Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression.

The impact of regulatory T cells (T reg cells) on the course of HIV and SIV disease is unknown. T reg cells could suppress protective antiviral responses and accelerate disease progression. Alternatively, these cells might block T cell activation and thereby limit viral replication as well as activation-associated immunopathology. Given the higher frequency of T reg cells known to be present during human fetal ontogeny, such influences may be most important in the context of perinatal infection. We found that infant macaques had higher fractions of CD4(+)CD25(+)CD127(low)FoxP3(+) T reg cells in the peripheral blood and in lymphoid tissues, and that these T reg cells showed greater in vitro suppressive activity on a per cell basis. Infant and adult macaques were infected with SIVmac251 to test the influence of the T reg cell compartment on SIV-specific immune responses. After infection with SIV, most (three out of four) infant macaques had persistently high viral loads, weak and transient SIV-specific CD4(+) and CD8(+) T cell responses, and rapid disease progression. T reg cells in the infant but not in the adult directly suppressed SIV-specific CD4(+) T cell responses, which were detectable only after depletion of T reg cells. In the case of both the infant and the adult macaque, T reg cells were not able to directly suppress SIV-specific CD8(+) T cell responses and had no apparent effect on T cell activation. In aggregate, these observations suggest that the T reg cell compartment of the infant macaque facilitates rapid disease progression, at least in part by incapacitating SIV-specific CD4(+) T cell responses

Teilhabeorientiert lehren und lernen: ein Seminar zur Anbahnung professions-spezifischer digitaler Kompetenzen in DaF und DaZ an der Universität Augsburg

Der klassische DaF-Unterricht wird zunehmend durch die Verwendung von mobilen Geräten, digitalen Kommunikationstools, durch Distanzlernen, digitale Eins-zu-eins-Betreuungen u.a. ergänzt. Die fachdidaktische Ausbildung angehender DaF- (und DaZ-)Lehrpersonen versucht, standortspezifisch nicht allein mit diesen Entwicklungen Schritt zu halten, sondern sie auch aktiv mitzugestalten und professionsspezifisch digitale Kompetenzen bei angehenden DaF/DaZ-Lehrpersonen zu entwickeln. Im folgenden Beitrag wird über eine kooperative und fachdidaktische Lehrveranstaltung zur Anbahnung digitaler Kompetenzen bei DaF- und DaZ-Studierenden berichtet, in der Studierende die Gelegenheit haben, professionsspezifische digitale Kompetenzen zu erwerben und dabei zu lernen, wie zweit- und fremdsprachliche Lernprozesse digital, kooperativ und teilhabeorientiert unterstützt werden können. Dabei spielen die Verzahnung von Theorie und Praxis sowie die Reflexion des eigenen Kompetenzerwerbs eine wichtige Rolle.Traditional GFL teaching is increasingly complemented by the use of mobile devices, digital communication tools, distance learning or digital one-to-one tutoring etc. The subject-specific didactic training of prospective GFL (and GDL) teachers tries not only to keep pace with these developments site-specifically, but also to actively shape them and to develop profession-specific digital competencies in prospective GFL/GSL teachers. In this paper, we report on a cooperative and subject-specific didactic course to initiate digital competencies among GFL and GSL students, in which bachelor students and teacher trainees have the opportunity to acquire profession-specific digital competencies and learn how second and foreign language learning processes can be supported digitally, cooperatively, and in a participatory manner. The connection of theory and practice as well as the reflection of one's own competence development play an important role

The Early Interferon Alpha Subtype Response in Infant Macaques Infected Orally With SIV

Type I interferons play an important role in the early defense against viral and other pathogens. These innate responses are also critically important in shaping the subsequent adaptive response. Thus, a more thorough knowledge of innate response types and mechanisms will improve our understanding of pathogenesis and guide the development of new therapeutics

Co-reminiscing with a caregiver about a devastating tornado: Association with adolescent anxiety symptoms

This study explores the association between caregivers’ style of co-reminiscing with their adolescents about an EF4 tornado and youth anxiety symptoms several years following the disaster. Caregiver reward of their children’s emotional expression, defined as attending to and validating emotionally salient content, is generally associated with adaptive youth psychosocial outcomes. However, caregiver reward of youth recollections that are centered around the youth’s negative emotional expression could be an indicator that both caregivers and adolescents are engaged in co-rumination regarding negative emotional experiences. This process may contribute to relatively higher levels of anxiety over time. Adolescents (N = 169) drawn from an ongoing study for aggressive youth (ages 12 to 17; 82% African American) provided individual recollections about their experiences during a devastating tornado 4 to 5 years following the disaster. Caregivers and youth then co-reminisced about their tornado-related experiences. Individual youth recollections were coded for negative personal impact and use of negative emotion words; caregiver–adolescent conversations were coded for caregiver reward of negative emotional expression. Youth who noted more negative personal impacts and used more negative emotion words were higher in parent-rated youth anxiety, and these associations were moderated by caregiver reward of negative emotional expression. The associations between youth recollection qualities and anxiety emerged only when caregivers exhibited high levels of reward of negative emotional expression. These patterns were generally stronger for girls compared to boys. Findings suggest that excessively discussing and rehashing negative experiences, especially several years after the disaster, may be a risk factor for anxiety among disaster-exposed adolescents

