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Background: Periodontal Disease (PD) associated with Type 2 Diabetes Mellitus (T2DM) is a chronic condition that affects the oral cavity of people living with T2DM. The mechanisms of the interaction between type 2 Diabetes Mellitus and Periodontal diseases are complex and involve multiple pathophysiological pathways related to the systemic inflammatory process and oxidative stress. Non-surgical periodontal treatment (NSTP) is considered the standard for the management of this disease; however, patients with systemic conditions such as type 2 Diabetes Mellitus do not seem to respond adequately. For this reason, the use of complementary treatments has been suggested to support non-surgical periodontal treatment to reduce the clinical consequences of the disease and improve the systemic conditions of the patient. The use of zinc gluconate and magnesium oxide as an adjunct to non-surgical periodontal treatment and its effects on periodontal clinical features and oxidative stress in patients with Periodontal diseases -type 2 Diabetes Mellitus is poorly understood., Methods: A quasi-experimental study was performed in patients with periodontal diseases associated with T2DM. Initially, 45 subjects who met the selection criteria were included. 19 were assigned to a control group [non-surgical periodontal treatment] and 20 to the experimental group (non-surgical periodontal treatment + 500 mg of magnesium oxide and 50 mg of zinc gluconate for oral supplementation for 30 days) and the data of 6 patients were eliminated. Sociodemographic characteristics, physiological factors, biochemical parameters, and clinical features of periodontal diseases were assessed., Results: In this research a change in periodontal clinical characteristics was observed, which has been associated with disease remission. Additionally, a shift in MDA levels was presented for both groups. Furthermore, the supplementation group showed an increase in antioxidant enzymes when compared to the group that only received NSPT., Conclusion: The use of Zinc gluconate and magnesium oxide can serve as a complementary treatment to non-surgical periodontal treatment, that supports the remission of PD as a result of regulation-reduction of oxidative biomarkers and increase in antioxidant enzymes activity., Trial Registration: https://www.isrctn.com ISRCTN 14,092,381. September 13º 2023. Retrospective Registration., (© 2024. The Author(s).)

Introduction: Lipopolysaccharide-responsive and beige-like anchor (LRBA) is a scaffolding protein that interacts with proteins such as CTLA-4 and PKA, the importance of which has been determined in various cell types, including T regulatory cells, B cells, and renal cells. LRBA deficiency is associated with an inborn error in immunity characterized by immunodeficiency and autoimmunity. In addition to defects in T regulatory cells, patients with LRBA deficiency also exhibit B cell defects, such as reduced cell number, low memory B cells, hypogammaglobulinemia, impaired B cell proliferation, and increased autophagy. Although Lrba -/- mice do not exhibit the immunodeficiency observed in humans, responses to B cell receptors (BCR) in B cells have not been explored. Therefore, a murine model is for elucidating the mechanism of Lrba mechanism in B cells., Aim: To compare and evaluate spleen-derived B cell responses to BCR crosslinking in C57BL6 Lrba -/- and Lrba +/+ mice., Materials and Methods: Spleen-derived B cells were obtained from 8 to 12-week-old mice. Subpopulations were determined by immunostaining and flow cytometry. BCR crosslinking was assessed by the F(ab')2 anti-μ chain. Activation, proliferation and viability assays were performed using flow cytometry and protein phosphorylation was evaluated by immunoblotting. The nuclear localization of p65 was determined using confocal microscopy. Nur77 expression was evaluated by Western blot., Results: Lrba -/- B cells showed an activated phenotype and a decreased proportion of transitional 1 B cells, and both proliferation and survival were affected after BCR crosslinking in the Lrba-/- mice. The NF-κB pathway exhibited a basal activation status of several components, resulting in increased activation of p50, p65, and IκBα, basal p50 activation was reduced by the Plcγ2 inhibitor U73122. BCR crosslinking in Lrba -/ - B cells resulted in poor p50 phosphorylation and p65 nuclear localization. Increased levels of Nur77 were detected., Discussion: These results indicate the importance of Lrba in controlling NF-κB activation driven by BCR. Basal activation of NF-κB could impact cellular processes, such as, activation, differentiation, proliferation, and maintenance of B cells after antigen encounter., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pérez-Pérez, Fuentes-Pananá, Flores-Hermenegildo, Romero-Ramirez, Santos-Argumedo, Kilimann, Rodríguez-Alba and Lopez-Herrera.)

