Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular modeling of the transmembrane domain of envelope glycoproteins from flaviviridae viruses

The putative transmembrane (TM) domains of the envelope glycoproteins from the family Flaviviridae consist of a highly polar segment in between two hydrophobic stretches. This type of sequence pattern does not yet exist in the database of high resolution structures of membrane proteins. Mutagenesis studies have shown that the TM domains act as membrane and signal anchors, and are responsible for heterodimerization. In hepatitis C virus (HCV), the TM domains of the envelope glycoproteins E1 and E2 were hypothesized to heterodimerize via an ion pair of Lys-Asp. Our MD simulations showed that the E1-E2 heterodimer formed by the charged residues located in the core of the lipid bilayer stabilized the helical conformation of E2. We compared the effect of other types of ion pair interactions using engineered peptides and obtained similar results. We found that an Asp amino acid had the strongest kink-inducing effect on the helix when it was located in the middle of a single-pass TM helix. The extended analyses on dengue, Japanese encephalitis, West Nile and bovine viral diarrhea viruses again showed that their putative TM domains behave similarly. All the TM domains of the E1/prM tended to tilt and remain helical in membrane bilayer. In contrast, the TM domains of the E2/E that contain a central Asp residue were severely kinked. Altogether, these TM domains illustrated a similar structural behavior in the lipid bilayer milieu. Die mutmaslichen Transmembran (TM)-Domanen der Hullglykoproteine der Familie Flaviviridae bestehen aus einem hochpolaren Segment zwischen zwei hydrophilen Abschnitten. Diess Sequenzmuster sind noch nicht in der Datenbank hochaufgeloster Strukturen von Membranproteinen enthalten. Gemas Mutagenesestudien agieren die TM-Domanen als Membran- und Signalanker und sind fur die Heterodimerisierung verantwortlich. Im Hepatitis C-Virus (HCV) heterodimerisieren die TM-Domanen der Hullglykoproteine E1 und E2 moglicherweise uber ein Ionenpaar zwischen Lys-Asp. Unsere MD-Simulationen zeigten, dass das E1-E2-Dimer, das durch die geladenen Residuen im Kern der Lipiddoppelschicht gebildet wird, die helikale Konformation von E2 stabilisiert. Der Effekt anderer Ionenpaarinteraktionen in kunstlichen Peptiden fuhrte zu ahnlichen Ergebnissen. Asp in der Mitte einer TM-Helix verursachte den starksten Krummungseffekt. Weitere Analysen mit anderen Flaviviridae (Dengue, Japanese encephalitis, West Nile und bovine viral diarrhea virus) zeigten ebenfalls ein ahnliches Verhalten ihrer mutmaslichen TM-Domanen. Alle TM-Domanen von E1/prM tendierten zur Krummung und blieben in der Membrandoppelschicht helikal. Hingegen waren die TM-Domanen von E2/E, die ein zentrales Asp enthalten, stark gekrummt. Insgesamt zeigten diese mutmaslichen TM-Domanen ein ahnliches strukturelles Verhalten in der Membran.
Effect of Youth Enterprise Development Fund Services on the Growth of Micro and Small Enterprises in Nyando Constituency, Kenya

Article History Received: 05.08. 2018 Accepted: 13.08. 2018 Published: 30.08. 2018 Abstract: The Kenyan government is currently supporting the start-up as well as the growth of youth enterprises, in line with the Medium Term Plan of Vision 2030, by creating a conducive environment and support programmes in order to develop the sector. Despite these efforts, the performance of youth enterprises in Kenya has been miserable. The breadth to which this huge amount of money has influenced the growth and profit margins of these many youth enterprises remains unexplored. Furthermore, there is a lack of enough literature as far as the effect of youth enterprise development fund on the growth of MSEs. This research, therefore, sought to establish the effect of Youth Enterprise Development Fund services on the growth of MSEs in Nyando Constituency. The objectives that guided this study include: to determine the effect of YEDF lending financing services on growth of youth MSEs in Nyando Constituency; to determine the effect of YEDF linkage services with large enterprises on growth of youth MSEs in Nyando Constituency; to establish the effect of YEDF marketing services on growth of youth MSEs locally and internationally in Nyando Constituency and to determine the extent to which YEDF provides Business Development Services to Youth MSEs in Nyando Constituency. A descriptive survey research design was employed. This study was carried out in Nyando Constituency and targeted 1,348 beneficiaries of Youth Enterprise Development Fund in Nyando Constituency funded from January 2015 to December 2017. The study employed stratified sampling and simple random sampling techniques to sample 308 respondents from the 5 wards in Nyando constituency. Data was collected using self-administered structured questionnaires and analysed using both descriptive and inferential statistics. Frequencies and percentages were used to analyse the demographic data, and the multiple regression model equation was used to determine if the independent variables (YEDF Services) together predicted the dependent variable (MSEs Growth). The findings are presented in the form of bar graphs, pie charts, and tables. The study established that YEDF Lending Financing Services, Business Development, Marketing Services significantly (p < 0.05) predicts MSEs growth. Nonetheless, the findings established that there was no significant association (p > 0.05) between Market Linkage Services and MSEs Growth. In summary, Youth Enterprise Development Fund offers MSEs a good chance of accessing the funds needed for them to either start or expand their businesses. However, the study established that YEDF has not achieved the MSEs growth as it was anticipated. While it seems to have made some impact on MSEs growth, some of the YEDF services such as market linkage services still lagged behind. Therefore, YEDF needs to strengthen market linkages services to balance the supply side and the demand side for the objective of developing a specific enterprise.
Rewriting History II: The (Un)Predictable Past of ESG Ratings

The explosion in ESG research has lead to a strong reliance on ESG rating providers. We document widespread changes to the historical ratings of Refinitiv ESG, formerly ASSET4, a key rating provider. Across two downloads in 2018 and 2020, we document large rewritings in ESG ratings, which are systematic and partially related to firm characteristics. The retrospective rating changes have important implications for researchers and investment professionals. Depending on whether the original or rewritten data are used, rankings and classifications of firms into ESG quintiles change. We demonstrate that these changes affect tests that relate ESG ratings to stock returns.
Modeling pesticide removal efficiency by vegetative filter strip under PWC scenarios

Vegetative filter strip (VFS) is an agricultural best management practice (BMP) recommended by U.S. Natural Resources Conservation Service to reduce pesticide pollution to surface water (USDA, 2000). VFS has been required or recommended for agricultural applications of some pesticide products including pyrethroids and neonicotinoids. For example, many bifenthrin product labels required a 10-ft VFS between the field edges and down gradient aquatic habitat (USEPA, 2008). For imidacloprid, applications within 10 ft of aquatic areas are prohibited to allow growth of a VFS. There is no standard procedure to evaluate pesticide fate and transport in a VFS under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) modeling framework. Therefore, the mitigation effectiveness of a VFS has not been considered in the recent ecological risk assessments (ERAs) on pyrethroids and imidacloprid by U.S. Environmental Protection Agency (USEPA, 2016b, a). For research and development purpose, quantitative assessment of VFS is usually implemented with the Vegetative Filter Strip Model (VFSMOD) (Muñoz-Carpena et al., 1999; Muñoz-Carpena and Parsons, 2004) for hydrological simulations and customized procedures for pesticide trapping effects (including adsorption, infiltration, and dissipation).
Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response

