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Central noradrenergic (NA) neurons are key constituents of the respiratory homeostatic network. NA dysfunction is implicated in several developmental respiratory disorders including Congenital Central Hyperventilation Syndrome (CCHS), Sudden Infant Death Syndrome (SIDS), and Rett Syndrome. The current unchallenged paradigm in the field, supported by multiple studies, is that glutamate co-transmission in subsets of central NA neurons plays a role in breathing control. If true, NA-glutamate co-transmission may also be mechanistically important in respiratory disorders. However, the requirement of NA-derived glutamate in breathing has not been directly tested and the extent of glutamate co-transmission in the central NA system remains uncharacterized. Therefore, we fully characterized the cumulative fate maps and acute adult expression patterns of all three vesicular glutamate transporters ( Slc17a7 (Vglut1), Slc17a6 (Vglut2), and Slc17a8 (Vglut3)) in NA neurons, identifying a novel, dynamic expression pattern for Vglut2 and an undescribed co-expression domain for Vglut3 in the NA system. In contrast to our initial hypothesis that NA-derived glutamate is required to breathing, our functional studies showed that loss of Vglut2 throughout the NA system failed to alter breathing or metabolism under room air, hypercapnia, or hypoxia in unrestrained and unanesthetized mice. These data demonstrate that Vglut2-based glutamatergic signaling within the central NA system is not required for normal baseline breathing and hypercapnic, hypoxic chemosensory reflexes. These outcomes challenge the current understanding of central NA neurons in the control of breathing and suggests that glutamate may not be a critical target to understand NA neuron dysfunction in respiratory diseases., Competing Interests: YC, SL, AC, CW, RR No competing interests declared, (© 2023, Chang et al.)

Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia., (© 2024. The Author(s).)

Despite the millions of dollars awarded annually by the United States Department of Education to build implementation capacity through technical assistance (TA), data on TA effectiveness are severely lacking. Foundational to the operationalization and consistent research on TA effectiveness is the development and use of standardized TA core competencies, practices, and structures. Despite advances toward a consistent definition of TA, a gap still exists in understanding how these competencies are used within an operationalized set of TA practices to produce targeted outcomes at both individual and organizational levels to facilitate implementation of evidence-based practices. The current article describes key insights derived from the evaluation of an operationalized set of TA practices used by a nationally funded TA center, the State Implementation & Scaling Up of Evidence Based Practices (SISEP) Center. The TA provided by the Center supports the uptake of evidence-based practices in K-12 education for students with disabilities. Lessons learned include: (1) the need to understand the complexities and dependencies of operationalizing TA both longitudinally and at multiple levels of the system (state, regional, local); (2) the relative importance of building general and innovation-specific capacity for implementation success; (3) the value of using a co-design and participatory approach for effective TA delivery; (4) the need to develop TA providers' educational and implementation fluency across areas and levels of the system receiving TA; and (5) the need to ensure coordination and alignment of TA providers from different centers. Gaining an understanding into optimal TA practices will not only provide clarity of definition fundamental to TA research, but it will also inform the conceptual framing and practice of TA., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Winam Gulf (Kenya) is frequently impaired by cyanobacterial harmful algal blooms (cHABs) due to inadequate wastewater treatment and excess agricultural nutrient input. While phytoplankton in Lake Victoria have been characterized using morphological criteria, our aim is to identify potential toxin-producing cyanobacteria using molecular approaches. The Gulf was sampled over two successive summer seasons, and 16S and 18S ribosomal RNA gene sequencing was performed. Additionally, key genes involved in production of cyanotoxins were examined by quantitative PCR. Bacterial communities were spatially variable, forming distinct clusters in line with regions of the Gulf. Taxa associated with diazotrophy were dominant near Homa Bay. On the eastern side, samples exhibited elevated cyrA abundances, indicating genetic capability of cylindrospermopsin synthesis. Indeed, near the Nyando River mouth in 2022, cyrA exceeded 10 million copies L -1 where there were more than 6000 Cylindrospermopsis spp. cells mL -1 . In contrast, the southwestern region had elevated mcyE gene (microcystin synthesis) detections near Homa Bay where Microcystis and Dolichospermum spp. were observed. These findings show that within a relatively small embayment, composition and toxin synthesis potential of cHABs can vary dramatically. This underscores the need for multifaceted management approaches and frequent cyanotoxin monitoring to reduce human health impacts., (© 2024 The Author(s). Environmental Microbiology Reports published by John Wiley & Sons Ltd.)

