Berberine inhibits the progression of breast cancer by regulating METTL3-mediated m6A modification of FGF7 mRNA.

BACKGROUND: Berberine (BBR), an isoquinoline alkaloid from Coptidis rhizoma, has been found to have powerful activities against various human malignancies, including breast cancer. However, the underlying antitumor mechanisms of BBR in breast cancer remain poorly understood. METHODS: Breast cancer cells were cultured and treated with different doses (0, 20, 40, and 60 µM) of BBR for 48 h. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. Fibroblast growth factor 7 (FGF7), methyltransferase-like 3 (METTL3), and insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) mRNA levels and protein levels were measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Interaction between METTL3 and FGF7 m6A was assessed using methylated RNA immunoprecipitation (MeRIP)-qPCR and RNA immunoprecipitation (RIP) assay. Binding ability between IGF2BP3 and FGF7 mRNA was analyzed using RIP assay. RESULTS: BBR treatment hindered breast cancer cell proliferation, invasion, migration, and induced apoptosis. FGF7 expression was upregulated in breast cancer tissues, while its level was reduced in BBR-treated tumor cells. FGF7 upregulation relieved the repression of BBR on breast cancer cell malignant behaviors. In mechanism, METTL3 stabilized FGF7 mRNA through the m6A-IGF2BP3-dependent mechanism and naturally improved FGF7 expression. BBR treatment inhibited breast cancer growth in vivo. CONCLUSION: BBR treatment blocked breast cancer cell growth and metastasis partly by regulating METTL3-mediated m6A modification of FGF7 mRNA, providing a promising therapeutic target for breast cancer treatment.

SLC7A11 as a therapeutic target to attenuate phthalates-driven testosterone level decline in mice.

INTRODUCTION: Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. OBJECTIVES: Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. METHODS: We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe2+ levels and glutathione system to confirm the occurrence of ferroptosis. RESULTS: In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. CONCLUSION: Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and "The Global Plastic Toxicity Debt".

Molecular characterization and expression profile of the ALDH1A1 gene and its functions in yak luteal cells.

The ALDH1A1 gene encodes a cytoplasmic member of the aldehyde dehydrogenase 1 family, which plays an important role in regulating animal reproductive performance, including estrus cycle and embryonic development. The aim of this study was to characterize ALDH1A1 activity in ovaries of 3-5 year-old yaks and to determine its effects on cell proliferation, apoptosis, and progesterone secretion in luteal cells (LCs). The coding sequence (CDS) of the ALDH1A1 gene was cloned by reverse transcription-PCR and immunohistochemical analysis was used to confirm localization of the ALDH1A1 protein in the ovary. To assess the activity of ALDH1A1 in regulating progesterone secretion, si-ALDH1A1 was transfected into LCs in vitro and progesterone levels in LC supernatants were measured by ELISA. The interference efficiency was assessed by real-time quantitative PCR (RT-qPCR) and immunofluorescence staining, and cell proliferation and apoptosis were evaluated by EdU and TUNEL staining, respectively. The cloned ALDH1A1 sequence contained 1462 bp, encoding 487 amino acids. Immunohistochemical analysis showed that ALDH1A1 protein expression, which was significantly higher in LCs, was mainly found in antral follicles and the corpus luteum (CL). The expression of ALDH1A1 mRNA in LCs was effectively inhibited by si-ALDH1A1transfection, and progesterone secretion was markedly decreased along with the significant down-regulation of progesterone pathway-related genes, STAR, CYP11A1, CYP19A1, CYP17A1, 3ß-HSD, and HSD17B1. Knockdown of ALDH1A1 mRNA expression decreased cell proliferation and increased apoptosis in LCs. The mRNA expression of the proliferation-related genes, PCNA, CCND1, CCNB1 and CDC25A, was significantly down-regulated, while expression of the apoptosis-promoting CASP3 gene was significantly increased. In summary, we characterized the yak ALDH1A1 gene and revealed that ALDH1A1 knockdown promoted apoptosis, repressed cell proliferation, and decreased progesterone secretion by yak LCs, potentially by regulating the mRNA expression of genes related to proliferation, apoptosis, and progesterone synthesis and secretion.

