Sodium alginate/carboxycellulose/polydopamine composite microspheres for rapid hemostasis of deep irregular wounds.

Hemostasis of deep irregular wounds is a severe problem in clinical practice. The development of rapid-acting hemostatic agents for deep and irregular wound is urgently needed. Here, sodium alginate/carboxycellulose/polydopamine (SA/CNF/PDA) microspheres was prepared by reverse emulsification and crosslinking with Ca2+, and SA/CNF/PDA composite hemostatic microspheres with porous structure were obtained by freeze-drying. SA/CNF/PDA composite hemostatic microspheres exhibited excellent porosity and water absorption which could rapidly absorb blood on the wound surface. Moreover, SA/CNF/PDA composite microspheres demonstrated remarkable hemostatic capabilities both in vitro and in vivo. It exhibited strong hemostatic performance in models of mouse tail-break and liver damage. Especially in liver injury model, it was completely hemostatic in 95 s, and blood loss (19.3 mg). The hemostatic efficacy of the SA/CNF/PDA composite microspheres was amplified through the stimulation of both exogenous and endogenous coagulation pathways. Therefore, SA/CNF/PDA composite hemostatic microspheres are suitable for rapid hemostasis of deep irregular wounds which are potential rapid hemostatic material for surgical application.

Pyrogallol protects against influenza A virus-triggered lethal lung injury by activating the Nrf2-PPAR-γ-HO-1 signaling axis.

Pyrogallol, a natural polyphenol compound (1,2,3-trihydroxybenzene), has shown efficacy in the therapeutic treatment of disorders associated with inflammation. Nevertheless, the mechanisms underlying the protective properties of pyrogallol against influenza A virus infection are not yet established. We established in this study that pyrogallol effectively alleviated H1N1 influenza A virus-induced lung injury and reduced mortality. Treatment with pyrogallol was found to promote the expression and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Notably, the activation of Nrf2 by pyrogallol was involved in elevating the expression of PPAR-γ, both of which act synergistically to enhance heme oxygenase-1 (HO-1) synthesis. Blocking HO-1 by zinc protoporphyrin (ZnPP) reduced the suppressive impact of pyrogallol on H1N1 virus-mediated aberrant retinoic acid-inducible gene-I-nuclear factor kappa B (RIG-I-NF-κB) signaling, which thus abolished the dampening effects of pyrogallol on excessive proinflammatory mediators and cell death (including apoptosis, necrosis, and ferroptosis). Furthermore, the HO-1-independent inactivation of janus kinase 1/signal transducers and activators of transcription (JAK1/STATs) and the HO-1-dependent RIG-I-augmented STAT1/2 activation were both abrogated by pyrogallol, resulting in suppression of the enhanced transcriptional activity of interferon-stimulated gene factor 3 (ISGF3) complexes, thus prominently inhibiting the amplification of the H1N1 virus-induced proinflammatory reaction and apoptosis in interferon-beta (IFN-ß)-sensitized cells. The study provides evidence that pyrogallol alleviates excessive proinflammatory responses and abnormal cell death via HO-1 induction, suggesting it could be a potential agent for treating influenza.

Insights into the mechanism of action of pterostilbene against influenza A virus-induced acute lung injury.

BACKGROUND: Severe respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC. PURPOSE: Our study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection. STUDY DESIGN AND METHODS: A murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed. RESULTS: PTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner. CONCLUSION: In conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases.

Single-Nucleus Multiomic Analyses Identifies Gene Regulatory Dynamics of Phenotypic Modulation in Human Aneurysmal Aortic Root.

Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single-nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell-type-specific transcriptomic and cis-regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.

Improving osseointegration and antimicrobial properties of titanium implants with black phosphorus nanosheets-hydroxyapatite composite coatings for vascularized bone regeneration.

