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During morphogenesis, molecular mechanisms that orchestrate biomechanical dynamics across cells remain unclear. Here, we show a role of guidance receptor Plexin-B2 in organizing actomyosin network and adhesion complexes during multicellular development of human embryonic stem cells and neuroprogenitor cells. Plexin-B2 manipulations affect actomyosin contractility, leading to changes in cell stiffness and cytoskeletal tension, as well as cell-cell and cell-matrix adhesion. We have delineated the functional domains of Plexin-B2, RAP1/2 effectors, and the signaling association with ERK1/2, calcium activation, and YAP mechanosensor, thus providing a mechanistic link between Plexin-B2-mediated cytoskeletal tension and stem cell physiology. Plexin-B2-deficient stem cells exhibit premature lineage commitment, and a balanced level of Plexin-B2 activity is critical for maintaining cytoarchitectural integrity of the developing neuroepithelium, as modeled in cerebral organoids. Our studies thus establish a significant function of Plexin-B2 in orchestrating cytoskeletal tension and cell-cell/cell-matrix adhesion, therefore solidifying the importance of collective cell mechanics in governing stem cell physiology and tissue morphogenesis. Biomechanical mechanisms orchestrating stem cell dynamics in development remain unclear. Here the authors show that guidance receptor Plexin-B2 organizes actomyosin contractility, cytoskeletal tension and adhesion during multicellular development of human embryonic stem cells and neuroprogenitor cells.

Abstract Family-based treatment (FBT) has emerged as a promising approach for medically stable youth with anorexia nervosa (AN). While there is evidence that therapists embrace the core principles of FBT, most face barriers in implementing the model with fidelity. Little research has been conducted to determine whether adhering to the core methods of placing parents in charge are sufficient in restoring weight in youth with AN. This study involved a chart review of youth under 16 years of age, treated by a Canadian tertiary care health centre-based eating disorders team (EDT). The purpose was to compare the weight gain of youth treated before and after the team was trained in FBT and shifted to empowering parents to be in charge of weight gain. As predicted, youth who participated in family sessions adhering to the ‘parents in charge’ approach (PIC, N=32) made greater gains in percentage of ideal body weight (%IBW) and were more likely to reach body weights within a healthy range as compared with youth (N=14) who participated in a ‘non-specific therapy’ (NST) involving expert driven psycho-educational family sessions. Youth whose parents were placed in charge of weight gain were also significantly less likely to be hospitalized on the psychiatry unit for weight restoration, had significantly shorter mean duration of stays on this unit, and required tube-feeding less frequently than youth who participated in NST. Collectively, the results suggest that placing parents in charge of refeeding promotes efficient weight gain, while decreasing the need for more intensive intervention.

Background In eating disorders (EDs), treatment outcome measurement has traditionally focused on symptom reduction rather than functioning or quality of life (QoL). The Eating Disorders Quality of Life Scale (EDQLS) was recently developed to allow for measurement of broader outcomes. We examined responsiveness of the EDQLS in a longitudinal multi-site study. Methods The EDQLS and comparator generic QoL scales were collected in person at baseline, and 3 and 6 months from 130 participants (mean age 25.6 years; range 14-60) in 12 treatment programs in four Canadian provinces. Total score differences across the time points and responsiveness were examined using both anchor- and distribution-based methods. Results 98 (75%) and 85 (65%) responses were received at 3 and 6 months respectively. No statistically significant differences were found between the baseline sample and those lost to follow-up on any measured characteristic. Mean EDQLS total scores increased from 110 (SD = 24) to 124.5 (SD = 29) at 3 months and 129 (SD = 28) at 6 months, and the difference by time was tested using a general linear model (GLM) to account for repeated measurement (p < .001). Responsiveness was good overall (Cohen's d = .61 and .80), and confirmed using anchor methods across 5 levels of self-reported improvement in health status (p < .001). Effect sizes across time were moderate or large for for all age groups. Internal consistency (Chronbach's alpha=.96) held across measurement points and patterns of responsiveness held across subscales. EDQLS responsiveness exceeded that of the Quality of Life Inventory, the Short Form-12 (mental and physical subscales) and was similar to the 16-dimension quality of life scale. Conclusions The EDQLS is responsive to change in geographically diverse and clinically heterogeneous programs over a relatively short time period in adolescents and adults. It shows promise as an outcome measure for both research and clinical practice.

