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Background Hereditary ataxias with similar phenotypes were reported in the Smooth-Haired Fox Terrier, the Jack Russell Terrier and the Parson Russell Terrier. However, segregation analyses showed differing inheritance modes in these breeds. Recently, molecular genetic studies on the Russell group of terriers found independent mutations in KCNJ10 and CAPN1 , each associated with a specific clinical subtype of inherited ataxia. The aim of this study was to clarify whether or not Smooth-Haired Fox Terriers with hereditary ataxia and dogs of other related breeds harbor either of the same mutations. A sub goal was to update the results of KCNJ10 genotyping in Russell group terriers. Findings Three Smooth-Haired Fox Terriers with hereditary ataxia and two Toy Fox Terriers with a similar phenotype were all homozygous for the KCNJ10 mutation. The same mutation was also found in a heterozygous state in clinically unaffected Tenterfield Terriers (n = 5) and, in agreement with previous studies, in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers. Conclusions A KCNJ10 mutation, previously associated with an autosomal recessive spinocerebellar ataxia in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers segregates in at least three more breeds descended from British hunting terriers. Ataxic members of two of these breeds, the Smooth-Haired Fox Terrier and the Toy Fox Terrier, were homozygous for the mutation, strengthening the likelihood that this genetic defect is indeed the causative mutation for the disease known as “hereditary ataxia” in Fox Terriers and “spinocerebellar ataxia with myokymia, seizures or both” in the Russell group of terriers.

We here describe the identification of causal mutations for three different canine diseases in orthologs of genes with orthologous human diseases. We used Next Generation Sequencing in order to generate Whole Genome Sequences for 145 dogs from 69 different breeds with various inherited canine diseases, most of which were suspected to be inherited recessively. We here report the discovery of the causes of; Spinocerebellar Ataxia with Myokymia and Seizures in Russell-Group Terriers, Neuronal Ceroid Lipofuscinosis in Golden Retrievers and Dilated Cardiomyopathy in Standard Schnauzers. While all three were identified via whole genome sequencing, different methodologies and techniques were used to discover and validate the findings. Our objective was to identify the mutation causing the spinocerebellar ataxia associated with myokymia and/or seizures and distinguish the phenotype from other ataxias seen in Jack Russell Terriers and related Russell group terriers (RGTs). We collected DNA samples from 16 RGTs with signs of spinocerebellar ataxia beginning from 2-to-12 months of age, 640 control RGTs, and 383 dogs from 144 other breeds along with the medical records of affected dogs in order to elucidate the genetic cause of this disease. Whole-genome sequencing was performed on one RGT with ataxia and myokymia. Unique, homozygous variants were identified in this dog by comparing its sequence to whole-genome sequences from 81 other canids. We found a missense mutation in the gene coding for the inward rectifying potassium channel Kir4.1 (KCNJ10:c.627C>G) that was significantly associated with the disease. Dogs homozygous for the mutant allele all showed spinocerebellar ataxia with varying combinations of myokymia, seizures and other signs. The identification of a mutation in KCNJ10 in dogs with spinocerebellar ataxia with myokymia and/or seizures (SAMS) clarifies the multiple forms of ataxia seen in these breeds and provides a DNA test to identify carriers. Understanding the role the Kir4.1 channel plays in extracellular potassium buffering by astrocytes could shed light on other conditions characterized by excessive neuronal membrane excitability such as other forms of ataxia, epilepsy and myokymia. We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletionallele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever. To identify the molecular genetic cause of Standard Schnauzer dilated cardiomyopathy (DCM), DNA from an affected dog was used to generate a whole genome sequence with 31-fold average coverage. Among the sequence variants in this whole genome sequence was a 22-bp deletion and frameshift in RBM20, the canine ortholog of a gene previously associated with human DCM. The RBM20 deletion allele was homozygous in the whole genome sequence of the affected Schnauzer, but absent from 101 whole genome sequences of normal canids or dogs with other diseases. An additional 753 Standard Schnauzers, including 21 with DCM, were genotyped for the RBM20 deletion. In this cohort, all 20 of the deletionallele homozygotes had DCM, only one of the 183 heterozygous dogs had DCM, and all of the reference-allele homozygotes were DCM free. RBM20 deficiency is known to alter exon-splicing patterns and produced aberrant titin isoforms in a rat model and in human DCM patients. To determine if the Standard Schnauzers with DCM had similar exon-splicing abnormalities, RNA prepared from their left ventricular walls was compared by RT-PCR to similarly prepared RNA from normal adult dogs. Titin transcripts with extensive exon skipping were detected in the normal RNA but not in the RNA from the dogs with DCM. Conversely, titin transcripts with retained exons were detected in the RNA from dogs with DCM but not in the normal-dog RNA. Thus, we have identified a canine model for human RBM20-associated DCM. (Abstract shortened by ProQuest.)

