Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Autophagy during Group B Streptococcus Infection of Blood-Brain Barrier Endothelium*

Background: Penetration of brain endothelium by Group B streptococcus (GBS) is the first step in the development of meningitis. Results: Autophagy is activated in response to GBS infection. Conclusion: Autophagy induction occurs through GBS toxin expression, while key autophagic proteins contribute to GBS destruction. Significance: Understanding the role of autophagy in brain endothelium may inform novel strategies to prevent the pathogenesis of bacterial meningitis. Bacterial meningitis occurs when bloodborne pathogens invade and penetrate the blood-brain barrier (BBB), provoking inflammation and disease. Group B Streptococcus (GBS), the leading cause of neonatal meningitis, can enter human brain microvascular endothelial cells (hBMECs), but the host response to intracellular GBS has not been characterized. Here we sought to determine whether antibacterial autophagy, which involves selective recognition of intracellular organisms and their targeting to autophagosomes for degradation, is activated in BBB endothelium during bacterial infection. GBS infection resulted in increased punctate distribution of GFP-microtubule-associated protein 1 light chain 3 (LC3) and increased levels of endogenous LC3-II and p62 turnover, two hallmark indicators of active autophagic flux. Infection with GBS mutants revealed that bacterial invasion and the GBS pore-forming β-hemolysin/cytolysin (β-h/c) trigger autophagic activation. Cell-free bacterial extracts containing β-h/c activity induced LC3-II conversion, identifying this toxin as a principal provocative factor for autophagy activation. These results were confirmed in vivo using a mouse model of GBS meningitis as infection with WT GBS induced autophagy in brain tissue more frequently than a β-h/c-deficient mutant. Elimination of autophagy using Atg5-deficient fibroblasts or siRNA-mediated impairment of autophagy in hBMECs led to increased recovery of intracellular GBS. However, electron microscopy revealed that GBS was rarely found within double membrane autophagic structures even though we observed GBS-LC3 co-localization. These results suggest that although autophagy may act as a BBB cellular defense mechanism in response to invading and toxin-producing bacteria, GBS may actively thwart the autophagic pathway.
The Value of Standardized Case Definitions in Encephalitis Clinical Research

Encephalitis is a poorly defined disease entity. Encephalitic symptoms may be vague and unspecific, especially in the neonatal and pediatric age groups. Early signs and symptoms such as fever, malaise, headache and fatigue are fairly common and shared with many disease entities, infectious and non-infectious. Even if neurologic symptoms prevail and an encephalitis diagnosis has moved to the top of the list of differential diagnoses, overlap with other disease entities remains a possibility in particular with meningitis, cerebellitis, myelitis and acute disseminated encephalomyelitis (ADEM). Encephalitis appears to be under-diagnosed and in the majority of cases of encephalitis, the pathogen or cause remain unknown.1-5 Furthermore, surveillance programs in Scandinavia revealed that 60% of the children with encephalitis had persisting symptoms at the time of discharge. Systematic evidence-based research and prospective surveillance are warranted to learn more about the clinical spectrum, underlying causes, and prognostic factors of encephalitis. The ultimate goal of encephalitis clinical research should be to improve treatment modalities and disease outcomes in all patients, regardless of age and geographic background. Meaningful epidemiologic investigations of encephalitis disease outcomes, incidence and prevalence require large-scale studies, multi-centric approaches, and the pooling and metaanalysis of significant amounts of data from different parts of the world. For data comparability purposes, pre-defined standards should be used for the inclusion of patients into encephalitis surveillance cohorts. Inclusion criteria for encephalitis studies should be based on observerindependent, widely accepted clinical case definitions and ideally, international consensus. This paper aims to raise awareness of the challenges of defining and diagnosing encephalitis as a disease entity, while presenting a number of practical approaches to facilitate encephalitis screening for pediatric clinical research and public health purposes.
Transforming Family Planning Outlook and Practice in Egypt : A Rights-Based Approach

