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BACKGROUND: Myocardial fibrosis is a common feature in various cardiac diseases. It causes adverse cardiac remodeling and is associated with poor clinical outcomes. Late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) are the standard MRI techniques for detecting focal and diffuse myocardial fibrosis. However, these contrast-enhanced techniques require the administration of gadolinium contrast agents, which is not applicable to patients with gadolinium contraindications. To eliminate the need of contrast agents, we develop and apply an endogenous free-breathing T1ρ dispersion imaging technique (FB-MultiMap) for diagnosing diffuse myocardial fibrosis in a cohort with suspected cardiomyopathies. METHODS: The proposed FB-MultiMap technique, enabling T2, T1ρ and their difference (myocardial fibrosis index, mFI) quantification in a single scan was developed in phantoms and 15 healthy subjects. In the clinical study, 55 patients with suspected cardiomyopathies were imaged using FB-MultiMap, conventional native T1 mapping, LGE, and ECV imaging. The accuracy of the endogenous parameters for predicting increased ECV was evaluated using receiver operating characteristic (ROC) curve analysis. In addition, the correlation of native T1, T1ρ, and mFI with ECV was respectively assessed using Pearson correlation coefficients. RESULTS: FB-MultiMap showed a good agreement with conventional separate breath-hold mapping techniques in phantoms and healthy subjects. Considering all the patients, T1ρ was more accurate than mFI and native T1 for predicting increased ECV, with area under the curve (AUC) values of 0.91, 0.79 and 0.75, respectively, and showed stronger correlation with ECV (correlation coefficient r: 0.72 vs. 0.52 vs. 0.40). In the subset of 47 patients with normal T2 values, the diagnostic performance of mFI was significantly strengthened (AUC=0.90, r=0.83), outperforming T1ρ and native T1. CONCLUSION: The proposed free-breathing T1ρ dispersion imaging technique enabling simultaneous quantification of T2, T1ρ and mFI in a single scan has shown great potential for diagnosing diffuse myocardial fibrosis in patients with complex cardiomyopathies without contrast agents.

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BACKGROUND: Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy. METHODS: A retrospective analysis of patients with early-stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all-cause mortality after RFA. RESULTS: A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non-SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver-related and all-cause mortality after a median follow-up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all-cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45-0.996; p = .048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42-1.00; p = .049). Poor liver functional reserve (high albumin-bilirubin grades) increased all-cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis-4 index were predictors for HCC recurrence, whereas SLD was not. CONCLUSIONS: Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all-cause mortality compared to those with poor liver functional reserve. PLAIN LANGUAGE SUMMARY: The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease. Maintaining good liver function is an important prognostic factor for survival.

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Diabetic wounds tend to develop into nonhealing wounds associated with the complex inflammatory microenvironment of uncontrollable bacterial infection, reactive oxygen species (ROS) accumulation, and chronic hypoxia. Damaged blood vessels hinder metabolic circulation, aggravating hypoxia, and ROS accumulation and further exacerbating the diabetic wound microenvironment. However, existing treatments with a single functionality have difficulty healing complicated diabetic wounds. Therefore, developing an integrative strategy to improve the hostility of the diabetic wound microenvironment is urgently needed. Herein, multifunctional genipin (GP)-crosslinked chitosan (CS)-based hydrogels decorated with the biomimetic metal-organic framework (MOF)-nanozymes and the natural antibacterial agent chlorogenic acid (CGA), which is named MOF/CGA@GP-CS (MCGC), are prepared. With catalase (CAT)-like activity, these dual-metal MOF-nanozymes are promising bioreactors for simultaneously alleviating ROS accumulation and hypoxia by converting elevated endogenous H2O2 into dissolved oxygen in diabetic wounds. In addition, the other component of natural polyphenolic CGA acts as a mild antibacterial agent, efficiently inhibiting wound infection and avoiding antibiotic resistance. Impressively, the MCGC hydrogels accelerate infected diabetic wound healing by eliminating oxidative stress, increasing oxygenation, and reversing bacterial infection in vivo. In this work, an effective strategy based on multifunctional hydrogel wound dressings is successfully developed and applied in diabetic wound management.

