Investigation into the potential mechanism of Bacillus amyloliquefaciens in the fermentation of broad bean paste by metabolomics and transcriptomics.

Pixian broad bean paste is a renowned fermented seasoning. The fermentation of broad bean is the most important process of Pixian broad bean paste. To enhance the flavor of tank-fermented broad bean paste, salt-tolerant Bacillus amyloliquefaciens strain was inoculated, resulting in an increase in total amount of volatile compounds, potentially leading to different flavor characteristics. To investigate the fermentation mechanism, monoculture simulated fermentation systems were designed. Metabolomics and transcriptomics were used to explore Bacillus amyloliquefaciens' transcriptional response to salt stress and potential aroma production mechanisms. The results highlighted different metabolite profiles under salt stress, and the crucial roles of energy metabolism, amino acid metabolism, reaction system, transportation system in Bacillus amyloliquefaciens' hypersaline stress response. This study provides a scientific basis for the industrial application of Bacillus amyloliquefaciens and new insights into addressing the challenges of poor flavor quality in tank fermentation products.

Thermally Stable and Chemically Recyclable Poly(ketal-ester)s Regulated by Floor Temperature.

Chemical recycling to monomers (CRM) offers a promising closed-loop approach to transition from current linear plastic economy toward a more sustainable circular paradigm. Typically, this approach has focused on modulating the ceiling temperature (Tc) of monomers. Despite considerable advancements, polymers with low Tc often face challenges such as inadequate thermal stability, exemplified by poly(γ-butyrolactone) (PGBL) with a decomposition temperature of ∼200 °C. In contrast, floor temperature (Tf)-regulated polymers, particularly those synthesized via the ring-opening polymerization (ROP) of macrolactones, inherently exhibit enhanced thermodynamic stability as the temperature increases. However, the development of those Tf regulated chemically recyclable polymers remains relatively underexplored. In this context, by judicious design and efficient synthesis of a biobased macrocyclic diester monomer (HOD), we developed a type of Tf -regulated closed-loop chemically recyclable poly(ketal-ester) (PHOD). First, the entropy-driven ROP of HOD generated high-molar mass PHOD with exceptional thermal stability with a Td,5% reaching up to 353 °C. Notably, it maintains a high Td,5% of 345 °C even without removing the polymerization catalyst. This contrasts markedly with PGBL, which spontaneously depolymerizes back to the monomer above its Tc in the presence of catalyst. Second, PHOD displays outstanding closed-loop chemical recyclability at room temperature within just 1 min with tBuOK. Finally, copolymerization of pentadecanolide (PDL) with HOD generated high-performance copolymers (PHOD-co-PPDL) with tunable mechanical properties and chemical recyclability of both components.

Taste Mechanism of Umami Molecules from Fermented Broad Bean Paste Based on In Silico Analysis and Peptidomics.

In this study, in silico analysis and peptidomics were performed to examine the generation mechanism of the umami taste of fermented broad bean paste (FBBP). Based on the information from peptidomics, a total of 470 free peptides were identified from FBBP, most of which were increased after fermentation. Additionally, the increase of the content of umami peptides, organic acids, and amino acids during fermentation contributed to the perception of umami taste in FBBP. Molecule docking results inferred that these umami molecules were easy to connect with Ser, Glu, His, and Gln in the T1R3 subunit through hydrogen bonds and electrostatic interaction force. The binding sites His145, Gln389, and Glu301 particularly contributed to the formation of the ligand-receptor complexes. The aromatic interaction, hydrogen bond, hydrophilicity, and solvent-accessible surface (SAS) played key roles in the receptor-peptide interaction. Sensory evaluation and electronic tongue results showed that EDEDE, DLSESV, SNGDDE, DETL, CDLSD, and TDEE screened from FBBP had umami characteristics and umami-enhancing effects (umami threshold values ranging from 0.131 to 0.394 mmol/L). This work provides new insight into the rapid and efficient screening of novel umami peptides and a deeper understanding of the taste mechanisms of umami molecules from FBBP.

IgG4-related autoimmune pancreatitis and sclerosing cholangitis: A case report and literature review.

