Localisation of RNAs into the germ plasm of vitellogenic xenopus oocytes

We have studied the localisation of mRNAs in full-grown Xenopus laevis oocytes by injecting fluorescent RNAs, followed by confocal microscopy of the oocyte cortex. Concentrating on RNA encoding the Xenopus Nanos homologue, nanos1 (formerly Xcat2), we find that it consistently localised into aggregated germ plasm ribonucleoprotein (RNP) particles, independently of cytoskeletal integrity. This implies that a diffusion/entrapment-mediated mechanism is active, as previously reported for previtellogenic oocytes. Sometimes this was accompanied by localisation into scattered particles of the “late”, Vg1/VegT pathway; occasionally only late pathway localisation was seen. The Xpat RNA behaved in an identical fashion and for neither RNA was the localisation changed by any culture conditions tested. The identity of the labelled RNP aggregates as definitive germ plasm was confirmed by their inclusion of abundant mitochondria and co-localisation with the germ plasm protein Hermes. Further, the nanos1/Hermes RNP particles are interspersed with those containing the germ plasm protein Xpat. These aggregates may be followed into the germ plasm of unfertilized eggs, but with a notable reduction in its quantity, both in terms of injected molecules and endogenous structures. Our results conflict with previous reports that there is no RNA localisation in large oocytes, and that during mid-oogenesis even germ plasm RNAs localise exclusively by the late pathway. We find that in mid oogenesis nanos1 RNA also localises to germ plasm but also by the late pathway. Late pathway RNAs, Vg1 and VegT, also may localise into germ plasm. Our results support the view that mechanistically the two modes of localisation are extremely similar, and that in an injection experiment RNAs might utilise either pathway, the distinction in fates being very subtle and subject to variation. We discuss these results in relation to their biological significance and the results of others

Comparative Performance Information Plays No Role in the Referral Behaviour of GPs

Comparative performance information (CPI) about the quality of hospital care is information used to identify high-quality hospitals and providers. As the gatekeeper to secondary care, the general practitioner (GP) can use CPI to reflect on the pros and cons of the available options with the patient and choose a provider best fitted to the patient’s needs. We investigated how GPs view their role in using CPI to choose providers and support patients. Method: We used a mixed-method, sequential, exploratory design to conduct explorative interviews with 15 GPs about their referral routines, methods of referral consideration, patient involvement, and the role of CPI. Then we quantified the qualitative results by sending a survey questionnaire to 81 GPs affiliated with a representative national research network. Results: Seventy GPs (86% response rate) filled out the questionnaire. Most GPs did not know where to find CPI (87%) and had never searched for it (94%). The GPs reported that they were not motivated to use CPI due to doubts about its role as support information, uncertainty about the effect of using CPI, lack of faith in better outcomes, and uncertainty about CPI content and validity. Nonetheless, most GPs believed that patients would like to be informed about quality-of- care differences (62%), and about half the GPs discussed quality-of-care differences with their patients (46%), though these discussions were not based on CPI. Conclusion: Decisions about referrals to hospital care are not based on CPI exchanges during GP consultations. As a gatekeeper, the GP is in a good position to guide patients through the enormous amount of quality information that is available. Nevertheless, it is unclear how and whether the GP’s role in using information about quality of care in the referral process can grow, as patients hardly ever initiate a discussion based on CPI, though they seem to be increasingly more critical about differences in quality of care. Future research should address the conditions needed to support GPs’ ability and willingness to use CPI to guide their patients in the referral process

Impairment of Vowel Articulation as a Possible Marker of Disease Progression in Parkinson's Disease

Purpose: The aim of the current study was to survey if vowel articulation in speakers with Parkinson’s disease (PD) shows specific changes in the course of the disease. Method: 67 patients with PD (42 male) and 40 healthy speakers (20 male) were tested and retested after an average time interval of 34 months. Participants had to read a given text as source for subsequent calculation of the triangular vowel space area (tVSA) and vowel articulation index (VAI). Measurement of tVSA and VAI were based upon analysis of the first and second formant of the vowels /a/, /i/and /u / extracted from defined words within the text. Results: At first visit, VAI values were reduced in male and female PD patients as compared to the control group, and showed a further decrease at the second visit. Only in female Parkinsonian speakers, VAI was correlated to overall speech impairment based upon perceptual impression. VAI and tVSA were correlated to gait impairment, but no correlations were seen between VAI and global motor impairment or overall disease duration. tVSA showed a similar reduction in the PD as compared to the control group and was also found to further decline between first and second examination in female, but not in male speakers with PD. Conclusions: Measurement of VAI seems to be superior to tVSA in the description of impaired vowel articulation and its further decline in the course of the disease in PD. Since impairment of vowel articulation was found to be independent fro

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

Background Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania). Results The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact. Conclusions The community should consider how to maximise this collective resource in future therapeutic programmes

