Miracle-dz/UniFAR-FTUs huggingface dataset:
Calmodulin Kinase IV–dependent CREB activation is required for neuroprotection via NMDA receptor‐PSD95 disruption

NMDA‐type glutamate receptors mediate both trophic and excitotoxic signalling in CNS neurons. We have previously shown that blocking NMDAR‐ post‐synaptic density‐95 (PSD95) interactions provides significant protection from excitotoxicity and in vivo ischaemia; however, the mechanism of neuroprotection is unclear. Here, we report that blocking PSD‐95 interactions with the Tat‐NR2B9c peptide enhances a Ca2 + ‐dependent protective pathway converging on cAMP Response Element binding protein (CREB) activation. We provide evidence that Tat‐NR2B9c neuroprotection from oxygen glucose deprivation and NMDA toxicity occurs in parallel with the activation of calmodulin kinase signalling and is dependent on a sustained phosphorylation of the CREB transcription factor and its activator CaMKIV. Tat‐NR2B9c‐dependent neuroprotection and CREB phosphorylation are blocked by coapplication of CaM kinase (KN93 and STO‐609) or CREB (KG‐501) inhibitors, and by siRNA knockdown of CaMKIV. These results are mirrored in vivo in a rat model of permanent focal ischaemia. Tat‐NR2B9c application significantly reduces infarct size and causes a selective and sustained elevation in CaMKIV phosphorylation; effects which are blocked by coadministration of KN93. Thus, calcium‐dependent nuclear signalling via CaMKIV and CREB is critical for neuroprotection via NMDAR‐PSD95 blockade, both in vitro and in vivo. This study highlights the importance of maintaining neuronal function following ischaemic injury. Future stroke research should target neurotrophic and pro‐survival signal pathways in the development of novel neuroprotective strategies.
Pharmacologic Management of Types 1 and 2 Diabetes Mellitus and Their Complications in Women of Childbearing Age

The numbers of women of childbearing age with pregestational diabetes mellitus (diabetes existing before pregnancy) are increasing, primarily because more patients are developing type 2 diabetes at younger ages. The teratogenicity associated with hyperglycemia in early pregnancy is well documented, and tight glucose control minimizes the risk of congenital malformation. Preconception planning is essential; thus contraception that does not worsen complications of diabetes is desirable. In addition, because contraceptives are not 100% effective, the treatment of elevated blood glucose levels, hypertension, and dyslipidemia in these women requires consideration of unplanned pregnancy. We summarized the literature to aid clinicians in choosing individualized treatment that minimizes risk in case pregnancy occurs and maximizes benefit in preventing the complications of diabetes. In women with well‐controlled diabetes without vascular disease, all contraceptive methods are safe. Intrauterine devices are recommended due to their minimal effects on risk factors for diabetic complications and their lack of reliance on patient adherence for efficacy. Among insulins, the insulin analogs—insulin lispro, insulin aspart, and insulin detemir—offer patients greater convenience than regular insulin and NPH insulin, and they are safe in case of unplanned pregnancy. Of the noninsulin agents, glyburide and metformin are the safest during pregnancy, but many of the other agents pose minimal risk as long as they are withdrawn during early pregnancy. The risks and benefits of angiotensin‐converting enzyme inhibitors in women with compelling indications must be weighed individually. In hypertensive patients at a high risk for unplanned pregnancy, nifedipine should be considered due to literature supporting its safety during early pregnancy. Pravastatin is recommended for women with dyslipidemia who are using effective contraception because there have been no reports of birth defects with this statin when used during early pregnancy in humans and animals.
Freud's Methodology

X E OF THE MOST critical problems in psychoanalytic thinking has to do with the methodological bases oE its evidence and 0 concepts. The validity and adequacy of psychoanalytic concepts and formulations require a firm methodological underpinning in order that the scientific demands of validation and verification can be met. I t is immediately evident, however, that psychoanalysis cannot submit itself to the validation and verification procedures available to more objective sciences. The nature of the material with which psychoanalysis works imposes severe limitations and qualifications (Neissner, 1966). Freud himself stands out as one of the great scientific figures of his era. His schooling in scientific method and thinking was quite thorough, particularly as a result of his excellent training in neurology and his experience in research before coming to the study oE neuroses (Jones, 1961). Because psychoanalysis is the child of Freud’s scientific thinking, it would serve us well to investigate the way in which he dealt with the intricate and difficult problems of scientific methodology as his thinking about psychoanalysis evolved. Freud’s comments on methodological issues are scattered throughout his works. Our objective in the present study will be to pull together some of the observations in order to get a more consistent and systematic picture of his methodology.
Histoplasma capsulatum Depends on De Novo Vitamin Biosynthesis for Intraphagosomal Proliferation

