TGFß1 Stimulates the Proliferation of Quiescent Oogonial Stem Cells in Chicken.

Oogonial stem cells (OSCs) are a type of germ stem cell present in the adult ovary. They have the ability to self-renew through mitosis and differentiate into oocytes through meiosis. We have previously identified a population of OSCs in chicken ovary, but the underlying mechanism control their activation and proliferation were unclear. In this study, we observed that OSCs showed robust proliferation when cultured on a layer of chicken embryo fibroblasts (CEF), suggesting that CEF may secrete certain crucial factors that activate OSC proliferation. We further detected Transforming Growth Factor beta 1 (TGF-ß1) as a potent signaling molecule to promote OSC proliferation. Additionally, we revealed the signaling pathways that play important roles in the downstream of TGF-ß1-induced OSC proliferation. These findings provide insights into the mechanisms underlying OSC proliferation in chickens and offer a foundation for future research on in situ activation of OSC proliferation in ovary and improvement of egg-laying performance in chickens.

Mild hypothermia promotes neuronal differentiation of human neural stem cells via RBM3-SOX11 signaling pathway.

Both therapeutic hypothermia and neural stem cells (NSCs) transplantation have shown promise in neuroprotection and neural repair after brain injury. However, the effects of therapeutic hypothermia on neuronal differentiation of NSCs are not elucidated. In this study, we aimed to investigate whether mild hypothermia promoted neuronal differentiation in cultured and transplanted human NSCs (hNSCs). A significant increase in neuronal differentiation rate of hNSCs was found when exposed to 35°C, from 33% to 45% in vitro and from 7% to 15% in vivo. Additionally, single-cell RNA sequencing identified upregulation of RNA-binding motif protein 3 (RBM3) in neuroblast at 35°C, which stabilized the SRY-box transcription factor 11 (SOX11) mRNA and increased its protein expression, leading to an increase in neuronal differentiation of hNSCs. In conclusion, our study highlights that mild hypothermia at 35°C enhances hNSCs-induced neurogenesis through the novel RBM3-SOX11 signaling pathway, and provides a potential treatment strategy in brain disorders.

Use of cardiac contractility modulation combined with left bundle branch pacing CRT-P in a female with a 22-year history of non-ischemic dilated cardiomyopathy: A case report.

Cardiac contractility modulation (CCM) is a novel device-based therapy used to treat patients with heart failure with reduced ejection fraction (HFrEF). In both randomized clinical trials and real-life studies, CCM has been shown to improve exercise tolerance and quality of life, reverse left ventricular remodeling, and reduce hospitalization in patients with HFrEF. In this case report, we describe for the first time the use of CCM combined with left bundle branch pacing (LBBP) cardiac resynchronization therapy pacemaker (CRT-P) implantation therapy in a female with a 22-year history of non-ischemic dilated cardiomyopathy. With the optimal medical therapy and cardiac resynchronization therapy (CRT) strategies, the patient's quality of life initially recovered to some extent, but began to deteriorate in the past year. Additionally, heart transplantation was not considered due to economic reasons and late stage systolic heart failure. This is the first case of CCM implantation in Fujian Province and the first report of a combined CCM and left bundle branch pacing CRT-P implantation strategy in a patient with non-ischemic etiology dilated cardiomyopathy in China.

Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway.

Intranasal delivery provides a direct and non-invasive method for drugs to reach the central nervous system. Nanoparticles play a crucial role as carriers in augmenting the efficacy of brain delivery. However, the interaction between nanoparticles and the nose-to-brain pathway and how the various biopharmaceutical factors affect brain delivery efficacy remains unclear. In this review, we comprehensively summarized the anatomical and physiological characteristics of the nose-to-brain pathway and the obstacles that hinder brain delivery. We then outlined the interaction between nanoparticles and this pathway and reviewed the biomedical applications of various nanoparticulate drug delivery systems for nose-to-brain drug delivery. This review aims at inspiring innovative approaches for enhancing the effectiveness of nose-to-brain drug delivery in the treatment of different brain disorders.

