Dostoevsky and Tolstoy are the titans of Russian literature. As mature artists, they led very different lives and wrote vastly different works, but their early lives and writings display provocative ...kinships, while also indicating the divergent paths the two authors would take en route to literary greatness. The ten new critical essays here, written by leading specialists in nineteenth-century Russian literature, give fresh, sophisticated readings to works from the first decade of the literary life of each Russian author—for Dostoevsky, the 1840s; for Tolstoy, the 1850s. Collectively, these essays yield composite portraits of these two artists as young men finding their literary way. At the same time, they show how the early works merit appreciation for themselves, before their authors were Titans.
Autophagy in animal development Allen, Elizabeth A; Baehrecke, Eric H
Cell death and differentiation,
03/2020, Letnik:
27, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Macroautophagy (autophagy) delivers intracellular constituents to the lysosome to promote catabolism. During development in multiple organisms, autophagy mediates various cellular processes, ...including survival during starvation, programmed cell death, phagocytosis, organelle elimination, and miRNA regulation. Our current understanding of autophagy has been enhanced by developmental biology research during the last quarter of a century. Through experiments that focus on animal development, fundamental mechanisms that control autophagy and that contribute to disease were elucidated. Studies in embryos revealed specific autophagy molecules that mediate the removal of paternally derived mitochondria, and identified autophagy components that clear protein aggregates during development. Importantly, defects in mtDNA inheritance, or removal of paternal mtDNA via mitochondrial autophagy, can contribute to mitochondrial-associated disease. In addition, impairment of the clearance of protein aggregates by autophagy underlies neurodegenerative diseases. Experiments in multiple organisms also reveal conserved mechanisms of tissue remodeling that rely on the cooperation between autophagy and apoptosis to clear cell corpses, and defects in autophagy and apoptotic cell clearance can contribute to inflammation and autoimmunity. Here we provide an overview of key developmental processes that are mediated by autophagy in multiple animals.
Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for ...this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019
and is responsible for the coronavirus disease 2019 (COVID-19) pandemic
. Vaccines are an essential ...countermeasure and are urgently needed to control the pandemic
. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime-boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.
Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine ...modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1
CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.
Inhibitors of VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) are commonly used in the clinic, but their beneficial effects are only observed in a ...subset of patients and limited by induction of diverse relapse mechanisms. We describe the up-regulation of an adaptive immunosuppressive pathway during antiangiogenic therapy, by which PD-L1 (programmed cell death ligand 1), the ligand of the negative immune checkpoint regulator PD-1 (programmed cell death protein 1), is enhanced by interferon-γ-expressing T cells in distinct intratumoral cell types in refractory pancreatic, breast, and brain tumor mouse models. Successful treatment with a combination of anti-VEGFR2 and anti-PD-L1 antibodies induced high endothelial venules (HEVs) in PyMT (polyoma middle T oncoprotein) breast cancer and RT2-PNET (Rip1-Tag2 pancreatic neuroendocrine tumors), but not in glioblastoma (GBM). These HEVs promoted lymphocyte infiltration and activity through activation of lymphotoxin β receptor (LTβR) signaling. Further activation of LTβR signaling in tumor vessels using an agonistic antibody enhanced HEV formation, immunity, and subsequent apoptosis and necrosis in pancreatic and mammary tumors. Finally, LTβR agonists induced HEVs in recalcitrant GBM, enhanced cytotoxic T cell (CTL) activity, and thereby sensitized tumors to antiangiogenic/anti-PD-L1 therapy. Together, our preclinical studies provide evidence that anti-PD-L1 therapy can sensitize tumors to antiangiogenic therapy and prolong its efficacy, and conversely, antiangiogenic therapy can improve anti-PD-L1 treatment specifically when it generates intratumoral HEVs that facilitate enhanced CTL infiltration, activity, and tumor cell destruction.
BACKGROUND:Although the Affordable Care Act has been successful in expanding Medicaid to >17 million people, insurance alone may not translate into access to health care. Even among the insured, ...substantial barriers to accessing services inhibit health care utilization.
OBJECTIVES:We examined the effect of selected barriers to health care access and the magnitude of those barriers on health care utilization.
RESEARCH DESIGN:Data come from a 2008 survey of adult enrollees in Minnesota’s public health care programs. We used multivariate logistic regression to estimate the effects of perceived patient, provider, and system-level barriers on past year delayed, foregone, and lack of preventive care.
