747 research outputs found
Differential Subcellular Localization of the Splice Variants of the Zinc Transporter ZnT5 Is Dictated by the Different C-Terminal Regions
Zinc is emerging as an important intracellular signaling molecule, as well as fulfilling essential structural and catalytic functions through incorporation in a myriad of zinc metalloproteins so it is important to elucidate the molecular mechanisms of zinc homeostasis, including the subcellular localizations of zinc transporters.Two splice variants of the human SLC30A5 Zn transporter gene (ZnT5) have been reported in the literature. These variants differ at their N- and C-terminal regions, corresponding with the use of different 5' and 3' exons. We demonstrate that full length human ZnT5 variant B is a genuine transcript in human intestinal cells and confirm expression of both variant A and variant B in a range of untreated human tissues by splice variant-specific RT-PCR. Using N- or C-terminal GFP or FLAG fusions of both isoforms of ZnT5 we identify that the differential subcellular localization to the Golgi apparatus and ER respectively is a function of their alternative C-terminal sequences. These different C-terminal regions result from the incorporation into the mature transcript of either the whole of exon 14 (variant B) or only the 5' region of exon 14 plus exons 15-17 (variant A).We thus propose that exons 15 to 17 include a signal that results in trafficking of ZnT5 to the Golgi apparatus and that the 3' end of exon 14 includes a signal that leads to retention in the ER
Postoperative spinal infection mimicking systemic vasculitis with titanium-spinal implants
<p>Abstract</p> <p>Background</p> <p>Secondary systemic vasculitis after posterior spinal fusion surgery is rare. It is usually related to over-reaction of immune-system, to genetic factors, toxicity, infection or metal allergies.</p> <p>Case Description</p> <p>A 14 year-old girl with a history of extended posterior spinal fusion due to idiopathic scoliosis presented to our department with diffuse erythema and nephritis (macroscopic hemuresis and proteinuria) 5 months post surgery. The surgical trauma had no signs of inflammation or infection. The blood markers ESR and CRP were increased. Skin tests were positive for nickel allergy, which is a content of titanium alloy. The patient received corticosteroids systematically (hydrocortisone 10 mg) for 6 months, leading to total recess of skin and systemic reaction. However, a palpable mass close to the surgical wound raised the suspicion of a late infection. The patient had a second surgery consisting of surgical debridement and one stage revision of posterior spinal instrumentation. Intraoperative cultures were positive to Staphylococcus aureus. Intravenous antibiotics were administered. The patient is now free of symptoms 24 months post revision surgery without any signs of recurrence of either vasculitis or infection.</p> <p>Literature Review</p> <p>Systemic vasculitis after spinal surgery is exceptionally rare. Causative factors are broad and sometimes controversial. In general, it is associated with allergy to metal ions. This is usually addressed with metal on metal total hip bearings. In spinal surgery, titanium implants are considered to be inert and only few reports have presented cases with systemic vasculitides. Therefore, other etiologies of immune over-reaction should always be considered, such as drug toxicity, infection, or genetic predisposition.</p> <p>Purposes and Clinical Relevance</p> <p>Our purpose was to highlight the difficulties during the diagnostic work-up for systemic vasculitis and management in cases of posterior spinal surgery.</p
The burden and risks of pediatric pneumonia in Nigeria: A deskβbased review of existing literature and data
Background: Pneumonia is a leading killer of children underβ5 years, with a high burden in Nigeria. We aimed to quantify the regional burden and risks of pediatric pneumonia in Nigeria, and specifically the states of Lagos and Jigawa. /
Methods: We conducted a scoping literature search for studies of pneumonia morbidity and mortality in underβ5 children in Nigeria from 10th December 2018 to 26th April 2019, searching: Cochrane, PubMed, and Web of Science. We included grey literature from stakeholders' websites and information shared by organizations working in Nigeria. We conducted multivariable logistic regression using the 2016 to 2017 Multiple Cluster Indicators Survey data set to explore factors associated with pneumonia. Descriptive analyses of datasets from 2010 to 2019 was done to estimate trends in mortality, morbidity, and vaccination coverage. /
Results: We identified 25 relevant papers (10 from Jigawa, 8 from Lagos, and 14 national data). None included data on pneumonia or acute respiratory tract infection burden in the health system, inpatient caseβfatality rates, severity, or ageβspecific pneumonia mortality rates at state level. Secondary data analysis found that no household or caregiver socioeconomic indicators were consistently associated with selfβreported symptoms of cough and/or difficulty breathing, and seasonality was inconsistently associated, dependant on region. /
Conclusion: There is a clear evidence gap around the burden of pediatric pneumonia in Nigeria, and challenges with the interpretation of existing household survey data. Improved survey approaches are needed to understand the risks of pediatric pneumonia in Nigeria, alongside the need for investment in reliable routine data systems to provide data on the clinical pneumonia burden in Nigeria
Health system challenges for improved childhood pneumonia case management in Lagos and Jigawa, Nigeria