For decades, titanium implants have shown impressive advantages in bone repair. However, the preparation of implants with excellent antimicrobial properties as well as better osseointegration ability remains difficult for clinical application. In this study, black phosphorus nanosheets (BPNSs) were doped into hydroxyapatite (HA) coatings using electrophoretic deposition. The coatings' surface morphology, roughness, water contact angle, photothermal properties, and antibacterial properties were investigated. The BP/HA coating exhibited a surface roughness of 59.1 nm, providing an ideal substrate for cell attachment and growth. The water contact angle on the BP/HA coating was measured to be approximately 8.55°, indicating its hydrophilic nature. The BPNSs demonstrated efficient photothermal conversion, with a temperature increase of 42.2°C under laser irradiation. The BP/HA composite coating exhibited a significant reduction in bacterial growth, with inhibition rates of 95.6% and 96.1% against Staphylococcus aureus and Escherichia coli. In addition, the cytocompatibility of the composite coating was evaluated by cell adhesion, CCK8 and AM/PI staining; the effect of the composite coating in promoting angiogenesis was assessed by scratch assay, transwell assay, and protein blotting; and the osteoinductivity of the composite coating was evaluated by alkaline phosphatase assay, alizarin red staining, and Western blot. The results showed that the BP/HA composite coating exhibited superior performance in promoting biological functions such as cell proliferation and adhesion, antibacterial activity, osteogenic differentiation, and angiogenesis, and had potential applications in vascularized bone regeneration.

Optimization of tight gas reservoir fracturing parameters via gradient boosting regression modeling.

In China, the exploitation of most unconventional oil and gas reservoirs is dependent on hydraulic fracturing, which is a key method employed when developing tight gas formations. Numerous scholars and field engineers, both domestically and internationally, have conducted extensive numerical simulations and physical experiments to study crack propagation and predict post-fracturing productivity in hydraulic fracturing. Although some progress has been reported in this regard, it is difficult to accurately predict the well productivity using mechanistic models owing to the vertical multilayered development of tight gas reservoirs. In this study, vertical fractured wells in a block of Sulige gas field were examined. The block relied on hydraulic fracturing to produce tight gases. However, as development progressed, the available reservoir environment deteriorated, large differences emerged between wells after fracturing, and the fracturing results did not meet the expectations. In this study, geological, construction, and generation data for this block that had been collected since 2007 were analyzed. After applying multiple machine-learning methods to filter outliers and fill in missing values, k-means clustering, classification enhancement, extreme gradient enhancement, and LightGBM algorithms were used to establish a regression model. The analysis results revealed that the regression accuracy of the cluster test set was as high as 70% and that the LightGBM model had the best regression effect among the 227 stripper wells in the block. After optimizing the fracturing construction parameters (fracturing fluid volume, proppant volume, liquid-nitrogen volume, and pumping rate), the average fracturing fluid and liquid-nitrogen volumes per well decreased, whereas the unit reservoir proppant and liquid-nitrogen volumes increased. The results also revealed that 182 wells showed an improved initial production capacity during fracturing. The average gas production index per meter increased by 22.04%. This approach enabled rapid and efficient production forecasting and construction optimization. Moreover, this represents a novel fracture design method that is applicable to onsite engineers in tight gas production fields in the Ordos region.

Preparation of black phosphorus@sodium alginate microspheres with bone matrix vesicle structure via electrospraying for bone regeneration.

