Deep Learning-Based Approach for Identifying and Measuring Focal Liver Lesions on Contrast-Enhanced MRI.

BACKGROUND: The number of focal liver lesions (FLLs) detected by imaging has increased worldwide, highlighting the need to develop a robust, objective system for automatically detecting FLLs. PURPOSE: To assess the performance of the deep learning-based artificial intelligence (AI) software in identifying and measuring lesions on contrast-enhanced magnetic resonance imaging (MRI) images in patients with FLLs. STUDY TYPE: Retrospective. SUBJECTS: 395 patients with 1149 FLLs. FIELD STRENGTH/SEQUENCE: The 1.5 T and 3 T scanners, including T1-, T2-, diffusion-weighted imaging, in/out-phase imaging, and dynamic contrast-enhanced imaging. ASSESSMENT: The diagnostic performance of AI, radiologist, and their combination was compared. Using 20 mm as the cut-off value, the lesions were divided into two groups, and then divided into four subgroups: <10, 10-20, 20-40, and ≥40 mm, to evaluate the sensitivity of radiologists and AI in the detection of lesions of different sizes. We compared the pathologic sizes of 122 surgically resected lesions with measurements obtained using AI and those made by radiologists. STATISTICAL TESTS: McNemar test, Bland-Altman analyses, Friedman test, Pearson's chi-squared test, Fisher's exact test, Dice coefficient, and intraclass correlation coefficients. A P-value <0.05 was considered statistically significant. RESULTS: The average Dice coefficient of AI in segmentation of liver lesions was 0.62. The combination of AI and radiologist outperformed the radiologist alone, with a significantly higher detection rate (0.894 vs. 0.825) and sensitivity (0.883 vs. 0.806). The AI showed significantly sensitivity than radiologists in detecting all lesions <20 mm (0.848 vs. 0.788). Both AI and radiologists achieved excellent detection performance for lesions ≥20 mm (0.867 vs. 0.881, P = 0.671). A remarkable agreement existed in the average tumor sizes among the three measurements (P = 0.174). DATA CONCLUSION: AI software based on deep learning exhibited practical value in automatically identifying and measuring liver lesions. TECHNICAL EFFICACY: Stage 2.

PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide-isomerase A3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein (CRP) level and disease activity score 28 (DAS28). Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor (TCR) signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing Th1 and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. METHODS: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult-to-treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). RESULTS: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (-13.0 vs. -8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (-13.0 vs. -9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication-overuse headache (MOH) (-13.3 vs. -9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (-42.2 vs. -11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. CONCLUSIONS: In this multicenter, real-world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

Value of magnetic resonance imaging for diagnosis of LR­3 and LR-4 lesions coexisting with hepatocellular carcinoma.

PURPOSE: To explore which preoperative clinical data and conventional magnetic resonance imaging (MRI) features may indicate the presence of hepatocellular carcinoma (HCC) in HCC patients coexisting with LR-3 and LR-4 lesions. METHODS: HCC Patients coexisting with LR-3 and LR-4 lesions who participated in a prospective clinical trial (XX) were included in this study. Two radiologists independently assessed the preoperative MRI features and each lesion was assigned according to the liver imaging reporting and data system (LI-RADS). The preoperative clinical data were also evaluated. The relative values of these parameters were assessed as potential predictors of HCC for coexisting LR-3 and LR-4 lesions. RESULTS: We enrolled 102 HCC patients (58.1 ± 11.5 years; 84.3% males) coexisting with 110 LR-3 and LR-4 lesions (HCCs group [n = 66]; non-HCCs group [n = 44]). The presence of restricted diffusion (OR: 18.590, p < 0.001), delayed enhancement (OR: 0.113, p < 0.001), and mild-moderate T2 hyperintensity (OR: 3.084, p = 0.048) were found to be independent predictors of HCC diagnosis. The sensitivity and specificity of the above independent variables for the diagnosis of HCC ranged from 66.7 to 80.3% and 56.8 to 88.6%, respectively. ROC analysis showed that, in discriminating HCC, the AUCs of the above factors were 0.777, 0.686, and 0.670, respectively. Combining these three findings for the prediction of HCC resulted in a specificity greater than 97%, and the AUC further increased to 0.874. CONCLUSION: The presence of restricted diffusion, delayed enhancement, and mild-moderate T2 hyperintensity can be useful features for risk stratification of coexisting LR-3 and LR-4 lesions in HCC patients. Trial registration a prospective clinical trial (ChiCTR2000036201).

