Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

The complex disorder Cantu syndrome (CS) arises from gainof-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb-) efflux assays and patchclamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS-Associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS

Lung_PAYNet: a pyramidal attention based deep learning network for lung nodule segmentation

Accurate and reliable lung nodule segmentation in computed tomography (CT) images is required for early diagnosis of lung cancer. Some of the difficulties in detecting lung nodules include the various types and shapes of lung nodules, lung nodules near other lung structures, and similar visual aspects. This study proposes a new model named Lung_PAYNet, a pyramidal attention-based architecture, for improved lung nodule segmentation in low-dose CT images. In this architecture, the encoder and decoder are designed using an inverted residual block and swish activation function. It also employs a feature pyramid attention network between the encoder and decoder to extract exact dense features for pixel classification. The proposed architecture was compared to the existing UNet architecture, and the proposed methodology yielded significant results. The proposed model was comprehensively trained and validated using the LIDC-IDRI dataset available in the public domain. The experimental results revealed that the Lung_PAYNet delivered remarkable segmentation with a Dice similarity coefficient of 95.7%, mIOU of 91.75%, sensitivity of 92.57%, and precision of 96.75%

Bringing high-grade arteriovenous malformations under control: clinical outcomes following multimodality treatment in children.

OBJECTIVE:Brain arteriovenous malformations (AVMs) consist of dysplastic blood vessels with direct arteriovenous shunts that can hemorrhage spontaneously. In children, a higher lifetime hemorrhage risk must be balanced with treatment-related morbidity. The authors describe a collaborative, multimodal strategy resulting in effective and safe treatment of pediatric AVMs. METHODS:A retrospective analysis of a prospectively maintained database was performed in children with treated and nontreated pediatric AVMs at the University of California, San Francisco, from 1998 to 2017. Inclusion criteria were age ≤ 18 years at time of diagnosis and an AVM confirmed by a catheter angiogram. RESULTS:The authors evaluated 189 pediatric patients with AVMs over the study period, including 119 ruptured (63%) and 70 unruptured (37%) AVMs. The mean age at diagnosis was 11.6 ± 4.3 years. With respect to Spetzler-Martin (SM) grade, there were 38 (20.1%) grade I, 40 (21.2%) grade II, 62 (32.8%) grade III, 40 (21.2%) grade IV, and 9 (4.8%) grade V lesions. Six patients were managed conservatively, and 183 patients underwent treatment, including 120 resections, 82 stereotactic radiosurgery (SRS), and 37 endovascular embolizations. Forty-four of 49 (89.8%) high-grade AVMs (SM grade IV or V) were treated. Multiple treatment modalities were used in 29.5% of low-grade and 27.3% of high-grade AVMs. Complete angiographic obliteration was obtained in 73.4% of low-grade lesions (SM grade I-III) and in 45.2% of high-grade lesions. A periprocedural stroke occurred in a single patient (0.5%), and there was 1 treatment-related death. The mean clinical follow-up for the cohort was 4.1 ± 4.6 years, and 96.6% and 84.3% of patients neurologically improved or remained unchanged in the ruptured and unruptured AVM groups following treatment, respectively. There were 16 bleeding events following initiation of AVM treatment (annual rate: 0.02 events per person-year). CONCLUSIONS:Coordinated multidisciplinary evaluation and individualized planning can result in safe and effective treatment of children with AVMs. In particular, it is possible to treat the majority of high-grade AVMs with an acceptable safety profile. Judicious use of multimodality therapy should be limited to appropriately selected patients after thorough team-based discussions to avoid additive morbidity. Future multicenter studies are required to better design predictive models to aid with patient selection for multimodal pediatric care, especially with high-grade AVMs

