Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD

IRX-2, a Novel Immunotherapeutic, Enhances Functions of Human Dendritic Cells

Background: In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Methodology/Principal Findings: Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Conclusion: Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy. © 2013 Schilling et al

Ethnic Speech and Ethnic Action as Ethnic Behavior: Part 1. Construction of the Brunel Ethnic Behavior Inventory

© 2016 Taylor & Francis.This article reports the construction of a new survey—specifically, the Brunel Ethnic Behavior Inventory (BEBI)—designed to measure ethnic speech and ethnic action as separate, yet related, aspects of individuals’ ethnic behavior. Using Tajfel’s social identity theory as a conceptual frame of reference, this study sought an answer to the research question of how many factors actually are measured by the BEBI, and tested the hypothesis that a two-factor model (i.e., Ethnic Speech and Ethnic Action as two correlated factors) would provide significantly better goodness of fit to the correlational data than would a one-factor model (i.e., Ethnic Behavior as one undifferentiated factor). Across one pilot sample (n = 101) and two main samples (n = 120 for Sample 1, n = 148 for Sample 2), the study found that not only did the BEBI measure two factors at most (i.e., Ethnic Speech and Ethnic Action) but, consistent with the hypothesis, the two-factor model yielded better goodness of fit than did the one-factor model. Implications for the conceptualization and measurement of Verkuyten’s “ways of ethnicity” are discussed

Immunological profiles in HIV positive patients following Haart initiation in Kigali, Rwanda

Background: Interleukin-10, IL-2 and IFN -γ are some of the crucial cytokines associated with HIV infection and pathogenesis. While IL-2 and IFN-γ play critical roles in host resistance to infection, IL-10 inhibits the synthesis IFN-γ, IL-2 at mRNA and protein level; exacerbating damage to immune system.Objective: To determine the levels of, changes in and correlation between CD4 count, viral load, IL-10, IL-2 and IFN-γ before HAART and at six months of HAART among HIV positive patients in Kigali; with a view to understand cytokine networks particularly in relation to HAART ; and to see whether they can be used as alternative markers of the disease progression.Design: Longitudinal study.Setting: Kagugu, Kimironko, Biryogo, Gitega Health Centres and Centre Medico-Social Cornum; all located in Kigali.Subjects: Thirty three (33) HAART initiation eligible HIV positive patients including 13 women and 20 men.Results: A drop in viral load (though only a small number of patients achieved an undetectable viraemia); a recovery of CD4+ cells, a decrease in IL-10 (though it remained high for many patients especially those with unchanged viraemia); and an increase in IL-2 and IFN-γ indicated a successful HAART . A negative correlation between CD4 count and viral load and between CD4 count and IL-10 (but r &lt;-0.5) was observed. IL-10 correlated positively and strongly with viremia (r &gt; 0.5 at both time points: p-values &lt;0.05). There was no significant correlation between CD4 count, IL-2 and IFN-γ.Conclusion: Results demonstrated the down-regulatory effect of IL-10 on Th1 cytokines and that a shift from Th1 to Th2 cytokine is associated with HIV disease progression. A successful HAART results in CD4+ cells recovery, drop in viraemia and IL-10 with up-regulation of Th1 cytokines. Also, findings show potential usefulness of IL-10 as a marker of HIV disease progression

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME)