RATIONALE: Immunoglobulin G4-related disease (IgG4-RD) can involve various organs throughout the body, primarily manifesting as endocrine dysfunction, visual impairment, jaundice, and limited sexual function. IgG4-related autoimmune pancreatitis is triggered by autoimmune reactions and characterized by structural changes in the pancreas and pancreatic ducts. The disease mainly affects middle-aged and elderly males, typically presenting as progressive painless jaundice and misdiagnosed as cholangiocarcinoma or pancreatic cancer. PATIENT CONCERNS: This study reports a 54-year-old male who consulted with different institutions multiple times due to diabetes, pancreatitis, elevated liver enzymes, and jaundice. DIAGNOSES: Magnetic resonance imaging revealed swollen head of the pancreas and atrophic tail. Liver and pancreatic tissue pathology showed IgG4 plasma cell infiltration, while liver biopsy indicated interface hepatitis, liver fibrosis, and pseudolobule formation, with no evidence of bile duct damage. INTERVENTIONS: Following hormone therapy, the patient's serum IgG4 levels and liver enzyme levels returned to normal. OUTCOMES: The disease relapsed 2 years after maintaining hormone therapy, and the patient underwent additional hormone-induced remission therapy combined with azathioprine. LESSONS: The purpose of this research report is to enhance the awareness and understanding of IgG4-RD, emphasizing the necessity for personalized treatment strategies that take into account its recurrence, associations, and imaging features. This report provides valuable insights and guidance for clinicians in managing and diagnosing patients with IgG4-RD.

N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in nonalcoholic steatohepatitis (NASH) is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with Western diet and sugar water (WD + SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation accompanied with hyperglycemia. In vitro, the enhanced N-glycosylation by high glucose increased the protein stability of SCAP and hence increased its total protein levels, whereas the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, SCAP N-glycosylation increased not only the SREBP-1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in the nuclear abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.NEW & NOTEWORTHY N-glycosylation of SCAP exacerbates inflammation and lipid accumulation in hepatocytes through ACSS2-mediated H3K27ac. Our data suggest that SCAP N-glycosylation plays a key role in regulating histone H3K27 acetylation and targeting SCAP N-glycosylation may be a new strategy for treating nonalcoholic steatohepatitis (NASH).

High intrinsic phase stability of ultrathin 2M WS2.

Metallic 2M or 1T'-phase transition metal dichalcogenides (TMDs) attract increasing interests owing to their fascinating physicochemical properties, such as superconductivity, optical nonlinearity, and enhanced electrochemical activity. However, these TMDs are metastable and tend to transform to the thermodynamically stable 2H phase. In this study, through systematic investigation and theoretical simulation of phase change of 2M WS2, we demonstrate that ultrathin 2M WS2 has significantly higher intrinsic thermal stabilities than the bulk counterparts. The 2M-to-2H phase transition temperature increases from 120 °C to 210 °C in the air as thickness of WS2 is reduced from bulk to bilayer. Monolayered 1T' WS2 can withstand temperatures up to 350 °C in the air before being oxidized, and up to 450 °C in argon atmosphere before transforming to 1H phase. The higher stability of thinner 2M WS2 is attributed to stiffened intralayer bonds, enhanced thermal conductivity and higher average barrier per layer during the layer(s)-by-layer(s) phase transition process. The observed high intrinsic phase stability can expand the practical applications of ultrathin 2M TMDs.

Hi-Tag: a simple and efficient method for identifying protein-mediated long-range chromatin interactions with low cell numbers.

Protein-mediated chromatin interactions can be revealed by coupling proximity-based ligation with chromatin immunoprecipitation. However, these techniques require complex experimental procedures and millions of cells per experiment, which limits their widespread application in life science research. Here, we develop a novel method, Hi-Tag, that identifies high-resolution, long-range chromatin interactions through transposase tagmentation and chromatin proximity ligation (with a phosphorothioate-modified linker). Hi-Tag can be implemented using as few as 100,000 cells, involving simple experimental procedures that can be completed within 1.5 days. Meanwhile, Hi-Tag is capable of using its own data to identify the binding sites of specific proteins, based on which, it can acquire accurate interaction information. Our results suggest that Hi-Tag has great potential for advancing chromatin interaction studies, particularly in the context of limited cell availability.

