Specifically targeted modification of human aldose reductase by physiological disulfides

Aldose reductase is inactivated by physiological disulfides such as GSSG and cystine. To study the mechanism of disulfide-induced enzyme inactivation, we examined the rate and extent of enzyme inactivation using wild-type human aldose reductase and mutants containing cysteine-to-serine substitutions at positions 80 (C80S), 298 (C298S), and 303 (C303S). The wild-type, C80S, and C303S enzymes lost >80% activity following incubation with GSSG, whereas the C298S mutant was not affected. Loss of activity correlated with enzyme thiolation. The binary enzyme-NADP+ complex was less susceptible to enzyme thiolation than the apoenzyme. These results suggest that thiolation of human aldose reductase occurs predominantly at Cys-298. Energy minimization of a hypothetical enzyme complex modified by glutathione at Cys-298 revealed that the glycyl carboxylate of glutathione may participate in a charged interaction with His-110 in a manner strikingly similar to that involving the carboxylate group of the potent aldose reductase inhibitor Zopolrestat. In contrast to what was observed with GSSG and cystine, cystamine inactivated the wild-type enzyme as well as all three cysteine mutants. This suggests that cystamine-induced inactivation of aldose reductase does not involve modification of cysteines exclusively at position 80, 298, or 303

NebulaStream: Complex Analytics Beyond the Cloud

The arising Internet of Things (IoT) will require significant changes to current stream processing engines (SPEs) to enable large-scale IoT applications. In this paper, we present challenges and opportunities for an IoT data management system to enable complex analytics beyond the cloud. As one of the most important upcoming IoT applications, we focus on the vision of a smart city. The goal of this paper is to bridge the gap between the requirements of upcoming IoT applications and the supported features of an IoT data management system. To this end, we outline how state-of-the-art SPEs have to change to exploit the new capabilities of the IoT and showcase how we tackle IoT challenges in our own system, NebulaStream. This paper lays the foundation for a new type of systems that leverages the IoT to enable large-scale applications over millions of IoT devices in highly dynamic and geo-distributed environments

MRI-targeted or standard biopsy for prostate-cancer diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .)

Building a Personal Protective Equipment Monitor Team as Part of a Comprehensive COVID-19 Prevention Strategy

We instituted Personal Protective Equipment (PPE) Monitors as part of our care of COVID-19 patients in high-risk zones. PPE Monitors aided healthcare personnel (HCP) in donning and doffing, which contributed to nearly zero transmission of COVID-19 to HCP, despite their care of over 1400 COVID-19 patients

Development of Sensory, Motor and Behavioral Deficits in the Murine Model of Sanfilippo Syndrome Type B

BACKGROUND: Mucopolysaccharidosis (MPS) IIIB (Sanfilippo Syndrome type B) is caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes. PRINCIPAL FINDINGS: To more thoroughly assess MPS IIIB in mice, alterations in circadian rhythm, activity level, motor function, vision, and hearing were tested. The suprachiasmatic nucleus (SCN) developed pathologic changes and locomotor analysis showed that MPS IIIB mice start their daily activity later and have a lower proportion of activity during the night than wild-type controls. Rotarod assessment of motor function revealed a progressive inability to coordinate movement in a rocking paradigm. Purkinje cell counts were significantly reduced in the MPS IIIB animals compared to age matched controls. By electroretinography (ERG), MPS IIIB mice had a progressive decrease in the amplitude of the dark-adapted b-wave response. Corresponding pathology revealed shortening of the outer segments, thinning of the outer nuclear layer, and inclusions in the retinal pigmented epithelium. Auditory-evoked brainstem responses (ABR) demonstrated progressive hearing deficits consistent with the observed loss of hair cells in the inner ear and histologic abnormalities in the middle ear. CONCLUSIONS/SIGNIFICANCE: The mouse model of MPS IIIB has several quantifiable phenotypic alterations and is similar to the human disease. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

The X-ray Polarization Probe mission concept

The X-ray Polarization Probe (XPP) is a second generation X-ray polarimeter following up on the Imaging X-ray Polarimetry Explorer (IXPE). The XPP will offer true broadband polarimetery over the wide 0.2-60 keV bandpass in addition to imaging polarimetry from 2-8 keV. The extended energy bandpass and improvements in sensitivity will enable the simultaneous measurement of the polarization of several emission components. These measurements will give qualitatively new information about how compact objects work, and will probe fundamental physics, i.e. strong-field quantum electrodynamics and strong gravity.Comment: submitted to Astrophysics Decadal Survey as a State of the Profession white pape

The Imaging X-ray Polarimetry Explorer (IXPE): Technical Overview

The Imaging X-ray Polarimetry Explorer (IXPE) will expand the information space for study of cosmic sources, by adding linear polarization to the properties (time, energy, and position) observed in x-ray astronomy. Selected in 2017 January as a NASA Astrophysics Small Explorer (SMEX) mission, IXPE will be launched into an equatorial orbit in 2021. The IXPE mission will provide scientifically meaningful measurements of the x-ray polarization of a few dozen sources in the 2-8 keV band, including polarization maps of several x-ray-bright extended sources and phase-resolved polarimetry of many bright pulsating x-ray sources

Discovery of X-ray polarization angle rotation in active galaxy Mrk 421

The magnetic field conditions in astrophysical relativistic jets can be probed by multiwavelength polarimetry, which has been recently extended to X-rays. For example, one can track how the magnetic field changes in the flow of the radiating particles by observing rotations of the electric vector position angle $\Psi$. Here we report the discovery of a $\Psi_{\mathrm x}$ rotation in the X-ray band in the blazar Mrk 421 at an average flux state. Across the 5 days of Imaging X-ray Polarimetry Explorer (IXPE) observations of 4-6 and 7-9 June 2022, $\Psi_{\mathrm x}$ rotated in total by $\geq360^\circ$. Over the two respective date ranges, we find constant, within uncertainties, rotation rates ($80 \pm 9$ and $91 \pm 8 ^\circ/\rm day$) and polarization degrees ($\Pi_{\mathrm x}=10\%\pm1\%$). Simulations of a random walk of the polarization vector indicate that it is unlikely that such rotation(s) are produced by a stochastic process. The X-ray emitting site does not completely overlap the radio/infrared/optical emission sites, as no similar rotation of $\Psi$ was observed in quasi-simultaneous data at longer wavelengths. We propose that the observed rotation was caused by a helical magnetic structure in the jet, illuminated in the X-rays by a localized shock propagating along this helix. The optically emitting region likely lies in a sheath surrounding an inner spine where the X-ray radiation is released