Chronic Fatigue Syndrome (CFS/ME) is a complex multisystem disease of unknown aetiology which causes debilitating symptoms in up to 1% of the global population. Although a large cohort of genes have been shown to exhibit altered expression in CFS/ME patients, it is currently unknown whether microRNA (miRNA) molecules which regulate gene translation contribute to disease pathogenesis. We hypothesized that changes in microRNA expression in patient leukocytes contribute to CFS/ME pathology, and may therefore represent useful diagnostic biomarkers that can be detected in the peripheral blood of CFS/ME patients.miRNA expression in peripheral blood mononuclear cells (PBMC) from CFS/ME patients and healthy controls was analysed using the Ambion Bioarray V1. miRNA demonstrating differential expression were validated by qRT-PCR and then replicated in fractionated blood leukocyte subsets from an independent patient cohort. The CFS/ME associated miRNA identified by these experiments were then transfected into primary NK cells and gene expression analyses conducted to identify their gene targets.Microarray analysis identified differential expression of 34 miRNA, all of which were up-regulated. Four of the 34 miRNA had confirmed expression changes by qRT-PCR. Fractionating PBMC samples by cell type from an independent patient cohort identified changes in miRNA expression in NK-cells, B-cells and monocytes with the most significant abnormalities occurring in NK cells. Transfecting primary NK cells with hsa-miR-99b or hsa-miR-330-3p, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity, suggesting that defective NK cell function contributes to CFS/ME pathology.This study demonstrates altered microRNA expression in the peripheral blood mononuclear cells of CFS/ME patients, which are potential diagnostic biomarkers. The greatest degree of miRNA deregulation was identified in NK cells with targets consistent with cellular activation and altered effector function

Large-scale unit commitment under uncertainty: an updated literature survey

The Unit Commitment problem in energy management aims at finding the optimal production schedule of a set of generation units, while meeting various system-wide constraints. It has always been a large-scale, non-convex, difficult problem, especially in view of the fact that, due to operational requirements, it has to be solved in an unreasonably small time for its size. Recently, growing renewable energy shares have strongly increased the level of uncertainty in the system, making the (ideal) Unit Commitment model a large-scale, non-convex and uncertain (stochastic, robust, chance-constrained) program. We provide a survey of the literature on methods for the Uncertain Unit Commitment problem, in all its variants. We start with a review of the main contributions on solution methods for the deterministic versions of the problem, focussing on those based on mathematical programming techniques that are more relevant for the uncertain versions of the problem. We then present and categorize the approaches to the latter, while providing entry points to the relevant literature on optimization under uncertainty. This is an updated version of the paper "Large-scale Unit Commitment under uncertainty: a literature survey" that appeared in 4OR 13(2), 115--171 (2015); this version has over 170 more citations, most of which appeared in the last three years, proving how fast the literature on uncertain Unit Commitment evolves, and therefore the interest in this subject

The prognostic significance of tertiary lymphoid structures in oral squamous cell carcinomas: a systematic review

IntroductionUpper aerodigestive tract cancers are prevalent, with a global incidence surpassing 500,000 new cases in 2018. Among these, oral squamous cell carcinomas (OSCC) constitute the majority. OSCC has a low 5-year survival rate due to late-stage diagnosis. Risk factors include alcohol and tobacco use. However, non-smokers and non-drinkers are also affected, especially young patients with tongue cancer. The impact of tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) on OSCC prognosis remains debated. Remarkably, Tertiary Lymphoid Structures (TLS) identified in solid tumors have shown associations with favorable outcomes, yet their prognostic significance in OSCC remains understudied.ObjectiveThus, this systematic review aims to explore the value of TLS in OSCC reported in the literature.MethodA scoping review was conducted and six retrospective cohort studies involving 1,203 patients met the inclusion criteria.ResultsPredominantly male patients, with an average age of 49.3 years were included. Immunohistochemistry was the primary method to identify TLS, present in 21% up to 100% of cases. TLS were predominantly located in the peri-tumoral area (75.4%–84.8%) compared to the intra-tumoral area (33.8%–33.9%). Our review shows that the presence of TLS is associated with improved survival in OSCC.DiscussionHowever, variations in TLS detection and classification methods across studies introduce potential biases, hindering direct comparisons between findings. For instance, reports that are based solely on examining HES-stained slides for TLS identification may raise reliability concerns. Standardization of methodologies is imperative to ensure consistency in criteria utilization, thereby facilitating meaningful data comparisons.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023428010, PROSPERO (CRD42023428010)