Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.

PURPOSE: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. METHODS: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. RESULTS: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. CONCLUSION: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.

Dengue virus and the 2024 Paris Olympics.

The 2024 Paris Olympics and Paralympics face concerns over dengue virus transmission, despite Paris's lower mosquito activity. Preventive measures include eliminating breeding sites, insecticide spraying, and public awareness. Health systems will monitor and respond to cases. Large gatherings like the Olympics can amplify disease spread, as seen with Zika in Rio 2016. Recent reports confirm dengue presence in Europe, highlighting global risks. While Paris's overall dengue risk is low, even a few cases could impact global health. Collaboration among health authorities, researchers, and event organizers is crucial to ensure participant and public safety during the games.

Innate Immune Response to Monkeypox Virus Infection: Mechanisms and Immune Escape.

BACKGROUND: The reemergence of monkeypox virus (Mpox, formerly monkeypox) in 2022 in non-endemic countries has raised significant concerns for global health due to its high transmissibility and mortality rate. A major challenge in combating Mpox is its ability to evade the host's innate immune system, the first line of defense against viral infections. SUMMARY: Mpox encodes various proteins that interfere with key antiviral pathways and mechanisms, such as the nuclear factor kappa B signaling, cytokine production, complement and inflammasome activation, and chemokine binding. These proteins modulate the expression and function of innate immune mediators, such as interferons, interleukins, and Toll-like receptors, and impair the recruitment and activation of innate immune cells, such as natural killer cells. By suppressing or altering these innate immune responses, Mpox enhances its replication and infection in the host tissues and organs, leading to systemic inflammation, tissue damage, and organ failure. KEY MESSAGES: This study reveals new insights into the molecular and cellular interactions between Mpox and the host's innate immune system. It identifies potential targets and strategies for antiviral interventions, highlighting the importance of understanding these interactions to develop effective treatments and improve global health responses to Mpox outbreaks.

PANAMA-enabled high-sensitivity dual nanoflow LC-MS metabolomics and proteomics analysis.

High-sensitivity nanoflow liquid chromatography (nLC) is seldom employed in untargeted metabolomics because current sample preparation techniques are inefficient at preventing nanocapillary column performance degradation. Here, we describe an nLC-based tandem mass spectrometry workflow that enables seamless joint analysis and integration of metabolomics (including lipidomics) and proteomics from the same samples without instrument duplication. This workflow is based on a robust solid-phase micro-extraction step for routine sample cleanup and bioactive molecule enrichment. Our method, termed proteomic and nanoflow metabolomic analysis (PANAMA), improves compound resolution and detection sensitivity without compromising the depth of coverage as compared with existing widely used analytical procedures. Notably, PANAMA can be applied to a broad array of specimens, including biofluids, cell lines, and tissue samples. It generates high-quality, information-rich metabolite-protein datasets while bypassing the need for specialized instrumentation.

KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis.

Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth-promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.

Postpartum depression and its relationship with the positive and negative perfectionism.

BACKGROUND: Depression is a common mental disorder after childbirth, which has serious consequences for the mother, baby, and family. A wide range of causes, including some personality traits of mothers, are involved in its etiology. Therefore, this study was conducted aiming to determine the factors related to postpartum depression (PPD) and its relationship with positive and negative perfectionism in Qom, Iran. MATERIALS AND METHODS: This cross-sectional analytical study was conducted on 162 mothers who had been referred to health centers in Qom during 6-8 weeks after normal vaginal delivery (NVD) in 2020. After randomly classifying the health centers, the convenience sampling method was carried out. Data collection tools included social-individual information form, Edinburg Postnatal Depression Scale (EPDS), and Positive and Negative Perfectionism Questionnaire of Terry-Short. The data were analyzed using the Chi-square and Pearson correlation tests and multivariate logistic regression analysis. RESULT: The prevalence of PPD in this study was 29.6%. The results showed that with the increase in the negative dimension of perfectionism, the chance of PPD in people increases by 14% (OR = 1.14, CI = 1.06-1.21), while there was no significant correlation between the positive dimension of perfectionism and PPD (r = 0.006, P > 0.05). Furthermore, the chance of PPD was higher in student mothers, mothers who had a history of PPD, and unintended pregnancy. Moreover, some factors such as multigravidity, breastfeeding, and not worrying about body image reduce the chance of occurrence. CONCLUSION: Since mothers' negative perfectionism is associated with PPD, it is recommended to identify perfectionist individuals during pregnancy and after delivery and provide counseling service to them.

