Geographic hierarchical population genetic structuring in British European whitefish (Coregonus lavaretus) and its implications for conservation

The European whitefish Coregonus lavaretus complex represents one of the most diverse radiations within salmonids, with extreme morphological and genetic differentiation across its range. Such variation has led to the assignment of many populations to separate species. In Great Britain, the seven native populations of C. lavaretus (two in Scotland, four in England, one in Wales) were previously classified into three species, and recent taxonomic revision resurrected the previous nomenclature. Here we used a dataset of 15 microsatellites to: (1) investigate the genetic diversity of British populations, (2) assess the level of population structure and the relationships between British populations. Genetic diversity was highest in Welsh (HO = 0.50, AR = 5.29), intermediate in English (HO = 0.41–0.50, AR = 2.83–3.88), and lowest in Scottish populations (HO = 0.28–0.35, AR = 2.56–3.04). Population structure analyses indicated high genetic differentiation (global FST = 0.388) between all populations but for the two Scottish populations (FST = 0.063) and two English populations (FST = 0.038). Principal component analysis and molecular ANOVA revealed separation between Scottish, English, and Welsh populations, with the Scottish populations being the most diverged. We argue that the data presented here are not sufficient to support a separation of the British European whitefish populations into three separate species, but support the delineation of different ESUs for these populations

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Increased Inducible Nitric Oxide Synthase Expression in Organs Is Associated with a Higher Severity of H5N1 Influenza Virus Infection

BACKGROUND: The mechanisms of disease severity caused by H5N1 influenza virus infection remain somewhat unclear. Studies have indicated that a high viral load and an associated hyper inflammatory immune response are influential during the onset of infection. This dysregulated inflammatory response with increased levels of free radicals, such as nitric oxide (NO), appears likely to contribute to disease severity. However, enzymes of the nitric oxide synthase (NOS) family such as the inducible form of NOS (iNOS) generate NO, which serves as a potent anti-viral molecule to combat infection in combination with acute phase proteins and cytokines. Nevertheless, excessive production of iNOS and subsequent high levels of NO during H5N1 infection may have negative effects, acting with other damaging oxidants to promote excessive inflammation or induce apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: There are dramatic differences in the severity of disease between chickens and ducks following H5N1 influenza infection. Chickens show a high level of mortality and associated pathology, whilst ducks show relatively minor symptoms. It is not clear how this varying pathogenicty comes about, although it has been suggested that an overactive inflammatory immune response to infection in the chicken, compared to the duck response, may be to blame for the disparity in observed pathology. In this study, we identify and investigate iNOS gene expression in ducks and chickens during H5N1 influenza infection. Infected chickens show a marked increase in iNOS expression in a wide range of organs. Contrastingly, infected duck tissues have lower levels of tissue related iNOS expression. CONCLUSIONS/SIGNIFICANCE: The differences in iNOS expression levels observed between chickens and ducks during H5N1 avian influenza infection may be important in the inflammatory response that contributes to the pathology. Understanding the regulation of iNOS expression and its role during H5N1 influenza infection may provide insights for the development of new therapeutic strategies in the treatment of avian influenza infection

Multisite Phosphorylation Provides an Effective and Flexible Mechanism for Switch-Like Protein Degradation

Phosphorylation-triggered degradation is a common strategy for elimination of regulatory proteins in many important cell signaling processes. Interesting examples include cyclin-dependent kinase inhibitors such as p27 in human and Sic1 in yeast, which play crucial roles during the G1/S transition in the cell cycle. In this work, we have modeled and analyzed the dynamics of multisite-phosphorylation-triggered protein degradation systematically. Inspired by experimental observations on the Sic1 protein and a previous intriguing theoretical conjecture, we develop a model to examine in detail the degradation dynamics of a protein featuring multiple phosphorylation sites and a threshold site number for elimination in response to a kinase signal. Our model explains the role of multiple phosphorylation sites, compared to a single site, in the regulation of protein degradation. A single-site protein cannot convert a graded input of kinase increase to much sharper output, whereas multisite phosphorylation is capable of generating a highly switch-like temporal profile of the substrate protein with two characteristics: a temporal threshold and rapid decrease beyond the threshold. We introduce a measure termed temporal response coefficient to quantify the extent to which a response in the time domain is switch-like and further investigate how this property is determined by various factors including the kinase input, the total number of sites, the threshold site number for elimination, the order of phosphorylation, the kinetic parameters, and site preference. Some interesting and experimentally verifiable predictions include that the non-degradable fraction of the substrate protein exhibits a more switch-like temporal profile; a sequential system is more switch-like, while a random system has the advantage of increased robustness; all the parameters, including the total number of sites, the threshold site number for elimination and the kinetic parameters synergistically determine the exact extent to which the degradation profile is switch-like. Our results suggest design principles for protein degradation switches which might be a widespread mechanism for precise regulation of cellular processes such as cell cycle progression

