Identification and Functional Analysis of a de novo IKZF3 Mutation in a Pediatric Patient with Combined Immunodeficiency.

AIOLOS, a vital member of the IKAROS protein family, plays a significant role in lymphocyte development and function through DNA binding and protein-protein interactions. Mutations in the IKZF3 gene, which encodes AIOLOS, lead to a rare combined immunodeficiency often linked with infections and malignancy. In this study, we evaluated a 1-year-4-month-old female patient presenting with recurrent infections, diarrhea, and failure to thrive. Laboratory investigations revealed decreased T lymphocyte and immunoglobulin levels. Through whole-exome and Sanger sequencing, we discovered a de novo mutation in IKZF3 (NM_012481; exon 5 c.571G > C, p.Gly191Arg), corresponding to the third DNA-binding zinc finger region of the encoded protein AIOLOS. Notably, the patient with the AIOLOS G191R mutation showed reduced recent thymic emigrants in naïve CD4+T cells compared to healthy counterparts of the same age, while maintaining normal levels of Th1, Th2, Th17, Treg, and Tfh cells. This mutation also resulted in decreased switched memory B cells and lower CD23 and IgM expression. In vitro studies revealed that AIOLOS G191R does not impact the expression of AIOLOS but compromises its stability, DNA binding and pericentromeric targeting. Furthermore, AIOLOS G191R demonstrated a dominant-negative effect over the wild-type protein. This case represents the first reported instance of a mutation in the third DNA-binding zinc finger region of AIOLOS highlighting its pivotal role in immune cell functionality.

Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations.

PURPOSES: STAT1 is a transduction and transcriptional regulator that functions within the classical JAK/STAT pathway. In addition to chronic mucocutaneous candidiasis, bacterial infections are a common occurrence in patients with STAT1 gain-of-function (GOF) mutations. These patients often exhibit skewing of B cell subsets; however, the impact of STAT1-GOF mutations on B cell-mediated humoral immunity remains largely unexplored. It is also unclear whether these patients with IgG within normal range require regular intravenous immunoglobulin (IVIG) therapy. METHODS: Eleven patients (harboring nine different STAT1-GOF mutations) were enrolled. Reporter assays and immunoblot analyses were performed to confirm STAT1 mutations. Flow cytometry, deep sequencing, ELISA, and ELISpot were conducted to assess the impact of STAT1-GOF on humoral immunity. RESULTS: All patients exhibited increased levels of phospho-STAT1 and total STAT1 protein, with two patients carrying novel mutations. In vitro assays showed that these two novel mutations were GOF mutations. Three patients with normal total IgG levels received regular IVIG infusions, resulting in effective control of bacterial infections. Four cases showed impaired affinity and specificity of pertussis toxin-specific antibodies, accompanied by reduced generation of class-switched memory B cells. Patients also had a disrupted immunoglobulin heavy chain (IGH) repertoire, coupled with a marked reduction in the somatic hypermutation frequency of switched Ig transcripts. CONCLUSION: STAT1-GOF mutations disrupt B cell compartments and skew IGH characteristics, resulting in impaired affinity and antigen-specificity of antibodies and recurrent bacterial infections. Regular IVIG therapy can control these infections in patients, even those with normal total IgG levels.

Current understanding of ELF4 deficiency: a novel inborn error of immunity.

BACKGROUND: ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity (IEIs), specifically categorized as a "disease of immune dysregulation." Cases of this condition, reported by our team and others, are very limited worldwide. As such, our current knowledge of this new disease remains preliminary. This review aims to provide a brief overview of the clinical manifestations, pathogenesis, and treatment strategies for this novel IEI. DATA SOURCES: A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 deficiency. Our search strategy was "ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor" as of the time of manuscript submission. RESULTS: The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer, abdominal pain, and diarrhea in pediatric males. In some cases, immunodeficiency and autoimmunity can also be prominent. Targeted Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 gene. Western blotting for ELF4 expression of the patient's cells can confirm the pathogenic effect of the variant. To fully confirm the pathogenicity of the variant, further functional test is strongly advised. Glucocorticoid and biologics are the mainstream management of ELF4 deficiency disorder. CONCLUSIONS: Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of DEX. When atypical presentations are prominent, variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 function. Experience of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.