Bone matrix vesicles are commonly acknowledged as the primary site of biomineralization in human skeletal tissue. Black phosphorus has exhibited favorable properties across various chemical and physical domains. In this investigation, a novel composite microsphere was synthesized through the amalgamation of sodium alginate (ALG) with black phosphorus nanosheets (BP) utilizing the electrospray (ES) technique. These microspheres were tailored to mimic the regulatory function of matrix vesicles (MV) upon exposure to a biomimetic mineralization fluid (SBF) during the biomineralization process. Results revealed that black phosphorus nanosheets facilitated the generation of hydroxyapatite (HA) on the microsphere surface. Live-dead assays and cell proliferation experiments showcased a cell survival rate exceeding 85 %. Moreover, wound healing assessments unveiled that M-ALG-BP microspheres exhibited superior migration capacity, with a migration rate surpassing 50 %. Furthermore, after 7 days of osteogenic induction, M-ALG-BP microspheres notably stimulated osteoblast differentiation. Particularly noteworthy, M-ALG-BP microspheres significantly enhanced osteogenic differentiation of osteoblasts and induced collagen production in vitro. Additionally, experiments involving microsphere implantation into mouse skeletal muscle demonstrated the potential for ectopic mineralization by ALG-BP microspheres. This investigation underscores the outstanding mineralization properties of ALG-BP microspheres and their promising clinical prospects in bone tissue engineering.

Resolving the heterogeneous tumour microenvironment in cardiac myxoma through single-cell and spatial transcriptomics.

BACKGROUND: Cardiac myxoma (CM) is the most common (58%-80%) type of primary cardiac tumours. Currently, there is a need to develop medical therapies, especially for patients not physically suitable for surgeries. However, the mechanisms that shape the tumour microenvironment (TME) in CM remain largely unknown, which impedes the development of targeted therapies. Here, we aimed to dissect the TME in CM at single-cell and spatial resolution. METHODS: We performed single-cell transcriptomic sequencing and Visium CytAssist spatial transcriptomic (ST) assays on tumour samples from patients with CM. A comprehensive analysis was performed, including unsupervised clustering, RNA velocity, clonal substructure inference of tumour cells and cell-cell communication. RESULTS: Unsupervised clustering of 34 759 cells identified 12 clusters, which were assigned to endothelial cells (ECs), mesenchymal stroma cells (MSCs), and tumour-infiltrating immune cells. Myxoma tumour cells were found to encompass two closely related phenotypic states, namely, EC-like tumour cells (ETCs) and MSC-like tumour cells (MTCs). According to RNA velocity, our findings suggest that ETCs may be directly differentiated from MTCs. The immune microenvironment of CM was found to contain multiple factors that promote immune suppression and evasion, underscoring the potential of using immunotherapies as a treatment option. Hyperactive signals sent primarily by tumour cells were identified, such as MDK, HGF, chemerin, and GDF15 signalling. Finally, the ST assay uncovered spatial features of the subclusters, proximal cell-cell communication, and clonal evolution of myxoma tumour cells. CONCLUSIONS: Our study presents the first comprehensive characterisation of the TME in CM at both single-cell and spatial resolution. Our study provides novel insight into the differentiation of myxoma tumour cells and advance our understanding of the TME in CM. Given the rarity of cardiac tumours, our study provides invaluable datasets and promotes the development of medical therapies for CM.

Enhancing osseointegration of titanium implants through MC3T3-E1 protein-gelatin polyelectrolyte multilayers.

Titanium and its alloys have found extensive use in the biomedical field, however, implant loosening due to weak osseointegration remains a concern. Improved surface morphology and chemical composition can enhance the osseointegration of the implant. Bioactive molecules have been utilized to modify the surface of the titanium-based material to achieve rapid and efficient osseointegration between the implant and bone tissues. In this study, the bioactive substance MC3T3-E1 protein-gelatin polyelectrolyte multilayers were constructed on the surface of the titanium implants by means of layer-by-layer self-assembly to enhance the strength of the bond between the bone tissue and the implant. The findings of the study indicate that the layer-by-layer self-assembly technique can enhance surface roughness and hydrophilicity to a considerable extent. Compared to pure titanium, the hydrophilicity of TiOH LBL was significantly increased with a water contact angle of 75.0 ± $$ \pm $$ 2.4°. The modified titanium implant exhibits superior biocompatibility and wound healing ability upon co-culture with cells. MC3T3-E1 cells were co-cultured with TiOH LBL for 1, 3, and 5 days and their viability was higher than 85%. In addition, the wound healing results demonstrate that TiOH LBL exhibited the highest migratory ability (243 ± 10 µm). Furthermore, after 7 days of osteogenic induction, the modified titanium implant significantly promotes osteoblast differentiation.

