Miracle-dz/UniFAR-FTUs huggingface dataset:
Current Advances in Pharmacotherapy and Technology for Diabetic Retinopathy: A Systematic Review

Diabetic retinopathy (DR) is classically defined by its vascular lesions and damage in the neurons of the retina. The cellular and clinical elements of DR have many features of chronic inflammation. Understanding the individual cell-specific inflammatory changes in the retina may lead to novel therapeutic approaches to prevent vision loss. The systematic use of available pharmacotherapy has been reported as a useful adjunct tool to laser photocoagulation, a gold standard therapy for DR. Direct injections or intravitreal anti-inflammatory and antiangiogenesis agents are widely used pharmacotherapy to effectively treat DR and diabetic macular edema (DME). However, their effectiveness is short term, and the delivery system is often associated with adverse effects, such as cataract and increased intraocular pressure. Further, systemic agents (particularly hypoglycemic, hypolipidemic, and antihypertensive agents) and plants-based drugs have also provided promising treatment in the progression of DR. Recently, advancements in pluripotent stem cells technology enable restoration of retinal functionalities after transplantation of these cells into animals with retinal degeneration. This review paper summarizes the developments in the current and potential pharmacotherapy and therapeutic technology of DR. Literature search was done on online databases, PubMed, Google Scholar, clinitrials.gov, and browsing through individual ophthalmology journals and leading pharmaceutical company websites.
Identification of bottlenecks in the accumulation of cyclic fatty acids in camelina seed oil

Summary Modified fatty acids (mFA) have diverse uses; for example, cyclopropane fatty acids (CPA) are feedstocks for producing coatings, lubricants, plastics and cosmetics. The expression of mFA‐producing enzymes in crop and model plants generally results in lower levels of mFA accumulation than in their natural‐occurring source plants. Thus, to further our understanding of metabolic bottlenecks that limit mFA accumulation, we generated transgenic Camelina sativa lines co‐expressing Escherichia coli cyclopropane synthase (EcCPS) and Sterculia foetida lysophosphatidic acid acyltransferase (SfLPAT). In contrast to transgenic CPA‐accumulating Arabidopsis, CPA accumulation in camelina caused only minor changes in seed weight, germination rate, oil accumulation and seedling development. CPA accumulated to much higher levels in membrane than storage lipids, comprising more than 60% of total fatty acid in both phosphatidylcholine (PC) and phosphatidylethanolamine (PE) versus 26% in diacylglycerol (DAG) and 12% in triacylglycerol (TAG) indicating bottlenecks in the transfer of CPA from PC to DAG and from DAG to TAG. Upon co‐expression of SfLPAT with EcCPS, di‐CPA‐PC increased by ~50% relative to lines expressing EcCPS alone with the di‐CPA‐PC primarily observed in the embryonic axis and mono‐CPA‐PC primarily in cotyledon tissue. EcCPS‐SfLPAT lines revealed a redistribution of CPA from the sn‐1 to sn‐2 positions within PC and PE that was associated with a doubling of CPA accumulation in both DAG and TAG. The identification of metabolic bottlenecks in acyl transfer between site of synthesis (phospholipids) and deposition in storage oils (TAGs) lays the foundation for the optimizing CPA accumulation through directed engineering of oil synthesis in target crops.
Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells.

Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso- N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad.CMV)-iNOS or SNAP (100 μM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an N G-monomethyl-l-arginine (l-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an l-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1β-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.
The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier

Eukaryotic pathogens display multiple mechanisms for breaching the blood-brain barrier (BBB) and invading the central nervous system (CNS). Of the fungal spp. , that cause disease in mammals, only some cross brain microvascular endothelial cells which constitute the BBB, and invade the brain. Cryptococcus neoformans, the leading cause of fungal meningoencephalitis, crosses the BBB directly by transcytosis or by co-opting monocytes. We previously determined that Mpr1, a secreted fungal metalloprotease, facilitates association of fungal cells to brain microvascular endothelial cells and we confirmed that the sole expression of CnMPR1 endowed S. cerevisiae with an ability to cross the BBB. Here, the gain of function conferred onto S. cerevisiae by CnMPR1 (i.e., Sc strain) was used to identify targets of Mpr1 that might reside on the surface of the BBB. Following biotin-labeling of BBB surface proteins, Sc-associated proteins were identified by LC-MS/MS. Of the 62 proteins identified several were cytoskeleton-endocytosis-associated including AnnexinA2 (AnxA2). Using an in vitro model of the human BBB where AnxA2 activity was blocked, we found that the lack of AnxA2 activity prevented the movement of S. cerevisiae across the BBB (i.e., transcytosis of Sc strain) but unexpectedly, TEM analysis revealed that AnxA2 was not required for the association or the internalization of Sc. Additionally, the co-localization of AnxA2 and Sc suggest that successful crossing of the BBB is dependent on an AxnA2-Mpr1-mediated interaction. Collectively the data suggest that AnxA2 plays a central role in fungal transcytosis in human brain microvascular endothelial cells. The movement and exocytosis of Sc is dependent on membrane trafficking events that involve AnxA2 but these events appear to be independent from the actions of AnxA2 at the host cell surface. We propose that Mpr1 activity promotes cytoskeleton remodeling in brain microvascular endothelial cells and thereby engages AnxA2 in order to facilitate fungal transcytosis of the BBB.
Control of HIV-1 Pathogenesis in Viremic Nonprogressors Is Independent of Gag-Specific Cytotoxic T Lymphocyte Responses

