Targeting high circDNA2v levels in colorectal cancer induces cellular senescence and elicits an anti-tumor secretome.

The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T cell recruitment. circDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging the IGF2BP3 half-life, which in turn sustains mRNA levels of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and interleukin-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reductions in CD8+ T cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence, and tumor-infiltrating lymphocytes thus provides a rational approach for improving immunotherapy in CRC.

Research progress on the regulatory mechanisms of Irisin on cognitive dysfunction in patients with Alzheimer's disease and the interventional role of Irisin in associated diseases.

Irisin, a peptide produced during exercise, is believed to play a role in regulating energy levels within the body. Moreover, Irisin has the ability to traverse the blood-brain barrier and engage in various pathophysiological processes within the central nervous system. An increasing body of research identifies Irisin as a significant therapeutic target for neurodegenerative diseases, indicating a strong link between Irisin and the development of cognitive impairments. In this paper, we present a concise review of effects of different types of exercise on Irisin production, and the mechanisms underlying the Irisin's intervention in various diseases including metabolic diseases, kidney injury and depression. Following this, we delve into an in-depth exploration of its role in modulating cognitive dysfunction among patients with Alzheimer's disease (AD), focusing on recent advancements in three critical areas: neuroinflammation, mitochondrial dysfunction, and protein misfolding. Finally, we put forth 3 hypotheses: (1) exercise-induced fibronectin type III domain containing protein 5 (FNDC5) stimulation and subsequent Irisin cleavage may be associated with the stress response in energy metabolism; (2) Irisin, as a myokine, likely plays a role in mitochondrial repair mechanisms to ameliorate cognitive impairment in AD patients; (3) Irisin is a homeostatic factor that maintains energy homeostasis and is closely related to the dynamic stability of the body's internal environment.

3-Methyl-4-nitrophenol Exposure Deteriorates Oocyte Maturation by Inducing Spindle Instability and Mitochondrial Dysfunction.

3-methyl-4-nitrophenol (PNMC), a well-known constituent of diesel exhaust particles and degradation products of insecticide fenitrothion, is a widely distributed environmental contaminant. PNMC is toxic to the female reproductive system; however, how it affects meiosis progression in oocytes is unknown. In this study, in vitro maturation of mouse oocytes was applied to investigate the deleterious effects of PNMC. We found that exposure to PNMC significantly compromised oocyte maturation. PNMC disturbed the spindle stability; specifically, it decreased the spindle density and increased the spindle length. The weakened spindle pole location of microtubule-severing enzyme Fignl1 may result in a defective spindle apparatus in PNMC-exposed oocytes. PNMC exposure induced significant mitochondrial dysfunction, including mitochondria distribution, ATP production, mitochondrial membrane potential, and ROS accumulation. The mRNA levels of the mitochondria-related genes were also significantly impaired. Finally, the above-mentioned alterations triggered early apoptosis in the oocytes. In conclusion, PNMC exposure affected oocyte maturation and quality through the regulation of spindle stability and mitochondrial function.

Application of hand-sewn esophagojejunostomy in laparoscopic total gastrectomy.

OBJECTIVE: To investigate the clinical efficacy and prognostic implication of hand-sewn anastomosis in laparoscopic total gastrectomy (LTG). METHODS: Retrospective analysis is adopted to the clinicopathologic data of 112 patients with gastric cancer (GC) who went through LTG in the Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University between October 2020 and October 2022. Among them, 60 individuals receiving medical care were split into the hand-sewn anastomosis group (Group H, N = 60); while, 52 individuals were split into the circular stapler anastomosis group (Group C, N = 52) The clinical efficacy and prognostic conditions of hand-sewn anastomosis are compared with those of circular stapler anastomosis in the application of LTG. RESULTS: The analysis results indicated that no notable difference was observed in intraoperative bleeding volume, time to first flatus (TFF), postoperative hospitalization duration and postoperative complications among the two groups (P > 0.05). Group H had shorter esophagojejunal anastomosis duration (20.0 min vs. 35.0 min) and surgery duration (252.6 ± 19.4 min vs. 265.9 ± 19.8 min), smaller incisions (5.0 cm vs. 10.5 cm), and lower hospitalization costs (58415.0 CNY vs. 63382.5 CNY) compared to Group C (P < 0.05). CONCLUSION: The clinical efficacy and the postoperative complications of hand-sewn esophagojejunostomy are basically equivalent in comparison to the circular stapler anastomosis in the application of LTG. Its advantage lies in shorter esophagojejunal anastomosis duration, shorter surgery duration, smaller incisions, lower hospitalization costs and wider adaptability of the location of the tumor.

