Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 SPG4) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor ...impairment. Complicated forms (complicated HSP cHSP) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.
Prognosis of potentially curable (M0), completely resected gastric cancer is primarily determined by pathologic T and N staging criteria. The optimal regional dissection extent during gastrectomy for ...gastric adenocarcinoma continues to be debated.
A gastric cancer data set was created through structured queries to the Surveillance, Epidemiology, and End Results database (1973 to 1999). Relationships between the number of lymph nodes (LNs) examined and survival were analyzed for the stage subgroups T1/2N0, T1/2N1, T3N0, and T3N1.
In every stage subgroup, overall survival was highly dependent on the number of LNs examined. Multivariate prognostic variables in the T1/2N0M0 subgroup were number of LNs examined, age (for both, P < .0001), race (P = .0004), sex (P = .0006), and tumor size (P = .02). A linear trend for superior survival based on more LNs examined could be confirmed for all four stage subgroups. Baseline model-predicted 5-year survival with only one LN examined was 56% (T1/2N0), 35% (T1/2N1), 29% (T3N0), or 13% (T3N1). For every 10 extra LNs dissected, survival improved by 7.6% (T1/2N0), 5.7% (T1/2N1), 11% (T3N0), or 7% (T3N1). A cut-point analysis yielded the greatest survival difference at 10 LNs examined but continued to detect significantly superior survival differences for cut points at up to 40 LNs, always in favor of more LNs examined.
Although the impact of stage migration versus improved regional disease control cannot be separated on basis of the available information, the data provide support in favor of extended lymphadenectomy during potentially curative gastrectomy for gastric cancer.
In myelinated nerve fibres, action potentials are generated at nodes of Ranvier. These structures are located at interruptions of the myelin sheath, forming narrow gaps with small rings of axolemma ...freely exposed to the extracellular space. The mammalian node contains a high density of Na+ channels and K+‐selective leakage channels. Voltage‐dependent Kv1 channels are only present in the juxta‐paranode. Recently, the leakage channels have been identified as K2P channels (TRAAK, TREK‐1). K2P channels are K+‐selective ‘background’ channels, characterized by outward rectification and their ability to be activated, e.g. by temperature, mechanical stretch or arachidonic acid. We are only beginning to elucidate the peculiar functions of nodal K2P channels. I will discuss two functions of the nodal K2P‐mediated conductance. First, at body temperature K2P channels have a high open probability, thereby inducing a resting potential of about −85 mV. This negative resting potential reduces steady‐state Na+ channel inactivation and ensures a large Na+ inward current upon a depolarizing stimulus. Second, the K2P conductance is involved in nodal action potential repolarization. The identification of nodal K2P channels is exciting since it shows that the nodal K+ conductance is not a fixed value but can be changed: it can be increased or decreased by a broad range of K2P modulators, thereby modulating, for example, the resting potential. The functional importance of nodal K2P channels will be exemplified by describing in more detail the function of the K2P conductance increase by raising the temperature from room temperature to 37°C.
figure legend A, model of a myelinated nerve fibre. B, nerve fibre segments and distinct distribution of ion channels.
Current models of (exo)planet formation often rely on a large influx of so-called "pebbles" from the outer disk into the planet formation region. In this paper, we investigate how the ...formation/coagulation of pebbles in the cold outer regions of protoplanetary disks and their subsequent migration to the inner disk can alter the gas-phase CO distribution both interior and exterior to the midplane CO snowline. By simulating the resulting CO abundances in the midplane as well as the warm surface layer, we identify observable signatures of large-scale pebble formation and migration that can be used as "smoking guns" for this important process. Specifically, we find that after 1 Myr, the formation and settling of icy pebbles results in the removal of up to 80% of the CO vapor in the warm ( ) disk layers outside the CO snowline, while the radial migration of pebbles results in the generation of a plume of CO vapor inside the snowline, increasing the CO abundance by a factor ∼2-6 depending on the strength of the turbulence and the sizes of the individual pebbles. The absence of this plume of CO vapor in young nearby disks could indicate efficient conversion of CO into a more refractory species, or to the radial mass flux of pebbles being drastically reduced by, for example, disk inhomogeneities or early planetesimal formation.
