How can we establish animal models of HIV-associated lymphoma?

Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV-associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Association of visceral adipose tissue with albuminuria and interaction between visceral adiposity and diabetes on albuminuria.

AIMS: To explore the correlation between visceral adipose tissue and albuminuria, and whether there is interaction between visceral adipose tissue and diabetes on albuminuria. METHODS: The study subjects were adult subjects (age ≥ 18 years) from the National Health and Nutrition Examination Surveys (NHANES) database of the USA in 2017-2018. Visceral fat area (VFA) was measured by dual-energy X-ray absorptiometry (DXA). Subjects were divided into three groups according to VFA: low (VFA 0-60cm2), medium (VFA 60-120 cm2) and high (VFA ≥ 120 cm2). Albuminuria was defined as urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. The statistical analysis software used is STATA 17.0. RESULTS: Data pertaining to 2965 participants (2706 without albuminuria) were included in the analysis. High VFA is an independent risk factor for albuminuria (OR 1.367, 95% CI 1.023-1.827). In the low-VFA group, there is no significant association between diabetes and albuminuria (OR 1.415, 95% CI 0.145-13.849). In the medium-VFA group, diabetes is an independent risk factor for albuminuria (OR 2.217, 95% CI 1.095-4.488). In the high-VFA group, diabetes is also an independent risk factor for albuminuria (OR 5.150, 95% CI 3.150-8.421). There is an additive interaction between high VFA (VFA ≥ 120 cm2) and diabetes on the effect of albuminuria (RERI 3.757, 95% CI 0.927-6.587, p = 0.009), while no multiplication interaction (OR 1.881, 95% CI 0.997-1.023, p = 0.141). CONCLUSIONS: High VFA may represent an independent risk factor for albuminuria. The amount of visceral fat may affect the effect of diabetes on albuminuria. The higher the visceral fat, the stronger the correlation between diabetes and albuminuria should be present. We suppose an additive interaction between VFA and diabetes on the effect of albuminuria.

Construction of an Escherichia coli chassis for efficient biosynthesis of human-like N-linked glycoproteins.

The production of N-linked glycoproteins in genetically engineered Escherichia coli holds significant potential for reducing costs, streamlining bioprocesses, and enhancing customization. However, the construction of a stable and low-cost microbial cell factory for the efficient production of humanized N-glycosylated recombinant proteins remains a formidable challenge. In this study, we developed a glyco-engineered E. coli chassis to produce N-glycosylated proteins with the human-like glycan Gal-ß-1,4-GlcNAc-ß-1,3-Gal-ß-1,3-GlcNAc-, containing the human glycoform Gal-ß-1,4-GlcNAc-ß-1,3-. Our initial efforts were to replace various loci in the genome of the E. coli XL1-Blue strain with oligosaccharyltransferase PglB and the glycosyltransferases LsgCDEF to construct the E. coli chassis. In addition, we systematically optimized the promoter regions in the genome to regulate transcription levels. Subsequently, utilizing a plasmid carrying the target protein, we have successfully obtained N-glycosylated proteins with 100% tetrasaccharide modification at a yield of approximately 320 mg/L. Furthermore, we constructed the metabolic pathway for sialylation using a plasmid containing a dual-expression cassette of the target protein and CMP-sialic acid synthesis in the tetrasaccharide chassis cell, resulting in a 40% efficiency of terminal α-2,3- sialylation and a production of 65 mg/L of homogeneously sialylated glycoproteins in flasks. Our findings pave the way for further exploration of producing different linkages (α-2,3/α-2,6/α-2,8) of sialylated human-like N-glycoproteins in the periplasm of the plug-and-play E. coli chassis, laying a strong foundation for industrial-scale production.

[Determination of six halogenated solvent residues in olive oil by headspace gas chromatography].