Preoperative prediction of lymphovascular invasion and T-staging of rectal cancer via a dual-energy computed tomography iodine map: a feasibility study.

PURPOSE: To investigate the value of dual-energy computed tomography (DECT) in predicting lymphovascular invasion (LVI) and the accuracy of preoperative T-staging of rectal cancer (RC). METHODS: Forty-nine patients with RC who had not received radiotherapy were enrolled to undergo a DECT scan. All patients underwent surgical tumor resection within 3-5 days after the DECT scan. Preoperative T-staging of RC based on images was performed by experienced radiologists. The normalized iodine concentrations (NIC) of the tumor and the perirectal adipose tissue (PAT) from the arterial phase (AP) and venous phase (VP) were measured using DECT. The tumor LVI and T-staging confirmed by pathology were used as the gold standard for grouping (group A, LVI-; group B, LVI+; group C, T1-2; and group D, T3-4a). The NIC values between two groups were compared using the Mann-Whitney U test, with P < 0.05 indicating a statistically significant difference. The accuracy of NIC in predicting LVI and distinguishing T1-2 RC from T3-4a RC were determined via receiver operating characteristic curve analysis, and the optimal cut-off of NIC was determined using the area under the curve. RESULTS: The tumor NIC values were significantly higher in the LV+ group than in the LVI- group in the VP (0.728 ± 0.031 vs. 0.669 ± 0.034, P < 0.001). The NIC values of PAT were significantly higher in the T3-4a group than in the T1-2 group in both the AP (4.034 ± 0.991 vs. 3.115 ± 0.581, P < 0.05) and the VP (5.481 ± 1.054 vs. 3.450 ± 0.980, P < 0.001). The accuracy of using NIC values to distinguish between the LVI+ group and the LVI- group and to diagnose the T3-4a group were 85.7% and 89.8%, respectively. However, there was no statistically significant difference between the NIC value in the LVI+ group and in the LVI- group in the AP. There was also no statistical difference in the tumor NIC value between the T1-2 group and the T3-4a group. CONCLUSION: The tumor and PAT NIC are valuable indicators in RC that can preoperatively predict LVI and improve the accuracy of preoperative RC T-staging. CLINICAL SIGNIFICANCE: The use of DECT improves the T-staging and LVI prediction of RC, which is helpful in guiding the clinical selection of appropriate treatment modalities and improving prognostic outcomes.

DTI-ALPS index decreased in patients with Type 2 Diabetes Mellitus.

Backgrounds: Type 2 Diabetes Mellitus (T2DM) has become a significant global public health issue, characterized by a rising prevalence and associated deficits across multiple organ systems. Our study aims to utilize the DTI-ALPS technique to assess the change of ALPS index in T2DM patients, and to explore whether such changes are correlated with cognition level and diffusion parameters. Methods: The study involved 41 patients with T2DM (mean age, 60.49 ± 8.88 years) and 27 healthy controls (mean age, 58.00 ± 7.63 years). All subjects underwent MRI examination, cognitive assessment, and laboratory tests. Tract-based spatial statistics (TBSS) was used to evaluate white matter changes. GLM was performed to check the DTI-ALPS index difference between T2DM and HC groups. Spearman correlation analysis and partial correlation analysis were used to analyze the correlation between the DTI-ALPS index and diffusion properties & cognitive scores. Results: The results show that the ALPS index was lower in T2DM patients. MoCA score was significantly correlated with the ALPS index. Patients with T2DM had a significant increase in both mean diffusivity (MD) and radial diffusivity (RD) and decrease in fractional anisotropy (FA) compared to the HC group. Conclusion: The results suggest that the ALPS index is decreased in T2DM patients and associates with cognitive level.

CD44v5 domain regulates crosstalk between TNBC cells and tumor-associated macrophages by enhancing the IL-4R/STAT3 axis.

