Fatigue-inducing stimulation resolves myotonia in a drug-induced model

<p>Abstract</p> <p>Background</p> <p>Slowed muscle relaxation is the contractile hallmark of myotonia congenita, a disease caused by genetic CLC-1 chloride channel deficiency, which improves with antecedent brief contractions ("warm-up phenomenon"). It is unclear to what extent the myotonia continues to dissipate during continued repetitive contractions and how this relates temporally to muscle fatigue. Diaphragm, EDL, and soleus muscles were examined in vitro during repetitive 20 Hz and 50 Hz train stimulation in a drug-induced (9-AC) rat myotonia model.</p> <p>Results</p> <p>At the onset of stimulation, 9-AC treated diaphragm and EDL muscle had markedly prolonged half relaxation and late relaxation times (range 147 to 884 ms, 894 to 1324 ms). Half relaxation and late relaxation times reached near-normal values over the 5-10 and 10-40 subsequent contractions, respectively. In both muscles myotonia declined faster during repetitive 50 Hz than 20 Hz stimulation, and much faster than the rate of force loss during fatigue at both frequencies. Soleus muscle was resistant to the myotonic effects of 9-AC.</p> <p>Conclusions</p> <p>In a drug-induced model of mechanical myotonia, fatigue-inducing stimulation resolves the myotonia, which furthermore appears to be independent from the development of muscle fatigue.</p

Impaired Wheel Running Exercise in CLC-1 Chloride Channel-Deficient Myotonic Mice

Background: Genetic deficiency of the muscle CLC-1 chloride channel leads to myotonia, which is manifested most prominently by slowing of muscle relaxation. Humans experience this as muscle stiffness upon initiation of contraction, although this can be overcome with repeated efforts (the “warm-up” phenomenon). The extent to which CLC-1 deficiency impairs exercise activity is controversial. We hypothesized that skeletal muscle CLC-1 chloride channel deficiency leads to severe reductions in spontaneous exercise. Methodology/Principal Findings: To examine this quantitatively, myotonic CLC-1 deficient mice were provided access to running wheels, and their spontaneous running activity was quantified subsequently. Differences between myotonic and normal mice in running were not present soon after introduction to the running wheels, but were fully established during week 2. During the eighth week, myotonic mice were running significantly less than normal mice (322 ± 177 vs 5058 ± 1253 m/day, P = 0.025). Furthermore, there were considerable reductions in consecutive running times (18.8 ± 1.5 vs 59.0 ± 3.7 min, P < 0.001) and in the distance per consecutive running period (58 ± 38 vs 601 ± 174 m, P = 0.048) in myotonic compared with normal animals. Conclusion/Significance: These findings indicate that CLC-1 chloride deficient myotonia in mice markedly impairs spontaneous exercise activity, with reductions in both total distance and consecutive running times

Considerations and resources for vineyard establishment in the Pacific Northwest

Vineyard establishment requires careful planning and implementation. This guide addresses factors that landowners need to consider before planting new vineyards in Idaho, Oregon, and Washington. These initial decisions regarding land suitability and purchase, vineyard establishment, and marketing are key to the future success of a business. While this guide is primarily focused on the vineyard and grape production aspects of the industry, essential information regarding winery establishment is also included where issues for the two overlap

Growth Responses of Potted Vitis vinifera Cultivars Differ to a Mycorrhizal Inoculant and Phosphorus Fertilizer

Biological amendments, such as arbuscular mycorrhizal (AM) fungal inoculant products, are increasingly incorporated into agricultural management plans as a way to improve plant productivity. However, the effects of mycorrhizal inoculants on plant growth are context-dependent and can vary with soil fertility and among plant cultivars. To optimize the use of mycorrhizal inoculant products on wine grapes at the nursery stage, we tested the effect of a mycorrhizal inoculant product with and without the addition of phosphorus (P) fertilizer on the growth and tissue nutrients of two popular Vitis vinifera cultivars, Merlot and Chardonnay. We rooted dormant cuttings in the following respective treatments: no AM fungal inocula or P fertilizer; AM fungal inocula; P fertilizer; and co-amendment of AM fungal inocula and P fertilizer. We grew the grapevines in pots for 5 months in a greenhouse. Growth responses to treatments differed between cultivars. ‘Merlot’ vines had a stronger growth response to the mycorrhizal inoculant product than ‘Chardonnay’, especially when no P fertilizer was added. The co-amendment of AM fungi and P fertilizer resulted in larger root biomass for ‘Merlot’, but there was no effect of any treatment on the root biomass of ‘Chardonnay’. ‘Merlot’ vines grown with the AM fungal inoculant product also had higher tissue P than uninoculated vines, but there was no effect of inoculation on tissue nutrients of ‘Chardonnay’. This study provides evidence of grapevine cultivar-specific responses to an AM fungal inoculant product in a greenhouse, which may be useful when planning nursery management strategies for the incorporation of biological amendments into grapevine production

