CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Fabrication of fluorescence probe based on molecularly imprinted polymers on red emissive biomass-derived carbon dots coupled with smartphone readout for tyramine determination in fermented meat products.

A fluorescence probe based on molecularly imprinted polymers on red emissive biomass-derived carbon dots (r-BCDs@MIPs) was developed to detect tyramine in fermented meat products. The red emissive biomass-derived carbon dots (r-BCDs) were synthesized by the one-step solvothermal method using discarded passion fruit shells as raw materials. The fluorescence emission peak of r-BCDs was at 670 nm, and the relative quantum yield (QY) was about 2.44%. Molecularly imprinted sensing materials were prepared with r-BCDs as fluorescent centers for the detection of trace tyramine, which showed a good linear response in the concentration range of tyramine from 1 to 40 µg L-1. The linear correlation coefficient was 0.9837, and the limit of detection was 0.77 µg L-1. The method was successfully applied to the determination of tyramine in fermented meat products, and the recovery was 87.17-106.02%. The reliability of the results was verified through high-performance liquid chromatography (HPLC). Furthermore, we combined the r-BCDs@MIPs with smartphone-assisted signal readout to achieve real-time detection of tyramine in real samples. Considering its simplicity and convenience, the method could be used as a rapid and low-cost promising platform with broad application prospects for on-site detection of trace tyramine with smartphone-assisted signal readout.

An investigation of a strengthening polysaccharide interfacial membrane strategy utilizing an anionic polysaccharide-alkaline ligand interfacial assembly for all-liquid printing.

The applications of polysaccharides as emulsifiers are limited due to the lack of hydrophobicity. However, traditional hydrophobic modification methods used for polysaccharides are complicated and involve significant mechanical and thermal losses. In this study, soy hull polysaccharide (SHP) and terminally aminopropylated polydimethylsiloxane (NPN) were selected to investigate the feasibility of a simple and green interfacial membrane strengthening strategy based on the interfacial polymerization of anionic polysaccharides and fat-soluble alkaline ligands. Our results show that deprotonated SHP and protonated NPN can be complexed at the water/oil (W/O) interface, reduce interfacial tension, and form a strong membrane structure. Moreover, they can quickly form a membrane at the W/O interface upon the moment of contact to produce stable all-liquid printing products with complex patterns. However, the molecular weight of NPN affects the complexation reaction. Consequently, this study has long-term implications to expanding the areas of application for anionic polysaccharides.

Discovery of Highly Selective, Potent, Covalent, and Orally Bioavailable Factor XIIa Inhibitors for the Treatment of Thrombo-Inflammation.

Thrombo-inflammation is closely associated with a few severe cardiovascular and infectious diseases. Factor XIIa (FXIIa) in the intrinsic coagulation pathway plays a pivotal role in the development of thrombo-inflammation and its inhibition has emerged as a potential therapeutic approach for thrombo-inflammatory disorders. Nonetheless, as of now, few small-molecule FXIIa inhibitors have demonstrated notable effectiveness against thrombo-inflammation, with none progressing into clinical stages. Herein, we present potent, covalent, reversible, and selective small-molecule FXIIa inhibitors such as 4a and 4j obtained through structure-based drug design. Compounds 4a and 4j showed significant anticoagulation and substantial anti-inflammatory effects in vitro, coupled with exceptional plasma stability. Furthermore, in carrageenan-induced thrombosis models, 4a and 4j demonstrated remarkable dual antithrombotic and anti-inflammatory activity when administered orally. Compound 4j exhibited a favorable safety profile without obvious tissue toxicity in mice, suggesting its potential as an oral therapeutic option for thrombo-inflammation.

Relationship between gut microbiota and the pathogenesis of gestational diabetes mellitus: a systematic review.