[Progress in antibacterial coatings of titanium implants surfaces].

In recent years, bone implant materials such as titanium and titanium alloys have been widely used in the biomedical field due to their excellent mechanical properties and good biocompatibility. However, in clinical practice, bacterial adhesion to the material surface and postoperative infection issues may lead to implantation failure. Based on the antibacterial mechanism, this review elaborated on the antibacterial surface design of titanium implants from the aspects of anti-bacterial adhesion, contact sterilization and photocontrol sterilization. Surface modification of titanium or titanium-based alloy implants with different techniques can inhibit bacteria and promote osseointegration. Thus, the application range of multifunctional titanium-based implants in the field of orthopedics will be expanded.

Rhodobacteraceae methanethiol oxidases catalyze methanethiol degradation to produce sulfane sulfur other than hydrogen sulfide.

Methanethiol (MT) is a sulfur-containing compound produced during dimethylsulfoniopropionate (DMSP) degradation by marine bacteria. The C-S bond of MT can be cleaved by methanethiol oxidases (MTOs) to release a sulfur atom. However, the cleaving process remains unclear, and the species of sulfur product is uncertain. It has long been assumed that MTOs produce hydrogen sulfide (H2S) from MT. Herein, we studied the MTOs in the Rhodobacteraceae family-whose members are important DMSP degraders ubiquitous in marine environments. We identified 57 MTOs from 1,904 Rhodobacteraceae genomes. These MTOs were grouped into two major clusters. Cluster 1 members share three conserved cysteine residues, while cluster 2 members contain one conserved cysteine residue. We examined the products of three representative MTOs both in vitro and in vivo. All of them produced sulfane sulfur other than H2S from MT. Their conserved cysteines are substrate-binding sites in which the MTO-S-S-CH3 complex is formed. This finding clarified the sulfur product of MTOs and enlightened the MTO-catalyzing process. Moreover, this study connected DMSP degradation with sulfane sulfur metabolism, filling a critical gap in the DMSP degradation pathway and representing new knowledge in the marine sulfur cycle field. IMPORTANCE: This study overthrows a long-time assumption that methanethiol oxidases (MTOs) cleave the C-S bond of methanethiol to produce both H2S and H2O2-the former is a strong reductant and the latter is a strong oxidant. From a chemistry viewpoint, this reaction is difficult to happen. Investigations on three representative MTOs indicated that sulfane sulfur (S0) was the direct product, and no H2O2 was produced. Finally, the products of MTOs were corrected to be S0 and H2O. This finding connected dimethylsulfoniopropionate (DMSP) degradation with sulfane sulfur metabolism, filling a critical gap in the DMSP degradation pathway and representing new knowledge in the marine sulfur cycle field.

Perfect Excitation of Topological States by Supersymmetric Waveguides.

Topological photonic states provide intriguing strategies for robust light manipulations, however, it remains challenging to perfectly excite these topological eigenstates due to their complicated mode profiles. In this work, we propose to realize the exact eigenmode of the topological edge states by supersymmetric (SUSY) structures. By adiabatically transforming the SUSY partner to its main topological structure, the edge modes can be perfectly excited with simple single-site input. We experimentally verify our strategy in integrated silicon waveguides in telecommunication wavelength, showing a broad working bandwidth. Moreover, a shortcut-to-adiabaticity strategy is further applied to speed up the adiabatic pump process by inverse-design approaches, thus enabling fast mode evolutions and leading to reduced device size. Our method is universal and beneficial to the topology-based or complex eigenmodes systems, ranging from photonics and microwaves to cold atoms and acoustics.