Incidence and risk factors of postoperative delirium following hepatic resection: a retrospective national inpatient sample database study.

BACKGROUND: Postoperative delirium (POD) is a common complication after major surgery and can cause a variety of adverse effects. However, no large-scale national database was used to assess the occurrence and factors associated with postoperative delirium (POD) following hepatic resection. METHODS: Patients who underwent hepatic resection from 2015 to 2019 were screened using the International Classification of Diseases (ICD) 10th edition clinical modification code from the National Inpatient Sample (NIS) Database. Peri-operative factors associated with delirium were screened and underwent statistical analysis to identify independent predictors for delirium following hepatic resection. RESULTS: A total of 80,070 patients underwent hepatic resection over a five-year period from 2015 to 2019. The overall occurrence of POD after hepatic resection was 1.46% (1039 cases), with a slight upward trend every year. The incidence of elective admission was 6.66% lower (88.60% vs. 81.94%) than that of patients without POD after hepatic resection and 2.34% (45.53% vs. 43.19%) higher than that of patients without POD in teaching hospitals (P < 0.001). In addition, POD patients were 6 years older (67 vs. 61 years) and comprised 9.27% (56.69% vs. 47.42%) more male patients (P < 0.001) compared to the unaffected population. In addition, the occurrence of POD was associated with longer hospitalization duration (13 vs. 5 days; P < 0.001), higher total cost ($1,481,89 vs. $683,90; P < 0.001), and higher in-hospital mortality (12.61% vs. 4.11%; P < 0.001). Multivariate logistic regression identified hepatic resection-independent risk factors for POD, including non-elective hospital admission, teaching hospital, older age, male sex, depression, fluid and electrolyte disorders, coagulopathy, other neurological disorders, psychoses, and weight loss. In addition, the POD after hepatic resection has been associated with sepsis, dementia, urinary retention, gastrointestinal complications, acute renal failure, pneumonia, continuous invasive mechanical ventilation, blood transfusion, respiratory failure, and wound dehiscence / non-healing. CONCLUSION: Although the occurrence of POD after hepatic resection is relatively low, it is beneficial to investigate factors predisposing to POD to allow optimal care management and improve the outcomes of this patient population.

ROS-Responsive Injectable Hydrogel Loaded with SLC7A11-modRNA Inhibits Ferroptosis and Mitigates Intervertebral Disc Degeneration in Rats.

Intervertebral disc degeneration (IVDD) is the primary cause of low back pain, with oxidative stress being a recognized factor that causes its development. Presently, low back pain imposes a significant global economic burden. However, the effectiveness of treatments for IVDD remains extremely limited. Therefore, this study aims to explore innovative and effective IVDD treatments by focusing on oxidative stress as a starting point. In this study, an injectable reactive oxygen species-responsive hydrogel (PVA-tsPBA@SLC7A11 modRNA) is developed, designed to achieve rapid loading and selective release of chemically synthesized modified mRNA (modRNA). SLC7A11 modRNA is specifically used to upregulate the expression of the ferroptosis marker SLC7A11. The local injection of PVA-tsPBA@SLC7A11 modRNA into the degenerated intervertebral disc (IVD) results in the cleavage of PVA-tsPBA, leading to the release of enclosed SLC7A11 modRNA. The extent of SLC7A11 modRNA release is directly proportional to the severity of IVDD, ultimately ameliorating IVDD by inhibiting ferroptosis in nucleus pulposus cells (NPCs). This study proposes an innovative system of PVA-tsPBA hydrogel-encapsulated modRNA, representing a potential novel treatment strategy for patients with early-stage IVDD.

A complex case study: coexistence of multi-drug-resistant pulmonary tuberculosis, HBV-related liver failure, and disseminated cryptococcal infection in an AIDS patient.

