Identifying the Effects of a Human Dynein Mutation on GFP-Rab7 Axonal Transport in Embryonic Mouse Neurons

The first dynein mutation found in humans that caused disease was a cytoplasmic dynein 1 heavy chain (DYNC1H1 in humans) p.His306Arg mutation, first described by Weedon et al. in 2011. This mutation caused Charcot-Marie-Tooth (CMT) subtype 2O. CMT has a prevalence of approximately 1 in 2500 people, making it the most common hereditary neuromuscular disorder. Cytoplasmic dynein 1 is used by eukaryotic cells for minus-end directed microtubule-based transport of cargo. One such cargo is Rab7, a late endosomal marker. The purpose of this study is to identify the effects of this mutation on the transport of GFP-tagged Rab7 cargo in neurons from wild type (HH), heterozygous mutant (HR), and homozygous mutant (RR) mice harboring a DYNC1HI His306Arg mutation. Mouse embryos were euthanized, dissected to collect the hippocampal and cortical brain tissues, and these tissues were digested to isolate neurons. Nucleofection was used to introduce the exogenous GFP-Rab7 gene construct. These neurons were plated and imaged at 10 days in vitro using wide-field epifluorescence microscopy to generate image stacks of fluorescent GFP-Rab7 vesicles. Kymograph analysis was performed on the image stacks using MetaMorph software to measure several characteristics of movement. Statistical analysis of the data from each of the three genotypes shows there is no significant difference in Rab-7 transport between the three genotypes

Exome-wide association study of pancreatic cancer risk

We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P=3.27x10(-6); exome-wide statistical significance threshold P<2.5x10(-6)). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35, P=.045). At the suggestive threshold (P<.001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition

Qualitative documentary analysis of guidance on information provision and consent for the introduction of innovative invasive procedures including surgeries within NHS organisations' policies in England and Wales

OBJECTIVE: To review guidance, included in written local UK National Health Service (NHS) organisation policies, on information provision and consent for the introduction of new invasive procedures- including surgeries, and devices (IPs/Ds). DESIGN: A qualitative documentary analysis of data on patient information provision and consent extracted from policies for the introduction of IP/Ds from NHS organisations in England and Wales. SETTING: NHS trusts in England and health boards in Wales, UK. PARTICIPANTS: Between December 2017 and July 2018, 150 acute trusts in England and 7 health boards in Wales were approached for their policies for the introduction of new IP/Ds. In total, 123 policies were received, 11 did not fit the inclusion criteria and a further policy was included from a trust website resulting in 113 policies included for review. RESULTS: From the 113 policies, 22 did not include any statements on informed consent/information provision or lacked guidance on the information to be provided to patients and were hence excluded. Consequently, 91 written local NHS policies were included in the final dataset. Within the guidance obtained, variation existed on disclosure of the procedure’s novelty, potential risks, benefits, uncertainties, alternative treatments and surgeon’s experience. Few policies stated that clinicians should discuss the existing evidence associated with a procedure. Additionally, while the majority of policies referred to patients needing written information, this was often not mandated and few policies specified the information to be included. CONCLUSIONS: Nearly a fifth of all the policies lacked guidance on information to be provided to patients. There was variability in the policy documents regarding what patients should be told about innovative procedures. Further research is needed to ascertain the information and level of detail appropriate for patients when considering innovative procedures. A core information set including patients’ and clinicians’ views is required to address variability around information provision/consent for innovative procedures

Radiocarbon Analyses Quantify Peat Carbon Losses With Increasing Temperature in a Whole Ecosystem Warming Experiment

Climate warming is expected to accelerate peatland degradation and release rates of carbon dioxide (CO2) and methane (CH4). Spruce and Peatlands Responses Under Changing Environments is an ecosystem-scale climate manipulation experiment, designed to examine peatland ecosystem response to climate forcings. We examined whether heating up to +9 °C to 3 m-deep in a peat bog over a 7-year period led to higher C turnover and CO2 and CH4 emissions, by measuring 14C of solid peat, dissolved organic carbon (DOC), CH4, and dissolved CO2 (DIC). DOC, a major substrate for heterotrophic respiration, increased significantly with warming. There was no 7-year trend in the DI14 C of the ambient plots which remained similar to their DO14 C. At +6.75 °C and +9 °C, the 14C of DIC, a product of microbial respiration, initially resembled ambient plots but became more depleted over 7 years of warming. We attributed the shifts in DI14 C to the increasing importance of solid phase peat as a substrate for microbial respiration and quantified this shift via the radiocarbon mass balance. The mass-balance model revealed increases in peat-supported respiration of the catotelm depths in heated plots over time and relative to ambient enclosures, from a baseline of 20%–25% in ambient enclosures, to 35%–40% in the heated plots. We find that warming stimulates microorganisms to respire ancient peat C, deposited under prior climate (cooler) conditions. This apparent destabilization of the large peat C reservoir has implications for peatland-climate feedbacks especially if the balance of the peatland is tipped from net C sink to C source. Plain Language Summary Since the end of the last glacial period, about 20 thousand years ago, peatlands have taken up carbon and now store an amount nearly equivalent to the quantity in the atmosphere. Microorganisms consume and respire that peat C releasing it back to the atmosphere as CO2 and CH4. Until now, many studies have shown that microorganisms prefer to consume the most recently fixed carbon and that the deeply buried ancient peat carbon reservoir is relatively stable. However, climate warming is expected to upset that balance. The Spruce and Peatlands Responses Under Changing Environments is large-scale experimental warming of a Minnesota peatland designed to study these effects. We conducted radiocarbon analysis of the peat and the microbially produced CO2 and dissolved organic carbon in ambient and heated areas of the peatland and show that at warmer temperatures more of the ancient peat carbon is being mobilized and respired to CO2. This is troubling as it signifies a positive feedback loop wherein warming stimulates peat to produce more CO2 which further exacerbates climate change

