Miracle-dz/UniFAR-FTUs huggingface dataset:
Infection control awareness among healthcare providers in family health settings in Shebin El-kom district, Menoufia Governorate, Egypt

Objectives The aim of the study was to assess the knowledge, the attitude, and the practice of healthcare providers in family health settings regarding infection control measures in Shebin El-kom district. Background Hospital-acquired infections are among the leading causes of death; prevention of hospital-acquired infection therefore must be cost effective, but achievable even with the limited resources for infection control programs in primary healthcare. Participants and methods This was a cross-sectional study conducted in two urban and two rural family health settings in Shebin El-kom district, Menoufia Governorate. Four different settings were selected from cluster sampling followed by stratified random sampling. The self-administered anonymous questionnaire was administered to 412 participants including physicians, nurses, and paramedical personnel. Each healthcare facility was observed for infection control measures by an observation checklist, followed by comparative analysis of different categories of participants. Results The knowledge scores were low to moderate among all participants; only 32.5% had a high level of knowledge, in comparison with 96.6% of the participants who had a positive attitude towards infection control measures. However, 54.3% of the physicians showed a high practice score in comparison with 32.6% of the nurses. Conclusion Standards of infection control practices were not optimum at family healthcare settings, although the reported practice was better than the reported knowledge. Further studies are required to determine the other factors associated with compliance of infection control practices, and training courses on hospital-acquired infection for such personnel would be required.
The Calcium-binding Proteins S100A8 and S100A9 Initiate the Early Inflammatory Program in Injured Peripheral Nerves*

Background: In peripheral nerves, the initial immune response to injury influences regeneration. Results: S100a8 and S100a9 are the top induced genes in nerves post-injury. S100A8/A9 activate the chemotactic genes and pathways in Schwann cells and stimulate myeloid cell infiltration into the nerve. Conclusion: S100A8/A9 initiate immune cell transmigration into the nerve. Significance: S100A8/A9 are novel modulators of peripheral nerve injury. To shed light on the early immune response processes in severed peripheral nerves, we performed genome-wide transcriptional profiling and bioinformatics analyses of the proximal (P, regenerating) and distal (D, degenerating) nerve stumps on day 1 in the sciatic nerve axotomy model in rats. Multiple cell death-related pathways were activated in the degenerating D stump, whereas activation of the cytoskeletal motility and gluconeogenesis/glycolysis pathways was most prominent in the P stump of the axotomized nerve. Our bioinformatics analyses also identified the specific immunomodulatory genes of the chemokine, IL, TNF, MHC, immunoglobulin-binding Fc receptor, calcium-binding S100, matrix metalloproteinase, tissue inhibitor of metalloproteinase, and ion channel families affected in both the P and D segments. S100a8 and S100a9 were the top up-regulated genes in both the P and D segments. Stimulation of cultured Schwann cells using the purified S100A8/A9 heterodimer recapitulated activation of the myeloid cell and phagocyte chemotactic genes and pathways, which we initially observed in injured nerves. S100A8/A9 heterodimer injection into the intact nerve stimulated macrophage infiltration. We conclude that, following peripheral nerve injury, an immediate acute immune response occurs both distal and proximal to the lesion site and that the rapid transcriptional activation of the S100a8 and S100a9 genes results in S100A8/A9 hetero- and homodimers, which stimulate the release of chemokines and cytokines by activated Schwann cells and generate the initial chemotactic gradient that guides the transmigration of hematogenous immune cells into the injured nerve.
Identification and Pharmacological Inactivation of the MYCN Gene Network as a Therapeutic Strategy for Neuroblastic Tumor Cells*

