Amyloid β induces early changes in the ribosomal machinery, cytoskeletal organization and oxidative phosphorylation in retinal photoreceptor cells

Amyloid β (Aβ) accumulation and its aggregation is characteristic molecular feature of the development of Alzheimer’s disease (AD). More recently, Aβ has been suggested to be associated with retinal pathology associated with AD, glaucoma and drusen deposits in age related macular degeneration (AMD). In this study, we investigated the proteins and biochemical networks that are affected by Aβ in the 661 W photoreceptor cells in culture. Time and dose dependent effects of Aβ on the photoreceptor cells were determined utilizing tandem mass tag (TMT) labeling-based quantitative mass-spectrometric approach. Bioinformatic analysis of the data revealed concentration and time dependent effects of the Aβ peptide stimulation on various key biochemical pathways that might be involved in mediating the toxicity effects of the peptide. We identified increased Tau phosphorylation, GSK3β dysregulation and reduced cell viability in cells treated with Aβ in a dose and time dependent manner. This study has delineated for the first-time molecular networks in photoreceptor cells that are impacted early upon Aβ treatment and contrasted the findings with a longer-term treatment effect. Proteins associated with ribosomal machinery homeostasis, mitochondrial function and cytoskeletal organization were affected in the initial stages of Aβ exposure, which may provide key insights into AD effects on the photoreceptors and specific molecular changes induced by Aβ peptide

Agency culture, constitutional provisions and entrepreneurship: a cross-country analysis

Substantial and systematic cross-country variation in entrepreneurship rates has been found in vari- ous studies. We attempt to explain such differences focusing on the interaction between institutional factors and population psychological characteristics. Constitutional provisions supporting economic freedom are our measure of the institutional context, whereas we proxy psychological characteristics with a country’s endowment of agency culture. We apply an IV-GMM treatment to deal with endoge- 20 neity to a data set comprising 86 countries over the period 2004–2013, and we control for de facto vari- ables and other factors that are likely to influence entrepreneurship. Our results demonstrate that agency culture is indeed an important predictor of entrepreneurship and that this effect is moderated by constitutional provisions supporting economic freedom. In particular, the impact of agency culture on entrepreneurship becomes stronger as a country expands the constitutional protection of eco- 25 nomic rights

Conceptualizing and measuring distance in international business research:Recurring questions and best practice guidelines

Distance is a central concept in international business research, yet there is debate about the construct as well as its operationalization. In this editorial, we address three of the most important recurring questions posed by authors, editors, and reviewers by examining the theory, methods, and data of distance research. We discuss (1) how to theorize on distance, and (2) what method and (3) what data to use when constructing a distance index. We develop practical recommendations grounded in theory, illustrating and supporting them by calculating cross-country distance indices for all available country pairs and two of the most used distance indices: cultural and institutional. We show that, whereas a specific method to calculate distance may matter to some extent, the choice for a specific cultural or institutional framework to measure cultural or institutional distance has a major impact on country-pair distances. Overall, this editorial highlights the importance of matching data and method to the theoretical argument.</p

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Microbiological aspects of peritonitis in patients on continuous ambulatory peritoneal dialysis

