Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Anthropogenic Impacts on the Corner Rise Seamounts, North-West Atlantic Ocean

Here we report the first direct underwater observations of extensive human-caused impacts on two remote seamounts in the Corner Rise complex (north-western Atlantic). This note documents evidence of anthropogenic damage on the summits of Kukenthal peak (on Corner Seamount) and Yakutat Scamount, likely resulting from a limited Russian fishery from the mid- 1970s to the mid-1990s, highlighting how bottom trawling can have long-term detrimental effects oil deep-water benthic fauna.

Social Networking Obliterates Etiquette: Thumbs Drum in Rise of Multitasking Rudeness

This pilot study investigates selected etiquette issues that appear to have arisen with the prevalence of hand-held electronic communications. Researchers surveyed college undergraduates, graduates, and faculty about the appropriateness of multitasking when others are present, whether they thank people with a hand-written note, by telephone, or by email, and the appropriateness of their preferred means of saying thank you. This study raises questions about etiquette issues when using electronic communications.

Where Can Sea Level Rise?

There are some places along Connecticut's coast where marshes have a place to migrate as sea level rises.

The Rise and Fall of the Doctor-Patient Relationship

This talk will outline the history of the doctor-patient relationship in the West. It will touch briefly on medicine in Greek and Roman antiquity, using key texts from Hippocrates and Galen. It will also sketch the changing balance of the religious and the secular in medieval medicine. Finally, it will outline the rise of the modern personal doctor-patient relationship in the 18th century and analyze the chronic dissatisfaction that settled over relations between doctors and patients in the last quarter of the 20th century.

Modulation of high voltage -activated calcium channels by phosphorylation

High voltage-activated (HVA) calcium channels from rat brain and rabbit heart are expressed in Xenopus laevis oocytes and their modulation by protein kinases studied. A subtype of the HVA calcium current expressed by rat brain RNA is potentiated by the phospholipid- and calcium-dependent protein kinase (PKC). The calcium channel clone $\alpha\sb{\rm1C}$ from rabbit heart is modulated by the cAMP-dependent protein kinase (PKA), and another factor present in the cytoplasm.^ The HVA calcium channels from rat brain do not belong to the L-type subclass since they are insensensitive to dihydropyridine (DHP) agonists and antagonists. The expressed currents do contain a N-type fraction which is identified by inactivation at depolarized potentials, and a P-type fraction as defined by blockade by the venom of the funnel web spider Agelenopsis Aperta. A non N-type fraction of this current is potentiated, by using phorbol esters to activate PKC. This residual fraction of current resembles the newly described Q-type channel from cerebellar granule cells in its biophysical properties, and potentiation by activation of PKC.^ The $\alpha\sb{\rm1C}$ clone from rabbit heart is expressed in oocytes and single-channel currents are measured using the cell-attached and cell-excised patch clamp technique. The single-channel current runs down within two minutes after patch excision into normal saline bath solution. The catalytic subunit of PKA + MgATP is capable of reversing this rundown for over 15 minutes. There also appears to be an additional factor present in the cytoplasm necessary for channel activity as revealed in experiments where PKA failed to prevent rundown.^ These data are important in that these types of channels are involved in synaptic transmission at many different types of synapses. The mammalian synapse is not accessible for these types of studies, however, the oocyte expression system allows access to HVA calcium channels for the study of their modulation by phosphorylation. ^

Calcium-dependent mechanisms and long-term potentiation: Role of NMDA receptors, voltage -dependent calcium channels and persistent protein kinase activity