Triple-negative breast cancer (TNBC) has greater infiltration of M2-like macrophages (TAMs), which enhances cancer cell invasion and leads to a poor prognosis. TNBC progression is mediated by both tumor cells and the tumor microenvironment (TME). Here we elucidate the mechanism of the interaction between TNBC cells and TAMs. In this study, we confirmed that CD44v5 is highly expressed in TNBC, which drives TNBC cell metastasis and promotes TAM polarization by co-localizing with IL4Rα and inhibiting its internalization and degradation, thereby promoting activation of the STAT3/IL6 signaling axis. At the same time, TAMs also facilitate TNBC cell metastasis by secreting IL-4, IL-6, and other cytokines, in which the IL-4/IL-4R/STAT3/IL-6 signaling axis plays the same role for TNBC cells responding to TAMs. Moreover, we found that the above progress could be suppressed when the CD44v5 domain was blocked. We demonstrated that the CD44v5/IL-4R/STAT3/IL-6 signaling pathway plays a key role in TNBC cell metastasis, and in TNBC cells inducing TAM polarization and responding to TAMs, promoting metastasis. Collectively, we suggest that the CD44v5 domain may be a promising target for regulating the TME of TNBC as well as treating TNBC.

Myasthenia gravis with tongue muscle atrophy: A case series.

Here, we presented 6 patients who were admitted to our institution and diagnosed as myasthenia gravis (MG) with tongue muscle atrophy. All these 6 patients developed symptoms of bulbar muscle weakness in acetylcholine receptor antibodies positive MG (AChR-MG) (3/6), muscle-specific receptor tyrosine kinase antibodies positive MG (MuSK-MG) (1/6), and sero-negative MG (2/6). Most of patients had "triple-furrowed" tongue except for patient 2 with irregular atrophy of tongue muscle. Tongue muscle atrophy occurs in patients with MuSK-MG, AChR-MG, and sero-negative MG. Atrophied tongue muscles of five patients with MG were reversible after immunotherapy.

Insights into the cycling stability of manganese-based zinc-ion batteries: from energy storage mechanisms to capacity fluctuation and optimization strategies.

Manganese-based materials are considered as one of the most promising cathodes in zinc-ion batteries (ZIBs) for large-scale energy storage applications owing to their cost-effectiveness, natural availability, low toxicity, multivalent states, high operation voltage, and satisfactory capacity. However, their intricate energy storage mechanisms coupled with unsatisfactory cycling stability hinder their commercial applications. Previous reviews have primarily focused on optimization strategies for achieving high capacity and fast reaction kinetics, while overlooking capacity fluctuation and lacking a systematic discussion on strategies to enhance the cycling stability of these materials. Thus, in this review, the energy storage mechanisms of manganese-based ZIBs with different structures are systematically elucidated and summarized. Next, the capacity fluctuation in manganese-based ZIBs, including capacity activation, degradation, and dynamic evolution in the whole cycle calendar are comprehensively analyzed. Finally, the constructive optimization strategies based on the reaction chemistry of one-electron and two-electron transfers for achieving durable cycling performance in manganese-based ZIBs are proposed.

Berberine improves cognitive impairment by alleviating brain atrophy and promoting white matter reorganization in diabetic db/db mice: a magnetic resonance imaging-based study.

Diabetic cognitive impairment is a common complication in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid that has been shown to have neuroprotective effects against diabetes. This study aimed to investigate the effect of BBR on the gray and white matter of the brain by using magnetic resonance imaging (MRI) and to explore the underlying mechanisms. The study used diabetic db/db mice and administered BBR (50 and 100 mg/kg) intragastrically for twelve weeks. Morris water maze was applied to examine cognitive function. T2-weighted imaging (T2WI) was performed to assess brain atrophy, and diffusion tensor imaging (DTI) combined with fiber tracking was conducted to monitor the structural integrity of the white matter, followed by histological immunostaining. Furthermore, the protein expressions of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3ß (GSK-3ß) were detected. The results revealed that BBR significantly improved the spatial learning and memory of the db/db mice. T2WI exhibited ameliorated brain atrophy in the BBR-treated db/db mice, as evidenced by reduced ventricular volume accompanied by increased hippocampal volumes. DTI combined with fiber tracking revealed that BBR increased FA, fiber density and length in the corpus callosum/external capsule of the db/db mice. These imaging findings were confirmed by histological immunostaining. Notably, BBR significantly enhanced the protein levels of phosphorylated AKT at Ser473 and GSK-3ß at Ser9. Collectively, this study demonstrated that BBR significantly improved the cognitive function of the diabetic db/db mice through ameliorating brain atrophy and promoting white matter reorganization via AKT/GSK-3ß pathway.

