First Report of Xanthomonas perforans Causing Bacterial Spot of Pepper (Capsicum annuum) in North Carolina.

North Carolina (NC) is the fifth largest producer of bell pepper (Capsicum annuum) in the US with an estimated 2,400 acres in production (NASS-USDA, 2022). A survey of bacterial diseases of peppers was initiated in 2020 after numerous bacterial spot outbreaks were reported in NC. Bacterial spot is caused by a complex of four Xanthomonads: X. euvesicatoria, X. vesicatoria, X. perforans, and X. hortorum pv. gardneri (Larrahondo-Rodríguez et al., 2022). If not preemptively managed, bacterial spot can cause up to 40% yield loss (Kousik and Ritchie, 1998). During the 2020 and 2021 growing seasons, 103 yellow mucoid colonies were isolated from plants representing 51 pepper cultivars symptomatic of bacterial spot, i.e., water-soaked leaf lesions that become necrotic spots on leaves and fruits across 22 commercial fields in NC following published methods (Klein-Gordon et al., 2021). All colonies were characterized to species using the qPCR species-specific primers and probes described by Strayer et al. 2016. Of the 103 colonies, 12 isolates tested positive for X. perforans. To confirm qPCR results, a Multi-Locus Sequence Analysis (MLSA) was run using fusA, gapA, gltA, gyrB, and lacF following previously described methods (Almeida et al., 2010) on three representative isolates: AHX61, collected in September 2020 from a field with 20% disease severity in Wake County on cv. Canary Bell; AHX261, collected in July 2021 from a field with 50% disease severity in Sampson County on Jalapeño; and AHX426, collected in August 2021 from a field with 50% disease severity in Dublin County on Jalapeño. All gene sequences were deposited to NCBI (GenBank Accessions: OQ799538-OQ799552) and compared to those from X. euvesicatoria, X. hortorum pv. gardneri, X. perforans, and X. vesicatoria type strains (Almeida et al., 2010). The MLSA showed AHX61, AHX261, and AHX426 cluster with X. perforans ICMP16690T, sharing 99-100% nucleotide similarity. Koch's postulates were performed with the three strains, Xp1484T [ X. perforans type strain, (Wilson 1987)], and water as a negative control. Three 10-week-old bell pepper plants (cv. Early Cal Wonder) were dip-inoculated in 600 mL of a bacterial suspension at an OD600 of 0.3 (~5x108 CFU/mL) and 0.04% Silwet L-77 per strain or water. All 18 plants were individually incubated in a plastic bag for 48 h post-inoculation at 28°C, 80% relative humidity, and 14 h:10 h light-dark cycle in a growth chamber, after which plastic bags were removed. Water-soaking and necrotic spots characteristic of bacterial spot were first observed at six days post-inoculation (dpi). At 14 dpi, symptomatic leaves were removed from treated plants to attempt pathogen re-isolation. Yellow mucoid colonies similar in morphology to those originally inoculated were recovered from all plants and confirmed to be X. perforans through sequencing; no isolates were recovered from water-treated plants. To our knowledge, this is the first time X. perforans is isolated in commercial bell pepper and specialty pepper fields in the state. This is an indication that the Xanthomonas population on peppers in the state is more diverse than previously reported and that pathogen populations will require monitoring for possible species shifts for this crop in NC.

Development of a time-resolved immunochromatographic test strip for rapid and quantitative determination of retinol-binding protein 4 in urine.

