The schizophrenia risk gene C4 induces pathological synaptic loss by impairing AMPAR trafficking.

Neuroimmune interactions play a significant role in regulating synaptic plasticity in both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent synaptic elimination via the complement receptor 3 (CR3). Current models of pathological complement activity in the brain propose that accelerated synaptic loss resulting from overexpression of C4 (C4-OE), a gene associated with schizophrenia, follows this pathway. Here, we report that C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE triggers impaired GluR1 trafficking through an intracellular mechanism involving the endosomal protein SNX27, resulting in pathological synaptic loss. Moreover, C4 circuit alterations in the prefrontal cortex, a brain region associated with neuropsychiatric disorders, were rescued by increasing neuronal levels of SNX27, which we identify as an interacting partner of this neuroimmune protein. Our results link excessive complement activity to an intracellular endo-lysosomal trafficking pathway altering synaptic plasticity.

HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation.

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual-who is known as the 'Berlin patient'-underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin's lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression.

HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

Most recently developed polyester polymer alloy dialyzer: A new medium cut-off membrane?

BACKGROUND: New versions of the polyester polymer alloy (PEPA) membrane have appeared over the years, with increases in both the pore size and the amount of polyvinylpyrrolidone (PVP) to optimize hydrophilicity performance. This study aimed to assess the efficacy of the most recently developed PEPA dialyzer, the FDY series, in hemodialysis (HD) modality in terms of uremic toxin removal and albumin loss and to compare it with that of several high-flux dialyzers currently used in HD and post-dilution hemodiafiltration (HDF) treatments. METHODS: A prospective study was carried out in 21 patients. All patients underwent six dialysis sessions with the same routine dialysis parameters; only the dialyzer and/or the dialysis modality varied: FX80 in HD, FDY 180 in HD, Clearum HS17 in HDF, Elisio 19H in HDF, Vitapes 180 in HDF, and FX80 in post-dilution HDF. The reduction ratios (RR) of urea, creatinine, ß2-microglobulin, myoglobin, κFLC, prolactin, α1-microglobulin, α1-acid glycoprotein, λFLC, and albumin were compared intraindividually. Dialysate albumin loss was also measured. RESULTS: Both membranes FDY and FX80 are high-flux dialyzers and are applied here in high-flux HD. The average RR of ß2-microglobulin was slightly lower in the two HD treatments than in the HDF treatments. Comparison of dialysis treatments revealed that the PEPA FDY dialyzer in the HD modality was more effective than the FX80 dialyzer in high-flux HD and was as effective as post-dilution HDF, especially in terms of myoglobin, κFLC, prolactin, α1-microglobulin, and λFLC RRs. The FDY treatments obtained similar albumin RR in blood and slightly higher dialysate albumin loss, although the values were clinically acceptable. CONCLUSIONS: The most recently developed PEPA dialyzers in the HD modality were as effective as all treatments in the HDF modality and were clearly superior to high-flux helixone HD treatment. These results confirm that this dialyzer should be categorized within the medium cut-off (MCO) membrane classification.

Goiter, iodine bioavailability and intrauterine growth restriction in Indigenous and Afro-descendant pregnant women from six non-metropolitan areas of Colombia (2019-2020).