Introduction: Gestational diabetes mellitus (GDM) is a form of gestational diabetes mellitus characterized by insulin resistance and abnormal function of pancreatic beta cells. In recent years, genomic association studies have revealed risk and susceptibility genes associated with genetic susceptibility to GDM. However, genetic predisposition cannot explain the rising global incidence of GDM, which may be related to the increased influence of environmental factors, especially the gut microbiome. Studies have shown that gut microbiota is closely related to the occurrence and development of GDM. This paper reviews the relationship between gut microbiota and the pathological mechanism of GDM, in order to better understand the role of gut microbiota in GDM, and to provide a theoretical basis for clinical application of gut microbiota in the treatment of related diseases. Methods: The current research results on the interaction between GDM and gut microbiota were collected and analyzed through literature review. Keywords such as "GDM", "gut microbiota" and "insulin resistance" were used for literature search, and the methodology, findings and potential impact on the pathophysiology of GDM were systematically evaluated. Results: It was found that the composition and diversity of gut microbiota were significantly associated with the occurrence and development of GDM. Specifically, the abundance of certain gut bacteria is associated with an increased risk of GDM, while other changes in the microbiome may be associated with improved insulin sensitivity. In addition, alterations in the gut microbiota may affect blood glucose control through a variety of mechanisms, including the production of short-chain fatty acids, activation of inflammatory pathways, and metabolism of the B vitamin group. Discussion: The results of this paper highlight the importance of gut microbiota in the pathogenesis of GDM. The regulation of the gut microbiota may provide new directions for the treatment of GDM, including improving insulin sensitivity and blood sugar control through the use of probiotics and prebiotics. However, more research is needed to confirm the generality and exact mechanisms of these findings and to explore potential clinical applications of the gut microbiota in the management of gestational diabetes. In addition, future studies should consider the interaction between environmental and genetic factors and how together they affect the risk of GDM.

Enhancing Lactobacillus plantarum delivery: Impact of gluconolactone concentration on high-internal-phase emulsion gels and gastrointestinal viability.

In this study, the impact of Gluconolactone (GDL) concentration on the formation of high-internal-phase emulsion gels (HIPEGs) and the gastrointestinal digestive viability of Lactobacillus plantarum encapsulated within these HIPEGs were demonstrated. Increasing GDL concentrations led to cross-linking of particles at the oil-water interface, thereby stabilizing smaller oil droplets. The addition of GDL to HIPEs results in a significant increase in the secondary structure of SPI, specifically in ß-sheet and ß-turn formations, accompanied by a reduction in α-helix percentage. This alteration enhanced the binding effect of protein on water, leading to changes in intermolecular force. Notably, HIPEGs containing 3.0% GDL demonstrated superior encapsulation efficiency and delivery efficiency, reaching 99.0% and 84.5%, respectively. After 14 d of continuous zebrafishs feeding, the intestinal viable cells count of Lactobacillus plantarum reached 1.18 × 107 CFU/mL. This finding supports the potential use of HIPEGs as a probiotic delivery carrier, effectively enhancing the intestinal colonization rate.

Enhancing frozen dough quality: Investigating the impact of soy hull polysaccharide (SHP) on rheological properties and microstructure.

The effects of SHP on the texture, rheological properties, starch crystallinity and microstructure of frozen dough were investigated. The efficacy of SHP in enhancing dough quality is concentration-dependent, with frozen dough containing 1.5% SHP exhibiting hardness comparable to fresh dough without SHP (221.31 vs. 221.42 g). Even at 0.5% SHP, there is a noticeable improvement in frozen dough quality. The rheological results showed that the viscoelasticity of dough increased with higher SHP concentration. What's more, XRD and SEM results indicated that the SHP's hydrophilicity reduces the degree of starch hydrolysis, slows down the damage of starch particles during freezing, and consequently lowers the crystallinity of starch. Additionally, CLSM observations revealed that SHP enhances the gluten network structure, diminishing the appearance of holes. Therefore, the physical, chemical properties, and microstructure of frozen dough with SHP demonstrate significant enhancement, suggesting SHP's promising antifreeze properties and potential as a food antifreeze agent.

Nardosinone relieves metabolic-associated fatty liver disease and promotes energy metabolism through targeting CYP2D6.