BACKGROUND: Hepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates. CASE PRESENTATION: The 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient's condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management. CONCLUSION: Enhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates.

Pangenome and multi-tissue gene atlas provide new insights into the domestication and highland adaptation of yaks.

BACKGROUND: The genetic diversity of yak, a key domestic animal on the Qinghai-Tibetan Plateau (QTP), is a vital resource for domestication and breeding efforts. This study presents the first yak pangenome obtained through the de novo assembly of 16 yak genomes. RESULTS: We discovered 290 Mb of nonreference sequences and 504 new genes. Our pangenome-wide presence and absence variation (PAV) analysis revealed 5,120 PAV-related genes, highlighting a wide range of variety-specific genes and genes with varying frequencies across yak populations. Principal component analysis (PCA) based on binary gene PAV data classified yaks into three new groups: wild, domestic, and Jinchuan. Moreover, we proposed a 'two-haplotype genomic hybridization model' for understanding the hybridization patterns among breeds by integrating gene frequency, heterozygosity, and gene PAV data. A gene PAV-GWAS identified a novel gene (BosGru3G009179) that may be associated with the multirib trait in Jinchuan yaks. Furthermore, an integrated transcriptome and pangenome analysis highlighted the significant differences in the expression of core genes and the mutational burden of differentially expressed genes between yaks from high and low altitudes. Transcriptome analysis across multiple species revealed that yaks have the most unique differentially expressed mRNAs and lncRNAs (between high- and low-altitude regions), especially in the heart and lungs, when comparing high- and low-altitude adaptations. CONCLUSIONS: The yak pangenome offers a comprehensive resource and new insights for functional genomic studies, supporting future biological research and breeding strategies.

The complete chloroplast genome sequence of Hydrocotyle vulgaris L. (Araliaceae).

Hydrocotyle vulgaris is a perennial wetland clonal plant in the Araliaceae family, which was introduced to China as an ornamental plant in the 1990s. Although H. vulgaris is now considered a potential invasiveness species in China, it also plays a significant role in the remediation of water pollution. Here, we reported its complete chloroplast genome and analyzed the basic characteristics. The chloroplast genome was 153,165 bp in length, including a pair of inverted repeat (IR) regions of 25,072 bp separated by a large single-copy (LSC) region of 84,291 bp and a small single-copy (SSC) region of 18,730 bp. The H. vulgaris chloroplast genome contained 132 predicted genes, and its overall GC content was 37.60%. Phylogenetic analysis revealed that H. vulgaris was closely related to H. verticillata. The H. vulgaris chloroplast genome presented in this study will lay a foundation for further genetic and genomic studies of the genus Hydrocotyle.

The complete chloroplast genome sequence of Calystegia hederacea Wall. in Roxb. 1824 (Convolvulaceae) in Enshi, Hubei.

Calystegia hederacea Wall. in Roxb. 1824 is a perennial herbaceous vine in the family Convolvulaceae and has several biological effects. Herein, we reported the first complete chloroplast genome of C. hederacea. The chloroplast genome sequence was 152,057 bp in length, comparing a large single-copy (LSC) region of 87,891 bp, a small single-copy (SSC) region of 19,866 bp, and a pair of inverted repeat (IR) regions of 22,150 bp. This sequenced chloroplast genome contained 126 predicted genes, including 81 protein-coding genes, 37 tRNA genes, and eight rRNA genes, and the total GC content of the chloroplast genome was 37.79%. Phylogenetic analysis revealed that C. hederacea was closely related to C. soldanella. The chloroplast genome presented in this study will enrich the genome information of the genus Calystegia and provide deeper insights into the evolution study of the family Convolvulaceae.

Development and Validation of a Prognostic Nomogram for HR+ HER- Breast Cancer.