Water-Free Cyclosporine Ophthalmic Solution vs Vehicle for Dry Eye Disease: A Randomized Clinical Trial.

Importance: Dry eye disease (DED) is a prevalent eye disorder. Cyclosporine is an effective immunomodulator that is widely used in DED; however, due to its highly hydrophobic nature, delivery of cyclosporine to the ocular surface is challenging. Objective: To evaluate the efficacy and safety of SHR8028, a water-free cyclosporine ophthalmic solution, 0.1%, compared with vehicle in Chinese participants with DED. Design, Setting, and Participants: This was a multicenter, double-blind, vehicle-controlled, phase 3 randomized clinical trial conducted from March 4, 2021, to July 22, 2022. Adult participants with moderate to severe DED were recruited from 12 hospitals in China. Study data were analyzed April 2, 2022, for the primary analysis. Interventions: Following a 14-day run-in period with an artificial tear, participants were randomly assigned (1:1) to receive water-free cyclosporine or vehicle (1 eye drop in each eye twice daily). After a 29-day treatment, participants of both groups were given the option to receive water-free cyclosporine for an additional 12 weeks for longer-term safety assessment. Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS) using the National Eye Institute scale and in dryness score on a visual analog scale at day 29. Results: A total of 206 participants (mean [SD] age, 47.8 [14.2] years; 185 female [90%]) were enrolled, with 103 each in the cyclosporine group and the vehicle group. At day 29, the cyclosporine group experienced improved tCFS compared with vehicle (change [Δ] = -1.8; 95% CI, -2.7 to -1.0; P < .001), with a tCFS score decrease from baseline of -4.8 in the cyclosporine group and -3.0 in the vehicle group. Dryness score decreased from baseline in both groups (-19.2 vs -15.4; Δ = -3.8; 95% CI, -9.2 to 1.6; P = .17). During the 29-day treatment, treatment-related adverse events were reported in 15 participants (14.6%) in the cyclosporine group and 11 participants (10.7%) in the vehicle group. Conclusions And Relevance: Results demonstrated superiority of a water-free cyclosporine, 0.1%, eye solution over vehicle in improving tCFS score at day 29 in Chinese participants with DED. However, dryness score (VAS) was not improved at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT05841043.

HIF-1α induced by hypoxic condition regulates Treg/Th17 axis polarization in chronic immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired immune disorder characterized by increased platelet destruction and reduced platelet (Plt) production. Hypoxia-inducible factor-1α (HIF-1α) have regulatory effects on Treg/Th17 axis balance and may represent relevant factors in the pathogenesis of ITP. Treg/Th17 ratio, serum levels and gene expression were investigated in new diagnosed ITP (NITP) and chronic ITP (CITP). The Treg/Th17 ratio obviously decreased in CITP (P = 0.001). The ratio of Treg/Th17 was correlated with the level of HIF-1α level both in mRNA (r = 0.49, P < 0.0001) and serum level (r = 0.50, P < 0.0001). However, none statistical upregulation of HIF-1α was observed in CITP. In vitro, There was significant polarization difference of Treg/Th17 axis (P = 0.042) and Foxp3-MFI/IL17-MFI (P = 0.0003) in hypoxic condition between NITP and CITP. These findings suggest that HIF-1α induced by hypoxia plays a crucial role in the chronicity of ITP by mediating the imbalance of the Treg/Th17 axis.

Macromers for Encapsulating Perovskite Photovoltaics and Achieving High Stability.

Perovskite solar cells (pero-SCs) are highly unstable even under trace water. Although the blanket encapsulation (BE) strategy applied in the industry can effectively block moisture invasion, the commercial UV-curable adhesives (UVCAs) for BE still trigger power conversion efficiency deterioration, and the degradation mechanism remains unknown. For the first time, the functions of commercial UVCAs are revealed in BE-processed pero-SCs, where the small-sized monomer easily permeates to the perovskite surface, forming an insulating barrier to block charge extraction, while the high-polarity moiety can destroy perovskite lattice. To solve these problems, a macromer, named PIBA is carefully designed, by grafting two acrylate terminal groups on the highly gastight polyisobutylene and realizes an increased molecular diameter as well as avoided high-polarity groups. The PIBA macromer can stabilize on pero-SCs and then sufficiently crosslink, forming a compact and stable network under UV light without sacrificing device performance during the BE process. The resultant BE devices show negligible efficiency loss after storage at 85% relative humidity for 2000 h. More importantly, these devices can even reach ISO 20653:2013 Degrees of protection IPX7 standard when immersed in one-meter-deep water. This BE strategy shows good universality in enhancing the moisture stability of pero-SCs, irrespective of the perovskite composition or device structure.

A novel capitate bone Ilizarov external fixator for treating Kienböck's disease: an anatomical and biomechanical study.

This study aims to measure anatomical data of the capitate bone, develop an external fixator for treating late-stage osteonecrosis of lunate through Ilizarov technique, and evaluate its biomechanical performance. We selected eight wrist joint specimens to measure various parameters of the capitate bone, including its length, the distance from the junction of capitate head and body to the proximal end, as well as the width of its proximal head and distal body. Additionally, we measured these same indicators in 107 patients who had undergone wrist X-ray examination. Based on our measurements, we categorized the capitate bone into two groups and designed two types of capitate bone Ilizarov external fixator (CIEF) for it. Then, we compared it with the orthofix external fixator (OEF) through dynamic fatigue biomechanical experiments and pull-out resistance experiments. The results of the measurement revealed two categories of general patterns in the capitate bone. The first type maintains a consistent longitudinal axis between the proximal and distal ends. The second type is characterized by its proximal end being close to the radial side and its distal end being close to the ulnar side. In the dynamic tensile fatigue test, CIEF-A and CIEF-B had smaller maximum displacement values compared to the OEF (P < 0.05). In the anti-pull-out experiment, both CIEF-A and CIEF-B exhibited higher maximum pull-out force than the OEF (P < 0.05). CIFE is a treatment for advanced osteonecrosis of the lunate bone. It is specifically designed to align with the anatomical characteristics of the capitate bone, providing excellent biomechanical properties and a simple clinical procedure. However, additional clinical experiments are needed to confirm its effectiveness in the future.

Identification novel mutations and phenotypic spectrum expanding in PATL2 in infertile women with IVF/ICSI failure.

AIM: Abnormalities in oocyte maturation, fertilization, and early embryonic development are major causes of primary infertility in women who are undergoing IVF/ICSI attempts. Although many genetic factors responsible for these abnormal phenotypes have been identified, there are more additional pathogenic genes and variants yet to be discovered. Previous studies confirmed that bi-allelic PATL2 deficiency is an important factor for female infertility. In this study, 935 infertile patients with IVF/ICSI failure were selected for whole-exome sequencing, and 18 probands carrying PATL2 variants with a recessive inheritance pattern were identified. METHODS: We estimated that the prevalence contributed by PATL2 was 1.93% (18/935) in our study cohort. RESULTS: 15 novel variants were found in those families, including c.1093C > T, c.1609dupA, c.1204C > T, c.643dupG, c.877-2A > G, c.1228C > G, c.925G > A, c.958G > A, c.4A > G, c.1258T > C, c.1337G > A, c.1264dupA, c.88G > T, c.1065-2A > G, and c.1271T > C. The amino acids altered by the corresponding variants were highly conserved in mammals, and in silico analysis and 3D molecular modeling suggested that the PATL2 mutants impaired the physiologic function of the resulting proteins. Diverse clinical phenotypes, including oocyte maturation defect, fertilization failure, and early embryonic arrest might result from different variants of PATL2. CONCLUSIONS: These results expand the spectrum of PATL2 variants and provide an important reference for genetic counseling for female infertility, and they increase our understanding of the mechanisms of oocyte maturation arrest caused by PATL2 deficiency.

Bosea beijingensis sp. nov., Telluria beijingensis sp. nov. and Agrococcus beijingensis sp. nov., isolated from baijiu mash.

The baijiu fermentation environment hosts a variety of micro-organisms, some of which still remain uncultured and uncharacterized. In this study, the isolation, cultivation and characterization of three novel aerobic bacterial strains are described. The cells of strain REN20T were Gram-negative, strictly aerobic, motile and grew at 26-37 °C, at pH 6.0-9.0 and in the presence of 0-5.0   % (w/v) NaCl. The cells of strain REN29T were Gram-negative, strictly aerobic, motile and grew at 15-30 °C, at pH 6.0-9.0 and in the presence of 0-10.0   % (w/v) NaCl. The cells of strain REN33T were Gram-positive, strictly aerobic, motile and grew at 15-37 °C, at pH 5.0-10.0 and in the presence of 0-7.0   % (w/v) NaCl. The digital DNA-DNA hybridization and average nucleotide identity by orthology values between type strains in related genera and REN20T (20.3-36.8 % and 79.8-89.9  %), REN29T (20.3-36.8  % and 74.5-88.5  %) and REN33T (22.6-48.6  % and 75.8-84.2  %) were below the standard cut-off criteria for the delineation of bacterial species, respectively. Based on polyphasic taxonomy analysis, we propose three new species, Bosea beijingensis sp. nov. (=REN20T=GDMCC 1.2894T=JCM 35118T), Telluria beijingensis sp. nov. (=REN29T=GDMCC 1.2896T=JCM 35119T) and Agrococcus beijingensis sp. nov. (=REN33T=GDMCC 1.2898T=JCM 35164T), which were recovered during cultivation and isolation from baijiu mash.

Differential mRNA profiles reveal the potential roles of genes involved in lactate stimulation in mouse macrophages.

Lactate is a glycolysis end product, and its levels are markedly associated with disease severity, morbidity, and mortality in sepsis. It modulates key functions of immune cells, including macrophages. In this investigation, transcriptomic analysis was performed using lactic acid, sodium lactate, and hydrochloric acid-stimulated mouse bone marrow-derived macrophages (iBMDM), respectively, to identify lactate-associated signaling pathways. After 24 h of stimulation, 896 differentially expressed genes (DEG) indicated were up-regulation, whereas 792 were down-regulated in the lactic acid group, in the sodium lactate group, 128 DEG were up-regulated, and 41 were down-regulated, and in the hydrochloric acid group, 499 DEG were up-regulated, and 285 were down-regulated. Subsequently, clinical samples were used to further verify the eight genes with significant differences, among which Tssk6, Ypel4, Elovl3, Trp53inp1, and Cfp were differentially expressed in patients with high lactic acid, indicating their possible involvement in lactic acid-induced inflammation and various physiological diseases caused by sepsis. However, elongation of very long chain fatty acids protein 3 (Elovl3) was negatively correlated with lactic acid content in patients. The results of this study provide a necessary reference for better understanding the transcriptomic changes caused by lactic acid and explain the potential role of high lactic acid in the regulation of macrophages in sepsis.

Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice.

Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish ( Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse ( Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.

Varenicline solution nasal spray for dry eye disease in Chinese patients: a randomized phase 3 trial.

Background: Dry eye disease has a high prevalence and exerts a significant negative effect on quality of life. In China, there are currently no available nasal sprays to promote natural tear production in patients with dry eye disease. We therefore evaluated the efficacy and safety of OC-01 (varenicline solution) nasal spray versus vehicle in Chinese patients with dry eye disease. Methods: This was a randomized, multicenter, double-masked, vehicle-controlled, phase 3 clinical trial conducted at ophthalmology departments in 20 hospitals across China (NCT05378945). Eligible patients had a diagnosis of dry eye disease based on patient symptoms, Eye Dryness Score (EDS), Schirmer's Test (with topical anesthesia) Score (STS), and corneal fluorescein staining (CFS) score. Participants were randomly assigned 1:1 using an Interactive Web Response System (IWRS) to receive OC-01 0.6 mg/mL twice daily (BID) or vehicle nasal spray. Participants, investigators, and sponsor were all masked to treatment assignment. The primary endpoint was the percentage of subjects in the intention-to-treat population achieving ≥10 mm improvement in STS from baseline at week 4. Findings: In total, 340 patients were randomized from 21 July 2022 to 04 April 2023, 78.8% were female. Patients in the OC-01 group (n = 176) had significantly higher achievement of ≥10 mm improvement in STS (35.8% [n = 63] versus 17.7% [n = 29], stratified odds ratio: 2.67, 95% CI: 1.570-4.533, p = 0.0002) and a significantly greater increase from baseline STS (least-squares mean difference [SE]: 3.87 [0.794], p < 0.0001) at week 4 versus the vehicle group (n = 164). In addition, OC-01 led to a numerically greater reduction in mean EDS from baseline at week 4 compared to the vehicle group (LS mean [SE] difference: -1.3 [2.20]; 95% CI: -5.64 to 2.99, p = 0.5467). The most common adverse event was mild, transient sneezing (78% of OC-01 administrations). No serious adverse events related to nasal administration occurred. Interpretation: OC-01 (varenicline solution) nasal spray BID has clinically meaningful efficacy for reducing the signs (as measured by STS) and may improve the symptoms (as measured by EDS) of dry eye disease, with an excellent safety and tolerability profile, in the Chinese population. Funding: Jixing Pharmaceutical Co. Ltd.

Effectiveness of a broad-spectrum bivalent mRNA vaccine against SARS-CoV-2 variants in preclinical studies.

Vaccines utilizing modified messenger RNA (mRNA) technology have shown robust protective efficacy against SARS-CoV-2 in humans. As the virus continues to evolve in both human and non-human hosts, risk remains that the performance of the vaccines can be compromised by new variants with strong immune escape abilities. Here we present preclinical characterizations of a novel bivalent mRNA vaccine RQ3025 for its safety and effectiveness in animal models. The mRNA sequence of the vaccine is designed to incorporate common mutations on the SARS-CoV-2 spike protein that have been discovered along the evolutionary paths of different variants. Broad-spectrum, high-titer neutralizing antibodies against multiple variants were induced in mice (BALB/c and K18-hACE2), hamsters and rats upon injections of RQ3025, demonstrating advantages over the monovalent mRNA vaccines. Effectiveness in protection against several newly emerged variants is also evident in RQ3025-vaccinated rats. Analysis of splenocytes derived cytokines in BALB/c mice suggested that a Th1-biased cellular immune response was induced by RQ3025. Histological analysis of multiple organs in rats following injection of a high dose of RQ3025 showed no evidence of pathological changes. This study proves the safety and effectiveness of RQ3025 as a broad-spectrum vaccine against SARS-CoV-2 variants in animal models and lays the foundation for its potential clinical application in the future.

Ultraflexible Temperature-Strain Dual-Sensor Based on Chalcogenide Glass-Polymer Film for Human-Machine Interaction.

Skin-like thermoelectric (TE) films with temperature- and strain-sensing functions are highly desirable for human-machine interaction systems and wearable devices. However, current TE films still face challenges in achieving high flexibility and excellent sensing performance simultaneously. Herein, for the first time, a facile roll-to-roll strategy is proposed to fabricate an ultraflexible chalcogenide glass-polytetrafluoroethylene composite film with superior temperature- and strain-sensing performance. The unique reticular network of the composite film endows it with efficient Seebeck effect and flexibility, leading to a high Seebeck coefficient (731 µV/K), rapid temperature response (≈0.7 s), and excellent strain sensitivity (gauge factor = 836). Based on this high-performance composite film, an intelligent robotic hand for action feedback and temperature alarm is fabricated, demonstrating its great potential in human-machine interaction. Such TE film fabrication strategy not only brings new inspiration for wearable inorganic TE devices, but also sets the stage for a wide implementation of multifunctional human-machine interaction systems.

An Injectable silk-based hydrogel as a novel biomineralization seedbed for critical-sized bone defect regeneration.

The healing process of critical-sized bone defects urges for a suitable biomineralization environment. However, the unsatisfying repair outcome usually results from a disturbed intricate milieu and the lack of in situ mineralization resources. In this work, we have developed a composite hydrogel that mimics the natural bone healing processes and serves as a seedbed for bone regeneration. The oxidized silk fibroin and fibrin are incorporated as rigid geogrids, and amorphous calcium phosphate (ACP) and platelet-rich plasma serve as the fertilizers and loam, respectively. Encouragingly, the seedbed hydrogel demonstrates excellent mechanical and biomineralization properties as a stable scaffold and promotes vascularized bone regeneration in vivo. Additionally, the seedbed serves a succinate-like function via the PI3K-Akt signaling pathway and subsequently orchestrates the mitochondrial calcium uptake, further converting the exogenous ACP into endogenous ACP. Additionally, the seedbed hydrogel realizes the succession of calcium resources and promotes the evolution of the biotemplate from fibrin to collagen. Therefore, our work has established a novel silk-based hydrogel that functions as an in-situ biomineralization seedbed, providing a new insight for critical-sized bone defect regeneration.

Reciprocal regulation of lncRNA MEF and c-Myc drives colorectal cancer tumorigenesis.

More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.

PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes NRF2 nuclear accumulation, which induces PGD and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may therefore eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

Toxoplasma gondii infection and brain inflammation: A two-sample mendelian randomization analysis.

Background: Toxoplasma gondii is an opportunistic parasitic protozoan that can cause highly fatal toxoplasmic encephalitis when the host immune system is compromised. However, the transition from chronic to acute infection remains poorly understood. In this study, we conducted a 180-day observation of tissue damage and inflammation in the brains of mice infected with T. gondii. Subsequently, we investigated the inflammatory factors that T. gondii infection may alter using two-sample Mendelian randomization (MR) analysis. Methods: We first established a mouse model of T. gondii infection. Subsequently, the mice were euthanized, the brain tissue collected, and immunohistochemistry and hematoxylin and eosin staining performed to observe tissue damage and inflammatory conditions at various time points. Our study also included a published large-scale genome-wide association study meta-analysis that encompassed the circulating concentrations of 41 cytokines. This dataset included 8293 individuals from three independent population cohorts in Finland. Genetic association data for T. gondii were sourced from the Integrative Epidemiology Unit and European Bioinformatics Institute datasets, which included 5010 and 559 individuals of European ancestry, respectively. To assess the causal relationship between T. gondii infection and inflammatory biomarkers, we applied a two-sample MR. Results: Inflammation and damage resulting from T. gondii infection varied among the distinct regions of the mouse brain. Based on the MR analysis results, three inflammatory biomarkers were chemically assigned to Chemokines and Others, including IP10 (interferon gamma inducible protein-10), MCP1 (monocyte chemoattractant protein-1), and TRAIL (TNF-related apoptosis-inducing ligand). Conclusion: Our study commenced with the assessment of tissue damage and progression of inflammation in distinct regions of the mouse brain after T. gondii infection. Subsequently, using MR analysis, we detected potential alterations in inflammatory factors associated with this infection. These findings offer valuable insights into the mechanisms underlying toxoplasmic encephalitis and suggest directions for the prevention and treatment of T. gondii infections.

Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility.

Preimplantation embryonic arrest is an important pathogenesis of female infertility, but little is known about the genetic factors behind this phenotype. MEI4 is an essential protein for DNA double-strand break formation during meiosis, and Mei4 knock-out female mice are viable but sterile, indicating that MEI4 plays a crucial role in reproduction. To date, MEI4 has not been found to be associated with any human reproductive diseases. Here, we identified six compound heterozygous and homozygous MEI4 variants-namely, c.293C > T, p.(Ser98Leu), c.401C > G, p.(Pro134Arg), c.391C > G, p.(Pro131Ala), c.914A > T, p.(Tyr305Phe), c.908C > G, p.(Ala303Gly), and c.899A > T, p.(Gln300Leu)-in four independent families that were responsible for female infertility mainly characterized by preimplantation embryonic arrest. In vitro, we found that these variants reduced the interaction between MEI4 and DNA. In vivo, we generated a knock-in mouse model and demonstrated that female mice were infertile and were characterized by developmental defects during oogenesis. Our findings reveal the important roles of MEI4 in human reproduction and provide a new diagnostic marker for genetic counseling of clinical infertility patients.