Soil Metabolome Response to Whole-Ecosystem Warming at the Spruce and Peatland Responses Under Changing Environments Experiment

While peatlands have historically stored massive amounts of soil carbon, warming is expected to enhance decomposition, leading to a positive feedback with climate change. In this study, a unique whole-ecosystem warming experiment was conducted in northern Minnesota to warm peat profiles to 2 m deep while keeping water flow intact. After nearly 2 y, warming enhanced the degradation of soil organic matter and increased greenhouse gas production. Changes in organic matter quality with warming were accompanied by a stimulation of methane production relative to carbon dioxide. Our results revealed increased decomposition to be fueled by the availability of reactive carbon substrates produced by surface vegetation. The elevated rates of methanogenesis are likely to persist and exacerbate climate warming

Understanding, treating, and renaming grandiose delusions : a qualitative study

Background Grandiose delusions are arguably the most neglected psychotic experience in research. Objectives We aimed to discover from patients: whether grandiose delusions have harmful consequences; the psychological mechanisms that maintain them; and what help patients may want from clinical services. Design A qualitative interview design was used to explore patients’ experiences of grandiose delusions. Method Fifteen patients with past or present experiences of grandiose delusions who were attending psychiatric services were interviewed. Thematic analysis and grounded theory were used to analyse the data. Results Participants reported physical, sexual, social, occupational, and emotional harms from grandiose delusions. All patients described the grandiose belief as highly meaningful: it provided a sense of purpose, belonging, or self‐identity, or it made sense of unusual or difficult events. The meaning from the belief was not synonymous with extreme superiority or arrogance. The meaning obtained appeared to be a key driver of the persistence of the beliefs. Other maintenance factors were subjectively anomalous experiences (e.g., voices), symptoms of mania, fantasy elaboration, reasoning biases, and immersive behaviours. Participants described insufficient opportunities to talk about their grandiose beliefs and related experiences and were generally positive about the possibility of a psychological therapy. Conclusions We conclude that grandiosity is a psychologically rich experience, with a number of maintenance factors that may be amenable to a targeted psychological intervention. Importantly, the term ‘grandiose delusion’ is an imprecise description of the experience; we suggest ‘delusions of exceptionality’ may be a credible alternative. Practitioner points -Harm from grandiose delusions can occur across multiple domains (including physical, sexual, social, occupational, and emotional) and practitioners should assess accordingly. -However, grandiose delusions are experienced by patients as highly meaningful: they provide a sense of purpose, belonging, or self‐identity, or make sense of unusual or difficult events. -Possible psychological maintenance mechanisms that could be a target for intervention include the meaning of the belief, anomalous experiences, mania, fantasy elaboration, reasoning biases, and immersive behaviours. -Patients are keen to have the opportunity to access talking therapies for this experience. Taking extra time to talk at times of distress, ‘going the extra mile’, and listening carefully can help to facilitate trust

Syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance

Background Arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. Therefore, arbovirus infections are often neglected by travel diagnostics. Here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases in returning travelers. Method To map the patients high at risk of missed clinical arboviral infections we compared the quantity of all arboviral diagnostic requests by physicians in the Netherlands, from 2009 through 2013, with a literature-based assessment of the travelers’ likely exposure to an arbovirus. Results 2153 patients, with travel and clinical history were evaluated. The diagnostic assay for dengue virus (DENV) was the most commonly requested (86%). Of travelers returning from Southeast Asia with symptoms compatible with chikungunya virus (CHIKV), only 55% were tested. For travelers in Europe, arbovirus diagnostics were rarely requested. Over all, diagnostics for most arboviruses were requested only on severe clinical presentation. Conclusion Travel destination and syndrome were used inconsistently for triage of diagnostics, likely resulting in vast under-diagnosis of arboviral infections of public health significance. This study shows the need for more awareness among physicians and standardization of syndromic diagnostic algorithm

The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey

The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T_eff<5000 K and in metallicity estimates for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SDSS-III Sloan Extension for Galactic Understanding and Exploration-2 (SEGUE-2). The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) along with another year of data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at http://www.sdss3.org/dr