Simple Summary The future of cancer immunotherapy relies on a combination of individually targeted therapies. However, a lot of experiments are needed to define the most effective combinations of drugs. A computational and modelling approach could help reduce the number of experiments and suggest optimal treatments to test. This article presents a logical model of T cell activation influenced by immune checkpoints, and explores the effect of these checkpoints, suggests mechanisms that would explain why some treatments might be better suited than others. The model includes not only programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTL4) downstream pathways but also those of other immune checkpoints such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), cluster of differentiation 226 (CD226), inducible T-cell costimulator (ICOS), and tumour necrosis factor receptors (TNFRs). Abstract After the success of the new generation of immune therapies, immune checkpoint receptors have become one important center of attention of molecular oncologists. The initial success and hopes of anti-programmed cell death protein 1 (anti-PD1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapies have shown some limitations since a majority of patients have continued to show resistance. Other immune checkpoints have raised some interest and are under investigation, such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), inducible T-cell costimulator (ICOS), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which appear as promising targets for immunotherapy. To explore their role and study possible synergetic effects of these different checkpoints, we have built a model of T cell receptor (TCR) regulation including not only PD1 and CTLA4, but also other well studied checkpoints (TIGIT, TIM3, lymphocyte activation gene 3 (LAG3), cluster of differentiation 226 (CD226), ICOS, and tumour necrosis factor receptors (TNFRs)) and simulated different aspects of T cell biology. Our model shows good correspondence with observations from available experimental studies of anti-PD1 and anti-CTLA4 therapies and suggest efficient combinations of immune checkpoint inhibitors (ICI). Among the possible candidates, TIGIT appears to be the most promising drug target in our model. The model predicts that signal transducer and activator of transcription 1 (STAT1)/STAT4-dependent pathways, activated by cytokines such as interleukin 12 (IL12) and interferon gamma (IFNG), could improve the effect of ICI therapy via upregulation of Tbet, suggesting that the effect of the cytokines related to STAT3/STAT1 activity is dependent on the balance between STAT1 and STAT3 downstream signalling.
Do Eicosapentaenoic Acid and Docosahexaenoic Acid Have the Potential to Compete against Each Other?

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 polyunsaturated fatty acids (PUFAs) consumed in low abundance in the Western diet. Increased consumption of n-3 PUFAs may have beneficial effects for a wide range of physiological outcomes including chronic inflammation. However, considerable mechanistic gaps in knowledge exist about EPA versus DHA, which are often studied as a mixture. We suggest the novel hypothesis that EPA and DHA may compete against each other through overlapping mechanisms. First, EPA and DHA may compete for residency in membrane phospholipids and thereby differentially displace n-6 PUFAs, which are highly prevalent in the Western diet. This would influence biosynthesis of downstream metabolites of inflammation initiation and resolution. Second, EPA and DHA exert different effects on plasma membrane biophysical structure, creating an additional layer of competition between the fatty acids in controlling signaling. Third, DHA regulates membrane EPA levels by lowering its rate of conversion to EPA’s elongation product n-3 docosapentaenoic acid. Collectively, we propose the critical need to investigate molecular competition between EPA and DHA in health and disease, which would ultimately impact dietary recommendations and precision nutrition trials.
Lignin as a renewable aromatic resource for the chemical industry

Valorization of lignin plays a key role in the further development of lignocellulosic biorefinery processes for biofuels and biobased materials production. Today’s increased demand for alternatives to fossil carbon-based products expands the interest and the need to create added value to the unconverted lignin fraction. The aim of the research was to study the potential of lignin to become a renewable aromatic resource for the chemical industry. Lignin can be considered as an abundantly available and cheap raw material for the manufacturing of an array of products. Development of applications needs to go hand in hand with the anticipated increased production of technical lignins derived from the pulp and paper industry and the emerging lignocellulosic biorefinery industry. Two promising lignin applications are studied in this thesis: 1) the use of lignin in wood adhesives 2) the use of lignin for the production of aromatic chemicals PCA modeling was performed aimed at the prediction of the application potential of different technical lignins for wood adhesive production. The lignins and their fractions could be classified in different clusters based on their structure dependent properties. Lignins exhibiting sufficient reactive sites, medium molar mass and low level of impurities are most promising candidates for the development of lignin based wood adhesives. Both lignin reactivity and formaldehyde-free crosslinking agents are needed to develop emission-free adhesives. Periodate oxidation was studied as method to improve the lignin reactivity. Alternatives to formaldehyde- based glues are under investigation and a combination of lignin and furans might be an interesting concept to develop renewable adhesives. In this research a reliable SEC methodology was developed for the analysis of the molar mass distribution of a wide range of different lignins. The major drawback of this method is that the molar masses are calculated on a relative basis to sulfonated polystyrenes. Using MALDI-TOF-MS and prior fractionation of lignin did not solve all problems associated with the determination of the absolute molar mass of lignin. Supercritical depolymerisation of lignin using a carbon dioxide/acetone/water fluid resulted in a depolymerised lignin oil. In this oil some monomeric compounds are present in relatively high amounts up to 3.6% (based on dry lignin). These products maybe further isolated by downstream processing to obtain purified fine chemicals. For continuous operation of this supercritical process, the formation of char should be further limited. The results presented in this thesis are expected to contribute - together with the many on-going activities worldwide - to the increased commercial utilisation of lignin in the future. Moreover, the obtained results contribute to the increasing knowledge on lignin analysis, chemistry and reactivity.
Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein

Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the SERPINA1 gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.
Utility of tricuspid annular plane systolic excursion normalized by right ventricular size indices in dogs with postcapillary pulmonary hypertension

Abstract Background Tricuspid annular plane systolic excursion (TAPSE) is a common right ventricular (RV) function indicator. However, TAPSE was not decreased in dogs with myxomatous mitral valve disease (MMVD) and postcapillary pulmonary hypertension (PH) because of its load, angle, and body weight dependency, and TAPSE was considered a preload‐dependent index. Objectives To evaluate the utility of TAPSE normalized by RV size in dogs with postcapillary PH. Animals Twenty healthy dogs and 71 MMVD dogs with or without PH. Methods In this prospective observational study, end‐diastolic RV internal dimension (RVIDd), end‐diastolic and end‐systolic RV area, and end‐diastolic RV wall thickness were measured as RV size indices. The TAPSE was measured using B‐mode and M‐mode methods. Normalized TAPSE was calculated by dividing TAPSE by each RV size index. The RV strain was obtained as the detailed RV function using 2‐dimensional speckle tracking echocardiography. All indices were compared among the PH severity groups and in the presence of right‐sided congestive heart failure (R‐CHF). Results Although nonnormalized TAPSE was higher with PH severity progression, each normalized TAPSE showed a significant decrease in the severe PH group (P < .05). The TAPSEB‐mode/RVIDd ratio had high area under the curve to predict R‐CHF and had moderate correlation with RV strain (P < .05). The TAPSEB‐mode/RVIDd and left atrial‐to‐aortic diameter ratios were independent predictors for R‐CHF. Conclusions and Clinical Importance Normalized TAPSE could reflect RV systolic dysfunction in dogs with severe PH, which could not be detected by nonnormalized TAPSE. The TAPSEB‐mode/RVIDd ratio might predict R‐CHF with high sensitivity and reproducibility.
ΜiR-182-5p functions as a tumor suppressor to sensitize human ovarian cancer cells to cisplatin through direct targeting the cyclin dependent kinase 6 (CDK6).

PURPOSE Ovarian cancer has a difficult diagnosis and high mortality rate. Cisplatin, a platinum compound agent which has been widely used in the clinical treatment of ovarian cancer. However, development of chemoresistance is a major obstacle that limits the therapeutic efficacy. The precise roles and molecular mechanisms of cisplatin resistance in ovarian cancer remain unclear. METHODS The expressions of microRNA (miR)-182-5p and CDK6 mRNA from ovarian tumors and cell lines were detected by qRT-PCR. MiR and siRNA were transfected into ovarian cancer cells using Lipofectamine 2000 transfection reagent. Cisplatin resistant ovarian cancer cell line was established by exposing parental cells to gradually increased cisplatin doses. The binding of miR-182-5p on CDK6 3'UTR was predicted from Targetscan.org and validated by Western blot and dual luciferase reporter assay. The cell viability was determined by MTT assay. RESULTS miR-182-5p is downregulated in ovarian cancer tissues and cells. Overexpression of miR-182-5p significantly sensitized ovarian cancer cells to cisplatin. By creating cisplatin resistant cell line SKOV3, we observed miR-182-5p was apparently downregulated in cisplatin resistant cells. In addition, we identified cyclin-dependent kinase-6 (CDK6) as a direct target of miR-182-5p in both ovarian cancer cell line and patient tissues. Moreover, CDK6 was found to be upregulated in ovarian cancer and displayed and inverted expression pattern with miR-182-5p in ovarian cancer tissues. Silencing CDK6 by siRNA significantly increased the cisplatin sensitivity. Importantly, restoration of CDK6 in miR-182-5p overexpressed ovarian cancer cells successfully recovered the cisplatin resistance. CONCLUSIONS miR-182-5p plays a tumor suppressive role in cisplatin resistance via direct targeting the CDK6, showing miR-182-5p-CDK6 axis as a promising therapeutic target against chemoresistant ovarian cancer.
Dermoscopic characterization of guttate psoriasis, pityriasis rosea, and pityriasis lichenoides chronica in dark skin phototypes: An observational study