Introduction: Lrba is a cytoplasmic protein involved in vesicular trafficking. Lrba -deficient ( Lrba-/- ) mice exhibit substantially higher levels of IgA in both serum and feces than wild-type (WT) mice. Transforming growth factor β1 (TGFβ1) and its receptors (TGFβR I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGFβR signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown., Aim: Given the increased IgA levels in Lrba -/- mice, the goal in this work was to explore the lymph organs where the switch to IgA occurs, and if TGFβR function is affected., Methods: Non-immunized Lrba-/- mice were compared with Lrba+/+ mice. IgA levels in the serum and feces, as well as during peripheral B cell development, were determined. IgA+ B cells and plasma cells were assessed in the small intestine and secondary lymphoid organs, such as the spleen, mesenteric lymph nodes, and Peyer's patches. The TGFβR signaling pathway was evaluated by determining the expression of TGFβR on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGFβ. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGFβR in B cells., Results: Lrba-/- mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGFβR expression on the membrane of B cells was similar in both Lrba-/- and Lrba+/+ mice. However, intracellular TGFβR expression was reduced in Lrba-/- mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGFβ elicited a poorer response than in that in Lrba+/+ B cells. Finally, we found that Lrba colocalizes with TGFβR in B cells., Conclusion: Lrba is essential in controlling TGFβR signaling, subsequently regulating SMAD2 phosphorylation on B cells. This mechanism may explain the increased differentiation of IgA+ B cells and production of IgA-producing plasma cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Flores-Hermenegildo, Hernández-Cázares, Pérez-Pérez, Romero-Ramírez, Rodríguez-Alba, Licona-Limon, Kilimann, Santos-Argumedo and López-Herrera.)

LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective  Nocturnal animals forage and eat during the night and sleep during the day. When food is available only for a short period during the day, animals develop a catabolic state and exhibit locomotor behavior before accessing food, termed food anticipatory activity . Consequently, there is a disruption in the sleep pattern. The present study aimed to explore how anticipatory arousal emerges under circadian exposure to a palatable meal (PM) and disrupts sleep architecture. Materials and Methods  Adult male Wistar rats were implanted with electrodes for continuous sleep recording and housed under a light/dark 12/12-hour cycle with free access to food and water. After basal recordings, the rats had access to a PM during the light period for eight days. Results  The anticipatory arousal started on the third day. On the eighth day, we found an increase in wake time and a decrease in the non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) times 45 minutes before the PM compared with the basal recordings. The REMS transitions (events from NREMS to REMS) showed a significant reduction during the light period of the eighth day of PM. In contrast, the number of NREMS transitions (events from wakefulness to NREMS) remained unchanged. Conclusion  The results suggest that palatable food induces a motivational timing that leads the rat to wake by altering the sleep quota., Competing Interests: Conflict of Interests The authors have no conflict of interest to declare., (Brazilian Sleep Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Neuroglobin (Ngb) is a protein expressed in the central and peripherical nervous systems of the vertebrate. The Ngb has different functions in neurons, including regulating O 2 homeostasis, oxidative stress, and as a neuroprotector after ischemia/hypoxia events. The Ngb is a hemoprotein of the globin family, structurally like myoglobin and hemoglobin. Ngb has higher expression in the cortex, hypothalamus, thalamus, brainstem, and cerebellum in mammals. Interestingly, Ngb immunoreactivity oscillates according to the sleep-wake cycle and decreases after 24 hours of sleep deprivation, suggesting that sleep homeostasis regulates Ngb expression. In addition, Ngb expresses in brain areas related to REM sleep regulation. Therefore, in the present review, we discuss the potential role of the Ngb in the sleep-wake regulation of mammals., Competing Interests: Conflict of Interest Statement None declared., (Brazilian Sleep Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