Association between Gastric Cancer and 12 Autoimmune Diseases: A Mendelian Randomization Study.

BACKGROUND: Whether the positive associations of gastric cancer (GC) with autoimmune diseases are causal has always been controversial. This study aims to estimate the causal relationship between GC and 12 autoimmune diseases by means of Mendelian randomization (MR) analysis. METHODS: After rigorous evaluation, potential candidate single nucleotide polymorphisms (SNPs) for GC and 12 autoimmune diseases were extracted from genome-wide association study (GWAS) datasets. We performed the MR analyses using the inverse variance weighted (IVW) method as the primary approach to the analysis. Three sensitivity analysis methods were added to assess the robustness of the results. In addition, heterogeneity was measured using Cochran's Q-value, and horizontal pleiotropy was assessed using MR-Egger regression and leave-one-out analysis. RESULTS: The IVW result, which is the main method of analysis, shows no evidence of a causal association between GC and any autoimmune disease. The results of IVW analysis show the relationship between rheumatoid arthritis (p = 0.1389), systemic lupus erythematosus (p = 0.1122), Crohn's disease (p = 0.1509), multiple sclerosis (p = 0.3944), primary sclerosing cholangitis (p = 0.9022), primary biliary cirrhosis (p = 0.7776), type 1 diabetes (p = 0.9595), ulcerative colitis (p = 0.5470), eczema (p = 0.3378), asthma (p = 0.7436), celiac disease (p = 0.4032), and psoriasis (p = 0.7622) and GC susceptibility. The same result was obtained with the weighted median and the MR-egger (p > 0.05). CONCLUSION: Our study did not find a genetic causal relationship between susceptibility to these autoimmune diseases and GC, which suggests that unmeasured confounders (e.g., inflammatory processes) or shared genetic architecture may be responsible for the reported epidemiologic associations. Further studies of ancestral diversity are warranted to validate such causal associations.

Cellulose based composite sponges with oriented porous structure and superabsorptive capacity for quick hemostasis.

Excessive bleeding is the leading cause of death in accidents and operations. Ca2+ crosslinked carboxyl nanocellulose (CN)/montmorillonite (MMT) composite (CaCNMMT) sponges were prepared by uniform mixing and directional freeze-drying methods which was inspired by the coordination mechanism of blood clot formation and coagulation cascade activation in natural hemostasis process. Carboxyl nanocellulose (CaCN) sponge has instantaneous water absorption capacity, and CaCNMMT sponges could further activate clotting factors. Therefore, CaCNMMT sponges achieved quick hemostasis by efficient concentrating blood, inducing hemocyte aggregation and stimulating coagulation cascade activation based on the synergistic effects of CN and MMT. Blood clotting index of CaCNMMT (15.90 ± 0.52 %) was significantly lower than CaCN (59.3 ± 1.43 %), and APTT time (22 ± 2 s) was almost equivalent to MMT (20 ± 2 s). CaCNMMT sponge showed good quick hemostatic effect on massive hemorrhage in both tail-breaking and liver injury model which provided a new strategy for the application of MMT in hemostatic and trauma treatment fields.

Lymph node and bone metastasis of pulmonary intestinal adenocarcinoma: A case report.

Pulmonary enteric adenocarcinoma (PEAC) is a rare pathological type of lung adenocarcinoma, accounting for ~0.6% of primary lung adenocarcinoma, which has similar morphological and immunohistochemical characteristics to colorectal adenocarcinoma. Making a certain differential diagnosis of PEAC based on morphological and immunohistochemical results is difficult. It is known that PEAC may metastasize to the pancreas, skin, soleus muscle and intestine, but no bone metastasis has been reported. At our department, a rare case of PEAC with bone and lymph node metastasis was previously diagnosed. The present case study reports on a 58-year-old male patient encountered at our hospital with pain in the lumbar, back and right iliac with no obvious cause. Chest CT indicated a space-occupying lesion in the left upper lung lobe, enlarged lymph nodes in the mediastinum and left lung, and partial vertebral bone destruction. Enhanced CT results indicated multiple foci of active bone metabolism in the body, while rectal colonoscopy showed no obvious abnormalities. Histopathological and immunohistochemical results after right iliac bone puncture suggested stage IV PEAC with secondary malignancies in bones, mediastinal lymph node, hilar lymph node and left supraclavicular lymph node.

