LRG1 as a novel therapeutic target in eye disease

Retinal and choroidal diseases are major causes of blindness and visual impairment in the developed world and on the rise due to an ageing population and diabetes epidemic. Standard of care is centred around blockade of vascular endothelial growth factor (VEGF), but despite having halved the number of patients losing sight, a high rate of patient non-response and loss of efficacy over time are key challenges. Dysregulation of vascular homoeostasis, coupled with fibrosis and inflammation, are major culprits driving sight-threatening eye diseases. Improving our knowledge of these pathological processes should inform the development of new drugs to address the current clinical challenges for patients. Leucine-rich α-2 glycoprotein 1 (LRG1) is an emerging key player in vascular dysfunction, inflammation and fibrosis. Under physiological conditions, LRG1 is constitutively expressed by the liver and granulocytes, but little is known about its normal biological function. In pathological scenarios, such as diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD), its expression is ectopically upregulated and it acquires a much better understood pathogenic role. Context-dependent modulation of the transforming growth-factor β (TGFβ) pathway is one of the main activities of LRG1, but additional roles have recently been emerging. This review aims to highlight the clinical and pre-clinical evidence for the pathogenic contribution of LRG1 to vascular retinopathies, as well as extrapolate from other diseases, functions which may be relevant to eye disease. Finally, we will provide a current update on the development of anti-LRG1 therapies for the treatment of nvAMD

Description of an architeuthis from argentine waters

A specimen of the giant squid Architeuthis sp., caught by a trawler on the Patagonian inner shelf (46 &#176‹30'S. 66 &#176 ‹00'W) in April 1995, is described. The squid was a mature female of 1 625 mm mantle length with 321 growth lines in the statoliths. Internal and external anatomy and morphometric characters were studied as far as possible, given the very damaged condition of the animal

Analisis Pengaruh Price Perception, Service Quality Dan Store Location Terhadap Costomer Loyalty (Survei di Hypermart Solo Square, Surakarta)

This study aims to analyze the effect of price perception, service quality and store location on costomer loyalty in hypermart solo square. This research type is descriptive research. Population of this research is consumer of Hypermart Solo Square, Surakarta. The sample in this research is 75 consumers of hypermart solo square. Collection of samples by accidental sampling. The data used are primary data. Data collection techniques using questionnaire method (questionnaire). Data analysis techniques use validity test, reliability test, classical assumption test, multiple linear regression analysis, t test, F test, R2 test. The results showed that: price perception has positive and significant effect on costomer loyalty based on t value, t count> ttable (3,305> 2,000); Service quality has a positive and significant effect on costomer loyalty based on t value, tcount> ttable (4,110> 2,000); Store location has positive and significant effect on costomer loyalty based on t value, tcount> ttable (2,868> 2,000). Price perception, service quality, store location are connected together to costomer loyalty, proved by F test. F test obtained Fcount of 80.205 and Ftable 3.15 (H0 rejected, H1 accepted); Coefficient Determination (R2) test results show that price perception, service quality and store location are able to explain the variability of 51.4%

Differences in the properties of disrupted and surviving satellites of Milky-Way-mass galaxies in relation to their host accretion histories

From the chemo-dynamical properties of tidal debris in the Milky Way, it has been inferred that the dwarf satellites that have been disrupted had different chemical abundances from their present-day counterparts of similar mass that survive today, specifically, they had lower [Fe/H] and higher [Mg/Fe]. Here we use the ARTEMIS simulations to study the relation between the chemical abundances of disrupted progenitors of MW-mass galaxies and their stellar mass, and the evolution of the stellar mass - metallicity relations (MZR) of this population with redshift. We find that these relations have significant scatter, which correlates with the accretion redshifts (zacc) of satellites, and with their cold gas fractions. We investigate the MZRs of dwarf populations accreted at different redshifts and find that they have similar slopes, and also similar with the slope of the MZR of the surviving population (≈0.32). However, the entire population of disrupted dwarfs displays a steeper MZR, with a slope of ≈0.48, which can be explained by the changes in the mass spectrum of accreted dwarf galaxies with redshift. We find strong relations between the (mass-weighted) ⟨zacc⟩ of the disrupted populations and their global chemical abundances (⟨[Fe/H]⟩ and ⟨[Mg/Fe]⟩), which suggests that chemical diagnostics of disrupted dwarfs can be used to infer the types of merger histories of their hosts. For the case of the MW, our simulations predict that the bulk of the disrupted population was accreted at ⟨zacc⟩≈2, in agreement with other findings. We also find that disrupted satellites form and evolve in denser environments, closer to their hosts, than their present-day counterparts

PENGARUH LOKASI DAN PROMOSI PENJUALAN TERHADAP KEPUTUSAN PEMBELIAN PADA IN AND OUT URBAN EATERY BANDUNG (Survei Pada Konsumen In and Out Urban Eatery Bandung)