Corrigendum: Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease.

[This corrects the article DOI: 10.3389/fphar.2023.1243505.].

From the Rio 2016 Olympics to the Paris 2024 Olympics: Is there a risk of Dengue disease?

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Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease.

Background: We hypothesize that the poor survival outcomes of end-stage kidney disease (ESKD) patients undergoing hemodialysis are associated with a low filtering efficiency and selectivity. The current gold standard criteria using single or several markers show an inability to predict or disclose the treatment effect and disease progression accurately. Methods: We performed an integrated mass spectrometry-based metabolomic and proteomic workflow capable of detecting and quantifying circulating small molecules and proteins in the serum of ESKD patients. Markers linked to cardiovascular disease (CVD) were validated on human induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Results: We identified dozens of elevated molecules in the serum of patients compared with healthy controls. Surprisingly, many metabolites, including lipids, remained at an elevated blood concentration despite dialysis. These molecules and their associated physical interaction networks are correlated with clinical complications in chronic kidney disease. This study confirmed two uremic toxins associated with CVD, a major risk for patients with ESKD. Conclusion: The retained molecules and metabolite-protein interaction network address a knowledge gap of candidate uremic toxins associated with clinical complications in patients undergoing dialysis, providing mechanistic insights and potential drug discovery strategies for ESKD.

The association between MMP-13 rs478927 gene polymorphism and dental caries susceptibility in children with mixed dentition from Birjand, Iran: A case-control study.

Background and Aims: Gene polymorphisms are responsible for at least part of the variation in caries susceptibility despite similar environmental factors. Genes involved in enamel formation like matrix metalloproteinase-13 (MMP-13) may participate in caries process. The aim was to investigate the association between MMP-13 rs478927 polymorphism and caries susceptibility in 6-years-old children from Birjand, Iran. Methods: Six-years old children from Birjand, Iran, participated in this study. The total decayed, missing, and filled teeth were calculated and defined as caries index (CI). Based on this CI, two groups of high-caries (case) and low-caries (control) were taken into account. Saliva samples were collected and DNA was extracted. The allele and genotypes of MMP-13 rs478927 polymorphism were determined by tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method. p Value was significant if p < 0.05. Results: Three hundred sixty-seven children consisted of 186 low-caries children and 181 high-caries children were included in this study. The mean CI was 6.02 ± 0.81. There was no significant association between high and low-caries groups based on socioeconomic status, eating sweet snacks, parents' susceptibility to dental caries, duration of breastfeeding, and the brushing habit (p > 0.05). There wasn't any significant association between genotype distribution of MMP-13 rs478927 polymorphism and CI groups (p = 0.924). This polymorphism was associated with increased caries susceptibility under all genetic models but this effect was not significant (p > 0.05). Conclusion: The MMP-13 rs478927 gene polymorphism was not significantly associated with dental caries susceptibility in Birjandi children with mixed dentition. It is recommended to conduct studies on children of different dentitions to better understand the role of this polymorphism on caries susceptibility in primary and permanent teeth of children.

The Effect of Auriculotherapy on Nausea, Vomiting, and Anxiety in Patients Undergoing Elective Cesarean Section with Spinal Anesthesia: A Clinical Trial Study.