Sandusky Bay is the drowned mouth of the Sandusky River in the southwestern portion of Lake Erie. The bay is a popular recreation location and a regional source for drinking water. Like the western basin of Lake Erie, Sandusky Bay is known for being host to summer cyanobacterial harmful algal blooms (cHABs) year after year, fueled by runoff from the predominantly agricultural watershed and internal loading of legacy nutrients (primarily phosphorus). Since at least 2003, Sandusky Bay has harbored a microcystin-producing bloom of Planktothrix agardhii, a species of filamentous cyanobacteria that thrives in low light conditions. Long-term sampling (2003-2018) of Sandusky Bay revealed regular Planktothrix-dominated blooms during the summer months, but in recent years (2019-2022), 16S rRNA gene community profiling revealed that Planktothrix has largely disappeared. From 2017-2022, microcystin decreased well below the World Health Organization (WHO) guidelines. Spring TN:TP ratios increased in years following dam removal, yet there were no statistically significant shifts in other physicochemical variables, such as water temperature and water clarity. With the exception of the high bloom of Planktothrix in 2018, there was no statistical difference in chlorophyll during all other years. Concurrent with the disappearance of Planktothrix, Cyanobium spp. have become the dominant cyanobacterial group. The appearance of other potential toxigenic genera (i.e., Aphanizomenon, Dolichospermum, Cylindrospermopsis) may motivate monitoring of new toxins of concern in Sandusky Bay. Here, we document the regime shift in the cyanobacterial community and propose evidence supporting the hypothesis that the decline in the Planktothrix bloom was linked to the removal of an upstream dam on the Sandusky River., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Metagenome-assembled genomes were generated for two xenic cyanobacterial strains collected from aquatic sources in Kenya and sequenced by NovaSeq S4. Here, we report the classification and genome statistics of Microcystis panniformis WG22 and Limnospira fusiformis LS22., Competing Interests: The authors declare no conflict of interest.

Specialist nurses play a significant role in healthcare. This study investigated and evaluated the primary and extended roles and the development of specialist nurses in Malta., Methods: A qualitative case study design and purposive sampling techniques were used to gain a deep understanding of the complex issues surrounding specialist nurses from multiple data sets. A survey of the total specialist nurse population in 2013 ( n =27), in-depth interviews with a group of specialist nurses ( n =9) and four focus groups with key professionals and policy stakeholders (total n =28) were carried out. Data were collected between 2013 and 2015 and analysed using thematic analysis., Findings: Three themes emerged: the roles and attributes of specialist nurses in Malta; the development of specialist nurses; and the influences on the advancement of specialist nursing practice in Malta. Although these data are nearly a decade old, no further research has been carried out., Conclusions: A legally accepted set of definitions as well as preparation and evaluation of the specialist nurse role from a national policy perspective is needed. Attitudes and systems that limit specialist nurses need to be challenged.

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., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca 2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it's low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy., (© 2023. Springer Nature Limited.)

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice., (© 2023. The Author(s).)

