We recently reported, for the first time, the expression and regulation of the PDZ polarity proteins Scrib and Dlg1 in human APCs, and also described the viral targeting of these proteins by NS1 of ...influenza A virus in human dendritic cells (DCs). Scrib plays an important role in reactive oxygen species (ROS) production in Mϕs and uropod formation and migration in T cells, while Dlg1 is important for T cell downstream activation after Ag recognition. Nevertheless, the functions of these proteins in human DCs remain unknown. Here, we knocked‐down the expression of both Scrib and Dlg1 in human DCs and then evaluated the expression of co‐stimulatory molecules and cytokine production during maturation. We demonstrated that Scrib is necessary for adequate CD86 expression, while Dlg1 is important for CD83 up‐regulation and IL‐6 production upon maturation, suggesting that Scrib and Dlg1 participate in separate pathways in DCs. Additionally, both proteins are required for adequate IL‐12 production after maturation. Furthermore, we showed that the inefficient maturation of DCs induced by Scrib or Dlg1 depletion leads to impaired T cell activation. Our results revealed the previously unknown contribution of Scrib and Dlg1 in human DCs pivotal functions, which may be able to impact innate and adaptive immune response.
Contribution of Scrib and Dlg1 to human DC functions, which may impact innate and adaptive immune responses.
Overproduction of inflammatory cytokines is a keystone event in COVID-19 pathogenesis; TNF and its receptors (TNFR1 and TNFR2) are critical pro-inflammatory molecules. ADAM17 releases the soluble ...(sol) forms of TNF, TNFR1, and TNFR2. This study evaluated TNF, TNFRs, and ADAM17 at the protein, transcriptional, and gene levels in COVID-19 patients with different levels of disease severity. In total, 102 patients were divided into mild, moderate, and severe condition groups. A group of healthy donors (HD; n = 25) was included. Our data showed that solTNFR1 and solTNFR2 were elevated among the COVID-19 patients (p < 0.0001), without increasing the transcriptional level. Only solTNFR1 was higher in the severe group as compared to the mildly ill (p < 0.01), and the level was higher in COVID-19 patients who died than those that survived (p < 0.0001). The solTNFR1 level had a discrete negative correlation with C-reactive protein (p = 0.006, Rho = −0.33). The solADAM17 level was higher in severe as compared to mild disease conditions (p < 0.01), as well as in COVID-19 patients who died as compared to those that survived (p < 0.001). Additionally, a potential association between polymorphism TNFRSF1A:rs767455 and a severe degree of disease was suggested. These data suggest that solTNFR1 and solADAM17 are increased in severe conditions. solTNFR1 should be considered a potential target in the development of new therapeutic options.
Women’s reproduction, including conception, pregnancy, childbirth, breastfeeding, and other physical acts of motherhood (as well as the rejection of those roles), played a critical role in the ...evolution and management of Cuba’s population. While existing scholarship has approached Cuba’s demographic history through the lens of migration, both forced and voluntary, Race and Reproduction in Cuba challenges this male-normative perspective by centering women in the first book-length history of reproduction in Cuba.
Bonnie A. Lucero traces women’s reproductive lives, as well as key medical, legal, and institutional interventions influencing them, over four centuries. Her study begins in the early colonial period with the emergence of the island’s first charitable institutions dedicated to relieving poor women and abandoned white infants. The book’s centerpiece is the long nineteenth century, when elite interventions in women’s reproduction hinged not only on race but also legal status. It ends in 1965 when Cuba’s nascent revolutionary government shifted away from enforcing antiabortion laws that had historically targeted impoverished women of color.
Questioning how elite demographic desires—specifically white population growth and nonwhite population management—shaped women’s reproduction, Lucero argues that elite men, including judges, physicians, philanthropists, and public officials, intervened in women’s reproductive lives in racially specific ways. Lucero examines how white supremacy shaped tangible differences in the treatment of women and their infants across racial lines and outlines how those reproductive outcomes were crucial in sustaining racial hierarchies through moments of tremendous political, economic, and social change.
