The efficacy and safety of hydroxychloroquine at different doses and courses for COVID-19 prevention: a systematic review and network meta-analysis.

BACKGROUND: The optimal strategy for using hydroxychloroquine to prevent coronavirus disease 2019 (COVID-19) in patients, either before or after exposure, remains unclear. We evaluated the safety and efficacy of different doses and treatment durations of hydroxychloroquine for COVID-19 prevention. METHOD: Databases including PubMed, Web of Science, Cochrane Library, EMBASE, Medline, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) comparing different doses of hydroxychloroquine for COVID-19 prevention, from their inception to February 2024. RESULTS: A total of 20 RCTs involving 12,372 patients were included. Meta-analysis results showed no significant difference between the hydroxychloroquine and control groups in reducing the incidence of syndrome coronavirus type 2 (SARS-CoV-2) positivity (OR = 0.83, 95% CI = 0.67, 1.03). However, the subgroup receiving a daily dose of 200-400 mg (OR = 0.62, 95% CI = 0.51, 0.75) and a treatment duration of 5-8 weeks (OR = 0.52, 95% CI = 0.31, 0.88) showed statistically significant reductions in SARS-CoV-2 positivity. According to the surface under the cumulative ranking curve (SUCRA), the most effective intervention was a 200-400 mg dose for 5-8 weeks. . CONCLUSIONS: A hydroxychloroquine dose of 200-400 mg for a duration of 5-8 weeks may moderately reduce the risk of COVID-19 with a relatively low risk of adverse events.

Sm(â ¢), Gd(â ¢), and Eu(â ¢) complexes with 8-hydroxyquinoline derivatives as potential anticancer agents via inhibiting cell proliferation, blocking cell cycle, and inducing apoptosis in NCI-H460 cells.

Four lanthanide complexes with 8-hydroxyquinoline-2-aldehyde-2-hydrazinopyridine (H-L1), 8-hydroxyquinoline-2-aldehyde-2-hydrazimidazole (H-L2): [Sm(L1)2][Sm(L1)(NO3)3]·CHCl3·2CH3OH (1), [Gd(L1)2][Gd(L1)(NO3)3]·CHCl3·2CH3OH (2), [Sm(L2)(NO3)2]2·CH3OH (3), and [Eu(L2)(NO3)2]2·CH3OH (4) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex 1 showed the best antiproliferative activity against NCI-H460 tumor cells. Mechanistic studies demonstrated that complex 1 arrested the cell cycle of NCI-H460 cells in G1 phase and induced mitochondria-mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca2+ levels and reactive oxygen species generation. In addition, complex 1 affected the expression levels of intracellular apoptosis-related proteins and activated the caspase-3/9 in NCI-H460 cells. Therefore, complex 1 is a potential anticancer agent.

Causal factors for osteoarthritis risk revealed by mendelian randomization analysis.

Osteoarthritis (OA), a prevalent chronic disease among the elderly, presents a complex pathogenesis and currently lacks effective treatment. Traditional observational studies are time-consuming, labor-intensive, susceptible to confounding factors, and cannot establish causal relationships. Mendelian randomization (MR) analysis, leveraging genetic variation to assess causal associations between exposures and outcomes, offers a cost-effective and efficient alternative. Over the past decade, large-scale genome-wide association studies have identified numerous genetic variants linked to OA risk factors, facilitating MR study design. In this review, we systematically identified 52 MR studies meeting specific criteria and evaluated their quality, exploring the impact of lifestyle, nutrition, comorbidities, circulating metabolites, plasma proteins, and other health factors on OA risk. We discuss the results and potential mechanisms of MR findings, addressing conflicting evidence based on existing literature and our prior research. With the ongoing expansion of genome-wide association data, we anticipate MR's role in future OA studies to broaden, particularly in drug development research using targeted MR approaches. We thus aim for this paper to offer valuable insights for researchers and clinicians in related fields.

Proangiogenic effect and underlying mechanism of holmium oxide nanoparticles: a new biomaterial for tissue engineering.