The increased use of the stimulant drug, 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as Ecstasy, Molly or X, has been linked to the development of life-threatening hyperthermia in human and animal models. The current study aimed to investigate the role of the gut-adrenal axis in MDMA-induced hyperthermia by assessing the influence of the acute exogenous supplementation with norepinephrine (NE) or corticosterone (CORT) to adrenalectomized (ADX) rats following MDMA administration. MDMA (10 mg/kg, sc) resulted in significant increase of body temperature in SHAM animals compared to ADX animals at 30-, 60- and 90-min timepoints post-MDMA treatment. The attenuated MDMA-mediated hyperthermic response seen in ADX animals was partially restored by the exogenous administration of NE (3 mg/kg, ip) or CORT (3 mg/kg, ip) 30 min after MDMA treatment. Additionally, 16 S rRNA analysis revealed distinct changes in the gut microbiome composition and diversity notable by the higher abundance of minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX rats compared to control and SHAM rats. Furthermore, MDMA administration resulted in marked changes in the dominant phyla Firmicutes and Bacteroidetes and minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX animals. The most notable changes in the gut microbiome upon CORT treatment were reported with increase in Bacteroidetes and decrease in Firmicutes phyla whereas NE treatment resulted in increase in Firmicutes and decrease in Bacteroidetes and Proteobacteria post treatment. These results suggest a correlation between the sympathoadrenal axis, gut microbiome structure and diversity and MDMA-mediated hyperthermia., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Although the science of patient safety has been developed and implemented widely, there remains a large gap in the understanding of the chain of events that lead to safety incidents, as well as their cost to patients, healthcare staff and the organisation as a whole. The aim of the study was to evaluate nurses' knowledge and awareness of the local incident reporting system at Malta's acute general hospital. A quantitative, descriptive cross-sectional design was used and data were collected from nurses through an online survey. A total of 323 questionnaires were received with a response rate of 23%. Various shortages within the local setting were identified, including lack of feedback and awareness of the system. Therefore, it is suggested that incident reporting should be given a higher profile on the organisation's agenda and incorporate employed members of staff rather than volunteers.

Objective: To investigate the effect of bidirectional fecal microbial transplant (FMT) between male and female rats on methamphetamine (MA)-induced hyperthermia., Methods: FMT was performed between male and female rats prior to MA (10 mg/kg, sc) treatment. Core body temperature, plasma drug and norepinephrine (NE) levels were measured and compared between treatment groups. 16S rRNA gene sequencing of bacterial communities between male and female rats was performed., Results: MA treatment resulted in significantly higher core body temperatures in male groups (control and FMT-treated) compared to MA-treated female groups (control and FMT-treated). Plasma concentrations of MA and amphetamine were higher in females than males. Whereas, plasma norepinephrine (NE) levels were not different between male and female rats 90 minutes after MA treatment. At the phyla level, the microbiome of male and female control rats were dominated by Firmicutes and Bacteroidetes. Males had a higher relative abundance of Firmicutes and lower relative abundances of Bacteroidetes than females. The FMT procedure changed the recipient group towards their donor with males getting closer to their donors than females. In the control groups following MA treatment, Firmicutes increased and Bacteroides decreased in females and males. Conversely, in the FMT treatment groups following MA treatment, Firmicutes decreased while Bacteroidetes increased in females and males., Conclusions: Although definite differences in the structure and diversity of the gut microbiome were observed using 16S rRNA gene sequencing of bacterial communities between male and female rats, these differences do not seem to contribute to the sex-based differences in MA-induced hyperthermia.

