Objective To investigate whether being anesthesia administered at least once in early life influenced 3 main proxies of visual function: visual acuity, refractive error, and optic nerve health in ...young adulthood. Study design At age 20 years, participants of the Western Australian Pregnancy Cohort Study had comprehensive ocular examinations including visual acuity, postcycloplegic refraction, and multiple scans of the optic disc. We identified individuals who had at least 1 procedure requiring anesthesia during the first 3 years of life (between 1990 and 1994) and compared their visual outcomes with nonexposed individuals. We excluded 40 participants with strabismus or other ophthalmic disease or surgery and 136 with non-European background. Results Of 834 participants, 15.2% (n = 127) were exposed to anesthesia at least once before age 3 years. In both exposed and nonexposed groups, median visual acuity (measured using the logarithm of the minimum angle of resolution LogMAR chart) was −0.06 LogMAR in the right eye and −0.08 LogMAR in the left eye ( P > .05). Median spherical equivalent refractive error was +0.44 diopters (IQR −0.25, +0.63) and +0.31 diopters (IQR −0.38, +0.63) in the exposed and nonexposed group, respectively ( P = .126). No difference was detected in mean global retinal nerve fiber layer thickness of the 2 groups (100.7 vs 100.1 μm, P = .830). Conclusions We were unable to demonstrate an association of exposure to anesthesia as a child with reduced visual acuity or increased myopia or thinning of retinal nerve fiber layer. These findings support the view that anesthesia is unlikely to impair visual development, but further work is needed to establish whether more subtle defects are present and repeated exposures have any effects.
The blood-feeding hookworm Necator americanus infects hundreds of millions of people worldwide. In order to elucidate fundamental molecular biological aspects of this hookworm, the transcriptome of ...the adult stage of Necator americanus was explored using next-generation sequencing and bioinformatic analyses.
A total of 19,997 contigs were assembled from the sequence data; 6,771 of these contigs had known orthologues in the free-living nematode Caenorhabditis elegans, and most of them encoded proteins with WD40 repeats (10.6%), proteinase inhibitors (7.8%) or calcium-binding EF-hand proteins (6.7%). Bioinformatic analyses inferred that the C. elegans homologues are involved mainly in biological pathways linked to ribosome biogenesis (70%), oxidative phosphorylation (63%) and/or proteases (60%); most of these molecules were predicted to be involved in more than one biological pathway. Comparative analyses of the transcriptomes of N. americanus and the canine hookworm, Ancylostoma caninum, revealed qualitative and quantitative differences. For instance, proteinase inhibitors were inferred to be highly represented in the former species, whereas SCP/Tpx-1/Ag5/PR-1/Sc7 proteins ( = SCP/TAPS or Ancylostoma-secreted proteins) were predominant in the latter. In N. americanus, essential molecules were predicted using a combination of orthology mapping and functional data available for C. elegans. Further analyses allowed the prioritization of 18 predicted drug targets which did not have homologues in the human host. These candidate targets were inferred to be linked to mitochondrial (e.g., processing proteins) or amino acid metabolism (e.g., asparagine t-RNA synthetase).
This study has provided detailed insights into the transcriptome of the adult stage of N. americanus and examines similarities and differences between this species and A. caninum. Future efforts should focus on comparative transcriptomic and proteomic investigations of the other predominant human hookworm, A. duodenale, for both fundamental and applied purposes, including the prevalidation of anti-hookworm drug targets.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The barber's pole worm, Haemonchus contortus, is one of the most economically important parasites of small ruminants worldwide. Although this parasite can be controlled using anthelmintic drugs, ...resistance against most drugs in common use has become a widespread problem. We provide a draft of the genome and the transcriptomes of all key developmental stages of H. contortus to support biological and biotechnological research areas of this and related parasites.
The draft genome of H. contortus is 320 Mb in size and encodes 23,610 protein-coding genes. On a fundamental level, we elucidate transcriptional alterations taking place throughout the life cycle, characterize the parasite's gene silencing machinery, and explore molecules involved in development, reproduction, host-parasite interactions, immunity, and disease. The secretome of H. contortus is particularly rich in peptidases linked to blood-feeding activity and interactions with host tissues, and a diverse array of molecules is involved in complex immune responses. On an applied level, we predict drug targets and identify vaccine molecules.
The draft genome and developmental transcriptome of H. contortus provide a major resource to the scientific community for a wide range of genomic, genetic, proteomic, metabolomic, evolutionary, biological, ecological, and epidemiological investigations, and a solid foundation for biotechnological outcomes, including new anthelmintics, vaccines and diagnostic tests. This first draft genome of any strongylid nematode paves the way for a rapid acceleration in our understanding of a wide range of socioeconomically important parasites of one of the largest nematode orders.
Stroke is a leading cause of disability, and Magnetic Resonance Imaging (MRI) is routinely acquired for acute stroke management. Publicly sharing these datasets can aid in the development of machine ...learning algorithms, particularly for lesion identification, brain health quantification, and prognosis. These algorithms thrive on large amounts of information, but require diverse datasets to avoid overfitting to specific populations or acquisitions. While there are many large public MRI datasets, few of these include acute stroke. We describe clinical MRI using diffusion-weighted, fluid-attenuated and T1-weighted modalities for 1715 individuals admitted in the upstate of South Carolina, of whom 1461 have acute ischemic stroke. Demographic and impairment data are provided for 1106 of the stroke survivors from this cohort. Our validation demonstrates that machine learning can leverage the imaging data to predict stroke severity as measured by the NIH Stroke Scale/Score (NIHSS). We share not only the raw data, but also the scripts for replicating our findings. These tools can aid in education, and provide a benchmark for validating improved methods.
