Miracle-dz/UniFAR-FTUs huggingface dataset:
Yeast killer toxins, molecular mechanisms of their action and their applications

Abstract Killer toxins secreted by some yeast strains are the proteins that kill sensitive cells of the same or related yeast genera. In recent years, many new yeast species have been found to be able to produce killer toxins against the pathogenic yeasts, especially Candida albicans. Some of the killer toxins have been purified and characterized, and the genes encoding the killer toxins have been cloned and characterized. Many new targets including different components of cell wall, plasma membrane, tRNA, DNA and others in the sensitive cells for the killer toxin action have been identified so that the new molecular mechanisms of action have been elucidated. However, it is still unknown how some of the newly discovered killer toxins kill the sensitive cells. Studies on the killer phenomenon in yeasts have provided valuable insights into a number of fundamental aspects of eukaryotic cell biology and interactions of different eukaryotic cells. Elucidation of the molecular mechanisms of their action will be helpful to develop the strategies to fight more and more harmful yeasts.
Multiple Introductions of Dengue 2 Virus Strains into Saudi Arabia from 1992 to 2014.

INTRODUCTION Dengue is a significant arboviral infection that represents a major public health concern worldwide. The infection is endemic in most parts of South East Asia, sub-Saharan Africa, and Latin America. Among the four dengue virus (DENV) serotypes, DENV-2 has been reported to be the predominant serotype in Saudi Arabia since 1992. However, virological and epidemiological data of DENV-2 from Saudi Arabia are severely deficient and require further investigations. METHODS Full genome sequencing of a recent DENV-2 isolate and phylogenetic analysis of all available DENV-2 sequences from Saudi Arabia. RESULTS Based on full genome and envelope (E) gene sequence, we show that a recent isolate (DENV-2-Jeddah-2014) belongs to the Indian subcontinent lineage of the Cosmopolitan genotype with close similarity to recent strains from Pakistan. Interestingly, the E gene sequence of DENV-2-Jeddah-2014 isolate was slightly divergent from those previously identified in Saudi Arabia between 1992 and 2004 with three to nine amino acid (aa) substitutions. While our data show that the Cosmopolitan genotype is still circulating in Saudi Arabia, they highlight four distinct genetic groups suggesting at least four independent introductions into the Kingdom. CONCLUSIONS The close clustering of DENV-2 isolates reported from Saudi Arabia between 1992 and 2014 with strains from countries providing the highest numbers of pilgrims attending either Hajj or Umrah pilgrimages (Indonesia, Pakistan, India) clearly suggests a role for pilgrims or expatriates coming from DENV endemic countries in DENV-2 importation into Saudi Arabia. Accordingly, continuous monitoring of the circulation of DENVs in Saudi Arabia must be implemented to undertake effective control and management strategies in the Kingdom. Screening of the pilgrims coming to perform Hajj and Umrah might help prevent the introduction of new DENV strains, which is expected to increase the burden of the disease not only in Saudi Arabia but also in other countries.
A systematic review of antimicrobial resistance of typhoidal Salmonella in India

Background & objectives: The temporal trends in the development of antimicrobial resistance (AMR) among Salmonella Typhi and Salmonella Paratyphi in India have not been systematically reported. We aimed to systematically review the temporal AMR trends (phenotypic and molecular mechanisms) in bacterial isolates from patients with enteric fever over two decades in India. Methods: To identify trends in AMR in India, resistance patterns among 4611 individual S. Typhi isolates and 800 S. Paratyphi A isolates, reported from 1992 to 2017 in 40 publications, were analysed. Molecular resistance determinants were extracted from 22 publications and also reviewed in accordance with the PRISMA guidelines. Articles were sourced using a predefined search strategy from different databases. Results: The analyses suggested that multidrug-resistant (MDR) enteric fever was declining in India and being replaced by fluoroquinolone (FQ) resistance. Mutations in gyrA and parC were key mechanisms responsible for FQ resistance, whereas MDR was largely driven by resistance determinants encoded on mobile genetic elements (plasmids, transposons). Interpretation & conclusions: The results reflect the effect of antimicrobial pressure which has been driving AMR in typhoidal Salmonella in India. Understanding these trends is important in planning future approaches to therapy, which serve as a baseline for assessment of the impact of new typhoid conjugate vaccines against these resistant organisms.
Molecular characterization & epidemiology of carbapenem-resistant Acinetobacter baumannii collected across India

Background & objectives: Acinetobacter baumannii is an opportunistic pathogen responsible for causing nosocomial infections. A. baumannii develops resistance to various antimicrobial agents including carbapenems, thereby complicating the treatment. This study was performed to characterize the isolates for the presence of various β-lactamases encoding genes and to type the isolates to compare our clones with the existing international clones across five centres in India. Methods: A total 75 non-repetitive clinical isolates of A. baumannii from five different centres were included in this study. All the isolates were confirmed as A. baumannii by bl aOXA-51-likePCR. Multiplex PCR was performed to identify the presence of extended spectrum β-lactamases (ESBL) and carbapenemases. Multilocus sequence typing was performed to find the sequence type (ST) of the isolates. e-BURST analysis was done to assign each ST into respective clonal complex. Results: blaOXA-51-likewas present in all the 75 isolates. The predominant Class D carbapenemase was blaOXA-23-likefollowed by Class B carbapenemase, blaNDM-like. Class A carbapenemase was not observed. blaPER-likewas the predominant extended spectrum β-lactamase. ST-848, ST-451 and ST-195 were the most common STs. Eight-novel STs were identified. e-BURST analysis showed that the 75 A. baumannii isolates were clustered into seven clonal complexes and four singletons, of which, clonal complex 208 was the largest. Interpretation & conclusions: Most of the isolates were grouped under clonal complex 208 which belongs to the international clonal lineage 2. High occurrence of ST-848 carrying blaOXA-23-likegene suggested that ST-848 could be an emerging lineage spreading carbapenem resistance in India.
Relationship between anti-acetylcholine receptor antibody titres and severity of myasthenia gravis.

OBJECTIVE To study the relationship of anti acetylycholine receptor antibody (AchR-Ab) titres with the demographic profile and severity of myasthenia gravis (MG). METHODS This prospective study was carried out on inpatients and outpatients at the Department of Neurology at Pakistan Institute of Medical Sciences, Islamabad. Seropositive cases of myasthenia gravis were collected and were classified as having low AchR-Ab titres (< 50 nmol/L) and high AchR-Ab titres (> 50 nmol/L). The comparison of these patients was done using the following parameters: sex, age, clinical presentations, severity of the disease, repeated nerve stimulation test, prostigmine test, the association with thymus status, other autoimmune diseases, and therapeutic outcome. RESULTS Out of a total 71 seropositive MG patients enrolled in the study, forty one (57.7%) patients had low titres and thirty (42.2%) had high titres. Their mean age was 33.18 +/- 12.99 years (range 13-70) and thirty eight of them were females. The AchR-Ab titers were higher in the younger age group and in women than in men, however, the results were statistically insignificant. The most common presenting symptoms were ocular (91%), followed by generalized weakness with easy fatiguability (57%) and bulbar weakness (46.4%). Majority of the patients at the time of presentation were in Osserman's stage III (43%); while 26% and 19.7% were in stage IIA and IIB respectively. There was no association between the AchR-Ab titers and clinical grades of Osserman's classification. CONCLUSION Serum concentration of anti acetylcholine receptor antibodies do not relate with the clinical severity of myasthenia gravis.
GSK-3 Represses Growth Factor-inducible Genes by Inhibiting NF-κB in Quiescent Cells*

GSK-3 is active in the absence of growth factor stimulation and generally acts to induce apoptosis or inhibit cell proliferation. We previously identified a subset of growth factor-inducible genes that can also be induced in quiescent T98G cells solely by inhibition of GSK-3 in the absence of growth factor stimulation. Computational predictions verified by chromatin immunoprecipitation assays identified NF-κB binding sites in the upstream regions of 75% of the genes regulated by GSK-3. p50 bound to most of these sites in quiescent cells, and for one-third of the genes, binding of p65 to the predicted sites increased upon inhibition of GSK-3. The functional role of p65 in gene induction following inhibition of GSK-3 was demonstrated by RNA interference experiments. Furthermore, inhibition of GSK-3 in quiescent cells resulted in activation of IκB kinase, leading to phosphorylation and degradation of IκBα and nuclear translocation of p65 and p50. Taken together, these results indicate that the high levels of GSK-3 activity in quiescent cells repress gene expression by negatively regulating NF-κB through inhibition of IκB kinase. This inhibition of NF-κB is consistent with the role of GSK-3 in the induction of apoptosis or cell cycle arrest in cells deprived of growth factors.
Evaluating the effect of direct-acting agents on liver fibrosis, by real-time elastography, Fibroscan and FIB4 score in chronic HCV patients

Background One of the most important questions is what happens with liver fibrosis following a sustained virological response (SVR), although the current anti-HCV therapies were not designed to be antifibrotic. Liver biopsy was replaced by multiple noninvasive means, which were validated in chronic HCV patients, such as Fibroscan, seromarkers such as aminotransferase-to-platelet ratio index (APRI) and FIB4 scores, and new nonvalidated means such as real-time elastography (RTE). The aim of the study was to evaluate the early changes of liver fibrosis after direct-acting agents (DAAs) using these noninvasive means. Materials and methods This was a prospective study that included 200 chronic HCV-naive patients during the period spanning from December 2014 to January 2016. All patients received sofosbuvir − based treatment regimen (with or without pegylated interferon). They were evaluated using Fibroscan, RTE, APRI and FIB4 scores at the baseline and SVR24. Results All the studied patients showed a statistically significant decline in ALT, AST, liver stiffness (by Fibroscan), elasticity index (RTE), FIB4 score and APRI score, regardless of the response to DAAs. Moreover, there was a significant increase in platelet count from baseline to SVR24. The average improvement of the liver stiffness in different fibrosis stages was 22%. There was a positive correlation between stiffness score and all other fibrosis markers before and after treatment. Conclusion There was a significant improvement of liver stiffness after 12 weeks of end of treatment, regardless of the DAA regimen used, and regardless of the treatment outcome (response), as evidenced by Fibroscan, RTE, FIB4 and APRI scores.
Identifying and Aligning Expectations in a Mentoring Relationship

The mentoring relationship between a scholar and their primary mentor is a core feature of research training. Anecdotal evidence suggests this relationship is adversely affected when scholar and mentor expectations are not aligned. We examined three questions: (1) What is the value in assuring that the expectations of scholars and mentors are mutually identified and aligned? (2) What types of programmatic interventions facilitate this process? (3) What types of expectations are important to identify and align? We addressed these questions through a systematic literature review, focus group interviews of mentors and scholars, a survey of Clinical and Translational Science Award (CTSA) KL2 program directors, and review of formal programmatic mechanisms used by KL2 programs. We found broad support for the importance of identifying and aligning the expectations of scholars and mentors and evidence that mentoring contracts, agreements, and training programs facilitate this process. These tools focus on aligning expectations with respect to the scholar’s research, education, professional development and career advancement as well as support, communication, and personal conduct and interpersonal relations. Research is needed to assess test the efficacy of formal alignment activities. Clin Trans Sci 2011; Volume 4: 439–447
Antimicrobial Resistance Among Common Bacterial Pathogens in South Western Nigeria

The phenomenal increase in antibiotic resistant bacterial pathogens calls for regular review of antimicrobial sensitivity pattern among bacteria of clinical significance in an environment. This study was conducted to determine the common clinically significant bacterial pathogens in this environment and their antimicrobial susceptibility pattern. Bacterial pathogens isolated from various clinical specimens brought to the diagnostic laboratory of the University College Hospital between May and October 2005 were subjected to antimicrobial sensitivity testing using the disc diffusion and minimum inhibitory concentration tests. The most prevalent bacterial pathogen was found to be Staphylococcus aureus (47.5%), followed by Pseudomonas aeruginosa (24.6%), Klebsiella species (23%), Proteus species (3.3%) and Escherichia coli (1.6%). P. aeruginosa (24.6%) rated highest in frequency among the Gram-negative organisms while S. aureus was the main Gram-positive pathogen isolated. Generally, resistance rates to most of the antibiotics tested were high among both Gram-positive and Gram-negative isolates. However, both groups showed good susceptibilities to gentamycin and ciprofloxacin. Resistance to the old generation antibiotics such as streptomycin and chloramphenicol, nevertheless, remained persistently high. This study has further revealed that continued surveillance of changes in resistance patterns of bacterial pathogens to antibiotics is of utmost importance if effective management of infectious diseases is to be ensured.
LAW AND THE CONSUMER TRANSACTION : A CASE STUDY OF THE AUTOMOBILE WARRANTYt

Many people have made suggestions about what is the "best" approach to consumer protection regulation. However, Professor Whitford thinks that there has not been enough thought given to the relative effectiveness of these suggested approaches. In his article Professor Whitford analyzes the effectiveness of various approaches for consumer protection regulation of one particular consumer transaction and considers the effectiveness and other factors that together determine the most appropriate type of regulation.
Transmission of HCV infection by RIBA indeterminate and positive blood units

SUMMARY. A retrospective study was carried out on the recipients of 73 units of blood from 53 donors found reactive for anti‐HCV. The donors were screened with anti‐HCV enzyme‐linked immunosorbent assay (ELISA C‐100) and reactivity was confirmed with the first generation recombinant immunoblot assay (RIBA I). Fifty‐two patients were recipients of blood from donors reacting as RIBA I ‘indeterminate’ and 21 of blood from RIBA I ‘positive’ donors. Only three recipients (5.8%) from ‘indeterminate’ donors were anti‐HCV positive indicating that such donors are very seldom infectious. Eleven (52.4%) recipients from ‘positive’ donors had antibodies to HCV, indicating that not all RIBA‐positive donors are necessarily infectious. Pretransfusion samples of the seropositive recipients were unavailable. All samples were analysed with the first generation ELISA and with either the second‐generation ELISA or RIBA (RIBA II) in order to evaluate test sensitivity. RIBA II was more sensitive than RIBA I. One RIBA I indeterminate donor was positive by RIBA II. His recipient had antibodies to HCV. Twelve RIBA I indeterminate and three RIBA I positive donors were negative by RIBA II. All their recipients were anti‐HCV negative. The second‐generation ELISA was also shown to be more sensitive than ELISA C‐100. The second‐generation ELISA detected six confirmed anti‐HCV positive recipients who were negative by ELISA C‐100.
ON THE FORMAL NEIGHBORHOOD OF DEGENERATE ARCS

For any k-point x of a variety X and its image x in the arc space L(X) we prove a structure theorem for the formal neighborhood L(X)x in the case char(k) = 0. In particular, our result implies that, for x singular, there does not exist a decomposition for L(X)x as in the theorem of Grinberg, Kazhdan and Drinfeld.
Common mechanism for the estrogen agonist and antagonist activities of droloxifene

The incidence of postmenopausal osteoporosis is increasing as the population ages. Even though estrogen replacement therapy has proven beneficial in reducing the number of skeletal fractures, the known risks and associated side‐effects of estrogen replacement therapy make compliance poor. Recent research has focused on the development of tissue specific estrogen agonist/anatagonists such as droloxifene which can prevent estrogen deficiency‐induced bone loss without causing uterine hypertrophy. Furthermore, droloxifene acts as a full estrogen antagonist on breast tissue and is being evaluated for treatment of advanced breast cancer. In this report we propose a common mechanism of action for droloxifene that underlies its estrogen agonist and antagonist effects in different tissues. Droloxifene and estrogen, which have identical effects on bone in vivo, both induced p53 expression and apoptosis in cells of in vitro rat bone marrow cultures resulting in a decrease in the number of bone‐resorbing osteoclasts. Droloxifene is growth inhibitory in MCF‐7 human breast cancer cells and therefore acts as an antagonist, whereas estrogen is mitogenic to these cells and acts as an agonist. Droloxifene, but not estrogen, induced p53 expression and apoptosis in MCF‐7 cells. These results indicate that the induction of apoptosis by droloxifene may be the common mechanism for both its estrogen agonist effects in bone and its antagonist effects in breast tissue. J. Cell. Biochem. 65:159–171. © 1997 Wiley‐Liss, Inc.
Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis

Objective: To investigate distinct white matter and cortical gray matter pathology in neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS) at 7-T MRI in a cross-sectional study. Methods: We included 10 patients with NMOSDs and 18 patients with MS in our 7-T MRI study. The imaging protocol comprised T2*-weighted fast low angle shot and turbo inversion recovery magnitude sequences. White matter and cortical gray matter lesions were assessed with special regard to their (perivascular) localization as well as the expression of a hypointense rim. Results: In total, we detected 140 white matter lesions in 7 of 10 patients with NMOSDs. In contrast to MS plaques, which were nearly exclusively centered by a small vein (92%) and showed a characteristic hypointense rim (23%), white matter changes in patients with NMOSDs were nonspecific in appearance and were only infrequently neighbored by a blood vessel (49 lesions [35%], p = 0.003). Hypointense rims were very rarely detectable (3 lesions [2%], p < 0.001). Cortical pathology was absent in NMOSDs. In our MS cohort, we detected 36 leukocortical, 8 intracortical, and 8 subpial cortical lesions in 7 of 18 patients. Conclusion: The MRI features of white matter and the absence of cortical gray matter findings substantially differentiate NMOSDs from MS and can be used as a potential marker to distinguish these 2 entities. The fact that cortical pathology is common in MS but is not present in patients with NMOSDs may reflect the difference in the underlying pathogenesis.
Acetate-nonutilizing Mutants of Neurospora crassa II. Biochemical Deficiencies and the Roles of Certain Enzymes

The levels of Krebs cycle, glyoxylate cycle, and certain other enzymes were measured in a wild-type strain and in seven groups of acetate-nonutilizing (acu) mutants of Neurospora crassa, both after growth on a medium containing sucrose and after a subsequent 6-hr incubation in a similar medium, containing acetate as the sole source of carbon. In the wild strain, incubation in acetate medium caused a rise in the levels of isocitrate lyase, malate synthase, phosphoenolpyruvate carboxykinase, acetyl-coenzyme A synthetase, nicotinamide adenine dinucleotide phosphate-linked isocitrate dehydrogenase, citrate synthase, and fumarate hydratase. Isocitrate lyase activity was absent in acu-3 mutants; acu-5 mutants lacked acetyl-coenzyme A synthetase activity; and no oxoglutarate dehydrogenase activity (or only low levels) could be detected in acu-2 and acu-7 mutants. In acu-6 mutants, phosphoenolpyruvate carboxykinase activity was either very low or absent. No specific biochemical deficiencies could be attributed to the acu-1 and acu-4 mutations. The role of several of these enzymes during growth on acetate is discussed.
Functional studies of the PreP peptidasome in Arabidopsis thaliana

Two independent endosymbiotic events gave rise to mitochondria and chloroplasts. Despite the fact that both organelles have their own small genome the majority of organellar proteins are encoded in the nucleus, synthesized in the cytosol and imported into the organelles. The targeting information for most organellar proteins is located in an N-terminal extension called a targeting peptide. Targeting peptides are cleaved off after import by organellar processing peptidases. The cleaved targeting peptides are toxic to organellar functions and are degraded by the PreP peptidasome, the metalloendopeptidase which is the main topic of this thesis.We have overexpressed, purified and determined the first structure of a plant mitochondrial targeting peptide, the F1β presequence from Nicotiana plumbaginifolia, by NMR in a membrane mimetic environment. The structure showed that the targeting peptide formed two helices separated by an unstructured domain. The N-terminal helix being amphipatic. The F1β targeting peptide has been used as a model substrate for the mitochondrial and chloroplast PreP peptidasome. In Arabidopsis thaliana the PreP peptidasome is present as two isoforms, AtPreP1 and AtPreP2. We have shown that both forms are expressed and dually targeted to mitochondria and chloroplasts. Both AtPreP1 and AtPreP2 degrade targeting peptides and other non-related unstructured peptides up to 65 amino acid residues. Substrate specificity studies showed that both PreP isoforms have a preference for positively charged amino acid residues in the P1′ position and small uncharged residues in the P1 position. Mapping of cleavage sites revealed unique cleavage sites for both isoforms. We have generated and characterized both single and double AtPreP1 and AtPreP2 knockouts in A. thaliana. AtPreP1 was shown to be the major isoform. The double knockout exhibited a chlorotic phenotype with altered mitochondrial and chloroplast morphology. Furthermore,mitochondria were partially uncoupled. Throughout the development there was a slower growth rate and 40% lower biomass production. These results show that the PreP peptidasome is important for efficient organellar functions and normal plant development.