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Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 μg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells. [ABSTRACT FROM AUTHOR]

Comprehensive and accurate analysis of respiratory and metabolic data is crucial to modelling congenital, pathogenic and degenerative diseases converging on autonomic control failure. A lack of tools for high‐throughput analysis of respiratory datasets remains a major challenge. We present Breathe Easy, a novel open‐source pipeline for processing raw recordings and associated metadata into operative outcomes, publication‐worthy graphs and robust statistical analyses including QQ and residual plots for assumption queries and data transformations. This pipeline uses a facile graphical user interface for uploading data files, setting waveform feature thresholds and defining experimental variables. Breathe Easy was validated against manual selection by experts, which represents the current standard in the field. We demonstrate Breathe Easy's utility by examining a 2‐year longitudinal study of an Alzheimer's disease mouse model to assess contributions of forebrain pathology in disordered breathing. Whole body plethysmography has become an important experimental outcome measure for a variety of diseases with primary and secondary respiratory indications. Respiratory dysfunction, while not an initial symptom in many of these disorders, often drives disability or death in patient outcomes. Breathe Easy provides an open‐source respiratory analysis tool for all respiratory datasets and represents a necessary improvement upon current analytical methods in the field. Key points: Respiratory dysfunction is a common endpoint for disability and mortality in many disorders throughout life.Whole body plethysmography in rodents represents a high face‐value method for measuring respiratory outcomes in rodent models of these diseases and disorders.Analysis of key respiratory variables remains hindered by manual annotation and analysis that leads to low throughput results that often exclude a majority of the recorded data.Here we present a software suite, Breathe Easy, that automates the process of data selection from raw recordings derived from plethysmography experiments and the analysis of these data into operative outcomes and publication‐worthy graphs with statistics.We validate Breathe Easy with a terabyte‐scale Alzheimer's dataset that examines the effects of forebrain pathology on respiratory function over 2 years of degeneration. [ABSTRACT FROM AUTHOR]

Background and Aims. Shiraz (Syrah) is a dark-skinned cultivar of the wine grape Vitis vinifera that forms the basis of some of the world's most iconic wines. Worldwide, Shiraz is the fourth most planted grapevine cultivar; however, it represents the most planted cultivar in Australia. Given the importance of Shiraz to worldwide wine production, this study aimed to produce a reference genome for this cultivar while investigating the unique genetic variants and ancestral origins of this iconic variety. Methods and Results. Long-read ONT data were selected to produce a highly contiguous genome assembly for Shiraz. Phylogenetic reconstruction using high-quality genome assemblies for wine grape cultivars provided further support of a kinship between Shiraz and Pinot Noir. Harnessing long-read data, transposable element insertions potentially affecting gene function were characterized in Shiraz and assessed relative to other cultivars. This revealed a heterogenous landscape of transposon insertion points across cultivars and uncovered a specific combination of allelic variants at the VviTPS24 terpene synthase locus. Conclusions. This establishment of a Shiraz genome provides a detailed view of the genetics that underpin this cultivar, including the discovery of a specific combination of VviTPS24 variants, which when combined with appropriate environmental triggers may allow Shiraz to produce high levels of rotundone, the aroma compound responsible for the distinctive peppery characteristics of this cultivar. Significance of the Study. The availability of a reference genome for Shiraz expands the pool of genomes available for wine grapes while providing a foundation resource for whole-genome studies involving this iconic cultivar, including intracultivar variant identification and transcriptomic studies using a matching reference genome. [ABSTRACT FROM AUTHOR]

Fecal microbiota transplantation (FMT) is an increasingly employed treatment option for Clostridioides difficile infection (CDI), with growing data supporting its safety and effectiveness in patients with concurrent inflammatory bowel disease (IBD). Given that alterations in the gut microbiome are associated with both ulcerative colitis (UC) and Crohn's disease (CD), the use of FMT for the treatment of IBD itself is another area of active investigation. In this narrative review, we highlight the evidence for use of FMT in the treatment of CDI in patients with IBD, as well as for IBD alone, and provide insight into the future of microbiome therapeutics. [ABSTRACT FROM AUTHOR]

Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus in the later phases of the infection is often predominantly macrophage-tropic and this tropism contributes to a chronic inflammatory and immune activation state that is observed in HIV patients. Pattern recognition receptors of the innate immune system are the key molecules that recognise HIV and mount the inflammatory responses in macrophages. The innate immune response against HIV-1 is potent and elicits caspase-1-dependent pro-inflammatory cytokine production of IL-1β and IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating this response little is known about the pattern recognition receptors that trigger the "priming" signal for inflammasome activation, the NLRs involved or the HIV components that trigger the response. Using a combination of siRNA knockdowns in monocyte derived macrophages (MDMs) of different TLRs and NLRs as well as chemical inhibition, it was demonstrated that HIV Vpu could trigger inflammasome activation via TLR4/NLRP3 leading to IL-1β/IL-18 secretion. The priming signal is triggered via TLR4, whereas the activation signal is triggered by direct effects on Kv1.3 channels, causing K+ efflux. In contrast, HIV gp41 could trigger IL-18 production via NAIP/NLRC4, independently of priming, as a one-step inflammasome activation. NAIP binds directly to the cytoplasmic tail of HIV envelope protein gp41 and represents the first non-bacterial ligand for the NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets to resolve specific inflammatory pathologies associated with HIV-1 infection in macrophages. Author summary: It has been previously shown that inflammasome activation can be triggered during viral infection to produce the active cytokines IL-1β and IL-18. Our study represents a significant advance, as we now show that in fact there are distinct NLR inflammasome complexes and viral ligands for IL-1β secretion (Vpu) compared to IL-18 secretion (gp41) in response to HIV-1. Most importantly, we show that the HIV envelope protein gp41 represents the first non-bacterial ligand for the assembly of the NAIP/NLRC4 inflammasome. HIV gp41 is a viroporin, and thus our data demonstrates for the first time that the NAIP/NLRC4 inflammasome assembles for all pore-forming proteins, irrespective of whether they have a viral or bacterial origin. This is critical for the host antiviral response and has broad implications for innate immunity in general. [ABSTRACT FROM AUTHOR]