The residual amount of halogenated solvents in olive oil is an important indicator of its quality. The National Olive Oil Quality Standard GB/T 23347-2021 states that the residual amount of individual halogenated solvents in olive oil should be ≤0.1 mg/kg and that the total residual amount of halogenated solvents should be ≤0.2 mg/kg. COI/T.20/Doc. No. 8-1990, which was published by the International Olive Council, describes the standard method used for the determination of halogenated solvents in olive oil. Unfortunately, this method is cumbersome, has poor repeatability and low automation, and is unsuitable for the detection and analysis of residual halogenated solvents in large quantities of olive oil. At present, no national standard method for determining residual halogenated solvents in olive oil is available in China. Thus, developing simple, efficient, accurate, and stable methods for the determination of residual halogenated solvents in olive oil is imperative. In this paper, a method based on automatic headspace gas chromatography was established for the determination of residual halogenated solvents, namely, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, dibromochloromethane, tetrachloroethylene, and bromoform, in olive oil. The samples were processed as follows. After mixing, 2.00 g (accurate to 0.01 g) of the olive oil sample was added into a 20 mL headspace injection bottle and immediately sealed for headspace gas chromatography analysis. Blank virgin olive oil was used to prepare a standard working solution and the external standard method for quantification. The solvents used in the preparation of halogenated solvent standard intermediates were investigated and methanol was selected as a replacement for N,N-dimethylacetamide to prepare a halogenated solvent standard intermediate owing to its safety. The effects of different injection times (1, 2, 3, 4, 5, 6 s), equilibration temperatures (60, 70, 80, 90, 100, 110, 120 ℃), and equilibration times (4, 5, 8, 10, 20, 30, 40 min) of the headspace sampler on the detection of the residual amounts of the six halogenated solvents were investigated. The optimal injection time and equilibration temperature were 3 s and 90 ℃, respectively. The method demonstrated good analytical performance for the six halogenated solvents when the equilibration time was 30 min. A methodological study was conducted on the optimized method, and the results showed that the six halogenated solvents exhibited good linear relationships in the range of 0.002-0.200 mg/kg, with correlation coefficients of ≥0.9991. The limits of detection (LODs) and quantification (LOQs) of 1,1,1-trichloroethane and bromoform were 0.0006 and 0.002 mg/kg, respectively. The LODs and LOQs of chloroform, carbon tetrachloride, dibromochloromethane, and tetrachloroethylene were 0.0003 and 0.001 mg/kg, respectively. The average recoveries under different spiked levels were 85.53%-115.93%, and the relative standard deviations (n=6) were 1.11%-8.48%. The established method was used to analyze 13 olive oil samples available in the market. Although no halogenated solvents were detected in these samples, a limited number of samples does not represent all olive oils. Hence, monitoring residual halogenated solvents in olive oil remains necessary for its safe consumption. The LOQs of the method for the six halogenated solvents were significantly lower than that of the COI/T.20/Doc. No. 8-1990 standard method (0.02 mg/kg). In addition, the developed method can be conducted under short operation times with high precision and degree of automation as well as good accuracy. Thus, the proposed method is suitable for the determination and analysis of the residues of the six halogenated solvents in large batches of olive oil samples.

Alleviatory Role of Panax Notoginseng Saponins in Modulating Inflammation and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease: mechanisms and Implications.

COPD is an inflammatory lung disease that limits airflow and remodels the pulmonary vascular system. This study delves into the therapeutic potential and mechanistic underpinnings of Panax notoginseng Saponins (PNS) in alleviating inflammation and pulmonary vascular remodeling in a COPD rat model. Symmap and ETCM databases provided Panax notoginseng-related target genes, and the CTD and DisGeNET databases provided COPD-related genes. Intersection genes were subjected to protein-protein interaction analysis and pathway enrichment to identify downstream pathways. A COPD rat model was established, with groups receiving varying doses of PNS and a Roxithromycin control. The pathological changes in lung tissue and vasculature were examined using histological staining, while molecular alterations were explored through ELISA, RT-PCR, and Western blot. Network pharmacology research suggested PNS may affect the TLR4/NF-κB pathway linked to COPD development. The study revealed that, in contrast to the control group, the COPD model exhibited a significant increase in inflammatory markers and pathway components such as TLR4, NF-κB, HIF-1α, VEGF, ICAM-1, SELE mRNA, and serum TNF-α, IL-8, and IL-1ß. Treatment with PNS notably decreased these markers and mitigated inflammation around the bronchi and vessels. Taken together, the study underscores the potential of PNS in reducing lung inflammation and vascular remodeling in COPD rats, primarily via modulation of the TLR4/NF-κB/HIF-1α/VEGF pathway. This research offers valuable insights for developing new therapeutic strategies for managing and preventing COPD.

Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage.

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Influencing factors of kinesiophobia among stroke patients with hemiplegia: A mixed methods study.