Development of natural perfume as potential fungicide candidates: construction and biological evaluation of vanillin analogs bearing the 1,3,4-oxadiazole/1,3-thiazolidin-4-one fragments.

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 µg/ml) and 7a (38.15 µg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 µg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 µg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.

Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice.

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Trends in cardiovascular health metrics and associations with long-term mortality among US adults with coronary heart disease.

BACKGROUND AND AIMS: Our study examined the trends of cardiovascular health metrics in individuals with coronary heart disease (CHD) and their associations with all-cause and cardiovascular disease mortality in the US. METHODS AND RESULTS: The cohort study was conducted based on the National Health and Nutrition Examination Survey 1999-2018 and their linked mortality files (through 2019). Baseline CHD was defined as a composite of self-reported doctor-diagnosed coronary heart disease, myocardial infarction, and angina pectoris. Cardiovascular health metrics were assessed according to the American Heart Association recommendations. Long-term all-cause and cardiovascular disease mortality were the primary outcomes. Survey-adjusted Cox regression models were used to estimate hazard ratios and corresponding 95% confidence intervals for the associations between cardiovascular health metrics and all-cause and cardiovascular disease mortality. The prevalence of one or fewer ideal cardiovascular health metrics increased from 14.15% to 22.79% (P < 0.001) in CHD, while the prevalence of more than four ideal cardiovascular health metrics decreased from 21.65% to 15.70 % (P < 0.001) from 1999 to 2018, respectively. Compared with CHD participants with one or fewer ideal cardiovascular health metrics, those with four or more ideal cardiovascular health metrics had a 35% lower risk (hazard ratio, 0.65; 95% confidence interval: 0.51, 0.82) and a 44% lower risk (0.56; 0.38, 0.84) in all-cause and cardiovascular disease mortality, respectively. CONCLUSION: Substantial declines were noted in ideal cardiovascular health metrics in US adults with CHD. A higher number of cardiovascular health metrics was associated with lower all-cause and cardiovascular disease mortality in them.

Association of cardiovascular health metrics with all-cause and cardiovascular disease mortality in chronic kidney disease: A cohort study.

BACKGROUND AND AIMS: Since the global burden of chronic kidney disease (CKD) is rising rapidly, the study aimed to assess the association of cardiovascular health (CVH) metrics with all-cause and cardiovascular disease (CVD) mortality among individuals with CKD. METHODS AND RESULTS: The cohort study included 5834 participants with CKD from the National Health and Nutrition Examination Survey 1999-2018. A composite CVH score was calculated based on smoking status, physical activity, body mass index, blood pressure, total cholesterol, diet quality, and glucose control. Primary outcomes were all-cause and CVD mortality as of December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to estimate the association between CVH metrics and deaths in CKD patients. During a median follow-up of 7.2 years, 2178 all-cause deaths and 779 CVD deaths were documented. Compared to participants with ideal CVH, individuals with intermediate CVH exhibited a 46.0% increase in all-cause mortality (hazard ratio, 1.46; 95% confidence interval: 1.17, 1.83), while those with poor CVH demonstrated a 101.0% increase (2.01; 1.54, 2.62). For CVD mortality, individuals with intermediate CVH experienced a 56.0% increase (1.56; 1.02, 2.39), and those with poor CVH demonstrated a 143.0% increase (2.43; 1.51, 3.91). Linear trends were noted for the associations of CVH with both all-cause mortality (P for trend <0.001) and CVD mortality (P for trend = 0.02). CONCLUSIONS: Lower CVH levels were associated with higher all-cause and CVD mortality in individuals with CKD, which highlights the importance of maintaining good CVH in CKD patients.

Neuroimmunological effects of omega-3 fatty acids on migraine: a review.

