PGRN inhibits CD8+T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM.

BACKGROUND: Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. METHODS: We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn-/-) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. RESULTS: We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. CONCLUSION: These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.

Paenibacillus thermotolerans sp. nov., isolated from a hot spring in Yunnan Province, south-west China.

Two Gram-positive, rod-shaped, endospore-forming strains, YIM B05601 and YIM B05602T, were isolated from soil sampled at Hamazui hot spring, Tengchong City, Yunnan Province, PR China. Phylogenetic analysis based on 16S rRNA gene sequences suggested that the two strains fell within the genus Paenibacillus, appearing most closely related to Paenibacillus alkalitolerans YIM B00362T (96.9 % sequence similarity). Genome-based phylogenetic analysis confirmed that strains YIM B05601 and YIM B05602T formed a distinct phylogenetic cluster within the genus Paenibacillus. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values of strains YIM B05601 and YIM B05602T with the related species P. alkalitolerans YIM B00362T were within the ranges of 74.43-74.57 % and 12.1-18.5 %, respectively, which clearly indicated that strains YIM B05601, YIM B05602T represented a novel species. Strains YIM B05601 and YIM B05602T exhibited 99.6 % 16S rRNA gene sequence similarity. The ANI and dDDH values between the two strains were 99.8 and 100 %, respectively, suggesting that they belong to the same species. Optimum growth for both strains occurred at pH 7.0 and 45 °C. The diagnostic diamino acid in the cell-wall peptidoglycan of strains YIM B05601 and YIM B05602T was meso-diaminopimelic acid. MK-7 was the predominant menaquinone. The polar lipids of strain YIM B05602T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, four unidentified glycolipids, an unidentified polarlipid and phosphatidylinositol mannoside. The major fatty acids of the two stains were iso-C15 : 0 and anteiso-C15 : 0. Based on phylogenomic and phylogenetic analyses coupled with phenotypic and chemotaxonomic characterizations, strains YIM B05601 and YIM B05602T could be classified as a novel species of the genus Paenibacillus, for which the name Paenibacillus thermotolerans sp. nov. is proposed. The type strain is YIM B05602T (=CGMCC 1.60051T=KCTC 43460T=NBRC 115924T).

Dietary chenodeoxycholic acid attenuates high-fat diet-induced growth retardation, lipid accumulation and bile acid metabolism disorder in the liver of yellow catfish Pelteobagrus fulvidraco.

This experiment was conducted to investigate whether dietary chenodeoxycholic acid (CDCA) could attenuate high-fat (HF) diet-induced growth retardation, lipid accumulation and bile acid (BA) metabolism disorder in the liver of yellow catfish Pelteobagrus fulvidraco. Yellow catfish (initial weight: 4·40 (sem 0·08) g) were fed four diets: the control (105·8 g/kg lipid), HF diet (HF group, 159·6 g/kg lipid), the control supplemented with 0·9 g/kg CDCA (CDCA group) and HF diet supplemented with 0·9 g/kg CDCA (HF + CDCA group). CDCA supplemented in the HF diet significantly improved growth performance and feed utilisation of yellow catfish (P < 0·05). CDCA alleviated HF-induced increment of hepatic lipid and cholesterol contents by down-regulating the expressions of lipogenesis-related genes and proteins and up-regulating the expressions of lipololysis-related genes and proteins. Compared with the control group, CDCA group significantly reduced cholesterol level (P < 0·05). CDCA significantly inhibited BA biosynthesis and changed BA profile by activating farnesoid X receptor (P < 0·05). The contents of CDCA, taurochenodeoxycholic acid and glycochenodeoxycholic acid were significantly increased with the supplementation of CDCA (P < 0·05). HF-induced elevation of cholic acid content was significantly attenuated by the supplementation of CDCA (P < 0·05). Supplementation of CDCA in the control and HF groups could improve the liver antioxidant capacity. This study proved that CDCA could improve growth retardation, lipid accumulation and BA metabolism disorder induced by HF diet, which provided new insight into understanding the physiological functions of BA in fish.

Genome-wide identification of heat shock protein gene family and their responses to pathogen challenge in Trachinotus ovatus.