In cancer, the Epithelial to Mesenchymal Transition (EMT) is the process in which epithelial cells acquire mesenchymal features that allow metastasis, and chemotherapy resistance. Growth hormone (GH) has been associated with melanoma, breast, and endometrial cancer progression through an autocrine regulation of EMT. Since exogenous and autocrine expression of GH is known to have different molecular effects, we investigated whether exogenous GH is capable of regulating the EMT of cancer cells. Furthermore, we investigated whether exogenous GH could promote EMT in non-cancerous cells. To study the effect of GH (100 ng/ml) on cancer and non-cancer cells, we used HeLa and HEK293 cell lines, respectively. We evaluated the loss of cell-cell contacts, by cell scattering assay and migration by wound-healing assay. Additionally, we evaluated the morphological changes by phalloidin-staining. Finally, we evaluated the molecular markers E-cadherin and vimentin by flow cytometry. GH enhances cell scattering and the migratory rate and promotes morphological changes such as cell area increase and actin cytoskeleton filaments formation on HeLa cell line. Moreover, we found that GH favors the expression of the mesenchymal protein vimentin, followed by an increase in E-cadherin's epithelial protein expression, characteristics of an epithelial-mesenchymal hybrid phenotype that is associated with metastasis. On HEK293cells, GH promotes morphological changes, including cell area increment and filopodia formation, but not affects scattering, migration, nor EMT markers expression. Our results suggest that exogenous GH might participate in cervical cancer progression favoring a hybrid EMT phenotype but not on non-cancerous HEK293 cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cyclic AMP-dependent protein kinase A (PKA) is a ubiquitous enzymatic complex that is involved in a broad spectrum of intracellular receptor signaling. The activity of PKA depends on A-kinase anchoring proteins (AKAPs) that attach to PKAs close to their substrates to control signaling. Although the relevance of PKA-AKAP signaling in the immune system is evident in T cells, its relevance in B and other immune cells remains relatively unclear. In the last decade, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) has emerged as an AKAP that is ubiquitously expressed in B and T cells, specifically after activation. A deficiency of LRBA leads to immune dysregulation and immunodeficiency. The cellular mechanisms regulated by LRBA have not yet been investigated. Therefore, this review summarizes the functions of PKA in immunity and provides the most recent information regarding LRBA deficiency to deepen our understanding of immune regulation and immunological diseases.

Introduction: The Journal of Bone and Joint Surgery (JBJS) is one of most influential orthopaedic journals, with Total Joint Replacements (TJR) being a frequent topic. The importance of TJR research parallels it's high prevalence in American society., Objective: To compile and analyze the top 50 most frequently cited articles published in the Journal of Bone and Joint Surgery regarding total joint reconstruction or arthroplasty., Methods: Guidelines set by the Preferred Reporting Items for Systematic Reviews were used as the foundation for data collection and analysis. Scopus database was used to acquire the metric analyzed in the study. Data was then exported to an excel sheet for analysis., Results: The top 50 TJR publications analyzed for this study were cited a total of 35,850 times (including self-citations), with an average number of citations per article of 717. Kurtz and Neer II were the only authors contributing more than one. 38 of 50 articles analyzed met the criteria for Level II or III in terms of Level of Evidence (LOE). The United States contributed the most publications with a total of 34. Harvard University and Massachusetts General Hospital, with eight publications each, were the highest contributing institutions., Conclusion: The Journal of Bone and Joint Surgery has published very influential research papers as noted by the number of citations amassed by its most popular articles. JBJS's top cited publications hail largely from major institutions in the United States and are composed of high-quality reports of mostly Level 2 and Level 3 evidence classifications., Level of Evidence: 3., Competing Interests: The authors, their immediate family, and any research foundation with which they are affiliated did not receive any financial payments or other benefits from any commercial entity related to the subject of this article. There are no relevant disclosures. We have no conflicts of interest. All authors significantly contributed to the document and have reviewed the final manuscript.

Reducing sleep hours is a risk factor for developing cardiovascular, metabolic, and psychiatric disorders. Furthermore, previous studies have shown that reduction in sleep time is a factor that favors relapse in addicted patients. Additionally, animal models have demonstrated that both sleep restriction and sleep deprivation increase the preference for alcohol, methylphenidate, and the self-administration of cocaine. Therefore, the present review discusses current knowledge about the influence of sleep hours reduction on addictivebehaviors; likewise, we discuss the neuronal basis underlying the sleep reduction-addiction relationship, like the role of the orexin and dopaminergic system and neuronal plasticity (i.e., delta FosB expression). Potentially, chronic sleep restriction could increase brain vulnerability and promote addictive behavior., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Semaphorin 3A (Sema3a) is a chemotropic protein that acts as a neuronal guidance cue and plays a major role in dorsal root ganglion (DRG) sensory neurons projection during embryo development. The present study evaluated the impact of stiffness in the repulsive response of DRG neurons to Sema3a when cultured over substrates of variable stiffness. Stiffness modified DRG neurons morphology and regulated their response to Sema3a, reducing the collapse of growth cones when they were cultured on softer substrates. Sema3a receptors expression was also regulated by stiffness, neuropilin-1 was overexpressed and plexin A4 mRNA was downregulated in stiffer substrates. Cytoskeleton distribution was also modified by stiffness. In softer substrates, βIII-tubulin and actin co-localized up to the leading edge of the growth cones, and as the substrate became stiffer, βIII-tubulin was confined to the transition and peripheral domains of the growth cone. Moreover, a decrease in the α-actinin adaptor protein was also observed in softer substrates. Our results show that substrate stiffness plays an important role in regulating the collapse response to Sema3a and that the modulation of cytoskeleton distribution and Sema3a receptors expression are related to the differential collapse responses of the growth cones., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with the manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The type II transmembrane glycoprotein CD38 has recently been implicated in regulating metabolism and the pathogenesis of multiple conditions, including aging, inflammation and cancer. CD38 is overexpressed in several tumor cells and microenvironment tumoral cells, associated to migration, angiogenesis, cell invasion and progression of the disease. Thus, CD38 has been used as a progression marker for different cancer types as well as in immunotherapy. This review focuses on describing the involvement of CD38 in various non-hematopoietic cancers.