OBJECTIVES: There is a scarcity of data regarding the effects of kinesiophobia on stroke patients with hemiplegia. Therefore, this paper aims to evaluate the level of kinesiophobia experienced by stroke patients with hemiplegia in China, examine the elements that influence it, and investigate the unique psychological experience of kinesiophobia combined with a qualitative study. METHODS: This mixed study was conducted in two steps. Four approved scales were used to evaluate a total of 163 patients: (i) Tampa Scale of Kinesiophobia, (ii) Pain Catastrophizing Scale, (iii) Self-Efficacy for Exercise Scale, and (iv) Hospital Anxiety and Depression Scale. A multivariate linear regression model was used to evaluate the predictors of kinesiophobia in stroke patients with hemiplegia. Subsequently, semi-structured interviews with 15 stroke patients with hemiplegia were conducted using an objective sampling method, and the Colaizzi 7-step analysis process was utilized to analyze the interview data. RESULTS: A total of 163 stroke patients with hemiplegia were included in this study, of them, 47.9% reported kinesiophobia. Multiple linear regression revealed that the influencing factors of kinesiophobia in stroke patients with hemiplegia were a history of falls, exaggeration, helplessness, anxiety, depression, and low exercise self-efficacy (P<0.05). The qualitative research focuses on two main topics: personal adoption of negative coping styles and insufficient external support. CONCLUSION: Our study showed that the kinesiophobia in stroke patients with hemiplegia was high, with several factors influencing their kinesiophobia. Some of these factors are modifiable and should be considered when formulating kinesiophobia intervention strategies for stroke patients with hemiplegia.

mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

BACKGROUND: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. METHODS AND RESULTS: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models. CONCLUSIONS: Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum.

QTL Mapping of Adult Plant Resistance to Powdery Mildew in Chinese Wheat Landrace Baidatou.

Wheat powdery mildew, caused by the biotrophic fungus Blumeria graminis f. sp. tritici (Bgt), is one of the most devastating diseases affecting wheat throughout the world. Breeding and growing resistant wheat cultivars is one of the most economic and effective methods to control the disease, and as such, identifying and mapping the new and effective resistance genes is critical. Baidatou, a Chinese wheat landrace, shows excellent field resistance to powdery mildew. To identify the resistance gene(s) in Baidatou, 170 F7:8 recombinant inbred lines (RILs) derived from the cross Mingxian 169/Baidatou were evaluated for powdery mildew response at the adult-plant stage in the experimental fields in Yangling (YL) of Shaanxi Province and Tianshui (TS) in Gansu Province in 2019, 2020, and 2021. The relative area under disease progress curve (rAUDPC) of Mingxian 169/Baidatou F7:8 RILs indicated that the resistance of Baidatou to powdery mildew was controlled by quantitative trait loci (QTLs). Based on bulk segregation analysis combined with the 660K single nucleotide polymorphism (SNP) array and genotyping by target sequencing (16K SNP) of the entire RIL population, two QTLs, QPmbdt.nwafu-2AS and QPmbdt.nwafu-3AS, were identified, and these accounted for up to 44.5% of the phenotypic variation. One of the QTLs was located on the 3.32 cM genetic interval on wheat chromosome 2AS between the kompetitive allele-specific PCR markers AX-111012288 and AX_174233809, and another was located on the 9.6 cM genetic interval on chromosome 3AS between the SNP markers 3A_684044820 and 3A_686681822. These markers could be useful for successful breeding of powdery mildew resistance in wheat.

Design, Synthesis, Antifungal Activity, and Molecular Docking Studies of Novel Chiral Isoxazoline-Benzofuran-Sulfonamide Derivatives.

Succinate dehydrogenase (SDH) is one of the most important molecular targets for the development of novel fungicides. With the emerging problem of resistance in plant fungal pathogens, novel compounds with high fungicidal activity need to be developed, but the study of chiral pesticides for the inhibition of highly destructive plant pathogens has been rarely reported in recent years. Therefore, a series of novel chiral isoxazoline-benzofuran-sulfonamide derivatives were designed to investigate potential novel antifungal molecules. The chiral target compound 3a was cultured as a single crystal and confirmed using X-ray diffraction. All the target compounds were tested for antifungal activity, and compounds 3c, 3i, 3s, and 3r were found to have significant antifungal effects against S. sclerotiorum with EC50 values of 0.42 mg/L, 0.33 mg/L, 0.37 mg/L, and 0.40 mg/L, respectively, which were superior to the commercial fungicide fluopyram (EC50 = 0.47 mg/L). The IC50 value of compound 3i against the SDH of S. sclerotiorum was 0.63 mg/mL, which was further demonstrated by enzyme activity assays. Scanning electron microscopy showed that 3i had a significant inhibitory effect on S. sclerotiorum. In addition, the fluorescence quenching analysis assay indicated that compound 3i had a similar effect with the positive control fluopyram. Molecular docking exhibited that target compounds with chiral configuration had better affinity than racemic configuration, and 3i possessed stronger action than fluopyram, which was in keeping with the in vitro test results. These results would provide a basis and reference for the development of novel chiral fungicides.