Self-Disassembling and Oxygen-Generating Porphyrin-Lipoprotein Nanoparticle for Targeted Glioblastoma Resection and Enhanced Photodynamic Therapy.

The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self-disassembling porphyrin lipoprotein-coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence-guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self-quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO2) cores in PLCNP amplifies the fluorescence intensity of porphyrin-lipid. Furthermore, the CaO2 core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low-dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self-disassembling and oxygen-generating porphyrin-lipoprotein nanoparticle may serve as a promising all-in-one nanotheranostic platform for guiding precise GBM excision and empowering post-operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner.

Modulation of immune-responses by DSF/Cu enhances the anti-tumor effects of DTX for metastasis breast cancer.

Metastasis has been one of the most important causes of death from breast cancer, and chemotherapy remains the major option for metastatic breast cancer. However, drug resistance and higher toxicity from chemotherapy have been an obstacle for clinical practice, and the combination of chemotherapy with immunotherapy has emerged as a promising treatment strategy. Here, we describe a therapy based on the combination of disulfiram (DSF) and Cu2+ with widely used cytotoxic docetaxel (DTX). DSF/Cu-induced immunogenic cell death promoted the release of type I interferon and human monocyte-induced dendritic cell maturation, which established a foundation for the combination with chemotherapy. Consequently, the combination of DSF/Cu and DTX resulted in significantly more potent anti-tumor effects in 4T1-bearing mice than in single therapy. The present study has shed new light on combining DSF/Cu-induced immune responses with traditional chemotherapeutic agents to achieve greater benefits for patients with metastasis.

Causality of unsaturated fatty acids and psoriasis a Mendelian randomization study.

Background: Many observational studies have identified a link between unsaturated fatty acids and psoriasis. However, they contain reverse causality and confounding factors, and there is no definite causal study between unsaturated fatty acids and psoriasis. Objectives: Analysis of causality between unsaturated fatty acids and psoriasis by Mendelian randomization. Methods: We used IEU Open GWAS Project, omega-3 PUFA and omega-6 PUFA data from 114,999 subjects, MUFA data from 13,535 subjects, and psoriasis data from 4,510 cases and 212,242 controls were included. We employed the inverse-variance weighted (IVW) method as the primary analytical approach and four additional MR methods. Moreover, we performed heterogeneity and horizontal pleiotropy assessments using Cochrane's Q and MR-Egger intercept tests, respectively. Finally, we performed sensitivity analyses to enhance our findings' precision and veracity. Results: IVW results showed no causal effect of omega-3 PUFA on psoriasis (p = 0.334; OR, 0.909; 95% CI, 0.748-1.104), omega-6 PUFA cause psoriasis (p = 0.046; OR, 1.174; 95% CI, 1.003-1.374), MUFA cause psoriasis (p = 0.032; OR, 1.218; 95% CI, 1.018-1.457), no causal effect of omega-3 PUFA in psoriasis (p = 0.695; OR, 0.989; 95% CI, 0.937-1.044), no causal effect of omega-6 PUFA in psoriasis (p = 0.643; OR, 1.013; 95% CI, 0.960-1.068), psoriasis is not causal to MUFA (p = 0.986; OR, 1.000; 95% CI, 0.949-1.055). Heterogeneity, horizontal pleiotropy, and sensitivity analyses showed reliable results. Conclusion: We found that circulating omega-6 PUFA and MUFA cause psoriasis, while omega-3 PUFA do not. Treatments that lower circulating omega-6 PUFA and MUFA are effective in psoriasis. After a better understanding of fatty acid intake and circulation, the population can be advised to regulate their diet.

Intraoperative application of intelligent, responsive, self-assembling hydrogel rectifies oxygen and energy metabolism in traumatically injured brain.

In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS-lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.