Disturbances, here defined as events that directly alter microbial community composition, are commonly studied in host-associated and engineered systems. In spite of global change both altering environmental averages and increasing extreme events, there has been relatively little research into the causes, persistence and population-level impacts of disturbance in the dynamic coastal ocean. Here, we utilize 3 years of observations from a coastal time series to identify disturbances based on the largest week-over-week changes in the microbiome (i.e. identifying disturbance as events that alter the community composition). In general, these microbiome disturbances were not clearly linked to specific environmental factors and responsive taxa largely differed, aside from SAR11, which generally declined. However, several disturbance metagenomes identified increased phage-associated genes, suggesting that unexplained community shifts might be caused by increased mortality. Furthermore, a category 1 hurricane, the only event that would likely be classified a priori as an environmental disturbance, was not an outlier in microbiome composition, but did enhance a bloom in seasonally abundant phytoplankton. Thus, as extreme environmental changes intensify, assumptions of what constitutes a disturbance should be re-examined in the context of ecological history and microbiome responses., (© 2022 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Abstract: Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The synthetic cathinone ("bath salt") methylone induces a hyperthermia response and with chronic administration tolerance to this hyperthermia has been reported. The microbiome-gut-brain axis has been implicated in multiple bodily systems and pathologies, and intentional manipulation of the gut-microbiome has yielded clinically significant results. Here, we examined the effects of bi-directional Fecal Microbiota Transplantation (FMT) between methylone-induced hyperthermic tolerant (MHT) and methylone-naïve (MN) rats. Rats treated with methylone once per week developed tolerance to methylone-induced hyperthermia by the fourth week. Once tolerant, daily bi-directional FMT between the two groups were performed for seven days prior to the next methylone treatment. The FMT abated the developed tolerance in the MHT group. When treated with methylone for the first time following FMT, recipient MN rats displayed significant tolerance to hyperthermia despite it being their initial drug treatment. Post-FMT, MHT rats displayed elevations in norepinephrine and expression of UCP1, UCP3 and TGR5 in brown adipose tissue, with reductions in expression of TGR5 and UCP3 in skeletal muscle. The pre- and post-FMT methylone tolerance phenotypes of transplant recipients are concurrent with changes in the relative abundance of several classes of Proteobacteria, most evident for Gammaproteobacteria and Alphaproteobacteria. MHT recipients demonstrated a marked increase in the relative proportion of the Firmicutes class Erysipelotrichia. These findings suggest that transplantation of gut-microbiomes can confer phenotypic responses to a drug and that the microbiome may be playing a major role in sympathomimetic-mediated hyperthermia. Abbreviations: 3,4-methylenedioxymethamphetamine (MDMA); methylone-induced hyperthermic tolerant (MHT); methylone-naïve (MN); fecal microbiota transplantation (FMT); uncoupling protein (UCP); subcutaneous (sc); intraperitoneal (ip); brown adipose tissue (BAT); skeletal muscle (SKM); sympathetic nervous system (SNS); norepinephrine (NE); quantitative PCR (qRT-PCR); quantification cycle (Cq); High Performance Liquid Chromatography-Electrochemical Detection (HPLC-EC); amplicon sequence variants (ASVs); principal coordinates analysis (PCoA); permutational multivariate analysis (PERMANOVA)., Competing Interests: No potential conflict of interest was reported by the authors., (© 2022 Informa UK Limited, trading as Taylor & Francis Group.)

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease., (© 2022. The Author(s).)

In the last decade, the high-throughput and relatively low cost of short-read sequencing technologies have revolutionized prokaryotic genomics. This has led to an exponential increase in the number of bacterial and archaeal genome sequences available, as well as corresponding increase of genome assembly and annotation tools developed. Together, these hardware and software technologies have given scientists unprecedented options to study their chosen microbial systems without the need for large teams of bioinformaticists or supercomputing facilities. While these analysis tools largely fall into only a few categories, each may have different requirements, caveats and file formats, and some may be rarely updated or even abandoned. And so, despite the apparent ease in sequencing and analyzing a prokaryotic genome, it is no wonder that the budding genomicist may quickly find oneself overwhelmed. Here, we aim to provide the reader with an overview of genome annotation and its most important considerations, as well as an easy-to-follow protocol to get started with annotating a prokaryotic genome., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the 'readers, writers and erasers' of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 α-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of α-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Iatrogenic withdrawal syndrome is a well-known adverse effect of sedatives and analgesics commonly used in patients receiving mechanical ventilation in the pediatric intensive care unit, with an incidence of up to 64.6%. When standard sedative and analgesic treatment is inadequate, dexmedetomidine may be added. The effect of supplemental dexmedetomidine on iatrogenic withdrawal syndrome is unclear., Objective: To explore the potentially preventive effect of dexmedetomidine, used as a supplement to standard morphine and midazolam regimens, on the development of iatrogenic withdrawal syndrome in patients receiving mechanical ventilation in the pediatric intensive care unit., Methods: This retrospective observational study used data from patients on a 10-bed general pediatric intensive care unit. Iatrogenic withdrawal syndrome was measured using the Sophia Observation withdrawal Symptoms-scale., Results: In a sample of 102 patients, the cumulative dose of dexmedetomidine had no preventive effect on the development of iatrogenic withdrawal syndrome (P = .19). After correction for the imbalance in the baseline characteristics between patients who did and did not receive dexmedetomidine, the cumulative dose of midazolam was found to be a significant risk factor for iatrogenic withdrawal syndrome (P < .03)., Conclusion: In this study, supplemental dexmedetomidine had no preventive effect on iatrogenic withdrawal syndrome in patients receiving sedative treatment in the pediatric intensive care unit. The cumulative dose of midazolam was a significant risk factor for iatrogenic withdrawal syndrome., (©2021 American Association of Critical-Care Nurses.)