Heat Shock Proteins (HSPs) are a widely distributed family of proteins produced in response to heat and other stresses. To develop a deeper understanding of the mechanisms governing expression of HSPs in the bony fish Trachinotus ovatus, we carried out a whole genome analysis and identified 43 HSP genes. Based on their phylogenetic relationships with Danio rerio, Seriola dumerili, and Seriola lalandi, they were divided into four subfamilies: HSP20, HSP60, HSP70, and HSP90. We performed an analysis of the predicted physicochemical properties and subcellular localization of proteins encoded by these genes. The chromosomal localization results showed that the HSP genes are distributed across 20 chromosomes of T. ovatus.These genes were found to be expressed in different tissues, and they showed differential expression in the immune response against Streptococcus agalactiae. However, there was no significant differential expression in the different skin tissue locations of T. ovatus after infection by Cryptocaryon irritans Brown. This study provides basic information for further research on the evolution and structure and function of HSPs in teleosts.

Description and genomic characterization of Cohnella caldifontis sp. nov., isolated from hot springs in Yunnan province, south-west China.

A bacterial strain, Gram staining positive, strictly aerobic, rod-shaped, motile bacterium with flagellum and endospore-forming, designated strain YIM B05605T, was isolated from soil sampled in Hamazui hot springs, Tengchong City, Yunnan province, China. Optimum growth for the strain occurred at pH 7.0 and 45 °C. MK-7 was the main menaquinone in the strain YIM B05605T. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. Diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylmonomethylethanolamine (PME), unidentified glycolipid (GL), three unknown aminophospholipids (APLs) and unidentified polarlipid (PL) were part of the polar lipid profile. The major fatty acids were anteiso-C15:0 and iso-C16:0. The DNA G + C content of the type strain was 58.76%. Genome-based phylogenetic analysis confirmed that strain YIM B05605T formed a distinct phylogenetic cluster within the genus Cohnella. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values of strain YIM B05605T with the most related species C. fontinalis YT-1101T were 73.42% and 15.7%. Functional analysis by NR, Swiss-prot, Pfam, eggNOG, GO, KEGG databases revealed that strain YIM B05605T has 13 genes related to the sulfur cycle, 2 genes related to the nitrogen cycle. Based on phylogenomic and phylogenetic analyses coupled with phenotypic and chemotaxonomic characterizations, strain YIM B05605T could be classified as a novel species of the genus Cohnella, for which the name Cohnella caldifontis sp. nov., is proposed. The type strain is YIM B05605T (= CGMCC 1.60052T = KCTC 43462T = NBRC 115921T).

Non-linear association of atherogenic index of plasma with bone mineral density a cross-sectional study.

INTRODUCTION: Although there has been abundant evidence of the association between dyslipidemia as a single factor and osteoporosis, the non-linear relationship between osteoporosis and the Atherogenic Index of Plasma (AIP) has not yet been thoroughly investigated. This study aimed to investigate the complex relationship between AIP and bone mineral density (BMD) to elucidate their interrelationship. METHODS: An analysis of 2007-2018 National Health and Nutrition Survey (NHANES) data was conducted for this study. The study enrolled 5,019 participants. Logarithmically multiplying triglycerides and high-density lipoprotein cholesterol yields the AIP (base 10). The measured variables consisted of BMD in the total femur (TF), femoral neck (FN), and lumbar spine (LS). The association between AIP and BMD was examined using a range of statistical models, such as weighted multivariable logistic regression, generalized additive model, etc. RESULTS: It was found that AIP was positively associated with BMD after adjusting for age, gender, race, socioeconomic status, degree of education, income, Consuming alcoholic beverages, osteoporosis status (Yes or No), ALT, AST, serum creatinine, and total calcium levels. Further studies supported the association link between elevated BMD and AIP. Furthermore, compared to men, females had a higher positive connection between AIP and BMD. In general, there was a curve in the reverse L-shape seen, with a point of change around 0.877, indicating a relationship between AIP and TF BMD. Moreover, a curve exhibiting an L-formed pattern, with a point of inflection at around 0.702, was seen between AIP and FN BMD. In addition, a J-shaped curve was seen, with a point of inflection at 0.092, which demonstrates the association between AIP and LS BMD. CONCLUSION: The AIP and TF BMD curves resemble inverted L shapes, as do the AIP and FN BMD curves. The relationship between AIP and LS BMD was further demonstrated by a J-shaped curve. The results indicate a possible association between AIP and bone mineral density, which should be explored in more detail.

Validation of a scoring algorithm for the clinician-reported outcome tool 'prurigo activity and severity (PAS)' based on clinical studies of dupilumab in adults with prurigo Nodularis.