Background: Fragment analysis of exon 1 of the human androgen receptor, known as HUMARA, is a polymerase chain reaction (PCR)-based method for detecting X-linked agammaglobulinemia (XLA) carriers. This method takes advantage of X-chromosome inactivation (XCI) in female cells. XLA is caused by mutations in the Bruton tyrosine kinase ( BTK ) gene, located in Xq22.1. In this study, XCI is nonrandom or skewed in B-cells. B-cells with an active X-chromosome carrying a BTK mutation do not mature. Peripheral B-cells in XLA carriers inactivate the mutated X-chromosome. Methods: HUMARA was performed using DNA from purified B-cells and total leukocytes. DNA was digested using methylation-sensitive Hha I. The PCR of the HUMARA polymorphic marker was performed with the Hha I digested samples. The lengths of the PCR products were determined. If a suspected carrier showed skewed XCI in their B-cells, the marker length that corresponded with the length determined in the index patient indicated their carrier status. Results: HUMARA was conducted on purified B-cells; this allowed easier identification of the mutated or inactive allele, as the active allele was enzymatically digested. Analysis of 30 possible carriers using modified HUMARA corroborated that the carrier status in all samples that were heterozygous for the marker using XCI calculation for leukocytes showed a Gaussian distribution, while the carrier B-cell DNA showed a skewed XCI. Conclusion: Carrier status was successfully determined for most of the analyzed samples. B-cell enrichment resulted in precise carrier determination data, reduced the sample size, and facilitated inactive and active allele identification.

Background: The consumption of artificially sweetened beverages (ASBs) has been linked to metabolic alterations. The effect of reducing the regular consumption of these beverages on the metabolism is currently unknown., Objective: To evaluate the effect of reducing consumption of ASBs on the metabolism in overweight young adults., Design: A randomised, single-blind, controlled, 12-week, clinical trial was performed in overweight young adults who regularly consume ASBs. The 45 subjects who participated in the study were randomly divided into two groups: (1) control group (n=21) and (2) intervention group (no intake of ASBs, n=24). Body weight and composition, fasting plasma concentrations of glucose, triglycerides, insulin, cholesterol, low-density lipoproteins and high-density lipoproteins were measured at the beginning and end of the study. and the HOMA-IR was calculated., Results: At the end of 12 weeks, the intervention group showed a significant decrease (as opposed to an increase in the control group) in the percentage of change in body weight (-1.22% vs 1.31%, p<0.004), body fat (-6.28% vs 6.15%, p<0.001) and insulin resistance index (-12.06 vs 38.21%, p<0.00002), as well as in levels of glucose (-4.26% vs 0.51%, p<0.05), triglycerides (-14.74% vs 19.90%, p<0.006), insulin (-8.02% vs 39.23%, p<0.00005), cholesterol (-8.71% vs 0.77%, p<0.01) and LDL (-9.46% vs 9.92%, p<0.004)., Conclusion: A reduction in habitual consumption of ASBs in overweight young adults decreases biochemical measurements, body weight and composition, suggesting a participation in the metabolic processes., (Copyright © 2021 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38 + CD25 + T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38 + regulatory T-cells are more suppressive than CD38 - regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Fas lpr /J). Additionally, B6.MRL-Fas lpr /J mice showed a decreased proportion of CD38 + Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

