Gap junctions in Turing-type periodic feather pattern formation.

Periodic patterning requires coordinated cell-cell interactions at the tissue level. Turing showed, using mathematical modeling, how spatial patterns could arise from the reactions of a diffusive activator-inhibitor pair in an initially homogenous 2D field. Most activators and inhibitors studied in biological systems are proteins, and the roles of cell-cell interaction, ions, bioelectricity, etc. are only now being identified. Gap junctions (GJs) mediate direct exchanges of ions or small molecules between cells, enabling rapid long-distance communications in a cell collective. They are therefore good candidates for propagating nonprotein-based patterning signals that may act according to the Turing principles. Here, we explore the possible roles of GJs in Turing-type patterning using feather pattern formation as a model. We found 7 of the 12 investigated GJ isoforms are highly dynamically expressed in the developing chicken skin. In ovo functional perturbations of the GJ isoform, connexin 30, by siRNA and the dominant-negative mutant applied before placode development led to disrupted primary feather bud formation. Interestingly, inhibition of gap junctional intercellular communication (GJIC) in the ex vivo skin explant culture allowed the sequential emergence of new feather buds at specific spatial locations relative to the existing primary buds. The results suggest that GJIC may facilitate the propagation of long-distance inhibitory signals. Thus, inhibition of GJs may stimulate Turing-type periodic feather pattern formation during chick skin development, and the removal of GJ activity would enable the emergence of new feather buds if the local environment were competent and the threshold to form buds was reached. We further propose Turing-based computational simulations that can predict the sequential appearance of these ectopic buds. Our models demonstrate how a Turing activator-inhibitor system can continue to generate patterns in the competent morphogenetic field when the level of intercellular communication at the tissue scale is modulated.

Circulating hypervirulent Marek's disease viruses in vaccinated chicken flocks in Taiwan by genetic analysis of meq oncogene.

Marek's disease (MD) is an important neoplastic disease caused by serotype 1 Marek's disease virus (MDV-1), which results in severe economic losses worldwide. Despite vaccination practices that have controlled the MD epidemic, current increasing MD-suspected cases indicate the persistent viral infections circulating among vaccinated chicken farms in many countries. However, the lack of available information about phylogeny and molecular characterization of circulating MDV-1 field strains in Taiwan reveals a potential risk in MD outbreaks. This study investigated the genetic characteristics of 18 MDV-1 strains obtained from 17 vaccinated chicken flocks in Taiwan between 2018 and 2020. Based on the sequences of the meq oncogene, the phylogenetic analysis demonstrated that the circulating Taiwanese MDV-1 field strains were predominantly in a single cluster that showed high similarity with strains from countries of the East Asian region. Because the strains were obtained from CVI988/Rispens vaccinated chicken flocks and the molecular characteristics of the Meq oncoprotein showed features like vvMDV and vv+MDV strains, the circulating Taiwanese MDV-1 field strains may have higher virulence compared with vvMDV pathotype. In conclusion, the data presented demonstrates the circulation of hypervirulent MDV-1 strains in Taiwan and highlights the importance of routine surveillance and precaution strategies in response to the emergence of enhanced virulent MDV-1.

Modeling of Burial History, Source Rock Maturity, and Hydrocarbon Generation of Marine-Continental Transitional Shale of the Permian Shanxi Formation, Southeastern Ordos Basin.

The Ordos Basin is characterized by abundant natural gas resources, and the marine-continental transitional shale gas of the Permian Shanxi Formation has great exploration and development potential. However, few systematic studies have focused on the burial history, thermal maturity, and hydrocarbon generation of the shale, which limits the understanding of shale gas enrichment and resource evaluation. To reveal the shale gas resource potential, we focused on the Shanxi Formation shale in the southeastern Ordos Basin. Net erosion was estimated, and then one-dimensional (1D) and three-dimensional (3D) geological models were constructed using PetroMod to simulate the burial-thermal history and hydrocarbons generated in the Shanxi Formation shale, and finally, the gas generation intensity was evaluated. The results show that four periods of uplift and erosion events have occurred in the study area since the Mesozoic, of which the erosion in the Late Cretaceous was the most severe. The burial center gradually shifted from east to northwest in the study area, and the basin reached the maximum burial depth in the Late Cretaceous and then gradually changed to a monoclinal tilted east to west after uplift and erosion. The Shanxi Formation shale reached the hydrocarbon generation threshold at 233 Ma (Ro = 0.5%), reached the oil generation peak at 200 Ma (Ro = 1.0%), and entered the high maturity stage rapidly (Ro = 1.3%). Currently, the average maturity is approximately 2.48%, which is in the overmature stage. The center of shale maturity was in the southern part of the study area before the Late Jurassic and shifted northeast in the late Early Cretaceous. Cumulative gas generated to date is 44.0 × 1012 m3, and the center of gas generation was in the middle-eastern region of the study area before the Early-Middle Jurassic and shifted northwest in the Early Cretaceous. This study provides a theoretical basis and guidance for the exploration and development of marine-continental transitional shale in the Ordos Basin.

