The expansion of native mass spectrometry (MS) methods for both academic and industrial applications has created a substantial need for analysis of large native MS datasets. Existing software tools ...are poorly suited for high-throughput deconvolution of native electrospray mass spectra from intact proteins and protein complexes. The UniDec Bayesian deconvolution algorithm is uniquely well suited for high-throughput analysis due to its speed and robustness but was previously tailored towards individual spectra. Here, we optimized UniDec for deconvolution, analysis, and visualization of large data sets. This new module, MetaUniDec, centers around a hierarchical data format 5 (HDF5) format for storing datasets that significantly improves speed, portability, and file size. It also includes code optimizations to improve speed and a new graphical user interface for visualization, interaction, and analysis of data. To demonstrate the utility of MetaUniDec, we applied the software to analyze automated collision voltage ramps with a small bacterial heme protein and large lipoprotein nanodiscs. Upon increasing collisional activation, bacterial heme-nitric oxide/oxygen binding (H-NOX) protein shows a discrete loss of bound heme, and nanodiscs show a continuous loss of lipids and charge. By using MetaUniDec to track changes in peak area or mass as a function of collision voltage, we explore the energetic profile of collisional activation in an ultra-high mass range Orbitrap mass spectrometer.
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To evaluate the use of pars plana needle aspiration of retrolenticular fluid in the immediate management of an acute intraoperative rock-hard eye syndrome (AIRES).
Private practice, Sydney, ...Australia.
Retrospective case series.
Data over an 18-month period were collected to evaluate efficacy, complications, and visual outcomes in patients who had pars plana needle aspiration for management of AIRES, which is an acute intraoperative shallowing of the anterior chamber and a marked increase in intraocular pressure (IOP) during phacoemulsification cataract surgery but without evidence of a choroidal hemorrhage. Preoperative and postoperative (1 day, 1 week, and 1 month) data were evaluated. Resolution of AIRES and postoperative posterior segment status, IOP, and corrected distance visual acuity (CDVA) were the main outcome measures.
Acute intraoperative rock-hard eye syndrome occurred in 6 (1.45%) of 413 surgeries. All 6 patients were women with a mean age of 81 years. Four patients had dense nuclear cataracts. In each case, the anterior chamber depth and IOP normalized immediately after pars plana needle aspiration and the procedure concluded uneventfully. Mild vitreous hemorrhage was observed in 1 patient postoperatively. At 1 month, the IOP was normal in 5 of 6 cases, while the CDVA was 20/12 in 5 of 6 cases.
Although the etiology of AIRES is iatrogenic, immediate resolution was achieved uneventfully with pars plana needle aspiration, which appears to be a safe management technique with satisfactory outcomes.
To evaluate the effect of incorporating calcium advice into early pregnancy counseling on calcium intake during pregnancy in the Netherlands.
A multicenter prospective before-after cohort study was ...conducted introducing risk-based care including calculating individual pre-eclampsia risk. Part of the intervention was to incorporate calcium advice into routine counseling. We calculated individual daily calcium intake and adequacy of calcium intake (≥1,000 mg/day) at 16, 24 and 34 weeks of pregnancy. We performed a multiple logistic regression adjusting for covariates to identify any differences in the risk of inadequate calcium intake between RC and CAC.
In regular care (RC, 2013-2015, n=2,477) 60% had inadequate calcium intake, compared to 49% during calcium advice care (CAC, 2017-2018, n=774) (aOR 0.75, 95% CI 0.64-0.88). Specific calcium supplements were used by 2% and 29% in RC and CAC, respectively (OR 25.1, 95% CI 17.8-36.0). Determinants of an inadequate calcium intake were lower age (aOR per additional year 0.96, 95% CI: 0.94-0.98), nulliparity (aOR 1.22, 95% CI: 1.03-1.45) and non-Caucasian origin (aOR 1.83, 95% CI 1.09-3.09). In CAC, risk of inadequate intake decreased with increasing predicted pre-eclampsia risk, which was a trend reversal compared to RC.
Incorporating calcium advice into early pregnancy counseling was shown to lead to a decrease in the risk of inadequate calcium intake during pregnancy, but still inadequate intake in half of the women suggesting the need for further study on improving implementation. Awareness of individual increased PE risk had positive effect on calcium intake.
Recently, validated risk models predicting adverse obstetric outcomes combined with risk-dependent care paths have been made available for early antenatal care in the southeastern part of the ...Netherlands. This study will evaluate implementation progress and impact of the new approach in obstetric care.
The objective of this paper is to describe the design of a study evaluating the impact of implementing risk-dependent care. Validated first-trimester prediction models are embedded in daily clinical practice and combined with risk-dependent obstetric care paths.
A multicenter prospective cohort study consisting of women who receive risk-dependent care is being performed from April 2017 to April 2018 (Expect Study II). Obstetric risk profiles will be calculated using a Web-based tool, the Expect prediction tool. The primary outcomes are the adherence of health care professionals and compliance of women. Secondary outcomes are patient satisfaction and cost-effectiveness. Outcome measures will be established using Web-based questionnaires. The secondary outcomes of the risk-dependent care cohort (Expect II) will be compared with the outcomes of a similar prospective cohort (Expect I). Women of this similar cohort received former care-as-usual and were prospectively included between July 1, 2013 and December 31, 2015 (Expect I).
Currently, women are being recruited for the Expect Study II, and a total of 300 women are enrolled.
This study will provide information about the implementation and impact of a new approach in obstetric care using prediction models and risk-dependent obstetric care paths.
Netherlands Trial Register NTR4143; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4143 (Archived by WebCite at http://www.webcitation.org/6t8ijtpd9).
The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors ...with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo3,2-cpyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable ...cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido3,4-dpyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.
Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we ...report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido3,4-dpyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido3,4-dpyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.
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