Urine retinol-binding protein 4 (RBP4) has recently been reported as a novel earlier biomarker of chronic kidney disease (CKD) which is a global public health problem with high morbidity and mortality. Accurate and rapid detection of urine RBP4 is essential for early monitor of impaired kidney function and prevention of CKD progression. In the present study, we developed a time-resolved fluorescence immunochromatographic test strip (TRFIS) for the quantitative and rapid detection of urine RBP4. This TRFIS possessed excellent linearity ranging from 0.024 to 12.50 ng/mL for the detection of urine RBP4, and displayed a good linearity (Y = 239,581 × X + 617,238, R2 = 0.9902), with the lowest visual detection limit of 0.049 ng/mL. This TRFIS allows for quantitative detection of urine RBP4 within 15 min and shows high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 8%, respectively. Additionally, this TRFIS was applied to detect RBP4 in the urine samples from healthy donors and patients with CKD, and the results of TRFIS could efficiently discern the patients with CKD from the healthy donors. The developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range, and is suitable for rapid and quantitative determination of urine RBP4.

Interrelationships among abnormal P-wave axis, metabolic syndrome and its components, and mortality in US adults.

BACKGROUND: Metabolic syndrome (MetS) is associated with increased rates of cardiovascular disease and mortality and is linked to abnormal electrocardiogram (ECG) parameters. We aimed to explore the relationships and interactions among MetS and its components, abnormal P-wave axis (aPWA), and mortality rates. METHODS: We analyzed data from 7526 adult participants with sinus rhythm recruited from the National Health and Nutrition Examination Survey III. MetS was classified based on the NCEP ATP III-2005 definition. aPWA included all P-wave axis outside 0-75°. The National Death Index was utilized to identify survival status. Hazard ratios (HRs) and 95% confidence intervals (CIs) categorized by aPWA, MetS, and their components were analyzed using Cox proportional hazards models to investigate all-cause and cardiovascular mortalities. RESULTS: Within a median follow-up period of 20.76 years, 4686 deaths were recorded, of which 1414 were attributable to cardiovascular disease. Participants with both MetS and aPWA had higher all-cause (HR: 1.45, 95% CI: 1.29-1.64, interaction P = 0.043) and cardiovascular (HR: 1.36, 95% CI: 1.02-1.79, interaction P-value = 0.058) mortality rates than participants without MetS and with a normal P-wave axis. Participants with the greatest number of MetS components and aPWA had a higher risk of all-cause mortality (HR: 1.70, 95% CI: 1.13-2.55, P = 0.011). CONCLUSIONS: Individuals with both aPWA and MetS have a higher risk of mortality, and those with a greater number of MetS components and aPWA have a higher risk of all-cause mortality. These findings highlight the significance of integrating ECG characteristics with metabolic health status in clinical assessment.

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.

Epidemiological trends in serotypes distribution and antimicrobial resistance in Salmonella from humans in Taiwan, 2004-2022.

Objectives: Salmonella, a zoonotic pathogen, significantly impacts global human health. Understanding its serotype distribution and antimicrobial resistance is crucial for effective control measures and medical interventions. Methods: We collected Salmonella isolates and demographic data from Taiwanese hospitals between 2004 and 2022, analyzing their serotypes and antimicrobial susceptibility. Results: Among 40,595 isolates, salmonellosis predominated in children aged 0-4 (61.2%) years and among males (55.2%). Males also showed higher rates of extraintestinal infections (18.1% vs 16.0%, P <0.001), particularly, in the ≥65 years age group (52.4%). The top five serovars were S. Enteritidis (32.8%), S. Typhimurium (21.7%), S. Newport (6.2%), S. Stanley (4.7%), and S. Anatum (4.0%). Notably, S. Enteritidis prevalence increased from 23.9% (2004-2005) to 43.6% (2021-2022). Antimicrobial resistance was high, with a 51.6% multidrug resistance (MDR) rate. Disturbingly, MDR rates exceeded 90% in serovars Albany, Schwarzengrund, Choleraesuis, and Goldcoast. Resistance to key therapeutic agents, azithromycin, cefotaxime, and ciprofloxacin, exhibited concerning upward trends, and the surge in cefotaxime and ciprofloxacin resistance was closely linked to the emergence and spread of MDR S. Anatum and S. Goldcoast clones. Conclusions: Prioritizing control measures against S. Enteritidis and closely monitoring the prevalence and spread of MDR clones are imperative to mitigate Salmonella infections in Taiwan.

Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps".

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".

Effects of motor and cognitive complex training on obstacle walking and brain activity in people with Parkinson's disease: a randomized controlled trial.

BACKGROUND: The difficulties in obstacle walking are significant in people with Parkinson's disease (PD) leading to an increased fall risk. Effective interventions to improve obstacle walking with possible training-related neuroplasticity changes are needed. We developed two different exercise programs, complex walking training and motor-cognitive training, both challenging motor and cognitive function for people with PD to improve obstacle walking. AIM: To investigate the effects of these two novel training programs on obstacle walking and brain activities in PD. DESIGN: A single-center randomized, single-blind controlled study. SETTING: University laboratory; outpatient. POPULATION: Individuals with idiopathic PD. METHODS: Thirty-two participants were randomly assigned to the complex walking training group (N.=11), motor-cognitive training group (N.=11) or control group (N.=10). Participants in training groups received exercises for 40 minutes/session, with a total of 12-session over 6 weeks. Control group did not receive additional training. Primary outcomes included obstacle walking, and brain activities (prefrontal cortex (PFC), premotor cortex (PMC), and supplementary motor area (SMA)) during obstacle walking by using functional near-infrared spectroscopy. Secondary outcomes included obstacle crossing, timed up and go test (TUG), cognitive function in different domains, and fall efficacy scale (FES-I). RESULTS: The motor-cognitive training group demonstrated greater improvements in obstacle walking speed and stride length, SMA activity, obstacle crossing velocity and stride length, digit span test, and TUG than the control group. The complex walking training did not show significant improvement in obstacle walking or change in brain activation compared with control group. However, the complex walking training resulted in greater improvements in Rey-Osterrieth Complex Figure test, TUG and FES-I compared with the control group. CONCLUSIONS: Our 12-session of the cognitive-motor training improved obstacle walking performance with increased SMA activities in people with PD. However, the complex walking training did not lead such beneficial effects as the cognitive-motor training. CLINICAL REHABILITATION IMPACT: The cognitive-motor training is suggested as an effective rehabilitation program to improve obstacle walking ability in individuals with PD.

Toxic effect and mechanism of ß-cypermethrin and its chiral isomers on HTR-8/SVneo cells.

Beta-cypermethrin (ß-CYP) consists of four chiral isomers, acting as an environmental estrogen and causing reproductive toxicity, neurotoxicity, and dysfunctions in multiple organ systems. This study investigated the toxic effects of ß-CYP, its isomers, metabolite 3-phenoxybenzoic acid (3-PBA), and 17ß-estradiol (E2) on HTR-8/SVneo cells. We focused on the toxic mechanisms of ß-CYP and its specific isomers. Our results showed that ß-CYP and its isomers inhibit HTR-8/SVneo cell proliferation similarly to E2, with 100 µM 1S-trans-αR displaying significant toxicity after 48 h. Notably, 1S-trans-αR, 1R-trans-αS, and ß-CYP were more potent in inducing apoptosis and cell cycle arrest than 1R-cis-αS and 1S-cis-αR at 48 h. AO/EB staining and flow cytometry indicated dose-dependent apoptosis in HTR-8/SVneo cells, particularly at 100 µM 1R-trans-αS. Scratch assays revealed that ß-CYP and its isomers variably reduced cell migration. Receptor inhibition assays demonstrated that post-ICI 182780 treatment, which inhibits estrogen receptor α (ERα) or estrogen receptor ß (ERß), ß-CYP, its isomers, and E2 reduced HTR-8/SVneo cell viability, whereas milrinone, a phosphodiesterase 3 A (PDE3A) inhibitor, increased viability. Molecular docking studies indicated a higher affinity of ß-CYP, its isomers, and E2 for PDE3A than for ERα or ERß. Consequently, ß-CYP, its isomers, and E2 consistently led to decreased cell viability. Transcriptomics and RT-qPCR analyses showed differential expression in treated cells: up-regulation of Il24 and Ptgs2, and down-regulation of Myo7a and Pdgfrb, suggesting the PI3K-AKT signaling pathway as a potential route for toxicity. This study aims to provide a comprehensive evaluation of the cytotoxicity of chiral pesticides and their mechanisms.