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by loss of function of the transcriptional regulator Methyl-CpG-Binding Protein 2 (MeCP2). In addition to the characteristic loss of hand function and spoken language after the first year of life, people with RTT also have a variety of physiological and autonomic abnormalities including disrupted breathing rhythms characterized by bouts of hyperventilation and an increased frequency of apnea. These breathing abnormalities, that likely involve alterations in both the circuitry underlying respiratory pace making and those underlying breathing response to environmental stimuli, may underlie the sudden unexpected death seen in a significant fraction of people with RTT. In fact, mice lacking MeCP2 function exhibit abnormal breathing rate response to acute hypoxia and maintain a persistently elevated breathing rate rather than showing typical hypoxic ventilatory decline that can be observed among their wild-type littermates. Using genetic and pharmacological tools to better understand the course of this abnormal hypoxic breathing rate response and the neurons driving it, we learned that the abnormal hypoxic breathing response is acquired as the animals mature, and that MeCP2 function is required within excitatory, inhibitory, and modulatory populations for a normal hypoxic breathing rate response. Furthermore, mice lacking MeCP2 exhibit decreased hypoxia-induced neuronal activity within the nucleus tractus solitarius of the dorsal medulla. Overall, these data provide insight into the neurons driving the circuit dysfunction that leads to breathing abnormalities upon loss of MeCP2. The discovery that combined dysfunction across multiple neuronal populations contributes to breathing dysfunction may provide insight into sudden unexpected death in RTT., (Copyright © 2020 Ward, Huang, Herrera, Samaco, McGraw, Parra, Arvide, Ito-Ishida, Meng, Ure, Zoghbi and Neul.)

Rationale: We previously identified somatic activating mutations in the KRAS ( Kirsten rat sarcoma viral oncogene homologue ) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown., Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations., Methods and Results: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling., Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article.

Most studies of bacterial exposure to environmental contaminants focus on acute treatments; however, the impacts of single, high-dose exposures on microbial communities may not readily be extended to the more likely scenario of chronic, low-dose contaminant exposures. Here, in a year-long, wetland mesocosm experiment, we compared microbial community responses to pulse (single 450 mg dose of silver) and chronic (weekly 8.7 mg doses of silver for 1 year) silver nanoparticle (Ag 0 NP) treatments, as well as a chronic treatment of "aged" sulfidized silver nanoparticles (Ag 2 S NPs). While mesocosms exposed to Ag 2 S NPs never differed significantly from the controls, both Ag 0 NP treatments exhibited reduced microbial diversity and altered community composition; however, the effects differed in timing, duration, and magnitude. Microbial community-level impacts in the acute Ag 0 NP treatment were apparent only within the first weeks and then converged on the control mesocosm composition, while chronic exposure effects were observed several months after exposures began, likely due to interactive effects of nanoparticle toxicity and winter environmental conditions. Notably, there was a high level of overlap in the taxa which exhibited significant declines (>10×) in both treatments, suggesting a conserved toxicity response for both pulse and chronic exposures. Thus, this research suggests that complex, but short-term, acute toxicological studies may provide critical, cost-effective insights into identifying microbial taxa sensitive to long-term chronic exposures to Ag NPs.

