OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism

A human cytomegalovirus (HCMV) pentameric glycoprotein complex (PC), gH-gL-UL128-UL130-UL131A, is necessary for viral infection of clinically relevant cell types, including epithelial cells, which are important for interhost transmission and disease. We performed genome-wide CRISPR/Cas9 screens of different cell types in parallel to identify host genes specifically required for HCMV infection of epithelial cells. This effort identified a multipass membrane protein, OR14I1, as a receptor for HCMV infection. This olfactory receptor family member is required for HCMV attachment, entry, and infection of epithelial cells and is dependent on the presence of viral PC. OR14I1 is required for AKT activation and mediates endocytosis entry of HCMV. We further found that HCMV infection of epithelial cells is blocked by a synthetic OR14I1 peptide and inhibitors of adenylate cyclase and protein kinase A (PKA) signaling. Identification of OR14I1 as a PC-dependent HCMV host receptor associated with epithelial tropism and the role of the adenylate cyclase/PKA/AKT-mediated signaling pathway in HCMV infection reveal previously unappreciated targets for the development of vaccines and antiviral therapies

An empirical explanation of the natural-resource-based view of the firm

To date, the natural-resource-based view has been an abstract phenomenon, primarily used by academics to explain competitive sustainable operations. This paper attempts to go beyond this, responding to the need for an explanation of the practical existence of the four natural-resource-based view resources in industry. Assuming a critical realist qualitative approach, in-depth interviews with sustainability experts in UK agri-food are undertaken. Findings demonstrate the existence of pollution prevention, product stewardship, and clean technologies and align with Hart’s conceptualization of sustainability as competitive resources. Whilst the fourth resource, the base of the pyramid, cannot be empirically verified, the fifth resource of local philanthropy is uncovered and contributes to the growing body of knowledge surrounding competitive social sustainability. Findings also challenge the hierarchal presentation of the natural-resource-based view to implicate a more cyclical uptake. Thus, in offering the first empirical explanation of the natural-resource-based view, this paper overcomes a theory-practice gap to elucidate the feasibility, orchestration, and value of resources in competitive and sustainable operations

Viral Infection or IFN-α Alters Mitotic Spindle Orientation by Modulating Pericentrin Levels

Summary: Congenital microcephaly occurs in utero during Zika virus (ZIKV) infection. The single-gene disorder, Majewski osteodysplastic primordial dwarfism type II (MOPDII), also leads to microcephaly and is concomitant with a decrease in the centrosomal protein, pericentrin (PCNT). This protein is a known contributor of mitotic spindle misorientation and ultimately, microcephaly. Similar to MOPDII, either viral infection or interferon (IFN)-α exposure reduced PCNT levels at the mitotic spindle poles. We unexpectedly found that infection of cells with any one of a diverse set of viruses, such as ZIKV, dengue virus, cytomegalovirus, influenza A virus, or hepatitis B virus, or treatment of cells with the anti-viral cytokine, IFN-α, produced mitotic spindle misorientation. These findings demonstrate a related mechanism for the development of microcephaly in viral infection, the host's antiviral IFN response, and primordial dwarfism. : Biological Sciences; Pathophysiology; Virology; Cell Biology Subject Areas: Biological Sciences, Pathophysiology, Virology, Cell Biolog

Viral Infection or IFN-α Alters Mitotic Spindle Orientation by Modulating Pericentrin Levels

Summary: Congenital microcephaly occurs in utero during Zika virus (ZIKV) infection. The single-gene disorder, Majewski osteodysplastic primordial dwarfism type II (MOPDII), also leads to microcephaly and is concomitant with a decrease in the centrosomal protein, pericentrin (PCNT). This protein is a known contributor of mitotic spindle misorientation and ultimately, microcephaly. Similar to MOPDII, either viral infection or interferon (IFN)-α exposure reduced PCNT levels at the mitotic spindle poles. We unexpectedly found that infection of cells with any one of a diverse set of viruses, such as ZIKV, dengue virus, cytomegalovirus, influenza A virus, or hepatitis B virus, or treatment of cells with the anti-viral cytokine, IFN-α, produced mitotic spindle misorientation. These findings demonstrate a related mechanism for the development of microcephaly in viral infection, the host's antiviral IFN response, and primordial dwarfism. : Biological Sciences; Pathophysiology; Virology; Cell Biology Subject Areas: Biological Sciences, Pathophysiology, Virology, Cell Biolog