Background: Neuroblastic tumors are often addicted to the MYCN protooncogene. Results: Using a genome wide shRNA screen, we have identified key MYCN synthetic lethal genes. Conclusion: Chemical inhibition of the newly identified MYCN synthetic lethal genes selectively kills MYCN-amplified cell lines. Significance: Decoding the MYCN gene network will help to develop drugs for the treatment of neuroblastic tumors with activated MYCN. The MYC family of transcription factors consists of three well characterized members, c-MYC, L-MYC, and MYCN, deregulated in the majority of human cancers. In neuronal tumors such as neuroblastoma, MYCN is frequently activated by gene amplification, and reducing its expression by RNA interference has been shown to promote growth arrest and apoptosis of tumor cells. From a clinical perspective, RNA interference is not yet a viable option, and small molecule inhibitors of transcription factors are difficult to develop. We therefore planned to identify, at the global level, the genes interacting functionally with MYCN required to promote fitness of tumor cells facing oncogenic stress. To find genes whose inactivation is synthetically lethal to MYCN, we implemented a genome-wide approach in which we carried out a drop-out shRNA screen using a whole genome library that was delivered into isogenic neuroblastoma cell lines expressing or not expressing MYCN. After the screen, we selected for in-depth analysis four shRNAs targeting AHCY, BLM, PKMYT1, and CKS1B. These genes were chosen because they are directly regulated by MYC proteins, associated with poor prognosis of neuroblastoma patients, and inhibited by small molecule compounds. Mechanistically, we found that BLM and PKMYT1 are required to limit oncogenic stress and promote stabilization of the MYCN protein. Cocktails of small molecule inhibitors of CKS1B, AHCY, BLM, and PKMYT1 profoundly affected the growth of all neuroblastoma cell lines but selectively caused death of MYCN-amplified cells. Our findings suggest that drugging the MYCN network is a promising avenue for the treatment of high risk, neuroblastic cancers.
Adaptation processes of Japanese nurses in Australia

5 ACKNOWLEDGEMENTS 6 CHAPTER ONE INTRODUCTION 7 1. 1 Background 7 1.2 Purpose of the Study 10 1.3 Structure of Thesis 10 1.4 Summary 11 CHAPTER TWO LITERATURE REVIEW 12 2.1 Aim 12 2.2 Search Strategy 12 2.3 Results 17 CHAPTER THREE RESEARCH METHODS 30 3.1 The purpose, aim and significance of the study, domain of inquiry and the Research Question 30 3.2 Research Design 31 3.3 Ethical considerations 32 3.4 Data collection 33 3.4. 1 Selection criteria for informants 33 3.4. 2 Data collection technique 34 3.4. 3 Sample size 35 3.4. 4 Semi-structured interviews 35 3.5 Data analysis 37 CHAPTER FOUR FINDINGS AND DISCUSSION 42 4.
Urological Surgical Procedures Under Local Anesthesia

Surgical procedures under local anesthesia provide unique advantages. They are associated with less patient anxiety antecedent with the use of general or major regional anesthesia. It is also associated with quicker recovery, less day care recovery room stay and earlier returns to work. It is therefore not surprising that there is considerable interest both among patients and surgeons. The impetus for this has been to maximize anesthetic and postoperative resources by increasing patient turnover in the operating room and discharging patients more efficiently on the same day. Patients with significant co-morbidities, with relative or absolute contra-indication to general or major regional anesthesia can also undergo procedures safely. The use of local anesthesia has continued to expand the ability of urologists to perform a variety of procedures in a safer fashion, particularly in high-risk patients. Most of the local procedures are performed in an operating room setting with a nurse anesthetist in attendance that may administer small amounts of additional intravenous sedation during the procedure. The main goal is to have the patient comfortable during the procedure, but also to be awake and conversant. The local anesthesia techniques vary according to site and procedure. Patient selection is critical for the success of any procedure under local anesthesia. The patient must not be overly anxious and must be willing to accept the surgical technique and anesthesia that is described in detail during the preoperative discussion.
Male involvement in reproductive health: a management perspective.

AIMS The present study outlines the perceptions of participants on male involvement in reproductive health (RH) from a management perspective. BACKGROUND Namibia is one of the African countries affected by cultural and socio-economic influences that have persuaded gender roles in a way that hinders male-partner involvement in RH. METHOD A qualitative, exploratory, descriptive design was followed. The target population included all male and female partners attending a health facility and all nurse managers (registered nurses in charge) that provided RH services in the health facility in a northern region in Namibia. Individual interviews were conducted until data saturation occurred. RESULTS The results indicate that the management principles, policy and legislation, as well as resources to facilitate male involvement in RH, were indicated as barriers for nurse managers to facilitate male involvement. CONCLUSION Male involvement in RH care is needed for an interpersonal and interactive partnership. IMPLICATIONS FOR NURSE MANAGERS Recommendations are made to establish a partnership within the current health care framework in which reproductive health is provided.
Multiple Driving Forces Required for Efficient Secretion of Autotransporter Virulence Proteins*

