Conformational activation of ADAMTS13

A disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13) is a metalloprotease that regulates von Willebrand factor (VWF) function. ADAMTS13-mediated proteolysis is determined by conformational changes in VWF, but also may depend on its own conformational activation. Kinetic analysis of WT ADAMTS13 revealed ∼2.5-fold reduced activity compared with ADAMTS13 lacking its C-terminal tail (MDTCS) or its CUB1-2 domains (WTΔCUB1-2), suggesting that the CUB domains naturally limit ADAMTS13 function. Consistent with this suggestion, WT ADAMTS13 activity was enhanced ∼2.5-fold by preincubation with either an anti-CUB mAb (20E9) or VWF D4CK (the natural binding partner for the CUB domains). Furthermore, the isolated CUB1-2 domains not only bound MDTCS, but also inhibited activity by up to 2.5-fold. Interestingly, a gain-of-function (GoF) ADAMTS13 spacer domain variant (R568K/F592Y/R660K/Y661F/Y665F) was ∼2.5-fold more active than WT ADAMTS13, but could not be further activated by 20E9 mAb or VWF D4CK and was unable to bind or to be inhibited by the CUB1-2 domains, suggesting that the inhibitory effects of the CUB domains involve an interaction with the spacer domain that is disrupted in GoF ADAMTS13. Electron microscopy demonstrated a “closed” conformation of WT ADAMTS13 and suggested a more “open” conformation for GoF ADAMTS13. The cryptic spacer domain epitope revealed by conformational unfolding also represents the core antigenic target for autoantibodies in thrombotic thrombocytopenic purpura. We propose that ADAMTS13 circulates in a closed conformation, which is maintained by a CUB–spacer domain binding interaction. ADAMTS13 becomes conformationally activated on demand through interaction of its C-terminal CUB domains with VWF, making it susceptible to immune recognition

A Comparison of Photometric Redshift Techniques for Large Radio Surveys

Future radio surveys will generate catalogs of tens of millions of radio sources, for which redshift estimates will be essential to achieve many of the science goals. However, spectroscopic data will be available for only a small fraction of these sources, and in most cases even the optical and infrared photometry will be of limited quality. Furthermore, radio sources tend to be at higher redshift than most optical sources (most radio surveys have a median redshift greater than 1) and so a significant fraction of radio sources hosts differ from those for which most photometric redshift templates are designed. We therefore need to develop new techniques for estimating the redshifts of radio sources. As a starting point in this process, we evaluate a number of machine-learning techniques for estimating redshift, together with a conventional template-fitting technique. We pay special attention to how the performance is affected by the incompleteness of the training sample and by sparseness of the parameter space or by limited availability of ancillary multiwavelength data. As expected, we find that the quality of the photometric-redshift degrades as the quality of the photometry decreases, but that even with the limited quality of photometry available for all-sky-surveys, useful redshift information is available for the majority of sources, particularly at low redshift. We find that a template-fitting technique performs best in the presence of high-quality and almost complete multi-band photometry, especially if radio sources that are also X-ray emitting are treated separately, using specific templates and priors. When we reduced the quality of photometry to match that available for the EMU all-sky radio survey, the quality of the template-fitting degraded and became comparable to some of the machine-learning methods. Machine learning techniques currently perform better at low redshift than at high redshift, because of incompleteness of the currently available training data at high redshifts

A comparison of photometric redshift techniques for large radio surveys

Future radio surveys will generate catalogs of tens of millions of radio sources, for which redshift estimates will be essential to achieve many of the science goals. However, spectroscopic data will be available for only a small fraction of these sources, and in most cases even the optical and infrared photometry will be of limited quality. Furthermore, radio sources tend to be at higher redshift than most optical sources (most radio surveys have a median redshift greater than 1) and so a significant fraction of radio sources hosts differ from those for which most photometric redshift templates are designed. We therefore need to develop new techniques for estimating the redshifts of radio sources. As a starting point in this process, we evaluate a number of machine-learning techniques for estimating redshift, together with a conventional template-fitting technique. We pay special attention to how the performance is affected by the incompleteness of the training sample and by sparseness of the parameter space or by limited availability of ancillary multiwavelength data. As expected, we find that the quality of the photometric-redshift degrades as the quality of the photometry decreases, but that even with the limited quality of photometry available for all-sky-surveys, useful redshift information is available for the majority of sources, particularly at low redshift. We find that a template-fitting technique performs best in the presence of high-quality and almost complete multi-band photometry, especially if radio sources that are also X-ray emitting are treated separately, using specific templates and priors. When we reduced the quality of photometry to match that available for the EMU all-sky radio survey, the quality of the template-fitting degraded and became comparable to some of the machine-learning methods. Machine learning techniques currently perform better at low redshift than at high redshift, because of incompleteness of the currently available training data at high redshifts

Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.

Purpose Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin.Patients and methods This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies.Results Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate.Conclusion To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed

The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion.

OBJECTIVE AND BACKGROUND: Activation of sterile inflammation after hepatic ischemia/reperfusion (I/R) culminates in liver injury. The route to liver damage starts with mitochondrial oxidative stress and cell death during early reperfusion. The link between mitochondrial oxidative stress, damage-associate molecular pattern (DAMP) release, and sterile immune signaling is incompletely understood and lacks clinical validation. The aim of the study was to validate this relation in a clinical liver I/R cohort and to limit DAMP release using a mitochondria-targeted antioxidant in I/R-subjected mice. METHODS: Plasma levels of the DAMPs high-mobility group box 1 (HMGB1), mitochondrial DNA, and nucleosomes were measured in 39 patients enrolled in an observational study who underwent a major liver resection with (N = 29) or without (N = 13) intraoperative liver ischemia. Circulating cytokine and neutrophil activation markers were also determined. In mice, the mitochondria-targeted antioxidant MitoQ was intravenously infused in an attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury. RESULTS: In patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 levels correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine levels between the two groups. In mice, MitoQ neutralized hepatic oxidative stress and decreased HMGB1 release by ±50%. MitoQ suppressed transaminase release, hepatocellular necrosis, and cytokine production. Reconstituting disulfide HMGB1 during reperfusion reversed these protective effects. CONCLUSION: HMGB1 seems the most pertinent DAMP in clinical hepatic I/R injury. Neutralizing mitochondrial oxidative stress may limit DAMP release after hepatic I/R and reduce liver damage

A Comparison of Photometric Redshift Techniques for Large Radio Surveys

Future radio surveys will generate catalogs of tens of millions of radio sources, for which redshift estimates will be essential to achieve many of the science goals. However, spectroscopic data will be available for only a small fraction of these sources, and in most cases even the optical and infrared photometry will be of limited quality. Furthermore, radio sources tend to be at higher redshift than most optical sources (most radio surveys have a median redshift greater than 1) and so a significant fraction of radio sources hosts differ from those for which most photometric redshift templates are designed. We therefore need to develop new techniques for estimating the redshifts of radio sources. As a starting point in this process, we evaluate a number of machine-learning techniques for estimating redshift, together with a conventional template-fitting technique. We pay special attention to how the performance is affected by the incompleteness of the training sample and by sparseness of the parameter space or by limited availability of ancillary multiwavelength data. As expected, we find that the quality of the photometric-redshift degrades as the quality of the photometry decreases, but that even with the limited quality of photometry available for all-sky-surveys, useful redshift information is available for the majority of sources, particularly at low redshift. We find that a template-fitting technique performs best in the presence of high-quality and almost complete multi-band photometry, especially if radio sources that are also X-ray emitting are treated separately, using specific templates and priors. When we reduced the quality of photometry to match that available for the EMU all-sky radio survey, the quality of the template-fitting degraded and became comparable to some of the machine-learning methods. Machine learning techniques currently perform better at low redshift than at high redshift, because of incompleteness of the currently available training data at high redshifts

The MeerKAT 1.3 GHz Survey of the Small Magellanic Cloud

We present new radio continuum images and a source catalogue from the MeerKAT survey in the direction of the Small Magellanic Cloud (SMC). The observations, at a central frequency of 1.3 GHz across a bandwidth of 0.8 GHz, encompass a field of view ~7 x 7 degrees and result in images with resolution of 8 arcsec. The median broad-band Stokes I image Root Mean Squared noise value is ~11 microJy/beam. The catalogue produced from these images contains 108,330 point sources and 517 compact extended sources. We also describe a UHF (544-1088 MHz) single pointing observation. We report the detection of a new confirmed Supernova Remnant (SNR) (MCSNR J0100-7211) with an X-ray magnetar at its centre and 10 new SNR candidates. This is in addition to the detection of 21 previously confirmed SNRs and two previously noted SNR candidates. Our new SNR candidates have typical surface brightness an order of magnitude below those previously known, and on the whole they are larger. The high sensitivity of the MeerKAT survey also enabled us to detect the bright end of the SMC Planetary Nebulae (PNe) sample - point-like radio emission is associated with 38 of 102 optically known PNe, of which 19 are new detections. Lastly, we present the detection of three foreground radio stars amidst 11 circularly polarised sources, and a few examples of morphologically interesting background radio galaxies from which the radio ring galaxy ESO 029-G034 may represent a new type of radio object

Assessing the characteristics of 110 low- and middle-income countries' noncommunicable disease national action plans

Noncommunicable diseases (NCDs) are a leading contributor to preventable mortality and impoverishment in low- and middle-income countries (LMICs). To support countries in developing holistic and integrated NCD plans, the World Health Organization (WHO) has produced get rid of this a NCD Multisectoral Action Plan (MSAP) guidance. To date, over 160 countries have produced MSAPs and uploaded them to the WHO's NCD document repository. We examined the content and comprehensiveness of the MSAPs uploaded by all 110 LMICs, with reference to the WHO guidance. Overall, the MSAPs included 71% of the elements recommended by the WHO, however, there was a tendency to present situational analyses and recommended actions without providing costings or an overall funding plan. We found no correlation between MSAP comprehensiveness (alignment with the WHO guidance) and policy implementation. There were no significant differences in MSAP alignment by region or income group. Countries with higher universal health coverage indices had lower MSAP alignment score. We concluded that the existence of a comprehensive MSAP is not enough to guarantee policy implementation, and that the WHO should focus its support on helping countries to translate plans and policies into concrete actions to address NCDs