Introduction: Hepatobiliary overlap syndromes describe the coinciding presentation of more than one immune-mediated biliary and liver disease in a single patient and present complex challenges in diagnosis and treatment. We report a case of ulcerative colitis with primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome responsive to vancomycin. Case Presentation: The patient is a 30-year-old female with known ulcerative pancolitis and autoimmune hepatitis. She presented to the emergency department with a constellation of gastrointestinal symptoms, including diffuse lower abdominal pain, bloody diarrhea, and nausea with bilious vomiting. Subsequent imaging revealed the additional diagnosis of primary sclerosing cholangitis, and she was diagnosed with overlap syndrome. Multiple treatment regimens were trialed with minimal improvement. She eventually achieved normalization of both clinical status and biochemical markers after the addition of vancomycin. Conclusion: Vancomycin is an underutilized therapy; its potential role in primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome has not been previously reported. [ABSTRACT FROM AUTHOR]

The addition of gold nanorods to a commercial polyurethane enabled shape memory behavior activation via infrared irradiation. The fraction of the set strain recovered was found to be dependent on the nanorod loading and irradiation intensity. A nanocomposite consisting of gold nanorods with an aspect ratio of ~3.25 and a diameter of ~11.5 nm and the polyurethane IROGRAN PS455-203 was prepared via a simple solution blending technique. Gold loadings up to 3.2 ppm by weight were evaluated. The glass transition temperature and melting point of the hard-segment phase was slightly depressed at the highest loading evaluated. Other thermal properties were not affected by the addition of gold nanorods. Also, the thermally activated shape memory behavior of the composite material was not affected by the presence of the gold nanorods. [ABSTRACT FROM AUTHOR]

SUMMARY: The chance discovery of an 18th-century knuckle-bone floor at the National Trust property of Belton House in Lincolnshire prompted a review of all known post-medieval knuckle-bone floors in Britain to examine their date, context of creation and species composition. The identification of fallow deer bones within the Belton floor became the focus of genetic analysis to examine the relationship between ancient and modern deer from the estate and how these deer related to other medieval/post-medieval populations. This paper argues that both fallow deer and knuckle-bone floors were important elements of post-medieval estate landscapes and that more could be done to present their significance to the public. [ABSTRACT FROM AUTHOR]

This paper presents a step-by-step conversion of a face-to-face (F2F) entry level social work research methods course to a computer-mediated format. An overview of teaching practices and the important pedagogical foundations associated with this curricular effort are discussed followed by an introduction to the electronic platform utilized in the course. Five new teaching practices that guide the F2F-to-online course conversion of this introductory research methods course are presented with corresponding teaching activities and technological tools. A conversion matrix aligns the teaching practices, classroom activities, and provides references for the identified tools. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether a patient's proximity to the nurse's station or ward entrance at time of admission was associated with increased risk of adverse outcomes. Method: We conducted a retrospective cohort study of consecutive adult inpatients to 13 medical–surgical wards at an academic hospital from 2009 to 2013. Proximity of admission room to the nurse's station and to the ward entrance was measured using Euclidean distances. Outcomes of interest include development of critical illness (defined as cardiac arrests or transfer to an intensive care unit), inhospital mortality, and increase in length of stay (LOS). Results: Of the 83,635 admissions, 4,129 developed critical illness and 1,316 died. The median LOS was 3 days. After adjusting for admission severity of illness, ward, shift, and year, we found no relationship between proximity at admission to nurse's station our outcomes. However, patients admitted to end of the ward had higher risk of developing critical illness (odds ratio [ OR ] = 1.15, 95% confidence interval [CI] = [1.08, 1.23]), mortality (OR = 1.16, 95% CI [1.03, 1.33]), and a higher LOS (13-hr increase, 95% CI [10, 15] hours) compared to patients admitted closer to the ward entrance. Similar results were observed in sensitivity analyses adjusting for isolation room patients and considering patients without room transfers in the first 48 hr. Conclusions: Our study suggests that being away from the nurse's station did not increase the risk of these adverse events in ward patients, but being farther from the ward entrance was associated with increase in risk of adverse outcomes. Patient safety can be improved by recognizing this additional risk factor. [ABSTRACT FROM AUTHOR]

Myosin binding protein-C slow (sMyBP-C) comprises a family of accessory proteins in skeletal muscles that bind both myosin and actin filaments. Herein, we examined the role of sMyBP-C in adult skeletal muscles using in vivo gene transfer and clustered regularly interspaced short palindromic repeats technology to knock down all known sMyBP-C variants. Our findings, confirmed in two different skeletal muscles, demonstrated efficient knockdown (KD) of sMyBP-C (>70%) resulting in notably decreased levels of thick, but not thin, filament proteins ranging from ~50% for slow and fast myosin to ~20% for myomesin. Consistent with this, A bands were selectively distorted, and sarcomere length was significantly reduced. Contrary to earlier in vitro studies showing that addition of recombinant sMyBP-C slows down the formation of actomyosin crossbridges, our work demonstrates that KD of sMyBP-C in intact myofibers results in decreased contraction and relaxation kinetics under no-load conditions. Similarly, KD muscles develop markedly reduced twitch and tetanic force and contraction velocity. Taken together, our results show that sMyBP-C is essential for the regular organization and maintenance of myosin filaments into A bands and that its structural role precedes its ability to regulate actomyosin crossbridges. [ABSTRACT FROM AUTHOR]