Use of specific-pathogen-free (SPF) rhesus macaques to better model oral pediatric cytomegalovirus infection

Congenital human cytomegalovirus (HCMV) infection can result in lifelong neurological deficits. Seronegative pregnant woman often acquire primary HCMV from clinically asymptomatic, but HCMV-shedding children. Potential age-related differences in viral and immune parameters of primary RhCMV infection were examined in an oral rhesus CMV infection model in specific pathogen free macaques

Guanine Nucleotide Exchange Factor Vav1 Regulates Perivascular Homing and Bone Marrow Retention of Hematopoietic Stem and Progenitor Cells

Engraftment and maintenance of hematopoietic stem and progenitor cells (HSPC) depend on their ability to respond to extracellular signals from the bone marrow microenvironment, but the critical intracellular pathways integrating these signals remain poorly understood. Furthermore, recent studies provide contradictory evidence of the roles of vascular versus osteoblastic niche components in HSPC function. To address these questions and to dissect the complex upstream regulation of Rac GTPase activity in HSPC, we investigated the role of the hematopoietic-specific guanine nucleotide exchange factor Vav1 in HSPC localization and engraftment. Using intravital microscopy assays, we demonstrated that transplanted $Vav1^{−/−}$ HSPC showed impaired early localization near $nestin^+$ perivascular mesenchymal stem cells; only 6.25% of $Vav1^{−/−}$ HSPC versus 45.8% of wild-type HSPC were located less than 30 μm from a $nestin^+$ cell. Abnormal perivascular localization correlated with decreased retention of $Vav1^{−/−}$ HSPC in the bone marrow (44–60% reduction at 48 h posttransplant, compared with wild-type) and a very significant defect in short- and long-term engraftment in competitive and noncompetitive repopulation assays (<1.5% chimerism of $Vav1^{−/−}$ cells vs. 53–63% for wild-type cells). The engraftment defect of $Vav1^{−/−}$ HSPC was not related to alterations in proliferation, survival, or integrin-mediated adhesion. However, $Vav1^{−/−}$ HSPC showed impaired responses to $SDF1\alpha$, including reduced in vitro migration in time-lapse microscopy assays, decreased circadian and pharmacologically induced mobilization in vivo, and dysregulated Rac/Cdc42 activation. These data suggest that Vav1 activity is required specifically for $SDF1\alpha$-dependent perivascular homing of HSPC and suggest a critical role for this localization in retention and subsequent engraftment

Reduction of pyramidal and immature hippocampal neurons in pediatric simian immunodeficiency virus infection

Pediatric HIV infection remains a global health crisis with a worldwide infection rate of 2.5 million (WHO, Geneva Switzerland, 2009). Children are much more susceptible to HIV-1 neurological impairments than adults, which is exacerbated by co-infections. A major obstacle in pediatric HIV research is sample access. The proposed studies take advantage of ongoing pediatric SIV pathogenesis and vaccine studies to test the hypothesis that pediatric SIV infection diminishes neuronal populations and neurogenesis in the hippocampus. Newborn rhesus macaques (Macaca mulatta) that received intravenous inoculation of highly virulent SIVmac251 (n=3) or vehicle (control n=4) were used in this study. After a 6–18 week survival time, the animals were sacrificed and the brains prepared for quantitative histopathological analysis. Systematic sections through the hippocampus were either Nissl stained or immunostained for doublecortin (DCX+), a putative marker of neurogenesis. Using design-based stereology, we report a 42% reduction in the pyramidal neuron population of the CA1, CA2, and CA3 fields of the hippocampus (p < 0.05) in SIV-infected infants. The DCX+ neuronal population was also significantly reduced within the dentate gyrus of the hippocampus. The loss of hippocampal neurons and neurogenic capacity may contribute to the rapid neurocognitive decline associated with pediatric HIV infection. These data suggest that pediatric SIV infection, which leads to significant neuronal loss in the hippocampus within 3 months, closely models a subset of pediatric HIV infections with rapid progression

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses.

Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Various tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolomics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from eleven clear cell renal cell carcinoma (ccRCC) patients. COSMOS was able to capture relevant crosstalks within and between multiple omics layers, such as known ccRCC drug targets. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies

Compared to Subcutaneous Tenofovir, Oral Tenofovir Disoproxyl Fumarate Administration Preferentially Concentrates the Drug into Gut-Associated Lymphoid Cells in Simian Immunodeficiency Virus-Infected Macaques

ABSTRACT To compare tissue-based pharmacokinetics and efficacy of oral tenofovir disoproxyl fumarate (TDF) versus subcutaneous tenofovir (TFV), macaques were treated for 2 weeks starting 1 week after simian immunodeficiency virus inoculation. Despite lower plasma TFV levels in the oral TDF arm, similar TFV diphosphate levels and antiviral activities were measured in lymphoid cells of most tissues. In intestinal tissues, however, oral TDF resulted in higher active drug levels, associated with lower virus levels and better immune preservation