ABSTRACT During infection of the mammalian host, Histoplasma capsulatum yeasts survive and reside within macrophages of the immune system. Whereas some intracellular pathogens escape into the host cytosol, Histoplasma yeasts remain within the macrophage phagosome. This intracellular Histoplasma-containing compartment imposes nutritional challenges for yeast growth and replication. We identified and annotated vitamin synthesis pathways encoded in the Histoplasma genome and confirmed by growth in minimal medium that Histoplasma yeasts can synthesize all essential vitamins with the exception of thiamine. Riboflavin, pantothenate, and biotin auxotrophs of Histoplasma were generated to probe whether these vitamins are available to intracellular yeasts. Disruption of the RIB2 gene (riboflavin biosynthesis) prevented growth and proliferation of yeasts in macrophages and severely attenuated Histoplasma virulence in a murine model of respiratory histoplasmosis. Rib2-deficient yeasts were not cleared from lung tissue but persisted, consistent with functional survival mechanisms but inability to replicate in vivo. In addition, depletion of Pan6 (pantothenate biosynthesis) but not Bio2 function (biotin synthesis) also impaired Histoplasma virulence. These results indicate that the Histoplasma-containing phagosome is limiting for riboflavin and pantothenate and that Histoplasma virulence requires de novo synthesis of these cofactor precursors. Since mammalian hosts do not rely on vitamin synthesis but instead acquire essential vitamins through diet, vitamin synthesis pathways represent druggable targets for therapeutics.
Gender Analysis of Farmers from the Perspective of Food Security: A Case Study of Owan West Local Government Area of Edo State, Nigeria

This paper examines how three classes of farmers, namely, food -secured, medium food -secured and food -insecured, discriminate with selected variables. Analyses of the data obtained indicate that about 51.7 %, 30% and 18.3% of farmers in Owan Local Government Area are food -insecure, medium food -secure and food -secure, respectively. It was also observed that food -secured farmers cultivate high -value crops such as cocoa, rice, yams (Dioscorea rotundata), have larger farm sizes, operate longer fallow periods and have the capacity to cultivate all their own land. On the other hand, food -insecured farmers own smaller farm holdings, harvest the bounties of nature, notably, volunteer vegetables - Corchorus olitorius, Talinum trianqulare, etc. In addition, the food -insecure group operate shorter fallow periods due to limited land holdings. The medium food -secure farmers lie between these two extremes - food secure and foo- insecure groups. In order to remedy the plight of these rural poor, the paper recommends their inclusion in the nation's special programme for Food Security and the need to serve them through extension delivery.
Bisphenol a Inhibits Testicular Functions and Increases Luteinizing Hormone Secretion in Adult Male Rats

Effects of a xenoblotic estrogen, bisphenol A (BPA), on reproductive functions were investigated using adult male rats. BPA was dissolved into sesame oil and injected sc every day (1 mg/rat) for 14 days. Animals were killed by decapitation after the final administration of BPA, and the trunk blood, pituitary, and testes were collected. Plasma concentrations of prolactin were dramatically Increased and pituitary contents of prolactin were slightly increased in the BPA group compared to the control group. Plasma concentrations of testosterone were decreased and plasma concentrations of LH were increased in BPA-treated rats compared to control rats. Testicular contents of inhibin were decreased in BPA-treated rats compared to control rats, although plasma concentrations of inhibin were not changed after administration of BPA. The testicular response to hCG for progesterone and testosterone release was decreased in BPA-treated rats. Administration of BPA did not change the pituitary response to luteinizing hormone-releasing hormone (LH-RH) in castrated male rats treated with testosterone. Male sexual behavior also was not changed as a result of BPA treatment. These results suggest that BPA directly inhibits testicular functions and the increased level of plasma LH is probably due to a reduction in the negative feedback regulation by testosterone. The testis is probably a more sensitive site for BPA action than the hypothalamus–pitultary axis.
Delay Optimal Scheduling for Cognitive Radio Networks with Cooperative Beamforming