An Explanation of Why Dose-Corrected Area Under the Curve for Alternate Administration Routes Can Be Greater than for Intravenous Dosing.

It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F > 1.0 and studies for which F was measured using both AUC and urinary excretion dose-corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff's Laws, that these universally held concepts concerning bioavailability may not be valid in all situations. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of this paper is to demonstrate that studies resulting in F > 1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

Revealing the formation mechanisms of key flavors in fermented broad bean paste.

Pixian Douban (PXDB) is a popular Chinese condiment for its distinctive flavor. Broad bean fermentation (Meju) is the most important process in the formation of flavor substances. Key flavors were analyzed qualitatively and quantitatively, and metagenomic technology was applied to study the microbial diversity during broad bean fermentation. In addition, the main metabolic pathways of key flavors were explored. Results indicated that Staphylococcus_gallinarum was the main microorganism in the microbial community, accounting for 39.13%, followed by Lactobacillus_agilis, accounting for 13.76%. Aspergillus_flavus was the fungus with the highest species abundance, accounting for 3.02%. The KEGG Pathway enrichment analysis showed that carbohydrate metabolism and amino acid metabolism were the main metabolic pathways. Glycoside hydrolase and glycosyltransferase genes were the most abundant, accounting for more than 70% of the total number of active enzyme genes. A total of 113 enzymes related to key flavors and 39 microorganisms corresponding to enzymes were annotated. And Staphylococcus_gallinarum, Lactobacillus_agilis, Weissella_confusa, Pediococcus_acidilactici, Staphylococcus_kloosii, Aspergillus_oryzae, and Aspergillus_flavus played a key role in the metabolic pathway. This study reveals the formation mechanism of key flavors in fermented broad bean, it is important for guiding the industrial production of PXDB and improving product quality.

FDA Approval Summary: Tremelimumab in Combination with Durvalumab for the Treatment of Patients with Unresectable Hepatocellular Carcinoma.

On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma. The approval was based on the results from the HIMALAYA study, in which patients with unresectable hepatocellular carcinoma who were naïve to previous systemic treatment were randomly assigned to receive one of three study arms: tremelimumab in combination with durvalumab (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The primary objective of improvement in overall survival (OS) for tremelimumab in combination with durvalumab compared with sorafenib met statistical significance with a stratified HR of 0.78 [95% confidence interval (CI), 0.66-0.92; P = 0.0035]. The median OS was 16.4 months (95% CI, 14.2-19.6) with tremelimumab in combination with durvalumab and 13.8 months (95% CI, 12.3-16.1) with sorafenib. Adverse reactions occurring in ≥20% of patients receiving tremelimumab in combination with durvalumab were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg, i.v., as a single dose in combination with durvalumab 1,500 mg at cycle 1/day 1, followed by durvalumab 1,500 mg, i.v., every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg, i.v., as a single dose in combination with durvalumab 20 mg/kg, i.v., followed by durvalumab 20 mg/kg, i.v., every 4 weeks.

Inhibiting cholesterol de novo synthesis promotes hepatocellular carcinoma progression by upregulating prostaglandin E synthase 2-mediated arachidonic acid metabolism under high fatty acid conditions.

Inhibition of cholesterol de novo synthesis (DNS) by statins has controversial effects on the treatment of hepatocellular carcinoma (HCC). High fatty acid conditions have been reported to limit the effect of statins on metabolism diseases. Whether high fatty acid conditions interfere with the effect of statins on HCC remains unclear. Here, we reported that inhibiting cholesterol DNS with atorvastatin promoted the oncogenic capabilities of diethylnitrosamine (DEN) in mice fed high fatty acid diets (HFD). The combined analysis of metabolomics and transcriptomics revealed that arachidonic acid (AA) metabolism was the most significant changed pathway between mice with and without atorvastatin treatment. In vitro, in the presence of AA precursor linoleic acid (LA), atorvastatin promoted the proliferation and migration ability of HCC cell lines. However, in the absence of LA, these phenomena disappeared. TCGA and tissue microarray examination revealed that prostaglandin e synthase 2 (PTGES2), a key enzyme in AA metabolism, was associated with the poor outcome of HCC patients. Overexpression of PTGES2 promoted the proliferation and migration of HCC cell lines, and knockdown of PTGES2 inhibited the proliferation and migration of cells. Additionally, atorvastatin upregulated PTGES2 expression by enhancing Sterol-regulatory element binding protein 2 (SREBP2)-mediated transcription. Knockdown of PTGES2 reversed the proliferation and migration ability enhanced by atorvastatin. Overall, our study reveals that a high fatty acid background is one of the possible conditions limiting the application of statins in HCC, under which statins promote the progression of HCC by enhancing SREBP2-mediated PTGES2 transcription.