Statistical downscaling methods are popular post-processing tools which are widely used in many sectors to adapt the coarse-resolution biased outputs from global climate simulations to the ...regional-to-local scale typically required by users. They range from simple and pragmatic Bias Correction (BC) methods, which directly adjust the model outputs of interest (e.g. precipitation) according to the available local observations, to more complex Perfect Prognosis (PP) ones, which indirectly derive local predictions (e.g. precipitation) from appropriate upper-air large-scale model variables (predictors). Statistical downscaling methods have been extensively used and critically assessed in climate change applications; however, their advantages and limitations in seasonal forecasting are not well understood yet. In particular, a key problem in this context is whether they serve to improve the forecast quality/skill of raw model outputs beyond the adjustment of their systematic biases. In this paper we analyze this issue by applying two state-of-the-art BC and two PP methods to downscale precipitation from a multimodel seasonal hindcast in a challenging tropical region, the Philippines. To properly assess the potential added value beyond the reduction of model biases, we consider two validation scores which are not sensitive to changes in the mean (correlation and reliability categories). Our results show that, whereas BC methods maintain or worsen the skill of the raw model forecasts, PP methods can yield significant skill improvement (worsening) in cases for which the large-scale predictor variables considered are better (worse) predicted by the model than precipitation. For instance, PP methods are found to increase (decrease) model reliability in nearly 40% of the stations considered in boreal summer (autumn). Therefore, the choice of a convenient downscaling approach (either BC or PP) depends on the region and the season.
Staphylococcal enterotoxin B (SEB) is a protein produced by
, which is toxic to humans. It is well known for its ability to stimulate the exacerbated activation of proinflammatory CD4+ T cells (Th1 ...profile), and in vitro studies have been conducted to understand its mechanism of action and its potential use as an immune therapy. However, the efficiency of the SEB1741 aptamer in blocking SEB has not been experimentally demonstrated.
Enrichment CD4+ T cells were stimulated with SEB, and as a blocker, we used the SEB1741 aptamer, which was previously synthesised by an "in silico" analysis, showing high affinity and specificity to SEB. The efficiency of the SEB1741 aptamer in blocking CD4+ T cell activation was compared with that of an anti-SEB monoclonal antibody. Flow cytometry and Bio-Plex were used to evaluate the T-cell function.
In vitro, SEB induced the activation of CD4+ T cells and favoured a Th1 profile; however, the SEB1741 aptamer was highly efficient in decreasing the frequency of CD4+ T cells positive to ki-67 and CD69 cells, this means that proliferation and activation of CD4+ T cells was decreased. Moreover, the production of interleukin 2 (IL-2) and interferon-gamma (IFN-γ) was affected, suggesting that the Th1 profile is not present when the SEB1441 aptamer is used. Thus, the SEB1741 function was similar to that of anti-SEB.
The SEB1741 aptamer is a valuable tool for blocking CD4+ T cell activation and the subsequent release of proinflammatory cytokines by SEB stimulation.
Platelets play a major role in coagulation and hemostasis; evidence supports the hypothesis that they also contribute to immunological processes. Increased platelet counts have been associated with ...poor prognosis in tuberculosis (TB). Platelet–monocyte aggregates have been reported in patients with TB, but it is still unclear if only one monocyte subpopulation is correlated to the platelet count; moreover, the platelet–monocyte axis has not been studied during latent tuberculosis (LTB). In this study, mononuclear cells and plasma were obtained from patients diagnosed with active drug-sensitive TB (DS-TB, n = 10) and LTB (n = 10); cytokines and growth factors levels associated to platelets were evaluated, and correlations with monocyte subpopulations were performed to identify a relationship between them, as well as an association with the degree of lung damage. Our data showed that, compared to LTB, DS-TB patients had an increased frequency of platelets, monocytes, and neutrophils. Although DS-TB patients showed no significant difference in the frequency of classical and non-classical monocytes, the classical monocytes had increased CD14 intensity of expression and frequency of TLR-2+. Furthermore, the plasma levels of angiogenic factors such as vascular endothelial growth factor (VEGF-A), platelet-derived growth factor (PDGF-BB), and platelet factor-4 (PF4), and pro-inflammatory cytokines like interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and interferon-γ-inducible protein 10 (IP-10) were increased in DS-TB patients. In addition, PF-4 and VEGF-A correlated positively with the frequency of classical monocytes and the platelet count. Using a principal component analysis, we identified four groups of DS-TB patients according to their levels of pro-inflammatory cytokines, angiogenic factors, and degree of lung damage. This study establishes that there is a correlation between VEGF-A and PF4 with platelets and classical monocytes during active TB, suggesting that those cell subpopulations are the major contributors of these molecules, and together, they control the severity of lung damage by amplification of the inflammatory environment.
The PDZ (PSD95, Dlg and ZO-1) genes encode proteins that primarily function as scaffolds of diverse signaling pathways. To date, 153 PDZ genes have been identified in the human genome, most of which ...have multiple protein isoforms widely studied in epithelial and neural cells. However, their expression and function in immune cells have been poorly studied. Herein, we aimed to assess the transcriptional profiles of 83 PDZ genes in human macrophages (Mɸ) and dendritic cells (DCs) and changes in their relative expression during cell PRR stimulation. Significantly distinct PDZ gene transcriptional profiles were identified under different stimulation conditions. Furthermore, a distinct PDZ gene transcriptional signature was found in Mɸ and DCs under the same phagocytic stimuli. Notably, more than 40 PDZ genes had significant changes in expression, with potentially relevant functions in antigen-presenting cells (APCs). Given that several PDZ proteins are targeted by viral products, our results support that many of these proteins might be viral targets in APCs as part of evasion mechanisms. Our results suggest a distinct requirement for PDZ scaffolds in Mɸ and DCs signaling pathways activation. More assessments on the functions of PDZ proteins in APCs and their role in immune evasion mechanisms are needed.