A unique bacteriohopanetetrol stereoisomer of marine anammox

Anaerobic ammonium oxidation (anammox) is a major process of bioavailable nitrogen removal from marine systems. Previously, a bacteriohopanetetrol (BHT) isomer, with unknown stereochemistry, eluting later than BHT using high performance liquid chromatography (HPLC), was detected in ‘Ca. Scalindua profunda’ and proposed as a biomarker for anammox in marine paleo-environments. However, the utility of this BHT isomer as an anammox biomarker is hindered by the fact that four other, non-anammox bacteria are also known to produce a late-eluting BHT stereoisomer. The stereochemistry in Acetobacter pasteurianus, Komagataeibacter xylinus and Frankia sp. was known to be 17β, 21β(H), 22R, 32R, 33R, 34R (BHT-34R). The stereochemistry of the late-eluting BHT in Methylocella palustris was unknown. To determine if marine anammox bacteria produce a unique BHT isomer, we studied the BHT distributions and stereochemistry of known BHT isomer producers and of previously unscreened marine (‘Ca. Scalindua brodeae’) and freshwater (‘Ca. Brocadia sp.’) anammox bacteria using HPLC and gas chromatographic (GC) analysis of acetylated BHTs and ultra high performance liquid chromatography (UHPLC)-high resolution mass spectrometry (HRMS) analysis of non-acetylated BHTs. The 34R stereochemistry was confirmed for the BHT isomers in Ca. Brocadia sp. and Methylocella palustris. However, ‘Ca. Scalindua sp.’ synthesise a stereochemically distinct BHT isomer, with still unconfirmed stereochemistry (BHT-x). Only GC analysis of acetylated BHT and UHPLC analysis of non-acetylated BHT distinguished between late-eluting BHT isomers. Acetylated BHT-x and BHT-34R co-elute by HPLC. As BHT-x is currently only known to be produced by ‘Ca. Scalindua spp.’, it may be a biomarker for marine anammox

Early Detection and Monitoring of Gastrointestinal Infections Using Syndromic Surveillance: A Systematic Review.

The underreporting of laboratory-reported cases of community-based gastrointestinal (GI) infections poses a challenge for epidemiologists understanding the burden and seasonal patterns of GI pathogens. Syndromic surveillance has the potential to overcome the limitations of laboratory reporting through real-time data and more representative population coverage. This systematic review summarizes the utility of syndromic surveillance for early detection and surveillance of GI infections. Relevant articles were identified using the following keyword combinations: 'early warning', 'detection', 'gastrointestinal activity', 'gastrointestinal infections', 'syndrome monitoring', 'real-time monitoring', 'syndromic surveillance'. In total, 1820 studies were identified, 126 duplicates were removed, and 1694 studies were reviewed. Data extraction focused on studies reporting the routine use and effectiveness of syndromic surveillance for GI infections using relevant GI symptoms. Eligible studies (n = 29) were included in the narrative synthesis. Syndromic surveillance for GI infections has been implemented and validated for routine use in ten countries, with emergency department attendances being the most common source. Evidence suggests that syndromic surveillance can be effective in the early detection and routine monitoring of GI infections; however, 24% of the included studies did not provide conclusive findings. Further investigation is necessary to comprehensively understand the strengths and limitations associated with each type of syndromic surveillance system

Coral record of Younger Dryas Chronozone warmth on the Great Barrier Reef

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography and Paleoclimatology 35(12), (2020): e2020PA003962, doi:10.1029/2020PA003962.The Great Barrier Reef (GBR) is an internationally recognized and widely studied ecosystem, yet little is known about its sea surface temperature (SST) evolution since the Last Glacial Maximum (LGM) (~20 kyr BP). Here, we present the first paleo‐application of Isopora coral‐derived SST calibrations to a suite of 25 previously published fossil Isopora from the central GBR spanning ~25–11 kyr BP. The resultant multicoral Sr/Ca‐ and δ18O‐derived SST anomaly (SSTA) histories are placed within the context of published relative sea level, reef sequence, and coralgal reef assemblage evolution. Our new calculations indicate SSTs were cooler on average by ~5–5.5°C at Noggin Pass (~17°S) and ~7–8°C at Hydrographer's Passage (~20°S) (Sr/Ca‐derived) during the LGM, in line with previous estimates (Felis et al., 2014, https://doi.org/10.1038/ncomms5102). We focus on contextualizing the Younger Dryas Chronozone (YDC, ~12.9–11.7 kyr BP), whose Southern Hemisphere expression, in particular in Australia, is elusive and poorly constrained. Our record does not indicate cooling during the YDC with near‐modern temperatures reached during this interval on the GBR, supporting an asymmetric hemispheric presentation of this climate event. Building on a previous study (Felis et al., 2014, https://doi.org10.1038/ncomms5102), these fossil Isopora SSTA data from the GBR provide new insights into the deglacial reef response, with near‐modern warming during the YDC, since the LGM.This work was funded by National Science Foundation (NSF) award OCE 13‐56948 to B. K. L, with NSF GRFP support DGE‐11‐44155 to L. D. B., and the Australian Research Council (grant no. DP1094001) and ANZIC IODP. Partial support for B. K. L's work on this project also came from the Vetlesen Foundation via a gift to the Lamont‐Doherty Earth Observatory. T. F. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project number 180346848, through Priority Program 527 “IODP.” A. T. received support from the UK Natural Environment Research Council (NE/H014136/1 and NE/H014268/1). M. T. thanks Ministry of Earth Sciences for support (NCPOR contribution no. J‐84/2020‐21). L. D. B. would also like to thank Kassandra Costa for her input regarding error analysis.2021-06-1