Migraine is a highly prevalent disease worldwide, imposing enormous clinical and economic burdens on individuals and societies. Current treatments exhibit limited efficacy and acceptability, highlighting the need for more effective and safety prophylactic approaches, including the use of nutraceuticals for migraine treatment. Migraine involves interactions within the central and peripheral nervous systems, with significant activation and sensitization of the trigeminovascular system (TVS) in pain generation and transmission. The condition is influenced by genetic predispositions and environmental factors, leading to altered sensory processing. The neuroinflammatory response is increasingly recognized as a key event underpinning the pathophysiology of migraine, involving a complex neuro-glio-vascular interplay. This interplay is partially mediated by neuropeptides such as calcitonin gene receptor peptide (CGRP), pituitary adenylate cyclase activating polypeptide (PACAP) and/or cortical spreading depression (CSD) and involves oxidative stress, mitochondrial dysfunction, nucleotide-binding domain-like receptor family pyrin domain containing-3 (NLRP3) inflammasome formation, activated microglia, and reactive astrocytes. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), crucial for the nervous system, mediate various physiological functions. Omega-3 PUFAs offer cardiovascular, neurological, and psychiatric benefits due to their potent anti-inflammatory, anti-nociceptive, antioxidant, and neuromodulatory properties, which modulate neuroinflammation, neurogenic inflammation, pain transmission, enhance mitochondrial stability, and mood regulation. Moreover, specialized pro-resolving mediators (SPMs), a class of PUFA-derived lipid mediators, regulate pro-inflammatory and resolution pathways, playing significant anti-inflammatory and neurological roles, which in turn may be beneficial in alleviating the symptomatology of migraine. Omega-3 PUFAs impact various neurobiological pathways and have demonstrated a lack of major adverse events, underscoring their multifaceted approach and safety in migraine management. Although not all omega-3 PUFAs trials have shown beneficial in reducing the symptomatology of migraine, further research is needed to fully establish their clinical efficacy and understand the precise molecular mechanisms underlying the effects of omega-3 PUFAs and PUFA-derived lipid mediators, SPMs on migraine pathophysiology and progression. This review highlights their potential in modulating brain functions, such as neuroimmunological effects, and suggests their promise as candidates for effective migraine prophylaxis.

Inhibition of mTORC2 promotes natriuresis in Dahl salt-sensitive rats via the decrease of NCC and ENaC activity.

We have previously observed that prolonged administration of rapamycin, an inhibitor targeting the mammalian target of rapamycin 1 (mTORC1), partially reduced hypertension and alleviated kidney inflammation in Dahl salt-sensitive (SS) rats. In contrast, treatment with PP242, an inhibitor affecting both mTORC1/mTORC2, not only completely prevented hypertension but also provided substantial protection against kidney injury. Notably, PP242 exhibited potent natriuretic effects that were not evident with rapamycin. The primary objective of this study was to pinpoint the specific tubular sites responsible for the natriuretic effect of PP242 in SS rats subjected to either 0.4% NaCl (NS) or 4.0% NaCl (HS) diet. Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide (inhibitors of ENaC, NKCC2, or NCC, respectively) either administered alone or in combination. The findings indicate that the natriuretic effects of PP242 in SS rats stem predominantly from the inhibition of NCC and a reduction of ENaC open probability. Molecular analysis revealed that mTORC2 regulates NCC activity through protein phosphorylation and ENaC activity through proteolytic cleavage in vivo. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects.

Efficacy and Safety of Bojungikgi-Tang for Persistent Allergic Rhinitis: A Randomized, Double-Blinded, Placebo-Controlled, Phase II Trial.

Conventional treatments for allergic rhinitis (AR) exhibit insufficiency and long-term use-related side effects. Considering the reported anti-inflammatory and immunoregulatory effects of Bojungikgi-tang (BJIGT), we aimed to assess its efficacy on persistent AR (PAR). Patients with PAR were randomly assigned in a 1:1:1 ratio into high-dose BJIGT, standard-dose BJIGT, and placebo groups, followed by 1-week run-in and 4-week treatment periods. The primary outcome included the mean change in Total Nasal Symptom Score (TNSS), with secondary outcomes encompassing the Korean Allergic Rhinitis-Specific Quality of Life Questionnaire, biomarkers, overall assessment, TNSS by AR pattern identification, and the Sasang constitution. The mean TNSS change was more improved in the BJIGT group than in the placebo group; however, no statistically significant differences were observed. Additional interaction effect analysis revealed a statistically significant improvement in the high-dose BJIGT group compared with the placebo group from weeks 1-2 to weeks 3-4. Regarding secondary outcomes, the BJIGT group exhibited similar or improved results compared with the placebo group, showing no statistically significant differences. No serious adverse effects or clinically significant changes in safety assessments were observed. Given that this study validated clinical improvement and safety, it serves as potential groundwork for pertinent future studies.

Mother-reliant or Self-reliant: The germination strategy of seeds in a species-rich alpine meadow is associated with the existence of pericarps.