UCHL5 promotes hepatocellular carcinoma progression by promoting glycolysis through activating Wnt/ß-catenin pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is highly malignant with a dismal prognosis, although the available therapies are insufficient. No efficient ubiquitinase has been identified as a therapeutic target for HCC despite the complicating role that of proteins ubiquitination plays in the malignant development of HCC. METHODS: The expression of ubiquitin carboxyl terminal hydrolase L5 (UCHL5) in HCC tumor tissue and adjacent normal tissue was determined using the cancer genome atlas (TCGA) database and was validated using real-time quantitative polymerase chain reaction (RT-qRCR), Western blot and immunohistochemistry (IHC), and the relation of UCHL5 with patient clinical prognosis was explored. The expression of UCHL5 was knocked down and validated, and the effect of UCHL5 on the biological course of HCC was explored using cellular assays. To clarify the molecular mechanism of action of UCHL5 affecting HCC, expression studies of Adenosine triphosphate adenosine triphosphate (ATP), extracellular acidification (ECAR), and glycolysis-related enzymes were performed. The effects of UCHL5 on ß-catenin ubiquitination and Wnt signaling pathways were explored in depth and validated using cellular functionalities. Validation was also performed in vivo. RESULTS: In the course of this investigation, we discovered that UCHL5 was strongly expressed in HCC at both cellular and tissue levels. The prognosis of patients with high UCHL5 expression is considerably worse than that of those with low UCHL5 expression. UCHL5 has been shown to increase the degree of glycolysis in HCC cells with the impact of stimulating the proliferation and metastasis of HCC cells in both in vivo and in vitro. UCHL5 downregulates its degree of ubiquitination by binding to ß-catenin, which activates the Wnt/ß-catenin pathway and accelerates HCC cell glycolysis. Thereby promoting the growth of the HCC. CONCLUSIONS: In summary, we have demonstrated for the first time that UCHL5 is a target of HCC and promotes the progression of hepatocellular carcinoma by promoting glycolysis through the activation of the Wnt/ß-catenin pathway. UCHL5 may thus serve as a novel prognostic marker and therapeutic target for the treatment of HCC.

Crosstalk between endothelial cells and dermal papilla entails hair regeneration and angiogenesis during aging.

INTRODUCTION: Tissues maintain their function through interaction with microenvironment. During aging, both hair follicles and blood vessels (BV) in skin undergo degenerative changes. However, it is elusive whether the changes are due to intrinsic aging changes in hair follicles or blood vessels respectively, or their interactions. OBJECTIVE: To explore how hair follicles and blood vessels interact to regulate angiogenesis and hair regeneration during aging. METHODS: Single-cell RNA-sequencing (scRNA-seq) analyses were used to identify the declined ability of dermal papilla (DP) and endothelial cells (ECs) during aging. CellChat and CellCall were performed to investigate interaction between DP and ECs. Single-cell metabolism (scMetabolism) analysis and iPATH were applied to analyze downstream metabolites in DP and ECs. Hair-plucking model and mouse cell organoid model were used for functional studies. RESULTS: During aging, distance and interaction between DP and ECs are decreased. DP interacts with ECs, with decreased EDN1-EDNRA signaling from ECs to DP and CTF1-IL6ST signaling from DP to ECs during aging. ECs-secreted EDN1 binds to DP-expressed EDNRA which enhances Taurine (TA) metabolism to promote hair regeneration. DP-emitted CTF1 binds to ECs-expressed IL6ST which activates alpha-linolenic acid (ALA) metabolism to promote angiogenesis. Activated EDN1-EDNRA-TA signaling promotes hair regeneration in aged mouse skin and in organoid cultures, and increased CTF1-IL6ST-ALA signaling also promotes angiogenesis in aged mouse skin and organoid cultures. CONCLUSIONS: Our finding reveals reciprocal interactions between ECs and DP. ECs releases EDN1 sensed by DP to activate TA metabolism which induces hair regeneration, while DP emits CTF1 signal received by ECs to enhance ALA metabolism which promotes angiogenesis. Our study provides new insights into mutualistic cellular crosstalk between hair follicles and blood vessels, and identifies novel signaling contributing to the interactions of hair follicles and blood vessels in normal and aged skin.

