Fragmentation of Collapsar Disks and the Production of Gravitational Waves

We argue that gravitational instability in the outer parts of collapsar disks may lead to fragmentation near the radius where helium photodisintegrates, because of the strong cooling provided by this process. This physics sets clear physical scales for the fragmentation conditions and the properties of gravitationally bound clumps. Collapse of a fragment proceeds until the neutrons become degenerate; a neutron star of mass ~0.1-1Msun may result. We find that tidal disruption of a fragment and accretion by the central black hole are too rapid to account for the durations of observed X-ray flares from long gamma-ray bursts. Prior to disruption, migration of the fragment is driven by gravitational radiation and disk viscosity, which act together to produce a unique gravitational-wave signature. Advanced LIGO may be able to detect such sources within ~100 Mpc.Comment: Accepted for publication in The Astrophysical Journal, 5 pages, 2 figures; added noise estimates for enhanced LIGO and expanded discussion of rate

U–Pb zircon-rutile dating of the Llangynog Inlier, Wales: constraints on an Ediacaran shallow marine fossil assemblage from East Avalonia

The Llangynog Inlier of south Wales contains an assemblage of Ediacaran macrofossils from a shallow-marine environment, including discoidal morphs of Aspidella and rare examples of Hiemalora, Palaeopascichnus and Yelovichnus. These are taxa found in other sites in the Avalonian microcontinent (e.g. Charnwood Forest and eastern Newfoundland) and in the younger White Sea Ediacaran assemblages. As the Charnwood fossils reflect a deep-water environment, and no macrofossils have been found in the Ediacaran rocks of the Long Mynd, the fossils of the Llangynog Inlier represent a unique glimpse of shallow marine life in southern Britain (East Avalonia). However, the lack of absolute age constraints has hampered direct comparison with other assemblages. Here, we report in-situ zircon and rutile U–Pb dates from a rhyolitic ash-flow layer of the Coed Cochion Volcaniclastic Member, Llangynog Inlier, which constrains the age of the fossiliferous strata. A weighted mean single grain zircon ID-TIMS U–Pb age of 564.09 ± 0.70 Ma is interpreted as the rhyolite's crystallisation age. This age is consistent with in-situ LA-ICPMS zircon and rutile U–Pb dating. The Llangynog age temporally correlates these fossils to dated horizons within East Avalonia at the Beacon Hill Formation, Charnwood (565.22 ± 0.89 Ma), and the Stretton Shale Formation, Long Mynd (566.6 ± 2.9 Ma). Correlations to West Avalonia include the time-equivalent Fermeuse Formation, St John’s Group, eastern Newfoundland (564.13 ± 0.65 Ma). The data presented here establish the biota of the Llangynog Inlier as a lateral equivalent to the similarly shallow marine, tidally influenced ecosystem of the upper Fermeuse Formation. Intra-terrane depositional environmental variability also affects what is preserved in Avalonian fossil sites. Further, time-constrained geochemical data reinforce the Llangynog Inlier's classification within the Wrekin Terrane

Cucurbit[n]uril binding of platinum anticancer complexes

The encapsulation of cisplatin by cucurbit[7]uril (Q[7]) and multinuclear platinum complexes linked via a 4,4′-dipyrazolylmethane (dpzm) ligand by Q[7] and cucurbit[8]uril (Q[8]) has been studied by NMR spectroscopy and molecular modelling. The NMR studies suggest that some cisplatin binds in the cucurbituril cavity, while cis-[PtCl(NH3)2(H2O)]+ only binds at the portals. Alternatively, the dpzm-linked multinuclear platinum complexes are quantitatively encapsulated within the cavities of both Q[7] and Q[8]. Upon encapsulation, the non-exchangeable proton resonances of the multinuclear platinum complexes show significant upfield shifts in 1H NMR spectra. The H3/H3* resonances shift upfield by 0.08 to 0.55 ppm, the H5/H5* shift by 0.9 to 1.6 ppm, while the methylene resonances shift by 0.74 to 0.88 ppm. The size of the resonance shift is dependent on the cavity size of the encapsulating cucurbituril, with Q[7] encapsulation producing larger shifts than Q[8]. The upfield shifts of the dpzm resonances observed upon cucurbituril encapsulation indicate that the Q[7] or Q[8] is positioned directly over the dpzm linking ligand. The terminal platinum groups of trans-[{PtCl(NH3)2}2μ-dpzm]2+ (di-Pt) and trans-[trans-{PtCl(NH3)2}2-trans-{Pt(dpzm)2(NH3)2}]4+ (tri-Pt) provide a barrier to the on and off movement of cucurbituril, resulting in binding kinetics that are slow on the NMR timescale for the metal complex. Although the dpzm ligand has relatively few rotamers, encapsulation by the larger Q[8] resulted in a more compact di-Pt conformation with each platinum centre retracted further into each Q[8] portal. Encapsulation of the hydrolysed forms of di-Pt and tri-Pt is considerably slower than for the corresponding Cl forms, presumably due to the high-energy cost of passing the +2 platinum centres through the cucurbituril portals. The results of this study suggest that cucurbiturils could be suitable hosts for the pharmacological delivery of multinuclear platinum complexe

