Oldest evidence of tool making hominins in a grassland-dominated ecosystem.

BACKGROUND: Major biological and cultural innovations in late Pliocene hominin evolution are frequently linked to the spread or fluctuating presence of C(4) grass in African ecosystems. Whereas the deep sea record of global climatic change provides indirect evidence for an increase in C(4) vegetation with a shift towards a cooler, drier and more variable global climatic regime beginning approximately 3 million years ago (Ma), evidence for grassland-dominated ecosystems in continental Africa and hominin activities within such ecosystems have been lacking. METHODOLOGY/PRINCIPAL FINDINGS: We report stable isotopic analyses of pedogenic carbonates and ungulate enamel, as well as faunal data from approximately 2.0 Ma archeological occurrences at Kanjera South, Kenya. These document repeated hominin activities within a grassland-dominated ecosystem. CONCLUSIONS/SIGNIFICANCE: These data demonstrate what hitherto had been speculated based on indirect evidence: that grassland-dominated ecosystems did in fact exist during the Plio-Pleistocene, and that early Homo was active in open settings. Comparison with other Oldowan occurrences indicates that by 2.0 Ma hominins, almost certainly of the genus Homo, used a broad spectrum of habitats in East Africa, from open grassland to riparian forest. This strongly contrasts with the habitat usage of Australopithecus, and may signal an important shift in hominin landscape usage

Shoulder hemiarthroplasty for fractures of the proximal humerus

Proximal humeral fractures were managed with primary hemiarthroplasty in 57 patients, 53 women (93%) and 4 men (7%) aged 51–87 years (mean 72.2). The mean follow-up period was 52 months (range 12–98), and the mean Constant score was 59.2 (range 38–76). Patients were very satisfied (n = 19); satisfied (n = 32) or dissatisfied with the outcome (n = 5). One patient required early revision surgery. Surgical treatment of three- and four-part fractures of the proximal humerus with hemiarthroplasty is a safe and effective approach, the outcome of which appears to be related to the quality of the anatomical reconstruction of the tuberosities

Get Organised: The 'Do's' Preceding Successful Field Research

There is no shortage in the political science literature on field research regarding issues of research design, methodology, and data evaluation. Yet, the practical and organisational intricacies that precede successful fieldwork are frequently overlooked. This lack of methodical advice may be due to the impression that field research is highly contextual, and so case-specific that general guidelines, which apply to all field research endeavours alike, are inconceivable. While we acknowledge the organisational complexity of field research, we disagree with the notion that the preparatory dimension of fieldwork is by necessity unique for every undertaking. Rather, recommendations for common challenges that occur during the preparation and organisation phase of a field trip can be identified and formulated. Consequently, we present and discuss ten organisational ?do's? preceding successful field research. Current graduate students and future field researchers will regard these ten pointers as useful hints in the organisation of their own endeavour. While the list is by no means exhaustive, the ten recommendations will lower the organisational entry costs of aspiring field researchers, and enable them to hit the ground running when arriving in the field

Overexpression of microRNA-206 in the skeletal muscle from myotonic dystrophy type 1 patients

<p>Abstract</p> <p>Background</p> <p>MicroRNAs are highly conserved, noncoding RNAs involved in post-transcriptional gene silencing. They have been shown to participate in a wide range of biological processes, including myogenesis and muscle regeneration. The goal of this study is to test the hypothesis that myo-miRs (myo = muscle + miR = miRNA) expression is altered in muscle from patients affected by myotonic dystrophy type 1 (DM1), the most frequently inherited neuromuscular disease in adults. In order to gain better insights about the role of miRNAs in the DM1 pathogenesis, we have also analyzed the muscular expression of miR-103 and miR-107, which have been identified <it>in silico </it>as attractive candidates for binding to the <it>DMPK </it>mRNA.</p> <p>Methods</p> <p>To this aim, we have profiled the expression of miR-133 (miR-133a, miR-133b), miR-1, miR-181 (miR-181a, miR-181b, miR-181c) and miR-206, that are specifically induced during myogenesis in cardiac and skeletal muscle tissues. miR-103 and miR-107, highly expressed in brain, heart and muscle have also been included in this study. QRT-PCR experiments have been performed on RNA from vastus lateralis biopsies of DM1 patients (n = 7) and control subjects (n = 4). Results of miRNAs expression have been confirmed by Northern blot, whereas <it>in situ </it>hybridization technique have been performed to localize misexpressed miRNAs on muscle sections from DM1 and control individuals.</p> <p>Results</p> <p>Only miR-206 showed an over-expression in 5 of 7 DM1 patients (threshold = 2, fold change between 1.20 and 13.22, average = 5.37) compared to the control group. This result has been further confirmed by Northern blot analysis (3.37-fold overexpression, <it>R</it>²= 0.89). <it>In situ </it>hybridization localized miR-206 to nuclear site both in normal and DM1 tissues. Cellular distribution in DM1 tissues includes also the nuclear regions of centralized nuclei, with a strong signal corresponding to nuclear clumps.</p> <p>Conclusions</p> <p>This work provides, for the first time, evidences about miRNAs misexpression in DM1 muscle tissues, adding a new element in the pathogenesis of this complex genetic disease.</p