HIV-associated nephropathy is a clinicopathologic entity that includes proteinuria, focal segmental glomerulosclerosis often of the collapsing variant, and microcystic tubulointerstitial disease. Increasing evidence supports a role for HIV-1 infection of renal epithelium in the pathogenesis of HIV-associated nephropathy. Using in situ hybridization, we previously demonstrated HIV-1 gag and nef mRNA in renal epithelial cells of patients with HIV-associated nephropathy. Here, to investigate whether renal epithelial cells were productively infected by HIV-1, we examined renal tissue for the presence of HIV-1 DNA and mRNA by in situ hybridization and PCR, and we molecularly characterized the HIV-1 quasispecies in the renal compartment. Infected renal epithelial cells were removed by laser-capture microdissection from biopsies of two patients, DNA was extracted, and HIV-1 V3-loop or gp120-envelope sequences were amplified from individually dissected cells by nested PCR. Phylogenetic analysis of kidney-derived sequences as well as corresponding sequences from peripheral blood mononuclear cells of the same patients revealed evidence of tissue-specific viral evolution. In phylogenetic trees constructed from V3 and gp120 sequences, kidney-derived sequences formed tissue-specific subclusters within the radiation of blood mononuclear cell-derived viral sequences from both patients. These data, along with the detection of HIV-1-specific proviral DNA and mRNA in tubular epithelium cells, argue strongly for localized replication of HIV-1 in the kidney and the existence of a renal viral reservoir.

Interleukin 1 (IL-1) induces pleiotropic effects in many cell types during inflammation and immunity. We have recently shown how the IL-1 signal is transmitted to the nucleus: In T cells and in pituitary cells, IL-1 induced genes via activation of the nuclear factor AP-1. We now demonstrate how IL-1 activates the AP-1 factor in liver cells, which are a major target for IL-1 during the acute phase response in vivo. IL-1 induced gene transcription of both AP-1 components, c-jun and c-fos. IL-1 also increased the stability of c-jun mRNA. We define two enhancer sites in the jun promoter that are required for induction by IL-1. Although the binding sites share some similarity with the AP-1 binding site, the nuclear factors binding the jun motifs are not composed of Jun or Fos proteins. Thus these data identify two binding proteins that serve as one of the first nuclear targets for IL-1 signal transduction.

An HIV-1-based expression vector has been constructed that produces protective genes tightly regulated by HIV-1 Tat and Rev proteins. The vector contains either a single protective gene (HIV-1 gag dominant negative mutant (delta-gag)) or a combination of two different protective genes (delta-gag and eosinophil-derived neurotoxin (EDN), a human ribonuclease) which are expressed from a dicistronic mRNA. After stable transfection of CEM T cells and following challenge with HIV-1, viral production was completely inhibited in cells transduced with the vector producing both delta-gag and EDN and delayed in cells producing delta-gag alone. In addition, cotransfection of HeLa-Tat cells with an infectious HIV-1 molecular clone and either protective vector demonstrated that the HIV-1 packaging signals present in the constructs were functional and allowed the efficient assembly of the protective RNAs into HIV-1 virions, thus potentially transmitting protection to the HIV-1 target cells.

In eating disorders (EDs), treatment outcome measurement has traditionally focused on symptom reduction rather than functioning or quality of life (QoL). The Eating Disorders Quality of Life Scale (EDQLS) was recently developed to allow for measurement of broader outcomes. We examined responsiveness of the EDQLS in a longitudinal multi-site study. The EDQLS and comparator generic QoL scales were collected in person at baseline, and 3 and 6 months from 130 participants (mean age 25.6 years; range 14-60) in 12 treatment programs in four Canadian provinces. Total score differences across the time points and responsiveness were examined using both anchor- and distribution-based methods. 98 (75%) and 85 (65%) responses were received at 3 and 6 months respectively. No statistically significant differences were found between the baseline sample and those lost to follow-up on any measured characteristic. Mean EDQLS total scores increased from 110 (SD = 24) to 124.5 (SD = 29) at 3 months and 129 (SD = 28) at 6 months, and the difference by time was tested using a general linear model (GLM) to account for repeated measurement (p [less than] .001). Responsiveness was good overall (Cohen's d = .61 and .80), and confirmed using anchor methods across 5 levels of self-reported improvement in health status (p [less than] .001). Effect sizes across time were moderate or large for for all age groups. Internal consistency (Chronbach's alpha=.96) held across measurement points and patterns of responsiveness held across subscales. EDQLS responsiveness exceeded that of the Quality of Life Inventory, the Short Form-12 (mental and physical subscales) and was similar to the 16-dimension quality of life scale. The EDQLS is responsive to change in geographically diverse and clinically heterogeneous programs over a relatively short time period in adolescents and adults. It shows promise as an outcome measure for both research and clinical practice.