Mitochondrial genome sequence analysis: A custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy

BACKGROUND: Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate and accuracy for the Affymetrix MitoChip v2.0 platform. We used this custom pipeline to analyze MitoChip v2.0 data from 24 DNA samples representing a broad range of tissue types (18 whole blood, 3 skeletal muscle, 3 cell lines), mutations (a 5.8 kilobase pair deletion and 6 known heteroplasmic mutations), and haplogroup origins. All results were compared to those obtained by at least one other mitochondrial DNA sequence analysis method, including Sanger sequencing, denaturing HPLC-based heteroduplex analysis, and/or the Illumina Genome Analyzer II next generation sequencing platform. RESULTS: An average call rate of 99.75% was achieved across all samples with our custom pipeline. Comparison of calls for 15 samples characterized previously by Sanger sequencing revealed a total of 29 discordant calls, which translates to an estimated 0.012% for the base call error rate. We successfully identified 4 known heteroplasmic mutations and 24 other potential heteroplasmic mutations across 20 samples that passed quality control. CONCLUSIONS: Affymetrix MitoChip v2.0 analysis using our optimized MitoChip Filtering Protocol (MFP) bioinformatics pipeline now offers the high sensitivity and accuracy needed for reliable, high-throughput and cost-efficient whole mitochondrial genome sequencing. This approach provides a viable alternative of potential utility for both clinical diagnostic and research applications to traditional Sanger and other emerging sequencing technologies for whole mitochondrial genome analysis

C5 Palsy After Cervical Spine Surgery: A Multicenter Retrospective Review of 59 Cases.

STUDY DESIGN: A multicenter, retrospective review of C5 palsy after cervical spine surgery. OBJECTIVE: Postoperative C5 palsy is a known complication of cervical decompressive spinal surgery. The goal of this study was to review the incidence, patient characteristics, and outcome of C5 palsy in patients undergoing cervical spine surgery. METHODS: We conducted a multicenter, retrospective review of 13 946 patients across 21 centers who received cervical spine surgery (levels C2 to C7) between January 1, 2005, and December 31, 2011, inclusive. P values were calculated using 2-sample t test for continuous variables and χ(2) tests or Fisher exact tests for categorical variables. RESULTS: Of the 13 946 cases reviewed, 59 patients experienced a postoperative C5 palsy. The incidence rate across the 21 sites ranged from 0% to 2.5%. At most recent follow-up, 32 patients reported complete resolution of symptoms (54.2%), 15 had symptoms resolve with residual effects (25.4%), 10 patients did not recover (17.0%), and 2 were lost to follow-up (3.4%). CONCLUSION: C5 palsy occurred in all surgical approaches and across a variety of diagnoses. The majority of patients had full recovery or recovery with residual effects. This study represents the largest series of North American patients reviewed to date

Apoptosis is associated with triacylglycerol accumulation in Jurkat T-cells

Magnetic resonance spectroscopy is increasingly used as a non-invasive method to investigate apoptosis. Apoptosis was induced in Jurkat T-cells by Fas mAb. 1H magnetic resonance spectra of live cells showed an increase in methylene signal as well as methylene/methyl ratio of fatty acid side chains at 5 and 24 h following induction of apoptosis. To explain this observation, 1H magnetic resonance spectra of cell extracts were investigated. These demonstrated a 70.0±7.0%, 114.0±8.0% and 90.0±5.0% increase in the concentration of triacylglycerols following 3, 5 and 7 h of Fas mAb treatment (P<0.05). Confocal microscopy images of cells stained with the lipophilic dye Nile Red demonstrated the presence of lipid droplets in the cell cytoplasm. Quantification of the stained lipids by flow cytometry showed a good correlation with the magnetic resonance results (P⩾0.05 at 3, 5 and 7 h). 31P magnetic resonance spectra showed a drop in phosphatidylcholine content of apoptosing cells, indicating that alteration in phosphatidylcholine metabolism could be the source of triacylglycerol accumulation during apoptosis. In summary, apoptosis is associated with an early accumulation of mobile triacylglycerols mostly in the form of cytoplasmic lipid droplets. This is reflected in an increase in the methylene/methyl ratio which could be detected by magnetic resonance spectroscopy