Polymeric micellar nanoparticles for effective CRISPR/Cas9 genome editing in cancer.

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) gene editing has attracted extensive attentions in various fields, however, its clinical application is hindered by the lack of effective and safe delivery system. Herein, we reported a cationic micelle nanoparticle composed of cholesterol-modified branched small molecular PEI (PEI-CHO) and biodegradable PEG-b-polycarbonate block copolymer (PEG-PC), denoted as PEG-PC/PEI-CHO/pCas9, for the CRISPR/Cas9 delivery to realize genomic editing in cancer. Specifically, PEI-CHO condensed pCas9 into nanocomplexes, which were further encapsulated into PEG-PC nanoparticles (PEG-PC/PEI-CHO/pCas9). PEG-PC/PEI-CHO/pCas9 had a PEG shell, protecting DNA from degradation by nucleases. Enhanced cellular uptake of PEG-PC/PEI-CHO/pCas9 nanoparticles was observed as compared to that mediated by Lipo2k/pCas9 nanoparticles, thus leading to significantly elevated transfection efficiency after escaping from endosomes via the proton sponge effect of PEI. In addition, the presence of PEG shell greatly improved biocompatibility, and significantly enhanced the in vivo tumor retention of pCas9 compared to PEI-CHO/pCas9. Notably, apparent downregulation of GFP expression could be achieved both in vitro and in vivo by using PEG-PC/PEI-CHO/pCas9-sgGFP nanoparticles. Furthermore, PEG-PC/PEI-CHO/pCas9-sgMcl1 induced effective apoptosis and tumor suppression in a HeLa tumor xenograft mouse model by downregulating Mcl1 expression. This work may provide an alternative paradigm for the efficient and safe genome editing in cancer.

The Ca2+-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity.

Tumor necrosis factor receptor-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca2+) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca2+ signaling in the regulation of IFN-I, the relationship between Ca2+ and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca2+ levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca2+ increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca²+ was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca2+ in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca2+-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in TBK1 knockout cells. Together, our data demonstrate that NDV hijacks Ca2+ signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca2+ signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca2+ homeostasis in the viral innate immune response.IMPORTANCEViral infections disrupt intracellular Ca2+ homeostasis, which affects the regulation of various host processes to create conditions that are conducive for their own proliferation, including the host immune response. The mechanism by which viruses trigger TBK1 activation and IFN-I induction through viral pathogen-associated molecular patterns has been well defined. However, the effects of virus-mediated Ca2+ imbalance on the IFN-I pathway requires further elucidation, especially with respect to TBK1 activation. Herein, we report that NDV infection causes an increase in intracellular free Ca2+ that leads to activation of the serine/threonine phosphatase CaN, which subsequently dephosphorylates TBK1 and negatively regulates IFN-I production. Furthermore, depletion of Ca2+ or inhibition of CaN activity exerts antiviral effects by promoting the production of IFN-I and inhibiting viral replication. Thus, our results reveal the potential role of Ca2+ in the innate immune response to viruses and provide a theoretical reference for the treatment of viral infectious diseases.

Influence of vaccination on critical COVID-19 patients with acute respiratory failure: a retrospective cohort study.