Leptokurtic distributions of movement distances observed in field‐release studies, in which some individuals move long distances while most remain at or near their release point, are a common feature of mobile animals. However, because leptokurtosis is predicted to be transient in homogeneous populations, persistent leptokurtosis suggests a population heterogeneity. We found evidence for a heterogeneity that may generate persistent leptokurtosis. We tested individuals of the Trinidad killifishRivulus hartiifor boldness in a tank test and released them back into their native stream. Boldness in the tank test predicted distance moved in the field releases, even after effects of size and sex were removed. Further, data from a 19‐mo mark‐recapture study showed that individual growth correlated positively with movement in a predator‐threatened river zone where theRivuluspopulation is spatially fragmented and dispersal is likely to be a hazardous activity. In contrast, no such correlation existed in a predator‐absent zone where the population is unfragmented. These results show that a behavioral trait, not discernible from body size or sex, contributes to dispersal and that a component of fitness of surviving “dispersers” is elevated above that of “stayers,” a fundamental assumption or prediction of many models of the evolution of dispersal through hazardous habitat.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. The epithelial-to-mesenchymal transition (EMT) is a key contributor in the metastatic process. We previously showed the pan-deacetylase inhibitor LBH589 induces CDH1 expression in TNBC cells, suggesting regulation of EMT. The purpose of this study was to examine the effects of LBH589 on the metastatic qualities of TNBC cells and the role of EMT in this process. A panel of breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549), drugged with LBH589, was examined for changes in cell morphology, migration, and invasion in vitro. The effect on in vivo metastasis was examined using immunofluorescent staining of lung sections. EMT gene expression profiling was used to determine LBH589-induced changes in TNBC cells. ZEB overexpression studies were conducted to validate requirement of ZEB in LBH589-mediated proliferation and tumorigenesis. Our results indicate a reversal of EMT by LBH589 as demonstrated by altered morphology and altered gene expression in TNBC. LBH589 was shown to be a more potent inhibitor of EMT than other HDAC inhibitors, SAHA and TMP269. Additionally, we found that LBH589 inhibits metastasis of MDA-MB-231 cells in vivo. These effects of LBH589 were mediated in part by inhibition of ZEB , as overexpression of ZEB1 or ZEB2 mitigated the effects of LBH589 on MDA-MB-231 EMT-associated gene expression, migration, invasion, CDH1 expression, and tumorigenesis. These data indicate therapeutic potential of LBH589 in targeting EMT and metastasis of TNBC.

Background Tobacco smoking remains the leading preventable cause of death in the US. A hospital admission provides smokers with a unique opportunity to stop smoking because it requires temporary tobacco abstinence while illness may enhance motivation to quit. Hospital interventions must continue post-discharge to increase tobacco abstinence long-term, but how best to accomplish this remains unclear. Building on two previous randomized controlled trials, each of which tested smoking cessation interventions that began in hospital and continued after discharge, this trial compares two interventions that provide sustained smoking cessation treatment after hospital discharge with the goal of improving long-term smoking cessation rates among hospitalized smokers. Methods/design Helping HAND 4 is a three-site randomized controlled trial that compares the effectiveness of two active interventions for producing validated past 7-day tobacco abstinence 6 months after hospital discharge. Smokers who are admitted to three hospitals receive a standard in-hospital smoking intervention, and those who plan to quit smoking after discharge are recruited and randomly assigned to two interventions that begin at discharge, Personalized Tobacco Care Management (PTCM) or Quitline eReferral. Each lasts 3 months. At discharge, PTCM provides 8 weeks of free nicotine replacement (NRT; a participant’s choice of patch, gum, lozenge, or a combination) and then proactive smoking cessation support using an automated communication platform and live contact with a tobacco treatment specialist who is based in the health care system. In the eReferral condition, a direct referral is made from the hospital electronic health record to a community-based resource, the state’s telephone quitline. The quitline provides up to 8 weeks of free NRT and offers behavioral support via a series of phone calls from a trained coach. Outcomes are assessed at 1, 3, and 6 months after discharge. The study hypothesis is that PTCM will produce higher quit rates than eReferral. Discussion Helping HAND 4 is a pragmatic trial that aims to evaluate interventions in real-world conditions. This project will give hospital systems critical evidence-based tools for meeting National Hospital Quality Measures for tobacco treatment and maximizing their ability to improve cessation rates and overall health for the millions of smokers hospitalized annually in the US. Trial registration Prospectively registered prior to start of enrollment at Clinicaltrials.gov, NCT03603496 (July 27, 2018). https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S00084MJ&selectaction=Edit&uid=U00002G7&ts=2&cx=ff0oxn