Background Scleroderma (systemic sclerosis; SSc) is a clinically heterogeneous and often lethal acquired disorder of the connective tissue that is characterized by vascular, immune/inflammatory and fibrotic manifestations. Tissue fibrosis is the main cause of morbidity and mortality in SSc and an unmet medical challenge, mostly because of our limited understanding of the molecular factors and signalling events that trigger and sustain disease progression. Recent evidence has correlated skin fibrosis in SSc with stabilization of proto-oncogene Ha-Ras secondary to auto-antibody stimulation of reactive oxygen species production. The goal of the present study was to explore the molecular connection between Ha-Ras stabilization and collagen I production, the main read-out of fibrogenesis, in a primary dermal fibroblast culture system that replicates the early stages of disease progression in SSc. Results Forced expression of proto-oncogene Ha-Ras in dermal fibroblasts demonstrated the promotion of an immediate collagen I up-regulation, as evidenced by enhanced activity of a collagen I-driven luciferase reporter plasmid and increased accumulation of endogenous collagen I proteins. Moreover, normal levels of Tgfβ transcripts and active transforming growth factor-beta (TGFβ) implied Ha-Ras stimulation of the canonical Smad2/3 signalling pathway independently of TGFβ production or activation. Heightened Smad2/3 signalling was furthermore correlated with greater Smad3 phosphorylation and Smad3 protein accumulation, suggesting that Ha-Ras may target both Smad2/3 activation and turnover. Additional in vitro evidence excluded a contribution of ERK1/2 signalling to improper Smad3 activity and collagen I production in cells that constitutively express Ha-Ras. Conclusions Our study shows for the first time that constitutively elevated Ha-Ras protein levels can directly stimulate Smad2/3 signalling and collagen I accumulation independently of TGFβ neo-synthesis and activation. This finding therefore implicates the Ha-Ras pathway with the early onset of fibrosis in SSc and implicitly identifies new therapeutic targets in SSc.

3 studies were designed to examine the \"still-face\" paradigm, in which mothers stared at their 3- or 6-month-olds for a brief, still-face period interposed between 2 periods of normal face-to-face interaction. 6-month-olds decreased smiling and gazing at their mothers and grimaced more during the still-face period relative to the other periods; no period effects occurred in a no-change control group (Studies 1 and 2). Similar results were obtained when mothers and their infants observed and interacted with each other over closed-circuit color television monitors (Study 3). Moreover, the same relative decline in the infants' visual attention and positive affect during the still-face period occurred to a change in mothers' facial display (a televised, prerecorded, still face vs. a televised, live, interacting face) regardless of the presence or absence of their interactive voices (sound on the infants' monitor turned on or off). 3-month-olds exhibited a significant still-face effect, but only when maternal touch was a part of the manipulation (Study 1 vs. 2); therefore, the televised procedure was not conducted. The still-face effect is a robust phenomenon, produced with either \"live\" or \"televised\" procedures, both of which offer promising techniques for examining models of socioemotional perception/understanding of infants.3 studies were designed to examine the \"still-face\" paradigm, in which mothers stared at their 3- or 6-month-olds for a brief, still-face period interposed between 2 periods of normal face-to-face interaction. 6-month-olds decreased smiling and gazing at their mothers and grimaced more during the still-face period relative to the other periods; no period effects occurred in a no-change control group (Studies 1 and 2). Similar results were obtained when mothers and their infants observed and interacted with each other over closed-circuit color television monitors (Study 3). Moreover, the same relative decline in the infants' visual attention and positive affect during the still-face period occurred to a change in mothers' facial display (a televised, prerecorded, still face vs. a televised, live, interacting face) regardless of the presence or absence of their interactive voices (sound on the infants' monitor turned on or off). 3-month-olds exhibited a significant still-face effect, but only when maternal touch was a part of the manipulation (Study 1 vs. 2); therefore, the televised procedure was not conducted. The still-face effect is a robust phenomenon, produced with either \"live\" or \"televised\" procedures, both of which offer promising techniques for examining models of socioemotional perception/understanding of infants.

Mechanisms of dendritic cells (DCs) immunomodulation by parainfluenza viruses have not been characterized. We analyzed whether the human parainfluenza 3 (HPF3) virus hemagglutinin-neuraminidase glycoprotein (HN) might influence DC maturation. HN possesses a receptor binding function and a neuraminidase or desialidating activity. To assess whether the neuraminidase activity of HN affects DC maturation, human myeloid DCs were exposed to either live or UV-inactivated HPF3 viruses containing wild type or a mutated form of HN with decreased neuraminidase activity. Exposure of human DCs to either UV-inactivated or live virus induced up-regulation of CD83 and CD86 surface markers, morphological changes, and a cytokine expression pattern consistent with maturation. However, the level of maturation was found to be lower in DCs infected with the neuraminidase deficient variant as compared to the wild type. These results suggest that during the course of viral infection, HN's neuraminidase activity may play an important role contributing to maturation and activation of DCs.