BACKGROUND: Despite vaccines' effectiveness in reducing COVID-19 infection rates and disease severity, their impact on critical patients presenting with acute respiratory failure is elusive. The aim of this study was to further investigate the influence of vaccination on mortality rates among severely ill COVID-19 patients experiencing acute respiratory failure. METHODS: This retrospective cohort study was carried out at a tertiary medical center in Taiwan. From April to September 2022, patients who tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through reverse transcription polymerase chain reaction (RT-PCR) and subsequently experienced acute respiratory failure were included in the study. Baseline characteristics, including vaccination history, along with information regarding critical illness and clinical outcomes, were gathered and compared between patients who received the vaccine and those who did not. RESULTS: A total of 215 patients with COVID-19 exhibiting acute respiratory failure, as confirmed via RT‒PCR, were included in the analysis. Of this cohort, sixty-six (30.7%) patients died within 28 days. Neither administration of the vaccine nor achievement of primary series vaccination status had a significantly different effect on 28 day mortality, number of viral shedding events, acute respiratory distress syndrome (ARDS) incidence or other clinical outcomes. Patients who received the booster vaccine and completed the primary series showed a tendency of increased 28 days of ventilator-free status, though this difference was not statistically significant (p = 0.815). CONCLUSIONS: Vaccination status did not significantly influence mortality rates, the occurrence of ARDS, or the viral shedding duration in COVID-19 patients with acute respiratory failure.

Age and mean platelet volume-based nomogram for predicting the therapeutic efficacy of metoprolol in Chinese pediatric patients with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the most common type of orthostatic intolerance in children. We investigated whether platelet-related factors related to treatment efficacy in children suffering from VVS treated with metoprolol. METHODS: Metoprolol-treated VVS patients were recruited. The median duration of therapy was three months. Patients were followed and divided into two groups, treament-effective group and treatment-ineffective group. Logistic and least absolute shrinkage selection operator regressions were used to examine treatment outcome variables. Receiver-operating characteristic (ROC) curves, precision-recall (PR) curves, calibration plots, and decision curve analyses were used to evaluate the nomogram model. RESULTS: Among the 72 patients who complete the follow-up, treatment-effective group and treatment-ineffective group included 42 (58.3%) and 30 (41.7%) cases, respectively. The patients in the treatment-effective group exhibited higher mean platelet volume (MPV) [(11.0 ± 1.0) fl vs. (9.8 ± 1.0) fl, P < 0.01] and platelet distribution width [12.7% (12.3%, 14.3%) vs. 11.3% (10.2%, 12.2%), P < 0.01] than those in the treatment-ineffective group. The sex ratio was significantly different (P = 0.046). A fit model comprising age [odds ratio (OR) = 0.766, 95% confidence interval (CI) = 0.594-0.987] and MPV (OR = 5.613, 95% CI = 2.297-13.711) might predict therapeutic efficacy. The area under the curve of the ROC and PR curves was computed to be 0.85 and 0.9, respectively. The P value of the Hosmer-Lemeshow test was 0.27. The decision curve analysis confirmed that managing children with VVS based on the predictive model led to a net advantage ranging from 0.01 to 0.58. The nomogram is convenient for clinical applications. CONCLUSION: A novel nomogram based on age and MPV can predict the therapeutic benefits of metoprolol in children with VVS.

[Effect of Erchen Decoction on liver mitochondrial function by inhibiting mTORC1/SREBP1/CAV1 pathway in mice with high-fat diet].