BACKGROUND AND AIMS: Some plants germinate their seeds enclosed by a pericarp, while others lack the outer packaging. As a maternal tissue, may impart seeds with different germination strategies. Plants in a community with different flowering times may separately disperse and germinate their seeds; therefore, flowering time can be considered as one manifestation of maternal effects on offspring. The mass of the seed is another important factor influencing germination and represents the intrinsic resource of seed that supports the germination. Using seeds from a species-rich alpine meadow located in the Hengduan Mountains of China, a global biodiversity hotspot, we aim to illustrate whether and how the type of seed (with and without a pericarp) modulates the interaction of flowering time and seed mass with germination. METHODS: Seeds were germinated under a generally favorable condition and germination speed (estimated by mean germination time, MGT) was calculated. We quantified the maternal conditions by separation of flowering time for 67 species in the meadow, in which 31 produced seeds with pericarps and 36 yielded seeds without pericarps, respectively. We also weighed one hundred seeds to assess their mass. KEY RESULTS: The MGT varied between the two types of seed. For seeds with pericarps, MGT was associated with flowering time but not with seed mass. Plants with earlier flowering times in the meadow exhibited more rapid seed germination. For seeds without pericarp, the MGT depended on seed mass, with smaller seeds germinating more rapidly than larger seeds. CONCLUSIONS: The distinct responses of germination to flowering time and seed mass observed in seeds with and without pericarp suggest that germination strategies might be mother-reliant for seeds protected by pericarps but self-reliant for those without such protection. This novel finding improves our understanding of seed germination by integrating ecologically mediated maternal conditions and inherent genetic properties.

Pulmonary redox imbalance drives early fibroproliferative response in moderate/severe coronavirus disease-19 acute respiratory distress syndrome and impacts long-term lung abnormalities.

BACKGROUND: COVID-19-associated pulmonary fibrosis remains frequent. This study aimed to investigate pulmonary redox balance in COVID-19 ARDS patients and possible relationship with pulmonary fibrosis and long-term lung abnormalities. METHODS: Baseline data, chest CT fibrosis scores, N-terminal peptide of alveolar collagen III (NT-PCP-III), transforming growth factor (TGF)-ß1, superoxide dismutase (SOD), reduced glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) were first collected and compared between SARS-CoV-2 RNA positive patients with moderate to severe ARDS (n = 65, COVID-19 ARDS) and SARS-CoV-2 RNA negative non-ARDS patients requiring mechanical ventilation (n = 63, non-ARDS). Then, correlations between fibroproliferative (NT-PCP-III and TGF-ß1) and redox markers were analyzed within COVID-19 ARDS group, and comparisons between survivor and non-survivor subgroups were performed. Finally, follow-up of COVID-19 ARDS survivors was performed to analyze the relationship between pulmonary abnormalities, fibroproliferative and redox markers 3 months after discharge. RESULTS: Compared with non-ARDS group, COVID-19 ARDS group had significantly elevated chest CT fibrosis scores (p < 0.001) and NT-PCP-III (p < 0.001), TGF-ß1 (p < 0.001), GSSG (p < 0.001), and MDA (p < 0.001) concentrations on admission, while decreased SOD (p < 0.001) and GSH (p < 0.001) levels were observed in BALF. Both NT-PCP-III and TGF-ß1 in BALF from COVID-19 ARDS group were directly correlated with GSSG (p < 0.001) and MDA (p < 0.001) and were inversely correlated with SOD (p < 0.001) and GSH (p < 0.001). Within COVID-19 ARDS group, non-survivors (n = 28) showed significant pulmonary fibroproliferation (p < 0.001) with more severe redox imbalance (p < 0.001) than survivors (n = 37). Furthermore, according to data from COVID-19 ARDS survivor follow-up (n = 37), radiographic residual pulmonary fibrosis and lung function impairment improved 3 months after discharge compared with discharge (p < 0.001) and were associated with early pulmonary fibroproliferation and redox imbalance (p < 0.01). CONCLUSIONS: Pulmonary redox imbalance occurring early in COVID-19 ARDS patients drives fibroproliferative response and increases the risk of death. Long-term lung abnormalities post-COVID-19 are associated with early pulmonary fibroproliferation and redox imbalance.

Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors.

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 µg/mL that was superior to that of the agricultural fungicide boscalid (2.2 µg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 µM that was superior to that of boscalid (7.9 µM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.