Atypical familial hemophagocytic lymphohistiocytosis type 3 in children: A report of cases and literature review.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is caused by UNC13D variants. The clinical manifestations of FHL3 are highly diverse and complex. Some patients exhibit atypical or incomplete phenotypes, making accurate diagnosis difficult. Our study aimed to broaden the understanding of the atypical FHL3 clinical spectrum. METHODS: In our study, we analyzed in detail the clinical features of four Chinese patients with UNC13D variants. Additionally, we conducted a comprehensive review of the existing literature on previously reported atypical manifestations and summarized the findings. RESULTS: Two of our patients presented with muscle involvement, while the other two had hematological involvement; none of them met the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH). However, protein expression and functional analysis ultimately confirmed diagnostic criteria for FHL3 in all patients. From the literature we reviewed, many atypical FHL3 patients had neurological involvement, especially isolated neurological manifestations. At the same time, arthritis and hypogammaglobulinemia were also prone to occur. CONCLUSION: Our study highlights that the expression of the Munc13-4 protein may not fully indicate the pathogenicity of UNC13D variants, whereas CD107a analysis could be more sensitive for disease diagnosis. These findings contribute to a broader understanding of the FHL3 clinical spectrum and may offer new insights into the underlying pathogenesis of UNC13D variants. It is crucial to prioritize the timely and accurate diagnosis of atypical patients, as they may often be overlooked among individuals with rheumatic or hematological diseases.

Comparison of the therapeutic effects of febuxostat combined with a low-purine diet and allopurinol combined with a low-purine diet on the improvement of gout patients.

OBJECTIVE: To compare the clinical efficacy of febuxostat combined with a low-purine diet versus allopurinol combined with a low-purine diet in the treatment of gout. METHODS: In this prospective controlled trial, 98 gout patients admitted to our hospital from February 2021 to December 2022 were enrolled as study subjects. Patients were randomly assigned to the study group (febuxostat combined with a low-purine diet) and the control group (allopurinol combined with a low-purine diet), with 49 patients in each group. The therapeutic effect was evaluated based on joint function and serum uric acid levels after treatment, and classified into three levels: markedly effective, effective, and ineffective. The levels of inflammatory factors, including tumor necrosis factor-a (TNF-a), cytokine interleukin-1beta (IL-1ß), and interleukin (IL)-18 (IL-18), were collected. The Numeric Rating Scale (NRS) was used to assess the degree of pain in patients. Clinical indicators before and 6 months after treatment were compared between the two groups. RESULTS: There was no statistically significant difference in age and gender between the two groups. After 6 months of treatment, the effective rate in the study group (48 cases, 97.96%) was higher than that in the control group (42 cases, 85.71%), with a statistically significant difference (p = .027). At the same time, the study group had significantly lower levels of serum uric acid (162.39 µmol/L ± 17.23 µmol/L vs. S198.32 µmol/L ± 18.34 µmol/L, p < .001), creatinine (87.39 mmol/L ± 9.76 mmol/L vs. 92.18 mmol/L ± 9.27 mmol/L, p = .014), total cholesterol (3.65 mmol/L ± 0.65 mmol/L vs. 4.76 mmol/L ± 0.73 mmol/L, p < .001), and triglycerides (1.76 mmol/L ± 0.32 mmol/L vs. 2.28 mmol/L ± 0.41 mmol/L, p < .001) compared to the control group, with statistically significant differences (p < .05). After treatment, the levels of inflammatory factors and degree of pain in the study group were significantly lower than those in the control group (all p < .05). During the treatment process, the incidence of adverse reactions in the study group (2 cases, 4.08%) was lower than that in the control group (9 cases, 18.37%), with a statistically significant difference (p = .025). CONCLUSION: Febuxostat combined with a low-purine diet can reduce inflammatory factors and alleviate the degree of pain in gout patients, significantly improving their clinical symptoms.

Biomolecular budget of persistent, microbial-derived soil organic carbon: The importance of underexplored pools.