Background: Pediatric patients with any severity of traumatic intracranial hemorrhage (tICH) are often admitted to intensive care units (ICUs) for early detection of secondary injury. We hypothesize that there is a subset of these patients with mild injury and tICH for whom ICU care is unnecessary., Objectives: To quantify tICH frequency and describe disposition and to identify patients at low risk of inpatient critical care intervention (CCI)., Methods: We retrospectively reviewed patients aged 0 to 17 years with tICH at a single level I trauma center from 2008 to 2013. The CCI included mechanical ventilation, invasive monitoring, blood product transfusion, hyperosmolar therapy, and neurosurgery. Binary recursive partitioning analysis led to a clinical decision instrument classifying patients as low risk for CCI., Results: Of 296 tICH admissions without prior CCI in the field or emergency department, 29 had an inpatient CCI. The decision instrument classified patients as low risk for CCI when patients had absence of the following: midline shift, depressed skull fracture, unwitnessed/unknown mechanism, and other nonextremity injuries. This clinical decision instrument produced a high likelihood of excluding patients with CCI (sensitivity, 96.6%; 95% confidence interval, 82.2%-99.9%) from the low-risk group, with a negative likelihood ratio of 0.056 (95% confidence interval, -0.053-0.166). The decision instrument misclassified 1 patient with CCI into the low-risk group, but would have impacted disposition of 164 pediatric ICU admissions through 5 years (55% of the sample)., Conclusions: A subset of low-risk patients may not require ICU admission. The proposed decision rule identified low-risk children with tICH who may be observable outside an ICU, although this rule requires external validation before implementation.

There is a growing awareness of the ecological and biogeochemical importance of fungi in coastal marine systems. While highly diverse fungi have been discovered in these marine systems, still, little is known about their seasonality and associated drivers in coastal waters. Here, we examined fungal communities over 3 years of weekly sampling at a dynamic, temperate coastal site (Pivers Island Coastal Observatory [PICO], Beaufort, NC, USA). Fungal 18S rRNA gene abundance, operational taxonomic unit (OTU) richness, and Shannon's diversity index values exhibited prominent seasonality. Fungal 18S rRNA gene copies peaked in abundance during the summer and fall, with positive correlations with chlorophyll a , SiO 4 , and oxygen saturation. Diversity (measured using internal transcribed spacer [ITS] libraries) was highest during winter and lowest during summer; it was linked to temperature, pH, chlorophyll a , insolation, salinity, and dissolved inorganic carbon (DIC). Fungal communities derived from ITS libraries were dominated throughout the year by Ascomycota , with contributions from Basidiomycota , Chytridiomycota , and Mucoromycotina , and their seasonal patterns linked to water temperature, light, and the carbonate system. Network analysis revealed that while cooccurrence and exclusion existed within fungus networks, exclusion dominated the fungus-and-phytoplankton network, in contrast with reported pathogenic and nutritional interactions between marine phytoplankton and fungi. Compared with the seasonality of bacterial communities in the same samples, the timing, extent, and associated environmental variables for fungi community are unique. These results highlight the fungal seasonal dynamics in coastal water and improve our understanding of the ecology of planktonic fungi. IMPORTANCE Coastal fungal dynamics were long assumed to be due to terrestrial inputs; here, a high-resolution time series reveals strong, repeating annual patterns linked to in situ environmental conditions, arguing for a resident coastal fungal community shaped by environmental factors. These seasonal patterns do, however, differ from those observed in the bacterioplankton at the same site; e.g., fungal diversity peaks in winter, whereas bacterial diversity maxima occur in the spring and fall. While the dynamics of these communities are linked to water temperature and insolation, fungi are also influenced by the carbonate system (pH and DIC). As both fungi and heterotrophic bacteria are thought to be key organic-material metabolizers, differences in their environmental drivers may offer clues as to which group dominates secondary production at this dynamic site. Overall, this study suggests the unique ecological roles of mycoplankton and their potentially broad niche complementarities to other microbial groups in the coastal ocean., (Copyright © 2018 American Society for Microbiology.)

We present here the complete genomes of 18 phages that infect Paenibacillus larvae, the causative agent of American foulbrood in honeybees. The phages were isolated between 2014 and 2016 as part of an undergraduate phage discovery course at Brigham Young University. The phages were isolated primarily from bee debris and lysogens.