BACKGROUND: Nardosinone, a major extract of Rhizoma nardostachyos, plays a vital role in sedation, neural stem cell proliferation, and protection of the heart muscle. However, the huge potential of nardosinone in regulating lipid metabolism and gut microbiota has not been reported, and its potential mechanism has not been studied. PURPOSE: To explore the regulation of nardosinone on liver lipid metabolism and gut microbiota. METHODS: In this study, the role of nardosinone in lipid metabolism was investigated in vitro and in vivo by adding it to mouse feed and HepG2 cell culture medium. And 16S rRNA gene sequencing was used to explore its regulatory effect on gut microbiota. RESULTS: Results showed that nardosinone could improve HFD-induced liver injury and abnormal lipid metabolism by promoting mitochondrial energy metabolism in hepatocytes, alleviating oxidative stress damage, and regulating the composition of the gut microbiota. Mechanistically, combined with network pharmacology and reverse docking analysis, it was predicted that CYP2D6 was the target of nardosinone, and the binding was verified by cellular thermal shift assay (CETSA). CONCLUSIONS: This study highlights a novel mechanism function of nardosinone in regulating lipid metabolism and gut microbiota. It also predicts and validates CYP2D6 as a previously unknown regulatory target, which provides new possibilities for the application of nardosinone and the treatment of metabolic-associated fatty liver disease.

ATXN3 functions as a tumor suppressor through potentiating galectin-9-mediated apoptosis in human colon adenocarcinoma.

While deubiquitinase ATXN3 has been implicated as a potential oncogene in various types of human cancers, its role in colon adenocarcinoma remains understudied. Surprisingly, our findings demonstrate that ATXN3 exerts an antitumor effect in human colon cancers through potentiating Galectin-9-induced apoptosis. CRISPR-mediated ATXN3 deletion unexpectedly intensified colon cancer growth both in vitro and in xenograft colon cancers. At the molecular level, we identified ATXN3 as a bona fide deubiquitinase specifically targeting Galectin-9, as ATXN3 interacted with and inhibited Galectin-9 ubiquitination. Consequently, targeted ATXN3 ablation resulted in reduced Galectin-9 protein expression, thereby diminishing Galectin-9-induced colon cancer apoptosis and cell growth arrest. The ectopic expression of Galectin-9 fully reversed the growth of ATXN3-null colon cancer in mice. Furthermore, immunohistochemistry staining revealed a significant reduction in both ATXN3 and Galectin-9 protein expression, along with a positive correlation between them in human colon cancer. Our study identifies the first Galectin-9-specific deubiquitinase and unveils a tumor-suppressive role of ATXN3 in human colon cancer.

A smartphone-combined ratiometric fluorescence molecularly imprinted probe based on biomass-derived carbon dots for determination of tyramine in fermented meat products.

A ratiometric fluorescence molecularly imprinted probe employing two distinct emission wavelengths of biomass carbon dots was developed for highly selective and visual quantitative detection of tyramine in fermented meat products. The red emission biomass carbon dots were employed as responsive elements, and the blue ones were utilized as the reference elements. The molecularly imprinted polymers were incorporated in the ratiometric sensing to distinguish and adsorb tyramine. With the linear range of 1-60 µg/L, the ratiometric fluorescence molecularly imprinted probe was successfully applied to detect tyramine in real samples with the satisfactory recoveries of 79.74-112.12% and the detect limitation of 1.3 µg/kg, indicating that this probe has great potential applications for the detection of tyramine in real samples. Moreover, smartphone-based fluorescence signal recognition analysis on hand has been developed for the quantitative analysis of tyramine, providing a portable visual optical analysis terminal for rapid on-site determination of tyramine.

pH-responsive Aminated mesoporous silica microspheres modified with soybean hull polysaccharides for curcumin encapsulation and controlled release.