This study aims to investigate the effect of Erchen Decoction(ECD) on liver mitochondrial function in mice with a high-fat diet and its possible mechanism. A total of sixty C57BL/6J mice were randomly divided into a normal group, high-fat group, ECD group, mTORC1 activator(MHY) group, ECD+MHY group, and polyene phosphatidyl choline(PPC) group, with 10 rats in each group. The normal group was given a normal diet, and the other groups were fed a high-fat diet for 20 weeks. At the 17th week, the ECD group and ECD+MHY group were given ECD(8.7 g·kg~(-1)) daily, and the PPC group was given PPC(0.18 g·kg~(-1)) daily, while the remaining groups were given normal saline(0.01 mL·g~(-1)) daily for four weeks. In the 19th week, the MHY group and ECD+MHY group were injected intraperitoneally with MHY(5 mg·kg~(-1)) every other day for two weeks. During the experiment, the general conditions of the mice were observed. The contents of triglyceride(TG) and total cholesterol(TC) in serum were measured. Morphological changes in liver tissue were examined through HE and oil red O staining. The content of adenosine triphosphate(ATP) was determined using chemiluminescence, and mitochondrial membrane potential was assessed using a fluorescence probe(JC-1). Western blot was performed to detect the expression of rapamycin target protein complex 1(mTOR1), ribosomal protein S6 kinase B1(S6K), sterol regulatory element binding protein 1(SREBP1), and caveolin 1(CAV1). RESULTS:: revealed that compared with the normal group, the mice in the high-fat group exhibited significant increases in body weight and abdominal circumference(P<0.01). Additionally, there were significant increases in TG and TC levels(P<0.01). HE and oil red O staining showed that the boundaries of hepatic lobules were unclear; hepatocytes were enlarged, round, and irregularly arranged, with obvious lipid droplet deposition and inflammatory cell infiltration. The liver ATP content and mitochondrial membrane potential decreased significantly(P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 increased significantly(P<0.01), while the expression of CAV1 decreased significantly(P<0.01). Compared with the high-fat group, the body weight and TG content of mice in the ECD group and PPC group decreased significantly(P<0.05). Improvements were observed in hepatocyte morphology, lipid deposition, and inflammatory cell infiltration. Furthermore, there were significant increases in ATP content and mitochondrial membrane potential(P<0.05 or P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly in the ECD group(P<0.01), while CAV1 expression increased significantly(P<0.01). However, the indices mentioned above did not show improvement in the MHY group. When the ECD+MHY group was compared with the MHY group, there were significant reductions in body weight and TG contents(P<0.05). The morphological changes of hepatocytes, lipid deposition, and inflammatory cell infiltration were recovered. Moreover, there were significant increases in liver ATP content and mitochondrial membrane potential(P<0.05 or P<0.05). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly(P<0.01), while CAV1 expression increased significantly(P<0.01). In conclusion, ECD can improve mitochondrial function by regulating the mTORC1/SREBP1/CAV1 pathway. This mechanism may be involved in the resolution of phlegm syndrome and the regulation of lipid metabolism.

Theabrownin as a Potential Prebiotic Compound Regulates Lipid Metabolism via the Gut Microbiota, Microbiota-Derived Metabolites, and Hepatic FoxO/PPAR Signaling Pathways.

The dysregulation of lipid metabolism poses a significant health threat, necessitating immediate dietary intervention. Our previous research unveiled the prebiotic-like properties of theabrownin. This study aimed to further investigate the theabrownin-gut microbiota interactions and their downstream effects on lipid metabolism using integrated physiological, genomic, metabolomic, and transcriptomic approaches. The results demonstrated that theabrownin significantly ameliorated dyslipidemia, hepatic steatosis, and systemic inflammation induced by a high-fat/high-cholesterol diet (HFD). Moreover, theabrownin significantly improved HFD-induced gut microbiota dysbiosis and induced significant alterations in microbiota-derived metabolites. Additionally, the detailed interplay between theabrownin and gut microbiota was revealed. Analysis of hepatic transcriptome indicated that FoxO and PPAR signaling pathways played pivotal roles in response to theabrownin-gut microbiota interactions, primarily through upregulating hepatic Foxo1, Prkaa1, Pck1, Cdkn1a, Bcl6, Klf2, Ppara, and Pparg, while downregulating Ccnb1, Ccnb2, Fabp3, and Plin1. These findings underscored the critical role of gut-liver axis in theabrownin-mediated improvements in lipid metabolism disorders and supported the potential of theabrownin as an effective prebiotic compound for targeted regulation of metabolic diseases.