Health care is experiencing increasing pressure to implement evidence-based interventions that improve quality, control costs, and maximize value. Unfortunately, many clinical services and interventions to optimize medication use do not consistently produce the intended humanistic, clinical, and economic outcomes. The lack of conclusive results is believed to stem from the widely recognized research-to-practice gap. The field of implementation science seeks to discover and apply strategies designed to accelerate successful integration of interventions into routine practice. This primer provides an overview of implementation science principles for pharmacists and other health care providers interested in accelerating practice transformation to improve health care delivery and, ultimately, patient care., (© 2018 Pharmacotherapy Publications, Inc.)

In 1901, Abraham Flexner, a research scholar at the Carnegie Foundation for the Advancement of Teaching, visited 155 medical schools in the United States and Canada to assess medical education. Flexner's recommendations became the foundation for the Liaison Committee on Medical Education accreditation, a voluntary, peer-reviewed quality assurance process to determine whether a medical education program meets established standards. The Meharry Medical College School of Medicine, a historically Black college/university (HBCU) established the Office of Curriculum Evaluation and Effectiveness in 2013 to ensure the consistent monitoring of the medical education program's compliance with accreditation standards. The motto and logo, LCME 24/7, highlight the school's emphasis on meeting accreditation standards. The school uses the 1994 Plan-Do-Study-Act Cycle for Learning and Improvement for continuous review of course content, outcomes, and evaluations. This process identifies strengths, challenges, and opportunities for innovative steps for continuous quality improvements to the curriculum.

This corrects the article DOI: 10.1038/ismej.2017.4.

Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism-based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short-comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non-neurological diseases as well as to symptom-based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two-pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom-based approaches in addition to more mechanism-based approaches., (© 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.)

Respiration is a rhythmic activity as well as one that requires responsiveness to internal and external circumstances; both the rhythm and neuromodulatory responses of breathing are controlled by brainstem neurons in the preBötzinger complex (preBötC) and the retrotrapezoid nucleus (RTN), but the specific ion channels essential to these activities remain to be identified. Because deficiency of sodium leak channel, non-selective (Nalcn) causes lethal apnea in humans and mice, we investigated Nalcn function in these neuronal groups. We found that one-third of mice lacking Nalcn in excitatory preBötC neurons died soon after birth; surviving mice developed apneas in adulthood. Interestingly, in both preBötC and RTN neurons, the Nalcn current influences the resting membrane potential, contributes to maintenance of stable network activity, and mediates modulatory responses to the neuropeptide substance P. These findings reveal Nalcn's specific role in both rhythmic stability and responsiveness to neuropeptides within the respiratory network., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sudden unexpected death occurs in one quarter of deaths in Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). People with RTT show a variety of autonomic nervous system (ANS) abnormalities and mouse models show similar problems including QTc interval prolongation and hypothermia. To explore the role of cardiac problems in sudden death in RTT, we characterized cardiac rhythm in mice lacking Mecp2 function. Male and female mutant mice exhibited spontaneous cardiac rhythm abnormalities including bradycardic events, sinus pauses, atrioventricular block, premature ventricular contractions, non-sustained ventricular arrhythmias, and increased heart rate variability. Death was associated with spontaneous cardiac arrhythmias and complete conduction block. Atropine treatment reduced cardiac arrhythmias in mutant mice, implicating overactive parasympathetic tone. To explore the role of MeCP2 within the parasympathetic neurons, we selectively removed MeCP2 function from cholinergic neurons (MeCP2 ChAT KO), which recapitulated the cardiac rhythm abnormalities, hypothermia, and early death seen in RTT male mice. Conversely, restoring MeCP2 only in cholinergic neurons rescued these phenotypes. Thus, MeCP2 in cholinergic neurons is necessary and sufficient for autonomic cardiac control, thermoregulation, and survival, and targeting the overactive parasympathetic system may be a useful therapeutic strategy to prevent sudden unexpected death in RTT.

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., Competing Interests: The authors have declared that no competing interests exist.

Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a 'prototypical' neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures., (© The Author 2016. Published by Oxford University Press.)

Unlabelled: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings from in vitro brainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration., Significance Statement: Breathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations in the function of MeCP2, the protein encoded by the gene mutated in Rett syndrome, within the hindbrain are critical for control of normal breathing. Here we show that MeCP2 function plays distinct roles in specific brainstem regions in the genesis of various aspects of abnormal breathing. This provides insight into the pathogenesis of these breathing abnormalities in Rett syndrome, which could be used to target treatments to improve these symptoms. Furthermore, it provides further knowledge about the fundamental neural circuits that control breathing., (Copyright © 2016 the authors 0270-6474/16/365572-15$15.00/0.)