The impact of induced pluripotent stem cells in animal conservation.

It is widely acknowledged that we are currently facing a critical tipping point with regards to global extinction, with human activities driving us perilously close to the brink of a devastating sixth mass extinction. As a promising option for safeguarding endangered species, induced pluripotent stem cells (iPSCs) hold great potential to aid in the preservation of threatened animal populations. For endangered species, such as the northern white rhinoceros (Ceratotherium simum cottoni), supply of embryos is often limited. After the death of the last male in 2019, only two females remained in the world. IPSC technology offers novel approaches and techniques for obtaining pluripotent stem cells (PSCs) from rare and endangered animal species. Successful generation of iPSCs circumvents several bottlenecks that impede the development of PSCs, including the challenges associated with establishing embryonic stem cells, limited embryo sources and immune rejection following embryo transfer. To provide more opportunities and room for growth in our work on animal welfare, in this paper we will focus on the progress made with iPSC lines derived from endangered and extinct species, exploring their potential applications and limitations in animal welfare research.

Mesenchymal stem cells prevent H7N9 virus infection via rejuvenating immune environment to inhibit immune-overactivity.

BACKGROUND: Influenza is a clinically important infectious disease with a high fatality rate, which always results in severe pneumonia. Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on severe viral pneumonia, but whether MSCs prevent virus infection and contribute to the prevention of influenza remains unknown. METHODS: ICR mice were pretreated with human umbilical cord (hUC) MSCs and then infected with the influenza H7N9 virus. Weight, survival days, and lung index of mice were recorded. Serum antibody against influenza H7N9 virus was detected according to the hemagglutination inhibition method. Before and after virus infection, T cell and B cell subtypes in the peripheral blood of mice were evaluated by flow cytometry. Cytokines in the supernatants of MSCs, innate immune cells, and mouse broncho alveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA) or Luminex Assay. RESULTS: Pretreatment with MSCs protected mice against influenza H7N9 virus infection. Weight loss, survival rate, and structural and functional damage to the lungs of infected mice were significantly improved. Mechanistically, MSCs modulated T lymphocyte response in virus-infected mice and inhibited the cGAS/STING pathway. Importantly, the protective effect of MSCs was mediated by cell-to-cell communications and attenuation of cytokine storm caused by immune overactivation.

Erythropoietin improves pulmonary hypertension by promoting the homing and differentiation of bone marrow mesenchymal stem cells in lung tissue.

Pulmonary arterial hypertension (PAH) is a chronic disease thatultimately progresses to right-sided heart failure and death. Erythropoietin (EPO) has been shown to have therapeutic potential in cardiovascular diseases, including PAH. In this study, we aimed to investigate the improvement effect of EPO pretreated bone marrow mesenchymal stem cells (BMSCs) on PAH. BMSCs were obtained from the bone marrow of male SD rats. Female rats were randomly divided into six groups, including control group, monocrotaline (MCT)-induced group, and four groups with different doses of EPO pretreated BMSCs. Lung tissue was taken for testing at 2 weeks of treatment. Our results showed EPO promoted homing and endothelial cell differentiation of BMSCs in the lung tissues of PAH rats. EPO and BMSCs treatment attenuated pulmonary arterial pressure, polycythemia, and pulmonary artery structural remodeling. Furthermore, BMSCs inhibited pulmonary vascular endothelial-to-mesenchymal transition (EndoMT) in PAH rats, which was further suppressed by EPO in a concentration-dependent manner. Meanwhile, EPO and BMSC treatment elevated pulmonary angiogenesis in PAH rats. BMSCs inhibited TNF-α, IL-1ß, IL-6, and MCP-1 in lung tissues of PAH rats, which was further decreased by EPO in a concentration-dependent manner. Thus, EPO improved pulmonary hypertension (PH) by promoting the homing and differentiation of BMSCs in lung tissue.

