Echoes of a distant time: effects of historical processes on contemporary genetic patterns in Galaxias platei in Patagonia

Interpreting the genetic structure of a metapopulation as the outcome of gene flow over a variety of timescales is essential for the proper understanding of how changes in landscape affect biological connectivity. Here we contrast historical and contemporary connectivity in two metapopulations of the freshwater fish Galaxias platei in northern and southernmost Patagonia where paleolakes existed during the Holocene and Pleistocene, respectively. Contemporary gene flow was mostly high and asymmetrical in the northern system while extremely reduced in the southernmost system. Historical migration patterns were high and symmetric in the northern system and high and largely asymmetric in the southern system. Both systems showed a moderate structure with a clear pattern of isolation by distance (IBD). Effective population sizes were smaller in populations with low contemporary gene flow. An approximate Bayesian computation (ABC) approach suggests a late Holocene colonization of the lakes in the northern system and recent divergence of the populations from refugial populations from east and west of the Andes. For the southern system, the ABC approach reveals that some of the extant G. platei populations most likely derive from an ancestral population inhabiting a large Pleistocene paleolake while the rest derive from a higher‐altitude lake. Our results suggest that neither historical nor contemporary processes individually fully explain the observed structure and geneflow patterns and both are necessary for a proper understanding of the factors that affect diversity and its distribution. Our study highlights the importance of a temporal perspective on connectivity to analyse the diversity of spatially complex metapopulations.     

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer.     

Long-term evaluation of a selective retrograde coronary venous perfusion model in pigs (Sus scrofa domestica)

The lack of suitable target vessels remains a challenge for aortocoronary bypass grafting in end-stage coronary heart disease. This study aimed to investigate the arterialization of cardiac veins as an alternative myocardial revascularization strategy in an experimental long-term model in pigs. Selective retrograde perfusion of a coronary vein (aorta to coronary vein bypass, retrobypass) before ligation of the ramus interventricularis paraconalis (equivalent to the left anterior descending artery in humans) was performed in 20 German Landrace pigs (Sus scrofa domestica). Retroperfusion of the left anterior descending vein was performed in 10 pigs (RP+) but not in the other 10 (RP-), and the vena cordis magna was ligated (L+) in 5 pigs in each of these groups but left open (L-) in the remaining animals. Hemodynamic performance (for example, cardiac output) was significantly better in the group that underwent selective retroperfusion with proximal ligation of vena cordis magna (RP+L+; 4.1 L/min) compared with the other groups (RP+L-, 2.5 L/min; RP-L+, 2.2 L/min; RP-L-, 1.9 L/min). Long-term survival was significantly better in RP+L+ pigs (112±16 d) than in all other groups. Histologic follow-up studies showed significantly less necrosis in the RP+L+ group compared with all other groups. Venous retroperfusion is an effective technique to achieve long-term survival after acute occlusion of the left anterior descending artery in a pig model. In this model, proximal ligation of vena cordis magna is essential.     

Combined effects of speed and directional change on postural adjustments during gait initiation

The study of gait initiation (GI) has primarily focused on gait initiated in a forward direction, however, in everyday life, GI is often combined with a directional change. Ten young adults initiated gait with their right foot in four directions (to the left: −15°, straight ahead: 0°, to the right: 15° and 30°) at self-selected and fast gait speeds. The relationship between starting direction of GI and the lateral center of foot pressure displacement for normal (r² = 0.57) and fast gait speed (r² = 0.75) indicated that the lateral component plays an important role with regards to controlling the desired direction of gait. At the first step of the swing limb, the progression velocity of the center of mass (CM) remained slower for the 30° condition only, whereas no difference was found between directions for CM velocity perpendicular to the intended direction. These results suggest that postural adjustments are scaled to initiate gait in a predetermined direction. By the first step, the orientation of CM is toward the intended direction of gait, however, when gait is initiated in combination with a large change in direction, additional adjustments may be required to reach the intended progression velocity.     

Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors

Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.     