Background: The consumption of artificially sweetened beverages (ASBs) has been linked to metabolic alterations. The effect of reducing the regular consumption of these beverages on the metabolism is currently unknown., Objective: To evaluate the effect of reducing consumption of ASBs on the metabolism in overweight young adults., Design: A randomised, single-blind, controlled, 12-week, clinical trial was performed in overweight young adults who regularly consume ASBs. The 45 subjects who participated in the study were randomly divided into two groups: (1) control group (n=21) and (2) intervention group (no intake of ASBs, n=24). Body weight and composition, fasting plasma concentrations of glucose, triglycerides, insulin, cholesterol, low-density lipoproteins and high-density lipoproteins were measured at the beginning and end of the study. and the HOMA-IR was calculated., Results: At the end of 12 weeks, the intervention group showed a significant decrease (as opposed to an increase in the control group) in the percentage of change in body weight (-1.22% vs 1.31%, p<0.004), body fat (-6.28% vs 6.15%, p<0.001) and insulin resistance index (-12.06 vs 38.21%, p<0.00002), as well as in levels of glucose (-4.26% vs 0.51%, p<0.05), triglycerides (-14.74% vs 19.90%, p<0.006), insulin (-8.02% vs 39.23%, p<0.00005), cholesterol (-8.71% vs 0.77%, p<0.01) and LDL (-9.46% vs 9.92%, p<0.004)., Conclusion: A reduction in habitual consumption of ASBs in overweight young adults decreases biochemical measurements, body weight and composition, suggesting a participation in the metabolic processes., (Copyright © 2021 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

The respiratory syncytial virus (RSV) is one of the main etiological agents in acute respiratory infections. To date, the replicative cycle of this virus is not completely known, and the events as well as the role of cellular and viral proteins that participate in the infectious cycle of RSV are still a matter of intense research. An important protein that is a control point for many viruses is the helicase eIF4AI, which participates at the beginning of the cap-dependent translation of eukaryotes and cap-independent translation of certain viral mRNAs. Recently, eIF4AI has been considered as a potential viral therapeutic target. In order to understand the role of eIF4AI during the infectious cycle of RSV, we evaluated the effect of eIF4AI knockdown on the amount of positive-strand viral RNA and viral progeny of this virus. Our results showed a decrease for both parameters, suggesting a possible involvement of eIF4AI during replicative cycle of RSV. In addition, using confocal microscopy, it was observed that eIF4AI colocalized with RSV viral protein, supporting the possible participation of eIF4AI during the replicative cycle of RSV. Keywords: eIF4AI; RSV; translation; antiviral.

Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) protein was initially described as a monogenetic cause for common variable immune deficiency, a syndrome characterized by low levels of B cells, defects in memory B cell differentiation and hypogammaglobulinaemia. LRBA was identified as an LPS up-regulated gene in B cells, macrophages and T cells. LRBA weighs 320 kDa and has 2863 amino acids. Its sequence contains multiple domains, suggesting that LRBA can act as a scaffolding protein. It contains two putative binding sites for cAMP-dependent kinase (PKA) regulatory subunits, suggesting this protein can act as A-kinase anchor protein (AKAP); however, physical interactions involving LRBA and PKA have not been demonstrated to date, and functional roles for such interactions are unexplored. In this work, we investigated physical interactions involving LRBA with regulatory subunits of PKA in human B cell lines and primary human B cells. PKA is a holoenzyme composed of two regulatory subunits, which can be RIα, RIβ, RIIα or RIIβ, and two catalytic subunits, Cα or Cβ. We co-immunoprecipitated LRBA using Ramos B cell lymphoma cells and observed that LRBA interacts with RIIβ. Interestingly, St-Ht31, an inhibitory peptide that disrupts AKAP interactions with regulatory subunits, reduced the amount of interacting protein. Furthermore, in primary human B cells, LRBA was induced after CD40L and IL-4 stimulation, and under such activation, we found that LRBA interacts with RIIα and RIIβ, suggesting that LRBA acts as an AKAP and binds RII subunits. Interestingly, we also identified that LRBA interacts with activation-induced cytidine deaminase in primary B cells, suggesting that it is involved in B cell function., (© 2020 The Scandinavian Foundation for Immunology.)

Neuroglobin (Ngb) is a protein member of the globin family, expressed mainly in the central and peripheral nervous system. It is involved in the transport of oxygen in response to hypoxic/ischemic and oxidative stress-related insults. We recently showed that sleep deprivation reduces the number of Ngb-positive cells in brain areas related to sleep. However, it is poorly understood whether Ngb expression correlates with sleep occurrence. Here, we aimed to study if sleep recovery produced by 24 h of sleep deprivation restores the number of Ngb-positive cells in the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg), brain areas related to sleep-wake regulation. Male Wistar rats were sleep-deprived for 24 h using the gentle handling method. After sleep deprivation, rats were allowed a sleep recovery for three or six hours. After sleep recovery, rats were euthanized, and their brains processed for Ngb immunohistochemistry. We found that a 3 h sleep recovery is enough to restore the number of Ngb-positive cells in all the analyzed areas. A similar result was observed after a 6 h sleep recovery. These results suggest that Ngb expression is sleep dependent. We suggest that Ngb expression is involved in preventing cell damage due to prolonged wakefulness., Competing Interests: All authors have no conflicts of interest to declare., (Copyright © 2020 Montserrat Melgarejo-Gutiérrez et al.)