The details of how soil microorganisms contribute to stable soil organic carbon pools are a pressing knowledge gap with direct implications for soil health and climate mitigation. It is now recognized that microbial necromass contributes substantially to the formation of stable soil carbon. However, the quantification of necromass in soils has largely been limited to model molecules such as aminosugar biomarkers. The abundance and chemical composition of other persistent microbial residues remain unresolved, particularly concerning how these pools may vary with microbial community structure, soil texture, and management practices. Here we use yearlong soil incubation experiments with an isotopic tracer to quantify the composition of persistent residues derived from microbial communities inhabiting sand or silt dominated soil with annual (corn) or perennial (switchgrass) monocultures. Persistent microbial residues were recovered in diverse soil biomolecular pools including metabolites, proteins, lipids, and mineral-associated organic matter (MAOM). The relative abundances of microbial contributions to necromass pools were consistent across cropping systems and soil textures. The greatest residue accumulation was not recovered in MAOM but in the light density fraction of soil debris that persisted after extraction by chemical fractionation using organic solvents. Necromass abundance was positively correlated with microbial biomass abundance and revealed a possible role of cell wall morphology in enhancing microbial carbon persistence; while gram-negative bacteria accounted for the greatest contribution to microbial-derived carbon by mass at one year, residues from gram-positive Actinobacteria and Firmicutes showed greater durability. Together these results offer a quantitative assessment of the relative importance of diverse molecular classes for generating durable soil carbon.

Image quality characterization of an ultra-high-speed kilovoltage cone-beam computed tomography imaging system on an O-ring linear accelerator.

PURPOSE: The quality of on-board imaging systems, including cone-beam computed tomography (CBCT), plays a vital role in image-guided radiation therapy (IGRT) and adaptive radiotherapy. Recently, there has been an upgrade of the CBCT systems fused in the O-ring linear accelerators called HyperSight, featuring a high imaging performance. As the characterization of a new imaging system is essential, we evaluated the image quality of the HyperSight system by comparing it with Halcyon 3.0 CBCT and providing benchmark data for routine imaging quality assurance. METHODS: The HyperSight features ultra-fast scan time, a larger kilovoltage (kV) detector, a more substantial kV tube, and an advanced reconstruction algorithm. Imaging protocols in the two modes of operation, treatment mode with IGRT and the CBCT for planning (CBCTp) mode were evaluated and compared with Halcyon 3.0 CBCT. Image quality metrics, including spatial resolution, contrast resolution, uniformity, noise, computed tomography (CT) number linearity, and calibration error, were assessed using a Catphan and an electron density phantom and analyzed with TotalQA software. RESULTS: HyperSight demonstrated substantial improvements in contrast-to-noise ratio and noise in both IGRT and CBCTp modes compared to Halcyon 3.0 CBCT. CT number calibration error of HyperSight CBCTp mode (1.06%) closely matches that of a full CT scanner (0.72%), making it suitable for adaptive planning. In addition, the advanced hardware of HyperSight, such as ultra-fast scan time (5.9 s) or 2.5 times larger heat unit capacity, enhanced the clinical efficiency in our experience. CONCLUSIONS: HyperSight represented a significant advancement in CBCT imaging. With its image quality, CT number accuracy, and ultra-fast scans, HyperSight has a potential to transform patient care and treatment outcomes. The enhanced scan speed and image quality of HyperSight are expected to significantly improve the quality and efficiency of treatment, particularly benefiting patients.

Role of mitochondria in pathogenesis and therapy of renal fibrosis.

Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.

Prophylactic efficacy of an intranasal spray with 2 synergetic antibodies neutralizing Omicron.

BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).

Phonon softening induced phase transition of CeSiO4: a density functional theory study.

