Refining the genetic diagnostic puzzle: A case report on a Chinese ARPKD patient with a reciprocal balanced translocation and c.2507 T > C (p.V836A) in PKHD1.

INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD) ranks among the most severe chronic kidney diseases (CKD). Its primary cause is variants in the Polycystic Kidney and Hepatic Disease 1 gene (PKHD1). The clinical spectrum of ARPKD varies widely, ranging from mild late-onset symptoms to severe perinatal mortality. However, achieving an early genetic diagnosis in ARPKD patients before clinical symptoms appear proves challenging. CASE PRESENTATION: This case is a 4-year-old boy who experienced a convulsion characterized by a generalized tonic attack lasting approximately 3-5 minutes and later sought treatment to our hospital. However, routine abdominal ultrasound examination accidentally detected that he had diffuse liver lesions, splenomegaly, and bilateral renal enlargement with renal pelvis dilation. Given the uncertainty regarding the underlying cause of the patient's structural abnormalities and convulsions, karyotyping, whole exome sequencing (WES), structural variant analysis (SV analysis) of whole genome sequencing (WGS) were recommended. The result of SV analysis revealed that he has an RBT impacting PKHD1 and the precise location of breakpoints was confirmed through Long-Range Polymerase Chain Reaction (LR-PCR). However, WES did not screen out pathogenic variants initially, the WES data was reviewed subsequently based on SV analysis results. CONCLUSION: We identified an infrequent variant combination, c.2507T>C (p.V836A) in PKHD1 and an RBT with broken PKHD1, which extends the genetic spectrum of ARPKD, and provide a basis for further genetic counselling to the family.

Weight loss rather than weight gain has a detrimental effect on successful aging in older adults: A 4-year longitudinal study in China.

This study explored the effect of weight change on successful aging in older adults. A total of 1865 adults (≥65 years) were divided into the weight gain group (weight gain ≥5 %), the weight loss group (weight loss ≥5 %), and the weight stable group (weight change <5 %) according to weight changes over 4 years. Results showed that compared to the stable weight, the weight loss is associated with a lower rate of successful aging (OR=0.64, 95 % CI: 0.49-0.83), and the association was found greater in women (OR=0.61, 95 % CI: 0.43-0.86) and young-old adults (OR=0.66, 95 % CI: 0.41-0.88) than their counterparts. However, no significant association was found between weight gain and successful aging. The findings suggest that weight loss rather than weight gain in older adults has a detrimental impact on successful aging, and this detrimental impact is greater in women and young-old adults.

Ascle-A Python Natural Language Processing Toolkit for Medical Text Generation: Development and Evaluation Study.

BACKGROUND: Medical texts present significant domain-specific challenges, and manually curating these texts is a time-consuming and labor-intensive process. To address this, natural language processing (NLP) algorithms have been developed to automate text processing. In the biomedical field, various toolkits for text processing exist, which have greatly improved the efficiency of handling unstructured text. However, these existing toolkits tend to emphasize different perspectives, and none of them offer generation capabilities, leaving a significant gap in the current offerings. OBJECTIVE: This study aims to describe the development and preliminary evaluation of Ascle. Ascle is tailored for biomedical researchers and clinical staff with an easy-to-use, all-in-one solution that requires minimal programming expertise. For the first time, Ascle provides 4 advanced and challenging generative functions: question-answering, text summarization, text simplification, and machine translation. In addition, Ascle integrates 12 essential NLP functions, along with query and search capabilities for clinical databases. METHODS: We fine-tuned 32 domain-specific language models and evaluated them thoroughly on 27 established benchmarks. In addition, for the question-answering task, we developed a retrieval-augmented generation (RAG) framework for large language models that incorporated a medical knowledge graph with ranking techniques to enhance the reliability of generated answers. Additionally, we conducted a physician validation to assess the quality of generated content beyond automated metrics. RESULTS: The fine-tuned models and RAG framework consistently enhanced text generation tasks. For example, the fine-tuned models improved the machine translation task by 20.27 in terms of BLEU score. In the question-answering task, the RAG framework raised the ROUGE-L score by 18% over the vanilla models. Physician validation of generated answers showed high scores for readability (4.95/5) and relevancy (4.43/5), with a lower score for accuracy (3.90/5) and completeness (3.31/5). CONCLUSIONS: This study introduces the development and evaluation of Ascle, a user-friendly NLP toolkit designed for medical text generation. All code is publicly available through the Ascle GitHub repository. All fine-tuned language models can be accessed through Hugging Face.