Mesoporous silica microspheres (MSMs) possess poor biocompatibility. This study focuses on integrating MSMs with polymers to obtain hybrid materials with superior performance compared to the individual components and responsive release in specific environments. The synthesized MSMs were aminated, and subsequently, soybean hull polysaccharide (SHPs) was modified onto MSMs-NH2 to produce MSMs-NH2@SHPs nanoparticles. The encapsulation rate, loading rate of curcumin (Cur), and in vitro release behavior were investigated. Results indicated that the encapsulation efficiency of Cur by MSMs-NH2@SHPs nanoparticles reached 75.58%, 6.95 times that of MSMs-NH2 with a load capacity of 35.12%. It is noteworthy that these nanoparticles exhibit pH-responsive release capacity in vitro. The cumulative release rate of the three nanoparticles at pH 5.0 was higher than that at pH 7.4. MSMs-NH2@SHPs had a cumulative release rate of 56.55% at pH 7.4, increasing to 76.21% at pH 5.0. In vitro experiments have shown that MSMs-based nanoparticles have high delivery efficiency and can achieve pH-sensitive drug release, with a high release rate in a slightly acidic acid, highlighting the potential for controlled release of Cur.

Global synthesis on the response of soil microbial necromass carbon to climate-smart agriculture.

Climate-smart agriculture (CSA) supports the sustainability of crop production and food security, and benefiting soil carbon storage. Despite the critical importance of microorganisms in the carbon cycle, systematic investigations on the influence of CSA on soil microbial necromass carbon and its driving factors are still limited. We evaluated 472 observations from 73 peer-reviewed articles to show that, compared to conventional practice, CSA generally increased soil microbial necromass carbon concentrations by 18.24%. These benefits to soil microbial necromass carbon, as assessed by amino sugar biomarkers, are complex and influenced by a variety of soil, climatic, spatial, and biological factors. Changes in living microbial biomass are the most significant predictor of total, fungal, and bacterial necromass carbon affected by CSA; in 61.9%-67.3% of paired observations, the CSA measures simultaneously increased living microbial biomass and microbial necromass carbon. Land restoration and nutrient management therein largely promoted microbial necromass carbon storage, while cover crop has a minor effect. Additionally, the effects were directly influenced by elevation and mean annual temperature, and indirectly by soil texture and initial organic carbon content. In the optimal scenario, the potential global carbon accrual rate of CSA through microbial necromass is approximately 980 Mt C year-1, assuming organic amendment is included following conservation tillage and appropriate land restoration. In conclusion, our study suggests that increasing soil microbial necromass carbon through CSA provides a vital way of mitigating carbon loss. This emphasizes the invisible yet significant influence of soil microbial anabolic activity on global carbon dynamics.

Characterization of high-internal-phase emulsions based on soy protein isolate with varying concentrations of soy hull polysaccharide and their capabilities for probiotic delivery: In vivo and in vitro release and thermal stability.

In this study, the impact of soy hull polysaccharide (SHP) concentration on high-internal-phase emulsions (HIPEs) formation and the gastrointestinal viability of Lactobacillus plantarum within HIPEs were demonstrated. Following the addition of SHP, competitive adsorption with soy protein isolate (SPI) occurred, leading to increased protein adhesion to the oil-water interface and subsequent coating of oil droplets. This process augmented viscosity and enhanced HIPEs stability. Specifically, 1.8 % SHP had the best encapsulation efficiency and delivery efficiency, reaching 99.3 % and 71.1 %, respectively. After 14 d of continuous zebrafishs feeding, viable counts of Lactobacillus plantarum and complex probiotics in the intestinal tract was 1.1 × 107, 1.3 × 107, respectively. In vitro experiments further proved that HIPEs' ability to significantly enhance probiotics' intestinal colonization and provided targeted release for colon-specific delivery. These results provided a promising strategy for HIPEs-encapsulated probiotic delivery systems in oral food applications.

Unraveling a Small Secreted Peptide SUBPEP3 That Positively Regulates Salt-Stress Tolerance in Pyrus betulifolia.