Clinicopathological and molecular genetic analysis of 13 cases of primary retroperitoneal Ewing sarcoma.

Retroperitoneal Ewing sarcomas (RES) are very rare and mostly described in case reports. The purpose of this study was to retrospectively analyze the clinicopathology, molecular characteristics, biological behavior, and therapeutic information of 13 cases of primary RES with immunohistochemical staining, fluorescence in situ hybridization, RT-PCR and NGS sequencing detection techniques. The thirteen patients included eight males and five females with a mean age of 34 years. Morphologically, the tumors were comprised of small round or epithelial-like cells with vacuolated cytoplasm (6/13,46 %) arranged in diffuse, nested (8/13,62 %) and perivascular (7/13,54 %) patterns. Unusual morphologic patterns, such as meningioma-like swirling structures and sieve-like structures were relatively novel findings. Immunohistochemical studies showed CD99 (12/13; 92 %), CD56 (11/13; 85 %), NKX2.2 (9/13; 69 %), PAX7 (10/11;91 %) and CD117(6/9;67 %) to be positive.12 cases (92 %) demonstrated EWSR1 rearrangement and 3 cases displayed EWSR1::FLI1 fusion by FISH. ERCC4 splice-site variant, a novel pathogenic variant, was discovered for the first time via RNA sequencing. With a median follow-up duration of 14 months (6 to 79 months), 8/13 (62 %) patients died, while 5/13(38 %) survived. Three cases recurred, and five patients developed metastasis to the liver (2 cases), lung (2 cases) and bone (1 case). RES is an aggressive, high-grade tumor, prone to multiple recurrences and metastases, with distinctive morphologic, immunohistochemical, and molecular genetic features. ERCC4 splicing mutation, which is a novel pathogenic variant discovered for the first time, with possible significance for understanding the disease, as well as the development of targeted drugs.

Dihydrophenanthropyrans derived from the pseudobulbs of Pholidota chinensis alleviates neutrophilic inflammation by inhibiting MAPKs and calcium.

Five dihydrophenanthropyrans (1-5) were isolated from the pseudobulbs of Pholidota chinensis, among which 1,3-di(4'-hydroxybenzy)-imbricatin (3) was isolated from the nature for the first time. Their structures were elucidated and established through various spectroscopic methods. These compounds exhibited a potent inhibition effect on both N-formyl-methionyl-leucyl-phenylalanine (fMLF)-induced superoxide anion generation and elastase release with IC50 values ranging from 0.23 to 7.63 µM. Furthermore, dihydrophenanthropyrans (1-3) also demonstrated a dose-dependent reactive oxygen species (ROS) scavenging effect. In addition, dihydrophenanthropyrans (2-3) exhibited a dose-dependent reduction in the intracellular Ca2+ concentration ([Ca2+]i) in fMLF-activated human neutrophils. Moreover, dihydrophenanthropyrans (1-3) selectively inhibited the phosphorylation of c-Jun N-terminal kinases (JNKs) and p38, while only dihydrophenanthropyran (1) inhibited the phosphorylation of extracellular signal-regulated kinases (ERKs) in fMLF-activated human neutrophils. Notably, dihydrophenanthropyrans (1-3) did not affect protein kinase B (AKT) activity in these cells. These findings highlight the potent anti-inflammatory capabilities of dihydrophenanthropyrans, manifested through their ability to inhibit superoxide anion generation, suppress elastase release, and selectively modulate key signaling pathways in human neutrophils. This suggests that dihydrophenanthropyrans hold significant promise as therapeutic agents for conditions associated with neutrophil-mediated inflammation.

Melatonin ameliorates multiorgan injuries induced by severe acute pancreatitis in mice by regulating the Nrf2 signaling pathway.

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death.

Conserved regulatory switches for the transition from natal down to juvenile feather in birds.

