functional enrichment analysis of this subcluster suggested that it is related to interferon response. Cell-cell interaction analysis revealed enhanced CXCL8-CXCR1/2 interactions between the IFIT1+ neutrophil subcluster and NK cells, NKT cells, classical mononuclear phagocytes subcluster 1 (classical Mo1), classical mononuclear phagocytes subcluster 2 (classical Mo2) in NTM-PD patients compared to healthy controls. CONCLUSIONS: Our data revealed disease-specific immune cell subclusters and provided potential new targets of NTM-PD. Specific expansion of IFIT1+ neutrophil subclusters and the CXCL8-CXCR1/2 axis may be involved in the pathogenesis of NTM-PD. These insights may have implications for the diagnosis and treatment of NTM-PD.