ABSTRACT Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4+ T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell responses seem to be one of the main causes of HIV-1 control in elite controllers, we studied whether HIV-1 Gag-specific cytotoxic T lymphocyte (CTL) responses could also modulate disease control in VNPs. We characterized the immune responses from four VNPs compared to those of five standard progressors (SPs) during the first years of HIV-1 infection. We observed no differences in the breadth and frequency of Gag-specific cellular responses. Furthermore, we obtained 217 HIV-1Gag clonal sequences in which the viral variability of Gag increased over 3 years of infection for synonymous and nonsynonymous mutations in both VNPs and SPs. VNPs evolution rates in gag were comparable to SPs. This observation is in line with a similar accumulation of CTL putative escape mutations in Gag epitopes targeted by CTL responses. Altogether, the absence of viral pathogenesis in VNP individuals seems to be independent of HIV-Gag-specific CTL responses. This novel information guides to the study of alternative mechanism of HIV-1 pathogenesis control. IMPORTANCE Control of HIV infection has been widely studied in elite controllers or long-term nonprogressor models. However, there is a less-known group of individuals, termed viremic nonprogressors (VNPs), who maintain stable CD4+ T cell counts despite high plasma viremia. The mechanisms involved in this remarkable control of HIV-1 pathogenesis clearly have implications for the development of new drugs and vaccines. We show here for the first time that VNPs have immune responses and HIV-gag evolution similar to those of standard progressors. Remarkably, we demonstrate that the mechanism of pathogenesis control in these individuals differs from some elite controllers that are reported to have improved immune control. This is noteworthy since it opens the door to new, as-yet-unknown mechanisms for HIV control. Our novel results advance the understanding of mechanisms involved in viremic nonprogression and suggest that there are alternative mechanisms to the adaptive immune responses for an effective control of viral pathogenesis.
Uptake of human papillomavirus (HPV) vaccination in Hong Kong: Facilitators and barriers among adolescent girls and their parents

The present study is aimed at assessing the feasibility of delivering the HPV (human papillomavirus) vaccine to girls through a school-based program in Hong Kong, as well as to examine the facilitators and barriers associated with their participation. We approached 1,229 eligible girls aged 9 to 14 at eight schools in Hong Kong to join the program and then delivered the bivalent HPV vaccine at 0 and 6 months over the course of one school year. The students and their parents completed separate questionnaires to indicate their decision on whether or not to participate, and to assess their knowledge of cervical cancer and the HPV vaccine. The overall vaccine uptake was 81.4% (1,000/1,229) for the first dose and 80.8% (993/1,229) for the second dose. Parents and students were given separate questionnaires and asked whether or not they would like to participate in the vaccination program. 87.1% (1,010/1,160) of parents and 84.9% (974/1,147) of students indicated that they would join the program. The reasons associated with parents’ decision not to vaccinate their daughters primarily included concerns around side effects and safety. Multivariate regression analysis showed that parents who thought that the vaccine would protect their daughter from getting cervical cancer (OR = 3.16, 95% CI = 1.39–7.15, p < .01), and those who reported having a doctor’s recommendation (OR = 4.54, 95% CI = 1.05–19.57, p < .05) were more likely to join the program. In contrast, parents who had never heard of the vaccine (OR = .15, 95% CI = .03–.71, p < .02), those who were willing to pay more than HK$2,000 for the vaccine (OR = .39, 95% CI = .19–.81, p < .05), or had a preference to access it through a private clinic (OR = .44, 95% CI = .26–.75, p < .01) were significantly less likely to allow their daughter to join the program. Delivery of the HPV vaccine with high uptake rate in a school setting is feasible in Hong Kong. Engaging key stakeholders including school administrators, teachers and community physicians, and providing relevant information on safety and vaccine effectiveness to parents were important to the success of the program.
Amount and fate of egg protein escaping assimilation in the small intestine of humans.