Cryptic species are genetically distinct taxa without obvious variation in morphology and are occasionally discovered using molecular or sequence data sets of populations previously thought to be a single species. The world-wide Brassica pest, Plutella xylostella (diamondback moth), has been a problematic insect in Australia since 1882, yet a morphologically cryptic species with apparent endemism (P. australiana) was only recognized in 2013. Plutella xylostella and P. australiana are able to hybridize under laboratory conditions, and it was unknown whether introgression of adaptive traits could occur in the field to improve fitness and potentially increase pressure on agriculture. Phylogenetic reconstruction of 29 nuclear genomes confirmed P. xylostella and P. australiana are divergent, and molecular dating with 13 mitochondrial genes estimated a common Plutella ancestor 1.96 ± 0.175 Ma. Sympatric Australian populations and allopatric Hawaiian P. xylostella populations were used to test whether neutral or adaptive introgression had occurred between the two Australian species. We used three approaches to test for genomic admixture in empirical and simulated data sets including 1) the f3 statistic at the level of the population, 2) pairwise comparisons of Nei's absolute genetic divergence (d XY) between populations, and 3) changes in phylogenetic branch lengths between individuals across 50-kb genomic windows. These complementary approaches all supported reproductive isolation of the Plutella species in Australia, despite their ability to hybridize. Finally, we highlight the most divergent genomic regions between the two cryptic Plutella species and find they contain genes involved with processes including digestion, detoxification, and DNA binding. [ABSTRACT FROM AUTHOR]

Highlights • GsMTx4-D is a mechanosensitive ion channel inhibitor. • GsMTx4-D has a one-week half-life. • Six-week treatment of D2.mdx dystrophic mice: ○ reduced muscle loss. ○ decrease susceptibility to contraction induced injury. Abstract Duchenne muscular dystrophy is a life-limiting muscle disease that has no current effective therapy. Despite mounting evidence that dysregulation of mechanosensitive ion channels is a significant contributor to dystrophy pathogenesis, effective pharmacologic strategies targeting these channels are lacking. GsMTx4, and its enantiomer GsMTx4-D, are peptide inhibitors of mechanosensitive channels with identical activity. In previous studies, acute in vitro application of GsMTx4 to dystrophic murine muscle effectively reduced the excess MSC dependent calcium influx linked to contraction-induced muscle damage. Here we sought to determine if in vivo treatment with GsMTx4-D proffered benefit in the D2.mdx mouse. GsMTx4-D showed a 1-week half-life when administered by subcutaneous injection over four weeks. Informed by these results, D2. mdx mice were then treated by a subcutaneous injection regimen of GsMTx4-D for six weeks followed by determination of muscle mass, muscle susceptibility to eccentric contraction injury and multiple histological indicators of disease progression. The mice showed a reduction in the loss of muscle mass and a decrease in susceptibility to contraction induced injury. These protective effects were realized without reduction in fibrosis, supporting a model where GsMTx4-D acts directly on muscle cells. We propose GsMTx4-D represents a promising new therapy to slow disease progression and may complement other therapies such as anti-inflammatory agents and gene-replacement strategies. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation is a mainstay of therapy for numerous malignant and nonmalignant diseases. Endothelial activation and dysfunction occur after stem cell transplantation, driven by various patient‐ and transplant‐specific factors. This can manifest as one of the relatively uncommon endothelial injury syndromes, such as sinusoidal obstruction syndrome, transplant‐associated thrombotic microangiopathy, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome or posterior reversible encephalopathy syndrome. This review focuses on the pathogenesis, classification and diagnosis of these disorders, as well as provides guidance on risk mitigation and treatment. [ABSTRACT FROM AUTHOR]

Mechatronically-guided railway vehicles are of paramount importance in addressing the increasing interest in reducing wheel-rail wear and improving guidance and steering. Conventional passively-guided rail vehicles are limited by the mechanical constraints of the suspension elements. Currently, a typical rail vehicle suspension needs to be sufficiently stiff to stabilize the wheelsets while being complaint enough to negotiate curved track profiles. The suspension is therefore a compromise for the contradictory requirements of curving and stability. In mechatronic vehicles, actuators are used with the conventional suspension components to provide additional stiffness or damping forces needed to optimise a vehicle for a wide variety of scenarios, and not rely on a sub optimal combination of passive components. This research demonstrates the benefits of active guidance and steering when compared to a conventional vehicle using simulation results from a multi-body simulation software Simpack. It also provides insights into the relative performance of the mechatronic schemes. The Simpack modeling allows for a complex model with high fidelity, which provides an additional level of proof of the control algorithms working on a real rail vehicle. Each vehicle is assessed in terms of guidance on straight track, steering on curved track, actuation requirements and wheel-rail wear. Significant benefits are demonstrated in one of the guided vehicles with independently-rotating wheelsets. [ABSTRACT FROM AUTHOR]

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized. [ABSTRACT FROM AUTHOR]

The authors comments on a study on atrial fibrillation, anticoagulant stroke prophylaxis and bleeding risk with ibrutinib therapy used to manage chronic lymphocytic leukaemia and lymphoproliferative disorders, published in the journal. Topics include use of inhibitor of the Bruton Tyrosine Kinase (BTK) molecule in management of chronic lymphocytic leukaemia (CLL); finding inferring occurrence of atrial fibrillation (AF) associated with ibrutinib; and challenges facing management CLL, and AF.

There is a healthcare crisis in developing and resource-constrained countries that is attributable to the burden of communicable diseases and the rapid rise of non-communicable diseases. The first line of treatment for both communicable and non-communicable diseases is the use of pharmaceuticals. Almost all drugs deemed to be 'essential medicines' by the World Health Organization are off-patent and available as generics and nearly all of the patented, brand-name essential medicines are deeply discounted in developing countries, often matching generic prices. However, despite this, one-third of the world's population does not have access to essential medicines. There is no scientific evidence that patents or price are major barriers to market access, or causatively associated with worse health outcomes, in developing and resource-constrained markets. The pharmaceutical industry, like almost all industries, uses differential pricing worldwide wherein prices are inverted to the elasticity of demand. The real barriers to access in these countries are money, power, politics, and ideologies, which manifest themselves in market failure, corruption, and the lack of political will to create stable, ethical, and law-abiding government administrations that will ensure products arrive where they are destined without delay, diversion, theft, or unnecessary tariffs. There is a need for infrastructure, roads, communications, health human resources, provider compliance, patient adherence, political stability, and professional regulatory structures and protections. Enhanced state capacity to serve indigenous populations and the rule of law-including harmonized intellectual property protection-are integral to promoting global health and healthcare, in which pharmaceuticals play a vital role. There are no quick-fix solutions. [ABSTRACT FROM AUTHOR]