The Marine-Origin Exopolysaccharide-Producing Bacteria Micrococcus Antarcticus HZ Inhibits Pb Uptake in Pakchoi (Brassica chinensis L.) and Affects Rhizosphere Microbial Communities.

Exopolysaccharides (EPSs) produced by microorganisms play an important role in biotolerance and reducing heavy metal (HM) contamination by limiting the migration of HMs into plants. However, research on the application of EPS-producing marine bacteria for soil heavy metal remediation remains limited, particularly regarding their mechanisms of HM immobilization in soil and impact on plant growth. In this study, the EPS-producing marine bacterium Micrococcus antarcticus HZ was investigated for its ability to immobilize Pb and produce EPSs in soil filtrate. The effects on the growth quality and biomass of pakchoi (Brassica chinensis L.), as well as bacterial communities in inter-root soil contaminated with Pb, were also investigated. The results indicated that HZ could reduce the Pb concentration in the soil filtrate, achieving a removal rate of 43.25-63.5%. The EPS content and pH levels increased in the presence of Pb. Pot experiments showed that adding HZ significantly increased the biomass of pakchoi (9.45-14.69%), vitamin C (Vc) (9.69-12.92%), and soluble protein content (22.58-49.7%). HZ reduced the Pb content in the roots (17.52-47.48%) and leaves (edible tissues) (43.82-52.83%) of pakchoi. HZ increased soil enzyme activities (alkaline phosphatase, dehydrogenase, and urease), and the contents of ammonium nitrogen and nitrate nitrogen. Additionally, HZ also increased the relative abundance of beneficial bacteria (e.g., Proteobacteria, Cyanobacteria, and Chlorobacteria) in the inter-root soil, which have prophylactic and heavy-metal fixation functions. In summary, HZ reduces effective Pb content in edible tissues, roots, and inter-root soil by regulating inter-root soil microbial community structure, increasing soil pH, nitrogen content, and soil enzyme activity, and altering dominant phylum abundance.

Effect of childhood atropine treatment on adult choroidal thickness using sequential deep learning-enabled segmentation.

PURPOSE: To describe choroidal thickness measurements using a sequential deep learning segmentation in adults who received childhood atropine treatment for myopia control. DESIGN: Prospective, observational study. METHODS: Choroidal thickness was measured by swept-source optical coherence tomography in adults who received childhood atropine, segmented using a sequential deep learning approach. RESULTS: Of 422 eyes, 94 (22.3 %) had no previous exposure to atropine treatment, while 328 (77.7 %) had received topical atropine during childhood. After adjusting for age, sex, and axial length, childhood atropine exposure was associated with a thicker choroid by 32.1 µm (95 % CI, 9.2-55.0; P = 0.006) in the inner inferior, 23.5 µm (95 % CI, 1.9-45.1; P = 0.03) in the outer inferior, 21.8 µm (95 % CI, 0.76-42.9; P = 0.04) in the inner nasal, and 21.8 µm (95 % CI, 2.6-41.0; P = 0.03) in the outer nasal. Multivariable analysis, adjusted for age, sex, atropine use, and axial length, showed an independent association between central subfield choroidal thickness and the incidence of tessellated fundus (P < 0.001; OR, 0.97; 95 % CI, 0.96-0.98). CONCLUSIONS: This study demonstrated that short-term (2-4 years) atropine treatment during childhood was associated with an increase in choroidal thickness of 20-40 µm in adulthood (10-20 years later), after adjusting for age, sex, and axial length. We also observed an independent association between eyes with thicker central choroidal measurements and reduced incidence of tessellated fundus. Our study suggests that childhood exposure to atropine treatment may affect choroidal thickness in adulthood.

Insights into the distinct membrane targeting mechanisms of WDR91 family proteins.

WDR91 and SORF1, members of the WD repeat-containing protein 91 family, control phosphoinositide conversion by inhibiting phosphatidylinositol 3-kinase activity on endosomes, which promotes endosome maturation. Here, we report the crystal structure of the human WDR91 WD40 domain complexed with Rab7 that has an unusual interface at the C-terminus of the Rab7 switch II region. WDR91 is highly selective for Rab7 among the tested GTPases. A LIS1 homology (LisH) motif within the WDR91 N-terminal domain (NTD) mediates self-association and may contribute partly to the augmented interaction between full-length WDR91 and Rab7. Both the Rab7 binding site and the LisH motif are indispensable for WDR91 function in endocytic trafficking. For the WDR91 orthologue SORF1 lacking the C-terminal WD40 domain, a C-terminal amphipathic helix (AH) mediates strong interactions with liposomes containing acidic lipids. During evolution the human WDR91 ancestor gene might have acquired a WD40 domain to replace the AH for endosomal membrane targeting.

Extragastrointestinal stromal tumors with diffuse membranous distribution with bleeding: A case report.

BACKGROUND: Extragastrointestinal stromal tumors (EGIST) and gastrointestinal stromal tumors are of similar pathological type and form. Here we report a rare case of EGIST diffusely distributed in membranous tissue in abdominal cavity, the feature of which included diffuse tumors at membranous tissue in entire abdominal cavity and spontaneous bleeding of the tumors. CASE SUMMARY: The patient was a 71-year man and hospitalized due to continuous pain at lower abdomen for more than 10 days. Upon physical examination, the patient had flat and tough abdomen with mild pressing pain at lower abdomen, no obvious abdominal mass was touchable, and shifting dullness was positive. Positron emission tomography-computed tomography (CT) showed that in his peritoneal cavity, there were multiple nodules of various sizes, seroperitoneum, multiple enlarged lymph nodes in abdominal/pelvic cavity and right external ilium as well as pulmonary nodules. Plain CT scanning at epigastrium/hypogastrium/pelvic cavity + enhanced three-dimensional reconstruction revealed multiple soft tissue nodules in abdominal/pelvic cavity, peritoneum and right groin. Tumor marker of carbohydrate antigen 125 was 808 U/mL, diffuse tuberous tumor was seen in abdominal/pelvic cavity during operation with hematocelia, and postoperative pathological examination confirmed EGIST. Imatinib was administered with better therapeutic effect. CONCLUSION: Gene testing showed breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 and KIT genovariation, and the patient was treated with imatinib follow-up visit found that his clinical symptoms disappeared and the tumor load alleviated obviously via imageological examination.

Involvement of SIRT1-mediated cellular immune response in cancer.

The morbidity and mortality of cancer are rising rapidly worldwide and immunotherapy has become an effective means to curb the progress of cancer. Sirtuin-1(SIRT1) is a NAD+ -dependent deacetylase that plays a key role in cancer development and immune regulation through mediating a variety of signaling pathways. Targeting SIRT1 in immunotherapy could enhance or erod immune responses against cancer cells, while SIRT1 activator and inhibitors are being developed as potential antineoplastic agents with important implications in clinic. This review summarizes the impact of SIRT1 in different types of immune cells and mechanism of SIRT1-mediated immune responses in tumor progression as well as its therapeutic perspectives.

Effects of cellulase treatment on properties of lignocellulose-based biochar.

As the most abundant renewable carbon source, lignocellulose holds potential as a raw material for biofuels and biochar. The components required for biofuel production differ from those for biochar, so combining processes can reduce costs. Biofuel preparation necessitates cellulase treatment of lignocellulose. This study examines the effects of various enzyme treatment conditions (dosage, time, temperature) on lignocellulose, focusing on the properties of biochar derived from it (BC-SR). A mathematical model was constructed to study the relationship between enzyme treatment conditions and BC-SR properties. BC-SR exhibited high adsorption selectivity for bisphenol A and outperformed untreated biochar in fixed-bed column experiments, demonstrating greater removal efficiency and structural integrity. This study provides insights into the impact of enzymatic treatment on biochar and offers a cost-effective method for producing stable, efficient biochar. Additionally, a highly persistent biochar can enter the carbon trading market as a carbon-neutral technology, further realizing economic and environmental benefits.

Association between high-density lipoprotein-related inflammation index and periodontitis: insights from NHANES 2009-2014.