Interactive boxing-cycling on frailty and activity limitations in frail and prefrail older adults: A randomized controlled trial.

BACKGROUND: Frailty is common among older adults, often associated with activity limitations during physical and walking tasks. The interactive boxing-cycling combination has the potential to be an innovative and efficient training method, and our hypothesis was that interactive boxing-cycling would be superior to stationary cycling in improving frailty and activity limitations in frail and prefrail older adults. OBJECTIVE: To examine the impact of interactive boxing-cycling on frailty and activity limitations in frail and prefrail older adults compared to stationary cycling. MATERIALS AND METHODS: A single-blinded randomized controlled trial. Forty-five participants who met at least one frailty phenotype criteria were randomly assigned to receive either interactive boxing-cycling (n = 23) or stationary-cycling (n = 22) for 36 sessions over 12 weeks. The interactive boxing-cycling was performed on a cycle boxer bike with an interactive boxing panel fixed in front of the bike. The primary outcomes were frailty status, including score and phenotypes. Secondary outcomes included activity limitations during physical and walking tasks. The pre- and post-intervention data of both groups were analyzed using a repeated measures two-way ANOVA. RESULTS: Both types of cycling significantly improved frailty scores (p<0.001). Interactive boxing-cycling was more effective than stationary cycling in reversing the frailty phenotype of muscle weakness (p = 0.03, odds ratio 9.19) and demonstrated greater improvements than stationary cycling in arm curl (p = 0.002, η2=0.20), functional reach (p = 0.001, η2=0.22), and grip strength (p = 0.02, η2=0.12) tests. Additionally, interactive boxing-cycling exhibited a greater effect on gait speed (p = 0.02, η2=0.13) and gait variability (p = 0.01, η2=0.14) during dual-task walking. CONCLUSION: In frail and prefrail older adults, interactive boxing-cycling effectively improves frailty but is not superior to stationary cycling. However, it is more effective at improving certain activity limitations. REGISTRATION NUMBER: TCTR20220328001.

Assessment of Precision and Accuracy of Brain White Matter Microstructure using Combined Diffusion MRI and Relaxometry.

Joint modeling of diffusion and relaxation has seen growing interest due to its potential to provide complementary information about tissue microstructure. For brain white matter, we designed an optimal diffusion-relaxometry MRI protocol that samples multiple b-values, B-tensor shapes, and echo times (TE). This variable-TE protocol (27 min) has as subsets a fixed-TE protocol (15 min) and a 2-shell dMRI protocol (7 min), both characterizing diffusion only. We assessed the sensitivity, specificity and reproducibility of these protocols with synthetic experiments and in six healthy volunteers. Compared with the fixed-TE protocol, the variable-TE protocol enables estimation of free water fractions while also capturing compartmental T2 relaxation times. Jointly measuring diffusion and relaxation offers increased sensitivity and specificity to microstructure parameters in brain white matter with voxelwise coefficients of variation below 10%.

Association between the American Heart Association's new "Life's Essential 8" metrics and kidney stone.

PURPOSE: The incidence of kidney stone disease has increased worldwide, resulting in high medical costs and social burden. Kidney stone disease shares some common features with the risk factors of cardiovascular diseases (CVDs). We investigated the association between cardiovascular health (CVH) based on the Life's Essential 8 (LE8) score developed by the American Heart Association and the incidence of kidney stone disease. METHODS: We analyzed the data of 29,469 US adults aged 20 years or above from the National Health and Nutrition Examination Survey, 2007-2018. According to the LE8 score, CVH was divided into three categories: poor, intermediate, and ideal. Logistic regression was used to determine the association between CVH and the incidence of kidney stone disease by estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The average age of the participants was 48.6 years, and 50% of the participants were women. The numbers of participants with poor, intermediate, and ideal CVH were 4149, 19,782, and 5538, respectively. After adjusting for related confounding factors, ideal CVH was associated with a reduction in the odds of kidney stone occurrence as compared to poor CVH (adjusted OR [aOR]: 0.45, 95% CI: 0.35-0.57, p < 0.001). Moreover, if the ideal CVH metrics was ≥ 6, the odds of kidney stone occurrence decreased by up to 61% (aOR: 0.39, 95% CI: 0.30-0.51). CONCLUSIONS: In the present study, ideal CVH, a factor indicative of a healthy lifestyle, was associated with lower odds of kidney stone occurrence.