BACKGROUND: Early angiogenesis provides nutrient supply for bone tissue repair, and insufficient angiogenesis will lead tissue engineering failure. Lanthanide metal nanoparticles (LM NPs) are the preferred materials for tissue engineering and can effectively promote angiogenesis. Holmium oxide nanoparticles (HNPs) are LM NPs with the function of bone tissue "tracking" labelling. Preliminary studies have shown that HNPs has potential of promote angiogenesis, but the specific role and mechanism remain unclear. This limits the biological application of HNPs. RESULTS: In this study, we confirmed that HNPs promoted early vessel formation, especially that of H-type vessels in vivo, thereby accelerating bone tissue repair. Moreover, HNPs promoted angiogenesis by increasing cell migration, which was mediated by filopodia extension in vitro. At the molecular level, HNPs interact with the membrane protein EphrinB2 in human umbilical vein endothelial cells (HUVECs), and phosphorylated EphrinB2 can bind and activate VAV2, which is an activator of the filopodia regulatory protein CDC42. When these three molecules were inhibited separately, angiogenesis was reduced. CONCLUSION: Overall, our study confirmed that HNPs increased cell migration to promote angiogenesis for the first time, which is beneficial for bone repair. The EphrinB2/VAV2/CDC42 signalling pathway regulates cell migration, which is an important target of angiogenesis. Thus, HNPs are a new candidate biomaterial for tissue engineering, providing new insights into their biological application.

Three-Dimensional Mechanical Microenvironment Rescued the Decline of Osteogenic Differentiation of Old Human Jaw Bone Marrow Mesenchymal Stem Cells.

Resorption and atrophy of the alveolar bone, as two consequences of osteoporosis that remarkably complicate the orthodontic and prosthodontic treatments, contribute to the differentiated biological features and force-induced response of jaw bone marrow-derived mesenchymal stem cells (JBMSCs) in elderly patients. We isolated and cultured JBMSCs from adolescent and adult patients and then simulated the loading of orthodontic tension stress by constructing an in vitro three-dimensional (3D) stress loading model. The decline in osteogenic differentiation of aged JBMSCs was reversed by tensile stress stimulation. It is interesting to note that tension stimulation had a stronger effect on the osteogenic differentiation of elderly JBMSCs compared to the young ones, indicating a possible mechanism of aging rescue. High-throughput sequencing of microRNA (miRNAs) was subsequently performed before and after tension stimulation in all JBMSCs, followed by the comprehensive comparison of mechanically responsive miRNAs in the 3D strain microenvironment. The results suggested a significant reduction in the expression of miR-210-3p and miR-214-3p triggered by the 3D strain microenvironment in old-JBMSCs. Bioinformatic analysis indicated that both miRNAs participate in the regulation of critical pathways of aging and cellular senescence. Taken together, this study demonstrated that the 3D strain microenvironment efficiently rescued the cellular senescence of old-JBMSCs via modulating specific miRNAs, which provides a novel strategy for coordinating periodontal bone loss and regeneration of the elderly.

Unilateral biportal endoscopy vs. open decompression for lumbar epidural lipomatosis-cohort study using a prospective registry.

Objective: This study aimed to compare the outcomes of unilateral biportal endoscopy, unilateral laminectomy bilateral decompression (UBE-ULBD), and open lumbar decompression (OLD) in patients with lumbar epidural lipomatosis (LEL). Methods: This prospective observational study was conducted from March 2019 to May 2022 and encompassed 33 patients with LEL who underwent lumbar decompression. The study included 15 cases of UBE-ULBD decompression and 18 cases of open decompression, which were followed up for 1 year. The baseline characteristics, initial clinical manifestations, and surgical details [including estimated blood loss (EBL) and preoperative complications] of all patients were recorded. Radiographic evaluation included the cross-sectional area (CSA) of the thecal sac and paraspinal muscles on MRI. Clinical results were analyzed using the Short Form-36 Score (SF-36), the Numeric Pain Rating Scale (NRS) for lumbar and leg pain, creatine kinase, the Roland and Morris Disability Questionnaire (RMDQ), and the Oswestry Disability Index (ODI). Results: The dural sac CSA increased considerably at the 1-year postoperative follow-up in both groups (p < 0.001). The operative duration in the OLD group (48.2 ± 7.2 min) was shorter than that in the UBE-ULBD group (67.7 ± 6.3 min, p < 0.001). The OLD group (97.2 ± 19.8 mL) was associated with more EBL than the UBE-ULBD group (40.6 ± 13.6 mL, p < 0.001). The duration of hospitalization in the OLD group (5.4 ± 1.3 days) was significantly longer compared with the UBE-ULBD group (3.5 ± 1.2 days, p < 0.01). The SF-36, NRS, RMDQ, and ODI scores improved in both groups postoperatively (p < 0.001). Serum creatine kinase values in the UBE-ULBD group (101.7 ± 15.5) were significantly lower than those in the OLD group (330.8 ± 28.1 U/L) 1 day after surgery (p < 0.001). The degree of paraspinal muscle atrophy in the UBE-ULBD group (4.81 ± 1.94) was significantly lower than that in the OLD group (12.15 ± 6.99) at 1 year (p < 0.001). Conclusion: UBE-ULBD and OLD demonstrated comparable clinical outcomes in treating LEL. However, UBE-ULBD surgery was associated with shorter hospital stays, lower rates of incision infection, lighter paravertebral muscle injury, and lower EBL than OLD surgery. Consequently, UBE-ULBD can be recommended in patients with LEL if conservative treatment fails.

AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.

Due to the exclusive maternal transmission, oocyte mitochondrial dysfunction reduces fertility rates, affects embryonic development, and programs offspring to metabolic diseases. However, mitochondrial DNA (mtDNA) are vulnerable to mutations during oocyte maturation, leading to mitochondrial nucleotide variations (mtSNVs) within a single oocyte, referring to mtDNA heteroplasmy. Obesity (OB) accounts for more than 40% of women at the reproductive age in the USA, but little is known about impacts of OB on mtSNVs in mature oocytes. It is found that OB reduces mtDNA content and increases mtSNVs in mature oocytes, which impairs mitochondrial energetic functions and oocyte quality. In mature oocytes, OB suppresses AMPK activity, aligned with an increased binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions. Similarly, AMPK knockout increases the binding affinity of ATF5-POLG proteins to mutated mtDNA, leading to the replication of heteroplasmic mtDNA and impairing oocyte quality. Consistently, AMPK activation blocks the detrimental impacts of OB by preventing ATF5-POLG protein recruitment, improving oocyte maturation and mitochondrial energetics. Overall, the data uncover key features of AMPK activation in suppressing mtSNVs, and improving mitochondrial biogenesis and oocyte maturation in obese females.

Structural and pharmacological characterization of a medium-chain fatty acid receptor GPR84 in common carp (Cyprinus carpio).

The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp.

Comparative Genomic and Transcriptomic Analysis of Phenol Degradation and Tolerance in Acinetobacter lwoffii through Adaptive Evolution.

Microorganism-based methods have been widely applied for the treatment of phenol-polluted environments. The previously isolated Acinetobacter lwoffii NL1 strain could completely degrade 0.5 g/L phenol within 12 h, but not higher concentrations of phenol. In this study, we developed an evolutionary strain NL115, through adaptive laboratory evolution, which possessed improved degradation ability and was able to degrade 1.5 g/L phenol within 12 h. Compared with that of the starting strain NL1, the concentration of degradable phenol by the developed strain increased three-fold; its phenol tolerance was also enhanced. Furthermore, comparative genomics showed that sense mutations mainly occurred in genes encoding alkyl hydroperoxide reductase, phenol hydroxylase, 30S ribosomal protein, and mercury resistance operon. Comparative transcriptomics between A. lwoffii NL115 and NL1 revealed the enrichment of direct degradation, stress resistance, and vital activity processes among the metabolic responses of A. lwoffii adapted to phenol stress. Among these, all the upregulated genes (log2fold-change > 5) encoded peroxidases. A phenotypic comparison of A. lwoffii NL1 and NL115 found that the adapted strain NL115 exhibited strengthened antioxidant capacity. Furthermore, the increased enzymatic activities of phenol hydroxylase and alkyl hydroperoxide reductase in A. lwoffii NL115 validated their response to phenol. Overall, this study provides insight into the mechanism of efficient phenol degradation through adaptive microbial evolution and can help to drive improvements in phenol bioremediation.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives.

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor function in glioblastoma.

The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.

Rhodium(III)-Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy.

As a continuation of our endeavors in discovering metal-based drugs with cytotoxic and antimetastatic activities, herein, we reported the syntheses of 11 new rhodium(III)-picolinamide complexes and the exploration of their potential anticancer activities. These Rh(III) complexes showed high antiproliferative activity against the tested cancer cell lines in vitro. The mechanism study indicated that Rh1 ([Rh(3a)(CH3CN)Cl2]) and Rh2 ([Rh(3b)(CH3CN)Cl2]) inhibited cell proliferation by multiple modes of action via cell cycle arrest, apoptosis, and autophagy and inhibited cell metastasis via FAK-regulated integrin ß1-mediated suppression of EGFR expression. Furthermore, Rh1 and Rh2 significantly inhibited bladder cancer growth and breast cancer metastasis in a xenograft model. These rhodium(III) complexes could be developed as potential anticancer agents with antitumor growth and antimetastasis activity.

