Improving paste stabilities of cassava starch through molecular density after maltogenic amylase and transglucosidase.

To improve paste stability of cassava starch, including acid resistance, high-temperature shear resistance and freeze-thaw stability, cassava starch was modified by sequential maltogenic amylase and transglucosidase to form an optimally denser structure, or branched density (12.76 %), molecular density (15.17 g/mol/nm3), and the proportions of short-branched chains (41.41 % of A chains and 44.01 % of B1 chains). Viscosity stability (88.52 %) of modified starch was higher than that (64.92 %) of native starch. After acidic treatment for 1 h, the viscosity of modified starch and native starch decreased by 56.53 % and 65.70 %, respectively. Compared to native starch, modified starch had lower water loss in freeze-thaw cycles and less viscosity reduction during high-temperature and high-shear processing. So, the appropriate molecular density and denser molecule structure enhanced paste stabilities of modified starch. The outcome expands the food and non-food applications of cassava starch.

Crystallization ripening and erosion of calcium oxalate under the effect of bacteria and a polymer materials surface.

As typical examples of pathological biomineralization, urinary stones and stent encrustation have been associated with bacteria, yet the underlying mechanisms remain unclear. In this study, the effect of Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus on the nucleation and growth of calcium oxalate crystals both in solution and on material surfaces in vitro was investigated. Both bacteria can promote calcium oxalate crystallization, and E. coli shows a prominent ability to boost the nucleation and growth rate. Interestingly, we discovered an Ostwald ripening phenomenon after the initial nucleation on the material surfaces, where larger particles emerge upon the disappearance of small nuclei particles, evident in the case of S. aureas. Over an extended period of time, erosion and disintegration of the crystals was observed when bacteria were involved. Based on these understandings, we developed a new functional surface by synthesizing an antibacterial polypeptoid in-house and utilizing polyurethane as the substrate material. This surface exhibits a synergistic effect that inhibits the formation of calcium oxalate crystals. This study helps to elucidate the role of bacteria in calcium oxalate biomineralization and supports further development of treatment approaches such as anti-encrustation polymer materials.

Cryo-EM structure of the human subcortical maternal complex and the associated discovery of infertility-associated variants.

The functionally conserved subcortical maternal complex (SCMC) is essential for early embryonic development in mammals. Reproductive disorders caused by pathogenic variants in NLRP5, TLE6 and OOEP, three core components of the SCMC, have attracted much attention over the past several years. Evaluating the pathogenicity of a missense variant in the SCMC is limited by the lack of information on its structure, although we recently solved the structure of the mouse SCMC and proposed that reproductive disorders caused by pathogenic variants are related to the destabilization of the SCMC core complex. Here we report the cryogenic electron microscopy structure of the human SCMC and uncover that the pyrin domain of NLRP5 is essential for the stability of SCMC. By combining prediction of SCMC stability and in vitro reconstitution, we provide a method for identifying deleterious variants, and we successfully identify a new pathogenic variant of TLE6 (p.A396T). Thus, on the basis of the structure of the human SCMC, we offer a strategy for the diagnosis of reproductive disorders and the discovery of new infertility-associated variants.

Novel deep learning radiomics nomogram-based multiparametric MRI for predicting the lymph node metastasis in rectal cancer: A dual-center study.