One of the most paradoxical aspects of Cuban history is the coexistence of national myths of racial harmony with lived experiences of racial inequality. Here a historian addresses this issue by ...examining the ways soldiers and politicians coded their discussions of race in ideas of masculinity during Cuba's transition from colony to republic. Cuban insurgents, the author shows, rarely mentioned race outright. Instead, they often expressed their attitudes toward racial hierarchy through distinctly gendered language—revolutionary masculinity. By examining the relationship between historical experiences of race and discourses of masculinity, Lucero advances understandings about how racial exclusion functioned in a supposedly raceless society. Revolutionary masculinity, she shows, outwardly reinforced the centrality of color blindness to Cuban ideals of manhood at the same time as it perpetuated exclusion of Cubans of African descent from positions of authority.
Tuberculosis (TB) is a bacterial infection caused by
(
). B cells are the central mediator of the humoral response; they are responsible for producing antibodies in addition to mediating other ...functions. The role of the cellular response during the TB spectrum by B cells is still controversial.
In this study, we evaluated the distribution of the circulating B cell subsets in patients with active and latent TB (ATB and LTB, respectively) and how they respond to stimuli of protein or lipid from
Here, we show that ATB patients show an immune fingerprinting. However, patients with drug-sensitive- (DS-TB) or drug-resistant- (DR-TB) TB have altered frequencies of circulating B cells. DS-TB and DR-TB display a unique profile characterized by high systemic levels of IFN-γ, IL-10, IgG, IgG/IgM ratio, and total B cells. Moreover, B cells from DR-TB are less efficient in producing IL-10, and both DS-TB and DR-TB produce less IFN-γ in response to
antigens.
These results provide new insights into the population dynamics of the cellular immune response by B cells against
and suggest a fingerprinting to characterize the B-cell response on DR-TB.
New Findings
What is the central question of this study?
Continuous‐wave near‐infrared spectroscopy, coupled with venous and arterial occlusions, offers an economical, non‐invasive alternative to ...measuring skeletal muscle blood flow and oxygen consumption, but its reliability during exercise has not been established.
What is the main finding and its importance?
Continuous‐wave near‐infrared spectroscopy devices can reliably assess local skeletal muscle blood flow and oxygen consumption from the vastus lateralis in healthy, physically active adults. The patterns of response exhibited during exercise of varying intensity agree with other published results using similar methodologies, meriting potential applications in clinical diagnosis and therapeutic assessment.
Near‐infrared spectroscopy (NIRS), coupled with rapid venous and arterial occlusions, can be used for the non‐invasive estimation of resting local skeletal muscle blood flow (mBF) and oxygen consumption (mV̇O2), respectively. However, the day‐to‐day reliability of mBF and mV̇O2 responses to stressors such as incremental dynamic exercise has not been established. The aim of this study was to determine the reliability of NIRS‐derived mBF and mV̇O2 responses from incremental dynamic exercise. Measurements of mBF and mV̇O2 were collected in the vastus lateralis of 12 healthy, physically active adults seven men and five women; 25 (SD 6) years old during three non‐consecutive visits within 10 days. After 10 min rest, participants performed 3 min of rhythmic isotonic knee extension (one extension every 4 s) at 5, 10, 15, 20, 25 and 30% of maximal voluntary contraction (MVC), before four venous occlusions and then two arterial occlusions. The mBF and mV̇O2 increased proportionally with intensity from 0.55 to 7.68 ml min−1 (100 ml)−1 and from 0.05 to 1.86 ml O2 min−1 (100 g)−1, respectively up to 25% MVC, where they began to plateau at 30% MVC. Moreover, an mBF/mV̇O2 muscle oxygen consumption ratio of ∼5 was consistent for all exercise stages. The intraclass correlation coefficient for mBF indicated high to very high reliability for 10–30% MVC (0.82–0.9). There was very high reliability for mV̇O2 across all exercise stages (intraclass correlation coefficient 0.91–0.96). In conclusion, NIRS can reliably assess muscle blood flow and oxygen consumption responses to low‐ to moderate‐intensity exercise, meriting potential applications in clinical diagnosis and therapeutic assessment.
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