Low Glucose plus ß-Hydroxybutyrate Induces an Enhanced Inflammatory Response in Yak Alveolar Macrophages via Activating the GPR109A/NF-κB Signaling Pathway.

Yaks are often subject to long-term starvation and a high prevalence of respiratory diseases and mortality in the withered season, yet the mechanisms that cause this remain unclear. Research has demonstrated that ß-hydroxybutyrate (BHB) plays a significant role in regulating the immune system. Hence, we hypothesize that the low glucose and high BHB condition induced by severe starvation might have an effect on the pro-inflammatory response of the alveolar macrophages (AMs) in yaks. To validate our hypothesis, we isolated and identified primary AMs from freshly slaughtered yaks and cultured them in a medium with 5.5 mM of glucose or 2.8 mM of glucose plus 1-4 mM of BHB. Utilizing a real-time quantitative polymerase chain reaction (RT-qPCR), immunoblot assay, and enzyme-linked immunosorbent assay (ELISA), we evaluated the gene and protein expression levels of GPR109A (G-protein-coupled receptor 109A), NF-κB p65, p38, and PPARγ and the concentrations of pro-inflammatory cytokines interleukin (IL)-1ß and IL-6 and tumor necrosis factor (TNF)-α in the supernatant. The results demonstrated that AMs exposed to low glucose plus BHB had significantly higher levels of IL-1ß, IL-6, and TNF-α (p < 0.05) and higher activity of the GPR109A/NF-κB signaling pathway. A pretreatment of either pertussis toxin (PTX, inhibitor of GPR109A) or pyrrolidinedithiocarbamic (PDTC, inhibitor of NF-κB p65) was effective in preventing the elevated secretion of pro-inflammatory cytokines induced by low glucose plus BHB (p < 0.05). These results indicated that the low glucose plus BHB condition would induce an enhanced pro-inflammatory response through the activation of the GPR109A/NF-κB signaling pathway in primary yak AMs, which is probably the reason why yaks experience a higher rate of respiratory diseases and mortality. This study will offer new insight into the prevention and treatment of bovine respiratory diseases.

Drinking water disinfection byproduct iodoacetic acid affects thyroid hormone synthesis in Nthy-ori 3-1 cells.

Iodoacetic acid (IAA) is an emerging and the most genotoxic iodinated disinfection byproduct to date. IAA can disrupt the thyroid endocrine function in vivo and in vitro, but the underlying mechanisms remain unclear. In this work, transcriptome sequencing was used to investigate the effect of IAA on the cellular pathways of human thyroid follicular epithelial cell line Nthy-ori 3-1 and determine the mechanism of IAA on the synthesis and secretion of thyroid hormone (TH) in Nthy-ori 3-1 cells. Results of transcriptome sequencing indicated that IAA affected the TH synthesis pathway in Nthy-ori 3-1 cells. IAA reduced the mRNA expression of thyroid stimulating hormone receptor, sodium iodide symporter, thyroid peroxidase, thyroglobulin, paired box 8 and thyroid transcription factor-2, inhibited the cAMP/PKA pathway and Na+-K+-ATPase, and decreased the iodine intake. The results were confirmed by our previous findings in vivo. Additionally, IAA downregulated glutathione and the mRNA expression of glutathione peroxidase 1, leading to increased reactive oxygen species production. This study is the first to elucidate the mechanisms of IAA on TH synthesis in vitro. The mechanisms are associated with down-regulating the expression of genes related to TH synthesis, inhibiting iodine uptake, and inducing oxidative stress. These findings may improve future health risk assessment of IAA on thyroid in human.

Decompression via unilateral biportal endoscopy for severe degenerative lumbar spinal stenosis: A comparative study with decompression via open discectomy.

