Millennial climatic fluctuations are key to the structure of last glacial ecosystems

Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in “normal” and “hosing” experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The “hosing” experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the “normal” experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems.

Last glacial vegetation of northern Eurasia

In order to investigate the potential role of vegetation changes in megafaunal extinctions during the later part of the last glacial stage and early Holocene (42–10 ka BP), the palaeovegetation of northern Eurasia and Alaska was simulated using the LPJ-GUESS dynamic vegetation model. Palaeoclimatic driving data were derived from simulations made for 22 time slices using the Hadley Centre Unified Model. Modelled annual net primary productivity (aNPP) of a series of plant functional types (PFTs) is mapped for selected time slices and summarised for major geographical regions for all time slices. Strong canonical correlations are demonstrated between model outputs and pollen data compiled for the same period and region. Simulated aNPP values, especially for tree PFTs and for a mesophilous herb PFT, provide evidence of the structure and productivity of last glacial vegetation. The mesophilous herb PFT aNPP is higher in many areas during the glacial than at present or during the early Holocene. Glacial stage vegetation, whilst open and largely treeless in much of Europe, thus had a higher capacity to support large vertebrate herbivore populations than did early Holocene vegetation. A marked and rapid decrease in aNPP of mesophilous herbs began shortly after the Last Glacial Maximum, especially in western Eurasia. This is likely implicated in extinction of several large herbivorous mammals during the latter part of the glacial stage and the transition to the Holocene.

Inhibition of the cardiac Na+ channel Nav1.5 by carbon monoxide

Sub-lethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na+ channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na+ current observed in native tissue. Inhibition was associated with a hyperpolarizing shift in the steady-state inactivation properties of the channels and was unaffected by modification of channel gating induced by anemone toxin (rATX-II). Systematic pharmacological assessment indicated that no recognised CO-sensitive intracellular signalling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of nitric oxide (NO) formation, but NO donors did not mimic or occlude channel inhibition by CO, indicating that NO alone did not account for the actions of CO. Exposure of cells to dithiothreitol immediately before CO exposure also dramatically reduced the magnitude of current inhibition. Similarly, L-cysteine and N-ethylmaleimide significantly attenuated the inhibition caused by CO. In the presence of DTT and the NO inhibitor L-NAME, the ability of CO to inhibit Nav1.5 was almost fully prevented. Our data indicate that inhibition of peak Na+ current (which can lead to Brugada-syndrome like arrhythmias) occurs via a mechanism distinct from induction of the late current, requires NO formation and is dependent on channel redox state.

Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels

Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.2 T-type Ca2+ channels in HEK293 cells raised basal [Ca2+]i and increased proliferation as compared with non-transfected cells. Proliferation and [Ca2+]i levels were reduced to levels seen in non-transfected cells either by induction of HO-1 or exposure of cells to the HO-1 product, carbon monoxide (CO) (applied as the CO releasing molecule, CORM-3). In the aortic VSMC line A7r5, proliferation was also inhibited by induction of HO-1 or by exposure of cells to CO, and patch-clamp recordings indicated that CO inhibited T-type (as well as L-type) Ca2+ currents in these cells. Finally, in human saphenous vein smooth muscle cells, proliferation was reduced by T-type channel inhibition or by HO-1 induction or CO exposure. The effects of T-type channel blockade and HO-1 induction were non-additive. Collectively, these data indicate that HO-1 regulates proliferation via CO-mediated inhibition of T-type Ca2+ channels. This signalling pathway provides a novel means by which proliferation of VSMCs (and other cells) may be regulated therapeutically.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, nitric oxide and cGMP levels, as well as regulate MAP kinase signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Hydrogen sulfide inhibits Cav3.2 T-type Ca2+ channels