A comparative analysis of high-throughput platforms for validation of a circulating microRNA signature in diabetic retinopathy

MicroRNAs are now increasingly recognized as biomarkers of disease progression. Several quantitative real-time PCR (qPCR) platforms have been developed to determine the relative levels of microRNAs in biological fluids. We systematically compared the detection of cellular and circulating microRNA using a standard 96-well platform, a high-content microfluidics platform and two ultrahigh content platforms. We used extensive analytical tools to compute inter- and intra-run variability and concordance measured using fidelity scoring, coefficient of variation and cluster analysis. We carried out unprejudiced next generation sequencing to identify a microRNA signature for Diabetic Retinopathy (DR) and systematically assessed the validation of this signature on clinical samples using each of the above four qPCR platforms. The results indicate that sensitivity to measure low copy number microRNAs is inversely related to qPCR reaction volume and that the choice of platform for microRNA biomarker validation should be made based on the abundance of miRNAs of interest

Plasma proteome responses in salmonid fish following immunization

Data Availability Statement The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material. Ethics Statement The animal study was reviewed and approved by UK home office and University of Aberdeen’s Animal Welfare and Ethical Review Body (AWERB). Author Contributions Study conception and design: DM and HD. Animal work: MM and HD. Proteomics lab work: DS. Proteomic data analysis: FB, DC, AD. Data interpretation: FB, DM, and HD. Drafted figures and tables: FB and DM. Drafted manuscript: FB, DM, and HD. All authors contributed to the article and approved the submitted version. Funding This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) grant numbers: BB/M010996/1, BB/M026345/1, BBS/E/D/20002174, and BBS/E/D/10002071. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments Our thanks to Prof. Chris Secombes (University of Aberdeen) for the 4C10 anti-salmonid IgM mAb used in our ELISAs and for his valuable intellectual contributions during the planning of this project. We also gratefully acknowledge the supervisory support given by Prof. Sam Martin (University of Aberdeen) to FB.Peer reviewedPublisher PD

The Grizzly, October 15, 2009

Dr. Jekyll and Mr. Hyde Draws in Large Audiences • MRSA Awareness Month • UC Student Hit by Car on Main Street, Makes $50 • Omega Chi Sponsors Blood Drive • E-Mail Outsourcing and its Effects on the Ursinus Community • Study Abroad Programs Create Great Opportunities for Students •$10,000 Grant Brings Danny Buraczeski\u27s Swing Concerto to Dance Students • Senior Halloween Party Planners Leave Under 21-Year-Olds Out • Opinions: Obama\u27s Nobel Prize: Criticism Warranted?; Assisted Living: Call it Assisted Dying for Many • Women\u27s Rugby Gets Down and Dirty for 2009 Season • Record Falls After the Bears\u27 Big Defeat Over Gettysburghttps://digitalcommons.ursinus.edu/grizzlynews/1795/thumbnail.jp

Heterogeneity within and between physician-diagnosed asthma and/or COPD : NOVELTY cohort

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