INTRODUCTION: Iodine is an essential mineral for fetal growth and brain development. The aim of this research was to evaluate goiter, iodine deficiency and intrauterine growth restriction in pregnant women of minority ethnic groups in Colombia. METHODS: A cross-sectional study was performed in six non-metropolitan areas of Colombia. RESULTS: A total of 318 Indigenous and Afro-descendant pregnant women were invited to participate: 248 (83.2%) Indigenous and 50 (16.8%) Afro-descendants were studied. The mean age was 24 years (range 13-44 years). Of the women, 130 (43.5%) were from the department of Cauca, 72 (24.1%) were from Córdoba, 28 (9.4%) were from Guajira, 26 (8.8%) were from Sierra Nevada de Santa Marta, 22 (7.4%) were from Amazonas, 16 (5.4%) were from Meta and 4 (1.3%) were from the department of Cesar. A total of 244 (81.8%) were illiterate and 291 (97.7%) were of very low socioeconomic level. Goiter was observed in 69 (23.3%) pregnant women (38 (41.7%) from the department of Cauca, 10 (35.7%) from Guajira, 5 (31.2%) from Meta, 6 (27.2%) from Amazonas and 10 (13.8%) from Córdoba). Iodine deficiency (<100 µg/L) was observed in 42 (14.9%) pregnant women (16 (11.6%) mild (50-99 µg/L), 19 (13.8%) moderate (20-49 µg/L) and 7 (5.1%) severe (<20 µg/L)). Being literate was a protective factor for iodine deficiency (odds ratio (OR)=0.19, 95% confidence interval (CI) 0.04-0.84, p=0.016). Being illiterate and iodine deficient was only a risk factor for goiter (OR=6.72, 95%CI 3.9-9.5, p=0.038) in the department of Cauca. CONCLUSION: A high prevalence of goiter, iodine deficiency and intrauterine growth restriction was observed in minority ethnic groups of Colombia. The highest prevalence and risk was observed in the department of Cauca.

Impact of Obefazimod on Viral Persistence, Inflammation, and Immune Activation in People With Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy.

BACKGROUND: Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV. METHODS: We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks. RESULTS: The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P = .008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers. CONCLUSIONS: The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents.

Unraveling brain fog in post-COVID syndrome: Relationship between subjective cognitive complaints and cognitive function, fatigue, and neuropsychiatric symptoms.

BACKGROUND AND PURPOSE: "Brain fog" is a frequent and disabling symptom that can occur after SARS-CoV-2 infection. However, its clinical characteristics and the relationships among brain fog and objective cognitive function, fatigue, and neuropsychiatric symptoms (depression, anxiety) are still unclear. In this study, we aimed to examine the characteristics of brain fog and to understand how fatigue, cognitive performance, and neuropsychiatric symptoms and the mutual relationships among these variables influence subjective cognitive complaints. METHODS: A total of 170 patients with cognitive complaints in the context of post-COVID syndrome were evaluated using a comprehensive neuropsychological protocol. The FLEI scale was used to characterize subjective cognitive complaints. Correlation analysis, regression machine-learning algorithms, and mediation analysis were calculated. RESULTS: Cognitive complaints were mainly attention and episodic memory symptoms, while executive functions (planning) issues were less often reported. The FLEI scale, a mental ability questionnaire, showed high correlations with a fatigue scale and moderate correlations with the Stroop test, and anxiety and depressive symptoms. Random forest algorithms showed an R2 value of 0.409 for the prediction of FLEI score, with several cognitive tests, fatigue and depression being the best variables used in the prediction. Mediation analysis showed that fatigue was the main mediator between objective and subjective cognition, while the effect of depression was indirect and mediated through fatigue. CONCLUSIONS: Brain fog associated with COVID-19 is mainly characterized by attention and episodic memory, and fatigue, which is the main mediator between objective and subjective cognition. Our findings contribute to understanding the pathophysiology of brain fog and emphasize the need to unravel the main mechanisms underlying brain fog, considering several aspects.

Efficacy and Safety of the Medium Cut-Off Elisio HX Dialyzer.