COPD phenotypes in biomass smoke – versus tobacco smoke-exposed Mexican women

We hypothesized that biomass smoke exposure is associated with an airway-predominant COPD phenotype, while tobacco-related COPD is associated with an emphysema-predominant phenotype. In this cross-sectional study, female never-smokers with COPD and biomass exposure (n=21) and female ex-cigarette smokers with COPD without biomass exposure (n=22) completed computed tomography (CT) at inspiration and expiration, pulmonary function, blood gas, exercise tolerance, and quality of life measures. Two radiologists scored the extent of emphysema and air trapping on CT. Quantitative emphysema severity and distribution, and airway wall thickness were calculated using specialized software. Women in the tobacco group had significantly more emphysema than the biomass group (radiologist score 2·3 vs 0·7, p=0·001; % emphysema on CT scan 27% vs 19%, p=0·046; and a larger size of emphysematous spaces, p=0·006). Women in the biomass group had significantly more air trapping than the tobacco group (radiologist score = 2·6 and 1·5 respectively; p=0·02) and also scored lower on the symptom, activities and confidence domains of quality of life and had lower oxygen saturation at rest and during exercise (p<0·05). Biomass smoke exposure is associated with less emphysema but more air trapping than tobacco smoke exposure, suggesting an airway-predominant phenotype.Medicine, Faculty ofOther UBCNon UBCMedicine, Department ofPhysical Therapy, Department ofRadiology, Department ofReviewedFacultyResearche

RNASEK Is a V-ATPase-Associated Factor Required for Endocytosis and the Replication of Rhinovirus, Influenza A Virus, and Dengue Virus

Human rhinovirus (HRV) causes upper respiratory infections and asthma exacerbations. We screened multiple orthologous RNAi reagents and identified host proteins that modulate HRV replication. Here, we show that RNASEK, a transmembrane protein, was needed for the replication of HRV, influenza A virus, and dengue virus. RNASEK localizes to the cell surface and endosomal pathway and closely associates with the vacuolar ATPase (V-ATPase) proton pump. RNASEK is required for endocytosis, and its depletion produces enlarged clathrin-coated pits (CCPs) at the cell surface. These enlarged CCPs contain endocytic cargo and are bound by the scissioning GTPase, DNM2. Loss of RNASEK alters the localization of multiple V-ATPase subunits and lowers the levels of the ATP6AP1 subunit. Together, our results show that RNASEK closely associates with the V-ATPase and is required for its function; its loss prevents the early events of endocytosis and the replication of multiple pathogenic viruses

The dement in the community: Social work practice with people with dementia revisited

While social work practice with people with dementia and their families has a long but largely hidden history, it is an emerging area of specialism. The increased incidence, prevalence and recognition of dementia suggest that this area of practice will expand and so learning from previous practice may offer helpful insights. This paper describes and reflects upon social work practice with ‘dements’ in the 1950s in England. It draws on a reading of a small book written by a psychiatric social worker, Miss M (Muriel) H Bree, outlining her role in providing after-care to patients with neuro-syphilis who had been discharged from hospital to live with their families between 1942 and 1952 through her consideration of 275 case records and seven illustrative case studies. As a historical document, Bree’s account presents a rich description of the patients and their social circumstances in post-war Britain; an account of practice from a hospital based setting that reached into the community, and of the engagement of a social worker with her clients and their family members. Threads and continuities with contemporary social work practice with people with dementia are explored; particularly work with family carers, younger people with dementia, and the value placed upon continuity of care.</p

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function