Numerous preclinical and clinical studies investigating the neurodevelopmental and neurocognitive effects of exposure to anesthesia and the combination of anesthesia and surgery have demonstrated histopathological and both temporary and long-term cognitive and behavioral effects at the extremes of the human age spectrum. Increasing coverage in the lay press for both our youngest and oldest patient populations has led to heightened concerns regarding the potential harmful side effects of almost all commonly used anesthetic drug regimens. Although the majority of information regarding anesthetic risks in the developing brain derives from preclinical work in rodents, research involving the aged brain has identified a well-defined postoperative cognitive phenotype in humans. While preclinical and clinical data appear to support some association between anesthesia and surgery and the development of detrimental cognitive changes in both the developing and the aged brain, correlation between anesthesia and surgery and poor neurological outcomes does not imply causation. Given this information, no single anesthetic or group of anesthetics can be recommended over any other in terms of causing or preventing negative neurocognitive outcomes in either population. This review summarizes the growing body of preclinical and clinical literature dedicated to the detrimental effects of anesthesia on both the developing and the aging brain. [ABSTRACT FROM AUTHOR]

There is a growing recognition of the roles of marine microenvironments as reservoirs of biodiversity and as sites of enhanced biological activity and in facilitating biological interactions. Here, we examine the bacterial community inhabiting free-living and particle-associated seawater microenvironments at the Pivers Island Coastal Observatory (PICO). 16S rRNA gene libraries from monthly samples (July 2013 to August 2014) were used to identify microbes in seawater in four size fractions: >63 μm (zooplankton and large particles), 63 to 5 μm(particles), 5 to 1 μm(small particles/dividing cells), and <1 μm(free-living prokaryotes). Analyses of microbial community composition highlight the importance of the microhabitat (e.g., particle-associated versus free-living lifestyle) as communities cluster by size fraction, and the microhabitat explains more of the community variability than measured environmental parameters, including pH, particle concentration, projected daily insolation, nutrients, and temperature. While temperature is statistically associated with community changes in the <1-μmand 5- to 1-μmfractions, none of the measured bulk seawater environmental variables are statistically significant in the larger-particle-associated fractions. These results, combined with high particle-associated community variability, especially in the largest size fraction (i.e., >63 μm), suggest that particle composition, including eukaryotes and their associated microbiomes, may be an important factor in selecting for specific particle-associated bacteria. [ABSTRACT FROM AUTHOR]

Background Recent articles in both scholarly journals and the lay press about the topic of anesthetic related neurotoxicity have increased the awareness and discussion of this topic with parents and other pediatric medical specialties (i.e., surgeons, radiologists, and pediatricians). Aim The purpose of the present study was to survey how a subset of pediatric anesthesia departments in the US have responded to the issue of anesthetic related neurotoxicity in terms of clinical practice, training and communication with other medical specialties, and the frequency and timing of discussions with families. Methods A survey consisting of 22 questions was sent to PALC (Pediatric Anesthesia Leadership Council) & PAPDA (Pediatric Anesthesia Program Directors Association) via SurveyMonkey. The survey was divided into sections on Anesthesia Faculty/Trainees, Parents and Non-Anesthesia Providers. Responses to the survey were solicited via email to PALC and PAPDA, and then followed up with reminders to individual emails using the mailing lists of both organizations. Results The results of this survey demonstrate that pediatric anesthesia programs around the US do not have a consistent approach in managing the topic of anesthesia-related neurotoxicity with pediatric anesthesiologists, anesthesiology residents, pediatric anesthesiology fellows and their non-anesthesia medical and surgical colleagues, as well as the discussion of this topic with parents. Conclusion A significant need exists to provide information to other pediatric professionals and parents. A consistent message from all providers that includes what is known, and indeed more importantly what is not known may be a useful approach. [ABSTRACT FROM AUTHOR]

R6245 --> 615.12 --> Whole body barometric flow through plethysmography is used to study respiratory output in mouse and rat genetic and disease models. Turn‐key commercial and custom systems are both used to gather multiple data streams including respiratory‐pressure waveforms, O2 and CO2 measurement, and other data points for a reasonable estimation of tidal volume and key metabolic parameters. These experiments typically produce large amounts of data that are time‐consuming and difficult to analyze and organize. For analysis, the investigator may use cumbersome hand annotation subject to observer bias or several software products may be combined to manage raw data, calculated data, statistical analysis, and graphing. Commercial software, however, is prohibitively expensive or bundled with turn‐key systems that limit options for those using bespoke respiratory measurement systems. To address these deficiencies, we developed a software pipeline for processing raw respiratory recordings and associated metadata (experimental design, age, weight, temperature, etc.) into operative respiratory outcomes, publication‐worthy graphs, and robust statistical analyses. This pipeline consists of three modules. The first module is a Python‐based graphical user interface (GUI) for uploading all relevant data files and allows the user to define and label independent, dependent, and covariate variables relevant to the experimental design, statistical analysis, and graphical outputs. Additionally, parameters can be programmed to define waveform feature segmentation to include manual annotations. In the second module, BASSPRO, the data are processed with a Python program to segment the respiratory waveform based on user‐defined thresholds for movement artifacts and unique features. BASSPRO quantifies respiratory cycle components and demarks unique features including sighs, apneas, expiratory reflexes, and user‐defined entities. The module also allows for browsing the raw signals with markup of automatically annotated breaths to facilitate validation of breath detection and to permit manual annotation of features, if desired. The third module, STAGG, is an R‐based program that accepts the BASSPRO output along with configuration files from the GUI to graph the desired variables while performing a linear mixed effects statistical model analysis of the data with appropriate post‐hoc tests. Following graph generation, statistically significant differences in respiratory variables are automatically annotated in the graphs. Following statistical testing, residual analyses are provided that allow the user to determine if a transformation of their data may be appropriate. If so, transformations can be selected within the GUI so no external data analyses are necessary. The open‐source program offers a facile and highly customizable platform for automated handling and analysis of animal respiratory and metabolic data that sets the stage for high‐throughput studies and machine learning approaches on large data sets. [ABSTRACT FROM AUTHOR]