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Konjac glucomannan (KGM) molecular chains contain a small amount of acetyl groups and a large number of hydroxyl groups, thereby exhibiting exceptional water retention and gel-forming properties. To meet diverse requirements, KGM undergoes modification processes such as oxidation, acetylation, grafting, and cationization, which reduce its viscosity, enhance its mechanical strength, and improve its water solubility. Researchers have found that KGM and its derivatives can regulate the polarization of macrophages, inducing their transformation into classically activated M1-type macrophages or alternatively activated M2-type macrophages, and even facilitating the interconversion between M1 and M2 phenotypes. Concurrently, the modulation of macrophage polarization states holds significant importance for chronic wound healing, inflammatory bowel disease (IBD), antitumor therapy, tissue engineering scaffolds, oral vaccines, pulmonary delivery, and probiotics. Therefore, KGM has the advantages of both immunomodulatory effects (biological activity) and gel-forming properties (physicochemical properties), giving it significant advantages in a variety of biomedical engineering applications.

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Hematopoietic stem cell transplantation (HSCT) is pivotal in treating hematologic disorders, yet it poses the risk of post-transplantation pancytopenia. Prophylactic platelet transfusions are often administered to mitigate this risk. Utilizing practical markers, such as immature platelet fraction (IPF), to predict hematopoietic recovery in advance could reduce unnecessary prophylactic transfusions. Our prospective study, involving 53 HSCT patients at Taipei Veterans General Hospital between September 2022 and May 2023, utilized the Sysmex XN analyzer to assess peripheral blood cell parameters. We investigated whether IPF could predict platelet recovery early, determined the optimal cut-off value, and compared platelet usage. Neutrophil and platelet engraftment occurred 10 (median; range: 10-12) and 15 (median; range: 15-18) days post-HSCT. Notably, 71.7% of patients exhibited an IPF increase exceeding 2% before platelet recovery. The optimal cut-off IPF on day 10 for predicting platelet recovery within five days was 2.15% (specificity 0.89, sensitivity 0.65). On average, patients received 3.89 units of post-transplantation platelet transfusion. Our results indicate that IPF serves as a predictive marker for platelet engraftment, peaking before the increase in platelet count. This insight aids clinicians in assessing the need for prophylactic platelet transfusions. Integrating reference IPF values alongside platelet counts enhances the accuracy of evaluating a patient's hematopoietic recovery status. Anticipating the timing of platelet recovery optimizes blood product usage and mitigates transfusion reaction risks.

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Background: Sleep is critical in health problems including Parkinson's disease (PD). This study examined the association between sleep characteristics and the likelihood of prodromal PD. Methods: At baseline examination of the Heart and Brain Investigation in Taicang (HABIT) study, potential PD biomarkers were obtained for 8777 participants aged over 50 years, and the probability of prodromal PD was assessed based on the Chinese expert consensus and Movement Disorder Society (MDS) criteria. General and component sleep characteristics were evaluated by the Pittsburgh Sleep Quality Index (PSQI). Median regression was applied to examine the association between sleep and the probability of prodromal PD, adjusting for age, sex, education level, physical activity, obesity, fast plasma glucose, lipids, and hypertension. Results: Based on China criteria, a higher level of PSQI score was significantly associated with a higher probability of prodromal PD (ß = 0.02, 95% CI: 0.01-0.03) and a higher risk of having an increased probability of prodromal PD (OR = 1.04, 95% CI: 1.02-1.05). Compared to participants with good quality sleep, those with poor quality sleep had a 0.07% increased probability of prodromal PD (95% CI: 0.01-0.13) and a 19% increased risk of having a high prodromal PD probability (95% CI: 1.04-1.20). Similar associations between sleep quality and the probability of prodromal PD were also observed using the MDS criteria. Subjective sleep quality, sleep latency, habitual sleep efficiency, daytime dysfunction, and use of sleep medications were also associated with the probability of prodromal PD. Conclusion: Poor sleep quality was associated with a high probability of prodromal PD. Sleep may be helpful for understanding and intervention of prodromal PD.