Functional Copy-Number Alterations in Cancer

Understanding the molecular basis of cancer requires characterization of its genetic defects. DNA microarray technologies can provide detailed raw data about chromosomal aberrations in tumor samples. Computational analysis is needed (1) to deduce from raw array data actual amplification or deletion events for chromosomal fragments and (2) to distinguish causal chromosomal alterations from functionally neutral ones. We present a comprehensive computational approach, RAE, designed to robustly map chromosomal alterations in tumor samples and assess their functional importance in cancer. To demonstrate the methodology, we experimentally profile copy number changes in a clinically aggressive subtype of soft-tissue sarcoma, pleomorphic liposarcoma, and computationally derive a portrait of candidate oncogenic alterations and their target genes. Many affected genes are known to be involved in sarcomagenesis; others are novel, including mediators of adipocyte differentiation, and may include valuable therapeutic targets. Taken together, we present a statistically robust methodology applicable to high-resolution genomic data to assess the extent and function of copy-number alterations in cancer

Thermal Transport in Micro- and Nanoscale Systems

Small-scale (micro-/nanoscale) heat transfer has broad and exciting range of applications. Heat transfer at small scale quite naturally is influenced – sometimes dramatically – with high surface area-to-volume ratios. This in effect means that heat transfer in small-scale devices and systems is influenced by surface treatment and surface morphology. Importantly, interfacial dynamic effects are at least non-negligible, and there is a strong potential to engineer the performance of such devices using the progress in micro- and nanomanufacturing technologies. With this motivation, the emphasis here is on heat conduction and convection. The chapter starts with a broad introduction to Boltzmann transport equation which captures the physics of small-scale heat transport, while also outlining the differences between small-scale transport and classical macroscale heat transport. Among applications, examples are thermoelectric and thermal interface materials where micro- and nanofabrication have led to impressive figure of merits and thermal management performance. Basic of phonon transport and its manipulation through nanostructuring materials are discussed in detail. Small-scale single-phase convection and the crucial role it has played in developing the thermal management solutions for the next generation of electronics and energy-harvesting devices are discussed as the next topic. Features of microcooling platforms and physics of optimized thermal transport using microchannel manifold heat sinks are discussed in detail along with a discussion of how such systems also facilitate use of low-grade, waste heat from data centers and photovoltaic modules. Phase change process and their control using surface micro-/nanostructure are discussed next. Among the feature considered, the first are microscale heat pipes where capillary effects play an important role. Next the role of nanostructures in controlling nucleation and mobility of the discrete phase in two-phase processes, such as boiling, condensation, and icing is explained in great detail. Special emphasis is placed on the limitations of current surface and device manufacture technologies while also outlining the potential ways to overcome them. Lastly, the chapter is concluded with a summary and perspective on future trends and, more importantly, the opportunities for new research and applications in this exciting field

Expanded geographic distribution and dietary strategies of the earliest Oldowan hominins and Paranthropus

The oldest Oldowan tool sites, ca. 2.6 million years ago (Ma), have previously been confined to Ethiopia’s Afar Triangle. We describe sites at Nyayanga, Kenya, dated to 3.032-2.581 Ma, and expand this distribution by over 1300 km. Furthermore, we found two hippopotamid butchery sites associated with mosaic vegetation and a C4 grazer-dominated fauna. Tool flaking proficiency was comparable to younger Oldowan assemblages, but pounding activities were more common. Tool use-wear and bone damage indicate plant and animal tissue processing. Paranthropus sp. teeth, the first from southwestern Kenya, possessed carbon isotopic values indicative of a diet rich in C4 foods. We argue that the earliest Oldowan was more widespread than previously known, used to process diverse foods including megafauna, and associated with Paranthropus from its onset

Factors associated with serum 25-hydroxyvitamin D concentrations in older people in Europe: the EUREYE study.

BACKGROUND/OBJECTIVES: We aimed to describe serum 25-hydroxyvitamin D (25OHD) concentrations in older Europeans and to investigate associations between 25OHD and lifestyle factors, including dietary intake and supplement use. SUBJECTS/METHODS: Men and women aged ≥ 65 years were recruited from seven centres across north to south Europe. Serum 25OHD2 and 25OHD3 concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 4495 samples and total 25OHD (25OHD2 + 25OHD3) was adjusted for season of blood collection. RESULTS: The mean (25th, 75th quartile) of seasonally adjusted 25OHD was 46 (34, 65) nmol/L, with the highest concentration of 25OHD in Bergen [61 (49, 79) nmol/L], and the lowest in Paris [36 (24, 57) nmol/L)]. Vitamin D deficiency (25-50 nmol/L) and vitamin D insufficiency (50-75 nmol/L) were found in 41 and 33% of the population, respectively. In multivariable analysis controlled for confounders, seasonally adjusted 25OHD concentrations were significantly (p < 0.05) lower in smokers and participants with self-reported diabetes and higher with increasing dietary vitamin D, and supplement use with fish liver oil, omega-3, and vitamin D. Additionally, in further analysis excluding Bergen, 25OHD was associated with higher intakes of oily fish and increasing UVB exposure. We observed low concentrations of 25OHD in older people in Europe. CONCLUSIONS: Our findings of the higher 25OHD concentrations in supplement users (omega-3 fish oil, fish liver oil, vitamin D) add to current recommendations to reduce vitamin D deficiency. We were unable to fully assess the role of dietary vitamin D as we lacked information on vitamin D-fortified foods