PURPOSE: To develop and evaluate a nomogram that integrates clinical parameters with deep learning radiomics (DLR) extracted from Magnetic Resonance Imaging (MRI) data to enhance the predictive accuracy for preoperative lymph node (LN) metastasis in rectal cancer. METHODS: A retrospective analysis was conducted on 356 patients diagnosed with rectal cancer. Of these, 286 patients were allocated to the training set, and 70 patients comprised the external validation cohort. Preprocessed T2-weighted and diffusion-weighted imaging performed preoperatively facilitated the extraction of DLR features. Five machine learning algorithms-k-nearest neighbor, light gradient boosting machine, logistic regression, random forest, and support vector machine-were utilized to develop DLR models. The most effective algorithm was identified and used to establish a clinical DLR (CDLR) nomogram specifically designed to predict LN metastasis in rectal cancer. The performance of the nomogram was evaluated using receiver operating characteristic curve analysis. RESULTS: The logistic regression classifier demonstrated significant predictive accuracy using the DLR signature, achieving an Area Under the Curve (AUC) of 0.919 in the training cohort and 0.778 in the external validation cohort. The integrated CDLR nomogram exhibited robust predictive performance across both datasets, with AUC values of 0.921 in the training cohort and 0.818 in the external validation cohort. Notably, it outperformed both the clinical model, which had AUC values of 0.770 and 0.723 in the training and external validation cohorts, respectively, and the stand-alone DLR model. CONCLUSION: The nomogram derived from multiparametric MRI data, referred to as the CDLR model, demonstrates strong predictive efficacy in forecasting LN metastasis in rectal cancer.

GABAergic neuron dysregulation in a human neurodevelopmental model for major psychiatric disorders.

"GABA dysfunction" is a major hypothesis for the biological basis of schizophrenia with indirect supporting evidence from human post-mortem brain and genetic studies. Patient-derived induced pluripotent stem cells (iPSCs) have emerged as a valuable platform for modeling psychiatric disorders, and previous modeling has revealed glutamatergic synapse deficits. Whether GABAergic synapse properties are affected in patient-derived human neurons and how this impacts neuronal network activity remain poorly understood. Here we optimized a protocol to differentiate iPSCs into highly enriched ganglionic eminence-like neural progenitors and GABAergic neurons. Using a collection of iPSCs derived from patients of psychiatric disorders carrying a Disrupted-in-Schizophrenia 1 ( DISC1 ) mutation and their unaffected family member, together with respective isogenic lines, we identified mutation-dependent deficits in GABAergic synapse formation and function, a phenotype similar to that of mutant glutamatergic neurons. However, mutant glutamatergic and GABAergic neurons contribute differentially to neuronal network excitability and synchrony deficits. Finally, we showed that GABAergic synaptic transmission is also defective in neurons derived from several idiopathic schizophrenia patient iPSCs. Transcriptome analysis further showed some shared gene expression dysregulation, which is more prominent in DISC1 mutant neurons. Together, our study supports a functional GABAergic synaptic deficit in major psychiatric disorders.

Off-site production of plasma-activated water for efficient disinfection: The crucial role of high valence NOx and new chemical pathways.

Efficient disinfection of pathogens is a critical concern for environmental disinfection and clinical anti-infective treatment. Plasma-activated water (PAW) is a promising alternative to chemical disinfectants and antibiotics for its strong disinfection ability and not inducing any acute toxicity. Previous plasma sources are commonly placed near or fully in contact with water as possible for more efficient activation, but the risk of electrode corrosion and metal particle contamination of water threatens the safety and stability of PAW. In this work, plasma-activated gas (PAG) rich in high-valence NOx is generated by a hybrid plasma configuration and introduced into water for off-site PAW production. It is found that plasma-generated O3 dominates the gas-phase reactions for the formation of high-valence NOx. With the time-evolution of O3 concentration, the gaseous NO3 radicals are produced behind N2O5 formation, but will be decomposed before N2O5 quenching. By decoupling the roles of gaseous NO3, N2O5, and O3 in the water activation, results show that short-lived aqueous species induced by gaseous NO3 radicals play the most crucial role in PAW disinfection, and the acidic environment induced by N2O5 is also beneficial for microbial inactivation. Moreover, SEM photographs and biomacromolecule leakage assays demonstrate that PAW disrupts the cell membranes of bacteria and thus achieves inactivation. In real-life applications, an integrated device for off-site PAW production with a yield of 2 L/h and a bactericidal efficiency of >99.9 % is developed. The PAW of 50 mL produced in 3 min using this device is more effective in disinfection than 0.5 % NaClO and 3 % H2O2 with the same bacterial contact time. Overall, this work provides new avenues for efficient PAW production and deepens insights into the fundamental chemical processes that govern the reactive chemistry in PAW for environmental and biomedical applications.