INTRODUCTION: The medium cut-off Elisio HX dialyzer by Nipro became commercially available in Europe in 2021, but there are still no reports of in vivo data. This study aimed to evaluate the safety and efficacy of it compared with previously evaluated hemodialysis (HD), expanded HD (HDx), and postdilution hemodiafiltration (HDF) treatments. METHODS: A prospective study was carried out on 18 patients who underwent 5 dialysis sessions: FX80 Cordiax in HD, Elisio H19 in HD, Elisio HX19 in HDx, Theranova 400 in HDx, and FX80 Cordiax in HDF. The reduction ratios of urea, creatinine, ß2-microglobulin, myoglobin, kappa FLC, prolactin, α1-microglobulin, α1-acid glycoprotein, lambda FLC, and albumin were compared. Dialysate albumin loss was measured. RESULTS: The comparison between the different dialysis modalities revealed no difference for small molecules, but HDx and HDF were significantly more efficient than HD for medium and large molecule removal. The efficacy of Elisio HX19 dialyzer in HDx was similar to the Theranova 400, superior to both dialyzers in HD, and slightly lower than HDF. Albumin losses in dialysate with HD dialyzers were less than 1 g, but between 1.5 and 2.5 g in HDx and HDF. The global removal score (GRS) values with HDx treatments were statistically significantly higher than those with HD. The highest GRS was obtained with the helixone dialyzer in HDF. CONCLUSIONS: The new MCO dialyzer, Elisio HX, performs with excellent behavior and tolerance. It represents an upgrade compared to their predecessor and is very close to the removal capacity of HDF treatment.

Altered T-cell subset distribution in the viral reservoir in HIV-1-infected individuals with extremely low proviral DNA (LoViReTs).

BACKGROUND: HIV cure strategies aim to eliminate viral reservoirs that persist despite successful antiretroviral therapy (ART). We have previously described that 9% of HIV-infected individuals who receive ART harbor low levels of provirus (LoViReTs). METHODS: We selected 22 LoViReTs matched with 22 controls ART suppressed for more than 3 years with fewer than 100 and more than 100 HIV-DNA copies/106  CD4+ T cells, respectively. We measured HIV reservoirs in blood and host genetic factors. Fourteen LoViReTs underwent leukapheresis to analyze replication-competent virus, and HIV-DNA in CD4+ T-cell subpopulations. Additionally, we measured HIV-DNA in rectum and/or lymph node biopsies from nine of them. RESULTS: We found that LoViReTs harbored not only lower levels of total HIV-DNA, but also significantly lower intact HIV-DNA, cell-associated HIV-RNA, and ultrasensitive viral load than controls. The proportion of intact versus total proviruses was similar in both groups. We found no differences in the percentage of host factors. In peripheral blood, 71% of LoViReTs had undetectable replication-competent virus. Minimum levels of total HIV-DNA were found in rectal and lymph node biopsies compared with HIV-infected individuals receiving ART. The main contributors to the reservoir were short-lived transitional memory and effector memory T cells (47% and 29%, respectively), indicating an altered distribution of the HIV reservoir in the peripheral T-cell subpopulations of LoViReTs. CONCLUSION: In conclusion, LoViReTs are characterized by low levels of viral reservoir in peripheral blood and secondary lymphoid tissues, which might be explained by an altered distribution of the proviral HIV-DNA towards more short-lived memory T cells. LoViReTs can be considered exceptional candidates for future interventions aimed at curing HIV.

Diagnosis of Alzheimer's disease and behavioural variant frontotemporal dementia with machine learning-aided neuropsychological assessment using feature engineering and genetic algorithms.

BACKGROUND: Neuropsychological assessment is considered a valid tool in the diagnosis of neurodegenerative disorders. However, there is an important overlap in cognitive profiles between Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD), and the usefulness in diagnosis is uncertain. We aimed to develop machine learning-based models for the diagnosis using cognitive tests. METHODS: Three hundred and twenty-nine participants (170 AD, 72 bvFTD, 87 healthy control [HC]) were enrolled. Evolutionary algorithms, inspired by the process of natural selection, were applied for both mono-objective and multi-objective classification and feature selection. Classical algorithms (NativeBayes, Support Vector Machines, among others) were also used, and a meta-model strategy. RESULTS: Accuracies for the diagnosis of AD, bvFTD and the differential diagnosis between them were higher than 84%. Algorithms were able to significantly reduce the number of tests and scores needed. Free and Cued Selective Reminding Test, verbal fluency and Addenbrooke's Cognitive Examination were amongst the most meaningful tests. CONCLUSIONS: Our study found high levels of accuracy for diagnosis using exclusively neuropsychological tests, which supports the usefulness of cognitive assessment in diagnosis. Machine learning may have a role in improving the interpretation and test selection.