Density functional theory plus Hubbard U (DFT+U) methodology was used to calculate the structures and energetic landscapes of CeSiO4, including its stetindite and scheelite phases from ambient pressure to ∼24 GPa. To ensure accurate simulations of the high-pressure structures, assessments of strain-stress methods and stress-strain methods were conducted in prior, with the former found to have a better agreement with the experimental result. From DFT calculations the equation of states (EOS) of both stetindite and scheelite were further obtained, with the fitted bulk moduli being 182(2) GPa and 190.0(12) GPa, respectively. These results were found to be consistent with the experimental values of 177(5) GPa and 222(40) GPa. Furthermore, the calculated energetics suggest that the stetindite structure is more thermodynamically stable than the scheelite structure at a pressure lower than 8.35 GPa. However, the stetindite → scheelite phase transition was observed experimentally at a much higher pressure of ∼15 GPa. A further phonon spectra investigation by the density functional perturbation theory (DFPT) indicated the Eg1 mode is being softened with pressure and becomes imaginary after 12 GPa, which is a sign of the lattice instability. Consequently, it was concluded that the stetindite → scheelite transition is predominantly initiated by the lattice instability under high-pressure.

Ion channel TRPV2 is critical in enhancing B cell activation and function.

The function of transient receptor potential vanilloid (TRPV) cation channels governing B cell activation remains to be explored. We present evidence that TRPV2 is highly expressed in B cells and plays a crucial role in the formation of the B cell immunological synapse and B cell activation. Physiologically, TRPV2 expression level is positively correlated to influenza-specific antibody production and is low in newborns and seniors. Pathologically, a positive correlation is established between TRPV2 expression and the clinical manifestations of systemic lupus erythematosus (SLE) in adult and child SLE patients. Correspondingly, mice with deficient TRPV2 in B cells display impaired antibody responses following immunization. Mechanistically, the pore and N-terminal domains of TRPV2 are crucial for gating cation permeation and executing mechanosensation in B cells upon antigen stimulation. These processes synergistically contribute to membrane potential depolarization and cytoskeleton remodeling within the B cell immunological synapse, fostering efficient B cell activation. Thus, TRPV2 is critical in augmenting B cell activation and function.

Identification and functional characterization of a novel heterozygous splice­site mutation in the calpain 3 gene causes rare autosomal dominant limb­girdle muscular dystrophy.

Limb-girdle muscular dystrophies are a group of extremely heterogenous neuromuscular disorders that manifest with gradual and progressive weakness of both proximal and distal muscles. Autosomal dominant limb-girdle muscular dystrophy (LGMDD4) or calpainopathy is a very rare form of myopathy characterized by weakness and atrophy of both proximal and distal muscles with a variable age of onset. LGMDD4 is caused by germline heterozygous mutations of the calpain 3 (CAPN3) gene. Patients with LGMDD4 often show extreme phenotypic heterogeneity; however, most patients present with gait difficulties, increased levels of serum creatine kinase, myalgia and back pain. In the present study, a 16-year-old male patient, clinically diagnosed with LGMDD4, was investigated. The proband had been suffering from weakness and atrophy of both of their proximal and distal muscles, and had difficulty walking and standing independently. The serum creatine kinase levels (4,754 IU/l; normal, 35-232 IU/l) of the patient were markedly elevated. The younger sister and mother of the proband were also clinically diagnosed with LGMDD4, while the father was phenotypically normal. Whole exome sequencing identified a heterozygous novel splice-site (c.2440-1G>A) mutation in intron 23 of the CAPN3 gene in the proband. Sanger sequencing confirmed that this mutation was also present in both the younger sister and mother of the proband, but the father was not a carrier of this mutation. This splice-site (c.2440-1G>A) mutation causes aberrant splicing of CAPN3 mRNA, leading to the skipping of the last exon (exon 24) of CAPN3 mRNA and resulting in the removal of eight amino acids from the C-terminal of domain IV of the CAPN3 protein. Hence, this splice site mutation causes the formation of a truncated CAPN3 protein (p.Trp814*) of 813 amino acids instead of the wild-type CAPN3 protein that consists of 821 amino acids. This mutation causes partial loss of domain IV (PEF domain) in the CAPN3 protein, which is involved in calcium binding and homodimerization; therefore, this is a loss-of-function mutation. Relative expression of the mutated CAPN3 mRNA was reduced in comparison with the wild-type CAPN3 mRNA in the proband, and their younger sister and mother. This mutation was also not present in 100 normal healthy control individuals of the same ethnicity. The present study reported the first case of CAPN3 gene-associated LGMDD4 in the Chinese population.

Seasonal distribution of caffeine in the Bohai Sea, Yellow Sea, and estuaries of Yantai City, China.