ABSTRAK Penelitian ini dilakukan untuk menguji pengaruh lokasi dan promosi penjualan terjadap keputusan pembelian pada In and Out Urban Eatery Bandung baik secara parsial maupun simultan. Populasi dalam penelitian ini yaitu 3.566 orang konsumen dan jumlah sampel sebanyak 97 orang konsumen. Penelitian ini menggunakan pendekatan kuantitatif, analisis data yang digunakan yaitu metode analisis linier berganda, analisis korelasi berganda, analisis koefisien determinasi. Hasil dari penelitian ini menunjukkan bahwa lokasi memiliki pengaruh signifikan terhadap keputusan pembelian sebesar 43,6% dan promosi penjualan memiliki pengaruh signifikan sebesar 15,9%. Variabel yang paling mempengaruhi keputusan pembelian yaitu lokasi. Lokasi dan promosi penjualan memiliki pengaruh signifikan terhadap keputusan pembelian pada In and Out Urban Eatery Bandung sebesar 59,5% sedangkan sisanya sebesar 40,5% dipengaruhi oleh faktor-faktor lain yang tidak diteliti. Kata kunci : Lokasi, Promosi Penjualan dan Keputusan Pembelia

The Impact of Almonds and Almond Processing On Gastrointestinal Physiology, Luminal Microbiology and Gastrointestinal Symptoms: a Randomized Controlled Trial and Mastication Study.

BACKGROUND: Almonds contain lipid, fiber and polyphenols and possess physicochemical properties that impact nutrient bioaccessibility, which are hypothesized to impact gut physiology and microbiota. OBJECTIVES: Investigate the impact of whole almonds and ground almonds (almond flour) on fecal bifidobacteria (primary outcome), gut microbiota composition and transit time. DESIGN: Healthy adults (n = 87) participated in a parallel, 3-arm randomized controlled trial. Participants received whole almonds (56 g/d), ground almonds (56 g/d) or an isocaloric control muffin in place of habitual snacks for 4 weeks. Gut microbiota composition and diversity (16S rRNA gene sequencing), short-chain fatty acids (gas-chromatography), volatile organic compounds (gas-chromatography mass-spectrometry), gut transit time (wireless motility capsule), stool output and gut symptoms (7-day diary) were measured at baseline and endpoint. The impact of almond form on particle size distribution (PSD) and predicted lipid release was measured in a subgroup (n = 31). RESULTS: Modified intention-to-treat analysis was performed on 79 participants. There were no significant differences in abundance of fecal bifidobacteria following consumption of whole almonds (8.7%, SD 7.7%), ground almonds (7.8%, SD 6.9%) or control (13.0%, SD 10.2%; q = 0.613). Consumption of almonds (whole and ground pooled) resulted in higher butyrate (24.1 μmol/g, SD 15.0 μmol/g) in comparison to control (18.2 μmol/g, SD 9.1 μmol/g; p = 0.046). There was no effect of almonds on gut microbiota at the phylum level or diversity, gut transit time, stool consistency or gut symptoms. Almond form (whole versus ground) had no effect on study outcomes. Ground almonds resulted in significantly smaller PSD and higher predicted lipid release (10.4%, SD 1.8%) in comparison to whole almonds (9.3%, SD 2.0%; p = 0.017). CONCLUSIONS: Almond consumption has limited impact on gut microbiota composition but increases butyrate concentrations in adults, suggesting positive alterations to microbiota functionality. Almonds can be incorporated into the diet to increase fiber consumption without triggering gut symptoms. Clinical trial registry: ClinicalTrials.gov identifier - NCT03581812

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. / Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. / Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

Ex situ collections and their potential for the restoration of extinct plants

The alarming current and predicted species extinction rates have galvanized conservationists in their efforts to avoid future biodiversity losses but for species extinct in the wild, few options exist. We posed the question, can these be restored, and if so, what role can ex situ plant collections (i.e. botanic gardens, germplasm banks and herbaria) play in the recovery of plant genetic diversity? We reviewed the relevant literature to assess the feasibility of recovering lost plant genetic diversity using ex situ material and the chances of survival of subsequent translocations. Thirteen attempts of recovering species extinct in the wild were found, most of which from material preserved in botanic gardens (12) and seed banks (2). A single case of a locally extirpated population was recovered from herbarium material. Eight (60%) of these cases were successful or partially successful translocations of the focal species or population, while the other five failed or was too early to judge. Our review exposes the many constraints of using ex situ source material for the restoration of plant genetic diversity to the wild, but also highlight the opportunities that modern collecting practices present for plant conservation. Limiting factors are the scarcity of available source material stored ex situ, low viability and reduced longevity of the material, low genetic variation, lack of evolution (especially for material stored in germplasm banks and herbaria) and socio‐economic constraints. However, our review suggests that all types of ex situ collections may effectively contribute to plant species conservation, if their use is informed by a thorough understanding of the aforementioned issues. For these reasons, we conclude that the recovery of plant species currently classed as extinct in the wild is not 100% successful and the possibility to achieve this should not be used as a justification for insufficient in situ conservation efforts