Studies attempting to evaluate protein assimilation in humans have hitherto relied on either ileostomy subjects or intubation techniques. The availability of stable isotope-labeled protein allowed us to determine the amount and fate of dietary protein escaping digestion and absorption in the small intestine of healthy volunteers using noninvasive tracer techniques. Ten healthy volunteers were studied once after ingestion of a cooked test meal, consisting of 25 g of13C-,15N-, and2H-labeled egg protein, and once after ingestion of the same but raw meal. Amounts of 5.73% and 35.10% ( P < 0.005) of cooked and raw test meal, respectively, escaped digestion and absorption in the small intestine. A significantly higher percentage of the malabsorbed raw egg protein was recovered in urine as fermentation metabolites. These results 1) confirm that substantial amounts of even easily digestible proteins may escape assimilation in healthy volunteers and 2) further support the hypothesis that the metabolic fate of protein in the colon is affected by the amount of protein made available.
Low-Resource Speech-to-Text Translation

Speech-to-text translation has many potential applications for low-resource languages, but the typical approach of cascading speech recognition with machine translation is often impossible, since the transcripts needed to train a speech recognizer are usually not available for low-resource languages. Recent work has found that neural encoder-decoder models can learn to directly translate foreign speech in high-resource scenarios, without the need for intermediate transcription. We investigate whether this approach also works in settings where both data and computation are limited. To make the approach efficient, we make several architectural changes, including a change from character-level to word-level decoding. We find that this choice yields crucial speed improvements that allow us to train with fewer computational resources, yet still performs well on frequent words. We explore models trained on between 20 and 160 hours of data, and find that although models trained on less data have considerably lower BLEU scores, they can still predict words with relatively high precision and recall---around 50% for a model trained on 50 hours of data, versus around 60% for the full 160 hour model. Thus, they may still be useful for some low-resource scenarios.
Dead fungal mycelium in forest soil represents a decomposition hotspot and a habitat for a specific microbial community.

Turnover of fungal biomass in forest litter and soil represents an important process in the environment. To date, knowledge of mycelial decomposition has been derived primarily from short-term studies, and the guild of mycelium decomposers has been poorly defined. Here, we followed the fate of the fruiting bodies of an ectomycorrhizal fungus in litter and soil of a temperate forest over 21 wk. The community of associated microbes and enzymatic processes in this specific substrate were described. The decomposition of fungal fruiting bodies exhibited biphasic kinetics. The rapid initial phase, which included the disappearance of DNA, was followed by a slower turnover of the recalcitrant fraction. Compared with the surrounding litter and soil, the mycelium represented a hotspot of activity of several biopolymer-degrading enzymes and high bacterial biomass. Specific communities of bacteria and fungi were associated with decomposing mycelium. These communities differed between the initial and late phases of decomposition. The bacterial community associated with decomposing mycelia typically contained the genera Pedobacter, Pseudomonas, Variovorax, Chitinophaga, Ewingella and Stenotrophomonas, whereas the fungi were mostly nonbasidiomycetous r-strategists of the genera Aspergillus, Penicillium, Mortierella, Cladosporium and several others. Decomposing ectomycorrhizal fungal mycelium exhibits high rates of decomposition and represents a specific habitat supporting a specific microbial community.
Evaluation of Different Gases and Gas Combinations for On-Farm Euthanasia of Pre-Weaned Pigs

Simple Summary There are times on a swine farm when pigs become ill or injured and must be euthanised. Blunt force trauma to the head is currently the most commonly employed method for on-farm euthanasia of pre-weaned piglets. When performed correctly, loss of consciousness is rapid, but the potential for delivery of sub-lethal blows, along with aesthetic unacceptability to many operators, has led to the need for alternative methods to be developed. The practice of using carbon dioxide (CO2) to euthanise piglets during the pre-weaning period is becoming more common on-farm in the United States; however, animals may display behavioural and/or physiological signs of stress or aversion in response to CO2 inhalation. Inducing anoxia using argon (Ar) gas may cause less aversion or stress and thus be preferable to using CO2. Therefore, the aim of this research was to evaluate the effects of 100% CO2, 100% Ar or CO2 and Ar combined (60% Ar/40% CO2) on piglet welfare during euthanasia. The results from this research suggest that using CO2, Ar or a 60% Ar/40% CO2 mixture causes stress to piglets prior to loss of consciousness and hence alternative methods of euthanasia need to be evaluated. Abstract The aim of this research was to evaluate the welfare of pre-weaned piglets euthanised using three different gas treatments: 100% carbon dioxide (CO2), 100% argon (Ar) or a mixture of 60% Ar/40% carbon dioxide (Ar/CO2). Two studies (n = 5 piglets/treatment/study) were conducted: (1) behavioural and physiological data were collected from conscious piglets during exposure to test gases via immersion in a pre-filled chamber and (2) electrophysiological data were collected from lightly anaesthetised, intubated and mechanically ventilated piglets exposed to the same test gases. Based on the duration of escape attempts and laboured breathing, piglets exposed to 100% CO2 experienced more stress than piglets exposed to 100% Ar prior to loss of consciousness, but there appeared to be no advantage of mixing Ar with CO2 on indices of animal welfare. However, spectral analysis of the electroencephalogram revealed no changes consistent with nociception during exposure to any of the three gas treatments. Based on the behavioural response to gas exposure, all gases tested caused signs of stress prior to piglets losing consciousness and hence alternative methods of euthanasia need to be evaluated.
Edinburgh Research Explorer Self-Representation on Twitter Using Emoji Skin Color Modifiers