Long-term potentiation (LTP) is a rapidly induced and long lasting increase in synaptic strength and is the leading cellular model for learning and memory in the mammalian brain. LTP was first identified in the hippocampus, a structure implicated in memory formation. LTP induction is dependent on postsynaptic Ca2+ increases mediated by N-methyl-D-aspartate (NMDA) receptors. Activation of other postsynaptic routes of Ca2+ entry, such as voltage-dependent Ca2+ channels (VDCCs) have subsequently been shown to induce a long-lasting increase in synaptic strength. However, it is unknown if VDCC-induced LTP utilized similar cellular mechanisms as the classical NMDA receptor-dependent LTP and if these two forms of LTP display similar properties. This dissertation determines the similarities and differences in VDCC and NMDA receptor-dependent LTP in area CA1 of hippocampal slices and demonstrates that VDCCs and NMDA receptors activate similar cellular mechanisms, such as protein kinases, to induce LTP. However, VDCC and NMDA receptor activated LTP induction mechanisms are compartmentalized in the postsynaptic neuron, such that they do not interact. Consistent with activation properties of NMDA receptors and VDCCs, NMDA receptor and VDCC-dependent LTP have different induction properties. In contrast to NMDA-dependent LTP, VDCC-induced potentiation does not require evoked presynaptic stimulation or display input specificity. These results indicate that there are two different routes of postsynaptic Ca2+ which can induce LTP and the compartmentation of VDCCs and NMDA receptors and/or their resulting Ca2+ increases may account for the distinction between these LTP induction mechanisms.^ One of the molecular targets for postsynaptic Ca2+ that is required for the induction of LTP is protein kinases. Evidence for the role of protein kinase activity in LTP expression is either correlational or controversial. We have utilized a broad range and potent inhibitors of protein kinases to systematically examine the temporal requirement for protein kinases in the induction and expression of LTP. Our results indicate that there is a critical period of persistent protein kinase activity required for LTP induction activated by tetanic stimulation and extending until 20 min after HFS. In addition, our results suggest that protein kinase activity during and immediately after HFS is not sufficient for LTP induction. These results provide evidence for persistent and/or Ca2+ independent protein kinase activity involvement in LTP induction. ^

Benthic foraminiferal stable isotope record from ODP Site 138-849 on the East Pacific Rise

Benthic foraminifer and delta13C data from Site 849, on the west flank of the East Pacific Rise (0°11 'N, 110°31'W; 3851 m), give relatively continuous records of deep Pacific Ocean stable isotope variations between 0 and 5 Ma. The mean sample spacing is 4 k.y. Most analyses are from Cibicides wuellerstorfi, but isotopic offsets relative to Uvigerina peregrina appear roughly constant. Because of its location west of the East Pacific Rise, Site 849 yields a suitable record of mean Pacific Ocean delta13C, which approximates a global oceanic signal. The ~100-k.y.-period climate cycle, which is prevalent in delta18O does not dominate the long-term delta13C record. For delta13C, variations in the ~400- and 41-k.y. periods are more important. Phase lags of delta13C relative to ice volume in the 41- and 23-k.y. bands are consistent with delta13C as a measure of organic biomass. A model-calculated exponential response time of 1-2 k.y. is appropriate for carbon stored in soils and shallow sediments responding to glacial-interglacial climate change. Oceanic delta13C leads ice volume slightly in the 100-k.y. band, and this suggests another process such as changes in continental weathering to modulate mean river delta13C at long periods. The delta13C record from Site 849 diverges from that of Site 677 in the Panama Basin mostly because of decay of 13C-depleted organic carbon in the relatively isolated Panama Basin. North Atlantic to Pacific delta13C differences calculated using published data from Sites 607 and 849 reveal variations in Pliocene deep water within the range of those of the late Quaternary. Maximum delta13C contrast between these sites, which presumably reflects maximum influx of high-delta13C northern source water into the deep North Atlantic Ocean, occurred between 1.3 and 2.1 Ma, well after the initiation of Northern Hemisphere glaciation. Export of high-delta13C North Atlantic Deep Water from the Atlantic to the circumpolar Antarctic, as recorded by published delta13C data from Subantarctic Site 704, appears unrelated to the North Atlantic-Pacific delta13C contrast. To account for this observation, we suggest that deep-water formation in the North Atlantic reflects northern source characteristics, whereas export of this water into the circumpolar Antarctic reflects Southern Hemisphere wind forcing. Neither process appears directly linked to ice-volume variations.