The disease caused by Haemonchus contortus, a blood-feeding nematode of small ruminants, is of major economic importance worldwide. The infective third-stage larva (L3) of this gastric nematode is ...enclosed in a cuticle (sheath) and, once ingested with herbage by the host, undergoes an exsheathment process that marks the transition from the free-living (L3) to the parasitic (xL3) stage. This study explored changes in gene transcription associated with this transition and predicted, based on comparative analysis, functional roles for key transcripts in the metabolic pathways linked to larval development.
Totals of 101,305 (L3) and 105,553 (xL3) expressed sequence tags (ESTs) were determined using 454 sequencing technology, and then assembled and annotated; the most abundant transcripts encoded transthyretin-like, calcium-binding EF-hand, NAD(P)-binding and nucleotide-binding proteins as well as homologues of Ancylostoma-secreted proteins (ASPs). Using an in silico-subtractive analysis, 560 and 685 sequences were shown to be uniquely represented in the L3 and xL3 stages, respectively; the transcripts encoded ribosomal proteins, collagens and elongation factors (in L3), and mainly peptidases and other enzymes of amino acid catabolism (in xL3). Caenorhabditis elegans orthologues of transcripts that were uniquely transcribed in each L3 and xL3 were predicted to interact with a total of 535 other genes, all of which were involved in embryonic development.
The present study indicated that some key transcriptional alterations taking place during the transition from the L3 to the xL3 stage of H. contortus involve genes predicted to be linked to the development of neuronal tissue (L3 and xL3), formation of the cuticle (L3) and digestion of host haemoglobin (xL3). Future efforts using next-generation sequencing and bioinformatic technologies should provide the efficiency and depth of coverage required for the determination of the complete transcriptomes of different developmental stages and/or tissues of H. contortus as well as the genome of this important parasitic nematode. Such advances should lead to a significantly improved understanding of the molecular biology of H. contortus and, from an applied perspective, to novel methods of intervention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome3D, available at http://www.genome3d.eu, is a new collaborative project that integrates UK-based structural resources to provide a unique perspective on sequence-structure-function ...relationships. Leading structure prediction resources (DomSerf, FUGUE, Gene3D, pDomTHREADER, Phyre and SUPERFAMILY) provide annotations for UniProt sequences to indicate the locations of structural domains (structural annotations) and their 3D structures (structural models). Structural annotations and 3D model predictions are currently available for three model genomes (Homo sapiens, E. coli and baker's yeast), and the project will extend to other genomes in the near future. As these resources exploit different strategies for predicting structures, the main aim of Genome3D is to enable comparisons between all the resources so that biologists can see where predictions agree and are therefore more trusted. Furthermore, as these methods differ in whether they build their predictions using CATH or SCOP, Genome3D also contains the first official mapping between these two databases. This has identified pairs of similar superfamilies from the two resources at various degrees of consensus (532 bronze pairs, 527 silver pairs and 370 gold pairs).
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Hookworm activation-associated secreted proteins can be structurally classified into at least three different groups. The hallmark feature of Group 1 activation-associated secreted ...proteins is a prominent equatorial groove, which is inferred to form a ligand binding site. Furthermore, a conserved tandem histidine motif is located in the centre of the groove and believed to provide or support a yet to be determined catalytic activity.
Here, we report three-dimensional crystal structures of Na-ASP-2, an L3-secreted activation-associated secreted protein from the human hookworm Necator americanus, which demonstrate transition metal binding ability of the conserved tandem histidine motif. We further identified moderate phosphohydrolase activity of recombinant Na-ASP-2, which relates to the tandem histidine motif. By panning a random 12-mer peptide phage library, we identified a peptide with high similarity to the human calcium-activated potassium channel SK3, and confirm binding of the synthetic peptide to recombinant Na-ASP-2 by differential scanning fluorimetry. Potential binding modes of the peptide to Na-ASP-2 were studied by molecular dynamics simulations which clearly identify a preferred topology of the Na-ASP-2:SK3 peptide complex.
European treatment guidelines recommend the use of hormonal therapy for the treatment of advanced prostate cancer, including castration-resistant prostate cancer (CRPC), but there is little ...understanding of how common practices in prostate cancer treatment compare across Europe. The aim of this analysis was to evaluate the management of CRPC patients across five European countries (France, Germany, Italy, Spain and the UK).
Data were drawn from the Adelphi Real World Prostate Cancer Disease Specific Programme (DSP), a cross-sectional survey of patients undertaken between December 2009 and May 2010. The study is based on physician interviews, physician-completed detailed patient record forms, and a patient-completed questionnaire.
A total of 348 physicians (191 urologists and 157 oncologists) reported on 3477 patients with prostate cancer. Of the 3477 patients, 1405 (40%) were categorised as having CRPC, and 1119 of these had metastatic CRPC. Bone metastases were the most common (78%), followed by liver (37%) and lung (30%). The mean age of CRPC patients was 71 years, 35% were current or ex-smokers and 10% had a family history of prostate cancer. CRPC patients had a mean of 1.8 comorbidities; 66% had hypertension and 32% had diabetes. Most physicians estimated their patients would stop responding to initial hormone therapy after 19-24 months. Overall, addition of an anti-androgen to a luteinising-hormone-releasing hormone (LHRH) agonist was the most commonly prescribed therapy when patients failed initial LHRH agonist therapy, although there were considerable variations between countries. While 72% of physicians in Europe would choose chemotherapy as the next treatment option after diagnosis of CRPC, 31% of this group would initially prescribe this without an LHRH agonist.
Results from this analysis highlight inconsistencies in common hormonal therapy treatment patterns for CRPC and hormonal therapy across the EU.
Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a
C. elegans ...model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal, and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient receptor potential canonical) channels are defective in their response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus,
C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.
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