Miracle-dz/UniFAR-FTUs huggingface dataset:
Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria

Plasmid-borne resistance to fosfomycin in bacteria is due to modification of the antibiotic molecule by a glutathione S-transferase that catalyzes the formation of a covalent bond between the sulfhydryl residue of the cysteine in glutathione and the C-1 of fosfomycin. This reaction results in opening of the epoxide ring of the antibiotic to form an inactive adduct, the structure of which was confirmed by nuclear magnetic resonance. Dialyzed extracts prepared from resistant Escherichia coli strains were unable to modify fosfomycin unless exogenous glutathione was added to the reaction mixtures. Similarly, mutants defective in glutathione biosynthesis were susceptible to fosfomycin, despite harboring a resistance plasmid. Extracts of resistant but not susceptible strains could join glutathione to 1-chloro-2,4-dinitrobenzene, confirming the nature of the enzymatic activity. Adduct formation appeared to be specific for glutathione: none of the other thiols tested (cysteine, N-acetylcysteine, and dithiothreitol) could modify fosfomycin.
Prospects for neuroprotective therapies in prodromal Huntington's disease

Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder characterized by progressive cognitive deterioration, psychiatric disturbances, and a movement disorder. The genetic cause of the illness is a CAG repeat expansion in the huntingtin gene, which leads to a polyglutamine expansion in the huntingtin protein. The exact mechanism by which mutant huntingtin causes HD is unknown, but it causes abnormalities in gene transcription as well as both mitochondrial dysfunction and oxidative damage. Because the penetrance of HD is complete with CAG repeats greater than 39, patients can be diagnosed well before disease onset with genetic testing. Longitudinal studies of HD patients before disease onset have shown that subtle cognitive and motor deficits occur as much as 10 years before onset, as do reductions in glucose utilization and striatal atrophy. An increase in inflammation, as shown by elevated interleukin‐6, occurs approximately 15 years before onset. Detection of these abnormalities may be useful in defining an optimal time for disease intervention to try to slow or halt the degenerative process. Although reducing gene expression with small interfering RNA or short hairpin RNA is an attractive approach, other approaches targeting energy metabolism, inflammation, and oxidative damage may be more easily and rapidly moved into the clinic. The recent PREQUEL study of coenzyme Q10 in presymptomatic gene carriers showed the feasibility of carrying out clinical trials to slow or halt onset of HD. We review both the earliest detectable clinical and laboratory manifestations of HD, as well as potential neuroprotective therapies that could be utilized in presymptomatic HD. © 2014 International Parkinson and Movement Disorder Society
Remarks on Say on Pay: An Unjustified Incursion on Director Authority

These remarks were presented to the Penn Law and Economic Institute's Chancery Court Program on Say on Pay: A Positive Contribution To Corporate Effectiveness and Accountability Or An Unprincipled and Costly Incursion Into Director Authority? Proponents of H.R. 1257 or similar federal legislation entitling shareholders to vote on executive compensation must carry their burden of proving three distinct claims: First, that there is an executive compensation problem justifying legislative intervention. Second, say on pay is an effective solution to the problem. Third, that any such legislative intervention should be imposed at the federal level. If any of these claims fail, the case for a federal say on pay law collapses. In these remarks, I hope to demonstrate that none of the three holds up to close examination.
A Pilot Study of SMILE for Hyperopia: Corneal Morphology and Surface Characteristics of Concave Lenticules in Human Donor Eyes.

PURPOSE To evaluate the corneal morphology and surface characteristics of concave lenticules after small incision lenticule extraction (SMILE) for hyperopia. METHODS SMILE procedures were performed on two human autopsy corneas in vitro to correct +4.00 diopters of hyperopia. Slit-lamp microscopy and anterior optical coherence tomography (OCT) were performed after lenticule creation and extraction. The extracted lenticules and modified corneas were sent for transmission electron microscopy imaging. RESULTS Interlamellar gas bubbles were detected at 3 minutes and almost burst at 30 minutes after lenticule creation. A few interlamellar bubbles were detected after lenticule extraction. There was an obvious interlamellar concave gap under OCT. Transmission electron microscopy showed the front and back surfaces of the lenticules were smooth, with some tissue bridges, cavities, and grooves. CONCLUSIONS A good quality concave lenticule can be created via SMILE for hyperopia. The impact of interlamellar gap on visual quality needs further investigation. [J Refract Surg. 2016;32(10):713-716. ].
Associations Between Chronotype and Salivary Endocrinological Stress Markers