Movement by stream fish is known to be strongly influenced by abiotic factors such as floods and temperature, but roles of biotic factors, such as predation threat, and interactions of abiotic and biotic factors are less clear. Predation threat is known to fragment populations of killifish, Rivulus hartii, in Trinidad rivers by rendering habitat inhospitable. We asked whether such spatial fragmentation was accompanied by reduced movement by fish in the predator-occupied zone of a river, relative to a zone free of the strong piscivore, Hoplias malabaricus, that causes the fragmentation. We used a 19-mo marking study in a river with a predator barrier, field experiments in the river, and mesocosms to evaluate four hypotheses: (1) the predator reduces prey movement in the river; (2) for the special case of prey leaving refugia, the predator increases movement; (3) movement positively correlates with water level in the predator's presence; and (4) complex physical structure in hazardous habitat promotes prey movement. We marked 1467 Rivulus in the natural study areas and had 1015 recaptures. Contrary to Hypothesis 1 but in support of Hypothesis 2, prey showed greater movement along the river in the presence of the predator, regardless of whether the fish resided in a refuge at its previous capture. An experiment with introduced fish confirmed the findings that movement was elevated in the predator's presence. Effects of an abiotic factor (water level, Hypothesis 3) and a phenotypic trait (body size) depended upon whether the predator was present: movement was independent of water level and body size in the absence of the predator, but positively related to both variables in the predator's presence. Emigration from the river to tributaries was also independent of body size in the predator's absence, but positively size-dependent in the predator's presence. Complex physical structure (Hypothesis 4), in the form of cobble added to experimental pools, enhanced the transit of fish through hazardous pools. This study shows that spatial fragmentation does not necessarily imply that movement between fragments will be impeded (dynamical fragmentation). Rather, it is possible that movement among spatial fragments may be enhanced by the same factor, predation threat, that produced the spatial fragmentation in the first place. Because of the context-dependent effects of an abiotic factor (water level) and a phenotypic variable (body size) on movement, the study also emphasizes the need to clarify the exact role of predation as an agent promoting or retarding movement, and it suggests a need for incorporating such parameters into models of movement and metapopulation dynamics.

An amendment to this paper has been published and can be accessed via the original article.

We asked whether invasions by a predator in a patchy environment altered only the death rate of the prey, or whether there were also nonlethal effects, i.e., alternations in three other vital rates: net emigration, reproduction, and individual growth rates. Field studies documented the patch use of the guppy Poecilia reticulata and the killifish Rivulus hartii in pools of a second—order forest stream in Trinidad, before and after invasion by the piscivorous fish Hoplias malabaricus. Experiments revealed that the predator altered the within—pool use of space by Poecilia and Rivulus, and caused significant emigration of the prey from pools in which it was present. Further, intimidation by the predator in an experimental stream suppressed total egg production in Rivulus by °50%, and created spatial patchiness (more eggs laid in safer pools) and temporal patchiness (pulses of eggs) in egg production. The presence of the predator also induced shifts to shallow riffle areas and significantly reduced the growth rate of adult but not juvenile Rivulus. In contrast to the familiar paradigm that increased predation rates results in compensatory increases in per capita reproductive rates and/or growth rates as the population is thinned, we found that the threat of predation suppressed rates of reproduction and growth in predator—occupied patches.

The nonlethal effects of predation threat can be pervasive but are also easily overlooked. We investigated effects of predation threat on feeding by guppies (Poecilia reticulata), and how threat-induced temporal shifts in feeding activity affect reproductive behavior and growth. Contrary to the view of the guppy as a \"diurnal\" species, our observations revealed that guppies free from severe predation threat expand their foraging into the nocturnal period. We found such nocturnal foraging to be as profitable as diurnal foraging, and guppies under threat incurred a substantial growth penalty when predators inhibited night feeding. Denial of night feeding also decreased daytime courtship by males, facultatively duplicating a classical observation comparing courtship intensity in contrasting predator regimes, but providing a novel mechanism for the effect. Our findings support the view that evaluations of predator effects on life histories should consider potential predatorcaused alterations in size-specific energetic gain, along with the classical consideration of predator-altered mortality rates. The results of this study show that predation threat can induce a large, facultative shift in the temporal niche and vital rates of a prey species. We discuss some implications of the effect in the broader contexts of predator facilitation, evolution of life histories, and trait-dependent decisions to boost daily intake by expanded feeding times.

Animals commonly choose among habitats that differ both in foraging return and mortality hazard. However, no experimental study has attempted to predict the level of increase in resources, or the decrease in mortality hazard, which will induce a forager to shift from a safer to a more hazardous (but richer) foraging area. Here we present and test a model that specifies the choice of foraging areas (\"habitats\") that would minimize total mortality risk while allowing collection of some arbitrary net energy gain. We tested the model with juvenile creek chubs (Semotilus atromaculatus) in an experimental field stream in which the foragers could utilize a foodless refuge and choose between two foraging areas that differed in experimentally manipulated resource densities (Tubifex spp. worms in sediments) and mortality hazard (adult creek chubs). For the case tested, the model specified a simple rule: \"use the refuge plus the site with the lowest ratio of mortality rate (μ) to gross foraging rat (f),\" i.e., \"minimize μ./f.\" Independent prior measurements of mortality hazard (as a function of predator density) and gross foraging rate (as a function of resource density) allowed us to predict the resource level in the more hazardous foraging site that should induce a shift from the safer to the more hazardous site. The chubs' preferences in subsequent choice experiments agreed well with the theoretical predictions. The \"minimize μ/f\" rule (deaths per unit energy), perhaps in modified form, provides a simple alternative to the \"maximize f\" (energy per unit time) criterion that applies to long—term rate maximization when predation hazard does not differ among choices.