Small secreted peptides (SSPs) play important roles in regulating plants' growth and development in response to external stimulus, but the genes and functions of SSPs in many species are still unknown. Therefore, it is particularly significant to characterize and annotate SSP genes in plant genomes. As a widely used stock of pears, Pyrus betulifolia has strong resistance to biotic and abiotic stresses. In this study, we analyzed the SSPs genes in the genome of P. betulifolia according to their characteristics and homology. A total of 1195 SSP genes were identified, and most of them are signaling molecules. Among these, we identified a new SSP, subtilase peptide 3 (SUBPEP3), which derived from the PA region of preSUBPEP3, increasing the expression level under salt stress. Both adding synthetic peptide SUBPEP3 to the culture medium of pears and the overexpression of SUBPEP3 in tobacco can improve the salt tolerance of plants. In summary, we annotated the SSP genes in the P. betulifolia genome and identified a small secreted peptide SUBPEP3 that regulates the salt tolerance of P. betulifolia, which provides an important theoretical basis for further revealing the function of SSPs.

Degradation of Bisphenol A by Nitrogen-Rich ZIF-8-Derived Carbon Materials-Activated Peroxymonosulfate.

Bisphenol A (BPA), representing a class of organic pollutants, finds extensive applications in the pharmaceutical industry. However, its widespread use poses a significant hazard to both ecosystem integrity and human health. Advanced oxidation processes (AOPs) based on peroxymonosulfate (PMS) via heterogeneous catalysts are frequently proposed for treating persistent pollutants. In this study, the degradation performance of BPA in an oxidation system of PMS activated by transition metal sites anchored nitrogen-doped carbonaceous substrate (M-N-C) materials was investigated. As heterogeneous catalysts targeting the activation of peroxymonosulfate (PMS), M-N-C materials emerge as promising contenders poised to overcome the limitations encountered with traditional carbon materials, which often exhibit insufficient activity in the PMS activation process. Nevertheless, the amalgamation of metal sites during the synthesis process presents a formidable challenge to the structural design of M-N-C. Herein, employing ZIF-8 as the precursor of carbonaceous support, metal ions can readily penetrate the cage structure of the substrate, and the N-rich linkers serve as effective ligands for anchoring metal cations, thereby overcoming the awkward limitation. The research results of this study indicate BPA in water matrix can be effectively removed in the M-N-C/PMS system, in which the obtained nitrogen-rich ZIF-8-derived Cu-N-C presented excellent activity and stability on the PMS activation, as well as the outstanding resistance towards the variation of environmental factors. Moreover, the biological toxicity of BPA and its degradation intermediates were investigated via the Toxicity Estimation Software Tool (T.E.S.T.) based on the ECOSAR system.

Value of soluble fms-like tyrosine kinase 1 for predicting acute pancreatitis severity: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to explore the relationship between serum soluble fms-like tyrosine kinase 1 and the severity of acute pancreatitis and its diagnostic utility. METHODS: This study was carried out by searching Chinese and English literature from the establishment of the database to July 9, 2023, systematically, and assessing the quality and heterogeneity of the articles included. RESULTS: Thirteen studies with a total of 986 patients were included. Patients with severe acute pancreatitis showed higher levels of soluble fms-like tyrosine kinase 1 compared with mild acute pancreatitis [weighted mean difference=76.64 pg/mL, 95% confidence interval (95%CI 50.39-102.89, p<0.001)]. Soluble fms-like tyrosine kinase 1 predicted pooled sensitivity, specificity, and area under the curve were 79%, 74%, and 0.85 for severe acute pancreatitis, with some heterogeneity (I2>50% or p<0.05). In the subgroup analysis, cutoff >150 pg/mL was found to be a heterogeneous factor. CONCLUSION: Soluble fms-like tyrosine kinase 1 is a reliable tool for identifying acute pancreatitis severity, but only as a screening tool.

Global burden of pertussis in 204 countries and territories, from 1990 to 2019: results from the Global Burden of Disease Study 2019.