Novel sodium tauroursodeoxycholate-based multifunctional liposomal delivery system for encapsulation of oleanolic acid and combination therapy of type 2 diabetes mellitus.

Liposomes have demonstrated great potential for drug delivery and diabetes treatment. However, hydrolysis by enzymes and emulsification by endogenous bile salts make liposomes unstable in the gastrointestinal tract. In this study, sodium tauroursodeoxycholate (TUDCNa)-based multifunctional bilosomes were designed to address the deficiencies of conventional liposomes. In the designed bilosomes, cholesterol was replaced by TUDCNa, which served as both a membrane stabilizer and an antidiabetic drug. Oleanolic acid (OA) was encapsulated in both conventional liposomes (OA-Ch-Lip) and bilosomes (OA-Tu-Bil) to compare their properties. Firstly, OA-Tu-Bil exhibited similar encapsulation efficiency and drug loading compared to OA-Ch-Lip, but with a smaller particle size. Secondly, OA-Tu-Bil showed better stability than OA-Ch-Lip. Thirdly, bilosomes exhibited prolonged intestinal retention time and improved permeability and oral bioavailability. Fourthly, in type 2 diabetes mellitus (T2DM) mice model, TUDCNa synergized with OA to exhibit the strongest therapeutic effect. In conclusion, TUDCNa have demonstrated the ability to substitute cholesterol in conventional liposomes, it provided a new approach for oral delivery of hypoglycemic drugs, and offered an innovative strategy for combination therapy.

Identification of Key Genes Controlling Sugar and Organic Acid Accumulation in Wampee Fruit (Clausena lansium) via Genome Assembly and Genome-wide Association Analysis.

Wampee (Clausena lansium) is an economically significant subtropical fruit tree widely cultivated in Southern China. To provide high-quality genomic resources for C. lansium, we report a chromosome-level genome sequence for the "JinFeng" cultivar. The 297.1 Mb C. lansium genome contained nine chromosomes with a scaffold N50 of 29.2 Mb and encoded 23,468 protein-coding genes. Selective sweep analysis between sweet and sour C. lansium varieties and genome-wide association analysis identified 14 candidate genes putatively involved in sugar and acid accumulation. ClERF061, encoding an ethylene response factor, and ClSWEET7, encoding a Sugars Will Eventually be Exported Transporters (SWEET) family protein, were proposed as key regulators of the sweet and sour tastes of the wampee fruit. ClERF061 and ClSWEET7 overexpression in tomatoes increased the total sugar and acid content in fruits. ClSWEET7 promoter activation by ClERF061 was confirmed via Nicotiana benthamiana transient expression. Our study provides valuable genomic resources for C. lansium genetics and breeding.

Effects of SIPA1L1 on trabecular meshwork extracellular matrix protein accumulation and cellular phagocytosis in POAG.

Accumulation of extracellular matrix (ECM) proteins in trabecular meshwork (TM), which leads to increased outflow resistance of aqueous humor and consequently high intraocular pressure, is a major cause of primary open-angle glaucoma (POAG). According to our preliminary research, the RapGAP protein superfamily member, signal-induced proliferation-associated 1-like 1 protein (SIPA1L1), which is involved in tissue fibrosis, may have an impact on POAG by influencing ECM metabolism of TM. This study aims to confirm these findings and identify effects and cellular mechanisms of SIPA1L1 on ECM changes and phagocytosis in human TM (HTM) cells. Our results showed that the expression of SIPA1L1 in HTM cells was significantly increased by TGFß2 treatment in Label-free quantitative proteomics. The aqueous humor and TM cells concentration of SIPA1L1 in POAG patients was higher than that of control. In HTM cells, TGFß2 increased expression of SIPA1L1 along with accumulation of ECM, RhoA and p-Cofilin1. The effects of TGFß2 were reduced by si-SIPA1L1. TGFß2 decreased HTM cell phagocytosis by polymerizing cytoskeletal actin filaments, while si-SIPA1L1 increased phagocytosis by disassembling actin filaments. Simultaneously, overexpressing SIPA1L1 alone exhibited comparable effects to that of TGFß2. Our studies demonstrate that SIPA1L1 not only promotes the production of ECM, but also inhibits its removal by reducing phagocytosis. Targeting SIPA1L1 degradation may become a significant therapy for POAG.