In this paper, we propose an opportunistic scheduling scheme to serve bursty traffics in cognitive radios, where cooperative beamforming is exploited to access busy timeslots or spatial spectrum holes to forward messages without causing interference to primary users. Specifically, based on cooperative beamforming in the physical layer and automatic repeat request for error recovery in the link layer, our proposed scheme strives to balance available spectrum resources, namely temporal and spatial spectrum holes, between the source and the relays so as to greatly reduce the average delay. To analyze the proposed scheme, we then develop a tandem queueing analytical framework, which captures bursty traffic arrival, dynamic availability of spectrum holes, and time-varying channel fading. By modelling it with a multi-dimensional Markov chain, the average delay is derived using a structured matrix-analytical method. Finally, we obtain delay optimal scheduling schemes by jointly optimizing the scheduling parameters. Simulation results reveal that the proposed scheme provides significant quality of service gains over conventional scheduling schemes that access only temporal spectrum holes.
Studies of DNA polymerases alpha and beta from cultured human cells in various replicative states

DNA polymerase activities from HeLa cells and from cultured diploid human fibroblasts in various growth states were compared. α‐Polymerase activities from log phase fibroblasts treated with sodium butyrate and from stationary phase HeLa cells had DEAE‐cellulose elution patterns that differed from those of polymerases from dividing cells. Moreover, α‐ and β‐polymerases from nondividing cells replicated synthetic polymers less faithfully. Although similar changes were observed previously for polymerases from late‐passage and postconfluent early passage fibroblasts, amounts of α‐polymerase activity recovered from nondividing cells in this study did not dramatically decline as they had in the former cases. The α‐polymerase activities from HeLa cells and fibroblasts in various growth states sedimented near 7.5S in 0.4 M KCl and could be inhibited by a monoclonal lgG fraction prepared against KB cell α‐polymerase. By several criteria, there was no significant differences in levels of UV‐stimulated repair synthesis observed in early or late‐passage postconfluent fibroblasts or in log phase fibroblasts treated with sodium butyrate. In summary, levels of α‐polymerase do not necessarily correlate either with replicative activity or with apparent levels of repair synthesis. However, cells with decreased replicative activity always yielded enzyme with decreased fidelity in vitro and altered chromatographic behavior. It appears, therefore, that the alterations observed for α‐polymerase from late‐passage cells may be attributed more generally to the nondividing nature of these cells.
Strength of Partisan and Candidate Ties in India

This study estimates the impact of incumbency on re-election prospects of parties and candidates in India, between 1977 and 2014, for Lok Sabha elections. We make use of regression discontinuity design to estimate the causal effect of incumbency by comparing outcomes in closely fought elections. Results indicate that on an average, incumbent parties are significantly disadvantaged in comparison to non-incumbent parties. Similarly, the causal impact of incumbency on candidates highlights significant disadvantage to the incumbents. Moreover, on comparing the results, we conclude that it is a candidate who is more disadvantaged than a party. This is indicative of stronger ties amongst voters and parties rather than with candidates.
Alcohol home detoxification: a literature review.

There are various definitions, aims and objectives of, and settings for, detoxification. Careful assessment is essential before any client can be detoxified at home. Scales and biological markers exist to aid this process. Close supervision (i.e. two or three home visits a day) is then required for at least 3 days. Supervision of clients can be done by the client's general practitioner (GP) or any member of a primary health care team as long as there is adequate specialist support. Clients can usually complete home detoxification within 9 days. It is safe and clinically effective for the vast majority of problem drinkers. Despite increasing the demand for detoxification, it is also cost-effective because it allows better utilization of in-patient facilities in the short term and should prevent more resources being required further along the treatment continuum. Home detoxification has wide support from both clients and their GPs. Indeed, there are many advantages for the client in detoxifying at home. However in-patient detoxification can never be replaced entirely. There will always be some problem drinkers for whom home detoxification is not a viable alternative (such as those with severe withdrawal symptoms and those lacking a suitable home environment).
Comparative Evaluation of the Cockcroft‐Gault Equation and the Modification of Diet in Renal Disease (MDRD) Study Equation for Drug Dosing: An Opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer‐recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft‐Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 1 0–40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine‐based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.
Essays on Tax Benefit Reforms in a Discrete Choice Framework

