Agola JO, Jim PA, Ward HH, BasuRay S, Wandinger‐Ness A. Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities.
Rab GTPases are well‐recognized targets in human ...disease, although are underexplored therapeutically. Elucidation of how mutant or dysregulated Rab GTPases and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab GTPases or associated regulatory proteins causes numerous human genetic diseases. Cancer, neurodegeneration and diabetes represent examples of acquired human diseases resulting from the up‐ or downregulation or aberrant function of Rab GTPases. The broad range of physiologic processes and organ systems affected by altered Rab GTPase activity is based on pivotal roles in responding to cell signaling and metabolic demand through the coordinated regulation of membrane trafficking. The Rab‐regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate fusion with the target membranes control cell metabolism, viability, growth and differentiation. In this review, we focus on Rab GTPase roles in endocytosis to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab GTPase cascades alter endocytic trafficking that underlie neurologic, lipid storage, and metabolic bone disorders as well as cancer. Perspectives on potential therapeutic modulation of GTPase activity through small molecule interventions are provided.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Infantile nephronophthisis is associated with cystic kidneys, situs inversus, and
INVS mutations. The function of the
INVS product, inversin, is unknown but evidence suggests there are multiple ...inversin isoforms with differing molecular weights, cellular localization patterns, and binding partners. We used Northern blots, RT-PCR, and sequence analysis to identify alternative
INVS transcripts. Northern blots probed with
Invs cDNA detected four bands in normal mouse kidney. RT-PCR of mouse kidney RNA revealed
Invs transcripts with skipping of exon 5, 11, or 13. We sequenced canine (MDCK-II cells)
INVS and determined that the corresponding full-length protein shares identity with mouse (74%) and human (84%) inversin. Canine
INVS produces a transcript that skips exon 12. Exon skips cause loss of inversin protein motifs, including ankyrin repeats, IQ domains, destruction boxes, and nuclear localization signals. Identification of
INVS splice variants will help us determine which inversin protein motifs contribute to left-right asymmetry and kidney development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell ...transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Aim
To measure the stress levels of Doctor of Veterinary Medicine (DVM) students at the University of Sydney using the Kessler Psychological Distress Scale (K10) questionnaire.
Methods
DVM students ...in years 1 to 4 were surveyed in semester 2 of 2018. The voluntary online survey consisted of 6 demographic questions and the K10 scale, a standardised measure of stress commonly used in Australia by medical practitioners for evaluation and referral to mental health professionals. Academic year cohorts were compared to identify differences in stress levels. Cohorts were compared to published K10 scores from various populations including the Australian public, medical students, practicing veterinarians, and Junior Medical Officers (JMOs).
Results
The response rate was 54.4% (n = 237). DVM students experienced a higher level of psychological distress (mean 24, median 23, range 10‐50) than the Australian population (mean 14.5, median 13, range 10‐50), medical students (mean 18.4, median 16, range 10‐50), practicing veterinarians (mean 16.7, median 15.5, range 10‐30), and JMOs (mean 18.1, median 16, range 10‐50). Female students (median 23) had a significantly higher level of psychological distress compared to male students (median 18) (p = 0.0005). International students (median 23) had a higher level of psychological stress than domestic students (median 22) (p = 0.0488). Different year cohorts, age range, work hours, and exercise were not associated with difference in stress levels.
Conclusion
Based on higher levels of stress in DVM students than that of the general population, practicing veterinarians, JMOs and medical students, there is an urgent need for evidence‐based interventions to target stress in DVM students.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To define guidelines for BK polyomavirus (BKPyV)-associated haemorrhagic cystitis (BKPyV-HC) after paediatric and adult HSCT.
Review of English literature and evidence-based recommendations by expert ...consensus.
BKPyV-HC occurs in 8%-25% of paediatric and 7%-54% of adult recipients undergoing allogeneic HSCT. Diagnosis requires the triad of cystitis, macro-haematuria and high urine BKPyV loads >7 log10 copies/mL, and exclusion of other relevant aetiologies. BKPyV viraemia is frequent and may serve as a more specific semiquantitative follow-up marker. No randomized controlled trials are available to inform antiviral prophylaxis or treatment. However, hyper-hydration and/or bladder irrigation showed limited prophylactic value. Fluoroquinolones are not effective for prophylaxis or treatment, but rather increase antibiotic resistance. Hyperbaric oxygen or fibrin glue is marginally effective based on small case series from correspondingly equipped centres. Although cidofovir has been reported to improve and/or reduce BKPyV viraemia or viruria, the current data do not support its regular use.