Background: Many virulence proteins are secreted using the autotransporter system. Results: Autotransporter proteins do not fold until secreted and are secreted poorly in the absence of folding. Conclusion: Folding helps drive autotransporter secretion, but another energy source is required for its initiation. Significance: Our conclusions reconcile apparent contradictions in the literature and importantly contribute to understanding and manipulating autotransporter secretion. Autotransporter (AT) proteins are a broad class of virulence proteins from Gram-negative bacterial pathogens that require their own C-terminal transmembrane domain to translocate their N-terminal passenger across the bacterial outer membrane (OM). But given the unavailability of ATP or a proton gradient across the OM, it is unknown what energy source(s) drives this process. Here we used a combination of computational and experimental approaches to quantitatively compare proposed AT OM translocation mechanisms. We show directly for the first time that when translocation was blocked an AT passenger remained unfolded in the periplasm. We demonstrate that AT secretion is a kinetically controlled, non-equilibrium process coupled to folding of the passenger and propose a model connecting passenger conformation to secretion kinetics. These results reconcile seemingly contradictory reports regarding the importance of passenger folding as a driving force for OM translocation but also reveal that another energy source is required to initiate translocation.
Evaluation of self-management interventions for chronic obstructive pulmonary disease.

AIM To evaluate the benefits of self-management interventions on the quality of life of patients with chronic obstructive pulmonary disease. BACKGROUND Chronic obstructive pulmonary disease is one of the most widespread chronic conditions worldwide, and it is predicted to increase over the next decade. Although previous review studies have demonstrated the benefits of self-management interventions on health-care utilisation, their benefits on quality of life are still unclear. METHOD In this systematic review, we examined four randomised controlled trials undertaken between 2000 and 2011 to evaluate the benefits of chronic obstructive pulmonary disease self-management interventions on patient quality of life. RESULTS The main theme that emerged was that self-management interventions improved patient well-being, with three minor themes: reducing the burden on patients, improved patient activity and improved total patient health. CONCLUSION Self-management interventions tend to improve the quality of life of patients with chronic obstructive pulmonary disease. Further randomised controlled trials are recommended to evaluate self-management interventions in chronic obstructive pulmonary disease to confirm these benefits. IMPLICATIONS FOR NURSING MANAGEMENT Nursing management in health services is involved in caring for patients with chronic obstructive pulmonary disease and is responsible for liaising with other members of the health-care team. We recommend that nursing management be engaged in health-care services to develop and implement self-management interventions for chronic obstructive pulmonary disease patients to improve their quality of life.
Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy*

Background: Endoglin is a key regulator of TGF-β signaling in endothelial cells but its role in autophagy during angiogenesis is unknown. Results: Endoglin relieves Smad2-dependent BECN1 repression. Conclusion: Endoglin promotes autophagy during angiogenesis by regulating Smad2 function. Significance: Endoglin-mediated autophagy may be an effective vascular target. Autophagy is the targeted degradation of proteins and organelles critical for homeostasis and cell survival. Transforming growth factor β (TGF-β) differentially regulates autophagy in a context-specific manner, although the precise intracellular mechanisms remain less clear. Importantly, how TGF-β controls autophagic responses in endothelial cells (EC) during angiogenesis is unknown. Here we identified endoglin, an EC-specific TGF-β co-receptor essential for angiogenesis, as a key determinant of autophagy. Among the two opposing TGF-β Smad pathways in the EC system (Smad1/5/8 and Smad2/3), we found Smad2 as the major transcriptional regulator of autophagy that targets beclin1 (BECN1) gene expression. Smad2, but not Smad3, acts as a repressor upstream of the BECN1 promoter region. Overall, endoglin promotes autophagy by impeding Smad2 transcriptional repressor activity. Notably, increased beclin1 levels upon Smad2 knockdown directly correlated with enhanced autophagy during angiogenesis. Taken together, these results establish endoglin as a critical mediator of autophagy and demonstrate a new transcriptional mechanism by which Smad2 inhibits angiogenesis.
Russian mortality beyond vital statistics