Purpose: We aimed to develop a nomogram to predict prognosis of HR+ HER2- breast cancer patients and guide the application of postoperative adjuvant chemotherapy. Methods: We identified 310 eligible HR+ HER- breast cancer patients and randomly divided the database into a training group and a validation group. The endpoint was disease free survival (DFS). Concordance index (C-index), area under the curve (AUC) and calibration curves were used to evaluate predictive accuracy and discriminative ability of the nomogram. We also compared the predictive accuracy and discriminative ability of our nomogram with the eighth AJCC staging system using overall data. Results: According to the training group, platelet-to-lymphocyte ratio (PLR), tumor size, positive lymph nodes and Ki-67 index were used to construct the nomogram of DFS. The C-index of DFS was 0.708 (95% CI: 0.623-0.793) in the training group and 0.67 (95% CI: 0.544-0.796) in the validation group. The calibration curves revealed great consistencies in both groups. Conclusion: We have developed and validated a novel and practical nomogram that can provide individual prediction of DFS for patients with HR+ HER- breast cancer. This nomogram may help clinicians in risk consulting and guiding the application of postoperative adjuvant chemotherapy.

Clinical outcome and prognostic factors of T4N0M0 colon cancer after R0 resection: A retrospective study.

BACKGROUND: Paradoxically, patients with T4N0M0 (stage II, no lymph node metastasis) colon cancer have a worse prognosis than those with T2N1-2M0 (stage III). However, no previous report has addressed this issue. AIM: To screen prognostic risk factors for T4N0M0 colon cancer and construct a prognostic nomogram model for these patients. METHODS: Two hundred patients with T4N0M0 colon cancer were treated at Tianjin Medical University General Hospital between January 2017 and December 2021, of which 112 patients were assigned to the training cohort, and the remaining 88 patients were assigned to the validation cohort. Differences between the training and validation groups were analyzed. The training cohort was subjected to multivariate analysis to select prognostic risk factors for T4N0M0 colon cancer, followed by the construction of a nomogram model. RESULTS: The 3-year overall survival (OS) rates were 86.2% and 74.4% for the training and validation cohorts, respectively. Enterostomy (P = 0.000), T stage (P = 0.001), right hemicolon (P = 0.025), irregular review (P = 0.040), and carbohydrate antigen 199 (CA199) (P = 0.011) were independent risk factors of OS in patients with T4N0M0 colon cancer. A nomogram model with good concordance and accuracy was constructed. CONCLUSION: Enterostomy, T stage, right hemicolon, irregular review, and CA199 were independent risk factors for OS in patients with T4N0M0 colon cancer. The nomogram model exhibited good agreement and accuracy.

Astragaloside IV-PESV inhibits prostate cancer tumor growth by restoring gut microbiota and microbial metabolic homeostasis via the AGE-RAGE pathway.

BACKGROUND: Prostate cancer (PCa) is becoming the most common malignancy in men worldwide. We investigated the effect of astragaloside IV combined with PESV on the gut microbiota and metabolite of PCa mice and the process of treating PCa. METHODS: Nude mice were genetically modified to develop tumors characteristic of PCa. The treatment of PCa mice involved the administration of a combination of astragaloside IV and peptides derived from scorpion venom (PESV). Feces were collected for both 16 S rDNA and metabolic analysis. Fecal supernatant was extracted and used for fecal transplantation in PCa mice. Tumor development was observed in both PCa mice and nude mice. Tumor histopathology was examined, and the expression of inflammatory factors and the AGE-RAGE axis in PCa tissues were analyzed. RESULTS: PCa mice treated with Astragaloside IV in combination with PESV showed a significant reduction in tumor volume and weight, and stabilization of gut microbiota and metabolites. At the Genus level, significant differences were observed in Porphyromonas, Corynebacterium, Arthromitus and Blautia, and the differential metabolites were PA16_016_0, Astragaloside+, Vitamin A acid, Nardosinone, a-Nortestoster, D-Pantethine, Hypoxanthine, Pregnenolone, cinnamic acid, Pyridoxa, Cirtruline and Xanthurenate. There was a correlation between gut microbiota and metabolites. After the fecal transplantation, tumor growth was effectively suppressed in the PCa mice. Notably, both the mRNA and protein levels of the receptor for advanced glycation end products (RAGE) were significantly decreased. Furthermore, the expression of inflammatory factors, namely NF-κB, TNF-α, and IL-6, in the tumor tissues was significantly attenuated. Conversely, upregulation of RAGE led to increased inflammation and reversed tumor growth in the mice. CONCLUSION: Astragaloside IV combined with PESV could treat PCa by intervening in gut microbiota composition and metabolite by targeting RAGE.

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

First Report of Powdery Mildew on Cardamine violifolia in China.

Cardamine violifolia, also called Cardamine hupingshanensis, is an economically important medicinal plant renowned for accumulating selenium (Guo et al., 2022). Selenium is an essential trace element with anti-oxidant, anti-inflammatory, anti-cancer, and immune regulatory functions. In July 2023, an outbreak of powdery mildew was detected, infecting the leaves of numerous C. violifolia plants in Enshi (30°11'5.27''N; 109°48'48.45''E), Hubei Province, China. This disease caused severe damage to plant leaves and stems, starting as individual spots and merging into a large mold that covers the entire leaf. It affected nearly 25% all C. violifolia plants, resulting in significant yield loss, disruption of normal metabolism, and premature aging. The lower leaf blades and underside of the leaves were particularly vulnerable. The affected leaves were collected and subjected to morphological diagnostic analysis (Mori et al., 2000) (Fig. S1). The powdery mildew species aggressively spread throughout the leaves, pedicels, and pods, persisting until present and often covering the entire surface. The conidiophores were upright, cylindrical, composed of 3 to 4 cells, and measured 92.3 ± 12.9 × 9.2 ± 0.6 µm (n = 30). Conidial pedicels had 21.6 ± 3.4 µm (n = 50) long cylindrical podocytes. The monoconidia were columnar or barrel-columnar, 30.60-55.59 × 9.11-20.00 µm in size. Conidia lacked an obvious cellulose body. The bud tubes formed from the end of conidia, and papillary appressoria developed on the epiphytic mycelia. ITS region sequences were amplified using the specific powdery mildew universal primers ITS1 (5'-TCCGTAGGTGAACCTGCGG-3'), PM6 (5'-GYCRCYCTGTCGCGAG-3') for partial sequences of 18S and 28S ribosomal DNA genes (Takamatsu et al., 2001). The sequence was deposited in the GenBank under the accession number OR506156 and aligned with available sequences on NCBI, which were 99.2%(528/532) identical to the E. cruciferarum (MT309701, MF192845, and KY660929) sequences (Fig. S2). The ITS sequence from GenBank was used to conduct maximum likelihood phylogenetic analysis using MEGA 11.0. The analysis results showed both the strain and E. cruciferarum clustered on the same branch. To confirm Koch's postulates, pathogenicity testing was carried out using an illuminating incubator. Infected leaves were attached to healthy leaves of C. violifolia seedlings (n=8). All the plants were incubated under 25℃ and >80% relative humidity. After one month, all inoculated plants presented the same symptoms as those initially observed in the field. Morphological and molecular analysis confirmed the isolated fungi's identity as the same pathogen. Therefore, C. violifolia is a suitable host for E. cruciferarum in China. The growers must be informed of these findings to prevent serious economic losses caused by this pathogenic white powder and to prepare for proper management practices. To our knowledge, this is the first report of E. cruciferarum infecting C. violifolia in China.

Soy-Based High-Protein Spheric Foods with the Appearance of Familiar Sugary Snacks.