Family planning (FP) program contributed to Egypts progress in reducing infant and maternal mortality and the total fertility and population growth rates. The Arab spring has brought to the forefront long-held aspirations, which can only be fulfilled by a clear shift to a rights-based and person-centered family planning approach and away from an imposed top-down program with targets for family size and fertility rate. The essence of a rights-based approach to FP is interacting with people as individuals with rights to control ones lives, not as a target of a particular program. The FP program also needs to determine and mitigate the factors that make it difficult for the poor, young, and marginalized groups to exercise rights to receive the services needed. The authors of this report examined the challenges facing Egypts FP program through a human rights lens, exploring whether individuals and couples are able to exercise their rights to financial and physical access to good quality FP services. The research also investigated whether client demand for services, and the acceptability of those services, is guided by human rights aspects of service delivery, such as the rights to information, privacy, confidentiality, method choice, and the autonomy to choose the number and spacing of births. This report synthesizes the findings from three sources: (i) an analysis of legal and ethical codes and institutions for upholding reproductive rights in Egypt; (ii) a literature review of past studies and surveys in Egypt; and (iii) a field study in four governorates, using quantitative and qualitative methods to assess the accessibility and quality of FP services in family health units; the views of clients through in exit interviews; and the views of community members in focus group discussions with married women, husbands, and mothers-in-law on perception of FP, the quality of services, and service responsiveness to their needs. This study reconfirmed the need to focus on redressing staff turnover in rural primary health care (PHC) facilities, as well as improving the qualifications and skills of existing staff, both key constraints to quality improvement.
CHRONIC SINUSITIS AMONG PEDIATRIC PATIENTS WITH CHRONIC RESPIRATORY COMPLAINTS

Chronic sinusitis is a common pediatric problem in patients with chronic respiratory symptoms. Because the clinical symptoms alone are not sensitive enough to make the diagnosis, imaging studies of the sinus (eg, a Water's view x-ray) should be considered as part of a allergy evaion, especially in those less than 10 years old.
WASp Family Verprolin-homologous Protein-2 (WAVE2) and Wiskott-Aldrich Syndrome Protein (WASp) Engage in Distinct Downstream Signaling Interactions at the T Cell Antigen Receptor Site*

Background: The regulatory mechanisms and potential redundancy of the structurally related actin nucleation promoting factors, WAVE2 and WASp, are poorly understood. Results: Following T cell activation, WAVE2 and WASp are recruited to the TCR site and then dissociate. Conclusion: WAVE2 and WASp share similar recruitment mechanisms but differ in their subsequent molecular interactions and dynamics. Significance: These differences may explain their distinct functions in regulating actin-dependent processes. T cell antigen receptor (TCR) engagement has been shown to activate pathways leading to actin cytoskeletal polymerization and reorganization, which are essential for lymphocyte activation and function. Several actin regulatory proteins were implicated in regulating the actin machinery, such as members of the Wiskott-Aldrich syndrome protein (WASp) family. These include WASp and the WASp family verprolin-homologous protein-2 (WAVE2). Although WASp and WAVE2 share several structural features, the precise regulatory mechanisms and potential redundancy between them have not been fully characterized. Specifically, unlike WASp, the dynamic molecular interactions that regulate WAVE2 recruitment to the cell membrane and specifically to the TCR signaling complex are largely unknown. Here, we identify the molecular mechanism that controls the recruitment of WAVE2 in comparison with WASp. Using fluorescence resonance energy transfer (FRET) and novel triple-color FRET (3FRET) technology, we demonstrate how WAVE2 signaling complexes are dynamically regulated during lymphocyte activation in vivo. We show that, similar to WASp, WAVE2 recruitment to the TCR site depends on protein-tyrosine kinase, ZAP-70, and the adaptors LAT, SLP-76, and Nck. However, in contrast to WASp, WAVE2 leaves this signaling complex and migrates peripherally together with vinculin to the membrane leading edge. Our experiments demonstrate that WASp and WAVE2 differ in their dynamics and their associated proteins. Thus, this study reveals the differential mechanisms regulating the function of these cytoskeletal proteins.
Perspektiven des metabolischen Syndroms bei Kindern und Jugendlichen

Zusammenfassung Mit der steigenden Prävalenz von Adipositas im Kindes-und Jugendalter erhöht sich die Prävalenz entsprechender Komorbiditäten wie Hypertonie, Dyslipidämie und gestörter Glukosetoleranz. Einige Autoren sehen die Insulinresistenz als ursächlichen Faktor für die genannten Störungen an. Zur endgültigen Abklärung der zugrunde liegenden Pathomechanismen bedarf es jedoch noch weiterer Studien. Bei der Analyse möglicher ursächlicher Faktoren aus dem Fettgewebe fanden bisher vor allem Leptin und Adiponektin große Beachtung. Es herrscht weiterhin Uneinigkeit über die genaue Definition des metabolischen Syndroms bei Kindern. Entsprechend aktueller Untersuchungen sollten die bestehenden Definitionen um die nichtalkoholisch bedingte Steatohepatitis erweitert werden. Ungeachtet einer fehlenden einheitlichen Definition besteht jedoch kein Zweifel an der Notwendigkeit einer engen Verlaufsbeobachtung adipöser Kinder und einer frühen therapeutischen Intervention sich aufzeigender Komorbiditäten.
A Novel Protein-Protein Interaction in the RES (REtention and Splicing) Complex*