Dermoscopy as a diagnostic tool is attaining impetus in inflammatory dermatoses with the cumulative description of characteristic findings in most dermatoses obviating at times the need of biopsy. In this retrospective observational study, 20 histopathology confirmed cases each of pityriasis rosea (PR), guttate psoriasis (GP), and pityriasis lichenoides chronica (PLC) seen over a period of 3 years were included. Dermoscopy images were extracted from photography archives for evaluation and three lesions from each patient (60 lesions each) were analyzed. Comparison of dermoscopy characters was done among PR, GP, and PLC in pairs using chi‐square test and a P‐value of less than . 05 was considered significant. Most common background color in PR (86.7%) and PLC (96.7%) was yellow to yellow‐orange and in GP was dull red to pink (70%). Vessels were visualized in all lesions of GP and most characteristic pattern was regular (93.3%), dotted vessels (95%). In PR 63.3% lesions had dotted vessels mostly in a patchy distribution (56.7%). Most prominent scale color in PR was yellow‐white (88.3%) and in GP was white‐gray (80%). In PLC varying colors were seen, most prominent being brown (53.3%). Characteristic findings seen only in PLC were hypopigmented areas (13.3%), brown dots and globules (53.3%) and orange‐yellow structureless areas (61.7%) GP, PR, and PLC reveal specific dermoscopic findings that can help in differentiating them. Further, the known dermoscopic criteria for GP, PR, and PLC also apply for dark skin phototypes.
Scrotal erythema and geographic tongue subsequent to multikinase inhibiting therapy with Pazopanib

Dear Editor, Pazopanib is a multikinase inhibitor acting on VEGFR (vascular endothelial growth factor receptor) and related tyrosine kinases. It is approved for the treatment of metastatic renal cell carcinoma and advanced soft tissue sarcoma. Skin reactions are among the most common adverse effects of kinase inhibitors. For Sorafenib or Sunitinib, multikinase inhibitors with a similar VEGFR-centered spectrum as Pazopanib, a wide range of cutaneous manifestations, including scrotal erythema and exanthematous eruptions, have been described. However, skin changes secondary to Pazopanib are rarely documented. In trials with Pazopanib, dermatologic reactions did not play a dose-limiting role. In the phase 1 study, hair depigmentation, alopecia, skin hypopigmentation, and rash were observed while the phase 2 study does not mention skin reactions. Benign migratory glossitis secondary to VEGF inhibitors has been described by different authors. In contrast to the asymptomatic spontaneous form, patients with drug induced migratory glossitis often reported dysgeusia, burning sensations, and pain. In June 2019, a 54-year-old patient was referred to our clinic. He reported itchy skin changes on the abdomen and the genitals and a strange feeling on his tongue with impaired taste sensation. He had been diagnosed with a metastatic fibrous epithelioid spindle cell tumor 6 years ago. After extensive treatment including surgery and radiation, he started systemic treatment with Pazopanib in April 2019, about 4 weeks prior to the occurrence of dermatologic side effects. Clinical examination of his tongue revealed demarcated erythematous areas of atrophy with surrounding hyperkeratosis, the typical features of benign migratory glossitis (Figure 1). On the trunk, a discrete papular exanthema was observed (Figure 2). The genital area showed hypopigmentation in the inguinal folds and erythema with slight maceration on the scrotum and the perineum (Figure 3 A). Swabs of the scrotal folds ruled out fungal infection.