Directed acyclic graph kernels for structural RNA analysis

<p>Abstract</p> <p>Background</p> <p>Recent discoveries of a large variety of important roles for non-coding RNAs (ncRNAs) have been reported by numerous researchers. In order to analyze ncRNAs by kernel methods including support vector machines, we propose stem kernels as an extension of string kernels for measuring the similarities between two RNA sequences from the viewpoint of secondary structures. However, applying stem kernels directly to large data sets of ncRNAs is impractical due to their computational complexity.</p> <p>Results</p> <p>We have developed a new technique based on directed acyclic graphs (DAGs) derived from base-pairing probability matrices of RNA sequences that significantly increases the computation speed of stem kernels. Furthermore, we propose profile-profile stem kernels for multiple alignments of RNA sequences which utilize base-pairing probability matrices for multiple alignments instead of those for individual sequences. Our kernels outperformed the existing methods with respect to the detection of known ncRNAs and kernel hierarchical clustering.</p> <p>Conclusion</p> <p>Stem kernels can be utilized as a reliable similarity measure of structural RNAs, and can be used in various kernel-based applications.</p

Gene Transcription and Splicing of T-Type Channels Are Evolutionarily-Conserved Strategies for Regulating Channel Expression and Gating

T-type calcium channels operate within tightly regulated biophysical constraints for supporting rhythmic firing in the brain, heart and secretory organs of invertebrates and vertebrates. The snail T-type gene, LCav3 from Lymnaea stagnalis, possesses alternative, tandem donor splice sites enabling a choice of a large exon 8b (201 aa) or a short exon 25c (9 aa) in cytoplasmic linkers, similar to mammalian homologs. Inclusion of optional 25c exons in the III–IV linker of T-type channels speeds up kinetics and causes hyperpolarizing shifts in both activation and steady-state inactivation of macroscopic currents. The abundant variant lacking exon 25c is the workhorse of embryonic Cav3 channels, whose high density and right-shifted activation and availability curves are expected to increase pace-making and allow the channels to contribute more significantly to cellular excitation in prenatal tissue. Presence of brain-enriched, optional exon 8b conserved with mammalian Cav3.1 and encompassing the proximal half of the I–II linker, imparts a ∼50% reduction in total and surface-expressed LCav3 channel protein, which accounts for reduced whole-cell calcium currents of +8b variants in HEK cells. Evolutionarily conserved optional exons in cytoplasmic linkers of Cav3 channels regulate expression (exon 8b) and a battery of biophysical properties (exon 25c) for tuning specialized firing patterns in different tissues and throughout development

Sentinel lymph node biopsy as guidance for radical trachelectomy in young patients with early stage cervical cancer

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to assess the feasibility and accuracy of sentinel lymph nodes (SLNs) detection using 99mTc phytate in predicting pelvic lymph nodes status for radical abdominal trachelectomy (RAT) in patients with early stage cervical cancer.</p> <p>Methods</p> <p>Sixty-eight women with stage IA2-IB1 cervical cancer and scheduled to undergo fertility-sparing surgery enrolled in this study. 99mTc-labeled phytate was injected before surgery. Intraoperatively, SLNs were identified, excised, and submitted to fast frozen section. Systematic bilateral pelvic lymphadenectomy and/or para-aortic lymph node dissection was performed. Then RAT was performed in patients with negative SLNs. All nodes were sent for routine pathological examination and immunostained with anti-cytokeratin antibody to detect micrometastases. Outcomes of follow up and fertility were observed.</p> <p>Results</p> <p>SLNs were identified in 64 of 68 patients (94.1%). Of these, SLNs of 8 patients (11.8%) were positive on frozen sections and proved to be metastasis by final pathologic examination. The sensitivity, accuracy, and false negative rates were 100%, 100%, and 0%, respectively. All 60 patients with negative SLN underwent RAT successfully. Two relapses occurred and no one died of tumor progression during follow-up. Five of the 15 patients with procreative desire conceived 8 pregnancies (3 term delivery, 2 premature birth, 1 spontaneous abortion, and 2 were still in the duration of pregnancy) after surgery.</p> <p>Conclusions</p> <p>The identification of SLN using 99mTc-labeled phytate is accurate and safe to assess pelvic nodes status in patients with early cervical cancer. SLNs biopsy guided RAT is feasible for patients who desire to have fertility preservation.</p

Efficacy of customised foot orthoses in the treatment of achilles tendinopathy : study protocol for a randomised trial