SUBJECTS:A total of 2194 adults enrolled in Minnesota Health Care Programs who were mostly female (66%), high school graduates (76%), unemployed (62%), and living in metro areas (67%) were included in the analysis.
RESULTS:Reporting problems across all barriers increased the odds of delayed care from 2 times for provider-related barriers (OR=2.0; 95% CI, 1.2–3.3) to >6 times for access barriers (OR=6.2; 95% CI, 3.8–10.2) and foregone care from 2.6 times for family/work barriers (OR=2.6; 95% CI, 1.3–5.1) to >7 times for access barriers (OR=7.1; 95% CI, 3.9–13.1). Perceived discrimination was the only barrier consistently associated with all 3 utilization outcomes.
CONCLUSIONS:Multiple types of barriers are associated with delayed and foregone care. System-level barriers and discrimination have the greatest effect on health care seeking behavior.
•Partners accommodate PTSD by changing their behaviors in response to symptoms.•We investigated links between accommodation and partner distress over time.•PTSD symptoms predict increases in partner ...depression through accommodation.•Partners who accommodate more are more depressed if accommodating to avoid conflict.•Partners who accommodate more are less relationally satisfied.
Romantic partners’ accommodation of trauma survivors’ posttraumatic stress disorder (PTSD) symptoms (e.g., participating in avoidance and safety behaviors, not expressing one’s thoughts and feelings) is a putative mechanism linking PTSD symptoms and partner distress, but this hypothesis has never been empirically tested. The current study investigated this proposed within-couple mediation process from service members’ PTSD symptoms to partners’ depressive symptoms and relationship satisfaction through partner accommodation, as well as between-couple associations among these constructs and the possible moderating role of partners’ conflict avoidance and helplessness (CAH) motivations for accommodating service members’ PTSD symptoms. We examined these questions in 272 male service member/female civilian couples assessed four times over an 18-month period using the multiple-group version of the random intercept cross-lagged panel model. Within couples, service members’ higher levels of PTSD symptoms at one time point significantly predicted partners being more accommodating at the next time point (βs = .14–.19), which, in turn, significantly predicted higher levels of partner depressive symptoms at the subsequent time point (βs = .09–.19) but did not predict partners’ subsequent relationship satisfaction. At the between-couple level, partner accommodation was significantly positively associated with partners’ depressive symptoms only among those endorsing high CAH motivations for accommodation (r = .50). In addition, accommodation was significantly negatively associated with partners’ relationship satisfaction regardless of CAH motivation level (rs = −.43 to −.49). These findings are discussed in light of the potential for couple-based treatments for PTSD to enhance partner individual and relational well-being.
A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 ...full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 μg and 10 μg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.
Display omitted
The LUNAR-COV19 SARS-CoV-2 vaccine is a self-replicating RNA-based vaccine that increases antigen expression and also duration of expression. This increased antigen expression combined with the self-activation of the innate immune system produces a low-single-dose vaccine that yields protective immunity against SARS-CoV-2 virus infection.
In the context of service member posttraumatic stress disorder (PTSD) symptoms, intimate partners may experience pressure to take over parenting roles and run interference between the service member ...and the children; that is, to engage in partner accommodation focal to parenting. The current study quantitatively assessed potential pressures to engage in parenting accommodation (PPEPA) in a sample of 207 female partners married to male service members with at least one child in the home and the convergence of PPEPA with service member PTSD symptoms, general partner accommodation, couple functioning, parenting, and child functioning. Partners' reports of PPEPA were associated with higher levels of service member PTSD symptoms and partners' general accommodation of PTSD symptoms. When controlling for service member PTSD symptoms and general partner accommodation, partner reports of PPEPA still accounted for unique variance in lower parenting alliance (as reported by both service member and partner), lower levels of service members' reports of closeness with children in the home, higher levels of harsh parenting by both the service member and partner, and greater child behavioral difficulties. Findings support PPEPA as related to partners' accommodative responses to PTSD but demonstrating unique associations with parenting alliance, parenting, and child outcomes. Parenting interventions in the context of PTSD may benefit from conjoint or family approaches that attend to the intersection of PTSD and broader family functioning, including pressures to engage in accommodation focal to the parenting domain.
PDF