Background: Previous studies have shown that the Unilateral Biportal Endoscopy is an effective and safety surgery for sufficient decompression of degenerative lumbar spinal stenosis. However, data are lacking in terms of its benefits when compared with conventional open lumbar discectomy (OLD), especially in patients with severe degenerative lumbar spinal stenosis (DLSS). Aim: To compare the clini cal outcomes of two types decompressive surgery: unilateral biportal endoscopy-unilateral laminectomy bilateral decompression (UBE-ULBD) and conventional open lumbar discectomy (OLD) in severe degenerative lumbar spinal stenosis (DLSS). Methods: We retrospectively analyzed patients who underwent UBE-ULBD (n = 50, operated at 50 levels; UBE-ULBD group) and conventional open lumbar discectomy (n = 59, operated at 47 levels; OLD group) between February 2019 and July 2021. All patients were diagnosed with severe stenosis based on the Schizas classification (Grade C or D) on MRI. We compared radiographic and clinical outcome scores [including the visual analog scale (VAS), Oswestry Disability Index (ODI), and Zurich Claudication Questionnaire (ZCQ)] between the 2 groups at 1 year of follow-up. The radiographic evaluation included the cross-sectional area (CSA) of the thecal sac and paraspinal muscles on MRI. Fasting blood was drawn before and 1 and 7 days after the operation to detect creatine kinase (CK). Surgical data perioperative complications were also investigated. Results: The baseline demographic data of the 2 groups were comparable, including VAS, ODI and ZCQ scores, the cross-sectional area of the thecal sac and paraspinal muscles and creatine kinase levels. The dural sac CSA significantly increased post -operatively in both groups, which confirmed they benefited from comparable decompressive effects. The operative duration in the OLD group was less than the UBE-ULBD group (43.9 ± 5.6 min vs. 74.2 ± 9.3 min, p < 0.05). The OLD group was associated with more estimated blood loss than the UBE-ULBD group (111.2 ± 25.0 ml vs. 41.5 ± 22.2 ml, P < 0.05). The length of hospital stay (HS) was significantly longer in the OLD group than in the UBE-ULBD group (6.8 ± 1.6 vs. 4.0 ± 1.4 days, P < 0.05). The VAS, ODI, and ZCQ scores improved in both groups after the operation. Serum creatine kinase values in the UBE-ULBD group were significantly lower than in the OLD group at 1 day after surgery (108. 1 ± 11.9 vs. 347.0 ± 19.5 U/L, P < 0.05). The degree of paraspinal muscle atrophy in the UBE-ULBD group was significantly lower than in the OLD group at 1 year (4.50 ± 0.60 vs. 11.42 ± 0.87, P < 0.05). Conclusions: UBE-ULBD and conventional OLD demonstrate comparable short-term clinical outcomes in treating severe DLSS. However, UBE-ULBD surgery was associated with a shorter hospital stay, less EBL and paravertebral muscle injury than OLD surgery.

RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.

Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt+ Tregs) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt+ Tregs. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt+ Tregs. T cell-specific Ddx5 knockout (DDX5ΔT) mice have augmented RORγt+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5ΔT mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.

Digital Subtraction Angiography-Guided Percutaneous Kyphoplasty in Treatment of Multi-Segmental Osteoporotic Vertebral Compression Fracture: A retrospective single-Center study.

Purpose: This study aimed to explore the effectiveness and safety of digital subtractionangiography (DSA)-guided percutaneous kyphoplasty (PKP) in treating multi-segmental osteoporotic vertebral compression fracture (OVCF). Methods: We retrospectively reviewed 68 patients with multi-segmental OVCF who had unilateral PKP surgeries using DSA and C arm guiding at our hospital between October 2016 and June 2020 and were followed for at least two years. All patients were divided into two groups: DSA guidance (n = 31) and C-arm guidance (n=37). In addition, we collected the clinical and radiological evaluation results during postoperative and last follow-up periods. Results: Our findings revealed that the DSA guidance group required lesser time for channel establishment and surgery than the C-arm guidance group at P < 0.05. The incidences of bone cement leakage, fluoroscopy times, and radiation dose of the DSA guidance group were significantly lesser than the C-arm guidance group (P < 0.05). Compared to the C-arm guidance group, the deviation of puncture in the DSA guidance group was significantly lower, the puncture angle in the DSA guidance group was significantly larger, and better bone cement distribution was obtained (P < 0.05). Compared to preoperative data, the VAS score, median vertebral height, and Cobb angle were significantly improved one day after surgery and the final follow-up in both groups (P < 0.05). However, the VAS score, the median vertebral height, average length of stay, and Cobb angle were not significantly different between the two groups (P > 0.05). Conclusion: DSA-guided PKP in treating multi-segmental OVCF can shorten the operation time, improve puncture accuracy, reduce the times and dose of fluoroscopy, reduce the leakage of bone cement, and achieve better cement distribution.

