Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance.

Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive (ER+) breast cancer. However, the efficacy of agents such as tamoxifen (Tam) is often compromised by the development of resistance. Here we report that cytokines-activated nuclear IKKα confers Tam resistance to ER+ breast cancer by inducing the expression of FAT10, and that the expression of FAT10 and nuclear IKKα in primary ER+ human breast cancer was correlated with lymphotoxin ß (LTB) expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam. IKKα activation or enforced FAT10 expression promotes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity. The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKα attenuates p53-directed repression of FAT10. Thus, our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+ breast cancer.

Abscisic acid ameliorates d-galactose -induced aging in mice by modulating AMPK-SIRT1-p53 pathway and intestinal flora.

Abscisic acid (ABA) is a plant hormone with various biological activities. Aging is a natural process accompanied by cognitive and physiological decline, and aging and its associated diseases pose a serious threat to public health, but its mechanisms remain insufficient. Therefore, the purpose of this study was to investigate the ameliorative effects of ABA on d-galactose (D-Gal)-induced aging in mice and to delve into its molecular mechanisms. Aging model was es-tablished by theintraperitoneal injection of D-Gal. We evaluated the oxidative stress by measuring superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) levels in serum. Proteins content in brain were determined by Western blot. D-Gal-induced brain damage was monitored by measuring the levels of acetylcholinesterase (AChE) content and hematoxylin-eosin staining (H&E). To evaluate the effects of ABA on aging, we measured the gut microbiota. The results demonstrated that ABA increased SOD, CAT and AChE, decreased MDA level. H&E staining showed that ABA could improve D-Gal-induced damage. In addition, ABA regulated the B-cell-lymphoma-2 (BCL-2) family and Phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling pathway, while further regulating the acetylation of p53 protein by modulating the AMPK pathway and activating SIRT1 protein, thereby inhibiting the apoptosis of brain neurons and thus regulating the aging process. Interestingly, ABA improved the ratio of intestinal bacteria involved in regulating multiple metabolic pathways in the aging process, such as Bacteroides, Firmicutes, Lactobacillus and Ak-kermansia. In conclusion, the present study suggests that ABA may be responsible for improving and delaying the aging process by enhancing antioxidant activity, anti-apoptosis and regulating intestinal flora.

Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Acute Lymphoblastic Leukemias, Mixed-Phenotype Acute Leukemias, Myeloid/Lymphoid Neoplasms With Eosinophilia, Dendritic/Histiocytic Neoplasms, and Genetic Tumor Syndromes.

This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms, and genetic tumor syndromes of the 5th edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The diagnostic, clinicopathologic, cytogenetic, and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the World Health Organization classification of hematolymphoid neoplasms are highlighted.

SPRY1 Deficiency in Keratinocytes Induces Follicular Melanocyte Stem Cell Migration to the Epidermis through p53/Stem Cell Factor/C-KIT Signaling.

The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes (KCs). KCs and melanocytes respond to UV exposure by eliciting a tanning response. However, how KCs and melanocytes interact in the absence of UV exposure is unknown. In this study, we demonstrate that after SPRY1 knockout in epidermal KCs, melanocyte stem cells in the hair follicle exit the niche without depleting the pool of these cells. We also found that melanocyte stem cells migrate to the epidermis in a p53/stem cell factor/C-KIT-dependent manner induced by a tanning-like response resulting from SPRY1 loss in epidermal KCs. Once there, these cells differentiate into functional melanocytes. These findings provide an example in which the migration of melanocyte stem cells to the epidermis is due to loss of SPRY1 in epidermal KCs and show the potential for developing therapies for skin pigmentation disorders by manipulating melanocyte stem cells.

The identification of a novel compound heterozygous mutation in hereditary human coagulation factor VII deficiency following a bamboo leaf green snake bite.

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

Readthrough events in plants reveal plasticity of stop codons.

Stop codon readthrough (SCR) has important biological implications but remains largely uncharacterized. Here, we identify 1,009 SCR events in plants using a proteogenomic strategy. Plant SCR candidates tend to have shorter transcript lengths and fewer exons and splice variants than non-SCR transcripts. Mass spectrometry evidence shows that stop codons involved in SCR events can be recoded as 20 standard amino acids, some of which are also supported by suppressor tRNA analysis. We also observe multiple functional signals in 34 maize extended proteins and characterize the structural and subcellular localization changes in the extended protein of basic transcription factor 3. Furthermore, the SCR events exhibit non-conserved signature, and the extensions likely undergo protein-coding selection. Overall, our study not only characterizes that SCR events are commonly present in plants but also identifies the recoding plasticity of stop codons, which provides important insights into the flexibility of genetic decoding.

Comparison of changes in adipokine and inflammatory cytokine levels in patients with newly diagnosed type 2 diabetes treated with exenatide, insulin, or pioglitazone: A post-hoc study of the CONFIDENCE trial.

Background: Adipokines and inflammatory cytokines (ADICs) play important roles in type 2 diabetes mellitus (T2DM). This study aimed to compare the changes of ADIC levels (ΔADICs) in patients with newly diagnosed T2DM treated with different antihyperglycemic agents, and further investigate the impact of these changes on metabolic indices, ß-cell function and insulin resistance (IR). Methods: Four hundred and sixteen patients with newly diagnosed T2DM from 25 centers in China randomly received 48-week intervention with exenatide, insulin or pioglitazone. Anthropometric and laboratory data, indices of ß-cell function and IR, and levels of AIDCs, including interleukin-1 beta (IL-1ß), interferon-gamma (IFN-γ), leptin, and fibroblast growth factor 21 (FGF21) were detected at baseline and the end of the study. Results: In total, 281 participants (68 % male, age: 50.3 ± 9.4 years) completed the study. After 48- week treatment, IL-1ß and IFN-γ were significantly decreased with exenatide treatment (P < 0.001 and P = 0.001, respectively), but increased with insulin (P = 0.009 and P = 0.026, respectively). However, pioglitazone treatment had no impact on ADICs. No significant change in leptin or FGF21 was detected with any of the treatments. After adjustment for baseline values and changes of body weight, waist and HbA1c, the between-group differences were found in ΔIL-1ß (exenatide vs. insulin: P = 0.048; and exenatide vs. pioglitazone: P = 0.003, respectively) and ΔIFN-γ (exenatide vs. insulin: P = 0.049; and exenatide vs. pioglitazone: P < 0.001, respectively). Multiple linear regression analysis indicated that Δweight was associated with ΔIL-1ß (ß = 0.753; 95 % CI, 0.137-1.369; P = 0.017). After adjusting for treatment effects, Δweight was also be correlated with ΔFGF21 (ß = 1.097; 95%CI, 0.250-1.944; P = 0.012); furthermore, ΔHOMA-IR was correlated with Δleptin (ß = 0.078; 95%CI, 0.008-0.147; P = 0.029) as well. However, ΔHOMA-IR was not significantly associated with ΔIL-1ß after adjusting for treatment effects (P = 0.513). Conclusion: Exenatide treatment led to significant changes of inflammatory cytokines levels (IL-1ß and IFN-γ), but not adipokines (leptin and FGF21), in newly diagnosed T2DM patients. The exenatide-mediated improvement in weight and IR may be associated with a decrease in inflammatory cytokine levels.

Synergically regulated silver species and surface oxygen on manganese oxide for promoted activity of formaldehyde oxidation.

Formaldehyde (HCHO) is a common indoor pollutant that is detrimental to human health. Its efficient removal has become an urgent demand to reduce the public health risk. In this work, Ag-MnOx-based catalysts were prepared and activated under different atmosphere (i.e., air, hydrogen (H2) and carbon monoxide (CO)) for efficient oxidation of HCHO. The catalyst activated with CO (Ag/Mn-CO) displayed the highest activity among the tested samples with 90% conversion at 100°C under a gas space velocity of 75,000 mL/(gcat·hr). Complementary characterizations demonstrate that CO reduction treatment resulted in synergically regulated content of surface oxygen on support to adsorb/activate HCHO and size of Ag particle to dissociate oxygen to oxidize the adsorbed HCHO. In contrast, other catalysts lack for either abundant surface oxygen species or metallic silver with the appropriate particle size, so that the integrate activity is limited by one specific reaction step. This study contributes to elucidating the mechanisms regulating the oxidation activity of Ag-based catalysts.

Incorporation of Epoxy Carbon onto CeO2-Supported Pt to Tackle the CO Self-Poisoning Issue.

The catalytic oxidation of carbon monoxide (CO) under ambient conditions plays a crucial role in the abatement of indoor CO, which poses risks to human health. Despite the notable activity exhibited by Pt-based catalysts in CO oxidation, their efficacy is usually diminished by the CO self-poisoning issue. In this work, three different Pt/CeO2-based catalysts, which have distinct coordinative environments of Pt but an identical Pt/CeO2 substrate structure, were synthesized by activating the catalyst with CO using different temperatures and durations. Compared with clean and graphite-covered Pt on CeO2, the one modified by epoxy carbon showed higher activity and stability. The combination of characterizations and density functional theory modeling demonstrated that the clean Pt on CeO2 rapidly deactivated due to the CO self-poisoning albeit high initial activity, and conversely, low initial activity was observed for the more stable graphite-covered catalyst due to the obstruction of the Pt site. In contrast, epoxy carbon species on Pt shifted the d-band of Pt to lower energy, weakening the Pt-CO binding strength. Such a modification mitigated the self-poisoning effect while maintaining ample active sites and enabling the complete oxidative removal of CO under ambient conditions. This work may provide a general approach to tackling the self-poisoning issue.

Epidermal keratinocyte-specific STAT3 deficiency aggravated atopic dermatitis-like skin inflammation in mice through TSLP upregulation.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.

Chromosome-scale genome assembly of sweet tea (Lithocarpus polystachyus Rehder).

Lithocarpus, with >320 species, is the second largest genus of Fagaceae. However, the lack of a reference genome limits the molecular biology and functional study of Lithocarpus species. Here, we report the chromosome-scale genome assembly of sweet tea (Lithocarpus polystachyus Rehder), the first Lithocarpus species to be sequenced to date. Sweet tea has a 952-Mb genome, with a 21.4-Mb contig N50 value and 98.6% complete BUSCO score. In addition, the per-base consensus accuracy and completeness of the genome were estimated at 60.6 and 81.4, respectively. Genome annotation predicted 37,396 protein-coding genes, with repetitive sequences accounting for 64.2% of the genome. The genome did not undergo whole-genome duplication after the gamma (γ) hexaploidy event. Phylogenetic analysis showed that sweet tea diverged from the genus Quercus approximately at 59 million years ago. The high-quality genome assembly and gene annotation resources enrich the genomics of sweet tea, and will facilitate functional genomic studies in sweet tea and other Fagaceae species.

DDX5 Functions as a Tumor Suppressor in Tongue Cancer.

DEAD-box polypeptide 5 (DDX5), a DEAD-box RNA helicase, is a multifunctional protein that plays important roles in many physiological and pathological processes. Contrary to its documented oncogenic role in a wide array of cancers, we herein demonstrate that DDX5 serves as a tumor suppressor in tongue cancer. The high expression of DDX5 is correlated with better prognosis for clinical tongue cancer patients. DDX5 downregulates the genes associated with tongue cancer progression. The knockdown of DDX5 promotes, while the overexpression of DDX5 inhibits, tongue cancer proliferation, development, and cisplatin resistance. Furthermore, the expression of DDX5 in tongue cancer is associated with immune cell infiltration in the tumor microenvironment. Specifically, the expression of DDX5 is associated with the reduced infiltration of M2 macrophages and increased infiltration of T cell clusters, which may contribute to anticancer effects in the tumor microenvironment. In this study, we establish DDX5 as a valuable prognostic biomarker and an important tumor suppressor in tongue cancer.

Fu Brick Tea as a Staple Food Supplement Attenuates High Fat Diet Induced Obesity in Mice.

Fu brick tea (FBT), a product of microbial fermentation from primary dark tea, also known as raw material tea (RMT), has been extensively studied for its functional properties. However, its potential as a staple food supplement for weight loss remains poorly understood. This study compared the weight loss effects of orlistat, traditional plain noodles (NN), and noodles supplemented with varying amounts of RMT (RMTN) and FBT (FBTN), with the aim to elucidate their lipid-reducing effects and underlying mechanisms. Experimental trials on high fat diet fed mice revealed significant weight loss, lipid-lowering, and hypoglycemic effects upon supplementation with orlistat, RMTN, and FBTN. Moreover, supplementation with orlistat, RMTN, and FBTN effectively restored serum and liver-related index levels, mitigating high-fat diet-induced dyslipidemia. Additionally, these supplements ameliorated liver and kidney damage by inhibiting oxidative stress and inflammatory responses. Furthermore, orlistat, RMTN, and FBTN exert their anti-obesity effects primarily by modulating genes associated with lipid metabolism and inflammatory responses and through regulation of the composition and structure of the gut microbiota. Importantly, FBTN demonstrated a significantly stronger lipid-lowering effect compared to RMTN, particularly at higher tea addition ratios. In contrast, NN supplementation exhibited minimal to no weight loss effects. Based on these findings, it could be inferred that FBT holds promise as a staple food supplement to ameliorate high-fat diet-induced obesity and its associated health conditions.

Flow Cytometric Assessment of Myelodysplastic Syndromes/Neoplasms.

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous class of hematopoietic stem cell neoplasms characterized by ineffective hematopoiesis leading to peripheral cytopenias. This group of diseases is typically diagnosed using a combination of clinical, morphologic, and genetic criteria. Many studies have described the value of multiparametric flow cytometry (MFC) in the diagnosis, classification, and prognostication of MDS. This review summarizes the approach to MDS diagnosis and immunophenotypic characterization using MFC and describes the current state while highlighting future opportunities and potential pitfalls.

Clinical Validation of FusionPlex RNA Sequencing and Its Utility in the Diagnosis and Classification of Hematologic Neoplasms.

Recurrent gene rearrangements result in gene fusions that encode chimeric proteins, driving the pathogenesis of many hematologic neoplasms. The fifth edition World Health Organization classification and International Consensus Classification 2022 include an expanding list of entities defined by such gene rearrangements. Therefore, sensitive and rapid methods are needed to identify a broad range of gene fusions for precise diagnosis and prognostication. In this study, we validated the FusionPlex Pan-Heme panel analysis using anchored multiplex PCR/targeted RNA next-generation sequencing for routine clinical testing. Furthermore, we assessed its utility in detecting gene fusions in myeloid and lymphoid neoplasms. The validation cohort of 61 cases demonstrated good concordance between the FusionPlex Pan-Heme panel and other methods, including chromosome analysis, fluorescence in situ hybridization, RT-PCR, and Sanger sequencing, with an analytic sensitivity and specificity of 95% and 100%, respectively. In an independent cohort of 28 patients indicated for FusionPlex testing, gene fusions were detected in 21 patients. The FusionPlex Pan-Heme panel analysis reliably detected fusion partners and patient-specific fusion sequences, allowing accurate classification of hematologic neoplasms and the discovery of new fusion partners, contributing to a better understanding of the pathogenesis of the diseases.

Glycyl-tRNA Synthetase Induces Psoriasis-Like Skin by Facilitating Skin Inflammation and Vascular Endothelial Cell Angiogenesis.

Psoriasis is characterized by excessive keratinocyte proliferation and immunocyte infiltration, but the underlying pathogenesis remains unclear. Aminoacyl-tRNA synthetases are universally expressed enzymes that catalyze the first step of protein synthesis. Glycyl-tRNA synthetase (GARS) is a member of the aminoacyl-tRNA synthetase family. In addition to its canonical function, we found that GARS was overexpressed in the serum and skin lesions of patients with psoriasis. Moreover, GARS was highly expressed in human skin keratinocytes, and GARS knockdown in keratinocytes suppressed cell proliferation and promoted apoptosis through NF-κB/MAPK signaling pathway. Moreover, intradermal injection of recombinant GARS protein caused skin thickening, angiogenesis, and IFN/TNF-driven skin inflammation. Intriguingly, the reported functional receptor for GARS, cadherin 6 (CDH6), was specifically expressed in vascular endothelial cells, and we found that keratinocyte-derived GARS promotes inflammation and angiogenesis of vascular endothelial cells through CDH6. In addition, intradermal injection of GARS aggravated the phenotype and angiogenesis in imiquimod-induced psoriasiform dermatitis models, whereas the psoriatic phenotype and angiogenesis were relieved after knockdown of GARS by adeno-associated virus. Taken together, the results of this study identify the critical role of GARS in the pathogenesis of psoriasis and suggest that blocking GARS may be a therapeutic approach for alleviating psoriasis.