Mental Health Literacy Among Urban and Rural Residents of Guangdong Province, China.

Purpose: The study aims to understanding the mental health literacy level of urban and rural residents in Guangdong Province, the first major province in China, and its influencing factors is crucial. Methods: A multi-stage stratified equal-volume random sampling method was adopted in October-December 2022 to select permanent residents aged 18 years and above in Guangdong Province for the questionnaire survey, which consisted of a general demographic information questionnaire and a national mental health literacy questionnaire. Rao-Scott χ²-test with correction based on sampling design, independent samples t-test and binary multivariate logistic regression analysis were performed. Results: A total of 51744 individuals completed the questionnaire, including 31822 urban residents and 19200 rural residents. The rate of achievement of mental health literacy was 13.6% among urban residents, which was significantly higher compared to the rate of 8.6% among rural residents. Logistic regression analysis showed that female, higher education, being mental worker, being a retiree, having a higher monthly household income, maintaining a regular diet, and using electronic products for 2-6 hours per day were protective factors for mental health literacy attainment in urban residents, while having chronic diseases, being a smoker and having a history of drinking were identified as risk factors in urban residents. Among in rural residents, married, younger, higher education, being mental worker and using electronic products for 2-6 hours per day, maintaining a regular diet, and engaging in regular exercise were protective factors for achieving mental health literacy, while previous smoking was a risk factor. Conclusion: The study revealed a low level of mental health literacy among urban and rural residents of Guangdong Province, with a significant disparity between the two areas. These findings highlight the need for continuing efforts to increase the dissemination of mental health knowledge in rural communities and improve levels of mental health literacy.

Anti-inflammatory effects of Tao Hong Si Wu Tang in mice with lung cancer and chronic obstructive pulmonary disease.

BACKGROUND: Lung cancer (LC) combined with chronic obstructive pulmonary disease (COPD) is a common combination of comorbidities. Anti-inflammation and modulation of oxidative/antioxidative imbalance may prevent COPD-induced LC, and are also crucial to the treatment of LC combined with COPD. Modern studies have shown that Tao Hong Si Wu Tang (THSW) has vasodilatory, anti-inflammatory, anti-fatigue, anti-shock, immunoregulatory, lipid-reducing, micronutrient-supplementing, and anti-allergy effects. AIM: To observe the effects of THSW on COPD and LC in mice. METHODS: A total of 100 specific pathogen-free C57/BL6 mice were randomly divided into five groups: Blank control group (group A), model control group (group B), THSW group (group C), IL-6 group (group D), and THSW + IL-6 group (group E), with 20 mice in each group. A COPD mouse model was established using fumigation plus lipopolysaccharide intra-airway drip, and an LC model was replicated by in situ inoculation using the Lewis cell method. RESULTS: The blank control group exhibited a clear alveolar structure. The model control and IL-6 groups had thickened alveolar walls, with smaller alveolar lumens, interstitial edema, and several inflammatory infiltrating cells. Histopathological changes in the lungs of the THSW and THSW + IL-6 groups were less than those of the model control group. The serum IL-1ß, IL-6, and TNF-α levels and IL-6R, JAK, p-JAK, STAT1/3, p-STAT1/3, FOXO, p-FOXO, and IL-7R expression levels in lung tissues of mice in the rest of the groups were significantly higher than those of the blank control group (P < 0.01). Compared with the model control group, the IL-6 group demonstrated significantly higher levels for the abovementioned proteins in the serum and lung tissues (P < 0.01), and the THSW group had significantly higher serum IL-1ß, IL-6, and TNF-α levels and IL-7R expression levels in lung tissues (P < 0.01) but significantly decreased IL-6R, JAK, p-JAK, STAT1/3, p-STAT1/3, FOXO, p-FOXO, and IL-7R levels (P < 0.01). CONCLUSION: THSW reduces the serum IL-1ß, IL-6, and TNF-α levels in the mouse model with anti-inflammatory effects. Its anti-inflammatory mechanism lies in inhibiting the overactivation of the JAK/STAT1/3 signaling pathway.