R6062 --> 615.11 --> Background: Sudden Infant Death Syndrome is thought to partly result from unseen brain abnormalities affecting cardio‐respiratory function, but for which no clear genetic or environmental mechanisms are known. Mouse genetic and exposure models present an opportunity to uncover molecular and environmental mechanisms. However, measuring cardio‐respiratory function in neonate mice is expensive, difficult, and inefficient. One major challenge is the time needed to carry out such measurements. The neonate autoresuscitation assay, consisting of repeated anoxic exposures followed by recovery, requires the full attention of an observer for the multi‐hour duration of a single‐subject assay, limiting throughput. To address this, we developed a closed‐loop feature detection platform for automated neonate cardio‐respiratory measurements. Methods: Our platform design consists of:1) a pneumotachograph face‐mask for precise respiratory measurements. 2) a micro‐controller automated bell‐housing gas switching system for rapid induction of respiratory challenges. 3) a micro‐computer‐based data‐acquisition system with real‐time feature detection and outputs for controlling gas exposure. 4) a data analysis suite that assists with study recordkeeping and provides a facile method to extract key outcome measures from acquired data. Results: Gas challenges are administered via the rotating bell housing system. A python program detects waveform features in real‐time, such as apnea and bradycardia. Upon apnea detection, the system switches to a rescue gas. Resumption of normal breathing and heart rate can also be detected and incorporated into criteria for automated initiation of the next anoxic exposure trial. Data is stored for later offline automated analysis using the data analysis suite. Conclusions: The system offers a relatively inexpensive approach for automated high throughput neonate cardio‐respiratory assessment for facile screening to yield important clues in developmental pathophysiology. [ABSTRACT FROM AUTHOR]

This chapter is about a unique partnership between Ravenscroft, a pre-K-12th grade independent school in Raleigh, North Carolina, and the Center for Creative Leadership. Starting in pre-K, Ravenscroft students embark on the Lead From Here initiative that inspires and empowers them to become citizen leaders. [ABSTRACT FROM AUTHOR]

This work proposes a novel Linear Quadratic Gaussian (LQG)-based blade pitch control method for floating offshore wind turbines, in which a state-space model of the turbine and water hydrodynamics is included in the LQG design. The actuation considered is collective blade pitch control with the objective of generator power stabilisation and platform motion reduction. A linear Kalman filter is used to estimate un-measurable states relating to wave excitation and radiation through measurements of generator speed, platform pitch, and wind disturbance. Controller design models were validated with the full order nonlinear model under various testing conditions. The new controller design is tested on a nonlinear high-fidelity simulation model of the 15 Mega-Watt (MW) floating semi-submersible wind turbine. In simulations with realistic stochastic wind and wave disturbances, the new controller achieves 32% lower generator speed Root Mean Square Error (RMSE) and 16% lower platform pitch RMSE compared to a standard LQG controller that does not include hydrodynamic states, for equivalent levels of pitch actuation and with a 2 ° /sec rate limit on pitch. The inclusion of hydrodynamics in the controller design not only reduced platform pitching fluctuation, but also had a strong effect of hub-height factors such as the generator speed. • Evaluate LQG controllers on the recently released IEA 15 MW floating wind turbine. • Incorporate wave excitation and radiation state space approximations in LQG control. • Estimate non-measurable states for control of hydrodynamics using Kalman filters. • Test controllers on stochastic wind and wave elevation cases in OpenFAST. [ABSTRACT FROM AUTHOR]

Significance: Mechanical activation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occurs in striated muscle and affects Ca2+ signaling and contractile function. ROS/RNS signaling is tightly controlled, spatially compartmentalized, and source specific. Recent Advances: Here, we review the evidence that within the contracting myocyte, the trans-membrane protein NADPH oxidase 2 (Nox2) is the primary source of ROS generated during contraction. We also review a newly characterized signaling cascade in cardiac and skeletal muscle in which the microtubule network acts as a mechanotransduction element that activates Nox2-dependent ROS generation during mechanical stretch, a pathway termed X-ROS signaling. Critical Issues: In the heart, X-ROS acts locally and affects the sarcoplasmic reticulum (SR) Ca2+ release channels (ryanodine receptors) and tunes Ca2+ signaling during physiological behavior, but excessive X-ROS can promote Ca2+-dependent arrhythmias in pathology. In skeletal muscle, X-ROS sensitizes Ca2+-permeable sarcolemmal 'transient receptor potential' channels, a pathway that is critical for sustaining SR load during repetitive contractions, but when in excess, it is maladaptive in diseases such as Duchenne Musclar dystrophy. Future Directions: New advances in ROS/RNS detection as well as molecular manipulation of signaling pathways will provide critical new mechanistic insights into the details of X-ROS signaling. These efforts will undoubtedly reveal new avenues for therapeutic intervention in the numerous diseases of striated muscle in which altered mechanoactivation of ROS/RNS production has been identified. Antioxid. Redox Signal. 20, 929-936. [ABSTRACT FROM AUTHOR]

The effects of the seed reaction conditions on the two-step seed-mediated growth of gold nanorods and the effect of gold and reducing agent content in the growth solution were evaluated. Results indicate that the reaction conditions used to produce the seeds have a significant impact on the aspect ratio of the gold nanorods produced. Increasing the concentration of gold or the reaction temperature in the seed production step results in lower length to diameter (aspect ratio) gold rods. In addition, the amount of prepared seed added to the growth solution impacts the rod aspect ratio, with increasing amounts of seed reducing the aspect ratio. The effects of reducing agent, ascorbic acid (AA), and gold content of the growth solution on the aspect ratio of the produced rods are strongly interrelated. There exists a minimum ascorbic acid to gold concentration below which rods will not form; however, increasing the ratio above this minimum results in shorter rods being formed. Characterization of nanorod growth is performed by UV-vis-NIR spectrophotometry and transmission electron microscopy (TEM). [ABSTRACT FROM AUTHOR]