[Application of anterior region suture of popliteal hiatus in treatment of discoid lateral meniscus injury with instability in popliteal tendon region].

Objective: To discuss the application of anterior region suture of the popliteal hiatus (PH) under arthroscopy in the treatment of discoid lateral meniscus (DLM) injury with instability in the popliteal tendon region. Methods: The clinical data of 53 patients (56 knees) with DLM injury who met the selection criteria between March 2014 and November 2022 were retrospectively analyzed. There were 15 males and 38 females, aged 8-55 years with an average age of 36.5 years. Fourteen cases had a history of trauma, while the remaining 39 cases had no clear history of trauma. The disease duration ranged from 1 day to 6 years, with an average duration of 15.6 months. According to the Watanabe classification, there were 40 knees of complete type and 16 knees of incomplete type. The preoperative International Knee Documentation Committee (IKDC) knee joint score was 51.2±8.3, the Lysholm score was 59.6±11.2, and the visual analogue scale (VAS) score was 4.7±1.3. After the arthroscopic meniscal plasty, the instability of the popliteal tendon region meniscus was checked by probing traction. Subsequently, the Out-inside technique or a combination of Out-inside and All-inside techniques was used to suture the anterior region of the PH. The stability of the meniscus after suturing was assessed, and if necessary, further suturing using the All-inside technique at the posterior region of the PH, the posterior horn of the meniscus, and using the Out-inside technique at the anterior horn of the meniscus was performed. Postoperative complications were recorded. The effectiveness was evaluated using pre- and post-operative IKDC scores, Lysholm scores, and VAS scores. Results: After operation, knee joint pain, crepitus, and locking disappeared, with McMurray and grinding tests turning negative. All patients were followed up 12-93 months with an average of 57.5 months. There was no complication such as common peroneal nerve injury, deep vein thrombosis of the lower limbs, joint infection, or joint stiffness. At last follow-up, the IKDC knee joint score was 76.7±5.5, the Lysholm score was 94.0±4.1, and the VAS score was 1.1±0.8. The differences compared with preoperative scores were significant ( t=-22.090, P<0.001; t=-23.704, P<0.001; t=19.767, P<0.001). Conclusion: Suturing of the anterior region of the PH is crucial in the treatment of DLM injury with instability in the popliteal tendon region.

Highly catalytic Prussian blue analogues and their application on the three-dimensional origami paper-based sweat sensors.

Prussian blue analogues (PBAs) are promising materials due to their rich active sites and straightforward synthesis. However, their limited conductivity and electron transfer inefficiency hinder practical applications. This study utilizes a simple one-pot synthesis approach to produce a tungsten-disulfide (WS2) and iron-cobalt Prussian blue analogue composite (WS2-PBA), enhancing conductivity and electron transfer rate performance. Through the inclusion of sodium citrate into the solution, the S-edge site concentration of WS2 increases. This augmentation introduces additional active sites and defects into the catalyst, enhancing its catalytic activity. The effectiveness of the WS2-PBA 3D-Origami paper device for lactate detection in sweat is also evaluated for biomedical applications. The device demonstrated a robust relationship between the lactate concentration and current intensity (R2 = 0.997), with a detection limit of 1.83 mM. Additionally, this platform has successfully detected lactate in clinical sweat, correlating with the high-performance liquid chromatography test results, suggesting promising prospects for clinical diagnosis. In the future, the excellent catalytic and Rct performance of the WS2-PBA will enable its use in biomedical applications.