Nutrient Solution Flowing Environment Affects Metabolite Synthesis Inducing Root Thigmomorphogenesis of Lettuce (Lactuca sativa L.) in Hydroponics.

The principal difference between hydroponics and other substrate cultivation methods is the flowing liquid hydroponic cultivation substrate. Our previous studies have revealed that a suitable flowing environment of nutrient solution promoted root development and plant growth, while an excess flow environment was unfavorable for plants. To explain the thigmomorphogenetic response of excess flow-induced metabolic changes, six groups of lettuce (Lactuca sativa L.), including two flow conditions and three time periods, were grown. Compared with the plants without flow, the plants with flow showed decreased root fresh weight, total root length, root surface area, and root volume but increased average root diameter and root density. The roots with flow had more upregulated metabolites than those without flow, suggesting that the flow may trigger metabolic synthesis and activity. Seventy-nine common differential metabolites among six groups were screened, and enrichment analysis showed the most significant enrichment in the arginine biosynthesis pathway. Arginine was present in all the groups and exhibited greater concentrations in roots with flow than without flow. It can be speculated from the results that a high-flowing environment of nutrient solution promotes arginine synthesis, resulting in changes in root morphology. The findings provide insights on root thigmomorphogenesis affected by its growing conditions and help understand how plants respond to environmental mechanical forces.

Asymmetric Electrolytes Design for Aqueous Multivalent Metal Ion Batteries.

With the rapid development of portable electronics and electric road vehicles, high-energy-density batteries have been becoming front-burner issues. Traditionally, homogeneous electrolyte cannot simultaneously meet diametrically opposed demands of high-potential cathode and low-potential anode, which are essential for high-voltage batteries. Meanwhile, homogeneous electrolyte is difficult to achieve bi- or multi-functions to meet different requirements of electrodes. In comparison, the asymmetric electrolyte with bi- or multi-layer disparate components can satisfy distinct requirements by playing different roles of each electrolyte layer and meanwhile compensates weakness of individual electrolyte. Consequently, the asymmetric electrolyte can not only suppress by-product sedimentation and continuous electrolyte decomposition at the anode while preserving active substances at the cathode for high-voltage batteries with long cyclic lifespan. In this review, we comprehensively divide asymmetric electrolytes into three categories: decoupled liquid-state electrolytes, bi-phase solid/liquid electrolytes and decoupled asymmetric solid-state electrolytes. The design principles, reaction mechanism and mutual compatibility are also studied, respectively. Finally, we provide a comprehensive vision for the simplification of structure to reduce costs and increase device energy density, and the optimization of solvation structure at anolyte/catholyte interface to realize fast ion transport kinetics.

CRISPR-Cas9-Mediated Cytosine Base Editing Screen for the Functional Assessment of CALR Intron Variants in Japanese Encephalitis Virus Replication.

The Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes viral encephalitis in humans, pigs and other mammals across Asia and the Western Pacific. Genetic screening tools such as CRISPR screening, DNA sequencing and RNA interference have greatly improved our understanding of JEV replication and its potential antiviral approaches. However, information on exon and intron mutations associated with JEV replication is still scanty. CRISPR-Cas9-mediated cytosine base editing can efficiently generate C: G-to-T: A conversion in the genome of living cells. One intriguing application of base editing is to screen pivotal variants for gene function that is yet to be achieved in pigs. Here, we illustrate that CRISPR-Cas9-mediated cytosine base editor, known as AncBE4max, can be used for the functional analysis of calreticulin (CALR) variants. We conducted a CRISPR-Cas9-mediated cytosine base editing screen using 457 single guide RNAs (sgRNAs) against all exons and introns of CALR to identify loss-of-function variants involved in JEV replication. We unexpectedly uncovered that two enriched sgRNAs targeted the same site in intron-2 of the CALR gene. We found that mutating four consecutive G bases in the intron-2 of the CALR gene to four A bases significantly inhibited JEV replication. Thus, we established a CRISPR-Cas9-mediated cytosine-base-editing point mutation screening technique in pigs. Our results suggest that CRISPR-mediated base editing is a powerful tool for identifying the antiviral functions of variants in the coding and noncoding regions of the CALR gene.

Expression and clinical significance of RBBP4 gene in lower-grade glioma: An integrative analysis.

This study investigated the expression pattern of retinoblastoma binding protein 4 (RBBP4) gene in glioma and explored its associations with clinicopathologic characteristics and prognosis of patients. Data retrieved from the GEPIA, CGGA, HPA and TIMER databases were processed to analyze RBBP4 expression in glioma and investigate its relationship with clinicopathologic characteristics, tumor immune infiltration and prognosis in glioma patients. Immunohistochemistry was applied to determine the expression of RBBP4 protein in glioma tissue. Additionally, the Coexpedia database was visited to identify co-expressed genes for RBBP4 gene, while the Cytoscape software was run to visualize the enriched GO entries and KEGG pathways of these co-expressed genes. The expression levels of RBBP4 in lower-grade glioma (LGG) and glioblastoma (GBM) tissues were markedly elevated when compared to normal tissues (both p < 0.05). The up-regulation of RBBP4 expression was associated with an increase in WHO grade (II-IV), wild-type IDH, and 1p/19q non-codeletion (all p < 0.05). Multi-variate Cox regression analysis showed that both increased abundance of infiltrating macrophages and up-regulated RBBP4 expression independently predicted poor survival outcomes in LGG patients (both p < 0.05). Furthermore, RBBP4 expression exhibited significant positive correlations with the abundance of infiltrating B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell in LGG (all p < 0.05). Functional enrichment analyses indicated that the co-expressed genes associated with RBBP4 were highly involved in pathways such as the p53 signaling pathway, cell cycle, DNA replication, glutathione metabolism, as well as biological processes including cell cycle process, DNA replication, and DNA repair. High levels of RBBP4 are predictive for the poor survival outcome of LGG patients. RBBP4 gene, therefore, is expected to be a potential biomarker for prognosis of LGG and a target for immunotherapy.

Operational and Intervention Effects of Targeted Tuina in Lumbar Intervertebral Disc Degeneration Model Rabbits.

Tui Na or massage therapy alleviates symptoms related to intervertebral disc degeneration (IDD). However, precise, repeatable, standardized instructions for Tuina manipulation are lacking. This study establishes IDD model rabbits induced by fibrous ring puncture, creates targeted Tuina stimulation protocols at the acupuncture points in the lumbar region, and describes in detail the operation methods and requirements of kneading, pointing, and flicking. New Zealand male white rabbits (n = 15) were selected and randomly divided into a blank group, a model group, and a Tuina group. The rabbits in the model group and the Tuina group were molded by fibrous ring puncture; the rabbits in the model group were only immobilized on the operating table without treatment. In contrast, the Tuina group used the "8N/10N, 30 cycles/min" prescription for kneading, pointing, and flicking to perform the intervention, using tactile sensory aids to monitor and regulate the intensity of the Tuina operation. Imaging diagnosis and pathological tests were used to assess the effect of Tuina in rabbits, and the results showed improved imaging features and significantly lowered pathology scores of lumbar disc degeneration in the Tuina group compared to the model group (P < 0.01). Targeted Tuina in the lumbar region may be beneficial in the alleviation of lumbar disc degeneration, but further verification is needed. By regularly performing Tuina and recording the mechanical information involved enables reproducible manipulation prescriptions and helps to observe the basic features of the underlying mechanism of Tuina for IDD.

Synergistic Effect of N-NiMoO4 /Ni Heterogeneous Interface with Oxygen Vacancies in N-NiMoO4 /Ni/CNTs for Superior Overall Water Splitting.