Encoding of Interval Time within the Rat Hindlimb Sensorimotor Cortex: the Effects of Temporal Context, Brain-Machine Interface Control, and the Impact of Spinal Cord Injury

Temporal intervals, on the order of seconds to minutes, have been shown to be encoded by neurons in several brain regions including the forelimb representation in primary motor cortex (Lebedev et al. 2008; Roux et al. 2003). Many studies have demonstrated encoding of temporal intervals by single neurons through a `scaling' of the average rate of change of the firing rate of the cell proportional to the length of an interval (slope scaled). Essentially, for two given intervals, a neuron will reach a conserved peak discharge at a rate scaled to the length of the interval. This information could prove useful in decoding temporal sequences of movements in a brain-machine interface (BMI) paradigm, however it is unclear if this type of activity occurs in the absence of timed movements and after spinal cord injury. The long term goal motivating this doctoral thesis is to be able to decode temporal intervals on a single trial basis for use in a brain-machine interface that controls the temporal sequence of hindlimb movements after spinal cord injury. The goal of this project is to understand the encoding of temporal intervals on a single trial basis (1) during hindlimb movements, (2) during a BMI paradigm in the absence of movement and (3) after a complete spinal transection. The project's central hypothesis is that the temporal context which defines the behavioral relevancy of the interval is necessary for temporal scaling but temporal scaling is not dependent on the part of body used in the task (AIM I), whether any part of the body moves in response to encoding (AIM II) or whether the brain is still connected to that part of the body (AIM III). This central hypothesis is addressed by three Specific Aims: Specific AIM I: Identify the role of temporal context (i.e. relevancy of press interval) in the encoding of temporal intervals in the hindlimb motor cortex (HLSMC) when rats plan and perform a skilled hindlimb movement. Hypothesis: Despite the fact that animals can make presses of varying intervals under different temporal contexts, neurons within HLSMC will encode interval time through patterns of temporally scaled activity only when the temporal interval is behaviorally relevant (i.e. the animal is rewarded for a specific interval). AIM Ia: Determine if neurons within the infragranular layers of rat hindlimb sensorimotor cortex (HLSMC) utilize temporal scaling to encode for temporal intervals AIM Ib: Determine if the temporal scaling is required for producing presses of varying intervals. Specific AIM II: To investigate the effects of a brain-machine interface on the encoding of temporal intervals Hypothesis: Neurons will continue to use temporal scaling to encode for abstracted temporal intervals, despite no longer explicitly timing behavioral movements. Specific AIM III: Identify the impact of a complete spinal cord transection on the encoding of temporal intervals. Hypothesis: Despite complete disconnect of HLSMC circuitry from the periphery, HLSMC neurons will continue to encode abstracted temporal intervals through temporally scaled patterns of activity.Ph.D., Biomedical Engineering -- Drexel University, 201

Encoding of temporal intervals in the rat hindlimb sensorimotor cortex

The gradual buildup of neural activity over experimentally imposed delay periods, termed climbing activity, is well documented and is a potential mechanism by which interval time is encoded by distributed cortico-thalamico-striatal networks in the brain. Additionally, when multiple delay periods are incorporated, this activity has been shown to scale its rate of climbing proportional to the delay period. However, it remains unclear whether these patterns of activity occur within areas of motor cortex dedicated to hindlimb movement. Moreover, the effects of behavioral training (e.g. motor tasks) under different reward conditions but with similar behavioral output are not well addressed. To address this, we recorded activity from the hindlimb sensorimotor cortex (HLSMC) of two groups of rats performing a skilled hindlimb press task. In one group, rats were trained only to a make a valid press within a finite window after cue presentation for reward (non-interval trained, nIT; n=5), while rats in the second group were given duration-specific cues in which they had to make presses of either short or long duration to receive reward (interval trained, IT; n=6). Using PETH analyses, we show that cells recorded from both groups showed climbing activity during the task in similar proportions (35% IT and 47% nIT), however only climbing activity from IT rats was temporally scaled to press duration. Furthermore, using single trial decoding techniques (Wiener filter), we show that press duration can be inferred using climbing activity from IT animals (R=0.61) significantly better than nIT animals (R=0.507, p<0.01), suggesting IT animals encode press duration through temporally scaled climbing activity. Thus, if temporal intervals are behaviorally relevant then the activity of climbing neurons is temporally scaled to encode the passage of time