Sedimentology of cores from the continental rise west of the Antarctic Peninsula

The continental rise west of the Antarctic Peninsula includes a number of large sediment mounds interpreted as contourite drifts. Cores from six sediment drifts spanning some 650 km of the margin and 48 of latitude have been dated using chemical and isotopic tracers of palaeoproductivity and diatom biostratigraphy. Interglacial sedimentation rates range from 1.1 to 4.3 cm/ka. Glacial sedimentation rates range from 1.8 to 13.5 cm/ka, and decrease from proximal to distal sites on each drift. Late Quaternary sedimentation was cyclic, with brown, biogenic, burrowed mud containing ice-rafted debris (IRD) in interglacials and grey, barren, laminated mud in glacials. Foraminiferal intervals occur in interglacial stages 5 and 7 but not in the Holocene. Processes of terrigenous sediment supply during glacial stages differed; meltwater plumes were more important in stages 2-4, turbidity currents and ice-rafting in stage 6. The terrigenous component shows compositional changes along the margin, more marked in glacials. The major oxides Al2O3 and K2O are higher in the southwest, and CaO and TiO2 higher in the northeast. There is more smectite among the clay minerals in the northeast. Magnetic susceptibility varies along and between drifts. These changes reflect source variations along the margin. Interglacial sediments show less clear trends, and their IRD was derived from a wider area. Downslope processes were dominant in glacials, but alongslope processes may have attained equal importance in interglacials. The area contrasts with the East Antarctic continental slope in the SE Weddell Sea, where ice-rafting is the dominant process and where interglacial sedimentation rates are much higher than glacial. The differences in glacial setting and margin physiography can account for these contrasts.

Strike-slip faults mediate the rise of crustal-derived fluids and mud volcanism in the deep sea

We report on newly discovered mud volcanoes located at about 4500 m water depth 90 km west of the deformation front of the accretionary wedge of the Gulf of Cadiz, and thus outside of their typical geotectonic environment. Seismic data suggest that fluid flow is mediated by a >400-km-long strike-slip fault marking the transcurrent plate boundary between Africa and Eurasia. Geochemical data (Cl, B, Sr, 87Sr/86Sr, Delta18O, DeltaD) reveal that fluids originate in oceanic crust older than 140 Ma. On their rise to the surface, these fluids receive strong geochemical signals from recrystallization of Upper Jurassic carbonates and clay-mineral dehydration in younger terrigeneous units. At present, reports of mud volcanoes in similar deep-sea settings are rare, but given that the large area of transform-type plate boundaries has been barely investigated, such pathways of fluid discharge may provide an important, yet unappreciated link between the deeply buried oceanic crust and the deep ocean.

Mass accumulation rates, age, sedimentation rate and bulk density at the East Pacific Rise

The rate at which hydrothermal precipitates accumulate, as measured by the accumulation rate of manganese, can be used to identify periods of anomalous hydrothermal activity in the past. From a preliminary study of Sites 597 and 598, four periods prior to 6 Ma of anomalously high hydrothermal activity have been identified: 8.5 to 10.5 Ma, 12 to 16 Ma, 17 to 18 Ma, and 23-to-27 Ma. The 18-Ma anomaly is the largest and is associated with the jump in spreading from the fossil Mendoza Ridge to the East Pacific Rise, whereas the 23-to-27-Ma anomaly is correlated with the birth of the Galapagos Spreading Center and resultant ridge reorganization. The 12-to-16-Ma and 8.5-to-10.5-Ma anomalies are correlated with periods of anomalously high volcanism around the rim of the Pacific Basin and may be related to other periods of ridge reorganization along the East Pacific Rise. There is no apparent correlation between periods of fast spreading at 19°S and periods of high hydrothermal activity. We thus suggest that periods when hydrothermal activity and crustal alteration at mid-ocean ridges are the most pronounced may be periods of large-scale ridge reorganization.