Efficacy of fractional CO2 laser therapy combined with hyaluronic acid dressing for treating facial atrophic acne scars: a systematic review and meta-analysis of randomized controlled trials.

The present work aimed to systematically identify the efficacy and safety of fractional carbon dioxide (CO2) laser plus hyaluronic acid (HA) dressing in dealing with facial atrophic acne scars. Randomized controlled trials (RCTs) concerning fractional CO2 laser in combination with HA dressing for treating atrophic acne scars were screened in 8 electronic databases (containing PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Internet, Wanfang, Sinomed as well as VIP). Besides, for the purpose of evaluating the risk of bias of the enrolled RCTs, the Cochrane Collaboration tool was adopted. Statistical analysis was completed using Revman5.3 software and Stata 14.0 software. Meanwhile, the quality of evidence was assessed by the GRADE system. Finally, 6 studies involving 623 patients were enrolled. According to the findings in this study, compared with fractional CO2 laser alone, fractional CO2 laser therapy combined with HA dressing reduced the scores of ECCA (échelle d'évaluation clinique des cicatrices d'acné) grading scale (MD=-3.37,95% CI [-5.03, -1.70], P<0.0001), shortened the time of crust formation (MD=-0.42,95% CI [-0.80, -0.04], P=0.03) and the time of crust removal(MD=-1.31,95% CI [-1.67, -0.95], P<0.00001), enhanced patient satisfaction (RR=1.85, 95% CI [1.44, 2.38], P<0.00001). All the reported adverse events including hyperpigmentation, erythema, edema, mild itching, and slight burning pain were controllable. In addition, fractional CO2 laser combined with HA dressing therapy had a lower incidence of hyperpigmentation than fractional CO2 laser alone (RR=0.37, 95% CI [0.23, 0.61], P<0.0001). The level of evidence for outcomes was classified to be low to moderate. According to our findings, fractional CO2 laser combined with HA dressing is efficacious and safe option for facial atrophic acne scars. Nevertheless, more high-quality trials are required for further verification in the future.

The regulation of Tfh cell differentiation by ß-hydroxybutyrylation modification of transcription factor Bcl6.

Transcriptional repressor B cell lymphoma 6 (Bcl6) is a major transcription factor involved in Tfh cell differentiation and germinal center response, which is regulated by a variety of biological processes. However, the functional impact of post-translational modifications, particularly lysine ß-hydroxybutyrylation (Kbhb), on Bcl6 remains elusive. In this study, we revealed that Bcl6 is modified by Kbhb to affect Tfh cell differentiation, resulting in the decrease of cell population and cytokine IL-21. Furthermore, the modification sites are identified from enzymatic reactions to be lysine residues at positions 376, 377, and 379 by mass spectrometry, which is confirmed by site-directed mutagenesis and functional analyses. Collectively, our present study provides evidence on the Kbhb modification of Bcl6 and also generates new insights into the regulation of Tfh cell differentiation, which is a starting point for a thorough understanding of the functional involvement of Kbhb modification in the differentiations of Tfh and other T cells.

The Synchronized Progression from Mitosis to Meiosis in Female Primordial Germ Cells between Layers and Broilers.

Layer and broiler hens show a dramatic difference in the volume and frequency of egg production. However, it is unclear whether the intrinsic competency of oocyte generation is also different between the two types of chicken. All oocytes were derived from the primordial germ cells (PGC) in the developing embryo, and female PGC proliferation (mitosis) and the subsequent differentiation (meiosis) determine the ultimate ovarian pool of germ cells available for future ovulation. In this study, we systematically compared the cellular phenotype and gene expression patterns during PGC mitosis (embryonic day 10, E10) and meiosis (E14) between female layers and broilers to determine whether the early germ cell development is also subjected to the selective breeding of egg production traits. We found that PGCs from E10 showed much higher activity in cell propagation and were enriched in cell proliferation signaling pathways than PGCs from E14 in both types of chicken. A common set of genes, namely insulin-like growth factor 2 (IGF2) and E2F transcription factor 4 (E2F4), were identified as the major regulators of cell proliferation in E10 PGCs of both strains. In addition, we found that E14 PGCs from both strains showed an equal ability to initiate meiosis, which was associated with the upregulation of key genes for meiotic initiation. The intrinsic cellular dynamics during the transition from proliferation to differentiation of female germ cells were conserved between layers and broilers. Hence, we surmise that other non-cell autonomous mechanisms involved in germ-somatic cell interactions would contribute to the divergence of egg production performance between layers and broilers.

