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Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIV AD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8 + CD69 + T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy. In this work, the authors study the immunological and virological effects of administering either wild-type anti-HIV-1 broadly neutralizing antibodies (bNAbs) or bNAbs with a mutation that increases binding to Fc-gamma receptors (FcγRs) to rhesus macaques in the acute phase of SHIV AD8-EO infection.

Forms of selective autophagy have now been recognized to regulate flux in many intracellular processes. Specific pathways and functions have been identified for mitophagy, ERphagy, and other selective autophagies; yet there is no consensus in whether and how autophagy regulates protein maintenance in and around the nucleus. Such processes are of interest for potential degradation of DNA and nuclear envelope proteins in various disease states. The mechanistic details of such nucleus-related autophagic processes remain elusive due to the lack of chemical or genetic regulators to manipulate and follow the process in vitro. Here, we describe a high content screen from which we identified small chemical compounds that can modulate the localization of the autophagy marker MAP1LC3B (LC3) in renal carcinoma cells. We also describe a pipeline designed for the execution and analysis of high content screens. The chemical tools discerned from this screen will allow for the deeper exploration of the mechanism, regulation, and molecular targets of nuclear-localized LC3 in perturbed cellular states.

Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIV infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8 CD69 T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy.

This study investigates the synthesis of 1-hydroperoxyadamantane, addressing discrepancies in the prior literature. Our results demonstrate that previous authors were unable to obtain the claimed compound under the conditions they described. We confirmed that 1-hydroperoxyadamantane can be synthesized in good yields via the reaction of 1,3-dehydroadamantane with concentrated hydrogen peroxide in DCM. Structure of 1-hydroperoxyadamantane was confirmed by SC XRD analysis. These findings clarify the conditions necessary for successful synthesis of this compound and highlight the importance of comprehensive analytical verification. This study also provides a very detailed, repeatedly verified method for synthesizing 1,3-dehydroadamantane and a description of the necessary laboratory equipment.

The period following the end of World War II is marked by increased international cooperation aimed, among other things, at promoting economic integration. As part of these efforts, national governments adopted policies to remove/reduce barriers to the exchange of goods and services as well as the movement of capital and labor. Although the impact of international trade and investment treaties on trade has been extensively documented, little to no attention has been paid to the potential impact of bilateral labor agreements (BLAs) on commerce flows. This study uses a novel dataset of BLAs within a gravity framework and finds that, over 5 years following signature, BLAs have a positive and significant effect on aggregate exports and exports of differentiated goods (i.e., chemicals and miscellaneous manufactured goods).

Human cytomegalovirus (CMV) remains a major cause of morbidity and mortality in pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT), where its high genetic variability and the limitations of current antiviral therapies pose significant clinical challenges. Despite standard antiviral prophylaxis, CMV infection affects up to 80% of allo-HSCT recipients, necessitating the evaluation of alternative strategies to overcome the limitations of conventional treatments. This single-center ambispective study investigates the application of CMV-specific immunoglobulin (Ig) prophylaxis, focusing on its impact on viral clearance, transplant outcomes, immunological readouts, and efficacy across diverse ethnic cohorts (European vs. non-European). A analysis was performed on 71 hematopoietic stem cell recipients who received CMV-specific Ig (Study Group) and historical controls (Control Group). A pharmacokinetic analysis was performed on the Study Group. The Control Group exhibited higher rates of first-blood CMV DNA detection post-transplant (p = 0.0024), second-blood CMV DNA detection post-transplant (p = 0.00042), CMV DNA viral load (p = 0.0016), reduced hospital stays (p = 0.007) and improved immune reconstitution (p < 0.0001). No significant differences in hospital stay emerged between European and non-European patients. However, Europeans had better results in first-blood CMV DNA detection (p = 0.006), second reactivation (p = 0.00032), immune reconstitution at day +90 (p = 0.0443), clearance rates, and reduced need for second-line therapy (p < 0.001). The terminal half-life of CMV-specific Ig was approximately 15 days. These findings demonstrate that CMV-specific Ig serves as an effective molecular immunotherapy, significantly improving immunological readouts and clinical outcomes in pediatric allo-HSCT. Furthermore, the observed ethnic disparities underscore the importance of personalized molecular strategies to address CMV genome variability and global health challenges.

Purpose To describe the effectiveness and safety of fostamatinib off-label use in a pediatric patient with autoimmune cytopenia and autoimmune hepatitis following allogeneic hematopoietic stem cell transplantation (HSCT). Methods We report the detailed changes in clinical, histopathological, and cytokine profiling in a pediatric HSCT recipient during treatment with fostamatinib. Results Fostamatinib administration was well-tolerated with no adverse events observed, leading to sustained hematological recovery and a significant improvement in liver enzyme levels. Histological features confirmed the complete remission of autoimmune hepatitis. Cytokine profiling demonstrated substantial normalization of pro-inflammatory markers, downregulated at onset. Conclusion Fostamatinib demonstrated a dual benefit in resolving autoimmune cytopenia and immune-mediated liver inflammation, supporting its potential as a therapeutic option for immune dysregulation following allogeneic HSCT.

Background/Objectives: Pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by iron overload and hypomagnesemia, both contributing to immune dysfunction and post-transplant morbidity. The combined impact of these metabolic disturbances on pediatric allo-HSCT outcomes remains unexplored. This study aims to determine whether hypomagnesemia can serve as a prognostic biomarker for delayed immune reconstitution and explores its interplay with iron overload in predicting post-transplant complications and survival outcomes. Methods: A retrospective analysis was conducted on 163 pediatric allo-HSCT recipients. Serum magnesium levels were measured at defined intervals post-transplant, and outcomes were correlated with CD4+ T cell recovery, time to engraftment, incidence of graft-versus-host disease (GVHD), and survival within 12 months. Iron status, including siderosis severity, was evaluated using imaging and laboratory parameters obtained from clinical records. Results: Patients who died within 12 months post-transplant exhibited significantly lower magnesium levels. Hypomagnesemia was associated with delayed CD4+ T cell recovery, prolonged engraftment, and an increased risk of acute GVHD. A strong inverse correlation was observed between magnesium levels and the severity of siderosis. Iron overload appeared to exacerbate magnesium deficiency. Additionally, the coexistence of hypomagnesemia and siderosis significantly increased the risk of immune dysfunction and early mortality. No significant association was found with chronic GVHD. Conclusions: Hypomagnesemia is a significant, early predictor of poor outcomes in pediatric allo-HSCT, particularly in the context of iron overload, underscoring the need for early intervention, including iron chelation and MRI, to improve outcomes.

Essentuki mineral groundwater (EMGW) basin is characterized by unique and complex geological and hydrogeological settings due to monoclinal character of the geological structure, breaking by north-eastern faults, significant stratum of clays, overlaying major aquifers, volcanic laccolite peaks. EMGW area involves the unique wide variety of mineral waters with different TDS, pH, chemical, and gas composition. TDS changes from fresh (0.5–0.9 g/L) to high salinity (10–13 g/L) and strongly depends on the chemical composition of water. The region is characterized by a wide spread of high pCO2 sparkling Ca–Na–HCO3–Cl waters, which are the trademark of “Essentuki 4” and “Essentuki 17”. Such waters have strong therapeutic properties. Geothermal conditions, major- and micro-elements, isotopic characteristics of water (δ18O and δ2H) and gas (δ13C in CO2 and CH4, 3He/4He) phases of carbon dioxide mineral waters of EMGW basin were analyzed in this paper. The CO2free gas is probably a mixture of gas from deep (volcanic) and biogenic sources, although methane has the marine microbial origin and evolves from the degradation of dispersed organic matter in the host rocks. 3He/4He values prove that the free associated gas in mineral groundwaters of the region is a mixture of several sources of gas (mantle, crustal, and biogenic).

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder affecting <1/1,000,000 people. It is caused by mutations in the CLDN16 (FHHNC Type 1) or CLDN19 (FHHNC Type 2) genes, which are located on Chromosomes 3q27 and 1p34.2, respectively. There are no drug therapies for this condition. Although magnesium salts represent an important class of compounds and exhibit various therapeutic actions as a supplement for magnesium deficiency in FHHNC, various formulations on the market have different bioavailability. We report the case of a patient with FHNNC first treated, in our Pediatric Institute, with high doses of magnesium pidolate and magnesium and potassium citrate. The patient began to neglect this therapy after experiencing frequent daily episodes of diarrhoea. Our pharmacy received a request for an alternative magnesium supplement that would better comply by ensuring a good magnesium intake which will result in adequate blood magnesium levels. In response, we developed a galenic compound in the form of effervescent magnesium. Here, we report on the promise of this formulation not only for better compliance than pidolate, but also for better bioavailability.