Mammalian ether‐à‐go‐go (EAG) channels are voltage‐gated K+ channels. They are encoded by the KCNH gene family and divided into three subfamilies, eag (Kv10), erg (eag‐related gene; Kv11) and elk ...(eag‐like; Kv12). All EAG channel subtypes are expressed in the brain where they effectively modulate neuronal excitability. This Topical Review describes the biophysical properties of each of the EAG channel subtypes, their function in neurons and the neurological diseases induced by EAG channel mutations. In contrast to the function of erg currents in the heart, where they contribute to repolarization of the cardiac action potential, erg currents in neurons are involved in the maintenance of the resting potential, setting of action potential threshold and frequency accommodation. They can even support high frequency firing by preventing a depolarization‐induced Na+ channel block. EAG channels are modulated differentially, e.g. eag channels by intracellular Ca2+, erg channels by extracellular K+ and GPCRs, and elk channels by changes in pH. So far, only currents mediated by erg channels have been recorded in neurons with the help of selective blockers. Neuronal eag and elk currents have not been isolated due to the lack of suitable channel blockers. However, findings in KO mice indicate a physiological role of eag1 currents in synaptic transmission and an involvement of elk2 currents in cognitive performance. Human eag1 and eag2 gain‐of‐function mutations underlie syndromes associated with epileptic seizures.
Current knowledge of the physiology and pathophysiology of neuronal EAG K+ channels is based on experimental use of high affinity channel blockers, which allows isolation of neuronal erg currents (left) and cellular assessment of channel function (middle), on the analysis of elk2 and eag1 KO mice as well as on human eag channel mutations associated with epileptic activity (right panel).
Recent observations show that the CO gas abundance, relative to H2, in many 1-10 Myr old protoplanetary disks may be heavily depleted by a factor of 10-100 compared to the canonical interstellar ...medium (ISM) value of 10−4. When and how this depletion happens can significantly affect compositions of planetesimals and atmospheres of giant planets. It is therefore important to constrain whether the depletion occurs already at the earliest protostellar disk stage. Here we present spatially resolved observations of C18O, C17O, and 13C18O J = 2−1 lines in three protostellar disks. We show that the C18O line emits from both the disk and the inner envelope, while C17O and 13C18O lines are consistent with a disk origin. The line ratios indicate that both C18O and C17O lines are optically thick in the disk region, and only the 13C18O line is optically thin. The line profiles of the 13C18O emissions are best reproduced by Keplerian gaseous disks at similar sizes as their mm-continuum emissions, suggesting small radial separations between the gas and mm-sized grains in these disks, in contrast to the large separation commonly seen in protoplanetary disks. Assuming a gas-to-dust ratio of 100, we find that the CO gas abundances in these protostellar disks are consistent with the ISM abundance within a factor of 2, nearly one order of magnitude higher than the average value of 1-10 Myr old disks. These results suggest that there is a fast, ∼1 Myr, evolution of the abundance of CO gas from the protostellar disk stage to the protoplanetary disk stage.
The gas-phase CO abundance (relative to hydrogen) in protoplanetary disks decreases by up to two orders of magnitude from its interstellar medium value of ∼10−4, even after accounting for freeze-out ...and photodissociation. Previous studies have shown that while local chemical processing of CO and the sequestration of CO ice on solids in the midplane can both contribute, neither of these processes appears capable of consistently reaching the observed depletion factors on the relevant timescale of 1-3 Myr. In this study, we model these processes simultaneously by including a compact chemical network (centered on carbon and oxygen) to 2D (r + z) simulations of the outer (r > 20 au) disk regions that include turbulent diffusion, pebble formation, and pebble dynamics. In general, we find that the CO/H2 abundance is a complex function of time and location. Focusing on CO in the warm molecular layer, we find that only the most complete model (with chemistry and pebble evolution included) can reach depletion factors consistent with observations. In the absence of pressure traps, highly efficient planetesimal formation, or high cosmic-ray ionization rates, this model also predicts a resurgence of CO vapor interior to the CO ice-line. We show the impact of physical and chemical processes on the elemental (C/O) and (C/H) ratios (in the gas and ice phases), discuss the use of CO as a disk mass tracer, and, finally, connect our predicted pebble ice compositions to those of pristine planetesimals as found in the Cold Classical Kuiper Belt and debris disks.
Abstract
Constraining planet formation based on the atmospheric composition of exoplanets is a fundamental goal of the exoplanet community. Existing studies commonly try to constrain atmospheric ...abundances, or to analyze what abundance patterns a given description of planet formation predicts. However, there is also a pressing need to develop methodologies that investigate how to transform atmospheric compositions into planetary formation inferences. In this study we summarize the complexities and uncertainties of state-of-the-art planet formation models and how they influence planetary atmospheric compositions. We introduce a methodology that explores the effect of different formation model assumptions when interpreting atmospheric compositions. We apply this framework to the directly imaged planet HR 8799e. Based on its atmospheric composition, this planet may have migrated significantly during its formation. We show that including the chemical evolution of the protoplanetary disk leads to a reduced need for migration. Moreover, we find that pebble accretion can reproduce the planet’s composition, but some of our tested setups lead to too low atmospheric metallicities, even when considering that evaporating pebbles may enrich the disk gas. We conclude that the definitive inversion from atmospheric abundances to planet formation for a given planet may be challenging, but a qualitative understanding of the effects of different formation models is possible, opening up pathways for new investigations.
KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential ...role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits.
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