Naringenin is flavonoid mainly found in citrus fruits which has shown several biological properties. In this work, we evaluated the therapeutic potential of the flavonoid Naringenin. Five-month-old B6.MRL-Faslpr/J lupus-prone mice were administered daily orally with Naringenin for seven months. We showed that Naringenin treatment at 50 or 100 mg/kg inhibited the splenomegaly and decreased the levels of anti-nuclear and anti-dsDNA autoantibodies. Furthermore, a reduction in serum concentration of TNF-α, IFN-γ and IL-6 was observed in the mice provided with Naringenin. Interestingly, serum levels of IL-10 increased. Naringenin decreased the frequency and absolute numbers of splenic effector memory T cells. Additionally, in order to be able to evaluate whether Naringenin prevented kidney damage, twelve-week-old MRL/MpJ-Faslpr/J mice, an accelerated lupus model, were orally administered with Naringenin at 100 mg/kg for six weeks. Surprisingly, Naringenin treatment prevented kidney damage and reduced the development of fibrosis similar to cyclophosphamide group. Moreover, Naringenin treatment increased the percentage of regulatory T cells in this aggressive model of lupus. Together, these results suggest a potential ability of Naringenin to reduce the autoimmunity in lupus-prone mice by modulation of T-cell subsets and cytokines profile that mitigate the development of important lupus clinical manifestations., Competing Interests: The authors have declared that no competing interests exist.

Despite abundant evidence associating CD38 overexpression and CD4 T cell depletion in HIV infection, no causal relation has been investigated. To address this issue, a series of mechanisms are proposed, supported by evidence from different fields, by which CD38 overexpression can facilitate CD4 T cell depletion in HIV infection. According to this model, increased catalytic activity of CD38 may reduce CD4 T cells' cytoplasmic nicotin-amide adenine dinucleotide (NAD), leading to a chronic Warburg effect. This will reduce mitochondrial function. Simultaneously, CD38's catalytic products ADPR and cADPR may be transported to the cytoplasm, where they can activate calcium channels and increase cytoplasmic Ca 2+ concentrations, further altering mitochondrial integrity. These mechanisms will decrease the viability and regenerative capacity of CD4 T cells. These hypotheses can be tested experimentally, and might reveal novel therapeutic targets. Also see the video abstract here https://youtu.be/k1LTyiTKPKs., (© 2018 WILEY Periodicals, Inc.)

A novel cell population denominated IFN-γ-producing killer dendritic cells (IKDCs) have been recently described. These cells are lymphocytes lacking B- or T- receptors, but they can be identified by the presence of B220 + CD38 + CD49b + and low CD11c, among other cell surface markers. The main characteristics of IKDCs are the production of IFN-γ and the ability to spontaneously kill tumor cells. We found that this population increases in B6.MLR-Fas lpr /J mice. Interestingly, IKDCs increase with age and are more abundant in mice older than 6 months onward. To analyze whether these cells have any role in the induction of the lupus-like phenotype in the B6.MLR-Fas lpr /J mice, IKDCs were purified and transferred into 6-month-old B6.MRL-Fas lpr /J mice, then the presence of anti-nuclear antibodies (ANAS) and anti-dsDNA antibodies were analyzed 2 and 4 months after the transfer. The results showed a reduction in the levels of these autoantibodies and increased survival of these mice, indicating that these cells may have a regulatory function. In vitro assays demonstrated that IKDCs reduced the proliferation of both autoreactive B and T cells, suggesting that these may be the mechanisms used by these cells to ameliorate the lupus-like phenotype in the B6.MRL-Fas lpr /J mice., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

CD38 is a transmembrane protein expressed in B lymphocytes, and is able to induce responses as proliferation, differentiation or apoptosis. Several reports propose that CD38 deficiency accelerates autoimmune processes in murine models of autoimmune diabetes, lymphoproliferation and rheumatoid arthritis. Other reports have shown elevated CD38 expression in B and T cells from patients with autoimmunity; however, the role of CD38 is still unclear in the development of autoimmunity. Recently, it has been characterized as CD1d hi CD5 + regulatory B cell subpopulation able to produce IL-10, and the loss of these cells exacerbates the autoimmunity in murine models. Here, we report that CD38 -/- mice exhibited elevated titres of ANAS, anti-dsDNA autoantibodies from 12 months of age and were higher by 16 months of age and mice presented kidney damage. Interestingly, there is a reduction in the survival of CD38 -/- mice compared to the WT. Furthermore, CD38 is highly expressed by CD1d high CD5 + regulatory B cells, and the agonistic anti-CD38 stimulus plus LPS was able to increase the percentage of this cell subset and its ability to induce IL-10 production. Together, these results suggest that CD38 could play a role in the control of autoimmune diseases through their expression on regulatory B cells., (© 2018 The Foundation for the Scandinavian Journal of Immunology.)