Objectives. To investigate the effect of chronotype on salivary cortisol or salivary α-amylase (sAA). Methods. From 108 male university students, saliva samples were collected in the afternoon (between 15:00 and 17:00). The salivary cortisol and sAA levels were determined with commercial kits. Chronotype was quantitatively evaluated using the Horne and Östberg Morningness–Eveningness Questionnaire. Subjects were categorized into morning types and evening types. Results. The sAA levels were lower in the morning types than in the evening types. We found no significant difference in salivary cortisol levels between the two groups. Conclusions. These findings suggest that the sAA levels may be associated with chronotype.
Regulators of macrophage activation

Macrophages are ubiquitous phagocytes that can constitute up to 15% of the cellular content of tissues. These heterogeneous cells of the innate immune system perform important functions during health and disease. Equipped with receptors for the T helper cell cytokines INF‐γ and IL‐4, macrophages undergo specific activation programs during Th1 or Th2 immune responses. These activation profiles, termed classical (M1) or alternative (M2) activation respectively, are further tuned by the presence and recognition of microbial‐associated molecular patterns, other cytokines, lipids, and even adhesion to the substratum. The activation of macrophages also relies on the maturation background of the cells, elicitation of complicated intracellular signalling cascades, and the crosstalk between the different signalling elements. Of interest, not all genes participating in the activation‐related signalling cascades are equally important for the elicitation of functional profiles and a regulator gene hierarchy is emerging for the different types of activation. In this issue of the European Journal of Immunology, two papers add to our understanding of how cellular kinases and phosphatases, related to the PI3K pathway, regulate M1 or M2 activation programmes in macrophages.
Intercellular communication in the immune system: differential expression of connexin40 and 43, and perturbation of gap junction channel functions in peripheral blood and tonsil human lymphocyte subpopulations

The distribution and function of connexins (integral membrane proteins assembled into gap junction intercellular communication channels) were studied in human lymphocyte subpopulations. The expression of mRNA encoding connexins in peripheral blood and tonsil‐derived T, B and natural killer (NK) lymphocytes was examined. Connexin43 (Cx43) mRNA was expressed in peripheral blood and tonsil lymphocytes, but Cx40 mRNA expression was confined to tonsil‐derived T and B lymphocytes; Cx26, Cx32, Cx37 and Cx45 were not detected by reverse transcription–polymerase chain reaction (RT–PCR). Western blot analysis also demonstrated the presence of Cx40 and Cx43 proteins in T and B lymphocytes in a manner coincidental to the mRNA detection. Stimulation in vitro of T and B lymphocytes with phytohaemagglutinin (PHA) and lipopolysaccharide (LPS), respectively, increased Cx40 and Cx43 protein expression. Flow cytometric analysis, using antibodies to extracellular loop amino acid sequences of connexins, confirmed the surface expression of connexins in all lymphocyte subpopulations. Assembly of connexins into gap junctions providing direct intercellular channels linking attached lymphocytes was demonstrated by using a dye transfer technique. The exchange of dye between lymphocytes was inhibited by a connexin extracellular loop mimetic peptide and α‐glycyrrhetinic acid, two reagents that restrict intercellular communication across gap junctions. Dye coupling occurred between homologous and heterologous co‐cultures of T and B lymphocytes, and was not influenced by their stimulation with PHA and LPS. The connexin mimetic peptide caused a significant decrease in the in vitro synthesis of immunoglobulin M (IgM) by T‐ and B‐lymphocyte co‐cultured populations in the presence or absence of stimulation by PHA. The results identify connexins as important cell surface components that modulate immune processes.
The Implications of Non-timber Forest Products’ Access By-laws on Household Food Security in Semi-arid Zones of Iringa District, Tanzania