Photoresponse in the heterotrophic marine dinoflagellate Oxyrrhis marina

Expressed rhodopsins were detected by proteomic analysis in an investigation of potential signal receptors in the cell membrane of the marine heterotrophic dinoflagellate Oxyrrhis marina (CCMP604). We inferred these to be sensory rhodopsins, a type of G-protein-coupled receptor trans-membrane signaling molecule. Because phototactic behavior based on sensory rhodopsins has been reported in other protists, we investigated the photosensory response of O. marina. This dinoflagellate exhibited strongest positive phototaxis at low levels (2-3 μE/m(2)/s) of white light when the cells were previously light adapted and well fed. Positive phototaxis was also found for blue (450 nm), green (525 nm), and red (680 nm) wavelengths. In a further test, O. marina showed significantly greater phototaxis toward concentrated algal food illuminated by blue light to stimulate red chlorophyll-a autofluorescence in the prey, compared with using bleached algae as prey. Concentration of a cytoplasmic downstream messenger molecule, cyclic adenosine monophosphate, a component of the signaling pathway of G-protein-coupled receptor molecules, rapidly increased in O. marina cells after exposure to white light. In addition, treatment with hydroxylamine, a rhodopsin signaling inhibitor, significantly decreased their phototactic response. Our results demonstrate that a heterotrophic marine dinoflagellate can orient to light based on rhodopsins present in the outer cell membrane and may be able to use photosensory response to detect algal prey based on chlorophyll autofluorescence.     

Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations

Background

Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate.

Methodology/Principal Findings

We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls.

Conclusions/Significance

Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.     

Serotonin receptor expression in human prefrontal cortex: balancing excitation and inhibition across postnatal development

Serotonin and its receptors (HTRs) play critical roles in brain development and in the regulation of cognition, mood, and anxiety. HTRs are highly expressed in human prefrontal cortex and exert control over prefrontal excitability. The serotonin system is a key treatment target for several psychiatric disorders; however, the effectiveness of these drugs varies according to age. Despite strong evidence for developmental changes in prefrontal Htrs of rodents, the developmental regulation of HTR expression in human prefrontal cortex has not been examined. Using postmortem human prefrontal brain tissue from across postnatal life, we investigated the expression of key serotonin receptors with distinct inhibitory (HTR1A, HTR5A) and excitatory (HTR2A, HTR2C, HTR4, HTR6) effects on cortical neurons, including two receptors which appear to be expressed to a greater degree in inhibitory interneurons of cerebral cortex (HTR2C, HTR6). We found distinct developmental patterns of expression for each of these six HTRs, with profound changes in expression occurring early in postnatal development and also into adulthood. However, a collective look at these HTRs in terms of their likely neurophysiological effects and major cellular localization leads to a model that suggests developmental changes in expression of these individual HTRs may not perturb an overall balance between inhibitory and excitatory effects. Examining and understanding the healthy balance is critical to appreciate how abnormal expression of an individual HTR may create a window of vulnerability for the emergence of psychiatric illness.     

Residual Cx45 and its relationship to Cx43 in murine ventricular myocardium

Gap junction channels in ventricular myocardium are required for electrical and metabolic coupling between cardiac myocytes and for normal cardiac pump function. Although much is known about expression patterns and remodeling of cardiac connexin(Cx)43, little is known about the less abundant Cx45, which is required for embryonic development and viability, is downregulated in adult hearts, and is pathophysiologically upregulated in human end-stage heart failure. We applied quantitative immunoblotting and immunoprecipitation to native myocardial extracts, immunogold electron microscopy to cardiac tissue and membrane sections, electrophysiological recordings to whole hearts, and high-resolution tandem mass spectrometry to Cx45 fusion protein, and developed two new tools, anti-Cx45 antisera and Cre(+);Cx45 floxed mice, to facilitate characterization of Cx45 in adult mammalian hearts. We found that Cx45 represents 0.3% of total Cx protein (predominantly 200 fmol Cx43 protein/μg ventricular protein) and colocalizes with Cx43 in native ventricular gap junctions, particularly in the apex and septum. Cre(+);Cx45 floxed mice express 85% less Cx45, but do not exhibit overt electrophysiologic abnormalities. Although the basal phosphorylation status of native Cx45 remains unknown, CaMKII phosphorylates 8 Ser/Thr residues in Cx45 in vitro. Thus, although downregulation of Cx45 does not produce notable deficits in electrical conduction in adult, disease-free hearts, Cx45 is a target of the multifunctional kinase CaMKII, and the phosphorylation status of Cx45 and the role of Cx43/Cx45 heteromeric gap junction channels in both normal and diseased hearts merits further investigation.