We employed a validated method to assess the seasonal variation and distribution of caffeine in the Bohai and Yellow Seas, as well as in Yantai urban estuaries and offshore region in northern China. Caffeine concentrations were highest during the summer in the Yellow Sea (1436.4 ng/L) and lowest in the Yantai urban offshore region during the spring and autumn and in the Yantai urban estuarine area and Bohai Sea during the winter (0.1 ng/L). There was significant variation in maximum caffeine levels among seasons across all regions examined, reaching a difference of 5980.5 times at the same sampling site between summer and winter. The caffeine concentration in the Yantai offshore region was significantly higher than in the Bohai and Yellow Seas. This study is the first investigation of seasonal fluctuations in the pollution levels of neurotoxic substances in the northern seas of China.

A novel model incorporating chromatin regulatory factors for risk stratification, prognosis prediction, and characterization of the microenvironment in Wilms tumor.

BACKGROUND: Wilms tumor, also known as nephroblastoma, a pediatric most-frequent malignant-kidney tumor, may be regulated and influenced by transcriptional and epigenetic mechanisms. Chromatin regulatory factors (CRs) play key roles in epigenetic regulation. The present study aimed to explore the involvement of CRs in the development of nephroblastoma. METHODS: RNA-sequencing and clinical information of nephroblastoma samples were obtained by downloading data from the TARGET database. The Limma package was utilized to perform differential expression analysis of genes (DEGs) between the tumor group and the control group. A Venn map was used for intersection of differential genes and CRs and to perform Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of DEGs using the clusterProfiler package. LASSO and Cox analyses were used to construct CR-related risk models and were evaluated based on clinical parameters. A receiver operating characteristic curve was employed to assess the diagnostic performance of risk model. Furthermore, we used a single-sample gene set enrichment analysis algorithm for immune cell infiltration analysis. Finally, to confirm the transcriptome expression of pivotal genes in human nephroblastoma cell lines, a quantitative real-time PCR was employed. RESULTS: Fifteen key CRs were obtained through analysis in nephroblastoma and then the risk model based on 13 important CRs was constructed using the transcriptome data of nephroblastoma. Using the risk model, pediatric nephroblastoma patients were stratified into high- and low-risk groups based on their individual risk scores. The risk score of CRs can predict adverse outcomes in pediatric nephroblastoma, and this gene cluster is closely related to various immunity characteristics of nephroblastoma. Moreover, the nephroblastoma cell line exhibited higher expression levels of prognostic genes (VRK1, ARNTL, RIT1, PRDM6, and TSPY1) compared to the HEK293 T cell line. CONCLUSIONS: The risk characteristics derived from CRs have tremendous significance in predicting prognosis and guiding clinical classification and intervention strategies for pediatric nephroblastoma.

Technical note: Preprocessing of portal images to improve image quality of VMAT-CT.

BACKGROUND: The concept of volumetric modulated arc therapy-computed tomography (VMAT-CT) was proposed more than a decade ago. However, its application has been very limited mainly due to the poor image quality. More specifically, the blurred areas in electronic portal imaging device (EPID) images collected during VMAT heavily degrade the image quality of VMAT-CT. PURPOSE: The goal of this study was to propose systematic methods to preprocess EPID images and improve the image quality of VMAT-CT. METHODS: Online region-based active contour method was introduced to binarize portal images. Multi-leaf collimator (MLC) motion modeling was developed to remove the MLC motion blur. Outlier filtering was then applied to replace the remaining artifacts with plausible data. To assess the impact of these preprocessing methods on the image quality of VMAT-CT, 44 clinical VMAT plans for several treatment sites (lung, esophagus, and head & neck) were delivered to a Rando phantom, and several real-patient cases were also acquired. VMAT-CT reconstruction was attempted for all the cases, and image quality was evaluated. RESULTS: All three preprocessing methods could effectively remove the blurred edges of EPID images. The combined preprocessing methods not only saved VMAT-CT from distortions and artifacts, but also increased the percentage of VMAT plans that can be reconstructed. CONCLUSIONS: The systematic preprocessing of portal images improves the image quality of VMAT-CT significantly, and facilitates the application of VMAT-CT as an effective image guidance tool.