The objective of the study was to identify the microbiological spectrum and drug-sensitivity pattern of peritonitis in patients on continuous ambulatory peritoneal dialysis. This was a prospective study done over a period of a year-and-a-half at a tertiary-care hospital in a hilly state of India. The effluent dialysate bags from 36 consecutive patients with peritonitis were studied. One hunderd ml dialysate fluid was processed under aseptic conditions by lysis centrifugation method. Microscopy and culture was done from the deposits for bacteriological, fungal, and mycobacterial isolates. They were identified by colony morphology and their biochemical reactions. Drug susceptibility testing was done by Kirby-Bauer disc diffusion method. In 36 dialysates, 33 (91.6%) dialysates were culture-positive and in 3 (8.4%), the culture was negative. A total of 36 microorganisms were isolated in 33 cultures. Among the 36 microorganisms, 19 (52.8%) isolates were gram-positive, 10 (27.8%) were gram-negative, 5 (13.9%) were fungi, and 2 (5.6%) were mycobacterial isolates. All gram-positive organisms were sensitive to ampicillin, amoxi-clavulanic acid, cefazolin, clindamycin, and vancomycin. Neither a methicillin-resistant Staphylococci aureus nor a vancomycin-resistant Enterococcus was isolated in gram-positive isolates. Gram-negative organisms were sensitive to ciprofloxacin, ceftriaxone, ceftazidime, cefepime, gentamicin, piperacillin-tazobactam and imipenem. One of the gram-negative isolate was an extended spectrum beta-lactamase producer. Gram-positive peritonitis was more frequent than gram-negative peritonitis in our continuous ambulatory peritoneal dialysis patients. Mycobacterial causes were responsible for peritonitis in patients with culture-negative peritonitis which was not responding to the conventional antimicrobial therapy

Diurnal pastoralism does not reduce juvenile recruitment nor elevate allostatic load in spotted hyenas

Anthropogenic activity can have substantial effects on wildlife. These effects may vary according to the characteristics of the activity and the species involved. Although effects on behaviour are well studied, studies of effects on fitness and physiology are scarce, particularly for groupâliving species. We exploited a natural experimental setup to investigate the effect of diurnal pastoralism on juvenile recruitment and allostatic load in a population of freeâranging spotted hyenas in the Ngorongoro Crater, Tanzania, over a 24âyear period. Pastoralism was restricted to the territories of two of the eight study clans, allowing us to compare juvenile recruitment in exposed and unexposed clans. We also compared faecal glucocorticoid metabolite concentrations (fGMC)âa biomarker of an organism's allostatic loadâbetween exposed and unexposed clans using 975 faecal samples from 475 hyenas. We found no detectable difference in juvenile recruitment nor fGMC between the exposed and unexposed clans, indicating that the pastoralism had no substantial deleterious effect on the spotted hyenas. The lack of a deleterious effect likely stems from the combined effect of the predictable and undisruptive nature of the pastoralism, the socioâecology of spotted hyenas and the Ngorongoro Crater's consistently abundant prey. Our findings demonstrate that exposure to anthropogenic activity may be compatible with the persistence of certain groupâliving species, especially if the overlap between the species' critical behaviours and the activity is limited. Our study thereby provides new perspectives for ecologists, conservation biologists and stakeholders who seek to assess humanâwildlife conflicts and balance the needs of local human communities and wildlife

Amyloid β accumulation and inner retinal degenerative changes in Alzheimer's disease transgenic mouse

© 2016 Elsevier Ireland Ltd. The APP-PS1δE9 mouse model of Alzheimer's disease (AD) exhibits age dependent amyloid β (Aβ) plaque formation in their central nervous system due to high expression of mutated human APP and PSEN1 transgenes. Here we evaluated Aβ deposition and changes in soluble Aβ accumulation in the retinas of aged APP-PS1 mice using a combination of immunofluorescence, retinal flat mounts and western blotting techniques. Aβ accumulation in the retina has previously been shown to be associated with retinal ganglion cell apoptosis in animal models of glaucoma. This study investigated changes in the inner retinal function and structure in APP-PS1 mice using electrophysiology and histological approaches respectively. We report for the first time a significant decline in scotopic threshold response (STR) amplitudes which represents inner retinal function in transgenic animals compared to the wild type counterparts (p < 0.0001). Thinning of the retina particularly involving inner retinal layers and reduction in axonal density in the optic nerve was also observed. TUNEL staining was performed to examine neuronal apoptosis in the inner retina. Intraocular pressure (IOP) measurements showed that APP-PS1δE9 mice had a slightly elevated IOP, but the significance of this finding is not yet known. Together, these results substantiate previous observations and highlight that APP-PS1δE9 mice show evidence of molecular, functional and morphological degenerative changes in the inner retina