BKPyV-HC remains a disabling unmet clinical need in HSCT that requires novel approaches supported by proper clinical trials.
Abbreviations: IEDB, Immune Epitope Database and Analysis Resource; NIAID, National Institute for Allergy and Infectious Diseases; TCR, T cell receptor Introduction Recent concerns about bioterrorism ...and emerging diseases have led to a new focus on the development of vaccines and drugs targeting infectious pathogens. ...tools to visualize data will be provided, such as those that display antibody antigen interactions where 3D structural information is available.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Myoglobin (Myg) is an oxygen-binding hemoprotein that is widely thought to be expressed exclusively in oxidative skeletal and cardiac myocytes, where it plays a key role in coping with chronic ...hypoxia. We now show in a hypoxia-tolerant fish model, that Myg is also expressed in a range of other tissues, including liver, gill, and brain. Moreover, expression of Myg transcript was substantially enhanced during chronic hypoxia, the fold-change induction being far greater in liver than muscle. By using 2D gel electrophoresis, we have confirmed that liver expresses a protein corresponding to the Myg-1 transcript and that it is significantly up-regulated during hypoxia. We have also discovered a second, unique Myg isoform, distinct from neuroglobin, which is expressed exclusively in the neural tissue but whose transcript expression was unaffected by environmental hypoxia. Both observations of nonmuscle expression and a brain-specific isoform are unprecedented, indicating that Myg may play a much wider role than previously understood and that Myg might function in the protection of tissues from deep hypoxia and ischemia as well as in reoxygenation and reperfusion injury.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
This study was designed to assess the prevalence and clinical significance of exaggerated nonculprit lesion stenosis in the setting of acute (<12 h) myocardial infarction (AMI).
Although ...microvascular spasm may reduce nonculprit artery flow during AMI, it is unknown whether increased tone may exaggerate nonculprit lesion severity.
In patients with additional angiography within nine months of AMI, and significant nonculprit lesions imaged in matching views, stenosis severity was compared between studies in a random blinded fashion using validated quantitative coronary angiography software. Baseline demographics, medications, hemodynamics at each study, and clinical status at follow-up (infarct/unstable angina/stable angina) were used to determine the independent influence of the infarct presentation on stenosis exaggeration.
From 548 patients with AMI (1/99 to 6/01, 321 with multivessel disease), 112 had additional angiography; of these 48 had 59 lesions suitable for analysis. Between infarct and noninfarct angiograms there was a significant change in minimal lumen diameter (1.53 ± 0.51 mm vs. 1.78 ± 0.65 mm, p < 0.001) and percentage stenosis (49.3 ± 14.5% vs. 40.4 ± 16.6%, p < 0.0001) of the nonculprit lesion without significant change in reference segment diameter, which was not predicted by changes in medication or hemodynamics. Twenty-one percent of patients had lesions >50% at AMI that were <50% at non-AMI angiography. Infarct versus noninfarct setting was the only significant independent predictor of change in nonculprit stenosis.
Significant exaggeration of nonculprit lesion stenosis severity occurs at infarct angiography, which may affect revascularization decision making in an appreciable number of patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The use of nickel-titanium rotary instruments in endodontic practice is increasing. One frequently mentioned problem is fracture of an instrument within the root canal. To date, there is no ...consistently safe and successful technique for removing these fractured instruments. This study evaluates the use of an ultrasonic technique to remove fractured rotary nickel-titanium instruments from narrow, curved canals in both simulated (resin blocks) and mesiolingual canals of extracted mandibular first molars. A technique using ultrasonic tips, combined with the creation of a “staging platform” and the use of the dental operating microscope, was consistently successful and safe at removing fractured rotary nickel-titanium instruments from curved root canals, when some part of the fractured instrument segment was located in the straight portion of the canal. When the fractured instrument segment was located entirely around the curve, the success rate was significantly decreased and major canal damage often occurred.
A charge density wave (CDW) is a periodic symmetry-lowering redistribution of charge within a material, accompanied by a rearrangement of electronic bands and usually a small periodic lattice ...distortion. The observation and characterization of a reversible, temperature-induced CDW localized at the lead-coated (111) surface of a germanium crystal are reported.
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