BACKGROUND: Periodontitis, a persistent inflammatory condition, significantly impairs individuals' overall quality of life. Lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), and platelet-to-high-density lipoprotein cholesterol ratio (PHR) are new convenient and economical biomarkers. However, whether the above high-density lipoprotein-related inflammatory biomarkers are associated with periodontitis has rarely been investigated. Therefore, the research endeavor focused on uncovering potential relationships. METHODS: The research encompassed a diverse and extensive sample, comprising 9,470 participants, selected from the National Health and Nutrition Examination Survey spanning the years 2009 to 2014. The association between high-density lipoprotein-related inflammatory biomarkers and periodontitis was explored utilizing a multivariable logistic regression model with weighted analysis. Additionally, the study employed smoothed curve fitting to explore potential nonlinear relationships. Further stratified analyses and interaction tests were performed. RESULTS: This study indicated no apparent association between MHR and PHR with periodontitis, whereas LHR and NHR demonstrated a statistically significant positive relationship with the prevalence of periodontitis. In the fully adjusted model, participants belonging to the highest tertile of both LHR and NHR showed a notably higher likelihood of having periodontitis compared to those in the lowest tertile (LHR: OR = 1.22, 95% CI: 1.06, 1.39; NHR: OR = 1.27, 95% CI: 1.09, 1.49). Furthermore, smooth curve fitting was employed to investigate the potential nonlinear relationship between LHR, NHR, and periodontitis. The results indicated that there was a significant increase in the occurrence of periodontitis when Log2 (LHR) exceeded 1.01 and Log2(NHR) surpassed 2.16 (Log2(LHR): OR = 1.42; 95% CI: 1.19, 1.69; Log2(NHR): OR = 1.40; 95% CI: 1.15, 1.71). The subgroup analysis revealed that the associations between periodontitis and either LHR or NHR, separately, were more pronounced among individuals under the age of 50 and those without hypertension. CONCLUSIONS: This cross-sectional study revealed a positive relationship between LHR、NHR and periodontitis, particularly when these indicators exceeded their thresholds. LHR and NHR may serve as potential inflammatory markers for identifying periodontitis, thereby facilitating early warning for both patients and dentists, and enabling early intervention in the oral environment. Besides, extensive prospective cohort investigations are essential to confirm and solidify this observation.

LINC00887 promotes GCN5-dependent H3K27cr level and CRC metastasis via recruitment of YEATS2 and enhancing ETS1 expression.

Recent observations have revealed upregulation of H3K27cr in colorectal cancer (CRC) tissues; however, the underlying cause remains elusive. This study aimed to investigate the mechanism of H3K27cr upregulation and its roles in CRC metastasis. Clinically, our findings showed that H3K27cr served as a highly accurate diagnostic marker to distinguish CRC tissues from healthy controls. Elevated levels of LINC00887 and H3K27cr were associated with a poorer prognosis in CRC patients. Functionally, LINC00887 and H3K27cr facilitated the migration and invasion of CRC cells. Mechanistically, LINC00887 interacted with SIRT3 protein. Overexpressed of LINC00887 obstructed the enrichment of SIRT3 within GCN5 promoter, thereby elevating H3K27ac but not H3K27cr level within this region, subsequently activating GCN5 expression. This activation increased the global level of H3K27cr, promoting the enrichment of GCN5, H3K27cr, and YEATS2 within ETS1 promoter, activating ETS1 transcription and ultimately promoting the metastasis of CRC. The in vivo study demonstrated that inhibition of LINC00887 suppressed CRC metastasis, but this inhibitory effect was nullified when mice were treated with NaCr. In conclusion, our results confirmed the diagnostic biomarker potential of H3K27cr in individuals with CRC, and proposed a functional model to elucidate the involvement of LINC00887 in promoting CRC metastasis by elevating H3K27cr level.

A vascular endothelial growth factor-loaded chitosanhyaluronic acid hydrogel scaffold enhances the therapeutic effect of adipose-derived stem cells in the context of stroke.