Starch granules and their size distribution in wheat: Biosynthesis, physicochemical properties and their effect on flour-based food systems.

Starch is a vital component of wheat grain and flour, characterized by two distinct granule types: A-type starch (AS) with granules larger than 10 µm in diameter, and B-type starch (BS) with granules measuring no more than 10 µm in diameter. This review comprehensively evaluates the isolation, purification, and biosynthesis processes of these types of granules. In addition, a comparative analysis of the structure and properties of AS and BS is presented, encompassing chemical composition, molecular, crystalline and morphological structures, gelatinization, pasting and digestive properties. The variation in size distribution of granules leads to differences in physicochemical properties of starch, influencing the formation of polymeric proteins, secondary and micro-structures of gluten, chemical and physical interactions between gluten and starch, and water absorption and water status in dough system. Thus, starch size distribution affects the quality of dough and final products. In this review, we summarize the up-to-date knowledge of AS and BS, and propose the possible strategies to enhance wheat yield and quality through coordinated breeding efforts. This review serves as a valuable reference for future advancements in wheat breeding.

Decoding Human Biology and Disease Using Single-cell Omics Technologies.

Over the past decade, advances in single-cell omics (SCO) technologies have enabled the investigation of cellular heterogeneity at an unprecedented resolution and scale, opening a new avenue for understanding human biology and disease. In this review, we summarize the developments of sequencing-based SCO technologies and computational methods, and focus on considerable insights acquired from SCO sequencing studies to understand normal and diseased properties, with a particular emphasis on cancer research. We also discuss the technological improvements of SCO and its possible contribution to fundamental research of the human, as well as its great potential in clinical diagnoses and personalized therapies of human disease.

Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway.

Breast cancer is the most prevalent malignancy among women. Doxorubicin (Dox) resistance was one of the major obstacles to improving the clinical outcome of breast cancer patients. The purpose of this study was to investigate the relationship between the FABP signaling pathway and Dox resistance in breast cancer. The resistance property of MCF-7/ADR cells was evaluated employing CCK-8, Western blot (WB), and confocal microscopy techniques. The glycolipid metabolic properties of MCF-7 and MCF-7/ADR cells were identified using transmission electron microscopy, PAS, and Oil Red O staining. FABP5 and CaMKII expression levels were assessed through GEO and WB approaches. The intracellular calcium level was determined by flow cytometry. Clinical breast cancer patient's tumor tissues were evaluated by immunohistochemistry to determine FABP5 and p-CaMKII protein expression. In the presence or absence of FABP5 siRNA or the FABP5-specific inhibitor SBFI-26, Dox resistance was investigated utilizing CCK-8, WB, and colony formation methods, and intracellular calcium level was examined. The binding ability of Dox was explored by molecular docking analysis. The results indicated that the MCF-7/ADR cells we employed were Dox-resistant MCF-7 cells. FABP5 expression was considerably elevated in MCF-7/ADR cells compared to parent MCF-7 cells. FABP5 and p-CaMKII expression were increased in resistant patients than in sensitive individuals. Inhibition of the protein expression of FABP5 by siRNA or inhibitor increased Dox sensitivity in MCF-7/ADR cells and lowered intracellular calcium, PPARγ, and autophagy. Molecular docking results showed that FABP5 binds more powerfully to Dox than the known drug resistance-associated protein P-GP. In summary, the PPARγ and CaMKII axis mediated by FABP5 plays a crucial role in breast cancer chemoresistance. FABP5 is a potentially targetable protein and therapeutic biomarker for the treatment of Dox resistance in breast cancer.