Sclerosing epithelioid fibrosarcoma of the pancreas: A case report.

BACKGROUND: A sclerosing epithelioid fibrosarcoma (SEF) is a rare malignant fibroblastic soft tissue tumor that rarely occurs in intra-abdominal organs. A case of a SEF in the pancreatic head is reported herein, including its clinical manifestations, preoperative imaging features, gross specimen and pathological findings. CASE SUMMARY: A 33-year-old male patient was admitted to Peking Union Medical College Hospital in December 2023 due to a one-year history of intermittent upper abdominal pain and the discovery of a pancreatic mass. The patient underwent an enhanced computed tomography scan of the abdomen, which revealed a well-defined, round mass with clear borders and calcifications in the pancreatic head. The mass exhibited progressive, uneven mild enhancement, measuring approximately 6.6 cm × 6.3 cm. The patient underwent laparoscopic pylorus-preserving pancreaticoduodenectomy. Postoperative pathological examination revealed that the lesion was consistent with a SEF. At the 3-month postoperative follow-up, the patient did not report any short-term complications, and there were no signs of tumor recurrence. CONCLUSION: SEFs are rare malignant fibrous soft tissue tumors. SEFs rarely develop in the pancreas, and its preoperative diagnosis depends on imaging findings, with confirmation depending on pathological examination and immunohistochemistry. Currently, only four cases of pancreatic SEF have been reported in studies written in English. This case is the first reported case of a pancreatic SEF by a clinical physician.

Predicting Gene Comutation of EGFR and TP53 by Radiomics and Deep Learning in Patients With Lung Adenocarcinomas.

PURPOSE: This study was designed to construct progressive binary classification models based on radiomics and deep learning to predict the presence of epidermal growth factor receptor (EGFR) and TP53 mutations and to assess the models' capacities to identify patients who are suitable for TKI-targeted therapy and those with poor prognoses. MATERIALS AND METHODS: A total of 267 patients with lung adenocarcinomas who underwent genetic testing and noncontrast chest computed tomography from our hospital were retrospectively included. Clinical information and imaging characteristics were gathered, and high-throughput feature acquisition on all defined regions of interest (ROIs) was carried out. We selected features and constructed clinical models, radiomics models, deep learning models, and ensemble models to predict EGFR status with all patients and TP53 status with EGFR-positive patients, respectively. The validity and reliability of each model were expressed as the area under the curve (AUC), sensitivity, specificity, accuracy, precision, and F1 score. RESULTS: We constructed 7 kinds of models for 2 different dichotomies, namely, the clinical model, the radiomics model, the DL model, the rad-clin model, the DL-clin model, the DL-rad model, and the DL-rad-clin model. For EGFR- and EGFR+, the DL-rad-clin model got the highest AUC value of 0.783 (95% CI: 0.677-0.889), followed by the rad-clin model, the DL-clin model, and the DL-rad model. In the group with an EGFR mutation, for TP53- and TP53+, the rad-clin model got the highest AUC value of 0.811 (95% CI: 0.651-0.972), followed by the DL-rad-clin model and the DL-rad model. CONCLUSION: Our progressive binary classification models based on radiomics and deep learning may provide a good reference and complement for the clinical identification of TKI responders and those with poor prognoses.

Systemic immune-inflammation index combined with pediatric appendicitis score in assessing the severity and prognosis for paediatric appendicitis.