Adipose-derived stem cell, one type of mesenchymal stem cells, is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery. However, its application has been limited by the complexities of the ischemic microenvironment. Hydrogel scaffolds, which are composed of hyaluronic acid and chitosan, exhibit excellent biocompatibility and biodegradability, making them promising candidates as cell carriers. Vascular endothelial growth factor is a crucial regulatory factor for stem cells. Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells, thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke. Here, we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells. Subsequently, we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemia-reperfusion injury. When loaded with adipose-derived stem cells, this vascular endothelial growth factor-loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology. Further in vivo experiments revealed that this vascular endothelial growth factor-loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells, leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion. It also helped maintain mitochondrial integrity and axonal morphology, greatly improving rat motor function and angiogenesis. Therefore, utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.

Proteomics reveals dynamic metabolic changes in human hematopoietic stem progenitor cells from fetal to adulthood.

BACKGROUND: Hematopoietic stem progenitor cells (HSPCs) undergo phenotypical and functional changes during their emergence and development. Although the molecular programs governing the development of human hematopoietic stem cells (HSCs) have been investigated broadly, the relationships between dynamic metabolic alterations and their functions remain poorly characterized. METHODS: In this study, we comprehensively described the proteomics of HSPCs in the human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM). The metabolic state of human HSPCs was assessed via a Seahorse assay, RT‒PCR, and flow cytometry-based metabolic-related analysis. To investigate whether perturbing glutathione metabolism affects reactive oxygen species (ROS) production, the metabolic state, and the expansion of human HSPCs, HSPCs were treated with buthionine sulfoximine (BSO), an inhibitor of glutathione synthetase, and N-acetyl-L-cysteine (NAC). RESULTS: We investigated the metabolomic landscape of human HSPCs from the fetal, perinatal, and adult developmental stages by in-depth quantitative proteomics and predicted a metabolic switch from the oxidative state to the glycolytic state during human HSPC development. Seahorse assays, mitochondrial activity, ROS level, glucose uptake, and protein synthesis rate analysis supported our findings. In addition, immune-related pathways and antigen presentation were upregulated in UCB or aBM HSPCs, indicating their functional maturation upon development. Glutathione-related metabolic perturbations resulted in distinct responses in human HSPCs and progenitors. Furthermore, the molecular and immunophenotypic differences between human HSPCs at different developmental stages were revealed at the protein level for the first time. CONCLUSION: The metabolic landscape of human HSPCs at three developmental stages (FL, UCB, and aBM), combined with proteomics and functional validations, substantially extends our understanding of HSC metabolic regulation. These findings provide valuable resources for understanding human HSC function and development during fetal and adult life.

Environmental cadmium-induced circRNA-miRNA-mRNA network regulatory mechanism in human normal liver cell model.

At present, hundreds of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been confirmed to be related to the toxicity of cadmium (Cd). However, the role of circular RNAs (circRNAs) in the toxicity of Cd and the underlying regulatory mechanisms remain unclear. In this study, we chose human normal liver cells (L-02) as a model to investigate changes in transcriptome expression levels following exposure to Cd. Total RNA of each sample was extracted by Trizol method, and the expression profiles of circRNAs, miRNAs and mRNAs of each sample were determined by microarray hybridization and scanning. After standardizing the data, differential circRNAs, miRNAs, and mRNAs associated with the toxic effects of Cd were identified. By screening the predicted circRNAs, miRNAs, and mRNAs, we constructed a competing endogenous RNA (ceRNA) network, and predicted the main biological functions and metabolic pathways influenced by Cd toxicity. Our comprehensive screening strategy led to the identification of 266 different circRNAs, 223 different miRNAs and 519 different mRNAs exhibiting differential expression. Following further screening, even circRNAs, 10 miRNAs and 97 mRNAs were incorporated into the ceRNA network. After performing GO enrichment and KEGG pathway analyses on the 97 mRNAs within the ceRNA network, which indicated that the circRNAs in the ceRNA network are poised to modulate key cellular processes, including cell proliferation, apoptosis, oxidative stress and inflammatory responses under the toxic effects of Cd-induced damage in L-02 cells.

Multi-omics analyses reveal the mechanisms underlying the responses of Casuarina equisetifolia ssp. incana to seawater atomization and encroachment stress.