Multiomics atlas-assisted discovery of transcription factors enables specific cell state programming.

The same types of cells can assume diverse states with varying functionalities. Effective cell therapy can be achieved by specifically driving a desirable cell state, which requires the elucidation of key transcription factors (TFs). Here, we integrated epigenomic and transcriptomic data at the systems level to identify TFs that define different CD8 + T cell states in an unbiased manner. These TF profiles can be used for cell state programming that aims to maximize the therapeutic potential of T cells. For example, T cells can be programmed to avoid a terminal exhaustion state (Tex Term ), a dysfunctional T cell state that is often found in tumors or chronic infections. However, Tex Term exhibits high similarity with the beneficial tissue-resident memory T states (T RM ) in terms of their locations and transcription profiles. Our bioinformatic analysis predicted Zscan20 , a novel TF, to be uniquely active in Tex Term . Consistently, Zscan20 knock-out thwarted the differentiation of Tex Term in vivo , but not that of T RM . Furthermore, perturbation of Zscan20 programs T cells into an effector-like state that confers superior tumor and virus control and synergizes with immune checkpoint therapy. We also identified Jdp2 and Nfil3 as powerful Tex Term drivers. In short, our multiomics-based approach discovered novel TFs that enhance anti-tumor immunity, and enable highly effective cell state programming. One sentence summary: Multiomics atlas enables the systematic identification of cell-state specifying transcription factors for therapeutic cell state programming.

Epigenetic regulation of osteogenic differentiation of periodontal ligament stem cells in periodontitis.

Periodontitis is an inflammatory disease characterized by alveolar bone loss. Periodontal ligament stem cells (PDLSCs) have osteogenic differentiation potential, which can be influenced by epigenetics regulation in periodontitis. Therefore, this review aimed to shed light on the role of different epigenetic mechanisms in the osteogenic differentiation of PDLSCs and to consider the prospects of their possible therapeutic applications in periodontitis. Databases MEDLINE (through PubMed) and Web of Science were searched for the current knowledge of epigenetics in osteogenic differentiation of PDLSCs using the keywords "periodontal ligament stem cells", "epigenetic regulation", "epigenetics", "osteogenic differentiation", and "osteogenesis". All studies introducing epigenetic regulation and PDLSCs were retrieved. This review shows that epigenetic factors like DNMT, KDM6A, HDACi, some miRNAs, and lncRNAs can induce the osteogenic differentiation of PDLSCs in the noninflammatory microenvironment. However, the osteogenic differentiation of PDLSCs is inhibited in the inflammatory microenvironment through the upregulated DNA methylation of osteogenesis-related genes and specific changes in histone modification and noncoding RNA. Epigenetics of osteogenic differentiation of PDLSCs in inflammation exhibits the contrary effect compared with a noninflammatory environment. The application of epigenetic drugs to regulate the abnormal epigenetic status in periodontitis and focus on alveolar bone regeneration is promising.

Molecular cloning, tissue distribution, and pharmacologic function of melanocortin-3 receptor in common carp (Cyprinus carpio).

Melanocortin-3 receptor (MC3R) not only regulates energy homeostasis in animals, but also is an important regulator of inflammation. As one of the most widely farmed freshwater fish, common carp has attracted great interest for its feeding and inflammation regulation. In this study, we cloned the coding sequence (CDS) of common carp Mc3r (ccMc3r), examined its tissue expression profile, and investigated the function of this receptor in mediating downstream signaling pathways. The results showed that the CDS of ccMc3r was 975 bp, encoding a putative protein of 324 amino acids. Homology, phylogeny, and chromosomal synteny analyses revealed that ccMc3r is evolutionarily close to the orthologs of cyprinids. Quantitative real-time PCR (qPCR) indicated that ccMc3r was highly expressed in the brain and intestine. The luciferase reporter systems showed that four ligands, ACTH (1-24), α-MSH, ß-MSH, and NDP-MSH, were able to activate the cAMP and MAPK/ERK signaling pathways downstream of ccMc3r with different potencies. For the cAMP signaling pathway, ACTH (1-24) had the highest activation potency; while for the MAPK/ERK signaling pathway, ß-MSH had the greatest activation effect. In addition, we found that the four agonists were able to inhibit TNF-α-induced NF-κB signaling in approximately the same order of potency as cAMP signaling activation. This study may facilitate future studies on the role of Mc3r in common carp feed efficiency and immune regulation.