Identification of oogonial stem cells in chicken ovary.

OBJECTIVES: Oogonial stem cells (OSCs) are germ cells that can sustain neo-oogenesis to replenish the pool of primary follicles in adult ovaries. In lower vertebrates, fresh oocytes are produced by numerous OSCs through mitosis and meiosis during each reproduction cycle, but the OSCs in adult mammals are rare. The birds have retained many conserved features and developed unique features of ovarian physiology during evolution, and the presence of OSCs within avian species remain unknown. MATERIALS AND METHODS: In this study, we investigated the existence and function of OSCs in adult chickens. The chicken OSCs were isolated and expanded in culture. We then used cell transplantation system to evaluate their potential for migration and differentiation in vivo. RESULTS: DDX4/SSEA1-positive OSCs were identified in both the cortex and medulla of the adult chicken ovary. These putative OSCs undergo meiosis in the reproductively active ovary. Furthermore, the isolated OSCs were expanded in vitro for months and found to express germline markers similar to those of primordial germ cells. When transplanted into the bloodstream of recipient embryos, these OSCs efficiently migrated into developing gonads, initiated meiosis, and then derived oocytes in postnatal ovaries. CONCLUSIONS: This study has confirmed the presence of functional OSCs in birds for the first time. The identification of chicken OSCs has great potential for improving egg laying and preserving endangered species.

Recombinant High-Density Lipoprotein Boosts the Therapeutic Efficacy of Mild Hypothermia in Traumatic Brain Injury.

Traumatic brain injury (TBI) leads to neuropsychiatric symptoms and increased risk of neurodegenerative disorders. Mild hypothermia is commonly used in patients suffering from severe TBI. However, its effect for long-term protection is limited, mostly because of its insufficient anti-inflammatory and neuroprotective efficacy and restricted treatment duration. Recombinant high-density lipoprotein (rHDL), which possesses anti-inflammatory and antioxidant activity and blood-brain barrier (BBB) permeability, was expected to potentially strengthen the therapeutic effect of mild hypothermia in TBI treatment. To test this hypothesis and optimize the regimen for combination therapy, the efficacy of mild hypothermia plus concurrent or sequential rHDL on oxidative stress, inflammatory reaction, and cell survival in the damaged brain cells was evaluated. It was found that the effect of combining mild hypothermia with concurrent rHDL was modest, as mild hypothermia inhibited the cellular uptake and lesion-site-targeting delivery of rHDL. In contrast, the combination of mild hypothermia with sequential rHDL more powerfully improved the anti-inflammatory and antioxidant activities, promoted nerve cell survival and BBB restoration, and ameliorated neurologic changes, which thus remarkably restored the spatial learning and memory ability of TBI mice. Collectively, these findings suggest that rHDL may serve as a novel nanomedicine for adjunctive therapy of TBI and highlight the importance of timing of combination therapy for optimal treatment outcome.

Brain Extract of Subacute Traumatic Brain Injury Promotes the Neuronal Differentiation of Human Neural Stem Cells via Autophagy.