Highlights: [•] Breathing disturbances in Rett Syndrome consist of hypo- and hyperventilation. [•] Disturbances exhibit large inter- and intraindividual variations. [•] Breath holds in human and mouse models of Rett Syndrome may involve overexcited expiration. [•] Irregular breathing is characterized by increased amplitude and frequency variability. [•] Animal models offer promising pre-clinical therapies, but so far no therapy has been translated to human patients. [Copyright &y& Elsevier]

Aims A sustained, single stretch of a cardiomyocyte activates a transient production of reactive oxygen species by membrane-located NADPH oxidase 2 (Nox2). This NoX2-dependent ROS (X-ROS) tunes cardiac Ca2+ signalling by reversibly sensitizing sarcoplasmic reticulum Ca2+ release channels. In contrast to static length changes, working heart cells are cyclically stretched and shortened in the living animal. Additionally, this stretch cycle is constantly varied by changes in the pre-load and heart rate. Thus, the objective of this study was (i) to characterize X-ROS signalling during stretch-shortening cycles and (ii) to evaluate how the amplitude (pre-load) and frequency (heart rate) of cell stretch affects X-ROS and Ca2+ signalling. Methods and results Single adult rat cardiomyocytes were attached to MyoTak™-coated micro-rods and stretched, while ROS production and Ca2+ signals were monitored optically. Although a sustained stretch led to only a transient burst of ROS, cyclic stretch-shortening cycles led to a steady-state elevation of ROS production. Importantly, this new redox state was graded by both the amplitude of stretch (3–15%) and cycle frequency (1–4 Hz). Elevated ROS production enhanced Ca2+ signalling sensitivity as measured by the Ca2+ spark rate. Conclusion The steady-state level of ROS production in a cardiomyocyte is graded by the amplitude and frequency of cell stretch. Thus, mechanical changes that depend on the pre-load and heart rate regulate a dynamic redox balance that tunes cellular Ca2+ signalling. [ABSTRACT FROM PUBLISHER]

:Histone deacetylase (HDAC) inhibitors have emerged as effective antineoplastic agents in the clinic. Studies from our lab and others have reported that magnetic resonance spectroscopy (MRS)-detectable phosphocholine (PC) is elevated following SAHA treatment, providing a potential noninvasive biomarker of response. Typically, elevated PC is associated with cancer while a decrease in PC accompanies response to antineoplastic treatment. The goal of this study was therefore to elucidate the underlying biochemical mechanism by which HDAC inhibition leads to elevated PC. We investigated the effect of SAHA on MCF-7 breast cancer cells using 13C MRS to monitor [1,2-13C] choline uptake and phosphorylation to PC. We found that PC synthesis was significantly higher in treated cells, representing 154±19% of control. This was within standard deviation of the increase in total PC levels detected by 31P MRS (129±7% of control). Furthermore, cellular choline kinase activity was elevated (177±31%), while cytidylyltransferase activity was unchanged. Expression of the intermediate-affinity choline transporter SLC44A1 and choline kinase α increased (144% and 161%, respectively) relative to control, as determined by mRNA microarray analysis with protein-level confirmation by Western blotting. Taken together, our findings indicate that the increase in PC levels following SAHA treatment results from its elevated synthesis. Additionally, the concentration of glycerophosphocholine (GPC) increased significantly with treatment to 210±45%. This is likely due to the upregulated expression of several phospholipase A2 (PLA2) isoforms, resulting in increased PLA2 activity (162±18%) in SAHA-treated cells. Importantly, the levels of total choline (tCho)-containing metabolites, comprised of choline, PC and GPC, are readily detectable clinically using 1H MRS. Our findings thus provide an important step in validating clinically translatable non-invasive imaging methods for follow-up diagnostics of HDAC inhibitor treatment. [ABSTRACT FROM AUTHOR]

A procedure based on an analytical inverse method is developed to calculate heat-flux distributions on a model using a time sequence of temperature-sensitive-paint images acquired in the Purdue quiet Mach-6 Ludwieg tube. Temperature-sensitive-paint measurements are conducted on a 7-deg half-angle sharp circular metal cone at Mach 6 to evaluate the accuracy of this method. It is found that the historical effect of the warming-up process of a model in sequential runs becomes significant. Therefore, it must be corrected by in situ calibration to obtain accurate heat-flux distributions. After this historical effect and the effect of the nonuniform coating thickness and other potential factors are corrected, the temperature-sensitive-paint-derived heat-flux distributions on the cone are in good agreement with those given by the similarity solution and the reference temperature method. The error sources in temperature-sensitive-paint heat-flux measurements in the Ludwieg tube are discussed. [ABSTRACT FROM AUTHOR]

Background Atrial fibrillation (AF) is a common tachyarrhythmia in Australia, with a prevalence over 10% in older patients. AF is the leading preventable cause of ischaemic stroke, and strokes due to AF have a higher mortality and morbidity. Stroke prevention is therefore a key management strategy for AF patients, in addition to rate and rhythm control. Anticoagulation with warfarin has been an enduring gold standard for stroke prevention in NVAF patients. In Australia, three novel oral anticoagulants (NOACs), apixaban, dabigatran and rivaroxaban are now approved and reimbursed for stroke prevention in patients with non-valvular AF (NVAF). International European Cardiology guidelines now recommend either a NOAC or warfarin for NVAF patients with a CHA2DS2-VASc score ≥2, unless contraindicated. Apixaban is a direct factor Xa inhibitor with a 12-hour half-life and 25% renal excretion that was found in a large trial of NVAF patients to be superior to warfarin in preventing stroke or systemic embolism. In this trial population, apixaban also resulted in less bleeding and a lower mortality rate than warfarin. Methods Clinical experience with apixaban outside of clinical trials has been limited, and there is currently little evidence to guide the management of bleeding or invasive procedures in patients taking apixaban. The relevant currently available animal and ex vivo human data were collected, analyzed and summarized. Results This multi-disciplinary consensus statement has been written to serve as a guide for healthcare practitioners prescribing apixaban in Australia, with a focus on acute and emergency management. Conclusions The predictable pharmacokinetics and minimal drug interactions of apixaban should allow for safe anticoagulation in the majority of patients, including temporary interruption for elective procedures. In the absence of published data, patients actively bleeding on apixaban should receive standard supportive treatment. Quantitative assays of apixaban level such as chromogenic anti-Xa assays are becoming available but their utility is unproven in this setting. Specific antidotes for novel anticoagulants, including apixaban, are in clinical development. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1+/null mice are normal, Pkd1RC/null mice have rapidly progressive disease, and Pkd1RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkdl product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/ trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD patho-genesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing. [ABSTRACT FROM AUTHOR]