Proteomics Platform Reveals Broad-Spectrum Nanobodies for SARS-CoV-2 Variant Neutralization.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of different variants of concerns with immune evasion that have been prevalent over the past three years. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, have garnered interest in developing neutralizing antibodies due to their smaller size, structural stability, ease of production, high affinity, and low immunogenicity, among other characteristics. In this work, we describe an integrated proteomics platform for the high-throughput screening of nanobodies against different SARS-CoV-2 spike variants. To demonstrate this platform, we immunized a camel with subunit 1 (S1) of the wild-type spike protein and constructed a nanobody phage library. The binding and neutralizing activities of the nanobodies against 72 spike variants were then measured, resulting in the identification of two nanobodies (C-282 and C-39) with broad neutralizing activity against six non-Omicron variants (D614G, Alpha, Beta, Gamma, Delta, Kappa) and five Omicron variants (BA.1-5). Their neutralizing capability was validated using in vitro pseudovirus-based neutralization assays. All these results demonstrate the utility of our proteomics platform to identify new nanobodies with broad neutralizing capability and to develop a treatment for patients with SARS-CoV-2 variant infection in the future.

Establishment of pregnancy-specific lipid reference intervals in pregnant women in a single-centre and assessment of the predictive value of early lipids for gestational diabetes mellitus: a prospective cohort study.

INTRODUCTION: This study was aimed at establishing a pregnancy-specific lipid reference interval (RI) in pregnant women in a single-centre in the Beijing area of China, simultaneously exploring the predictive value of lipid levels in early pregnancy for gestational diabetes mellitus (GDM). MATERIAL AND METHODS: From October 2017 to August 2019, Peking University International Hospital established records for 1588 pregnant women, whose lipid profiles were determined during the first and third trimesters. The Hoffmann technique was used to calculate gestation-specific lipid RI. The 95% reference range for gestational lipids was also estimated for 509 healthy pregnant women screened according to the Clinical and Laboratory Standards Institute guideline. Multivariate logistic regression analysis was used to calculate odds ratios (OR) and their 95% confidence interval (CI), and the receiver operating characteristic (ROC) curve was applied to assess the predictive value of lipids in the first trimester for the diagnosis of GDM. RESULTS: Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in the third trimester (p < 0.05). Hoffmann technique RI of the lipid profiles and the 95% reference range of the lipid profiles in healthy pregnant women did not differ statistically (p > 0.05). TC, TG, and LDL-C levels were higher in the GDM group in the first trimester (p < 0.05), and the risk of GDM was 2.1 times higher in women with higher TG (95% CI: 1.13-3.77, p < 0.05). The optimal ROC cut-off for TG to predict GDM was 2.375 mmol / L, and the area under the ROC curve was 0.622 (95% CI: 0.592-0.751), with a sensitivity of 73.7% and a specificity of 59.3%. CONCLUSIONS: This study established pregnancy-specific lipid RI for pregnant women in a single centre in the Beijing area of China. Pregnant women with TG ≥ 2.375 mmol/L in the first trimester were at significantly increased risk for GDM.

Population genetic patterns across the native and invasive range of a widely distributed seagrass: Phylogeographic structure, invasive history and conservation implications.

Aim: The seagrass Zostera japonica is a dramatically declined endemic species in the Northwestern Pacific from the (sub)tropical to temperate areas, however, it is also an introduced species along the Pacific coast of North America from British Columbia to northern California. Understanding the population's genetic patterns can inform the conservation and management of this species. Location: North Pacific. Methods: We used sequences of the nuclear rDNA internal transcribed spacer (ITS) and chloroplast trnK intron maturase (matK), and 24 microsatellite loci to survey 34 native and nonnative populations (>1000 individuals) of Z. japonica throughout the entire biogeographic range. We analysed the phylogeographic relationship, population genetic structure and genetic diversity of all populations and inferred possible origins and invasion pathways of the nonnative ones. Results: All markers revealed a surprising and significant deep divergence between northern and southern populations of Z. japonica in the native region separated by a well-established biogeographical boundary. A secondary contact zone was found along the coasts of South Korea and Japan. Nonnative populations were found to originate from the central Pacific coast of Japan with multiple introductions from at least two different source populations, and secondary spread was likely aided by waterfowl. Main Conclusions: The divergence of the two distinct clades was likely due to the combined effects of historical isolation, adaptation to distinct environments and a contemporary physical barrier created by the Yangtze River, and the warm northward Kuroshio Current led to secondary contact after glacial separation. Existing exchanges among the nonnative populations indicate the potential for persistence and further expansion. This study not only helps to understand the underlying evolutionary potential of a widespread seagrass species following global climate change but also provides valuable insights for conservation and restoration.

Emergence of Poultry-Associated Human Salmonella enterica Serovar Abortusovis Infections, New South Wales, Australia.

