Search

A model of HIV replication is presented to explain why antiretroviral drugs do not completely eradicate the virus from the body. HIV replication may occur in bursts in various tissues and drugs can reduce the size of the burst but not completely abolish it.

Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.

Therapeutic proteins, including monoclonal antibodies, are typically manufactured using clonally derived, stable host cell lines, since consistent and predictable cell culture performance is highly desirable. However, selecting and preparing banks of stable clones takes considerable time, which inevitably extends overall development timelines for new therapeutics by delaying the start of subsequent activities, such as the scale‐up of manufacturing processes. In the context of the coronavirus disease 2019 (COVID‐19) pandemic, with its intense pressure for accelerated development strategies, we used a novel transposon‐based Leap‐In Transposase® system to rapidly generate high‐titer stable pools and then used them directly for large scale‐manufacturing of an anti‐severe acute respiratory syndrome coronavirus 2 monoclonal antibody under cGMP. We performed the safety testing of our non‐clonal cell bank, then used it to produce material at a 200L‐scale for preclinical safety studies and formulation development work, and thereafter at 2000L scale for supply of material for a Phase 1 clinical trial. Testing demonstrated the comparability of critical product qualities between the two scales and, more importantly, that our final clinical trial product met all pre‐set product quality specifications. The above expediated approach provided clinical trial material within 4.5 months, in comparison to 12–14 months for production of clinical trial material via the conventional approach. [ABSTRACT FROM AUTHOR]

Background: This study evaluated two risk pathways that may account for increases in child internalizing and externalizing problems during the COVID‐19 pandemic: one pathway operating through pre‐existing family vulnerability and a second pathway operating through disruption in family functioning occurring in response to the pandemic. We assessed family disruption and family functioning with measures of key family‐level and parenting dimensions, including family cohesion, conflict and routines, and parents' harsh discipline, lax discipline and warmth. In all models, pre‐pandemic parent emotional distress, financial strain and child maladjustment were included as covariates. Methods: The sample included 204 families, comprised of parents who had children (MAge = 4.17; 45.1% girls). Parents (MAge = 27.43) completed the first survey prior to COVID‐19 onset in the United States, a second survey after COVID‐19 onset in May 2020 and a third survey two weeks later. Results: Analyses were conducted in a model‐building fashion, first computing structural equation models for each family and parenting dimension separately, then advancing significant dimensions into one integrated model for the family‐level factors and a second model for parenting quality factors. Results provided more support for the family disruption hypothesis across all tests. In the family‐level domain, decreases in family cohesion and increases in family conflict each uniquely predicted subsequent child maladjustment. In the parenting domain, increases in harsh discipline and lax discipline each uniquely predicted subsequent child maladjustment. Family routines and parental warmth were not associated with child adjustment. However, parents' emotional distress prior to the pandemic exhibited a robust association with children's internalizing problems. Conclusions: These findings indicate that efforts to support families in adapting to unique conditions of the pandemic will yield the greatest effect for child adjustment. Specifically, interventions should include efforts to help families maintain cohesion and manage conflict, and help parents minimize increases in harsh and lax discipline. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpression inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutralization improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity. [ABSTRACT FROM AUTHOR]

The ability of the thymus to reconstitute T cells expressing CD4 cell-surfaces antigens, lost during HIV infection, may be affected by age-related involution. Thymic output has been quantified through measurements of the excisional DNA products of TCR-gene rearrangement. Thymic function was found to decline with age, but considerable output is maintained into late adulthood.

CD[4.sup.+] T cell activation, required for virus replication in these cells, occurs in local microenvironmental domains in transient bursts. Thus, although most HIV originates from short-lived virus-producing cells, it is unlikely that chronic infection is generally sustained in rapid continuous cycles of productive infection as has been proposed. Such continuity of productive infection cycles would depend on efficient long-range transmission of HIV from one set of domains to another, in turn requiring the maintenance of sufficiently high concentrations of cell-free virus across lymphoid tissues at all times. By contrast, long-lived cellular sources of HIV maintain the capacity to infect newly activated cells at close range despite the temporal and spatial discontinuities of activation events. Such proximal activation and transmission (PAT) involving chronically and latently infected cells may be responsible for sustained infection, particularly when viral loads are low. Once CD4 cells are productively infected through PAT, they can infect other activated cells in their immediate vicinity. Such events propagate locally but generally do not spread systemically, unlike in the acute phase of the infection, because of the early establishment of protective anergy. Importantly, antiretroviral drug treatment is likely to differentially impact long-range transmission and PAT.

The purpose of our study was to examine how parental stress and coparenting relationship quality were related to dating violence perpetration and victimization among 114 Latinx adolescent mothers. We hypothesized that higher levels of parental stress and lower coparenting quality would be associated with increased dating violence perpetration and victimization. Prior to running a path analysis to test our hypotheses, we examined how frequently the Latinx adolescent mothers in our sample reported perpetrating at least one act of psychological or physical abuse against their partner in the past month. We found that 84.3% of the mothers in our study had perpetrated at least one act of violence against their partner in the past month and 74.7% reported they had been the victim of at least one act of violence by their partner in the past month. After accounting for frequency of contact with the father of their child, we found Latinx adolescent mothers were more likely to perpetrate abuse against, as well as be the victim of abuse by, their partner if they had a lower quality coparenting relationship. However, parental stress was not associated with dating violence perpetration or victimization after accounting for frequency of contact. Our findings show the importance of the quality of the coparenting relationship, above and beyond parental stress, as a predictor of dating violence victimization and perpetration, thus highlighting the importance of educating adolescent parents about how to navigate the coparenting relationship. [ABSTRACT FROM AUTHOR]