BACKGROUND: Pediatric appendicitis is a common cause of abdominal pain in children and is recognized as a significant surgical emergency. A prompt and accurate diagnosis is essential to prevent complications such as perforation and peritonitis. AIM: To investigate the predictive value of the systemic immune-inflammation index (SII) combined with the pediatric appendicitis score (PAS) for the assessment of disease severity and surgical outcomes in children aged 5 years and older with appendicitis. METHODS: Clinical data of 104 children diagnosed with acute appendicitis were analyzed. The participants were categorized into the acute appendicitis group and chronic appendicitis group based on disease presentation and further stratified into the good prognosis group and poor prognosis group based on prognosis. The SII and PAS were measured, and a joint model using the combined SII and PAS was constructed to predict disease severity and surgical outcomes. RESULTS: Significant differences were observed in the SII and PAS parameters between the acute appendicitis group and chronic appendicitis group. Correlation analysis showed associations among the SII, PAS, and disease severity, with the combined SII and PAS model demonstrating significant predictive value for assessing disease severity [aera under the curve (AUC) = 0.914] and predicting surgical outcomes (AUC = 0.857) in children aged 5 years and older with appendicitis. CONCLUSION: The study findings support the potential of integrating the SII with the PAS for assessing disease severity and predicting surgical outcomes in pediatric appendicitis, indicating the clinical utility of the combined SII and PAS model in guiding clinical decision-making and optimizing surgical management strategies for pediatric patients with appendicitis.

HNF1ß, LHX1, and GGNBP2 deletion contributed to kidney and reproductive dysfunction in 17q12 deletion syndrome: evidence from a case report.

17q12 deletion syndrome is a chromosomal abnormality, where there is a small missing piece (deletion) of genetic material on the long arm (q) of chromosome 17. Sign and symptoms can vary widely among different patients. Recently, a patient was diagnosed with 17q12 deletion syndrome in our hospital, and the clinical characteristics presented as absence of the right kidney, compensatory hypertrophy of the left kidney, multiple small cysts in the left kidney, pancreatic atrophy, hypomagnesemia, bowed uterus, multiple follicular cysts in both lobes of the thyroid gland, and maturity-onset diabetes of the young type 5 (MODY-5). A 1.5-Mb deletion with haploinsufficiency for 20 genes within the 17q12 region was found through copy number variation (CNV) analysis based on metagenomic next-generation sequencing (mNGS) technology. In addition to HNF1B absence, the LIM-class homeobox 1 transcription factor (LHX1) and GGNBP2 absence was also involved in regulation of kidney development and the reproductive system through bioinformatics analysis. The inheriting risk of 17q12 deletion syndrome is about 50%, and it is recommended to provide genetic counseling to all patients who are suspected or diagnosed with the syndrome.

Discovery, synthesis and biological evaluation of novel isoquinoline derivatives as potent indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase dual inhibitors.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) play a pivotal role in regulating kynurenine catabolism pathway and immunosuppressive environment, which are promising drug targets for cancer immunotherapy. In this work, a variety of isoquinoline derivatives were designed, synthesized and evaluated for the inhibitory activity against IDO1 and TDO. The enzymatic assay and structure-activity relationship studies led to the most potent compound 43b with IC50 values of 0.31 µM for IDO1 and 0.08 µM for TDO, respectively. Surface plasmon resonance (SPR) revealed direct binding affinity of compound 43b to IDO1 and TDO and molecular docking studies were performed to predict the possible binding mode. Further pharmacokinetic study and biological evaluation in vivo showed that 43b displayed acceptable pharmacokinetic profiles and potent antitumor efficacy with low toxicity in B16-F10 tumor model, which might provide some insights into the discovery of novel IDO1/TDO inhibitors for cancer immunotherapy.

Secondary activation on plasma-activated water by plasma-treated cotton for restoring and enhancing disinfection effect.