Background: Case fatality rates for childhood pneumonia in Nigeria remain high. There is a clear need for improved case management of pneumonia, through the sustainable implementation of the Integrated Management of Childhood Illnesses (IMCI) diagnostic and treatment algorithms. We explored barriers and opportunities for improved case management of childhood pneumonia in Lagos and Jigawa states, Nigeria. /
Methods: A mixedβmethod analysis was conducted to assess the current health system capacity to deliver quality care. This was done through audits of 16 facilities in Jigawa and 14 facilities in Lagos, questionnaires (nβ=β164) and 13 focus group discussions with providers. Field observations provided context for data analysis and triangulation. /
Results: There were more private providers in Lagos (4/8 secondary facilities) and more government providers in Jigawa (4/8 primary, 3/3 secondary, and 1/1 tertiary facilities). Oxygen and pulse oximeters were available in two of three in Jigawa and six of eight in Lagos of the sampled secondary care facilities. None of the eight primary facilities surveyed in Jigawa had oxygen or pulse oximetry available while in Lagos two of three primary facilities had oxygen and one of three had pulse oximeters. Other IMCI and emergency equipment were also lacking including respiratory rate timers, particularly in Jigawa state. Health care providers scored poorly on knowledge of IMCI, though previous IMCI training was associated with better knowledge. Key enabling factors in delivering pediatric care highlighted by health care providers included accountability procedures and feedback loops, the provision of free medication for children, and philanthropic acts. Common barriers to provide care included the burden of outβofβpocket payments, challenges in effective communication with caregivers, delayed presentation, and lack of clear diagnosis, and case management guidelines. /
Conclusion: There is an urgent need to improve how the prevention and treatment of pediatric pneumonia is directed in both Lagos and Jigawa. Priority areas for reducing pediatric pneumonia burden are training and mentoring of health care providers, community health education, and introduction of oximeters and oxygen supply
Biodiversity of the Deep-Sea Continental Margin Bordering the Gulf of Maine (NW Atlantic): Relationships among Sub-Regions and to Shelf Systems
Background: In contrast to the well-studied continental shelf region of the Gulf of Maine, fundamental questions regarding
the diversity, distribution, and abundance of species living in deep-sea habitats along the adjacent continental margin
remain unanswered. Lack of such knowledge precludes a greater understanding of the Gulf of Maine ecosystem and limits
development of alternatives for conservation and management.
Methodology/Principal Findings: We use data from the published literature, unpublished studies, museum records and
online sources, to: (1) assess the current state of knowledge of species diversity in the deep-sea habitats adjacent to the Gulf
of Maine (39β43uN, 63β71uW, 150β3000 m depth); (2) compare patterns of taxonomic diversity and distribution of
megafaunal and macrofaunal species among six distinct sub-regions and to the continental shelf; and (3) estimate the
amount of unknown diversity in the region. Known diversity for the deep-sea region is 1,671 species; most are narrowly
distributed and known to occur within only one sub-region. The number of species varies by sub-region and is directly
related to sampling effort occurring within each. Fishes, corals, decapod crustaceans, molluscs, and echinoderms are
relatively well known, while most other taxonomic groups are poorly known. Taxonomic diversity decreases with increasing
distance from the continental shelf and with changes in benthic topography. Low similarity in faunal composition suggests
the deep-sea region harbours faunal communities distinct from those of the continental shelf. Non-parametric estimators of
species richness suggest a minimum of 50% of the deep-sea species inventory remains to be discovered.
Conclusions/Significance: The current state of knowledge of biodiversity in this deep-sea region is rudimentary. Our ability
to answer questions is hampered by a lack of sufficient data for many taxonomic groups, which is constrained by sampling
biases, life-history characteristics of target species, and the lack of trained taxonomists
An End to Endless Forms: Epistasis, Phenotype Distribution Bias, and Nonuniform Evolution
Studies of the evolution of development characterize the way in which gene
regulatory dynamics during ontogeny constructs and channels phenotypic
variation. These studies have identified a number of evolutionary regularities:
(1) phenotypes occupy only a small subspace of possible phenotypes, (2) the
influence of mutation is not uniform and is often canalized, and (3) a great
deal of morphological variation evolved early in the history of multicellular
life. An important implication of these studies is that diversity is largely the
outcome of the evolution of gene regulation rather than the emergence of new,
structural genes. Using a simple model that considers a generic property of
developmental mapsβthe interaction between multiple genetic elements
and the nonlinearity of gene interaction in shaping phenotypic
traitsβwe are able to recover many of these empirical regularities. We
show that visible phenotypes represent only a small fraction of possibilities.
Epistasis ensures that phenotypes are highly clustered in morphospace and that
the most frequent phenotypes are the most similar. We perform phylogenetic
analyses on an evolving, developmental model and find that species become more
alike through time, whereas higher-level grades have a tendency to diverge.
