Dynamic Stimulation of Visual Cortex Produces Form Vision in Sighted and Blind Humans.

A visual cortical prosthesis (VCP) has long been proposed as a strategy for restoring useful vision to the blind, under the assumption that visual percepts of small spots of light produced with electrical stimulation of visual cortex (phosphenes) will combine into coherent percepts of visual forms, like pixels on a video screen. We tested an alternative strategy in which shapes were traced on the surface of visual cortex by stimulating electrodes in dynamic sequence. In both sighted and blind participants, dynamic stimulation enabled accurate recognition of letter shapes predicted by the brain's spatial map of the visual world. Forms were presented and recognized rapidly by blind participants, up to 86 forms per minute. These findings demonstrate that a brain prosthetic can produce coherent percepts of visual forms.

Fungal invasion-induced accumulation of salicylic acid promotes anthocyanin biosynthesis through MdNPR1-MdTGA2.2 module in apple fruits.

In the field, necrosis area induced by pathogens is usually surrounded by a red circle in apple fruits. However, the underlying molecular mechanism of this phenomenon remains unclear. In this study, we demonstrated that accumulated salicylic acid (SA) induced by fungal infection promoted anthocyanin biosynthesis through MdNPR1-MdTGA2.2 module in apple (Malus domestica). Inoculating apple fruits with Valsa mali or Botryosphaeria dothidea induced a red circle surrounding the necrosis area, which mimicked the phenotype observed in the field. The red circle accumulated a high level of anthocyanins, which was positively correlated with SA accumulation stimulated by fungal invasion. Further analysis showed that SA promoted anthocyanin biosynthesis in a dose-dependent manner in both apple calli and fruits. We next demonstrated that MdNPR1, a master regulator of SA signaling, positively regulated anthocyanin biosynthesis in both apple and Arabidopsis. Moreover, MdNPR1 functioned as a co-activator to interact with and enhance the transactivation activity of MdTGA2.2, which could directly bind to the promoters of anthocyanin biosynthetic and regulatory genes to promote their transcription. Suppressing expression of either MdNPR1 or MdTGA2.2 inhibited coloration of apple fruits, while overexpressing either of them significantly promoted fruit coloration. Finally, we revealed that silencing either MdNPR1 or MdTGA2.2 in apple fruits repressed SA-induced fruit coloration. Therefore, our data determined that fungal-induced SA promoted anthocyanin biosynthesis through MdNPR1-MdTGA2.2 module, resulting in a red circle surrounding the necrosis area in apple fruits.

Bioinformatics toolbox for exploring target mutation-induced drug resistance.

Drug resistance is increasingly among the main issues affecting human health and threatening agriculture and food security. In particular, developing approaches to overcome target mutation-induced drug resistance has long been an essential part of biological research. During the past decade, many bioinformatics tools have been developed to explore this type of drug resistance, and they have become popular for elucidating drug resistance mechanisms in a low cost, fast and effective way. However, these resources are scattered and underutilized, and their strengths and limitations have not been systematically analyzed and compared. Here, we systematically surveyed 59 freely available bioinformatics tools for exploring target mutation-induced drug resistance. We analyzed and summarized these resources based on their functionality, data volume, data source, operating principle, performance, etc. And we concisely discussed the strengths, limitations and application examples of these tools. Specifically, we tested some predictive tools and offered some thoughts from the clinician's perspective. Hopefully, this work will provide a useful toolbox for researchers working in the biomedical, pesticide, bioinformatics and pharmaceutical engineering fields, and a good platform for non-specialists to quickly understand drug resistance prediction.

Proteome Landscapes of Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

Liver cancer is among the top leading causes of cancer mortality worldwide. Particularly, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) have been extensively investigated from the aspect of tumor biology. However, a comprehensive and systematic understanding of the molecular characteristics of HCC and CCA remains absent. Here, we characterized the proteome landscapes of HCC and CCA using the data-independent acquisition (DIA) mass spectrometry (MS) method. By comparing the quantitative proteomes of HCC and CCA, we found several differences between the two cancer types. In particular, we found an abnormal lipid metabolism in HCC and activated extracellular matrix-related pathways in CCA. We next developed a three-protein classifier to distinguish CCA from HCC, achieving an area under the curve (AUC) of 0.92, and an accuracy of 90% in an independent validation cohort of 51 patients. The distinct molecular characteristics of HCC and CCA presented in this study provide new insights into the tumor biology of these two major important primary liver cancers. Our findings may help develop more efficient diagnostic approaches and new targeted drug treatments.

Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps.

BACKGROUND AND AIMS: Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression. METHODS: NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs. RESULTS: Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade. CONCLUSIONS: This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.

The liquid-liquid phase separation signature predicts the prognosis and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common and fatal malignancy characterized by poor patient prognosis and treatment outcome. The process of liquid-liquid phase separation in tumour cells alters the dysfunction of biomolecular condensation in tumour cells, which affects tumour progression and treatment. We downloaded the data of HCC samples from TCGA database and GEO database, and used a machine learning method to build a new liquid-liquid phase separation index (LLPSI) by liquid-liquid phase separation related genes. The LLPSI-related column line Figure was constructed to provide a quantitative tool for clinical practice. HCC patients were divided into high and low LLPSI groups based on LLPSI, and clinical features, tumour immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analysed. LLPSI, which consists of five liquid-liquid phase separation-associated genes (MAPT, WDR62, PLK1, CDCA8 and TOP2A), is a reliable predictor of survival in patients with HCC and has been validated in multiple external datasets. We found that the high LLPSI group showed higher levels of immune cell infiltration and better response to immunotherapy compared to the low LLPSI group, and LLPSI can also be used for prognostic prediction in various cancers other than HCC. In vitro experiments verified that knockdown of MAPT could inhibit the proliferation and migration of HCC. The LLPSI identified in this study can accurately assess the prognosis of patients with HCC and identify patient populations that will benefit from immunotherapy, providing valuable insights into the clinical management of HCC.

SMEK1 ablation promotes glucose uptake and improves obesity-related metabolic dysfunction via AMPK signaling pathway.

Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified in many metabolic functions, including the regulation of hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus, we investigated the function of SMEK1 in white adipose tissue and glucose uptake. GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism-related genes/obesity. Smek1 KO mice were generated to identify the role of SMEK1 in obesity and glucose homeostasis. Cell culture and differentiation of stromal-vascular fractions (SVFs) and 3T3-L1 were used to determine the mechanism. 2-NBDG was used to measure the glucose uptake. Compound C was used to confirm the role of AMPK. We elucidated that SMEK1 was correlated with obesity and adipogenesis. Smek1 deletion enhanced adipogenesis in both SVFs and 3T3-L1. Smek1 KO protected mice from obesity and had protective effects on metabolic disorders, including insulin resistance and inflammation. Smek1 KO mice had lower levels of fasting serum glucose. We found that SMEK1 ablation promoted glucose uptake by increasing p-AMPKα(T172) and the transcription of Glut4 when the effect on AMPK-regulated glucose uptake was due to the PP4 catalytic subunits (PPP4C). Our findings reveal a novel role of SMEK1 in obesity and glucose homeostasis, providing a potential new therapeutic target for obesity and metabolic dysfunction.NEW & NOTEWORTHY Our study clarified the relationship between SMEK1 and obesity for the first time and validated the conclusion in multiple ways by combining available data from public databases, human samples, and animal models. In addition, we clarified the role of SMEK1 in glucose uptake, providing an in-depth interpretation for the study of its function in glucose metabolism.

Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis.

BACKGROUND: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. METHODS: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. RESULTS: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05-1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. CONCLUSIONS: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Protective effect of low-intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation.

PURPOSE: Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. METHODS: An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. RESULTS: LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1-TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. CONCLUSION: LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

Scalable, Green, Flexible Photochromic Bacterial Cellulose for Multicolor Switching, Photo-patterning, and Daily Sunlight UV Monitoring.

Sustainable, durable, and diverse photochromic smart textiles based on bacterial cellulose (BC) have emerged as attractive candidates in UV-sensing applications due to the green and easy functionalization of BC. However, existing BC-based photochromic textiles lack photochromic efficiency and combining fastness. In this study, a green strategy for in situ fermentation is developed to achieve the directional distribution of functional particles and remarkable photochromism in photochromic bacterial cellulose (PBC). The unique functional design obtained by regulating the photochromic dye distribution in 3D nanonetworks of PBCs during in situ growth affords a more uniform distribution and high fastness. Benefiting from the uniform distribution of photochromic dyes and adequate utilization of the 3D network structure, more surface area is provided to receive and utilize the photon energy from the UV rays, making the photochromic process more effective. The as-prepared PBCs exhibited rapid (within 1 min) and stable (30 cycles) discoloration and multicolor selectivity. Their simple preparation process and exceptional wearability, e.g., their flexibility, lightweight, and air permeability, make them suitable for various applications, including tunable color switching systems, photopatterning, and daily sunlight UV monitoring. This study provides empirical value for the biofabrication of photochromic textiles and wearable flexible UV sensors.

A viroid-derived small interfering RNA targets bHLH transcription factor MdPIF1 to regulate anthocyanin biosynthesis in Malus domestica.

Fruit colour is a critical determinant for the appearance quality and commercial value of apple fruits. Viroid-induced dapple symptom severely affects the fruit coloration, however, the underlying mechanism remains unknown. In this study, we identified an apple dimple fruit viroid (ADFVd)-derived small interfering RNA, named vsiR693, which targeted the mRNA coding for a bHLH transcription factor MdPIF1 (PHYTOCHROME-INTERACTING FACTOR 1) to regulate anthocyanin biosynthesis in apple. 5' RLM-RACE and artificial microRNA transient expression system proved that vsiR693 directly targeted the mRNA of MdPIF1 for cleavage. MdPIF1 positively regulated anthocyanin biosynthesis in both apple calli and fruits, and it directly bound to G-box element in the promoter of MdPAL and MdF3H, two anthocyanin biosynthetic genes, to promote their transcription. Expression of vsiR693 negatively regulated anthocyanin biosynthesis in both apple calli and fruits. Furthermore, co-expression of vsiR693 and MdPIF1 suppressed MdPIF1-promoted anthocyanin biosynthesis in apple fruits. Infiltration of ADFVd infectious clone suppressed coloration surrounding the injection sites in apple fruits, while a mutated version of ADFVd, in which the vsiR693 producing region was mutated, failed to repress fruit coloration around the injection sites. These data provide evidence that a viroid-derived small interfering RNA targets host transcription factor to regulate anthocyanin biosynthesis in apple.

A Fluorination Strategy and Low-Acidity Anchoring Group in Self-Assembled Molecules for Efficient and Stable Inverted Perovskite Solar Cells.

Herein, we synthesized two donor-acceptor (D-A) type small organic molecules with self-assembly properties, namely MPA-BT-BA and MPA-2FBT-BA, both containing a low acidity anchoring group, benzoic acid. After systematically investigation, it is found that, with the fluorination, the MPA-2FBT-BA demonstrates a lower highest occupied molecular orbital (HOMO) energy level, higher hole mobility, higher hydrophobicity and stronger interaction with the perovskite layer than that of MPA-BT-BA. As a result, the device based-on MPA-2FBT-BA displays a better crystallization and morphology of perovskite layer with larger grain size and less non-radiative recombination. Consequently, the device using MPA-2FBT-BA as hole transport material achieved the power conversion efficiency (PCE) of 20.32 % and remarkable stability. After being kept in an N2 glove box for 116 days, the unsealed PSCs' device retained 93 % of its initial PCE. Even exposed to air with a relative humidity range of 30±5 % for 43 days, its PCE remained above 91 % of its initial condition. This study highlights the vital importance of the fluorination strategy combined with a low acidity anchoring group in SAMs, offering a pathway to achieve efficient and stable PSCs.

Incidence of endometrial cancer in BRCA mutation carriers.

OBJECTIVE: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. METHODS: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. RESULTS: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). CONCLUSIONS: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.

Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction.

BACKGROUND: Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI. METHODS: Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&Tag and RNA-sequencing analyses, we identified Lrg1, Vegf-a, and IL-10 as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR. RESULTS: We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1ß-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI. CONCLUSIONS: Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.

Vonoprazan and amoxicillin dual therapy for 14 days as the first-line treatment of Helicobacter pylori infection: A non-inferiority, randomized clinical trial.

BACKGROUND: We previously optimized the duration and dose of vonoprazan and amoxicillin dual therapy in China. The efficacy of vonoprazan with b.i.d. amoxicillin in comparison with vonoprazan-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection has not been adequately evaluated. METHODS: In a non-inferiority, randomized clinical trial, H. pylori infected and treatment-naïve patients were randomly assigned to receive 14 days of either vonoprazan dual (vonoprazan 20 mg and amoxicillin 1 g twice daily) or quadruple therapy (vonoprazan 20 mg + amoxicillin 1 g + furazolidone 100 mg + bismuth potassium citrate 600 mg twice daily). H. pylori status was confirmed using 13C-urea breath tests or fecal antigen test. The primary outcome was the H. pylori eradication rate following vonoprazan dual and quadruple therapy at 4-12 weeks. We also compared drug compliance to either regimen and documented their side effect. RESULTS: A total of 190 subjects were randomized. The eradication rate of vonoprazan dual and quadruple therapy were 87.4% and 92.6% (p = 0.23) by intention-to-treat analysis, respectively, and 96.5% and 97.7% (p = 0.63) by per-protocol analysis, respectively. The efficacy of vonoprazan dual therapy was non-inferior to vonoprazan-containing quadruple therapy in per-protocol analysis (p < 0.001; difference: -1.2%; 90% confidence interval: -5.4% to 3.0%). CONCLUSION: Vonoprazan with b.i.d. amoxicillin for 14 days provided similar satisfactory efficacy with vonoprazan-containing quadruple therapy as a first-line H. pylori treatment in China.

Fufang Zhenshu Tiaozhi capsule enhances bone formation and safeguards against glucocorticoid-induced osteoporosis through innovative Mekk2-mediated ß-catenin deubiquitination.

INTRODUCTION: Bone homeostasis depends on the regulation of ß-catenin in osteoblasts. Glucocorticoids (GCs) are known to diminish ß-catenin activity via Wnt pathway signaling, leading to osteoporosis. Conversely, activating ß-catenin in osteoblasts through mitogen-activated protein kinase kinase kinase 2 (Mekk2) offers an innovative approach to combat GC-induced osteoporosis (GIOP). Fufang Zhenshu Tiaozhi (FTZ) capsules have shown effectiveness in treating GIOP, but the mechanisms behind this are still unclear. MATERIALS AND METHODS: In this study, Mekk2 knockout mice (Mekk2-/-) was generated by CRISPR/Cas9. These mice were then subjected to Alcian Blue-Alizarin Red staining and immunofluorescence to assess their bone and cartilage development. To establish models of GIOP, both Mekk2-/- and wild-type (WT) mice were treated with dexamethasone (DXMS) and subsequently given FTZ capsules. We analyzed the resulting phenotypic changes in these mice using Micro-CT scans and histomorphological studies. Primary osteoblasts, isolated from both Mekk2-/- and WT mice, underwent qRT-PCR to measure key osteogenesis markers, including Runx2, Sp7, Bgalp, Col1a1 and Alp. Cells were then exposed to treatments with either FTZ or Wnt3a and the phosphorylation levels of ß-catenin and Mekk2, along with the protein expression of Runx2, were evaluated using Western blotting and immunoprecipitation. Additionally, C3H10T1/2 cells transfected with TOPflash-luciferase and Renilla luciferase reporters were treated with FTZ and Wnt3a to measure ß-catenin activity. RESULTS: In our study, administering FTZ in vivo effectively prevented bone loss typically induced by GCs. However, it's important to note that this protective effect was substantially reduced in mice lacking Mekk2. Additionally, FTZ showed a significant ability to enhance osteogenic differentiation in primary osteoblasts, doing so by altering the expression of Mekk2. Intriguingly, the impact of FTZ on Mekk2 appears to function through a pathway separate from the traditional Wnt signaling route. Furthermore, our findings indicate that FTZ also promotes the deubiquitination of ß-catenin, contributing further to its positive effects on bone health. CONCLUSIONS: This study suggests that FTZ plays a significant role in protecting bone mass in cases of GIOP. The mechanism through which FTZ confers this benefit involves the activation of Mekk2/ß-catenin signaling pathways, which represents a promising alternative strategy to counteract the deleterious effects of GIOP by augmenting osteoblastogenesis.

Design, synthesis and biological evaluation of tanshinone IIA derivatives as NLRP3 inflammasome inhibitors.