Background: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton's Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations., Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient., Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes., Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.

Btk is the protein affected in XLA, a disease identified as a B cell differentiation defect. Btk is crucial for B cell differentiation and activation, but its role in other cells is not fully understood. This review focuses on the function of Btk in monocytes, neutrophils, and platelets and the receptors and signaling cascades in such cells with which Btk is associated.

The suppressor effect of T regulatory lymphocytes in co-cultures with T effector cells obtained by magnetic columns from healthy donors and activated by CD3/CD28 was measured by a proliferation assay using BrdU incorporation and an ELISA test. Tritiated thymidine incorporation was used as a reference since it is the gold standard for proliferation assays. Both methods were used simultaneously in the same samples in order to compare them. Correlation between them was statistically significant (p < 0.001). The purification using magnetic columns was very efficient since CD4⁺CD25⁺ cells were also FOXP3⁺ therefore; they were identified as suppressor T cells. The use of BrdU incorporation in suppression assays is an excellent method that avoids the use of radioactive contaminating materials.

Marine planktonic archaea are widespread and abundant in deep oceanic waters but, despite their obvious ecological importance, little is known about them. Metagenomic analyses of large genome fragments allow access to both gene content and genome structure from single individuals of these cultivation-reluctant organisms. We present the comparative analysis of 22 archaeal genomic clones containing 16S rRNA genes that were selected from four metagenomic libraries constructed from meso- and bathypelagic plankton of different oceanic regions (South Atlantic, Antarctic Polar Front, Adriatic and Ionian Sea; depths from 500 to 3000 m). We sequenced clones of the divergent archaeal lineages Group 1A (Crenarchaeota) and Group III (Euryarchaeota) as well as clones from the more frequent Group I Crenarchaeota and Group II Euryarchaeota. Whenever possible, we analysed clones that had identical or nearly identical 16S rRNA genes and that were retrieved from distant geographical locations, that is, that defined pan-oceanic operational taxonomic units (OTUs). We detected genes involved in nitrogen fixation in Group 1A Crenarchaeota, and genes involved in carbon fixation pathways and oligopeptide importers in Group I Crenarchaeota, which could confirm the idea that these are mixotrophic. A two-component system resembling that found in ammonia-oxidizing bacteria was found in Group III Euryarchaeota, while genes for anaerobic respiratory chains were detected in Group II Euryarchaeota. Whereas gene sequence conservation was high, and recombination and gene shuffling extensive within and between OTUs in Group I Crenarchaeota, gene sequence conservation was low and global synteny maintained in Group II Euryarchaeota. This implies remarkable differences in genome dynamics in Group I Crenarchaeota and Group II Euryarchaeota with recombination and mutation being, respectively, the dominant genome-shaping forces. These observations, along with variations in GC content, led us to hypothesize that the two groups of organisms have fundamentally different lifestyles.

CD38 is a surface receptor able to induce activation, proliferation, and survival of human and mouse lymphocytes; this molecule is expressed on the surface of both mature and immature B cells. In this work, the function of CD38 in the maturation of murine B lymphocytes in the spleen was analyzed. The results showed that CD38 is highly expressed on Transitional 2 (T2) B lymphocytes with an intermediate expression on Transitional 1 (T1) and mature follicular B cells (M). Correlating with a high expression of CD38, T2 cells are also larger and more granular than T1 or M B cells. T2 cells also showed high levels of other molecules, which indicate an activated phenotype. CD38 crosslinking induced proliferation and maturation of T2 B lymphocytes; in contrast, T1 subset died by apoptosis. Finally, CD38 stimulation of T2 B lymphocytes obtained from Btk-, Lyn-, or Fyn-deficient mice showed a defective differentiation; similarly, drugs interfering with PI3K or ERK decreased the proliferation or differentiation of this subset. This suggests that these molecules participate in the CD38 signaling pathway. As a whole, the results indicate that CD38 plays an important role in the regulation of B-cell maturation in the spleen.

