Bis-Retinoid A2E Induces an Increase of Basic Fibroblast Growth Factor via Inhibition of Extracellular Signal-Regulated Kinases 1/2 Pathway in Retinal Pigment Epithelium Cells and Facilitates Phagocytosis.

Age-related macular degeneration (ARMD) is the leading cause of vision loss in developed countries. Hallmarks of the disease are well known; indeed, this pathology is characterized by lipofuscin accumulation, is principally composed of lipid-containing residues of lysosomal digestion. The N-retinyl-N-retinylidene ethanolamine (A2E) retinoid which is thought to be a cytotoxic component for RPE is the best-characterized component of lipofuscin so far. Even if no direct correlation between A2E spatial distribution and lipofuscin fluorescence has been established in aged human RPE, modified forms or metabolites of A2E could be involved in ARMD pathology. Mitogen-activated protein kinase (MAPK) pathways have been involved in many pathologies, but not in ARMD. Therefore, we wanted to analyze the effects of A2E on MAPKs in polarized ARPE19 and isolated mouse RPE cells. We showed that long-term exposure of polarized ARPE19 cells to low A2E dose induces a strong decrease of the extracellular signal-regulated kinases' (ERK1/2) activity. In addition, we showed that A2E, via ERK1/2 decrease, induces a significant decrease of the retinal pigment epithelium-specific protein 65 kDa (RPE65) expression in ARPE19 cells and isolated mouse RPE. In the meantime, we showed that the decrease of ERK1/2 activity mediates an increase of basic fibroblast growth factor (bFGF) mRNA expression and secretion that induces an increase in phagocytosis via a paracrine effect. We suggest that the accumulation of deposits coming from outer segments (OS) could be explained by both an increase of bFGF-induced phagocytosis and by the decrease of clearance by A2E. The bFGF angiogenic protein may therefore be an attractive target to treat ARMD

Impacts of environmental change on agroecosystems and livelihoods in Annapurna Conservation Area, Nepal

© 2017 Elsevier B.V. To understand local perceptions of the impacts of environmental change in two mountain districts of Nepal — Myagdi and Mustang — between 2010 and 2014, a survey, focus groups, town hall meetings, and extensive consultation with local stakeholders were conducted, supplemented by analyses of soil, rainfall, and temperature data. Mountain people in Nepal shared their perceptions of environmental change in their everyday lives, including agricultural practices and tourism activities. While ordinary individuals welcome the construction of new roads, elites still prefer to maintain trails and the status quo. People are concerned about the introduction of mosquitoes, increases in insect pests and plant pathogens, and other vectors along with roads. Snowfall has decreased and rainfall has been unpredictable. Mean minimum winter temperatures have increased and the mountains are experiencing shorter winters and less snow accumulation, which threaten the livelihoods of people that depend on fresh water. While people with means are replacing their traditional homes with modern homes, that is beyond reach for average Mustangi citizens. Expansion and diversification of agriculture, adoption of sound soil management techniques in Marpha village of Mustang and Shikha village of Myagdi, and growing forest cover in Shikha are some indicators of enhanced community managed practices. The coping strategies and indigenous practices adopted by local people in the region against hardship and environmental changes could serve as examples in similar mountain settings elsewhere

Transition from ion-coupled to electron-only reconnection: Basic physics and implications for plasma turbulence

Using kinetic particle-in-cell (PIC) simulations, we simulate reconnection conditions appropriate for the magnetosheath and solar wind, i.e., plasma beta (ratio of gas pressure to magnetic pressure) greater than 1 and low magnetic shear (strong guide field). Changing the simulation domain size, we find that the ion response varies greatly. For reconnecting regions with scales comparable to the ion Larmor radius, the ions do not respond to the reconnection dynamics leading to ''electron-only'' reconnection with very large quasi-steady reconnection rates. The transition to more traditional ''ion-coupled'' reconnection is gradual as the reconnection domain size increases, with the ions becoming frozen-in in the exhaust when the magnetic island width in the normal direction reaches many ion inertial lengths. During this transition, the quasi-steady reconnection rate decreases until the ions are fully coupled, ultimately reaching an asymptotic value. The scaling of the ion outflow velocity with exhaust width during this electron-only to ion-coupled transition is found to be consistent with a theoretical model of a newly reconnected field line. In order to have a fully frozen-in ion exhaust with ion flows comparable to the reconnection Alfv\'en speed, an exhaust width of at least several ion inertial lengths is needed. In turbulent systems with reconnection occurring between magnetic bubbles associated with fluctuations, using geometric arguments we estimate that fully ion-coupled reconnection requires magnetic bubble length scales of at least several tens of ion inertial lengths

Cervical cytological changes in HIV-infected patients attending care and treatment clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania

\ud Tanzania is among Sub-Saharan countries mostly affected by the HIV and AIDS pandemic, females being more vulnerable than males. HIV infected women appear to have a higher rate of persistent infection by high risk types of human papillomavirus (HPV) strongly associated with high-grade squamous intraepithelial lesions (HSIL) and invasive cervical carcinoma. Furthermore, although HIV infection and cervical cancer are major public health problems, the frequency and HIV/HPV association of cervical cancer and HSIL is not well documented in Tanzania, thus limiting the development of preventive and therapeutic strategies. A prospective unmatched, case-control study of HIV-seropositive, ≥ 18 years of age and consenting non-pregnant patients attending the care and treatment center (CTC) at Muhimbili National Hoospital (MNH) as cases was done between 2005 and 2006. HIV seronegative, non-pregnant and consenting women recruited from the Cervical Cancer Screening unit (CCSU) at ORCI were used as controls while those who did not consent to study participation and/or individuals under < 18 years were excluded. Pap smears were collected for routine cytodiagnosis and P53 immunohistochemistry (IHC). Cervical lesions were classified according to the Modified Bethesda System. A total of 170 participants from the two centers were recruited including 50 HIV-seronegative controls were from the CCSU. Ages ranged from 20-66 years (mean 40.5 years) for cases and 20-69 years (mean 41.6 years) for controls. The age group 36-45 years was the most affected by HIV (39.2%, n = 47). Cervicitis, squamous intraepithelial lesions (SIL) and carcinoma constituted 28.3% (n = 34), 38.3% (n = 46) and 5.8% (n = 7) respectively among cases, and 28% (n = 14), 34% (n = 17) and 2% (n = 1) for controls, although this was not statistically significant (P-value = 0.61). IHC showed that p53 was not detectable in HPV + Pap smears and cell blocks indicating possible degradation. The frequency of SIL and carcinoma appeared to be higher among HIV-infected women on HAART compared to seronegative controls and as expected increased with age. HIV seropositive patients appeared to present earlier with SIL compared to those HIV seronegative suggesting a role of HIV in altering the natural history of HPV infection and cervical lesions. The absence of p53 immunoreactivity in HPV + lesions is indicative of the ability of HPV E6 proteins to interact with the tumor suppressor gene and pave way for viral-induced oncogenesis in the studied Tanzanian women.\u

Parker Solar Probe observations of proton beams simultaneous with ion-scale waves

Parker Solar Probe (PSP), NASA's latest and closest mission to the Sun, is on a journey to investigate fundamental enigmas of the inner heliosphere. This paper reports initial observations made by the Solar Probe Analyzer for Ions (SPAN-I), one of the instruments in the Solar Wind Electrons Alphas and Protons (SWEAP) instrument suite. We address the presence of secondary proton beams in concert with ion-scale waves observed by FIELDS, the electromagnetic fields instrument suite. We show two events from PSP's 2nd orbit that demonstrate signatures consistent with wave-particle interactions. We showcase 3D velocity distribution functions (VDFs) measured by SPAN-I during times of strong wave power at ion-scales. From an initial instability analysis, we infer that the VDFs departed far enough away from local thermodynamic equilibrium (LTE) to provide sufficient free energy to locally generate waves. These events exemplify the types of instabilities that may be present and, as such, may guide future data analysis characterizing and distinguishing between different wave-particle interactions.Comment: 24 pages, 9 figures, 2 table

Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration.

Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects

Putamen volume and its clinical and neurological correlates in primary HIV infection

Objective: Little is known about the extent of cortical and subcortical volumetric alterations that may occur within the first year of HIV infection [primary HIV infection (PHI)]. Design: We used structural MRI in this prospective cross-sectional neuroimaging study to determine the extent of volumetric changes in early HIV infection. Methods: Cerebrospinal fluid, blood, neuropsychological testing, and structural T1 MRI scans were acquired from 18 HIV and 47 PHI age-matched antiretroviral-naïve male participants. Using FreeSurfer 5.1, volumetric measurements were obtained from the caudate, amygdala, corpus callosum, ventricles, putamen, thalamus, cortical white matter, and total gray matter. Regional volumes were compared groupwise and related to biomarkers in cerebrospinal fluid (viral load, neopterin, and neurofilament light chain), blood (viral load, CD4+, and CD8+ T-cell count), and neuropsychometric tests (digit-symbol, grooved pegboard, finger-tapping, and timed gait). Results: A trend-level moderate reduction of putamen volume (P = 0.076, adjusted Cohen's d = 0.5 after controlling for age) was observed for PHI compared with HIV-uninfected individuals. Within the PHI group, putamen volume associated with CD4+ cell count (P = 0.03), CD4+/CD8+ ratio (P = 0.045), infection duration (P = 0.009), and worsening psychomotor performance on the digit-symbol (P = 0.028), finger-tapping (P = 0.039), and timed gait (P = 0.009) tests. Conclusion: Our volumetric results suggest that the putamen is preferentially susceptible to early HIV-associated processes. Examining the natural course of early HIV infection longitudinally will allow for mapping of the trajectory of HIV-associated central nervous system changes, enabling creation of improved interventional strategies to potentially stabilize or reverse these observed structural changes

Ethnomedicinal landscape: distribution of used medicinal plant species in Nepal

Background The risk of losing traditional knowledge of medicinal plants and their use and conservation is very high. Documenting knowledge on distribution and use of medicinal plants by different ethnic groups and at spatial scale on a single platform is important from a conservation planning and management perspective. The sustainable use, continuous practice, and safeguarding of traditional knowledge are essential. Communication of such knowledge among scientists and policy makers at local and global level is equally important, as the available information at present is limited and scattered in Nepal. Methods In this paper, we aimed to address these shortcomings by cataloguing medicinal plants used by indigenous ethnic groups in Nepal through a systematic review of over 275 pertinent publications published between 1975 and July 2021. The review was complemented by field visits made in 21 districts. We determined the ethnomedicinal plants hotspots across the country and depicted them in heatmaps. Results The heatmaps show spatial hotspots and sites of poor ethnomedicinal plant use documentation, which is useful for evaluating the interaction of geographical and ethnobotanical variables. Mid-hills and mountainous areas of Nepal hold the highest number of medicinal plant species in use, which could be possibly associated with the presence of higher human population and diverse ethnic groups in these areas. Conclusion Given the increasing concern about losing medicinal plants due to changing ecological, social, and climatic conditions, the results of this paper may be important for better understanding of how medicinal plants in use are distributed across the country and often linked to specific ethnic groups.</p