The transition from natal downs for heat conservation to juvenile feathers for simple flight is a remarkable environmental adaptation process in avian evolution. However, the underlying epigenetic mechanism for this primary feather transition is mostly unknown. Here we conducted time-ordered gene co-expression network construction, epigenetic analysis, and functional perturbations in developing feather follicles to elucidate four downy-juvenile feather transition events. We report that extracellular matrix reorganization leads to peripheral pulp formation, which mediates epithelial-mesenchymal interactions for branching morphogenesis. α-SMA (ACTA2) compartmentalizes dermal papilla stem cells for feather renewal cycling. LEF1 works as a key hub of Wnt signaling to build rachis and converts radial downy to bilateral symmetry. Novel usage of scale keratins strengthens feather sheath with SOX14 as the epigenetic regulator. We show that this primary feather transition is largely conserved in chicken (precocial) and zebra finch (altricial) and discuss the possibility that this evolutionary adaptation process started in feathered dinosaurs.

Assessing ethical behavior and self-control in elite ultimate championships: a cross-sectional study using the spirit of the game scoring system.

Introduction: Implementing a self-refereeing system presents a unique challenge in sports education, particularly in academic and training settings where officiated sports prevail. However, Ultimate Frisbee stands out by entrusting players with both athlete and referee roles, introducing distinctive ethical complexities. This manuscript is intended to evaluate ethical behavior and self-control within the Spirit of the Game (SOTG) scoring system in Elite Ultimate. To address these, Ultimate employs the (SOTG) scoring system, integral since the sport's inception in the late 1980s. SOTG aims to enhance and evaluate athletes' ethical conduct. This study evaluates SOTG's effectiveness in elite-level Ultimate, analyzing variations across divisions and age groups in three high-level tournaments. Methods: Using a cross-sectional design, data were collected from five international Ultimate tournaments in 2022. Teams spanned diverse age groups (under 17 to over 50) and divisions (women's, mixed, open). Post-match, teams assessed opponents' SOTG in five domains: Rules knowledge, fouls, fairness, attitude/self-control, and communication. Ratings used a 5-point Likert scale ("poor" to "excellent"). An overall SOTG score was calculated by aggregating domain scores. Results: Our study consistently revealed high SOTG scores, reflecting strong sportsmanship. "Positive attitude and self-control" consistently ranked highest, while "Knowledge and use of the rules" scored lowest. Divisional differences in SOTG were statistically insignificant. Notably, WMUCC2022 (participants aged 30+) had significantly higher SOTG scores, possibly indicating age-related self-control improvement or evolving sport culture. Lower rules knowledge scores may stem from linguistic translation challenges. Conclusion: Self-refereeing promotes ethical behavior across divisions and age groups. SOTG underscores sportsmanship's importance and aligns with International Olympic Committee (IOC) and with Sustainable Development Goals (SDGs), particularly SDG 3, 4, 5 and 16 fostering a fairer, healthier, and more peaceful world.

Conv2Former: A Simple Transformer-Style ConvNet for Visual Recognition.

Vision Transformers have been the most popular network architecture in visual recognition recently due to the strong ability of encode global information. However, its high computational cost when processing high-resolution images limits the applications in downstream tasks. In this paper, we take a deep look at the internal structure of self-attention and present a simple Transformer style convolutional neural network (ConvNet) for visual recognition. By comparing the design principles of the recent ConvNets and Vision Transformers, we propose to simplify the self-attention by leveraging a convolutional modulation operation. We show that such a simple approach can better take advantage of the large kernels ( ≥ 7×7) nested in convolutional layers and we observe a consistent performance improvement when gradually increasing the kernel size from 5×5 to 21×21. We build a family of hierarchical ConvNets using the proposed convolutional modulation, termed Conv2Former. Our network is simple and easy to follow. Experiments show that our Conv2Former outperforms existent popular ConvNets and vision Transformers, like Swin Transformer and ConvNeXt in all ImageNet classification, COCO object detection and ADE20k semantic segmentation. Our code is available at https://github.com/HVision-NKU/Conv2Former.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

Mulberry leaf polysaccharide improves cyclophosphamide-induced growth inhibition and intestinal damage in chicks by modulating intestinal flora, enhancing immune regulation and antioxidant capacity.