Natural product structures have long provided valuable pharmacophores and even candidates for drug discovery. Tanshinone scaffold showed moderately inhibitory activity in NLRP3 inflammasome/IL-1ß pathway. Herein, we designed a series of derivatives on different regions of Tanshinone IIA (TNA) scaffold. The biological evaluation identified compound T10, a scaffold hybrid of TNA and salicylic acid, as a potent NLRP3 inflammasome inhibitor. Mechanistically, T10 inhibits the production of ROS and prevents NLRP3 inflammasome-dependent IL-1ß production. In addition, treatment with T10 significantly attenuated inflammatory response in DSS-induced peritonitis. Our work describes a potential tanshinone-based derivative, which needs to be further structurally optimized as NLRP3 inflammasome inhibitors for treating inflammatory disorders.

MOF-derived NiCo hydroxide for highly efficient non-enzymatic glucose biosensing.

An efficient and robust electrocatalyst is significant for glucose biosensing. The emergence of metal-organic framework (MOF) derived materials opens up new avenues for the development of high-performance glucose sensing catalysts. Herein, MOF derived nickel-cobalt hydroxide supported on conductive copper sheet (NiCo-OH/Cu sheet) is prepared at room temperature. The as-obtained NiCo-OH is endowed with three-dimensional network structure which enables the effective exposure of active materials, sufficient contact between glucose molecule and catalyst. The NiCo-OH/Cu sheet is revealed as good glucose electrochemical sensing material with a wide linear range of 0.05∼6.0 mM and a high sensitivity of 1340µA mM-1cm-2. Additionally, the as-fabricated NiCo-OH/Cu sheet displays good anti-interference ability and long-term stability.

Embolization alone is as effective as TACE for unresectable HCC: systematic review and meta-analysis of randomized controlled trails.

BACKGROUND: Despite transarterial chemoembolization (TACE) was recommended as first line therapy for intermediate hepatocellular carcinoma (HCC), the efficacy of transarterial embolization (TAE) has not been widely recognized. This work was to determine whether TAE was as effective and safe as TACE for unresectable HCC. METHODS: We performed a systematic search of electronic databases and other sources for randomized controlled studies (RCTs) comparing TAE with TACE for unresectable HCC. Results were expressed as Hazard Ratio (HR) for survival and Odds Ratio (OR) for dichotomous outcomes using RevMan 5.4.1. RESULTS: We included 6 trials with 683 patients. The risk of bias of included RCTs was from unclear to high risk. There were no significant differences between TACE and TAE for progression-free survival (HR 0.83, 95% CI 0.45-1.55; p = 0.57), overall survival (HR 1.10, 95% CI 0.90-1.35; p = 0.36), and objective response rate (OR 1.17, 95% CI 0.80-1.71; p = 0.42) without obvious publication bias. Sensitivity analyses confirmed the robustness of the results. TAE group reported similar or less adverse effects than TACE group in all the studies. CONCLUSIONS: Our study demonstrated that TAE was as effective as TACE. Since TAE was simpler, cheaper and had less adverse effects than TACE, TAE should be a better choice in most cases where TACE was indicated for unresectable HCC.

QTL detection for grain shape and fine mapping of two novel locus qGL4 and qGL6 in rice.

Rice grain size and grain weight, which have a great influence on rice quality and yield, are complex quantitative traits that are mediated by grain length (GL), grain width (GW), length-to-width ratio (LWR), and grain thickness (GT). In this study, the BC1F2 and BC1F2:3 populations derived from a cross between two indica rice varieties, Guangzhan 63-4S (GZ63-4S) and Dodda, were used to locate quantitative trait loci (QTL) related to grain size. A total of 30 QTL associated with GL, GW and LWR were detected, of which six QTL were scanned repeatedly in both populations. Two QTL, qGL4 and qGL6, were selected for genetic effect validation and were subsequently fine mapped to 2.359 kb and 176 kb, respectively. LOC_Os04g52240 (known as OsKS2/OsKSL2), which encoding an ent-beyerene synthase and as the only gene found in 2.359 kb interval, was proposed to be the candidate for qGL4. Moreover, the grains of qGL4 homozygous mutant plants generated by the CRISPR-Cas9 system became shorter and wider. In addition, the qGL4 allele from GZ63-4S contributes to the increase of yield per plant. Our study not only laid the foundation for further functional study of qGL4 and map-based cloning of qGL6, but also provided genetic resources for the development of high yield and good quality rice varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01502-8.