Excessive consumption of sugary foods increases the likelihood of obesity, as well as the preventable risk of lifestyle illnesses such as diabetes and cardiovascular diseases. Frequent intake of sweet snacks is considered to increase the risk of overweight/obesity in industrial nations. However, we cannot stop snacking against our better judgment. Therefore, in this study, we sought to develop high-protein, low-carb "mock snacks" to satisfy snack lovers' appetites and nutrition. Soy protein-based, ball-shaped food products with 57.7% (w/w) protein and 3.6% sugar have been developed. The addition of canola oil made them melty in the mouth without sacrificing their crispiness. Moreover, evaluation of the surface topography of the "soy balls" by 3D laser scanning demonstrated their high degree of sphericity. Conclusively, the snacks developed here may be one of the healthy alternatives for the current sugary ones.

A single dose for me, A wealth of protection for us: The public health cost of individualism in the rollout of COVID-19 vaccine.

OBJECTIVE: This study examines whether individualism weakens the effectiveness of the COVID-19 vaccine eligibility expansions in the United States in 2021, and assesses the associated social benefits or costs associated with individualism. METHODS: We construct a county-level composite individualism index as a proxy of culture and the fraction of vaccine eligible population as a proxy of vaccination campaign (mean: 41.34%). We estimate whether the COVID-19 vaccine eligibility policy is less effective in promoting vaccine coverage, reducing in COVID-19 related hospitalization and death using a linear two-way fixed effect model in a sample of 2866 counties for the period between early December 2020 and July 1, 2021. We also test whether individualism shapes people's attitudes towards vaccine using a linear probability model in a sample of 625,308 individuals aged 18-65 (mean age: 43.3; 49% male; 59.1% non-Hispanic white, 19.1% Hispanic, 12% African American; 5.9% Asian) from the Household Pulse Survey. RESULTS: The effects of expanded vaccine eligibility are diminished in counties with greater individualism, as evidenced by lower effectiveness in increasing vaccination rates and reducing outpatient doctor visits primarily for COVID-related symptoms and COVID deaths. Moreover, our results show that this cultural influence on attitudes towards vaccine is more pronounced among the less educated, but unrelated to race. CONCLUSION: Assuming an average level of vaccine eligibility policies and an average intensity of individualism across the nation, we calculate that the average social cost associated with an individualistic culture amid the pandemic is approximately $50.044 billion, equivalent to 1.32% of the total U.S. health care spending in 2019. Our paper suggests that strategies to promote public policy compliance should be tailored to accommodate cultural and social contexts.

Exploration of Molecular Nanoparticles as Soft Structural Materials and Their Structure-Property Relationship.

The search for alternative chemical systems other than polymers with chain topologies for soft structural materials raises general interests in fundamental materials and chemical sciences. It is also appealing from an engineering perspective for the urgent need to resolve the typical trade-offs of polymer systems. Herein, a subnanometer molecular cluster, polyhedral oligomeric silsesquioxanes, is assembled into molecular nanoparticles (MNPs) with star topology. Broadly tunable viscoelasticity can be realized by fine-tuning the MNPs' deformability. Being analogous to polymeric systems, the hierarchical structural relaxation dynamics can be observed, and their relaxation time and temperature dependence are dominated by the linker flexibilities. This not only provides microscopic understanding on MNP's unique viscoelasticity but also offers enormous opportunities for modulating their mechanical properties via linker engineering. Our work proves the possibility of applying structural units with particle topologies for the design of soft structural materials.

Biomechanics of the lower limb in patients with mild knee osteoarthritis during the sit-to-stand task.