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Sleep-wake disorder is one of the most common nonmotor symptoms of Parkinson's disease (PD). Melatonin has the potential to improve sleep-wake disorder, but its mechanism of action is still unclear. Our data showed that melatonin only improved the motor and sleep-wake behavior of a zebrafish PD model when melatonin receptor 1 was present. Thus, we explored the underlying mechanisms by applying a rotenone model. After the PD zebrafish model was induced by 10 nmol/L rotenone, the motor and sleep-wake behavior were assessed. In situ hybridization and real-time quantitative PCR were used to detect the expression of melatonin receptors and lipid-metabolism-related genes. In the PD model, we found abnormal lipid metabolism, which was reversed by melatonin. This may be one of the main pathways for improving PD sleep-wake disorder.

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Background: The association between Chinese herbal medicine (CHM) and the risk of developing major adverse cardiovascular events (MACEs) in patients with dialysis hypotension is unclear and has not yet been investigated. This study aimed to determine whether CMH intervention could reduce the risk of MACEs in patients with dialysis hypotension. Methods: The study data from the Taiwan National Health Insurance Research Database were analyzed to clarify this association. For this study, a case-control design with a cohort of patients who received hemodialysis (HD) from 2008 to 2018, 20 295 HD patients who had received blood pressure (BP) raising drugs were identified. After 1:1 frequency-matching, 730 patients were identified as CHM users and CHM non-users. Vascular access revision/reconstruction and MACEs were observed as the main outcomes during the follow-up period. Results: The occurrence of vascular access revision/reconstruction in HD patients receiving BP raising drugs was associated with a 0.34-fold lower risk in CHM users than in CHM non-users [adjusted hazard ratio (aHR) = 0.34, 95% confidence interval (CI) = 0.26, 0.45]. The occurrences of MACEs in HD patients receiving BP raising drugs was associated with a 0.41-fold lower risk in CHM users than in CHM non-users (aHR = 0.41, 95% CI = 0.33, 0.51). A markedly predominant effect was observed in those receiving CHM for more than 180 days (aHR = 0.32; 95% CI = 0.22, 0.45). Conclusion: The findings revealed lower vascular access dysfunction and MACEs risk correlated with the use of CHM treatment among HD patients who received BP raising drugs.

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Epidermal growth factor receptor (EGFR) mutations have emerged as the most well-studied oncogenic alterations in advanced non-small cell lung cancer. The presence of single common or rare EGFR mutations and extra complex EGFR mutations correlates with the response sensitivity to EGFR tyrosine kinase inhibitors. Therefore, given the lack of evidence for the emergence of rare EGFR mutation types, the pathogenic mechanisms of uncommon EGFR mutations and the optimal treatment strategies remain to be explored further. The present study describes the case of a patient diagnosed with lung adenocarcinoma (LUAD) carrying two rare EGFR exon 18 indel/G719C and exon 19 L747S mutations, in which persistent lesion shrinkage was exhibited within 16 months of osimertinib treatment. Given the paucity of clinical trials for the treatment of LUAD harboring complex EGER mutations, the present detailed case description may provide clinicians with effective clinical experience in treating patients.

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Human fungal pathogens could cause a broad plethora of infections in both the immunocompetent and immunocompromised host. Fungal infections have become important causes of morbidity and mortality in recent years, the current arsenal of anti-fungal therapies was restricted. Ibrexafungerp was a novel, highly bioavailable glucan synthase inhibitor formulated for both intravenous and oral administration being developed by Scynexis; it was also the first novel anti-fungal drug class approved in more than 20 years. Ibrexafungerp was one semi-synthetic derivative of enfumafungin, a natural product isolated from fungi. This review reported the discovery of enfumafungin and ibrexafungerp, their anti-fungal mechanism, summed up 63 fernane-type triterpenoids from natural products, including 49 from plants, 9 from fungi and 5 from lichen. In addition, the review summarized the progress of enzymes responsible for the biosynthesis of type II fernane triterpenoid (enfumafungin skeleton) and type I fernane triterpenoid (polytolypin skeleton). The good example kept our confidence up for searching for new leading compounds and discovering drugs from fungi.