Background: Nausea, vomiting, and anxiety are common complications during and after spinal anesthesia. Auriculotherapy as a complementary medicine can be useful for reducing nausea, vomiting, or anxiety. This study was performed to evaluate the effects of auriculotherapy on nausea, vomiting, and anxiety in patients undergoing elective Cesarean Section (CS) with spinal anesthesia. Materials and Methods: The present study was a clinical trial study that was performed on 56 pregnant women selected as CS candidates in Ommolbanin Hospital in Mashhad during the years 2016-2017. In the intervention group, 1 h before spinal anesthesia, auricular acupoint stimulation was performed at four points bilaterally, for 20-30 seconds at each point. Evaluations were done by the following questionnaires: State-Trait Anxiety Inventory (STAI), Visual Analog Scale (VAS), and Vomiting Assessment Form. Results: The mean anxiety (SD) before the intervention in the intervention group and the control group was 47.88 (8.67) and 47.84 (10.49), respectively, and 4 h after the intervention, it was 40.23 (10.19) and 42.88 (12.18) in the intervention and control groups, respectively. These results were significant in the intervention group (p = 0.008). 30-40 min before and 4 h after the surgery, the severity of nausea and vomiting was low in both groups and no significant difference was observed between the two groups during the surgery and in the recovery room (p > 0.05). Conclusions: According to the results, auriculotherapy could reduce anxiety in CS patients with spinal analgesia. The results also showed that auriculotherapy reduced the severity of nausea and vomiting, but these changes were not significant.

Attenuation of morphine conditioned place preference and reinstatement by vitamin D.

Opioid action in the brain involves the dopamine-reward system as well as non-dopamine pathways. Since vitamin D also modulates the brain's dopamine system, the question of this study was how vitamin D might affect the opioid influences on the reward system. Therefore, the objective of this study was to investigate the possible effect of vitamin D on the conditioned place preference (CPP) induced by morphine, as a valuable model of assessment of the reinforcing properties of opioids by associating the context to the rewarding properties of the addictive drugs. Male Wistar rats were randomly divided into two main groups that either received saline (morphine vehicle) or morphine (5 mg/kg, intraperitoneally) for CPP. Each of the main groups was divided into three vitamin D treatment subgroups: vitamin D vehicle and vitamin D (5 and 10 µg/kg, intraperitoneally). Vitamin D injections were started 1 week ahead of the experiment (two injections) or immediately after post-conditioning and in both cases, it was continued twice weekly throughout the CPP. Administration of vitamin D (10 µg/kg) before conditioning in CPP markedly attenuated morphine expression in the post-conditioning test. Receiving vitamin D (5 or 10 µg/kg) before or after conditioning significantly attenuated morphine reinstatement. Administration of vitamin D after opioid conditioning facilitated morphine memory extinction and attenuated morphine reinstatement. Vitamin D is probably a valuable addition to be considered as a part of the treatment for prevention or minimizing the dependency or relapse to opioids.

Novel 3D carbon fibers derived from Luffa wastes for oil/water separation.

In this study, the 3D structure of carbon fibers (CFs) was prepared from Luffa sponge wastes by H3PO4 impregnation with various ratios and a low-temperature carbonization process at 500 °C in a nitrogen atmosphere. The H3PO4-treated Luffa sponge had higher thermal stability and carbonic yield (∼60-70%) than neat-Luffa (∼21%). Characterization analyses exposed that the synthesized CFs derived from H3PO4-treated Luffa exhibited oleophilic and hydrophobic carbonic nature with 3D sponge skeletal, reflecting an ideal structure for oil sorption. The engine oil sorption properties on the CFs were studied by varying the contact time. The engine oil sorption equilibrium data for 3D CFs samples was explained by the pseudo-second-order and intraparticle diffusion models. The equilibrium oil sorption capacities of 3D CFs were as large as 23.1 ± 0.4 g/g for engine oil, 23.7 ± 1.0 g/g for gasoline, 28.1 ± 1.0 g/g for almond oil, and 29.2 ± 0.8 g/g for pomegranate seed oil in 20 min. Moreover, the optimized 3D CFs can be selectively for oil/water separation applications, such as high capacities for various oils, fast kinetic sorption, and reusability (>6 cycles). This research presented a facile and cost-effective process for the 3D CFs through recycling Luffa sponge wastes for rapid oil sorption.

Comparison of two methods of complementary medicine on postoperative pain and anxiety: A randomized clinical trial.