Electra: A Modular-Based Expansion of NASA's Supercomputing Capability

NASA has increasingly relied on high-performance computing (HPC) re- sources for computational modeling, simulation, and data analysis to meet the science and engineering goals of its missions in space exploration, aeronautics, and Earth and space science. The NASA Advanced Supercomputing (NAS) Division at Ames Research Center in Silicon Valley, Calif., hosts NASAs premier supercomputing resources, integral to achieving and enhancing the success of the agencys missions. NAS provides a balanced environment, funded under the High-End Computing Capability (HECC) project, comprised of world-class supercomputers, including its flagship distributed-memory cluster, Pleiades; high-speed networking; and massive data storage facilities, along with multi-disciplinary support teams for user support, code porting and optimization, and large-scale data analysis and scientific visualization. However, as scientists have increased the fidelity of their simulations and engineers are conducting larger parameter-space studies, the requirements for supercomputing resources have been growing by leaps and bounds. With the facility housing the HECC systems reaching its power and cooling capacity, NAS undertook a prototype project to investigate an alternative approach for housing supercomputers. Modular supercomputing, or container-based computing, is an innovative concept for expanding NASAs HPC capabilities. With modular supercomputing, additional containerssimilar to portable storage podscan be connected together as needed to accommodate the agencys ever-increasing demand for computing resources. In addition, taking advantage of the local weather permits the use of cooling technologies that would additionally save energy and reduce annual water usage. The first stage of NASAs Modular Supercomputing Facility (MSF) prototype, which resulted in a 1,000 square-foot module on a concrete pad with room for 16 compute racks, was completed in Fall 2016 and an SGI (now HPE) computer system, named Electra, was deployed there in early 2017. Cooling is performed via an evaporative system built into the module, and preliminary experience shows a Power Usage Effectiveness (PUE) measurement of 1.03. Electra achieved over a petaflop on the LINPACK benchmark, sufficient to rank number 96 on the November 2016 TOP500 list [14]. The system consists of 1,152 InfiniBand-connected Intel Xeon Broadwell-based nodes. Its users access their files on a facility-wide file system shared by all HECC compute assets via Mellanox MetroX InfiniBand extenders, which connect the Electra fabric to Lustre routers in the primary facility over fiber-optic links about 900 feet long. The MSF prototype has exceeded expectations and is serving as a blueprint for future expansions. In the remainder of this chapter, we detail how modular data center technology can be used to expand an existing compute resource. We begin by describing NASAs requirements for supercomputing and how resources were provided prior to the integration of the Electra module-based system

2024 pest management guide for grapes in Washington

The Pest Management Guide for Grapes in Washington presents various chemicals and their uses against pest problems in Washington vineyards. While the recommendations are based on eastern Washington conditions, the information may often be applied to similar pest problems found throughout the state. Specific and more detailed information on pests and diseases can be found in the Field Guide for Integrated Pest Management in Pacific Northwest Vineyards (PNW644). Recommendations are suggested guidelines. They are not intended to represent pest control programs. The use of other materials and varying rates and treatments for control of particular pests depends on individual circumstances

Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists

The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing. The Working Group considered the functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes and alleles across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9 testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9 alleles and additional warfarin sensitivity–associated genes and alleles

The Novel Phosphatase NUDT5 Is a Critical Regulator of Triple-Negative Breast Cancer Growth