The exploring of economical, high-efficiency, and stable bifunctional catalysts for hydrogen evolution and oxygen evolution reactions (HER/OER) is highly imperative for the development of electrolytic water. Herein, a 3D cross-linked carbon nanotube supported oxygen vacancy (Vo )-rich N-NiMoO4 /Ni heterostructure bifunctional water splitting catalyst (N-NiMoO4 /Ni/CNTs) is synthesized by hydrothermal-H2 calcination method. Physical characterization confirms that Vo -rich N-NiMoO4 /Ni nanoparticles with an average size of ≈19 nm are secondary aggregated on CNTs that form a hierarchical porous structure. The formation of Ni and NiMoO4 heterojunctions modify the electronic structure of N-NiMoO4 /Ni/CNTs. Benefiting from these properties, N-NiMoO4 /Ni/CNTs drives an impressive HER overpotential of only 46 mV and OER overpotential of 330 mV at 10 mA cm-2 , which also shows exceptional cycling stability, respectively. Furthermore, the as-assembled N-NiMoO4 /Ni/CNTs||N-NiMoO4 /Ni/CNTs electrolyzer reaches a cell voltage of 1.64 V at 10 mA cm-2 in alkaline solution. Operando Raman analysis reveals that surface reconstruction is essential for the improved catalytic activity. Density functional theory (DFT) calculations further demonstrate that the enhanced HER/OER performance should be attributed to the synergistic effect of Vo and heteostructure that improve the conductivity of N-NiMoO4 /Ni/CNTs and facilitatethe desorption of reaction intermediates.

Targeting DNA polymerase ß elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia.

Mismatch repair (MMR) deficiency has been linked to thiopurine resistance and hypermutation in relapsed acute lymphoblastic leukemia (ALL). However, the repair mechanism of thiopurine-induced DNA damage in the absence of MMR remains unclear. Here, we provide evidence that DNA polymerase ß (POLB) of base excision repair (BER) pathway plays a critical role in the survival and thiopurine resistance of MMR-deficient ALL cells. In these aggressive resistant ALL cells, POLB depletion and its inhibitor oleanolic acid (OA) treatment result in synthetic lethality with MMR deficiency through increased cellular apurinic/apyrimidinic (AP) sites, DNA strand breaks and apoptosis. POLB depletion increases thiopurine sensitivities of resistant cells, and OA synergizes with thiopurine to kill these cells in ALL cell lines, patient-derived xenograft (PDX) cells and xenograft mouse models. Our findings suggest BER and POLB's roles in the process of repairing thiopurine-induced DNA damage in MMR-deficient ALL cells, and implicate their potentials as therapeutic targets against aggressive ALL progression.

[Progress of researches on acupuncture treatment of allergic rhinitis].

Acupuncture therapy has been widely used in clinical treatment of allergic rhinitis (AR), and can induce a positive therapeutic effect through multi-targets and multi-aspects. In recent 10 years, the research on the mechanisms of acupuncture in treating AR mainly focused on humoral immunity, cellular immunity, cell apoptosis, inflammatory mediators and factors, neuropeptides, etc. By regulating the level of immunoglobulin in the blood, acupuncture intervention can restore the relative balance of cellular immune response, reduce the accumulation of eosinophils and promote apoptosis, down-regulate the expression of related inflammatory mediators and factors, regulate the excitability of related nerves, modulate the release of neuropeptides and other ways to diminish the inflammatory reaction of nasal mucosa, and enhance the repair and protection of nasal mucosa, relieve the nasal symptoms at last. On the basis of the existing studies, the follow-up research should make use of the advantages of acupuncture intervention, refine the treatment process, and deeply explore the feasibility of acupuncture treatment of AR, further promote the combination of mechanism study and clinical practice, provide references for clinical application. Moreover, some shortcomings exist, for example, the unknown correlation between the therapeutic effect and duration of treatment, the unknown correlation between the effect of acupuncture and various targets, and disconnection between experimental research achievements and clinical application, etc.

Correction: Zhang et al. Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B1-Induced Oxidative Damage. Antioxidants 2022, 11, 1787.

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