Analyses of routine data have established that the extreme mortality fluctuations among young and middle-aged men are the most important single component of both temporal changes in Russian life expectancy at birth and in the gap between male and female life expectancy. It is also responsible for the largest share of the life expectancy gap between Russia and other industrialised countries. A case-control study has been used to identify factors associated with mortality among men aged 20 to 55 in the five major cities of the Udmurt Republic in 1998-99. Men dying from external causes and circulatory disease are taken as cases. Matched controls were selected from men of the same age living in the same neighbourhood of residence. Information about characteristics of cases and controls was obtained by interviewing proxies who were family members or friends of the subjects. After exclusion of those deaths for which proxy informant could not be identified, a total of 205 circulatory disease and 333 external cause cases were included together with the same number of controls. Educational level was significantly associated with mortality from circulatory diseases and external causes in a crude analysis. However, this could largely be explained by adjustment for employment, marital status, smoking and alcohol consumption. Smoking was associated with mortality from circulatory disease (crude OR=2.44, 95% CI 1.36-4.36), this effect being slightly attenuated after adjustment for socio-economic factors and alcohol consumption. Unemployment was associated with a large increase in the risk of death from external causes (crude OR=3.63, 95% CI 2.17-6.08), an effect that was still substantial after adjustment for other variables (adjusted OR=2.52, 95% CI 1.43-4.43). A reported history of periods of heavy drinking was linked to both deaths from circulatory disease (crude OR=4.21, 95% CI 2.35-7.55) and external cause mortality (crude OR=2.65, 95% CI 1.69-4.17). Adjustment for other variables reduced the size of these odds ratios, but they remained strikingly large for circulatory disease (adjusted OR=3.54, 95% CI 1.76-7.13) and considerable for external causes (adjusted OR 1.75, 95% CI 1.02-3.00). These may be underestimates of the true effects as nearly all of them increased when employment status (which can in part at least be seen as being on the causal pathway) was excluded from the final model. In summary, however, our key finding is that a history of heavy drinking in the recent past is strongly associated with risk of death from circulatory disease. This provides the first individual-level evidence in support of the hypothesis that episodic heavy drinking is key to explaining the heavy burden of circulatory disease mortality among Russian men of working age.
Endoplasmic Reticulum Exit of Golgi-resident Defective for SREBP Cleavage (Dsc) E3 Ligase Complex Requires Its Activity*

Background: Proteolytic activation of fungal SREBP requires the five-subunit Golgi Dsc E3 ligase. Results: Dsc1 is an active E3 ligase; loss of Dsc E3 ligase activity leads to ER localization of the Dsc complex. Conclusion: ER exit of the Dsc E3 ligase requires E3 ligase activity. Significance: This is the first example of enzyme activity-dependent protein sorting in the secretory pathway. Layers of quality control ensure proper protein folding and complex formation prior to exit from the endoplasmic reticulum. The fission yeast Dsc E3 ligase is a Golgi-localized complex required for sterol regulatory element-binding protein (SREBP) transcription factor activation that shows architectural similarity to endoplasmic reticulum-associated degradation E3 ligases. The Dsc E3 ligase consists of five integral membrane proteins (Dsc1–Dsc5) and functionally interacts with the conserved AAA-ATPase Cdc48. Utilizing an in vitro ubiquitination assay, we demonstrated that Dsc1 has ubiquitin E3 ligase activity that requires the E2 ubiquitin-conjugating enzyme Ubc4. Mutations that specifically block Dsc1-Ubc4 interaction prevent SREBP cleavage, indicating that SREBP activation requires Dsc E3 ligase activity. Surprisingly, Golgi localization of the Dsc E3 ligase complex also requires Dsc1 E3 ligase activity. Analysis of Dsc E3 ligase complex formation, glycosylation, and localization indicated that Dsc1 E3 ligase activity is specifically required for endoplasmic reticulum exit of the complex. These results define enzyme activity-dependent sorting as an autoregulatory mechanism for protein trafficking.
Synaptotagmin-1 Is an Antagonist for Munc18-1 in SNARE Zippering*