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Cryogenic detection technology is essential to ensure safety and effectiveness in fields such as medical refrigeration, cold chain transport, and cryogenic bioengineering. In this paper, a time-responsive visual cryogenic detection strategy is developed based on the storage properties of CaZnOS: Pb2+, Pr3+ phosphors with shallow traps. Since the carrier release rate from the trap center receives the influence of ambient temperature and storage time, the storage time of the temperature-sensitive product can be determined by the different optical signals of CaZnOS: Pb2+, Pr3+ phosphors obtained under 980 nm laser irradiation. In addition, CaZnOS: Pb2+, Pr3+ phosphors with multimode luminescence enable time-responsive visual detection of ambient temperature under extreme conditions. This work not only demonstrates the potential of CaZnOS: Pb2+, Pr3+ phosphors for visual detection of temperature and time but also paves the way for the development of various applications relying on cryogenic monitoring.

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Plants encounter numerous adversities during growth, necessitating the identification of common stress activators to bolster their resistance. However, the current understanding of these activators' mechanisms remains limited. This study identified three anti-stress activators applicable to apple trees, all of which elevate plant proline content to enhance resistance against various adversities. The results showed that the application of these sugar substitutes increased apple proline content by two to three times compared to the untreated group. Even at a lower concentration, these activators triggered plant stress resistance without compromising apple fruit quality. Therefore, these three sugar substitutes can be exogenously sprayed on apple trees to augment proline content and fortify stress resistance. Given their effectiveness and low production cost, these activators possess significant application value. Since they have been widely used in the food industry, they hold potential for broader application in plants, fostering apple industry development.

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Three neutral Pt(II) complexes with diphenylamino-modified 2-phenylpyridine derivatives as cyclometalating ligands and acetylacetone as the ancillary ligand exhibit aggregation-induced phosphorescent emission (AIPE) properties in THF/H2O. The crystal structures of the complexes highlight the contributions of non-covalent Pt···Pt interactions and hydrogen bonds to the AIPE properties. These AIPE-active Pt(II) complexes 1-3 have been successfully applied to detect picric acid (PA) in aqueous media, affording the lowest limit of detection at 70 nM. Furthermore, three Pt(II) complexes are able to detect PA in common water samples. The quenching of luminescence in the detection can be attributed to photo-induced electron transfer.

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Lignin can affect the enzymatic hydrolysis efficiency of lignocellulose. In this study, the lignin isolated from sugarcane bagasse (SCB) pretreated with p-toluenesulfonic acid (PL) was firstly aminated, and then the effects of PL and aminated PL (APL) on the bagasse enzymatic hydrolysis efficiency (EHE) were investigated. The results showed that the addition of PL and APL promoted the EHE, and EHE with APL (73.82 %) was higher than PL (51.39 %). To explore the reason, the data were further analyzed including cellulase adsorption capacity, enzyme activity, cellulase-lignin interaction, and molecular docking. It was found that APL adsorbed more cellulase (27.83 mg protein/g lignin) than PL (4.96 mg protein/g lignin), resulting from the greater interaction force and lower binding free energy between APL and cellulase. The addition of APL more remarkably enhanced the cellobiohydrolase and endoglucanase activities than PL due to more effectively inducing cellulase conformation optimization.

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Acute promyelocytic leukemia (APL) is marked by a block at the promyelocyte stage. Treatments like ATRA and ATO face resistance and relapse issues. Plastrum testudinis, a traditional Chinese medicine, may offer therapeutic potential. This study investigated xtr-miR-22-3p from P. testudinis for treating APL. High expression of xtr-miR-22-3p was confirmed, with target prediction indicating interactions with key genes, including PML. xtr-miR-22-3p reduced HL-60 leukemia cell growth, altered the cell cycle, and selectively inhibited HL-60 proliferation while promoting BMSC growth, suggesting its potential as a targeted APL therapy.

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Kitaev chains in quantum dot-superconductor arrays are a promising platform for the realization of topological superconductivity. As recently demonstrated, even a two-site chain can host Majorana zero modes known as "poor man's Majorana". Harnessing the potential of these states for quantum information processing, however, requires increasing their robustness to external perturbations. Here, we form a two-site Kitaev chain using Yu-Shiba-Rusinov states in proximitized quantum dots. By deterministically tuning the hybridization between the quantum dots and the superconductor, we observe poor man's Majorana states with a gap larger than 70 µeV. The sensitivity to charge fluctuations is also greatly reduced compared to Kitaev chains made with non-proximitized dots. The systematic control and improved energy scales of poor man's Majorana states realized with Yu-Shiba-Rusinov states will benefit the realization of longer Kitaev chains, parity qubits, and the demonstration of non-Abelian physics.