Acknowledgements This thesis marks for me the end of my five year research period as an external PhD student at the VU University in Amsterdam. Pursuing a PhD can be a hard journey, but I always took great pleasure in doing that. However, this thesis would not have been possible without the help and support of many persons. I would like to thank those who contributed during this period. First of all, I would like to express my sincere gratitude to my co-promotor Dr. Hans Bloemen for his continuous guidance during this 5 year project. You are one of the few experts on discrete choice labor supply models, and you were always available for my questions and discussions. I would also like to thank my promotor Prof. dr. Maarten Lindeboom for his guidance during the end of my PhD. I would also like to thank the members of my thesis committee, Prof. for reading my thesis and providing valuable comments and suggestions. I am greatly indebted to Egbert Jongen who, as project leader of the MICSIM project, has asked me to join the CPB in 2012. Together we worked intensively on the MICSIM project, had many discussions on discrete choice models and visited many conferences and workshops around the world. I would also like to thank my colleagues at the CPB, particularly my former officemates Leon Bettendorf and Nicole Bosch, and my managers Arjan Lejour and Johannes Hers. I cannot think of a better work environment to finish a PhD. A special thanks to my parents and my sister who have always supported me. And most of all, Maike and my children Willem and Annemijn for all the sacrifices you had to make on my behalf. toename van het arbeidsaanbod met 35,000 voltijdsbanen. termijn 12 Summary As in many OECD countries, the tax system in the Netherlands is complex and tax policy has several objectives. On the one hand, the government implements policies to promote employment: for example, through in-work tax credits and subsidies for childcare. On the other hand, income protection is also an important policy aim of the tax system. This concerns, for example, social welfare as a safety net, insurances against unemployment or disability and various means-tested benefits providing income support. In designing the tax system, policy makers face a trade-off between income equality and economic efficiency. A lower degree of inequality is usually achieved by a …
Treatment of Active Cytomegalovirus Disease with Oral Ganciclovir in Renal Allograft Recipients: Monitoring Efficacy with Quantitative Cytomegalovirus Polymerase Chain Reaction

Treatment regimens of patients with active cytomegalovirus (CMV) disease require 2–3 weeks of intravenous ganciclovir (GCV) with/without CMV hyperimmune globulin. Oral GCV is effective as a prophylactic agent in prevention of CMV disease. Here we explored the utility of oral GCV as a treatment of active CMV disease. Fifteen renal allograft recipients (CMV donor +/recipient –{53%}, CMV donor +/recipient + {40%} or CMV donor –/recipient + {7%}) developed active CMV disease. Cytomegalovirus polymerase chain reaction (CMV‐PCR) tests were performed at the time of presentation and patients were treated with oral ganciclovir 1 g tid (adjusted for renal function). Patients were monitored for efficacy of treatment by assessment of clinical symptoms and CMV‐PCR. Treatment was continued until the CMV‐PCR copy number was negative and symptoms resolved. The mean CMV‐PCR copy number at the time of diagnosis was 580 copies/μg DNA (nl: < 5 copies/μg DNA). After 5–7 days of treatment, the mean copy number was 65 copies/μg DNA. Fourteen of 15 patients responded well to oral ganciclovir, with complete resolution of clinical symptoms and eradication of CMV‐PCR positivity. One patient did not respond to oral ganciclovir therapy due to probable noncompliance. Our data suggest that oral ganciclovir treatment, coupled with careful CMV‐PCR monitoring, may be a reasonable alternative to long‐term intravenous ganciclovir.
Outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients with persistent gestational trophoblastic tumor.

OBJECTIVE To determine the outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients treated with chemotherapy for gestational trophoblastic tumor. METHODS Retrospective record review of patients with gestational trophoblastic tumor who conceived before standard hCG follow-up was completed during 1973-1998. RESULTS Forty-three patients treated for gestational trophoblastic tumors conceived before human chorionic gonadotropin follow-up was completed. The antecedent pregnancy was complete mole in 31 (72.1%) and partial mole in 12 (27. 9%) patients. Of the 43 patients, 39 (90.7%) had stage I, 1 had stage II, and 3 had stage III disease. The mean interval from human chorionic gonadotropin remission to new pregnancy was 6.3 months (range 1-11 months). Ten patients underwent elective termination and four patients were lost to follow-up. Of the remaining 29 patients, 22 (75.9%) had term live births, 3 (10.3%) had preterm delivery, 3 had spontaneous abortion, and 1 (3.5%) had a repeat mole. Two cases of fetal anomalies were detected; one was inherited polydactyly and the other was hydronephrosis. One patient developed choriocarcinoma with lung involvement and underwent cesarean section at 28 weeks; a normal fetus was delivered and no choriocarcinoma was detected in the placenta. CONCLUSION Pregnancies occurring in patients treated for gestational trophoblastic tumor before standard human chorionic gonadotropin follow-up is completed may continue under close clinical surveillance since the majority have a favorable outcome. However, patients should also be advised of the low but important risk of delayed diagnosis in case tumor relapse develops during early subsequent pregnancy.