Background: The molecular mechanisms of the critical necessity of Munc18-1 protein for neurotransmitter release remain unclear. Results: Synaptotagmin-1 competes with Munc18-1 in SNARE zippering and fusion pore opening. Conclusion: Synaptotagmin-1 wins the tug-of-war in gaining control of the SNAREpin at the moment of membrane fusion. Significance: This work clarifies an ambiguity concerning the Munc18-1 function in neuroexocytosis. In neuroexocytosis, SNAREs and Munc18-1 may consist of the minimal membrane fusion machinery. Consistent with this notion, we observed, using single molecule fluorescence assays, that Munc18-1 stimulates SNARE zippering and SNARE-dependent lipid mixing in the absence of a major Ca2+ sensor synaptotagmin-1 (Syt1), providing the structural basis for the conserved function of Sec1/Munc18 proteins in exocytosis. However, when full-length Syt1 is present, no enhancement of SNARE zippering and no acceleration of Ca2+-triggered content mixing by Munc18-1 are observed. Thus, our results show that Syt1 acts as an antagonist for Munc18-1 in SNARE zippering and fusion pore opening. Although the Sec1/Munc18 family may serve as part of the fusion machinery in other exocytotic pathways, Munc18-1 may have evolved to play a different role, such as regulating syntaxin-1a in neuroexocytosis.
Anti-tumoral Effects of miR-3189-3p in Glioblastoma*

Background: miR-3189-3p is a putative mirtron of growth differentiation factor 15 (GDF15). Results: MiR-3189-3p is down-regulated in glial tumors. Conclusion: MiR-3189-3p has tumor suppressor activities in glioblastoma cells. Significance: MiR-3189-3p has potential therapeutic properties. Glioblastoma is one of the most aggressive brain tumors. We have previously found up-regulation of growth differentiation factor 15 (GDF15) in glioblastoma cells treated with the anticancer agent fenofibrate. Sequence analysis of GDF15 revealed the presence of a microRNA, miR-3189, in the single intron. We then asked whether miR-3189 was expressed in clinical samples and whether it was functional in glioblastoma cells. We found that expression of miR-3189-3p was down-regulated in astrocytoma and glioblastoma clinical samples compared with control brain tissue. In vitro, the functionality of miR-3189-3p was tested by RNA-binding protein immunoprecipitation, and miR-3189-3p coimmunoprecipitated with Argonaute 2 together with two of its major predicted gene targets, the SF3B2 splicing factor and the guanine nucleotide exchange factor p63RhoGEF. Overexpression of miR-3189-3p resulted in a significant inhibition of cell proliferation and migration through direct targeting of SF3B2 and p63RhoGEF, respectively. Interestingly, miR-3189-3p levels were increased by treatment of glioblastoma cells with fenofibrate, a lipid-lowering drug with multiple anticancer activities. The attenuated expression of miR-3189-3p in clinical samples paralleled the elevated expression of SF3B2, which could contribute to the activation of SF3B2 growth-promoting pathways in these tumors. Finally, miR-3189-3p-mediated inhibition of tumor growth in vivo further supported the function of this microRNA as a tumor suppressor.
HypE-specific Nanobodies as Tools to Modulate HypE-mediated Target AMPylation

Background: Nanobodies represent a specific means to modulate enzyme function. Results: HypE-specific nanobodies modulate AMPylation activity and identify HypE as localized to the nuclear envelope. Conclusion: HypE function can be interfered with and probed for with new tools. Significance: HypE nanobodies are the first known HypE activators and inhibitors. The covalent addition of mono-AMP to target proteins (AMPylation) by Fic domain-containing proteins is a poorly understood, yet highly conserved post-translational modification. Here, we describe the generation, evaluation, and application of four HypE-specific nanobodies: three that inhibit HypE-mediated target AMPylation in vitro and one that acts as an activator. All heavy chain-only antibody variable domains bind HypE when expressed as GFP fusions in intact cells. We observed localization of HypE at the nuclear envelope and further identified histones H2–H4, but not H1, as novel in vitro targets of the human Fic protein. Its role in histone modification provides a possible link between AMPylation and regulation of gene expression.