BACKGROUND: Postoperative pain and anxiety are unpleasant situations that are often experienced by women undergoing cesarean section. Since the routine methods of pain relief after surgery is still inadequate, the need for complementary treatments is felt. Foot Reflexology (FR) and Auricular Acupressure (AA) are two of the most popular and safe procedures of complementary and alternative medicine therapies. So, this study aimed to determine and compare the effectiveness of reflexology and AA on postoperative pain and anxiety. MATERIALS AND METHODS: This three-group randomized clinical trial study was performed on 101 pregnant women, admitted to Mashhad Omolbanin hospital, for a cesarean section, in 2015. In the intervention groups, 2-3 h after the operation, AA or FR was performed for 20 min. Routine care was provided for the control group. Pain and anxiety were evaluated by VAS and Spielberger anxiety questionnaire before and 1 and 2 h after the intervention. RESULTS: The results showed that immediately after the intervention, pain intensity was significantly lower in both AA and FR groups (P < 0.001) compared with the control group. In addition, 2 h after the interventions, pain intensity was significantly lower in the AA group compared with the control group (P = 0.006). However, no significant differences were observed between the FR and the control groups (P = 0.095). In addition, 1 and 2 h after the intervention, anxiety was significantly different between the three groups (P = 0.033 and P = 0.018), respectively. The results of the Tukey test showed that this difference was only between FR and control groups (P = 0.025 and P = 0.017), respectively. CONCLUSION: AA is more effective in reducing post-cesarean pain while FR effectively reduces post-cesarean anxiety. Therefore, these complementary medicine treatments as easy and noninvasive methods are recommended to be used during labor for improving maternal outcomes.

Electrical control of the spin-Seebeck coefficient in graphene nanoribbons with asymmetric zigzag edge extensions.

We investigate the effect of the electric field on the spin-dependent thermoelectric properties of graphene nanoribbons with asymmetric zigzag edge extensions. The Hubbard Hamiltonian predicts spin-semiconducting behavior with localized band structures due to the magnetic properties of the zigzag edge extensions. Applying a temperature gradient induces thermal spin-dependent currents, pure spin currents, and large spin-Seebeck coefficients, which are similar to other graphene-based structures. Considering the effect of the electric field sensitively reduces the spin gap and finally the threshold temperature. Moreover, the electric field slightly widens the localized band structures around the Fermi energy and could induce ten times more spin current in these nanoribbons.

The effect of chemical treatment of the sheep embryo zona pellucida on the ability of blastocysts to hatch after vitrification and warming.

BACKGROUND: The embryo release from the zona pellucida is of prerequisites of successful implantation. OBJECTIVES: Regarding the negative impact of embryo cryopreservation on the blastocysts hatchability, the aim of the present study was to investigate the effects of treating embryonic zona pellucida with pronase or acidic Tyrode's solution (ATS) before morula formation on the viability, freezability, and hatchability of vitrified-warmed resulted blastocysts. METHODS: In the first experiment, the zona pellucida of 3- and 4-day-old embryos were treated with the above compounds for 30 or 45 s. Then, the competency of the treated embryos to reach to blastocyst stage and the hatchability of resulting blastocysts were investigated. In the second experiment, the cryo-survivability and hatching rate of blastocysts resulting from 3-day-old embryos treated with pronase and ATS for 30 s were tested. RESULTS: In the first experiment and in contrast to the 45 s exposure, 30-s exposure of embryos to pronase or ATS did not have negative effect on the viability and development of embryos to blastocyst stage. In the second experiment, the freezability of blastocysts derived from 3-day-old embryos treated with pronase and ATS for 30 s was not different from that of the control group. However, the hatching rate of the pronase group was significantly higher than that of the control group. CONCLUSION: The results of the present study showed that reducing the thickness of zona pellucida of sheep embryos with pronase had no negative effect on the developmental competency and freezability of the treated embryos and improved the hatchability of vitrified-warmed blastocysts.

Sex-related Changes in Circadian Rhythm of Inflammatory and Oxidative Stress Markers in CKD.