Plasma-activated water (PAW) is a novel antimicrobial agent with negligible toxicity and environmental burden, holding promise as an alternative to chemical disinfectants and antibiotics. In practice, liquid disinfectants are often soaked with cotton materials before further use. Rich in reducing functional groups on the surface, cotton will inevitably react with PAW, leading to the deterioration of PAW's functions. To resolve this issue, this work proposes a new concept of "secondary activation" for retaining and enhancing PAW's bioactivity, i.e., pre-treating cotton with air plasma before soaking PAW. For the first time, we find that the PAW absorbed by raw cotton completely loses its bactericidal effect, while plasma-treated cotton (PTC) restores the disinfection capacity and prolongs its effective duration. This restoration is attributed to the absorption of plasma-generated reactive species by cotton with oxidizing and nitrifying modifications on the fiber surface. Consequently, the concentrations of aqueous species in PAW increase rather than decrease after absorption by PTC. In addition, the PTC after 28-day storage can still enable PAW to achieve a bacterial reduction of ∼3 logs. This work identifies and addresses a crucial limitation in the disinfection application of PAW and elucidates the mechanism underlying PTC production and secondary activation of PAW.

Structural Basis of Main Proteases of Coronavirus Bound to Bofutrelvir.

Globally, the continuous spread and evolution of SARS-CoV-2, along with its variants, profoundly impact human well-being, health, security, and the growth of socio-economic. In the field of development of drugs against COVID-19, the main protease (Mpro) is a critical target as it plays a core role in the lifecycle of SARS-CoV-2. Bofutrelvir acts as a potent inhibitor of SARS-CoV-2 Mpro, demonstrating high efficacy and broad-spectrum antiviral activity. Compared to therapies that require pharmacokinetic boosters, such as ritonavir, the monotherapy approach of Bofutrelvir reduces the risk of potential drug interactions, making it suitable for a wider patient population. However, further studies on the potency and mechanism of inhibition of Bofutrelvir against the Mpro of COVID-19 and its variants, together with other coronaviruses, are needed to prepare for the possibility of a possible re-emerging threat from an analogous virus in the future. Here, we reveal the effective inhibition of Bofutrelvir against the Mpro of SARS-CoV-2, SARS-CoV, and HCoV-229E through FRET and crystallographic analysis. Furthermore, the inhibitory mechanisms of Bofutrelvir against two SARS-CoV-2 Mpro mutants (G15S and K90R) were also elucidated through FRET and crystallographic studies. Through detailed analysis and comparison of these crystal structures, we identified crucial structural determinants of inhibition and elucidated the binding mode of Bofutrelvir to Mpros from different coronaviruses. These findings are hopeful to accelerate the development of safer and more potent inhibitors against the Mpro of coronavirus, and to provide important references for the prevention and treatment of similar viruses that may emerge in the future.

Topical Delivery of Dual Loaded Nano-Transfersomes Mediated Chemo-Photodynamic Therapy against Melanoma via Inducing Cell Cycle Arrest and Apoptosis.

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Restorer of fertility like 30, encoding a mitochondrion-localized pentatricopeptide repeat protein, regulates wood formation in poplar.

Nuclear-mitochondrial communication is crucial for plant growth, particularly in the context of cytoplasmic male sterility (CMS) repair mechanisms linked to mitochondrial genome mutations. The restorer of fertility-like (RFL) genes, known for their role in CMS restoration, remain largely unexplored in plant development. In this study, we focused on the evolutionary relationship of RFL family genes in poplar specifically within the dioecious Salicaceae plants. PtoRFL30 was identified to be preferentially expressed in stem vasculature, suggesting a distinct correlation with vascular cambium development. Transgenic poplar plants overexpressing PtoRFL30 exhibited a profound inhibition of vascular cambial activity and xylem development. Conversely, RNA interference-mediated knockdown of PtoRFL30 led to increased wood formation. Importantly, we revealed that PtoRFL30 plays a crucial role in maintaining mitochondrial functional homeostasis. Treatment with mitochondrial activity inhibitors delayed wood development in PtoRFL30-RNAi transgenic plants. Further investigations unveiled significant variations in auxin accumulation levels within vascular tissues of PtoRFL30-transgenic plants. Wood development anomalies resulting from PtoRFL30 overexpression and knockdown were rectified by NAA and NPA treatments, respectively. Our findings underscore the essential role of the PtoRFL30-mediated mitochondrion-auxin signaling module in wood formation, shedding light on the intricate nucleus-organelle communication during secondary vascular development.