Salmonella enterica serovar Abortusovis is a ovine-adapted pathogen that causes spontaneous abortion. Salmonella Abortusovis was reported in poultry in 2009 and has since been reported in human infections in New South Wales, Australia. Phylogenomic analysis revealed a clade of 51 closely related isolates from Australia originating in 2004. That clade was genetically distinct from ovine-associated isolates. The clade was widespread in New South Wales poultry production facilities but was only responsible for sporadic human infections. Some known virulence factors associated with human infections were only found in the poultry-associated clade, some of which were acquired through prophages and plasmids. Furthermore, the ovine-associated clade showed signs of genome decay, but the poultry-associated clade did not. Those genomic changes most likely led to differences in host range and disease type. Surveillance using the newly identified genetic markers will be vital for tracking Salmonella Abortusovis transmission in animals and to humans and preventing future outbreaks.

Expert Consensus on Ion Channel Drugs for Chronic Pain Treatment in China.

Ion channel drugs have been increasing used for chronic pain management with progress in the development of selective calcium channel modulators. Although ion channel drugs have been proven safe and effective in clinical practice, uncertainty remains regarding its use to treat chronic pain. To standardize the clinical practice of ion channel drug for the treatment of chronic pain, the National Health Commission Capacity Building and Continuing Education Center for Pain Diagnosis and Treatment Special Ability Training Project established an expert group to form an expert consensus on the use of ion channel drugs for the treatment of chronic pain after repeated discussions on existing medical evidence combined with the well clinical experience of experts. The consensus provided information on the mechanism of action of ion channel drugs and their recommendations, caution use, contraindications, and precautions for their use in special populations to support doctors in their clinical decision-making.

Enhanced synthesis of S-adenosyl-L-methionine through combinatorial metabolic engineering and Bayesian optimization in Saccharomyces cerevisiae.

S-Adenosyl-L-methionine (SAM) is a substrate for many enzyme-catalyzed reactions and provides methyl groups in numerous biological methylations, and thus has vast applications in the agriculture and medical field. Saccharomyces cerevisiae has been engineered as a platform with significant potential for producing SAM, but the current production has room for improvement. Thus, a method that consists of a series of metabolic engineering strategies was established in this study. These strategies included enhancing SAM synthesis, increasing ATP supply, down-regulating SAM metabolism, and down-regulating competing pathway. After combinatorial metabolic engineering, Bayesian optimization was conducted on the obtained strain C262P6S to optimize the fermentation medium. A final yield of 2972.8 mg·L-1 at 36 h with 29.7% of the L-Met conversion rate in the shake flask was achieved, which was 26.3 times higher than that of its parent strain and the highest reported production in the shake flask to date. This paper establishes a feasible foundation for the construction of SAM-producing strains using metabolic engineering strategies and demonstrates the effectiveness of Bayesian optimization in optimizing fermentation medium to enhance the generation of SAM.

Relations Between Posttraumatic Growth and Fear of Progression Among Young and Middle-Aged Primary Brain Tumor Patients: The Parallel Mediating Role of Perceived Social Support and Illness Uncertainty.

OBJECTIVE: This study aimed to investigate the mediating role of perceived social support and illness uncertainty in posttraumatic growth (PTG) and fear of progression (FoP) among young and middle-aged primary brain tumor (PBT) patients. METHODS: A total of 252 young and middle-aged benign PBT patients were investigated. Data were collected by using self-designed general and disease-related data questionnaires, PTG Inventory, FoP Questinaire-Short Form, Mischel Uncertainty in Illness Scale, and Perceived Social Support Scale. Parallel mediation effect models were used to explore the relationship between PTG and FoP mediation effects. Bootstrap analysis was conducted to examine the mediation effect of PTG on FoP. RESULTS: The total FoP and PTG scores were 35.15 ± 4.85 and 55.04 ± 7.86. Furthermore, mediation effect analyses revealed that perceived social support and illness uncertainty were partially associated with the mediated relationship between PTG and FoP. (std.ß = -0.026, P-value = 0.001, std. ß = -0.393, P value ＜0.001, respectively). CONCLUSIONS: Illness uncertainty and perceived social support were identified as partially parallel mediators between PTG and FoP. Thus, we should ensure adequate social support and improve the enthusiasm and input of family members for better patient recovery. Strengthening the nursing support, reducing the uncertainty of young and middle-aged PBT patients, and improving the patients' PTG can help reduce the fear of disease progression.

Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis.

Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.

Longitudinal plasma proteomic analysis identifies biomarkers and combinational targets for anti-PD1-resistant cancer patients.

The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10-12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.