Background: Metagenomics is emerging as a powerful method to study the function and physiology of the unexplored microbial biosphere, and is causing us to re-evaluate basic precepts of microbial ecology and evolution. Most marine metagenomic analyses have been nearly exclusively devoted to photic waters., Methodology/principal Findings: We constructed a metagenomic fosmid library from 3,000 m-deep Mediterranean plankton, which is much warmer (approximately 14 degrees C) than waters of similar depth in open oceans (approximately 2 degrees C). We analyzed the library both by phylogenetic screening based on 16S rRNA gene amplification from clone pools and by sequencing both insert extremities of ca. 5,000 fosmids. Genome recruitment strategies showed that the majority of high scoring pairs corresponded to genomes from Rhizobiales within the Alphaproteobacteria, Cenarchaeum symbiosum, Planctomycetes, Acidobacteria, Chloroflexi and Gammaproteobacteria. We have found a community structure similar to that found in the aphotic zone of the Pacific. However, the similarities were significantly higher to the mesopelagic (500-700 m deep) in the Pacific than to the single 4000 m deep sample studied at this location. Metabolic genes were mostly related to catabolism, transport and degradation of complex organic molecules, in agreement with a prevalent heterotrophic lifestyle for deep-sea microbes. However, we observed a high percentage of genes encoding dehydrogenases and, among them, cox genes, suggesting that aerobic carbon monoxide oxidation may be important in the deep ocean as an additional energy source., Conclusions/significance: The comparison of metagenomic libraries from the deep Mediterranean and the Pacific ALOHA water column showed that bathypelagic Mediterranean communities resemble more mesopelagic communities in the Pacific, and suggests that, in the absence of light, temperature is a major stratifying factor in the oceanic water column, overriding pressure at least over 4000 m deep. Several chemolithotrophic metabolic pathways could supplement organic matter degradation in this most depleted habitat.

The bacterial and archaeal assemblages at two offshore sites located in polar (Greenland Sea; depth: 50 and 2000 m) and Mediterranean (Ionian Sea; depth 50 and 3000 m) waters were studied by PCR amplification and sequencing of the last 450-500 bp of the 16S rRNA gene. A total of 1621 sequences, together with alignable 16S rRNA gene fragments from the Sargasso Sea metagenome database, were analysed to ascertain variations associated with geographical location and depth. The Ionian 50 m sample appeared to be the most diverse and also had remarkable differences in terms of the prokaryotic groups retrieved; surprisingly, however, many similarities were found at the level of large-scale diversity between the Sargasso database fragments and the Greenland 50 m sample. Most sequences with more than 97% sequence similarity, a value often taken as indicative of species delimitation, were only found at a single location/depth; nevertheless, a few examples of cosmopolitan sequences were found in all samples. Depth was also an important factor and, although both deep-water samples had overall similarities, there were important differences that could be due to the warmer waters at depth of the Mediterranean Sea.

Introduction and Objectives: There is little information about the management and prognosis of patients with acute myocardial infarction (AMI) who are not admitted to coronary care units (CCU) because of the lack of available beds. The aim of this study was to evaluate the characteristics and prognosis of the patients who were admitted to the intermediate care unit (INTCU) of a cardiology department., Methods: We compared the clinical profile, management, and 12-month prognosis of the patients admitted to the INTCU or general ward (Ward) instead of the CCU., Results: Out of 242 patients with AMI, 62 (23%) were not admitted to the CCU due to the lack of available beds. Of these, 29 (12%) were admitted to the INTCU and 26 (11%) to the Ward after being monitored for at least 24 h in the emergency room. Patients admitted to the CCU arrived at the hospital early, were younger, less frequently female, and had a lower prevalence of diabetes. ST-segment elevation AMI was more frequent in patients admitted to the CCU than in patients admitted to the INTCU or Ward (67 vs 17 and 23%, respectively; p < 0.0001), and non-Q wave AMI was less frequent (30 vs 76 and 81%; p < 0.0001). No differences were found between groups in the number of stress tests or revascularization procedures performed after the first 24 h, the duration of the hospital stay (median 8 days), or in-hospital mortality. The 12-month survival was 82, 80, and 64% in the patients admitted to the CCU, INTCU, or Ward (p < 0.05), respectively. These differences ceased to be significant after adjusting for the patients' baseline clinical profile and treatment received at admission., Conclusion: Compared to patients with AMI admitted to the CCU, patients admitted to the INTCU or Ward after being monitored at least 24 h had non-ST elevation and non-Q wave AMI more frequently, but a less favorable risk profile for long-term mortality. The different types of AMI were managed similarly and had a similar 12-month prognosis. Intermediate care units may be useful for palliating the lack of CCU beds and care for some patients with AMI.