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BACKGROUND: Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. METHODS: We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. RESULTS: Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. CONCLUSION: We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

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Pigeonpea (Cajanus cajan) is a nutrient-rich and versatile food legume crop of tropical and subtropical regions. In this study, we describe the de novo assembly of a high-quality genome for the ancient pigeonpea landrace 'D30', achieved through a combination of Pacific Biosciences high-fidelity (PacBio HiFi) and high-throughput chromatin conformation capture (Hi-C) sequencing technologies. The assembled 'D30' genome has a size of 813.54 Mb, with a contig N50 of 10.74 Mb, a scaffold N50 of 73.07 Mb, and a GC content of 35.67%. Genomic evaluation revealed that the 'D30' genome contains 99.2% of Benchmarking Universal Single-Copy Orthologs (BUSCO) and achieves a 29.06 long terminal repeat (LTR) assembly index (LAI). Genome annotation indicated that 'D30' encompasses 431.37 Mb of repeat elements (53.02% of the genome) and 37 977 protein-coding genes. Identification of single-nucleotide polymorphisms (SNPs), insertions/deletions (indels), and structural variations between 'D30' and the published genome of pigeonpea cultivar 'Asha' suggests that genes affected by these variations may play important roles in biotic and abiotic stress responses. Further investigation of genomic regions under selection highlights genes enriched in starch and sucrose metabolism, with 42.11% of these genes highly expressed in seeds. Finally, we conducted genome-wide association studies (GWAS) to facilitate the identification of 28 marker-trait associations for six agronomic traits of pigeonpea. Notably, we discovered a calmodulin-like protein (CcCML) that harbors a dominant haplotype associated with the 100-seed weight of pigeonpea. Our study provides a foundational resource for developing genomics-assisted breeding programs in pigeonpea.

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BACKGROUND: This study was conducted to determine optimal predictive ability of National Institutes of Health Stroke Scale (NIHSS) measurements at baseline, 24 hours, and change from baseline to 24 hours after thrombolysis on functional recovery in patients with acute ischemic stroke who participated in the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS AND RESULTS: ENCHANTED was an international, multicenter, 2×2 quasifactorial, prospective, randomized open trial of low-dose versus standard-dose intravenous alteplase and intensive versus guideline-recommended blood pressure lowering in thrombolysis-eligible patients with acute ischemic stroke. Absolute (baseline minus 24 hours) and percentage (absolute change/baseline × 100) changes in NIHSS scores were calculated. Receiver operating characteristic curve analyses assessed performance of different NIHSS measurements on 90-day favorable functional recovery (modified Rankin Scale [mRS] score 0-2) and excellent functional recovery (mRS score 0-1). Youden index was used to identify optimal predictor cutoff points. A total of 4410 patients in the ENCHANTED trial were enrolled. The 24-hour NIHSS score had the highest discriminative ability for predicting favorable 90-day functional recovery (mRS score 0-2; area under the curve 0.866 versus 0.755, 0.689, 0.764; P<0.001) than baseline, absolute, and percentage change of NIHSS score, respectively. The optimal cutoff point of 24-hour NIHSS score for predicting favorable functional recovery was ≤4 (sensitivity 66.5%, specificity 87.1%, adjusted odds ratio, 9.44 [95% CI, 7.77-11.48]). The 24-hour NIHSS score (≤3) was the best predictor of 90-day excellent functional recovery (mRS score 0-1). Findings were consistent across subgroups, including sex, race, baseline NIHSS score, stroke subtype, and age. CONCLUSIONS: In thrombolysis-eligible patients with acute ischemic stroke, 24-hour NIHSS score (optimal cutpoint of 4) is the strongest predictor of 90-day functional recovery over baseline and early change of NIHSS score. REGISTRATION: URL: https://clinicaltrials.gov. Unique Identifier: NCT01422616.

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