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target for TNBC. METHODS: The mRNA expression levels of NUDT5 in breast cancers were investigated using TCGA and METABRIC (Curtis) datasets. NUDT5 ablation was achieved through siRNA targeting and NUDT5 inhibition with the small molecule inhibitor TH5427. Xenograft TNBC animal models were employed to assess the effect of NUDT5 inhibition on in vivo tumor growth. Proliferation, death, and DNA replication assays were conducted to investigate the cellular biological effects of NUDT5 loss or inhibition. The accumulation of 8-oxo-guanine (8-oxoG) and the induction of γH RESULTS: In this study, we demonstrated the significant role of an overexpressed phosphatase, NUDT5, in regulating oxidative DNA damage in TNBCs. Our findings indicate that loss of NUDT5 results in suppressed growth of TNBC both in vitro and in vivo. This growth inhibition is not attributed to cell death, but rather to the suppression of proliferation. The loss or inhibition of NUDT5 led to an increase in the oxidative DNA lesion 8-oxoG, and triggered the DNA damage response in the nucleus. The interference with DNA replication ultimately inhibited proliferation. CONCLUSIONS: NUDT5 plays a crucial role in preventing oxidative DNA damage in TNBC cells. The loss or inhibition of NUDT5 significantly suppresses the growth of TNBCs. These biological and mechanistic studies provide the groundwork for future research and the potential development of NUDT5 inhibitors as a promising therapeutic approach for TNBC patients

Paired phase II trials evaluating cetuximab and radiotherapy for low risk HPV associated oropharyngeal cancer and locoregionally advanced squamous cell carcinoma of the head and neck in patients not eligible for cisplatin

BackgroundAlternative therapeutic strategies are needed for localized oropharyngeal carcinoma. Cetuximab represents a potential option for those ineligible for cisplatin or, until recently, an agent for de‐escalation in low risk HPV+ oropharyngeal carcinoma (OPSCC). Our objective was to define the toxicity and efficacy of cetuximab‐radiotherapy.MethodsWe conducted paired phase II trials evaluating cetuximab‐radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin ineligible. The mean follow‐up was 48 months.ResultsForty‐two patients were enrolled in cohort A with a 2‐year disease free survival (DFS) of 81%. Twenty‐one patients were enrolled in cohort B prior to closure due to adverse outcomes with a 2‐year DFS of 37%. Severe toxicities were seen in 60% of patients, 30% required enteral nutrition.ConclusionAmong cisplatin ineligible patients, cetuximab treatment engendered poor outcomes. Rates of severe toxicities were on par with platinum‐based regimens suggesting that cetuximab is not a benign treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156234/2/hed26085.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156234/1/hed26085_am.pd

The flood pulse in a semi-arid riparian forest:metabolic and biogeochemical responses to inter-flood interval

Flood pulse inundation of riparian forests alters rates of nutrient retention and organic matter processing in the aquatic ecosystems formed in the forest interior. Along the Middle Rio Grande (New Mexico, USA), impoundment and levee construction have created riparian forests that differ in their inter-flood intervals (IFIs) because some floodplains are still regularly inundated by the flood pulse (i.e., connected), while other floodplains remain isolated from flooding (i.e., disconnected). This research investigates how ecosystem responses to the flood pulse relate to forest IFI by quantifying nutrient and organic matter dynamics in the Rio Grande floodplain during three years of experimental flooding of the disconnected floodplain and during a single year of natural flooding of the connected floodplain. Surface and subsurface conditions in paired sites (control, flood) established in the two floodplain types were monitored to address metabolic and biogeochemical responses. Compared to dry controls, rates of respiration in the flooded sites increased by up to three orders of magnitude during the flood pulse. In the disconnected forest, month-long experimental floods produced widespread anoxia of four-week duration during each of the three years of flooding. In contrast, water in the connected floodplain remained well oxygenated (3-8 ppm). Material budgets for experimental floods showed the disconnected floodplain to be a sink for inorganic nitrogen and suspended solids, but a potential source of dissolved organic carbon (DOC). Compared to the main stem of the Rio Grande, flood-water on the connected floodplain contained less nitrate, but comparable concentrations of DOC, phosphate-phosphorus, and ammonium-nitrogen. Results suggest that floodplain IFI drives metabolic and biogeochemical responses during the flood pulse. Impoundment and fragmentation have altered floodplains from a mosaic of patches with variable IFI to a bimodal distribution. Relatively predictable flooding occurs in the connected forest, while inundation of the disconnected forest occurs only as the result of managed application of water. In semiarid floodplains, water is scarce except during the flood pulse. Ecosystem responses to the flood pulse are related to the IFI and other measures of flooding history that help describe spatial variation in ecosystem function