[Progress in preparation and application of sodium alginate microspheres].

Sodium alginate (SA) is a kind of natural polymer material extracted from kelp, which has excellent biocompatibility, non-toxicity, biodegradability and abundant storage capacity. The formation condition of sodium alginate gel is mild, effectively avoiding the inactivation of active substances. After a variety of preparation methods, sodium alginate microspheres are widely used in the fields of biomaterials and tissue engineering. This paper reviewed the common methods of preparing alginate microspheres, including extrusion, emulsification, electrostatic spraying, spray drying and coaxial airflow, and discussed their applications in biomedical fields such as bone repair, hemostasis and drug delivery.

Causal associations of Sjögren's syndrome with cancers: a two-sample Mendelian randomization study.

BACKGROUND: Several observational studies have explored the associations between Sjögren's syndrome (SS) and certain cancers. Nevertheless, the causal relationships remain unclear. Mendelian randomization (MR) method was used to investigate the causality between SS and different types of cancers. METHODS: We conducted the two-sample Mendelian randomization with the public genome-wide association studies (GWASs) summary statistics in European population to evaluate the causality between SS and nine types of cancers. The sample size varies from 1080 to 372,373. The inverse variance weighted (IVW) method was used to estimate the causal effects. A Bonferroni-corrected threshold of P < 0.0031 was considered significant, and P value between 0.0031 and 0.05 was considered to be suggestive of an association. Sensitivity analysis was performed to validate the causality. Moreover, additional analysis was used to assess the associations between SS and well-accepted risk factors of cancers. RESULTS: After correcting the heterogeneity and horizontal pleiotropy, the results indicated that patients with SS were significantly associated with an increased risk of lymphomas (odds ratio [OR] = 1.0010, 95% confidence interval [CI]: 1.0005-1.0015, P = 0.0002) and reduced risks of prostate cancer (OR = 0.9972, 95% CI: 0.9960-0.9985, P = 2.45 × 10-5) and endometrial cancer (OR = 0.9414, 95% CI: 0.9158-0.9676, P = 1.65 × 10-5). Suggestive associations were found in liver and bile duct cancer (OR = 0.9999, 95% CI: 0.9997-1.0000, P = 0.0291) and cancer of urinary tract (OR = 0.9996, 95% CI: 0.9992-1.0000, P = 0.0281). No causal effect of SS on other cancer types was detected. Additional MR analysis indicated that causal effects between SS and cancers were not mediated by the well-accepted risk factors of cancers. No evidence of the causal relationship was observed for cancers on SS. CONCLUSIONS: SS had significant causal relationships with lymphomas, prostate cancer, and endometrial cancer, and suggestive evidence of association was found in liver and bile duct cancer and cancer of urinary tract, indicating that SS may play a vital role in the incidence of these malignancies.

Early gene expression profiles of anabolic and catabolic molecules in murine bone after a single PTH injection.

The current study examined the gene expression profiles of anabolic and catabolic molecules after a single parathyroid hormone (PTH) injection in mice. No significant changes were observed in alkaline phosphatase area/tissue volume, tartrate-resistant acid phosphatase-positive osteoclasts, or static bone histomorphometry parameters. However, a sudden and significant decrease in Runx2 expression occurred at 1.5 h post-injection followed by immediate elevation, while sclerostin level was initially downregulated but gradually recovered. Meanwhile, Rankl expression initially increased and then returned to baseline. The prolonged elevation of anabolic molecules and transient increase in catabolic molecules may contribute to the anabolic effect of PTH treatment.