Local communities in semi-arid zones of Iringa district are vulnerable to household food insecurity. Their vulnerability is mainly due to their dependence on climatesensitive livelihood sources, especially rain-fed smallholder crop farming. Consumption and sale of non-timber forest products (NTFPs) from Kitapilimwa Forest Reserve (KFR) which is under Joint Forest Management (JFM) offer an opportunity to the local communities to improve their resilience to food insecurity. Though NTFPs are also affected by climate change they are more resilient compared to agricultural crops and livestock. Several management by-laws have been passed to protect KFR from anthropogenic degradation and loss. However, the extent to which the KFR access bylaws affect the availability of NTFPs for enhancing household food security had not been examined. Findings indicated that 76.2% of the respondents were food insecure. Also, it was found that 40.9% and 20.1% of the food insecure households ate and sold NTFPs to enhance household food security respectively. The few types of NTFPs they were permitted to collect, low quantity of NTFPs to be collected, a few visiting days and license fee were reported to be the main KFR management by-laws which impacted on availability of NTFPs for enhancing household security. It is noteworthy that forest conservation by-laws should not compromise local communities’ access to NTFPs. Also, it is good to mainstream customary forest management laws in the formulation of the conventional forest management by-laws.
Constitutional Bargaining, Eminent Domain, and the Quality of Contemporary African Institutions: A Test of the Incremental Reform Hypothesis

According to the incremental reform hypothesis, constitutions are rarely adopted whole cloth; thus the starting point, scope for bargaining, and number of reforms, jointly determine the trajectory of constitutional history. We test the relevance of this theory for Africa by analyzing the formation and reform of the independence constitutions negotiated and adopted during the 1950s and early 1960s. We find historical evidence that independence occurred incrementally and that the African countries that experienced the fewest constitutional moments and narrowest domain of bargaining after independence have better contemporary institutions than states that began with less restrictive constitutional rules and experienced more constitutional moments.
Psychotherapies for adult depression: recent developments

Purpose of review Much has been learned from the 400 randomized trials on psychotherapies for adult depression that have been conducted, but much is also still unknown. In this study some recent attempts to further reduce the disease burden of depression through psychotherapies are reviewed. Recent findings In the past, many new psychotherapies have promised to be more effective than existing treatments, usually without success. We describe recent research on two new therapies, acceptance and commitment therapy and cognitive bias modification, and conclude that both have also not shown to be more effective than existing therapies. A growing number of studies have also focused on therapies that may be successful in further reducing the disease burden, such as treatments for chronic depression and relapse prevention. Other studies are aimed at scaling up psychological services, such as the training of lay health counselors in low-income and middle-income countries, telephone-based, and internet-based therapies. Summary Psychotherapies are essential tools in the treatment of adult depression. Randomized trials have shown that these treatments are effective, and by focusing on key issues, such as chronic depression, relapse, and scaling them up, psychotherapies contribute more and more to the reduction of the disease burden of depression.
Risk factors for hepatitis C virus transmission in colonial Cameroon.

BACKGROUND In southern Cameroon, where SIV(cpz), the source of human immunodeficiency virus 1 (HIV-1) group M, is prevalent among wild chimpanzees, approximately 50% of some human birth cohorts have been infected with hepatitis C virus (HCV) through unclear mechanisms. METHODS To evaluate indirectly the hypothesis that medical interventions contributed to the early emergence of HIV-1, we conducted a cross-sectional study of 451 inhabitants of Ebolowa in southern Cameroon aged 60 years, using HCV as a marker of parenteral transmission of blood-borne viruses. We administered a questionnaire and tested serum for antibodies against HCV. Viral gene sequences were obtained from HCV-positive sera. Molecular clock analyses provided an independent source of information on epidemic history. RESULTS A total of 252 participants (56%) were HCV seropositive. HCV sequences were amplified and genotyped from 171 individuals. Independent risk factors for HCV seropositivity were older age, having received intravenous treatment against malaria, and having attended an ethnic school (women only), whereas having been circumcised by a traditional practitioner (men only) tended to be associated with HCV. In addition, transfusions were associated with HCV genotype 1 transmission. Molecular clock analyses of HCV genotypes 1, 2, and 4 revealed that each independently underwent exponential growth during the first half of the 20th century. CONCLUSIONS Medical interventions (intravenous antimalarial drugs, transfusions) and to a lesser extent traditional practices (circumcision) were associated with the massive transmission of HCV among this population decades ago. This finding supports the hypothesis that medical interventions contributed to the transmission of blood-borne viruses, perhaps including SIV(cpz) and HIV-1, in the same region during the early 20th century.
A prospective, longitudinal study of central venous catheter‐related deep venous thrombosis in boys with hemophilia