Casuarina equisetifolia trees are used as windbreaks in subtropical and tropical coastal zones, while C. equisetifolia windbreak forests can be degraded by seawater atomization (SA) and seawater encroachment (SE). To investigate the mechanisms underlying the response of C. equisetifolia to SA and SE stress, the transcriptome and metabolome of C. equisetifolia seedlings treated with control, SA, and SE treatments were analyzed. We identified 737, 3232, 3138, and 3899 differentially expressed genes (SA and SE for 2 and 24 h), and 46, 66, 62, and 65 differentially accumulated metabolites (SA and SE for 12 and 24 h). The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that SA and SE stress significantly altered the expression of genes related to plant hormone signal transduction, plant-pathogen interaction, and starch and sucrose metabolism pathways. The accumulation of metabolites associated with the biosynthetic pathways of phenylpropanoid and amino acids, as well as starch and sucrose metabolism, and glycolysis/gluconeogenesis were significantly altered in C. equisetifolia subjected to SA and SE stress. In conclusion, C. equisetifolia responds to SA and SE stress by regulating plant hormone signal transduction, plant-pathogen interaction, biosynthesis of phenylpropanoid and amino acids, starch and sucrose metabolism, and glycolysis/gluconeogenesis pathways. Compared with SA stress, C. equisetifolia had a stronger perception and response to SE stress, which required more genes and metabolites to be regulated. This study enhances our understandings of how C. equisetifolia responds to two types of seawater stresses at transcriptional and metabolic levels. It also offers a theoretical framework for effective coastal vegetation management in tropical and subtropical regions.

INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling.

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4+ T and CD8+ T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-γ (IFN-γ) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-γ-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade.

Chromosome-level genome assembly and annotation of Clanis bilineata tsingtauica Mell (Lepidoptera: Sphingidae).

The soybean hawkmoth Clanis bilineata tsingtauica Mell (Lepidoptera, Sphingidae; CBT), as one of the main leaf-chewing pests of soybeans, has gained popularity as an edible insect in China recently due to its high nutritional value. However, high-quality genome of CBT remains unclear, which greatly limits further research. In the present study, we assembled a high-quality chromosome-level genome of CBT using PacBio HiFi reads and Hi-C technologies for the first time. The size of the assembled genome is 477.45 Mb with a contig N50 length of 17.43 Mb. After Hi-C scaffolding, the contigs were anchored to 29 chromosomes with a mapping rate of 99.61%. Benchmarking Universal Single-Copy Orthologues (BUSCO) completeness value is 99.49%. The genome contains 252.16 Mb of repeat elements and 14,214 protein-coding genes. In addition, chromosomal synteny analysis showed that the genome of CBT has a strong synteny with that of Manduca sexta. In conclusion, this high-quality genome provides an important resource for future studies of CBT and contributes to the development of integrated pest management strategies.

Proteomic characterization of murine hematopoietic stem progenitor cells reveals dynamic fetal-to-adult changes in metabolic-related pathways.

Hematopoietic stem progenitor cells (HSPCs) give rise to the hematopoietic system, maintain hematopoiesis throughout the lifespan, and undergo molecular and functional changes during their development and aging. The importance of hematopoietic stem cell (HSC) biology has led to their extensive characterization at genomic and transcriptomic levels. However, the proteomics of HSPCs throughout the murine lifetime still needs to be fully completed. Here, using mass spectrometry (MS)-based quantitative proteomics, we report on the dynamic changes in the proteome of HSPCs from four developmental stages in the fetal liver (FL) and the bone marrow (BM), including E14.5, young (2 months), middle-aged (8 months), and aging (18 months) stages. Proteomics unveils highly dynamic protein kinetics during the development and aging of HSPCs. Our data identify stage-specific developmental features of HSPCs, which can be linked to their functional maturation and senescence. Our proteomic data demonstrated that FL HSPCs depend on aerobic respiration to meet their proliferation and oxygen supply demand, while adult HSPCs prefer glycolysis to preserve the HSC pool. By functional assays, we validated the decreased mitochondrial metabolism, glucose uptake, reactive oxygen species (ROS) production, protein synthesis rate, and increased glutathione S-transferase (GST) activity during HSPC development from fetal to adult. Distinct metabolism pathways and immune-related pathways enriched in different HSPC developmental stages were revealed at the protein level. Our study will have broader implications for understanding the mechanism of stem cell maintenance and fate determination and reversing the HSC aging process.