INTRODUCTION: Circadian system is deeply involved in renal function. The circadian timing system may be disrupted in chronic kidney disease (CKD) patients. Gender differences in CKD have been reported. This research aimed to investigate the gender differences in the circadian rhythm of inflammatory and oxidant markers of CKD. METHODS: Male, intact female, and ovariectomized (OVX) female rats (twenty-four in each group) were randomly assigned to control and CKD groups. The rats were further divided into day (12:00 p.m.) and night (12:00 a.m.) subgroups. Evaluations of each sample were carried out a day after the last day of adenine administration. RESULTS: Final results revealed that the circadian rhythm of plasma melatonin , kidney malondialdehyde (MDA), and transforming growth factor- ß (TGF-ß) levels in CKD group were the same as the control group. Melatonin and total antioxidant capacity (TAC) levels significantly decreased in the CKD group compared with the control group in day and night subgroups, whereas MDA and TGF-ß levels increased. Male group in comparison with the intact female group significantly showed less melatonin and TAC but higher MDA and TGF-ß levels which could be due to CKD. CONCLUSION: Findings of this study represent gender differences in circadian rhythm amplitude of inflammation, melatonin, and oxidative stress in CKD animals, probably in favor of female sex steroids. These findings emphasize on the importance of gender differences in CKD progression; therefore, considerable attention must be paid to gender in the treatment of CKD. INTRODUCTION: Circadian system is deeply involved in renal function. The circadian timing system may be disrupted in chronic kidney disease (CKD) patients. Gender differences in CKD have been reported. This research aimed to investigate the gender differences in the circadian rhythm of inflammatory and oxidant markers of CKD. METHODS: Male, intact female, and ovariectomized (OVX) female rats (twenty-four in each group) were randomly assigned to control and CKD groups. The rats were further divided into day (12:00 p.m.) and night (12:00 a.m.) subgroups. Evaluations of each sample were carried out a day after the last day of adenine administration. RESULTS: Final results revealed that the circadian rhythm of plasma melatonin , kidney malondialdehyde (MDA), and transforming growth factor- ß (TGF-ß) levels in CKD group were the same as the control group. Melatonin and total antioxidant capacity (TAC) levels significantly decreased in the CKD group compared with the control group in day and night subgroups, whereas MDA and TGF-ß levels increased. Male group in comparison with the intact female group significantly showed less melatonin and TAC but higher MDA and TGF-ß levels which could be due to CKD. CONCLUSION: Findings of this study represent gender differences in circadian rhythm amplitude of inflammation, melatonin, and oxidative stress in CKD animals, probably in favor of female sex steroids. These findings emphasize on the importance of gender differences in CKD progression; therefore, considerable attention must be paid to gender in the treatment of CKD. DOI: 10.52547/ijkd.6242.

Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer.

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined activating transcription factor 3 (ATF3), a mediator of the UPR that promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized that ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germline mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasG12D/+). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia (PanIN) formation and PDAC in Ptf1acreERT/+KrasG12D/+ mice. In response to injury, KRASG12D bypassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. Compared to Ptf1acreERT/+KrasG12D/+ mice, APK mice exhibited a significant decrease in pancreatic and total body weight, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.

Postpartum Depression and Quality of Life: A Path Analysis.

Purpose: The aim of this study was to model the relationship between risk factors of postpartum depression and quality of life in Iranian women. Methods: In this study, 306 women were included as a sample. The study tools of the Edinburgh Postpartum Depression Inventory included items such as socioeconomic characteristics, recent pregnancy history and outcome, and Quality of Life Questionnaire (SF-12). SPSS software was used for data analysis and a significance value of 0.05 was considered. Results: Most participants were homemakers with no instances of abortion, no stillbirth, no history of depression, no preterm delivery, no difficulties during pregnancy, no difficulties during delivery, no unplanned pregnancy, no smoking during pregnancy, had family support during pregnancy and after delivery, type of delivery was cesarean, had a healthy baby and satisfaction with neonatal sex, and never or rarely experienced partner violence. Their mean age, years of education, living arrangements, and breastfeeding of participants respectively were 29.73±5.42, 14.64±1.96, 1.09±0.53, and 5.61±2.98. The prevalence of postpartum depression was 5.6%. According to the path analysis, living arrangements with ß=0.73 had the most direct effect and occupation with ß=0.69 had the most indirect effect on postpartum depression. Conclusions: According to the path analysis model, postpartum depression is affected by many factors such as age, years of education, occupation, living arrangements, and quality of life.