Summary. Background: Central venous catheters (CVCs) are often inserted into boys with hemophilia to secure venous access for factor prophylaxis and immune tolerance induction therapy. Complications associated with CVCs include catheter‐related infections, local hemorrhage, and mechanical failure. Less frequently reported is CVC‐related deep venous thrombosis (DVT). We conducted a prospective study to determine the frequency and outcome of this complication. Methods: All boys (n = 16) with congenital hemophilia A or B with a CVC in place who were registered in the pediatric comprehensive care program at the Hospital for Sick Children, Toronto, were included in the study. They were prospectively assessed by imaging studies and clinical examinations for CVC‐related DVT at two time‐points, 2 years apart. Each boy was evaluated for inherited hypercoagulability. Results: Eleven (69%) of the 16 boys had radiological evidence of DVT at the first evaluation and 13/16 (81%) at the second evaluation. In two boys there was improvement in the venogram findings at the second evaluation. None of the CVC‐related DVTs completely resolved. Median age at the time of initial insertion of a CVC was 1.0 years (range 0.02–6.7 years). Median duration of CVC placement was 6.4 years (range 3.3–15.5 years). Only 4/13 boys with DVTs had clinical evidence of upper venous system obstruction. Only one boy, who did not develop a DVT, had a low protein C level. Conclusions: CVC‐related DVTs occur in the majority of boys with hemophilia who have CVCs inserted for a prolonged period of time. Annual screening with imaging is recommended for boys with CVCs in place for ≥ 3 years. Consideration should be given to removing CVCs as soon as peripheral venous access is feasible.
Comparison of the DNA-alkylating properties and mutagenic responses of a series of S-(2-haloethyl)-substituted cysteine and glutathione derivatives.

The mutagenicity of 1,2-dibromoethane is highly dependent upon its conjugation to glutathione by the enzyme glutathione S-transferase. The conjugates thus formed can react with DNA and yield almost exclusively N7-guanyl adducts. We have synthesized the S-haloethyl conjugates of cysteine and glutathione, as well as selected methyl ester and N-acetyl derivatives, and compared them for ability to produce N7-guanyl adducts with calf thymus DNA. The cysteine compounds were found to be more reactive toward calf thymus DNA and yielded higher adduct levels than did the glutathione compounds. Adduct levels tended to be suppressed when there was a net charge on the compound and were not affected by substitution of bromine for chlorine, as expected for a mechanism known to involve an intermediate episulfonium ion. Sequence-selective alkylation of fragments of pBR322 DNA was investigated. The compounds produced qualitatively similar patterns of alkylation, with higher levels of alkylation at runs of guanines. The compounds were also tested for their ability to act as direct mutagens in Salmonella typhimurium TA98 and TA100. None of the compounds caused mutations in the TA98 frameshift mutagenesis assay. In the strain TA100, where mutation of a specific guanine by base-pair substitution produces reversion, all compounds were found to produce mutations, but the levels of mutagenicity did not correlate at all with the levels of DNA alkylation. The ratio of mutations to adducts varied at least 14-fold among the various N7-guanyl adducts examined. (ABSTRACT TRUNCATED AT 250 WORDS)
A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.

BACKGROUND Eliciting an endogenous LH surge by GnRH-agonist for the induction of final oocyte maturation may be more physiological compared with the administration of HCG. However, the efficacy of this intervention in patients treated for IVF with GnRH antagonists remains to be assessed. METHODS 106 patients were randomized to receive either 10 000 IU urinary HCG or 0.2 mg Triptorelin for triggering final oocyte maturation. Ovarian stimulation for IVF was performed with a fixed dose of 200 IU recombinant FSH and GnRH antagonist was started on stimulation day 6. Luteal phase was supported with micronized vaginal progesterone and oral estradiol. The study was monitored continuously for safety and stopping rules were established. RESULTS No significant differences were present in the number of cumulus-oocyte complexes retrieved, in the proportion of metaphase II oocytes, in fertilization rates or in the number and quality of the embryos transferred between the two groups. However, a significantly lower probability of ongoing pregnancy in the GnRH agonist arm prompted discontinuation of the trial, according to the stopping rules established (odds ratio 0.11; 95% confidence interval 0.02-0.52). CONCLUSIONS Lower probability of ongoing pregnancy can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing ovarian stimulation for IVF with GnRH antagonists.
Utility of a modified mini‐mental state examination with extended delayed recall in screening for mild cognitive impairment and dementia among community dwelling elders

The objective of this study was to test the utility of additional delayed recall of the three recall items of the Folstein Mini Mental State Evaluation (MMSE) as a screening measure for mild cognitive impairment and dementia in the elderly. It used a cross‐sectional study of subjects, who were administered a brief memory screening battery which included the MMSE and extended delayed recall of the three MMSE recall items at 5 minute intervals. The criteria for cognitive status was determined on the basis of the neurological and neuropsychological evaluation. One hundred and two elderly persons who were recruited through a memory screening program were diagnosed as cognitively normal (N=52), mild cognitively impaired (N=24), or demented (N=26). The observed sensitivity of 83.3% and specificity of 90.4% was achieved across three delayed recall trials in differentiating cases with mild cognitive impairment (without dementia) from individuals with normal cognition and was superior to the total MMSE score alone (sensitivity/specificity: 70.8%/84.6%). Cumulative recall for the three MMSE items across only two delayed recall trials demonstrated a sensitivity of 96.2% and specificity of 90.4% in differentiating between cases of dementia versus cases diagnosed with no cognitive impairment. The three trial delayed recall score enhanced prediction of mild cognitive impairment in at‐risk elderly living with the community and may have promise in the development of future screening batteries. Copyright © 2000 John Wiley & Sons, Ltd.
Imperatives for Venture Success

This paper reports the findings from a qualitative study involving in-depth interviews with American and Canadian entrepreneurs who had conceptualized and started successful ventures. Respondents were asked to define venture success and then articulate the key imperatives for it. Respondents in this study defined venture success in terms of sales growth and profitability. The study confirms findings from previous studies, concluding that entrepreneurs' personal characteristics, including determination and commitment, work ethic, optimism, energy and fearlessness, are very important to venture success. Imperatives involving specific business activities and practices, including having the right idea/opportunity, the right management team, sharing rewards, and business planning, again, consistent with the literature, were confirmed as being important. However, three key imperatives rarely, if ever, cited in previous literature – focusing on the core business, staying close to the market and delivering customer satisfaction – were also articulated by the respondents.
The development of the board of trustees of Anglo-American College

COLLEGE: A CASE STUDY IN LEADERSHIP AND GOVERNANCE by ROBERT NELSON THOMAS Under the direction of Ronald D. Simpson ABSTRACT This is a study of the development of the board of trustees of Anglo-American College, a private institution of higher education established in Prague, Czech Republic in 1991. The author investigated the development of the board through models and theories used in assessing performance of governing boards in the academic and nonprofit communities in the United States. The findings suggest that these models are beneficial in analyzing the development of the board, but are limited in their potential application. Economic, legal, and cultural factors should be given more weight in advising boards of independent colleges and nonprofit organizations in developing countries. Issues of trust and the relationship between the board and the chief executive officer of the institution are critical to the development of the board.