BACKGROUND: After a traumatic brain injury (TBI), the cell environment is dramatically changed, which has various influences on grafted neural stem cells (NSCs). At present, these influences on NSCs have not been fully elucidated, which hinders the finding of an optimal timepoint for NSC transplantation. METHODS: Brain extracts of TBI mice were used in vitro to simulate the different phase TBI influences on the differentiation of human NSCs. Protein profiles of brain extracts were analyzed. Neuronal differentiation and the activation of autophagy and the WNT/CTNNB pathway were detected after brain extract treatment. RESULTS: Under subacute TBI brain extract conditions, the neuronal differentiation of hNSCs was significantly higher than that under acute brain extract conditions. The autophagy flux and WNT/CTNNB pathway were activated more highly within the subacute brain extract than in the acute brain extract. Autophagy activation by rapamycin could rescue the neuronal differentiation of hNSCs within acute TBI brain extract. CONCLUSIONS: The subacute phase around 7 days after TBI in mice could be a candidate timepoint to encourage more neuronal differentiation after transplantation. The autophagy flux played a critical role in regulating neuronal differentiation of hNSCs and could serve as a potential target to improve the efficacy of transplantation in the early phase.

Direct Current Electric Field Coordinates the Migration of BV2 Microglia via ERK/GSK3ß/Cofilin Signaling Pathway.

Direct current electric field (DCEF) steers the migration of various neural cells. Microglia, as macrophage of the central nervous system (CNS), however, have not been reported to engage in electrotaxis. Here, we applied electric fields to an in vitro environment and found directional migration of BV2 microglia toward the cathode, in a DCEF strength-dependent manner. Transcriptome analysis then revealed significant changes in the mitogen-activated protein kinase cascades. In terms of mechanism, DCEF coordinated microglia movement by regulating the ERK/GSK3ß/cofilin signaling pathway, and PMA (protein kinase C activator) reversed cell migration through intervention of the ERK/GSK3ß/cofilin axis. Meanwhile, LiCl (GSK3ß inhibitor) showed similar functions to PMA in the electrotaxis of microglia. Furthermore, pharmacological and genetic suppression of GSK3ß or cofilin also modulated microglia directional migration under DCEF. Collectively, we discovered the electrotaxis of BV2 microglia and the essential role of the ERK/GSK3ß/cofilin axis in regulating cell migration via modulation of F-actin redistribution. This research highlights new insight toward mediating BV2 directional migration and provides potential direction for novel therapeutic strategies of CNS diseases.

A Perioperative Paradigm of Cranioplasty With Polyetheretherketone: Comprehensive Management for Preventing Postoperative Complications.

Introduction: At present, lots of studies have discussed the effects and outcomes of cranioplasty using polyetheretherketone (PEEK). However, interventions or management for PEEK cranioplasty got less attention. This article presented a perioperative paradigm for preventing postoperative complications. Materials and Methods: Modified PEEK plates with certified safety were implanted in patients who received evolving perioperative paradigm. Serial perioperative managements were developed as a comprehensive paradigm to prevent correlated risk factors of postoperative complications, which mainly included managements of epidural collections and wound healing. The preparation of the surgical area and systemic state were essential before surgery. During the operation, the blood supply of the incision and the handling of dura and temporalis were highlighted in our paradigm. After cranioplasty, management of subcutaneous drainage and wound healing were stressed. Patients received conventional management from February 2017 to August 2018 in our center. After the evolving paradigm developed, patients received comprehensive perioperative management from September 2018 to August 2020. Results: A total of 104 patients who underwent PEEK cranioplasty were consecutively enrolled; 38 (36.5%) received conventional perioperative management, and 66 (63.5%) received evolving perioperative paradigm. The general information of the two groups was comparable. Notably, patients who received the evolving paradigm presented a significantly decreased incidence of postoperative complications from 47.4 to 18.2% (P < 0.01), among which the incidences of subcutaneous effusion, epidural hematoma, and subcutaneous infection decreased significantly. Conclusion: The evolving perioperative paradigm could effectively prevent risk factors and reduce related complications. It was valuable to promote these comprehensive managements and inspire more clinical practice on improving patients' outcomes after PEEK cranioplasty.