Background: The heterotrimeric retention and splicing (RES) complex is conserved from yeast to man. Results: Structural and biochemical analyses show an extended binding interface between the Snu17p RNA recognition motif (RRM) and Bud13p of the RES complex. Conclusion: The Snu17p RRM-Bud13p interaction represents a novel RRM-protein interface. Significance: The Snu17p-Bud13p complex may provide a platform for additional protein and RNA interactions in the RES complex. The retention and splicing (RES) complex is a conserved spliceosome-associated module that was shown to enhance splicing of a subset of transcripts and promote the nuclear retention of unspliced pre-mRNAs in yeast. The heterotrimeric RES complex is organized around the Snu17p protein that binds to both the Bud13p and Pml1p subunits. Snu17p exhibits an RRM domain that resembles a U2AF homology motif (UHM) and Bud13p harbors a Trp residue reminiscent of an UHM-ligand motif (ULM). It has therefore been proposed that the interaction between Snu17p and Bud13p resembles canonical UHM-ULM complexes. Here, we have used biochemical and NMR structural analysis to characterize the structure of the yeast Snu17p-Bud13p complex. Unlike known UHMs that sequester the Trp residue of the ULM ligand in a hydrophobic pocket, Snu17p and Bud13p utilize a large interaction surface formed around the two helices of the Snu17p domain. In total 18 residues of the Bud13p ligand wrap around the Snu17p helical surface in an U-turn-like arrangement. The invariant Trp232 in Bud13p is located in the center of the turn, and contacts surface residues of Snu17p. The structural data are supported by mutational analysis and indicate that Snu17p provides an extended binding surface with Bud13p that is notably distinct from canonical UHM-ULM interactions. Our data highlight structural diversity in RRM-protein interactions, analogous to the one seen for nucleic acid interactions.
Ethoxyquin prevents chemotherapy‐induced neurotoxicity via Hsp90 modulation

Peripheral neurotoxicity is a major dose‐limiting side effect of many chemotherapeutic drugs. Currently there are no effective disease‐modifying therapies for chemotherapy‐induced peripheral neuropathies, but these side effects of chemotherapy are potentially ideal targets for development of neuroprotective therapies, because candidate drugs can be co‐ or preadministered before the injury to peripheral axons takes place.
A Role for the Adaptor Proteins TRAM and TRIF in Toll-like Receptor 2 Signaling*

Background: Toll-like receptor 2 (TLR2) mediates innate immune responses by recognizing microbial components. Results: TLR2-mediated induction of the chemokines Ccl4 and Ccl5 and interferon-β is impaired in macrophages lacking the signaling molecules TRAM, TRIF, TBK-1, IRF1, and IRF3. Conclusion: The TRAM/TRIF pathway is involved in TLR2 signaling. Significance: TLR signaling pathways determine the immune response mounted against infectious organisms. Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin-1 receptor adaptors MyD88 and MAL, leading to NF-κB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF) 3. Here, we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine Ccl5 was impaired in TRAM or TRIF deficient macrophages. Inhibition of endocytosis reduced Ccl5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. Ccl5 release following lipoprotein challenge additionally involved the kinase Tbk-1 and Irf3, as well as MyD88 and Irf1. Induction of Interferon-β and Ccl4 by lipoproteins was also partially impaired in cells lacking TRIF cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2.
The Effect of AMP‐Activated Kinase Activation on Gonadotrophin‐Releasing Hormone Secretion in GT1‐7 Cells and its Potential Role in Hypothalamic Regulation of the Oestrous Cyclicity in Rats

Hypothalamic AMP‐activated kinase (AMPK) is a key regulator of food intake in mammals. Its role in reproduction at the central level and, more precisely, in gonadotrophin‐releasing hormone (GnRH) release has never been investigated. We showed that each subunit of AMPK is present in immortalised GnRH neurones (GT1‐7 cells). Treatment with 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribonucleoside (AICAR) and metformin, two activators of AMPK, increased dose‐dependent and time‐dependent phosphorylation of AMPKα atThr172 in GT1‐7 cells. Phosphorylation of acetyl‐coenzyme A carboxylase at ser79 also increased. Treatment with AICAR (5 mm) or metformin (5 mm) for 4 h inhibited GnRH release in the presence or absence of GnRH (10−8 m). Specific AMPK inhibitor compound C completely eliminated the effects of AICAR or metformin on GnRH release. Finally, we determined the central effects of AICAR in vivo on food intake and oestrous cyclicity. Ten‐week‐old female rats received a 50 μg AICAR or a saline i.c. v. injection. We detected increased AMPK and acetyl‐CoA carboxylase phosphorylation, specifically in the hypothalamus, 30 min after AICAR injection. Food intake was significantly higher (P < 0.05) in animals treated with AICAR than in animals injected with saline, 24 h after injection. This effect was abolished after 1 week. Moreover, during the 4 weeks following injection, the interval between two oestrous stages was significantly lower in the AICAR group than in the saline group. Our findings suggest that AMPK activation may act directly at the hypothalamic level to affect fertility by modulating GnRH release and oestrous cyclicity.
Approaches to teaching, learning and assessment and the subject area competences: nursing