BACKGROUND: Achilles tendinopathy is a common condition that can cause marked pain and disability. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. The exception to this is eccentric calf muscle exercises, which have become a standard non-surgical intervention for Achilles tendinopathy. Foot orthoses have also been advocated as a treatment for Achilles tendinopathy, but the long-term efficacy of foot orthoses for this condition is unknown. This manuscript describes the design of a randomised trial to evaluate the efficacy of customised foot orthoses to reduce pain and improve function in people with Achilles tendinopathy. METHODS: One hundred and forty community-dwelling men and women aged 18 to 55 years with Achilles tendinopathy (who satisfy inclusion and exclusion criteria) will be recruited. Participants will be randomised, using a computer-generated random number sequence, to either a control group (sham foot orthoses made from compressible ethylene vinyl acetate foam) or an experimental group (customised foot orthoses made from semi-rigid polypropylene). Both groups will be prescribed a calf muscle eccentric exercise program, however, the primary difference between the groups will be that the experimental group receive customised foot orthoses, while the control group receive sham foot orthoses. The participants will be instructed to perform eccentric exercises 2 times per day, 7 days per week, for 12 weeks. The primary outcome measure will be the total score of the Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire. The secondary outcome measures will be participant perception of treatment effect, comfort of the foot orthoses, use of co-interventions, frequency and severity of adverse events, level of physical activity and health-related quality of life (assessed using the Short-Form-36 questionnaire - Version two). Data will be collected at baseline, then at 1, 3, 6 and 12 months. Data will be analysed using the intention to treat principle. DISCUSSION: This study is the first randomised trial to evaluate the long-term efficacy of customised foot orthoses for the treatment of Achilles tendinopathy. The study has been pragmatically designed to ensure that the study findings are generalisable to clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number: ACTRN12609000829213

Gemcitabine and Arabinosylcytosin Pharmacogenomics: Genome-Wide Association and Drug Response Biomarkers

Cancer patients show large individual variation in their response to chemotherapeutic agents. Gemcitabine (dFdC) and AraC, two cytidine analogues, have shown significant activity against a variety of tumors. We previously used expression data from a lymphoblastoid cell line-based model system to identify genes that might be important for the two drug cytotoxicity. In the present study, we used that same model system to perform a genome-wide association (GWA) study to test the hypothesis that common genetic variation might influence both gene expression and response to the two drugs. Specifically, genome-wide single nucleotide polymorphisms (SNPs) and mRNA expression data were obtained using the Illumina 550K® HumanHap550 SNP Chip and Affymetrix U133 Plus 2.0 GeneChip, respectively, for 174 ethnically-defined “Human Variation Panel” lymphoblastoid cell lines. Gemcitabine and AraC cytotoxicity assays were performed to obtain IC50 values for the cell lines. We then performed GWA studies with SNPs, gene expression and IC50 of these two drugs. This approach identified SNPs that were associated with gemcitabine or AraC IC50 values and with the expression regulation for 29 genes or 30 genes, respectively. One SNP in IQGAP2 (rs3797418) was significantly associated with variation in both the expression of multiple genes and gemcitabine and AraC IC50. A second SNP in TGM3 (rs6082527) was also significantly associated with multiple gene expression and gemcitabine IC50. To confirm the association results, we performed siRNA knock down of selected genes with expression that was associated with rs3797418 and rs6082527 in tumor cell and the knock down altered gemcitabine or AraC sensitivity, confirming our association study results. These results suggest that the application of GWA approaches using cell-based model systems, when combined with complementary functional validation, can provide insights into mechanisms responsible for variation in cytidine analogue response

Residential Radon and Brain Tumour Incidence in a Danish Cohort

BACKGROUND: Increased brain tumour incidence over recent decades may reflect improved diagnostic methods and clinical practice, but remain unexplained. Although estimated doses are low a relationship between radon and brain tumours may exist. OBJECTIVE: To investigate the long-term effect of exposure to residential radon on the risk of primary brain tumour in a prospective Danish cohort. METHODS: During 1993-1997 we recruited 57,053 persons. We followed each cohort member for cancer occurrence from enrolment until 31 December 2009, identifying 121 primary brain tumour cases. We traced residential addresses from 1 January 1971 until 31 December 2009 and calculated radon concentrations at each address using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate-ratios (IRR) and 95% confidence intervals (CI) for the risk of primary brain tumours associated with residential radon exposure with adjustment for age, sex, occupation, fruit and vegetable consumption and traffic-related air pollution. Effect modification by air pollution was assessed. RESULTS: Median estimated radon was 40.5 Bq/m(3). The adjusted IRR for primary brain tumour associated with each 100 Bq/m(3) increment in average residential radon levels was 1.96 (95% CI: 1.07; 3.58) and this was exposure-dependently higher over the four radon exposure quartiles. This association was not modified by air pollution. CONCLUSIONS: We found significant associations and exposure-response patterns between long-term residential radon exposure radon in a general population and risk of primary brain tumours, adding new knowledge to this field. This finding could be chance and needs to be challenged in future studies