Polysaccharides are generally considered to have immune enhancing functions, and mulberry leaf polysaccharide is the main active substance in mulberry leaves, while there are few studies on whether mulberry leaf polysaccharide (MLP) has an effect on immunosuppression and intestinal damage caused by cyclophosphamide (CTX), we investigated whether MLP has an ameliorative effect on intestinal damage caused by CTX. A total of 210 1-day-old Mahuang cocks were selected for this experiment. Were equally divided into six groups and used to evaluate the immune effect of MLP. Our results showed that MLP significantly enhanced the growth performance of chicks and significantly elevated the secretion of cytokines (IL-1ß, IL-10, IL-6, TNF-α, and IFN-γ), immunoglobulins and antioxidant enzymes in the serum of immunosuppressed chicks. It attenuated jejunal damage and elevated the expression of jejunal tight junction proteins Claudin1, Zo-1 and MUC2, which protected intestinal health. MLP activated TLR4-MyD88-NF-κB pathway and enhanced the expression of TLR4, MyD88 and NF-κB, which served to protect the intestine. 16S rDNA gene high-throughput sequencing showed that MLP increased species richness, restored CTX-induced gut microbiome imbalance, and enhanced the abundance of probiotic bacteria in the gut. MLP improves cyclophosphamide-induced growth inhibition and intestinal damage in chicks by modulating intestinal flora and enhancing immune regulation and antioxidant capacity. In conclusion, this study provides a scientific basis for MLP as an immune enhancer to regulate chick intestinal flora and protect chick intestinal mucosal damage.

Light-driven phase transition of diffractive optical elements based on liquid crystal elastomers.

Diffractive optical element is advantageous for miniaturization, arraying and integration of optical systems. They have been widely used in beam shaping, diffractive imaging, generating beam arrays, spectral optimization and other aspects. Currently, the vast majority of diffractive optics are not tunable. This limits the applicability and functionality of these devices. Here we report a tunable diffractive optical element controlled by light in the visible band. The diffractive optical element consists of a square gold microarray deposited on a deformable substrate. The substrate is made of a liquid crystal elastomer. When pumped by a 532 nm laser, the substrate is deformed to change the crystal lattice. This changes the far-field diffraction pattern of the device. The proposed concept establishes a light-controlled soft platform with great potential for tunable/reconfigurable photonic devices, such as filters, couplers, holograms and structural color displays.

Strain-Induced Self-Assembly at Interface of Two-Dimensional Heterostructures Boosts CO2 Reduction to Methanol by H2O.

CO2 conversion with pure H2O into CH3OH and O2 driven by solar energy can supply fuels and life-essential substances for extraterrestrial exploration. However, the effective production of CH3OH is significantly challenging. Here we report an organozinc complex/MoS2 heterostructure linked by well-defined zinc-sulfur covalent bonds derived by the structural deformation and intensive coupling of dx2 - y2(Zn)-p(S) orbitals at the interface, resulting in distinctive charge transfer behaviors and excellent redox capabilities as revealed by experimental characterizations and first-principle calculations. The synthesis strategy is further generalized to more organometallic compounds, achieving various heterostructures for CO2 photoreduction. The optimal catalyst delivers a promising CH3OH yield of 2.57 mmol gcat-1 h-1 and selectivity of more than 99.5%. The reverse water gas shift mechanism is identified for methanol formation. Meanwhile, energy-unfavorable adsorption of methanol on MoS2, where the photogenerated holes accumulate, ensures the selective oxidation of water over methanol.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Long stem revision versus short stem revision with plate osteosynthesis for Vancouver type B2 periprosthetic femoral fracture: a comparative study of eighty five cases.

PURPOSE: Periprosthetic femoral fractures (PPFs) around the hip are challenging complications in orthopaedic surgery, particularly Vancouver type B2 (VTB2) fractures. The surgical management of these fractures is crucial and depends on various factors. Cementless short taper stem with plate osteosynthesis is an alternative surgical technique. This study aims to compare the outcomes of this surgical technique with revision arthroplasty (RA) with long stem in the treatment of VTB2 PPFs. METHODS: This retrospective study was conducted in a single medical institute from February 2010 to May 2019. Patients who had received either total hip arthroplasty or bipolar hemiarthroplasty and subsequently developed a VTB2 PPF were included; patients who sustained intra-operative fractures or received a cemented stem previously were excluded from the analysis. The patients were divided into two groups: group I received RA with cementless long stem, while group II underwent RA with cementless short taper stem with plate osteosynthesis. Demographic data, radiographic and functional outcomes, and complications were analyzed between the two groups. RESULTS: A total of 85 patients diagnosed with VTB2 PPFs were included in the study. There were no significant differences between the two groups in terms of demographic data, including age, gender, mean follow-up times, estimated blood loss, and operative times. The radiographic results showed that there was no significant difference in the incidence of subsidence and implant stability between the two groups. However, group II tended to have less subsidence and periprosthetic osteolysis. Patients in group II had significantly better functional scores (mean Harris hip score: post-operative: 60.2 in group I and 66.7 in group ii; last follow-up: 77.4 in group 1 and 83.2 in group II (both p < 0.05)). There were no significant differences in the overall complication rate, including infection, dislocation, re-fracture, and revision surgery, between the two groups. CONCLUSIONS: Both surgical techniques, cementless long stem and cementless short taper stem with plate osteosynthesis, are effective in the treatment of Vancouver B2 PPFs, with no significant differences in outcomes or complications. However, patients in cementless short taper stem with plate osteosynthesis had better functional scores at both post-operative and the last follow-up.

Novel BRD4-p53 Inhibitor SDU-071 Suppresses Proliferation and Migration of MDA-MB-231 Triple-Negative Breast Cancer Cells.

A promising alternative for cancer treatment involves targeted inhibition of the epigenetic regulator bromodomain-containing protein 4 (BRD4); however, available BRD4 inhibitors are constrained by their potency, oral bioavailability, and cytotoxicity. Herein, to overcome the drawback of the translational BRD4 inhibitors, we describe a novel BRD4-p53 inhibitor, SDU-071, which suppresses BRD4 interaction with the p53 tumor suppressor and its biological activity in MDA-MB-231 triple-negative breast cancer (TNBC) cells in vitro and in vivo. This novel small-molecule BRD4-p53 inhibitor suppresses cell proliferation, migration, and invasion by downregulating the expression of BRD4-targeted genes, such as c-Myc and Mucin 5AC, and inducing cell cycle arrest and apoptosis, as demonstrated in cultured MDA-MB-231 TNBC cells. Its antitumor activity is illustrated in an orthotopic mouse xenograft mammary tumor model. Overall, our results show that SDU-071 is a viable option for potentially treating TNBC as a new BRD4-p53 inhibitor.

Subdural effusion associated with COVID-19 encephalopathy: A case report.

BACKGROUND: The precise mechanism by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts the central nervous system remains unclear, with manifestations spanning from mild symptoms (e.g., olfactory and gustatory deficits, hallucinations, and headache) to severe complications (e.g., stroke, seizures, encephalitis, and neurally demyelinating lesions). The occurrence of single-pass subdural effusion, as described below, is extremely rare. CASE SUMMARY: A 56-year-old male patient presented with left-sided limb weakness and slurred speech as predominant clinical symptoms. Through comprehensive imaging and diagnostic assessments, he was diagnosed with cerebral infarction complicated by hemorrhagic transformation affecting the right frontal, temporal, and parietal regions. In addition, an intracranial infection with SARS-CoV-2 was identified during the rehabilitation process; consequently, an idiopathic subdural effusion developed. Remarkably, the subdural effusion underwent absorption within 6 d, with no recurrence observed during the 3-month follow-up. CONCLUSION: Subdural effusion is a potentially rare intracranial complication associated with SARS-CoV-2 infection.

Adaptive patterning of vascular network during avian skin development: Mesenchymal plasticity and dermal vasculogenesis.

A vasculature network supplies blood to feather buds in the developing skin. Does the vasculature network during early skin development form by sequential sprouting from the central vasculature or does local vasculogenesis occur first that then connect with the central vascular tree? Using transgenic Japanese quail Tg(TIE1p.H2B-eYFP), we observe that vascular progenitor cells appear after feather primordia formation. The vasculature then radiates out from each bud and connects with primordial vessels from neighboring buds. Later they connect with the central vasculature. Epithelial-mesenchymal recombination shows local vasculature is patterned by the epithelium, which expresses FGF2 and VEGF. Perturbing noggin expression leads to abnormal vascularization. To study endothelial origin, we compare transcriptomes of TIE1p.H2B-eYFP+ cells collected from the skin and aorta. Endothelial cells from the skin more closely resemble skin dermal cells than those from the aorta. The results show developing chicken skin vasculature is assembled by (1) physiological vasculogenesis from the peripheral tissue, and (2) subsequently connects with the central vasculature. The work implies mesenchymal plasticity and convergent differentiation play significant roles in development, and such processes may be re-activated during adult regeneration. SUMMARY STATEMENT: We show the vasculature network in the chicken skin is assembled using existing feather buds as the template, and endothelia are derived from local bud dermis and central vasculature.