BACKGROUND: Prurigo nodularis (PN) also known as chronic prurigo, is a chronic inflammatory skin disease characterized by intensely itchy nodules/lesions which occur due to intensive scratching. PN management is, in part, based on clinician evaluations of PN lesions, which can be supported by clinician-reported outcomes (ClinRO) such as the Prurigo Activity and Severity (PAS) instrument. A 5-item version of PAS was included in recent phase-3 dupilumab PN trials (PRIME [NCT04183335]/PRIME2 [NCT04202679]). The PAS score was derived using the unweighted sum of 3-items of the 5-item PAS (range, 0-11; higher score indicates worse activity and severity): Item 2 (number of lesions), Item 5a (percentage of lesions with excoriations/crusts) and Item 5b (percentage of healed lesions) for use in clinical practice and for communication of treatment benefit to physicians. OBJECTIVES: To evaluate the measurement properties of PAS score and derive within-patient (responder definition) and between-group improvement thresholds for interpreting changes in PAS score in patients with PN. METHODS: The data source was the pooled treatment group, intention-to-treat (ITT) data from the phase-3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. PAS score reliability, validity and sensitivity to change were evaluated, and anchor- and distribution-based methods were applied to derive meaningful change thresholds. RESULTS: The pooled ITT population included 311 patients (mean age 49.5 years, 65.3% female). Adequate to good psychometric properties were demonstrated for PAS score. The within-patient meaningful improvement threshold was estimated as 3.0 points (absolute change) and 37% (per cent change). A 1.7-point (absolute change) and 20% (per cent change) improvement were estimated to reflect a between-group meaningful change in PAS score. CONCLUSIONS: PAS score is a simple, clinically relevant indicator of PN lesion activity and severity supported by suitable psychometric performance.

Embryo development and live birth in women with one previously failed full IVF/ICSI cycle.

PURPOSE: To evaluate the embryological and pregnancy outcomes of women who failed in their first IVF treatment if they attempted a second cycle. METHODS: For evaluating the embryological outcomes, the study cohort included 1,227 women who failed to obtain a live birth after the initial IVF cycle from September 2018 to August 2021 and returned for a second attempt. To evaluate reproductive outcomes including live birth rates (LBRs), 1227 women who returned for a second attempt were compared with 13,195 women undergoing their first oocyte retrieval with blastocyst culture attempted during the same study period. RESULTS: In women who had a second cycle, the median number of oocyte retrieved (11 vs 9), fertilized oocytes (7 vs 5), usable embryos (6 vs 4) and blastocysts (3 vs 1) was higher in the second cycle compared to the first cycle (All p < 0.001). Blastocyst formation rates were significantly increased from 33% in the first cycle to 50% in the second cycle across the age group (p < 0.001). However, the primary transfer LBRs were significantly lower in the second cycle than that in the initial cycle (40.82% versus 51.79%, aOR: 0.74 [0.65, 0.84]). LBRs in the second cycle were 42.26%, 42.68%, 25.49% and 16.22% in women aged < 35, 35-37, 38-40, and > 40 years. CONCLUSION: There was a notable enhancement in laboratory outcomes following the second attempt in women whose initial IVF cycles were unsuccessful. However, the uncertainty inherent in the successful implantation and the consequent progression to live birth remains a significant challenge.

MeshID: Few-Shot Finger Gesture Based User Identification Using Orthogonal Signal Interference.

Radio frequency (RF) technology has been applied to enable advanced behavioral sensing in human-computer interaction. Due to its device-free sensing capability and wide availability on Internet of Things devices. Enabling finger gesture-based identification with high accuracy can be challenging due to low RF signal resolution and user heterogeneity. In this paper, we propose MeshID, a novel RF-based user identification scheme that enables identification through finger gestures with high accuracy. MeshID significantly improves the sensing sensitivity on RF signal interference, and hence is able to extract subtle individual biometrics through velocity distribution profiling (VDP) features from less-distinct finger motions such as drawing digits in the air. We design an efficient few-shot model retraining framework based on first component reverse module, achieving high model robustness and performance in a complex environment. We conduct comprehensive real-world experiments and the results show that MeshID achieves a user identification accuracy of 95.17% on average in three indoor environments. The results indicate that MeshID outperforms the state-of-the-art in identification performance with less cost.

Genomic structures of insulin-like growth factor from golden pompano (Trachinotus ovatus) and their expression responses to the feed types.

Golden pompano is an important aquaculture product in the coastal regions of southern China, which is highly dependent on insulin-like growth factor (IGF) for various biological processes. The cDNAs of ToIGF1, ToIGF2, and ToIGF3 are 1718 bp, 1658 bp, and 2272 bp in length, respectively, with corresponding amino acid sequences of 185 aa, 215 aa, and 194 aa. These sequences consist of 5 parts, including the signal peptide, the B domain, the C domain, the A domain, the D domain, and the E domain, which are also found in other species. While ToIGF1 has no SSR polymorphism, ToIGF2 and ToIGF3 have 3 and 1 SSR polymorphism sites, respectively. In terms of tissue expression, ToIGF1 is predominantly expressed in the liver, ToIGF2 shows its highest expression in the gills, and ToIGF3 also shows its highest expression in the gills, but no expression in the liver and spleen. These tissue distribution results suggest that ToIGFs are not only present in growth-related tissues such as the brain, muscle, and liver, but also in reproductive tissues, tissues that regulate osmotic pressure, and tissues related to food intake. This observation is consistent with other bony fish species and highlights the extensive biological functions of ToIGFs that need to be further explored and exploited. In addition, the expression levels of ToIGFs were found to be different in the different dietary groups, including the pelleted food group, the frozen squid group, and the frozen fish group. In the pelleted diet group, ToIGF1 and ToIGF2 were highly expressed in the liver and intestinal tissues, followed by the frozen fish group. These results suggest that the type of diet can affect the body's energy metabolism by influencing tissue expression of growth-related genes, which in turn affects individual growth.

Role of lipocalin 2 in stroke.

Stroke is the second leading cause of death worldwide; however, the treatment choices available to neurologists are limited in clinical practice. Lipocalin 2 (LCN2) is a secreted protein, belonging to the lipocalin superfamily, with multiple biological functions in mediating innate immune response, inflammatory response, iron-homeostasis, cell migration and differentiation, energy metabolism, and other processes in the body. LCN2 is expressed at low levels in the brain under normal physiological conditions, but its expression is significantly up-regulated in multiple acute stimulations and chronic pathologies. An up-regulation of LCN2 has been found in the blood/cerebrospinal fluid of patients with ischemic/hemorrhagic stroke, and could serve as a potential biomarker for the prediction of the severity of acute stroke. LCN2 activates reactive astrocytes and microglia, promotes neutrophil infiltration, amplifies post-stroke inflammation, promotes blood-brain barrier disruption, white matter injury, and neuronal death. Moreover, LCN2 is involved in brain injury induced by thrombin and erythrocyte lysates, as well as microvascular thrombosis after hemorrhage. In this paper, we review the role of LCN2 in the pathological processes of ischemic stroke; intracerebral hemorrhage; subarachnoid hemorrhage; and stroke-related brain diseases, such as vascular dementia and post-stroke depression, and their underlying mechanisms. We hope that this review will help elucidate the value of LCN2 as a therapeutic target in stroke.

PDK1-stabilized LncRNA SPRY4-IT1 promotes breast cancer progression via activating NF-κB signaling pathway.

Pyruvate dehydrogenase kinase 1 (PDK1) is a widely known glycolytic enzyme, and some evidence showed that PDK1 promoted breast cancer by multiple approaches. However, very few lncRNAs have been identified to be associated with PDK1 in breast cancer in previous research. In this study, we found that lncRNA sprouty4-intron transcript 1 (SPRY4-IT1) was regulated by PDK1 with correlation analysis, and PDK1 upregulated SPRY4-IT1 remarkably in breast cancer cells, as PDK1 interacted with SPRY4-IT1 in the nucleus and significantly enhanced the stability of SRPY4-IT1. Furthermore, SPRY4-IT1 was highly expressed in breast cancer, significantly promoted the proliferation and inhibited apoptosis of breast cancer cells. In terms of mechanism, SPRY4-IT1 inhibited the transcription of NFKBIA and the expression of IκBα, thus promoting the formation of p50/p65 complex and activating NF-κB signaling pathway, which facilitated survival of breast cancer cells. Therefore, our finding reveals that PDK1/SPRY4-IT1/NFKBIA axis plays a crucial role that promoting tumor progression, and SPRY4-IT1 knockdown incombined with PDK1 inhibitor is promising to be a new therapeutic strategy in breast cancer.

OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways.

BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

Construction of Functionalized α-Imino Ketones via Pd-Catalyzed C-H Addition to Nitriles/Aerobic Oxidation Sequences.

Pd(II)-catalyzed addition of sp2 C-H to nitrile/aerobic oxidation sequences for the preparation of functionalized α-imino ketones is described in which readily available heteroarenes and O-acyl cyanohydrins were employed. Various functionalized targeted molecules can be prepared in good yields with high atom and step economy. Moreover, a broad substrate scope and the ready manipulation and availability of the reaction partners enable this protocol to be appealing to explore the chemical space of the construction of functionalized α-imino ketones with high efficiency.

To cut or not to cut? A prospective randomized controlled trial on short-term outcomes of the uncut Roux-en-Y reconstruction for gastric cancer.

BACKGROUND: Roux-en-Y (R-Y) anastomoses have been widely used in distal gastrectomy, while the incidence of Roux stasis syndrome remains common. Uncut R-Y anastomosis maintains the neuromuscular continuity, thus avoiding the ectopic pacemaker of the Roux limb and reducing the occurrence of Roux stasis. However, retrospective studies of Uncut R-Y anastomosis remain scarce and randomized controlled trials have not been reported. METHODS: We conducted a randomized controlled trial to compare the surgical safety, nutritional status, and postoperative quality of life (QOL) between uncut and classic Roux-en-Y (R-Y) reconstruction patients. Patients with Stage I gastric cancer were randomly enrolled and underwent laparoscopic distal gastrectomy followed by uncut or classic R-Y reconstruction. Body mass index and blood test were used to evaluate the nutritional status. QOL was evaluated using European Organization for Research and Treatment of Cancer QOL Questionnaire (STO22) and laboratory examinations at postoperative month (POM) 3, 6, 9, and 12. Computed tomography scanning was used to evaluate the skeletal muscle index (SMI) at POM 6 and 12. Endoscopy was performed at POM 12. RESULTS: Operation time, blood loss, time to recovery, complication morbidities, and overall survival were similar between the two groups. Compared with the classic R-Y group, the uncut R-Y group displayed a significantly decreased QOL at POM 9, possibly due to loop recanalization, determined to be occupied 34.2% of the uncut R-Y group. Post-exclusion of recanalization, the QOL was still higher in the classic R-Y group than in the uncut R-Y group, despite their hemoglobin and total protein levels being better than those in the classic R-Y group. Preoperative pre-albumin level and impaired fasting glycemia significantly correlated with the postoperative recanalization. CONCLUSION: We found no significant benefit of uncut over classic R-Y reconstruction which challenges the superiority of the uncut R-Y reconstruction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02644148.

Dual-aptamer-engineered M1 macrophage with enhanced specific targeting and checkpoint blocking for solid-tumor immunotherapy.

Chimeric antigen receptor T (CAR-T) cell therapy has faced a series of challenges and has shown very little efficacy in solid tumors to date. Although genetically engineered macrophages have achieved definite therapeutic effect in solid tumors, heterogeneous expression of engineered proteins and the potential for toxicity limit further applications. Herein, we propose a nongenetic and simple macrophage cell engineering strategy through glycan metabolic labeling and click reaction for the treatment of solid tumors. The aptamer-engineered M1 macrophage (ApEn-M1) showed enhanced active targeting ability for tumor cells in vitro and in vivo, resulting in significant cytotoxicity effects. Moreover, ApEn-M1 exhibited superior antitumor efficacy in a breast cancer xenograft mouse model and a lung metastasis mouse model of breast cancer. Interestingly, the ApEn-M1 could reprogram the immunity microenvironment by increasing T cell infiltration and enhancing T cell activity in the tumor region. Additionally, the administration of ApEn-M1 showed no obvious systemic side effects. With glycan metabolic labeling, the macrophages could be efficiently labeled with aptamers on the cell surface via click reaction without genetic alteration or cell damage. Hence, this study serves as a proof of concept for cell-surface anchor engineering and expands the range of nongenetic macrophage cell engineering strategies.

Iron increases lipid deposition via oxidative stress-mediated mitochondrial dysfunction and the HIF1α-PPARγ pathway.

Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters (zip14 and fpn1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 α (HIF1α), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1α to the pparγ and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1α-PPARγ pathway are critical mediators of iron-induced lipid deposition.

Genome-Wide Identification of Trachinotus ovatus Antimicrobial Peptides and Their Immune Response against Two Pathogen Challenges.

Golden pompano, Trachinotus ovatus, as a highly nutritious commercially valuable marine fish, has become one of the preferred species for many fish farmers due to its rapid growth, wide adaptability, and ease of feeding and management. However, with the expansion of aquaculture scale, bacterial and parasitic diseases have also become major threats to the golden pompano industry. This study, based on comparative genomics, shows the possibility of preferential evolution of freshwater fish over marine fish by analyzing the phylogenetic relationships and divergence times of 14 marine fish and freshwater fish. Furthermore, we identified antimicrobial peptide genes from 14 species at the genomic level and found that the number of putative antimicrobial peptides may be related to species evolution. Subsequently, we classified the 341 identified AMPs from golden pompano into 38 categories based on the classification provided by the APD3. Among them, TCP represented the highest proportion, accounting for 23.2% of the total, followed by scolopendin, lectin, chemokine, BPTI, and histone-derived peptides. At the same time, the distribution of AMPs in chromosomes varied with type, and covariance analysis showed the frequency of its repeat events. Enrichment analysis and PPI indicated that AMP was mainly concentrated in pathways associated with disease immunity. In addition, our transcriptomic data measured the expression of putative AMPs of golden pompano in 12 normal tissues, as well as in the liver, spleen, and kidney infected with Streptococcus agalactiae and skin infected with Cryptocaryon irritans. As the infection with S. agalactiae and C. irritans progressed, we observed tissue specificity in the number and types of responsive AMPs. Positive selection of AMP genes may participate in the immune response through the MAPK signaling pathway. The genome-wide identification of antimicrobial peptides in the golden pompano provided a complete database of potential AMPs that can contribute to further understanding the immune mechanisms in pathogens. AMPs were expected to replace traditional antibiotics and be developed into targeted drugs against specific bacterial and parasitic pathogens for more precise and effective treatment to improve aquaculture production.

Biomechanical effects of internal fixation with self-lock compression anti-rotation blade for Pauwels type III femoral neck fractures: a comparative finite element analysis.

BACKGROUND: Self-lock compression anti-rotation blade (SCAB) is a novel internal fixation implant for femoral neck fractures (FNF). We conducted this finite element analysis study to evaluate the biomechanical performances of SCAB combined with a cannulated screw for fixation of Pauwels type III FNF. METHODS: Three finite element models of Pauwels type III FNF treated with various internal fixations were established: a: the inverted triangular parallel cannulated screw (3CS) model, b: the biplane double-supported screw fixation (BDSF) model, c: the SCAB combined with a cannulated screw model. Displacement and Von Mises stress of femurs and internal fixations under increasing loads as well as the average stress on fracture surfaces and maximum displacements on the X and Z axis of proximal fracture fragments at maximum load were measured and compared. RESULT: The SCAB-based internal fixation exhibited superior biomechanical performances compared with 3CS and BDSF configurations, as the former resulted in lower parameters including displacement of the femur, Von Mises stress of internal fixation, stress on fracture surfaces as well as X and Z axis displacement of fracture fragments. CONCLUSION: Internal fixation using SCAB combined with a cannulated screw for Pauwels type III FNFs shows enough stability, with satisfied resistance to varus and shearing forces, which may provide a new option for the treatment of FNFs.

The miR-345-3p/PPP2CA signaling axis promotes proliferation and invasion of breast cancer cells.

Breast cancer is the most common malignancy among women worldwide. Functional studies have demonstrated that miRNA dysregulation in many cases of cancer, in which miRNAs act as either oncogenes or tumor suppressor. Here we report that miR-345-3p is generally upregulated in breast cancer tissues and breast cancer cell lines. Overexpression and inhibition of miR-345-3p revealed its capacity in regulating proliferation and invasion of breast cancer cells. Further research identified protein phosphatase 2 catalytic subunit alpha (PPP2CA), a suppressor of AKT phosphorylation, as a candidate target of miR-345-3p. In vitro, miR-345-3p mimics promoted AKT phosphorylation by targeting its negative regulator, PPP2CA. Blocking miR-345-3p relieved its inhibition of PPP2CA, which attenuated PI3K-AKT signaling pathway. In vivo, inhibiting miR-345-3p by miR-345-3p-inhibition lentivirus suppressed tumor growth and invasiveness in mice. Together, the miR-345-3p/PPP2CA signaling axis exhibits tumor-promoting functions by regulating proliferation and invasion of breast cancer cells. These data provide a clue to novel therapeutic approaches for breast cancer.