The importance of H2S as a physiological signaling molecule continues to develop, and ion channels are emerging as a major family of target proteins through which H2S exerts many actions. The purpose of the present study was to investigate its effects on T-type Ca2+ channels. Using patch-clamp electrophysiology, we demonstrate that the H2S donor, NaHS (10 μM-1 mM) selectively inhibits Cav3.2 T-type channels heterologously expressed in HEK293 cells, whereas Cav3.1 and Cav3.3 channels were unaffected. The sensitivity of Cav3.2 channels to H2S required the presence of the redox-sensitive extracellular residue H191, which is also required for tonic binding of Zn2+ to this channel. Chelation of Zn2+ with N,N,N',N'-tetra-2-picolylethylenediamine prevented channel inhibition by H2S and also reversed H2S inhibition when applied after H2S exposure, suggesting that H2S may act via increasing the affinity of the channel for extracellular Zn2+ binding. Inhibition of native T-type channels in 3 cell lines correlated with expression of Cav3.2 and not Cav3.1 channels. Notably, H2S also inhibited native T-type (primarily Cav3.2) channels in sensory dorsal root ganglion neurons. Our data demonstrate a novel target for H2S regulation, the T-type Ca2+ channel Cav3.2, and suggest that such modulation cannot account for the pronociceptive effects of this gasotransmitter.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Heme oxygenase-1 protects against Alzheimer’s amyloid-β1-42 induced toxicity via carbon monoxide production

Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer‟s disease (AD), catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediate cellular K+ efflux as an early step in the apoptotic cascade. Since apoptosis contributes to the neuronal loss associated with amyloid β peptide (Aβ) toxicity in AD, we investigated the protective effects of HO-1 and CO against Aβ1-42 toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrPc, and rat primary hippocampal neurons. Aβ1-42 (containing protofibrils) caused a concentrationdependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrPc expressing cells showing greater susceptibility to Aβ1-42 toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of Aβ1-42. The CO-donor CORM-2 protected cells against Aβ1-42 toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Aβ1-42 treatment suggesting that K+ channel activity is unaffected in these cells. Instead, Aβ toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. Aβ also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against Aβ toxicity via production of CO. Protection does not arise from inhibition of apoptosis-associated K+ efflux, but rather by inhibition of AMPK activation, which has been recently implicated in the toxic effects of Aβ. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.

Older age of onset in child L2 acquisition can be facilitative: evidence from the acquisition of English passives by Spanish natives

We report a longitudinal comprehension study of (long) passive constructions in two native-Spanish child groups differing by age of initial exposure to L2 English (young group: 3;0-4;0 years; older group: 6;0-7;0 years); where amount of input, L2 exposure environment, and socio-economic status are controlled. Data from a forced-choice task show that both groups comprehend active sentences, not passives, initially (after 3.6 years of exposure). One year later, both groups improve, but only the older group reaches ceiling on both actives and passives. Two years from initial testing, the younger group catches up. Input alone cannot explain why the younger group takes 5 years to accomplish what the older group does in 4. We claim that some properties take longer to acquire at certain ages because language development is partially constrained by general cognitive and linguistic development (e.g. de Villiers, 2007; Long & Rothman, 2014; Paradis, 2008, 2010, 2011; Tsimpli, 2014).

Bound Variable, Split Antecedent and Ellipsis Interpretations in L2 Portuguese: Implications for L2 Acquisition Theories.

Recently, in light of minimalist assumptions, some partial UG accessibility accounts to adult second language acquisition have made a distinction between the post-critical period ability to acquire new features based on their LF-interpretability (i.e. interpretable vs. uninterpretable features) (HAWKINS, 2005; HAWKINS; HATTORI, 2006; TSIMPLI; MASTROPAVLOU, 2007; TSIMPLI; DIMITRAKOPOULOU, 2007). The Interpretability Hypothesis (TSIMPLI; MASTROPAVLOU, 2007; TSIMPLI; DIMITRAKOPOULOU, 2007) claims that only uninterpretable features suffer a post-critical period failure and, therefore, cannot be acquired. Conversely, Full Access approaches claim that L2 learners have full access to UG’s entire inventory of features, and that L1/L2 differences obtain outside the narrow syntax. The phenomenon studied herein, adult acquisition of the Overt Pronoun Constraint (OPC) (MONTALBETTI, 1984) and inflected infinitives in nonnative Portuguese, challenges the Interpretability hypothesis insofar as it makes the wrong predictions for what is observed. The present data demonstrate that advanced learners of L2 Portuguese acquire the OPC and the syntax and semantics of inflected infinitives with native-like accuracy. Since inflected infinitives require the acquisition of new uninterpretable φ-features, the present data provide evidence in contra Tsimpli and colleagues’ Interpretability Hypothesis.