Since 2015, it has been possible to modify certain emoji with a skin tone. The ﬁve different skin tones were introduced with the aim of representing more human diversity, but some commentators feared they might be used as a way to negatively represent other users/groups. This paper presents a quantitative analysis of the use of skin tone modiﬁers on emoji on Twitter, showing that users with darker-skinned proﬁle photos employ them more often than users with lighter-skinned proﬁle photos, and the vast majority of skin tone usage matches the color of a user’s proﬁle photo—i.e., tones represent the self, rather than the other. In the few cases where users do use opposite-toned emoji, we ﬁnd no evidence of negative racial sentiment. Thus, the introduction of skin tones seems to have met the goal of better representing human diversity.
Management of comorbid bipolar disorder and substance use disorders

ABSTRACT Background: The comorbidity of substance use disorders (SUDs) in bipolar disorder is among the highest in psychiatric disorders. Evidence-based controlled psychosocial or pharmacological interventions trials, which may guide treatment decisions, have not been systematically reviewed. Objective: To present a narrative review of the public health and clinical significance of this condition, including diagnostic and treatment implications, and to evaluate controlled trials conducted to date. Methods: Controlled trials reports in the English language were identified from multiple electronic databases and hand-searching bibliographies. We searched for treatment studies of bipolar disorder and comorbid SUDs (alcohol, cocaine, stimulants, opioid, tobacco, cannabis). Search period included all reports through September of 2016. We selected only randomized psychosocial studies or double-blind, placebo-controlled pharmacotherapy trials. We also reviewed reports of the public health and clinical significance and principle of managements of this condition. Results: We identified 16 treatment studies: 3 psychotherapy, and 13 pharmacotherapy trials. The following medications were evaluated: lithium carbonate, valproate, lamotrigine, topiramate, naltrexone, acamprosate, disulfiram, quetiapine, and citicoline. SUDs have substantial impact on the recognition and management of bipolar disorder. Integrated psychosocial interventions are helpful in decreasing substance abuse. Valproate and naltrexone may decrease alcohol use and citicoline may decrease cocaine use and enhance cognition. Conclusions: There is a very limited number of pharmacotherapy and an even smaller number of psychosocial interventions. Our review highlights the need for more research in this area and for larger, multisite studies with generalizable samples to provide more definite guidance for clinical practice.
Selective late sodium current inhibitor GS‐458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia

Enhanced late sodium current (late INa) in heart failure and long QT syndrome type 3 is proarrhythmic. This study investigated the antiarrhythmic effect and mode of action of the selective and potent late INa inhibitor GS‐458967 (GS967) against Torsades de Pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog.
Enhanced Sensitivity to Subphonemic Segments in Dyslexia: A New Instance of Allophonic Perception

Although dyslexia can be individuated in many different ways, it has only three discernable sources: a visual deficit that affects the perception of letters, a phonological deficit that affects the perception of speech sounds, and an audio-visual deficit that disturbs the association of letters with speech sounds. However, the very nature of each of these core deficits remains debatable. The phonological deficit in dyslexia, which is generally attributed to a deficit of phonological awareness, might result from a specific mode of speech perception characterized by the use of allophonic (i.e., subphonemic) units. Here we will summarize the available evidence and present new data in support of the “allophonic theory” of dyslexia. Previous studies have shown that the dyslexia deficit in the categorical perception of phonemic features (e.g., the voicing contrast between /t/ and /d/) is due to the enhanced sensitivity to allophonic features (e.g., the difference between two variants of /d/). Another consequence of allophonic perception is that it should also give rise to an enhanced sensitivity to allophonic segments, such as those that take place within a consonant cluster. This latter prediction is validated by the data presented in this paper.