Ancestral phenotypes, produced by early developmental programs with a low level
of gene interaction, are found to span a significantly greater volume of the
total phenotypic space than derived taxa. We suggest that early and late
evolution have a different character that we classify into micro- and
macroevolutionary configurations. These findings complement the view of
development as a key component in the production of endless forms and highlight
the crucial role of development in constraining biotic diversity and
evolutionary trajectories
A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus
The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses
Past Achievements and Future Challenges in 3D Photonic Metamaterials
Photonic metamaterials are man-made structures composed of tailored micro- or
nanostructured metallo-dielectric sub-wavelength building blocks that are
densely packed into an effective material. This deceptively simple, yet
powerful, truly revolutionary concept allows for achieving novel, unusual, and
sometimes even unheard-of optical properties, such as magnetism at optical
frequencies, negative refractive indices, large positive refractive indices,
zero reflection via impedance matching, perfect absorption, giant circular
dichroism, or enhanced nonlinear optical properties. Possible applications of
metamaterials comprise ultrahigh-resolution imaging systems, compact
polarization optics, and cloaking devices. This review describes the
experimental progress recently made fabricating three-dimensional metamaterial
structures and discusses some remaining future challenges
Burning in Banksia Woodlands: How Does the Fire-Free Period Influence Reptile Communities?
Fire is an important management tool for both hazard reduction burning and maintenance of biodiversity. The impact of time since last fire on fauna is an important factor to understand as land managers often aim for prescribed burning regimes with specific fire-free intervals. However, our current understanding of the impact of time since last fire on fauna is largely unknown and likely dependent on vegetation type. We examined the responses of reptiles to fire age in banksia woodlands, and the interspersed melaleuca damplands among them, north of Perth, Western Australia, where the current prescribed burning regime is targeting a fire-free period of 8β12 years. The response of reptiles to fire was dependent on vegetation type. Reptiles were generally more abundant (e.g. Lerista elegans and Ctenophorus adelaidensis) and specious in banksia sites. Several species (e.g. Menetia greyii, Cryptoblepharus buchananii) preferred long unburnt melaleuca sites (>16 years since last fire, YSLF) compared to recently burnt sites (<12 YSLF). Several of the small elapids (e.g. the WA priority listed species Neelaps calonotus) were only detected in older-aged banksia sites (>16 YSLF). The terrestrial dragon C. adelaidensis and the skink Morethia obscura displayed a strong response to fire in banksia woodlands only. Highest abundances of the dragon were detected in the recently burnt (<7 YSLF) and long unburnt (>35 YSLF) banksia woodlands, while the skink was more abundant in older sites. Habitats from a range of fire ages are required to support the reptiles we detected, especially the longer unburnt (>16 YSLF) melaleuca habitat. Current burning prescriptions are reducing the availability of these older habitats
Fluid-structure interaction in abdominal aortic aneurysms: effects of asymmetry and wall thickness
BACKGROUND: Abdominal aortic aneurysm (AAA) is a prevalent disease which is of significant concern because of the morbidity associated with the continuing expansion of the abdominal aorta and its ultimate rupture. The transient interaction between blood flow and the wall contributes to wall stress which, if it exceeds the failure strength of the dilated arterial wall, will lead to aneurysm rupture. Utilizing a computational approach, the biomechanical environment of virtual AAAs can be evaluated to study the affects of asymmetry and wall thickness on this stress, two parameters that contribute to increased risk of aneurysm rupture. METHODS: Ten virtual aneurysm models were created with five different asymmetry parameters ranging from Ξ² = 0.2 to 1.0 and either a uniform or variable wall thickness to study the flow and wall dynamics by means of fully coupled fluid-structure interaction (FSI) analyses. The AAA wall was designed to have a (i) uniform 1.5 mm thickness or (ii) variable thickness ranging from 0.5 β 1.5 mm extruded normally from the boundary surface of the lumen. These models were meshed with linear hexahedral elements, imported into a commercial finite element code and analyzed under transient flow conditions. The method proposed was then compared with traditional computational solid stress techniques on the basis of peak wall stress predictions and cost of computational effort. RESULTS: The results provide quantitative predictions of flow patterns and wall mechanics as well as the effects of aneurysm asymmetry and wall thickness heterogeneity on the estimation of peak wall stress. These parameters affect the magnitude and distribution of Von Mises stresses; varying wall thickness increases the maximum Von Mises stress by 4 times its uniform thickness counterpart. A pre-peak systole retrograde flow was observed in the AAA sac for all models, which is due to the elastic energy stored in the compliant arterial wall and the expansion force of the artery during systole. CONCLUSION: Both wall thickness and geometry asymmetry affect the stress exhibited by a virtual AAA. Our results suggest that an asymmetric AAA with regional variations in wall thickness would be exposed to higher mechanical stresses and an increased risk of rupture than a more fusiform AAA with uniform wall thickness. Therefore, it is important to accurately reproduce vessel geometry and wall thickness in computational predictions of AAA biomechanics
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