Development of a predictive nomogram for 28-day mortality risk in non-traumatic or post-traumatic subarachnoid hemorrhage patients.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with high rates of mortality and permanent disability. At present, there are few definite clinical tools to predict prognosis in SAH patients. The current study aims to develop and assess a predictive nomogram model for estimating the 28-day mortality risk in both non-traumatic or post-traumatic SAH patients. METHODS: The MIMIC-III database was searched to select patients with SAH based on ICD-9 codes. Patients were separated into non-traumatic and post-traumatic SAH groups. Using LASSO regression analysis, we identified independent risk factors associated with 28-day mortality and incorporated them into nomogram models. The performance of each nomogram was assessed by calculating various metrics, including the area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). RESULTS: The study included 999 patients with SAH, with 631 in the non-traumatic group and 368 in the post-traumatic group. Logistic regression analysis revealed critical independent risk factors for 28-day mortality in non-traumatic SAH patients, including gender, age, glucose, platelet, sodium, BUN, WBC, PTT, urine output, SpO2, and heart rate and age, glucose, PTT, urine output, and body temperature for post-traumatic SAH patients. The prognostic nomograms outperformed the commonly used SAPSII and APSIII systems, as evidenced by superior AUC, NRI, IDI, and DCA results. CONCLUSION: The study identified independent risk factors associated with the 28-day mortality risk and developed predictive nomogram models for both non-traumatic and post-traumatic SAH patients. The nomogram holds promise in guiding prognosis improvement strategies for patients with SAH.

Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression.

Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the key hallmarks of cancer is the reprogramming of metabolic pathways, especially abnormal lipid metabolism. Alterations in lipid uptake, lipid desaturation, de novo lipogenesis, lipid droplets, and fatty acid oxidation in cancer cells all contribute to cell survival in a changing microenvironment by regulating feedforward oncogenic signals, key oncogenic functions, oxidative and other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by fatty acids and act as core lipid sensors involved in the regulation of lipid homeostasis and cell fate. In addition to regulating whole-body energy homeostasis in physiological states, PPARs play a key role in lipid metabolism in cancer, which is receiving increasing research attention, especially the fundamental molecular mechanisms and cancer therapies targeting PPARs. In this review, we discuss how cancer cells alter metabolic patterns and regulate lipid metabolism to promote their own survival and progression through PPARs. Finally, we discuss potential therapeutic strategies for targeting PPARs in cancer based on recent studies from the last five years.

Exosomal circFAM63Bsuppresses bone regeneration of postmenopausal osteoporosis via regulating miR-578/HMGA2 axis.

Postmenopausal osteoporosis (PMOP) affects hundreds of millions of elderly women worldwide. The imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption is the key factor in the progression of PMOP. Recently, exosomal circular RNAs have been considered as critical regulators in physiological and pathological progress. However, their roles in PMOP still require further exploration. Herein, we identified that the expression of exosomal circFAM63B significantly increased in PMOP patients and is closely related to bone density. We further demonstrated that circFAM63B inhibits osteogenic differentiation of bone marrow stromal cells and bone formation in ovariectomy mice by using a combination of in vitro and in vivo experiment strategies. Mechanistically, circFAM63B promotes HMGA2 expression by inhibiting miR-578, thereby suppressing bone repair. Our study proved that exosomal circFAM63B suppresses the bone regeneration of PMOP by regulating the miR-578/HMGA2 axis, which may provide new insights into the pathogenesis and development of PMOP. Knocking down exosomal circFAM63B could be regarded as a new strategy for the treatment of PMOP.

Generation of a human iPSC line (CHCMUi002-A) from peripheral blood mononuclear cells from a chronic granulomatous disease patient.

Chronic granulomatous disease (CGD) is a rare X-linked recessive primary immunodeficiency disease (PID). Herein, a human induced pluripotent stem cell (iPSC) line was generated from the peripheral blood mononuclear cells (PBMCs) of a CGD patient with a mutation (c.785_786delTT) in the CYBB gene. These iPSCs showed the expression of pluripotency markers, the ability to differentiate into three germ layers. They offer a promising technique for studying the pathogenesis and conducting drug screening for CGD patients.