The Cardiomyopathy-associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)-related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for ...a number of diseases affecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn. Cmya5 and Fsd2 appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on different chromosomes. Using immunoaffinity purification and mass spectrometry we show that minispryn co-purifies with myospryn and the major cardiac ryanodine receptor (RyR2) from heart. Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cells whereas minispryn lacks this activity. Together these data suggest a novel role for the myospryn complex in the assembly of ryanodine receptor clusters in striated muscle.
Key Clinical Message
We report a case of lung adenocarcinoma‐associated hypercoagulability leading to venous limb gangrene, managed successfully with argatroban and then dabigatran. Use of ...idarucizumab permitted diagnostic investigations, leading to targeted antineoplastic therapy with crizotinib, surgical resection with curative intent, and continued survival over 2 years after the index event.
We report a case of lung adenocarcinoma‐associated hypercoagulability leading to venous limb gangrene, managed successfully with argatroban and then dabigatran. Use of idarucizumab permitted diagnostic investigations, leading to targeted antineoplastic therapy with crizotinib, surgical resection with curative intent, and continued survival over 2 years after the index event.
Main-sequence low-mass stars are known to spin down as a consequence of their magnetized stellar winds. However, estimating the precise rate of this spin-down is an open problem. The mass-loss rate, ...angular momentum loss rate, and magnetic field properties of low-mass stars are fundamentally linked, making this a challenging task. Of particular interest is the stellar magnetic field geometry. In this work, we consider whether non-dipolar field modes contribute significantly to the spin-down of low-mass stars. We do this using a sample of stars that have all been previously mapped with Zeeman-Doppler imaging. For a given star, as long as its mass-loss rate is below some critical mass-loss rate, only the dipolar fields contribute to its spin-down torque. However, if it has a larger mass-loss rate, higher-order modes need to be considered. For each star, we calculate this critical mass-loss rate, which is a simple function of the field geometry. Additionally, we use two methods of estimating mass-loss rates for our sample of stars. In the majority of cases, we find that the estimated mass-loss rates do not exceed the critical mass-loss rate; hence, the dipolar magnetic field alone is sufficient to determine the spin-down torque. However, we find some evidence that, at large Rossby numbers, non-dipolar modes may start to contribute.
Cation-π interactions drive the self-assembly and cohesion of many biological molecules, including the adhesion proteins of several marine organisms. Although the origin of cation-π bonds in isolated ...pairs has been extensively studied, the energetics of cation-π-driven self-assembly in molecular films remains uncharted. Here we use nanoscale force measurements in combination with solid-state NMR spectroscopy to show that the cohesive properties of simple aromatic- and lysine-rich peptides rival those of the strong reversible intermolecular cohesion exhibited by adhesion proteins of marine mussel. In particular, we show that peptides incorporating the amino acid phenylalanine, a functional group that is conspicuously sparing in the sequences of mussel proteins, exhibit reversible adhesion interactions significantly exceeding that of analogous mussel-mimetic peptides. More broadly, we demonstrate that interfacial confinement fundamentally alters the energetics of cation-π-mediated assembly: an insight that should prove relevant for diverse areas, which range from rationalizing biological assembly to engineering peptide-based biomaterials.
Low-mass stars are known to have magnetic fields that are believed to be of dynamo origin. Two complementary techniques are principally used to characterize them. Zeeman-Doppler imaging (ZDI) can ...determine the geometry of the large-scale magnetic field while Zeeman broadening can assess the total unsigned flux including that associated with small-scale structures such as spots. In this work, we study a sample of stars that have been previously mapped with ZDI. We show that the average unsigned magnetic flux follows an activity-rotation relation separating into saturated and unsaturated regimes. We also compare the average photospheric magnetic flux recovered by ZDI, , with that recovered by Zeeman broadening studies, . In line with previous studies, ranges from a few % to ∼20% of . We show that a power-law relationship between and exists and that ZDI recovers a larger fraction of the magnetic flux in more active stars. Using this relation, we improve on previous attempts to estimate filling factors, i.e., the fraction of the stellar surface covered with magnetic field, for stars mapped only with ZDI. Our estimated filling factors follow the well-known activity-rotation relation, which is in agreement with filling factors obtained directly from Zeeman broadening studies. We discuss the possible implications of these results for flux tube expansion above the stellar surface and stellar wind models.
Summary Background Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical ...trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. Methods The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% one-sided significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. Findings Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38–85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90–1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of −12·7 to 3·3. Interpretation Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. Funding Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.
During the first Southern Ocean Iron RElease Experiment (SOIREE), a suite of biogeochemical measurements (water column 234Th and δ13Corg inventories, particle fluxes from sediment traps, ...phytoplankton sinking rates) were undertaken to test the hypothesis that the vertical export of particulate organic carbon (POC) is enhanced due to iron‐induced increases in phytoplankton production. During the 13‐days that the SOIREE bloom was monitored, export fluxes within the iron‐fertilised patch were not substantially different to those in waters outside the bloom. On days 11–13, iron enrichment may have caused particle transformations that could lead to elevated future export via particle aggregation and/or diatom chain formation. The unknown time‐lag between increased production and export, the longevity of the SOIREE bloom, and the absence of nutrient limitation over days 1–13, however, prohibit prediction of any iron‐induced export. This conclusion highlights the difficulties of fully testing the “Iron Hypothesis” and for evaluating the implications for global climate change.
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients ...with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) have contributed substantially to reductions in the burden of malaria in the past 15 years. Building on this foundation, the ...goal is now to drive malaria towards elimination. Vector control remains central to this goal, but there are limitations to what is achievable with the current tools. Here we highlight how a broader appreciation of adult mosquito behavior is yielding a number of supplementary approaches to bolster the vector-control tool kit. We emphasize tools that offer new modes of control and could realistically contribute to operational control in the next 5 years. Promoting complementary tools that are close to field-ready is a priority for achieving the global malaria-control targets.
The past decade has seen a dramatic decline in the burden of malaria, with vector control playing a central role. The aim is now to build on this recent success and progress towards elimination.
Current core vector-control tools alone are insufficient to achieve this goal, as they fail to target all adult mosquitoes, and emerging insecticide resistance is threating their effectiveness.
By considering the full range of adult mosquito behaviors, a number of supplementary tools, now under development, complement the core tools and create opportunities for tackling resistance and improving overall control.
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