An O2-sensing diguanylate cyclase broadly affects the aerobic transcriptome in the phytopathogen Pectobacterium carotovorum.

Pectobacterium carotovorum is an important plant pathogen responsible for the destruction of crops through bacterial soft rot, which is modulated by oxygen (O2) concentration. A soluble globin coupled sensor protein, Pcc DgcO (also referred to as PccGCS) is one way through which P. carotovorum senses oxygen. DgcO contains a diguanylate cyclase output domain producing c-di-GMP. Synthesis of the bacterial second messenger c-di-GMP is increased upon oxygen binding to the sensory globin domain. This work seeks to understand regulation of function by DgcO at the transcript level. RNA sequencing and differential expression analysis revealed that the deletion of DgcO only affects transcript levels in cells grown under aerobic conditions. Differential expression analysis showed that DgcO deletion alters transcript levels for metal transporters. These results, followed by inductively coupled plasma-mass spectrometry showing decreased concentrations of six biologically relevant metals upon DgcO deletion, provide evidence that a globin coupled sensor can affect cellular metal content. These findings improve the understanding of the transcript level control of O2-dependent phenotypes in an important phytopathogen and establish a basis for further studies on c-di-GMP-dependent functions in P. carotovorum.

Novel models by machine learning to predict prognosis of breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBM) are the most fatal, with limited survival in all breast cancer distant metastases. These patients are deemed to be incurable. Thus, survival time is their foremost concern. However, there is a lack of accurate prediction models in the clinic. What's more, primary surgery for BCBM patients is still controversial. METHODS: The data used for analysis in this study was obtained from the SEER database (2010-2019). We made a COX regression analysis to identify prognostic factors of BCBM patients. Through cross-validation, we constructed XGBoost models to predict survival in patients with BCBM. Meanwhile, a BCBM cohort from our hospital was used to validate our models. We also investigated the prognosis of patients treated with surgery or not, using propensity score matching and K-M survival analysis. Our results were further validated by subgroup COX analysis in patients with different molecular subtypes. RESULTS: The XGBoost models we created had high precision and correctness, and they were the most accurate models to predict the survival of BCBM patients (6-month AUC = 0.824, 1-year AUC = 0.813, 2-year AUC = 0.800 and 3-year survival AUC = 0.803). Moreover, the models still exhibited good performance in an externally independent dataset (6-month: AUC = 0.820; 1-year: AUC = 0.732; 2-year: AUC = 0.795; 3-year: AUC = 0.936). Then we used Shiny-Web tool to make our models be easily used from website. Interestingly, we found that the BCBM patients with an annual income of over USD$70,000 had better BCSS (HR = 0.523, 95%CI 0.273-0.999, P < 0.05) than those with less than USD$40,000. The results showed that in all distant metastasis sites, only lung metastasis was an independent poor prognostic factor for patients with BCBM (OS: HR = 1.606, 95%CI 1.157-2.230, P < 0.01; BCSS: HR = 1.698, 95%CI 1.219-2.365, P < 0.01), while bone, liver, distant lymph nodes and other metastases were not. We also found that surgical treatment significantly improved both OS and BCSS in BCBM patients with the HER2 + molecular subtypes and was beneficial to OS of the HR-/HER2- subtype. In contrast, surgery could not help BCBM patients with HR + /HER2- subtype improve their prognosis (OS: HR = 0.887, 95%CI 0.608-1.293, P = 0.510; BCSS: HR = 0.909, 95%CI 0.604-1.368, P = 0.630). CONCLUSION: We analyzed the clinical features of BCBM patients and constructed 4 machine-learning prognostic models to predict their survival. Our validation results indicate that these models should be highly reproducible in patients with BCBM. We also identified potential prognostic factors for BCBM patients and suggested that primary surgery might improve the survival of BCBM patients with HER2 + and triple-negative subtypes.