OBJECTIVES: This study aimed to examine the impact of pertussis on the global, regional, and national levels between 1990 and 2019. METHODS: Data on pertussis on a global scale from 1990 to 2019 were collected from the 2019 Global Burden of Disease Study. We performed a secondary analysis to report the global epidemiology and disease burden of pertussis. RESULTS: During the period spanning from 1990 to 2019, pertussis exhibited a steady global decline in the age-standardized incidence rate (ASIR), age-standardized disability-adjusted life years rate (ASYR), and age-standardized death rate (ASDR). Nevertheless, upon delving into an in-depth analysis of various regions, it was apparent that ASIR in southern sub-Saharan Africa, ASYR and ASDR in high-income North America, and ASDR in Western Europe and Australasia, were witnessing an upward trajectory. Moreover, a negative correlation was observed between the Socio­demographic Index (SDI) and burden inflicted by pertussis. Notably, the incidence of pertussis was comparatively lower in men than in women, with 0-4-year-olds emerging as the most profoundly affected demographic. CONCLUSION: The global pertussis burden decreased from 1990 to 2019. However, certain regions and countries faced an increasing disease burden. Therefore, urgent measures are required to alleviate the pertussis burden in these areas.

Development and characterization of adhesives constructed by soy protein isolate and tea polyphenols for enhanced tensile strength in plant-protein meat applications.

The study aimed to evaluate a food adhesive developed using tea polyphenols (TPs) with soybean protein isolate (SPI) to create a cohesive bond between soy protein gel and simulated fat. Upon the addition of 5.0 % TPs, significant increases in viscosity, thermal stability, and crystallinity were noted in adhesives, suggesting the formation of a cohesive network. Furthermore, TPs effectively enhanced adhesion strength, with the optimal addition being 5.0 %. This enhancement can be attributed to hydrogen bonding, hydrophobic and electrostatic interactions between TPs and SPI molecules. TPs induced a greater expansion of the protein structure, exposing numerous buried hydrophobic groups to a more hydrophilic and polar environment. However, excessive TPs were found to diminish adhesion strength. This can be attributed to enhanced reactions between TPs and SPI, where high molecular weight SPI-TPs cooperatively aggregate to form agglomerates that eventually precipitated, rendering the adhesive network inhomogeneous, less stable, and more prone to disruption.

Development of nanocellulose hydrogels for application in the food and biomedical industries: A review.

As the most abundant and renewable natural resource, cellulose has attracted significant attention and research interest for the production of hydrogels (HGs). To address environmental issues and emerging demands, the benefits of naturally produced HGs include excellent mechanical properties and superior biocompatibility. HGs are three-dimensional networks created by chemical or physical cross-linking of linear or branched hydrophilic polymers and have high capacity for absorption of water and biological fluids. Although widely used in the food and biomedical fields, most HGs are not biodegradable. Nanocellulose hydrogels (NC-HGs) have been extensively applied in the food industry for detection of freshness, chemical additives, and substitutes, as well as the biomedical field for use as bioengineering scaffolds and drug delivery systems owing to structural interchangeability and stimuli-responsive properties. In this review article, the sources, structures, and preparation methods of NC-HGs are described, applications in the food and biomedical industries are summarized, and current limitations and future trends are discussed.

Halide Exchange in Perovskites Enables Bromine/Iodine Hybrid Cathodes for Highly Durable Zinc Ion Batteries.

With the increasing need for reliable storage systems, the conversion-type chemistry typified by bromine cathodes attracts considerable attention due to sizeable theoretical capacity, cost efficiency, and high redox potential. However, the severe loss of active species during operation remains a problem, leading researchers to resort to concentrated halide-containing electrolytes. Here, profiting from the intrinsic halide exchange in perovskite lattices, a novel low-dimensional halide hybrid perovskite cathode, TmdpPb2[IBr]6, which serves not only as a halogen reservoir for reversible three-electron conversions but also as an effective halogen absorbent by surface Pb dangling bonds, C─H…Br hydrogen bonds, and Pb─I…Br halogen bonds, is proposed. As such, the Zn||TmdpPb2[IBr]6 battery delivers three remarkable discharge voltage plateaus at 1.21 V (I0/I-), 1.47 V (I+/I0), and 1.74 V (Br0/Br-) in a typical halide-free electrolyte; meanwhile, realizing a high capacity of over 336 mAh g-1 at 0.4 A g-1 and high capacity retentions of 88% and 92% after 1000 cycles at 1.2 A g-1 and 4000 cycles at 3.2 A g-1, respectively, accompanied by a high coulombic efficiency of ≈99%. The work highlights the promising conversion-type cathodes based on metal-halide perovskite materials.