Intermediate filaments (IFs), composed of desmin and keratins, link myofibrils to each other and to the sarcolemma in skeletal muscle. Fast-twitch muscle of mice lacking the IF proteins, desmin and keratin 19 (K19), showed reduced specific force and increased susceptibility to injury in earlier studies. Here we tested the hypothesis that the number of malformed myofibers in mice lacking desmin (Des-/-), keratin 19 (K19-/-), or both IF proteins (double knockout, DKO) is increased and is coincident with altered excitation-contraction (EC) coupling Ca2+ kinetics, as reported for mdx mice. We quantified the number of branched myofibers, characterized their organization with confocal and electron microscopy (EM), and compared the Ca2+ kinetics of EC coupling in flexor digitorum brevis myofibers from adult Des-/-, K19-/-, or DKO mice and compared them to agematched wild type (WT) and mdx myofibers. Consistent with our previous findings, 9.9% of mdx myofibers had visible malformations. Des-/- myofibers had more malformations (4.7%) than K19-/- (0.9%) or DKO (1.3%) myofibers. Confocal and EM imaging revealed no obvious changes in sarcomere misalignment at the branch points, and the neuromuscular junctions in the mutant mice, while more variably located, were limited to one per myofiber. Global, electrically evoked Ca2+ signals showed a decrease in the rate of Ca2+ uptake (decay rate) into the sarcoplasmic reticulum after Ca2+ release, with the most profound effect in branched DKO myofibers (44% increase in uptake relative to WT). Although branched DKO myofibers showed significantly faster rates of Ca2+ clearance, the milder branching phenotype observed in DKO muscle suggests that the absence of K19 corrects the defect created by the absence of desmin alone. Thus, there are complex roles for desmin-based and K19-based IFs in skeletal muscle, with the null and DKO mutations having different effects on Ca2+ reuptake and myofiber branching. [ABSTRACT FROM AUTHOR]

Renal involvement is a frequent consequence of plasma cell dyscrasias. The most common entities are light chain amyloidosis, monoclonal immunoglobulin deposition disease and myeloma cast nephropathy. Despite a common origin, each condition has its own unique histologic and pathophysiologic characteristic which requires a renal biopsy to distinguish. Recent studies have shown urinary exosomes containing kidney-derived membrane and cytosolic proteins that can be used to probe the proteomics of the entire urinary system from the glomerulus to the bladder. In this study, we analyzed urine exosomes to determine the differences between exosomes from patients with light chain amyloidosis, multiple myeloma, monoclonal gammopathy of undetermined significance, and non-paraproteinemia related kidney disease controls. In patients with light chain amyloidosis, multiple myeloma and monoclonal gammopathy of undetermined significance, immunoreactive proteins corresponding to monomeric light chains were found in exosomes by western blot. In all of the amyloidosis samples with active disease, high molecular weight immunoreactive species corresponding to a decamer were found which were not found in exosomes from the other diseases or in amyloidosis exosomes from patients in remission. Few or no light chains monomeric bands were found in non-paraproteinemia related kidney disease controls. Our results showed that urinary exosomes may have tremendous potential in furthering our understanding of the pathophysiology and diagnosis of plasma cell dyscrasia related kidney diseases. [ABSTRACT FROM AUTHOR]

In this article, our focus is on the methodological issues in taking a situative approach to studying the interconnected development of motivation, identity, and learning in multiple social contexts. We illustrate our description with data acquired from a cross-context, longitudinal, ethnographic study of novice teachers' learning, motivation, and identity development (Horn, Mathematical Thinking and Learning, 10(3), 201-239 ; Nolen et al., Cognition and Instruction, 29(1), 88-122, ; Nolen et al. ; Ward et al., International Journal of Educational Research, 50(1), 14-20, ). We focus our methodological discussion on structuring longitudinal interviews and the interdependence of interview and observational techniques in understanding motivation in social contexts, including the methodological challenges inherent in ethnographic work. One challenge we consider in depth is accounting for the interview as a social context in which motivation and identity develop as learning occurs and how this challenge is particularly important to address in longitudinal work. We end by raising some additional methodological issues in studying motivation, identity, and learning from a situative perspective. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is a rare but potentially serious complication of heparin use. Prompt diagnosis is crucial and requires the integration of clinical assessment and laboratory testing. Pretest clinical scoring systems (i.e., 4 Ts) have been established. Immunoassays can detect the presence of antibodies directed toward heparin-platelet factor 4 (H-PF4) complexes, but provide no information about their ability to activate platelets. A low clinical score, when combined with a negative immunoassay result obviates the need for further testing. However, immunoassays and 4 Ts scores have only modest specificity. Functional testing (serotonin release assay or heparin-induced platelet activation) remain important in confirming the presence of pathogenic H-PF4 antibodies, but are technically demanding to perform and limited in guiding clinical decisions in the acute setting. This review evaluates current immuno- and functional assays available in the laboratory diagnosis of HIT, and describes recent attempts to improve the specificity of enzyme immunoassays, including adopting an immunoglobulin G-specific assay and raising the optical density value cutoff for a positive result. The importance of donor selection and newer functional assays, including flow cytometry-based assays, are also discussed. A current approach to integrating clinical scoring, immunoassays, and functional testing for HIT is also outlined. [ABSTRACT FROM AUTHOR]

Abstract: Despite our insufficient understanding of the exact molecular mechanisms of general anesthetics and sedatives, every year millions of children are treated with these drugs in a seemingly safe manner. However, increasing evidence particularly from animal studies has suggested the possibility for deleterious effects in pediatric patients. All currently clinically utilized anesthetic drugs have been found to induce neuronal cell death in the developing brain and to potentially cause long-term neurological impairment. Conversely, painful stimuli without analgesia and anesthesia have also been shown to initiate a harmful stress response in young children and to trigger neurotoxic effects in the developing brain, which can be blunted by anesthetics. Moreover, anesthetic drugs may also confer neurological protection during hypoxic and ischemic insults. The mechanisms and human applicability of anesthetic neurotoxicity and neuroprotection remain under intense investigation and this Perspectives article summarizes the current state of research. [Copyright &y& Elsevier]

The problem: Rehabilitation professionals recognize the need to adopt a social as well as a medical model of disability, but the full implications of a social orientation towards disability are less easily accepted. If the physical environment can both produce and alleviate disability, so also can the social environment. If disablement is not to be seen as the problem of one individual then problems in rehabilitation must be ‘owned’ not solely by a single patient but also by other people implicated in a situation. It follows that ‘patient-centred care’, where a professional directs assessments and interventions towards one person, has shortcomings in rehabilitation.Theoretical considerations: A human systems model, shifting the focus of rehabilitation towards relationships, enables rehabilitation problems to be seen as provisional and context-dependent; the relational context of problems is clarified, and the positive and negative effects of professional power are more apparent.Clinical implications: Rehabilitation practitioners using a systemic approach would no longer view ‘carers’ and other significant individuals as mere bystanders but would integrate them within rehabilitation’s ethical and therapeutic system. Professionals would more readily recognize their roles within such a system, and would be better positioned to manage their negative as well as their positive effects. [ABSTRACT FROM PUBLISHER]

The article presents information on the decisions by the courts regarding the fidelity and surety law of the U.S. The decision of the Supreme Court of the U.S. on the fidelity law was based on issues like employee dishonesty, forgery, robbery, computer fraud and termination. Five main issues are considered under the surety law namely the rights of surety, bankruptcy, performance bonds, payment bonds and other bonds like injunction bonds, customs and motor vehicle dealer bonds. Information on the decisions of the federal courts and the district courts of the U.S. on the law is also presented.

We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (N0X2) to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where N0X2 is located and sensitizes nearby ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This triggers a burst of Ca2+ sparks, the elementary Ca2+ release events in heart. Although this stretch-dependent "tuning" of RyRs increases Ca2+ signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca2+ sparks to trigger arrhythmogenic Ca2+ waves, in the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca2+ release from the SR. X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca2+ release in the heart and offers fresh therapeutic possibilities. [ABSTRACT FROM AUTHOR]

Rett syndrome is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), a transcriptional regulator. In addition to cognitive, communication, and motor problems, affected individuals have abnormalities in autonomic function and respiratory control that may contribute to premature lethality. Mice lacking Mecp2 die early and recapitulate the autonomic and respiratory phenotypes seen in humans. The association of autonomic and respiratory deficits with premature death suggests that Mecp2 is critical within autonomic and respiratory control centers for survival. To test this, we compared the autonomic and respiratory phenotypes of mice with a null allele of Mecp2 to mice with Mecp2 removed from their brainstem and spinal cord. We found that MeCP2 is necessary within the brainstem and spinal cord for normal lifespan, normal control of heart rate, and respiratory response to hypoxia. Restoration of MeCP2 in a subset of the cells in this same region is sufficient to rescue abnormal heart rate and abnormal respiratory response to hypoxia. Furthermore, restoring MeCP2 function in neural centers critical for autonomic and respiratory function alleviates the lethality associated with loss of MeCP2 function, supporting the notion of targeted therapy toward treating Rett syndrome. [ABSTRACT FROM AUTHOR]

The autosomal recessive polycystic kidney disease (ARPKD) gene, PKHD1, has been implicated in the genesis or growth of colorectal adenocarcinoma, as a high level of somatic mutations was found in colorectal tumor tissue. To determine whether carriers of a single PKHD1 mutation are at increased risk of colorectal carcinoma, we assessed the prevalence of the commonest European mutation, T36M. First, we assayed a European cohort of ARPKD patients and found T36M was responsible for 13.1% of mutations. We then investigated two European cohorts with colorectal adenocarcinoma versus two control cohorts of similar age and gender. Screening for the most common PKHD1 mutation, T36M, we detected 15:3,603 (0.42%) controls versus 1:3,767 (0.027%) colorectal cancer individuals, indicating that heterozygous PKHD1 mutations are not a risk factor and are protective ( p = 0.0002). We also show that the carriage rate for PKHD1 mutations in the European population is higher than previous accepted at 3.2% (1:31 genomes). [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1154Q/+ mice to mice lacking one allele of 14-3-3ϵ. 14-3-ϵ haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ϵ levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum. 14-3-3ϵ haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ϵ haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis. [ABSTRACT FROM AUTHOR]

The article discusses court cases related to fidelity and surety law in the U.S. The legal cases mentioned in the article include, plaintiff Alerus Financial National Association versus defendant Saint Paul Mercury Insurance Co., and petitioner Great American Insurance Co. versus respondent AFS/IBEX Financial Services Inc. The judgements taken by the U.S. courts in all these cases have also been discussed in the article.

Abstract: Student teaching is contested ground for teacher candidates’ learning. Struggling to implement practises when expectations of university and schools are inconsistent, they experience conflicts between these two worlds. In this article, we conceptualise student teaching as a space where conflicts can be generative for candidates’ learning. We use the idea of productive friction—dissonance experienced by teacher candidates when two or more social worlds conflict that leads to more sophisticated practise—to consider student teaching as a potential boundary space that benefits from diverse perspectives. Drawing on ethnographic data, we contrast the cases of four candidates’ productive and unproductive friction during student teaching. Furthermore, we discuss the qualities of student teaching that can promote productive friction for learning. [Copyright &y& Elsevier]

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is ‘The trainee demonstrates a knowledge of benefits and limitations of counselling approaches, specifically in this article systemic family therapy.’ [ABSTRACT FROM PUBLISHER]