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent and debilitating condition that markedly affects the sit-to-stand (STS) activity of patients, a prerequisite for daily activities. Biomechanical recognition of movements in patients with mild KOA is currently attracting attention. However, limited studies have been conducted solely on the observed differences in sagittal plane movement and muscle activation. AIM: This study aimed to identify three-dimensional biomechanical and muscle activation characteristics of the STS activity in patients with mild KOA. METHODS: A cross-sectional study was conducted to observe the differences between patients with mild KOA and a control group (CG). It was conducted to observe the differences in muscle activation, including root mean square (RMS%) and integrated electromyography (items), kinematic parameters like range of motion (ROM) and maximum angular velocity, as well as dynamic parameters such as joint moment and vertical ground reaction force (vGRF). RESULTS: Patients with mild KOA had a higher body mass index and longer task duration. In the sagittal plane, patients with KOA showed an increased ROM of the pelvic region, reduced ROM of the hip-knee-ankle joint, and diminished maximum angular velocity of the knee-ankle joint. Furthermore, patients with KOA displayed increased knee-ankle joint ROM in the coronal plane and decreased ankle joint ROM in the horizontal plane. Integrated vGRF was higher in both lower limbs, whereas the vGRF of the affected side was lower. Furthermore, patients showed a decreased peak adduction moment (PADM) and increased peak external rotation moment in the knee joint and smaller PADM and peak internal rotation moment in the ankle joint. The affected side exhibited decreased RMS% and iEMG values of the gluteus medius, vastus medialis, and vastus lateralis muscles, as well as a decreased RMS% of the rectus femoris muscle. Conversely, RMS% and iEMG values of the biceps femoris, lateral gastrocnemius, and medial gastrocnemius muscles were higher. CONCLUSION: The unbalanced activation characteristics of the anterior and posterior muscle groups, combined with changes in joint moment in the three-dimensional plane of the affected joint, may pose a potential risk of injury to the irritated articular cartilage.

The relationship of testicular stiffness with Johnsen score and sperm retrieval outcome in men with non-obstructive azoospermia.

Background: The pathological Johnsen score (JS) is a quantitative histological scoring system used to assess spermatogenesis in men with nonobstructive azoospermia (NOA), while elastic modulus derived from shear wave elastography (SWE) is a diagnostic tool for evaluating spermatogenic dysfunction. In this prospective observational study, we aimed to investigate whether testicular stiffness measured by SWE could serve as a substitute for JS in predicting sperm retrieval outcomes in men with NOA. Methods: This prospective cohort study analyzed 140 testes from 115 consecutive outpatient participants with NOA who had sought treatment at the reproductive medical center of a tertiary care hospital between January 2018 and October 2021. Testicular volume, elastic modulus, JS, and sperm retrieval outcomes were calculated. Statistical differences in parameters between the positive and negative sperm retrieval groups were determined using the Mann-Whitney test. Spearman rank correlation analysis was performed to determine the correlations between JS and either testicular volumes or elastic modulus. Receiver operating characteristic (ROC) curves were drawn to evaluate the diagnostic performance of the testicular elastic modulus and testicular volume. Results: The JS correlated positively with testicular volume and negatively with the maximum elastic modulus (Emax) and mean elastic modulus (Emean), with correlation coefficients of 0.804, -0.686, and -0.456, respectively (P<0.01). There were significant differences in JS, testicular volume, and Emax between participants with positive and negative sperm retrieval of microdissection testicular sperm extraction (micro-TESE) (P<0.01). ROC curves were plotted for JS, testicular volume, and Emax to distinguish between participants with positive and negative sperm retrieval. The areas under the ROC curves (AUCs) were 0.783 [95% confidence interval (CI): 0.707-0.859; P<0.01], 0.737 (95% CI: 0.651-0.823; P<0.01), and 0.729 (95% CI: 0.643-0.814; P<0.01), respectively. When the cutoff value of JS was 4.5, its sensitivity and specificity were 60.3% and 89.6%, respectively. When the cutoff value of Emax was 3.75 kPa, its sensitivity and specificity were 79.1% and 64.4%, respectively. The sensitivity and specificity were 68.5% and 83.6%, respectively when the cutoff value of testicular volume was 8.17 mL. Emax combined with testicular volume improved this diagnostic value, with an AUC of 0.742 (95% CI: 0.657-0.828; P<0.01), and sensitivity and specificity were 83.6% and 68.5%, respectively. Conclusions: Our study suggests that the combination of testicular stiffness and volume measurements may serve as a viable alternative to pathological JS in predicting the likelihood of successful sperm retrieval prior to micro-TESE procedures.