Unlabelled: 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-μm and 5- to 1-μm fractions, 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., Importance: By comparing levels of particle-associated and free-living bacterial diversity at a coastal location over the course of 14 months, we show that bacteria associated with particles are generally more diverse and appear to be less responsive to commonly measured environmental variables than free-living bacteria. These diverse and highly variable particle-associated communities are likely driven by differences in particle substrates both within the water column at a single time point and due to seasonal changes over the course of the year., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Introduction: Pneumatosis intestinalis (PI) and hepatic portal venous gas (HPVG) are typically associated and are likely to represent a spectrum of the same disease. The causes of both entities range from benign to life-threatening conditions. Ischaemic causes are known to be fatal without emergency surgical intervention., Presentation of Case: In this case a 93year old male experienced acute abdominal pain radiating to his back, with nausea and vomiting and a 2-week history of altered bowel habit. Examination revealed abdominal tenderness and distension. He had deranged white cell count (WCC) and renal function. Computed tomography (CT) revealed PI with associated HPVG. The cause was due to ischaemic pathology. The patient was managed conservatively with antibiotics and was discharged 7days later with resolution of his abdominal pain and WCC., Discussion: The pathogenesis of HPVG secondary to PI is poorly understood but usually indicates intestinal ischaemia, thought to carry a mortality of around 75%. HPVG in the older patient usually necessitates emergency surgery however this is not always in the patient's best interest., Conclusion: There are few reported cases of patient survival following conservative management of PI and HPVG secondary to ischaemic pathology. This case demonstrates the possibility of managing this condition without aggressive surgical intervention especially when surgery would likely result in mortality due to frailty and morbidity. Further work is required to identify suitable patients., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microbes numerically dominate aquatic ecosystems and play key roles in the biogeochemistry and the health of these environments. Due to their short generations times and high diversity, microbial communities are among the first responders to environmental changes, including natural and anthropogenic disturbances such as storms, pollutant releases, and upwelling. These disturbances affect members of the microbial communities both directly and indirectly through interactions with impacted community members. Thus, interactions can influence disturbance propagation through the microbial community by either expanding the range of organisms affected or buffering the influence of disturbance. For example, interactions may expand the number of disturbance-affected taxa by favoring a competitor or buffer the impacts of disturbance when a potentially disturbance-responsive clade's growth is limited by an essential microbial partner. Here, we discuss the potential to use inferred ecological association networks to examine how disturbances propagate through microbial communities focusing on a case study of a coastal community's response to a storm. This approach will offer greater insight into how disturbances can produce community-wide impacts on aquatic environments following transient changes in environmental parameters.

Time series studies have shown that some bacterial taxa occur only at specific times of the year while others are ubiquitous in spite of seasonal shifts in environmental variables. Here, we ask if these ubiquitous clades are generalists that grow over a wide range of environmental conditions, or clusters of strain-level environmental specialists. To answer this question, vibrio strains isolated at a coastal time series were phylogenetically and physiologically characterized revealing three dominant strategies within the vibrio: mesophiles, psychrophiles and apparently generalist broad thermal range clades. Thermal performance curves from laboratory growth rate experiments help explain field observations of relative abundances: the mesophilic clade grows optimally at temperatures 16°C higher than the psychrophilic clade. Strains in the broad thermal range clade all have similar optimal growth temperatures but also exhibit temperature-related tradeoffs with faster growth rates for warm temperature strains and broader growth ranges for strains from cool temperatures. Moreover, the mechanisms of thermal adaptation apparently differ based on evolutionary time scales: shifts in the temperature of maximal growth occur between deeply branching clades but thermal performance curve shape changes on shorter time scales. Thus, apparently ubiquitous clades are likely not generalists, but contain subclusters with distinct environmental preferences., (© 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.)

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT., (© 2015. Published by The Company of Biologists Ltd.)