An analysis of baseline data from the PROUD study: an open-label randomised trial of pre-exposure prophylaxis

Background: Pre-exposure prophylaxis (PrEP) has proven biological efficacy to reduce the sexual acquisition of the human immunodeficiency virus (HIV). The PROUD study found that PrEP conferred higher protection than in placebo-controlled trials, reducing HIV incidence by 86 % in a population with seven-fold higher HIV incidence than expected. We present the baseline characteristics of the PROUD study population and place the findings in the context of national sexual health clinic data. Methods: The PROUD study was designed to explore the real-world effectiveness of PrEP (tenofovir-emtricitabine) by randomising HIV-negative gay and other men who have sex with men (GMSM) to receive open-label PrEP immediately or after a deferral period of 12 months. At enrolment, participants self-completed two baseline questionnaires collecting information on demographics, sexual behaviour and lifestyle in the last 30 and 90 days. These data were compared to data from HIV-negative GMSM attending sexual health clinics in 2013, collated by Public Health England using the genitourinary medicine clinic activity database (GUMCAD). Results: The median age of participants was 35 (IQR: 29–43). Typically participants were white (81 %), educated at a university level (61 %) and in full-time employment (72 %). Of all participants, 217 (40 %) were born outside the UK. A sexually transmitted infection (STI) was reported to have been diagnosed in the previous 12 months in 330/515 (64 %) and 473/544 (87 %) participants reported ever having being diagnosed with an STI. At enrolment, 47/280 (17 %) participants were diagnosed with an STI. Participants reported a median (IQR) of 10 (5–20) partners in the last 90 days, a median (IQR) of 2 (1–5) were condomless sex acts where the participant was receptive and 2 (1–6) were condomless where the participant was insertive. Post-exposure prophylaxis had been prescribed to 184 (34 %) participants in the past 12 months. The number of STI diagnoses was high compared to those reported in GUMCAD attendees. Conclusions: The PROUD study population are at substantially higher risk of acquiring HIV infection sexually than the overall population of GMSM attending sexual health clinics in England. These findings contribute to explaining the extraordinary HIV incidence rate during follow-up and demonstrate that, despite broad eligibility criteria, the population interested in PrEP was highly selective. Trial registration: Current Controlled TrialsISRCTN94465371. Date of registration: 28 February 2013

Development of transgenic rats producing human β-amyloid precursor protein as a model for Alzheimer's disease: Transgene and endogenous APP genes are regulated tissue-specifically

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals. In addition to idiopathic disease, AD is also associated with autosomal dominant inheritance, which causes a familial form of AD (FAD). Some instances of FAD have been linked to mutations in the β-amyloid protein precursor (APP). Although there are numerous mouse AD models available, few rat AD models, which have several advantages over mice, have been generated.</p> <p>Results</p> <p>Fischer 344 rats expressing human APP driven by the ubiquitin-C promoter were generated via lentiviral vector infection of Fischer 344 zygotes. We generated two separate APP-transgenic rat lines, APP21 and APP31. Serum levels of human amyloid-beta (Aβ)₄₀were 298 pg/ml for hemizygous and 486 pg/ml for homozygous APP21 animals. Serum Aβ₄₂levels in APP21 homozygous rats were 135 pg/ml. Immunohistochemistry in brain showed that the human APP transgene was expressed in neurons, but not in glial cells. These findings were consistent with independent examination of enhanced green fluorescent protein (eGFP) in the brains of eGFP-transgenic rats. APP21 and APP31 rats expressed 7.5- and 3-times more APP mRNA, respectively, than did wild-type rats. Northern blots showed that the human APP transgene, driven by the ubiquitin-C promoter, is expressed significantly more in brain, kidney and lung compared to heart and liver. A similar expression pattern was also seen for the endogenous rat APP. The unexpected similarity in the tissue-specific expression patterns of endogenous rat APP and transgenic human APP mRNAs suggests regulatory elements within the cDNA sequence of APP.</p> <p>Conclusion</p> <p>This manuscript describes the generation of APP-transgenic inbred Fischer 344 rats. These are the first human AD model rat lines generated by lentiviral infection. The APP21 rat line expresses high levels of human APP and could be a useful model for AD. Tissue-specific expression in the two transgenic rat lines and in wild-type rats contradicts our current understanding of APP gene regulation. Determination of the elements that are responsible for tissue-specific expression of APP may enable new treatment options for AD.</p