There is a well established knowledge and evidence base associated with the learning, teaching and assessment of nursing and nurses: some illustrative texts are outlined at the end of this paper. Boyer’s scholarship typology can be aptly applied to nursing in so far as he considers four types of scholarship: that of discovery/research, integration, application/service and that of teaching itself. Nurse learners, whether before or after qualification, are by definition adult learners undertaking an academic, professional/vocational programme of studies that includes both theoretical and practical knowledge, behaviours and attitudes and the ability to perform in routine and unpredictable situations. The pedagogical knowledge base includes concepts and research associated with andragogy, experiential learning, work based learning, organisational cultures and learning, decision making, development of leadership skills, social psychology of learning, values, ethical and emotional literacy to name but a few.
MicroRNA-21 Promotes Glioblastoma Tumorigenesis by Down-regulating Insulin-like Growth Factor-binding Protein-3 (IGFBP3)*

Background: miR-21 is overexpressed in many human cancers, including glioblastoma. Results: Insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) is a novel miR-21 target gene and inhibits gliomagenesis in vitro and in vivo. Conclusion: miR-21 down-regulates IGFBP3, which acts as a tumor suppressor in human glioblastoma. Significance: IGFBP3 may have promise as a therapeutic target and prognostic marker for glioblastoma. Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.
DEPDC5 mutations in genetic focal epilepsies of childhood

Recent studies reported DEPDC5 loss‐of‐function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n = 11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes. Ann Neurol 2014;75:788–792
Anticancer Plants in Islamic Traditional Medicine

Islamic Traditional Medicine (ITM) is a holistic and comprehensive medical school that has antecedents over 12 centuries ago. In ITM, cancer was a known disease with many options for treatment. Razi (Razhes; 865-925 AD), Ahwazi (Haly Abbas; 930-994 AD), Avicenna (980-1037AD), Jorjani (1042-1136 AD), and Aqili Khorasani (18th century) are among eminent physicians who discussed different types of cancers and their management in their books. They used a large number of plant species for treatment of different tumors. Although modern medicine has made tremendous advances in cancer control, the effectiveness of its therapeutic approach is often limited by toxic effects on other organs. Moreover, a large number of people in the world have limited or no access to cancer treatment services. Accordingly, benefiting from traditional medicine schools and effective natural medicines to prevent and control cancer would be valuable. In addition, using the teachings of such schools can lead to the discovery of new bioactive compounds and therapeutic methods. In this chapter, a brief history of Islamic medicine and its approach to treat cancer as well as anticancer medicinal plants have been discussed. Out of 107 ITM suggested plant species, 59 plants or their chemical compounds have proven to possess cytotoxic and antitumor activities using pharmacological investigations. These findings show the profound insight of ITM physicians into cancer treatment.
Isokinetic dynamometry of weak muscles

The aims of the study were to assess the reproducibility and validity of very weak knee flexors and extensors muscle strength with a new isokinetic evaluation procedure. Subjects and methods: Reproducibility mean and maximal work without correction of gravity was first assessed in 14 neuromuscular patients, at 10°/s. Three patients suffering from Guillain-Barre Syndrome were then investigated at different states of recovery. Maximal concentric effort was performed at 10°/s and 30°/s. Acute correction of gravity was performed as forces values measured during passive mobilisation were removed from active measurements. Correlation between manual muscle testing and maximal moment and mean work was explored. Results: Reproducibility was judged acceptable. Intraclass correlation coefficients ranged from 0.7 to 0.84. In the correlation study, manual muscle assessment ranged from 2 to 4 and peak of forces ranged from 0.4 Nm to 51.88 Nm. There was a significant positive relationship as Spearman Correlation coefficients ranged from 0.77 to 0.89. Conclusion: Weak muscle isokinetic evaluation is reproducible and well correlated to clinical evaluation. This evaluation procedure could be of great interest in neurological diseases investigations.
The formation of inflammatory demyelinated lesions in cerebral white matter

Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset.