Views and experiences of people with intellectual disabilities regarding intimate relationships: a qualitative metasynthesis

The aims of this review were to systematically identify, critically appraise and synthesize the results of existing qualitative literature exploring the views and experiences of intimate relationships amongst people with intellectual disabilities. Fourteen peer-reviewed articles were identified through a systematic search of eight databases, reference lists, citations, and relevant journals. The identified articles were appraised for quality, then synthesized using a metaethnography approach. No study met all quality criteria and references to ethical approval were often lacking. Interpretation of the findings suggested three key themes: the meaning of intimate relationships, external constraints and facilitators, and managing external constraints. Though many people with intellectual disabilities desire and benefit from intimate relationships, they experience restrictions that others do not, which can lead to isolation and loneliness. Intimate relationships are not always necessarily linked with sexual behavior; therefore, intimate relationships warrant their own focus in future research, as well as in education and training for people with intellectual disabilities and their caregivers. Within this, a commitment to transparency over research processes is needed, in particular with reference to how ethical approval was obtained, since this has been a shortcoming of research with this focus to date

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

Localised climate change defines ant communities in human‐modified tropical landscapes

Abstract: Logging and habitat conversion create hotter microclimates in tropical forest landscapes, representing a powerful form of localised anthropogenic climate change. It is widely believed that these emergent conditions are responsible for driving changes in communities of organisms found in modified tropical forests, although the empirical evidence base for this is lacking. Here we investigated how interactions between the physiological traits of genera and the environmental temperatures they experience lead to functional and compositional changes in communities of ants, a key organism in tropical forest ecosystems. We found that the abundance and activity of ant genera along a gradient of forest disturbance in Sabah, Malaysian Borneo, was defined by an interaction between their thermal tolerance (CTmax) and environmental temperature. In more disturbed, warmer habitats, genera with high CTmax had increased relative abundance and functional activity, and those with low CTmax had decreased relative abundance and functional activity. This interaction determined abundance changes between primary and logged forest that differed in daily maximum temperature by a modest 1.1°C, and strengthened as the change in microclimate increased with disturbance. Between habitats that differed by 5.6°C (primary forest to oil palm) and 4.5°C (logged forest to oil palm), a 1°C difference in CTmax among genera led to a 23% and 16% change in relative abundance, and a 22% and 17% difference in functional activity. CTmax was negatively correlated with body size and trophic position, with ants becoming significantly smaller and less predatory as microclimate temperatures increased. Our results provide evidence to support the widely held, but never directly tested, assumption that physiological tolerances underpin the influence of disturbance‐induced microclimate change on the abundance and function of invertebrates in tropical landscapes. A free Plain Language Summary can be found within the Supporting Information of this article

Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use

Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a “resistant” variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching

Modelling the Role of the Hsp70/Hsp90 System in the Maintenance of Protein Homeostasis

Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis

Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52–4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05–3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma

Efficient and Directive Generation of Two Distinct Endoderm Lineages from Human ESCs and iPSCs by Differentiation Stage-Specific SOX17 Transduction

The establishment of methods for directive differentiation from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) is important for regenerative medicine. Although Sry-related HMG box 17 (SOX17) overexpression in ESCs leads to differentiation of either extraembryonic or definitive endoderm cells, respectively, the mechanism of these distinct results remains unknown. Therefore, we utilized a transient adenovirus vector-mediated overexpression system to mimic the SOX17 expression pattern of embryogenesis. The number of alpha-fetoprotein-positive extraembryonic endoderm (ExEn) cells was increased by transient SOX17 transduction in human ESC- and iPSC-derived primitive endoderm cells. In contrast, the number of hematopoietically expressed homeobox (HEX)-positive definitive endoderm (DE) cells, which correspond to the anterior DE in vivo, was increased by transient adenovirus vector-mediated SOX17 expression in human ESC- and iPSC-derived mesendoderm cells. Moreover, hepatocyte-like cells were efficiently generated by sequential transduction of SOX17 and HEX. Our findings show that a stage-specific transduction of SOX17 in the primitive endoderm or mesendoderm promotes directive ExEn or DE differentiation by SOX17 transduction, respectively

Diversity, Loss, and Gain of Malaria Parasites in a Globally Invasive Bird

Invasive species can displace natives, and thus identifying the traits that make aliens successful is crucial for predicting and preventing biodiversity loss. Pathogens may play an important role in the invasive process, facilitating colonization of their hosts in new continents and islands. According to the Novel Weapon Hypothesis, colonizers may out-compete local native species by bringing with them novel pathogens to which native species are not adapted. In contrast, the Enemy Release Hypothesis suggests that flourishing colonizers are successful because they have left their pathogens behind. To assess the role of avian malaria and related haemosporidian parasites in the global spread of a common invasive bird, we examined the prevalence and genetic diversity of haemosporidian parasites (order Haemosporida, genera Plasmodium and Haemoproteus) infecting house sparrows (Passer domesticus). We sampled house sparrows (N = 1820) from 58 locations on 6 continents. All the samples were tested using PCR-based methods; blood films from the PCR-positive birds were examined microscopically to identify parasite species. The results show that haemosporidian parasites in the house sparrows' native range are replaced by species from local host-generalist parasite fauna in the alien environments of North and South America. Furthermore, sparrows in colonized regions displayed a lower diversity and prevalence of parasite infections. Because the house sparrow lost its native parasites when colonizing the American continents, the release from these natural enemies may have facilitated its invasion in the last two centuries. Our findings therefore reject the Novel Weapon Hypothesis and are concordant with the Enemy Release Hypothesis

Multigene phylogeny of the Mustelidae: Resolving relationships, tempo and biogeographic history of a mammalian adaptive radiation

<p>Abstract</p> <p>Background</p> <p>Adaptive radiation, the evolution of ecological and phenotypic diversity from a common ancestor, is a central concept in evolutionary biology and characterizes the evolutionary histories of many groups of organisms. One such group is the Mustelidae, the most species-rich family within the mammalian order Carnivora, encompassing 59 species classified into 22 genera. Extant mustelids display extensive ecomorphological diversity, with different lineages having evolved into an array of adaptive zones, from fossorial badgers to semi-aquatic otters. Mustelids are also widely distributed, with multiple genera found on different continents. As with other groups that have undergone adaptive radiation, resolving the phylogenetic history of mustelids presents a number of challenges because ecomorphological convergence may potentially confound morphologically based phylogenetic inferences, and because adaptive radiations often include one or more periods of rapid cladogenesis that require a large amount of data to resolve.</p> <p>Results</p> <p>We constructed a nearly complete generic-level phylogeny of the Mustelidae using a data matrix comprising 22 gene segments (~12,000 base pairs) analyzed with maximum parsimony, maximum likelihood and Bayesian inference methods. We show that mustelids are consistently resolved with high nodal support into four major clades and three monotypic lineages. Using Bayesian dating techniques, we provide evidence that mustelids underwent two bursts of diversification that coincide with major paleoenvironmental and biotic changes that occurred during the Neogene and correspond with similar bursts of cladogenesis in other vertebrate groups. Biogeographical analyses indicate that most of the extant diversity of mustelids originated in Eurasia and mustelids have colonized Africa, North America and South America on multiple occasions.</p> <p>Conclusion</p> <p>Combined with information from the fossil record, our phylogenetic and dating analyses suggest that mustelid diversification may have been spurred by a combination of faunal turnover events and diversification at lower trophic levels, ultimately caused by climatically driven environmental changes. Our biogeographic analyses show Eurasia as the center of origin of mustelid diversity and that mustelids in Africa, North America and South America have been assembled over time largely via dispersal, which has important implications for understanding the ecology of mustelid communities.</p