bluuebunny/crossref_metadata_2025_split huggingface dataset:
When muscle Ca2+ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis
Authors: Allard Bruno , Fuster Clarisse 
Published: March 2018

AbstractPatients suffering from type 1 hypokalaemic periodic paralysis (HypoPP1) experience attacks of muscle paralysis associated with hypokalaemia. The disease arises from missense mutations in the gene encoding the α1 subunit of the dihydropyridine receptor (DHPR), a protein complex anchored in the tubular membrane of skeletal muscle fibres which controls the release of Ca2+ from sarcoplasmic reticulum and also functions as a Ca2+ channel. The vast majority of mutations consist of the replacement of one of the outer arginines in S4 segments of the α1 subunit by neutral residues. Early studies have shown that muscle fibres from HypoPP1 patients are abnormally depolarized at rest in low K+ to the point of inducing muscle inexcitability. The relationship between HypoPP1 mutations and depolarization has long remained unknown. More recent investigations conducted in the closely structurally related voltage‐gated Na+ and K+ channels have shown that comparable S4 arginine substitutions gave rise to elevated inward currents at negative potentials called gating pore currents. Experiments performed in muscle fibres from different models revealed such an inward resting current through HypoPP1 mutated Ca2+ channels. In mouse fibres transfected with HypoPP1 mutated channels, the elevated resting current was found to carry H+ for the R1239H arginine‐to‐histidine mutation in a S4 segment and Na+ for the V876E HypoPP1 mutation, which has the peculiarity of not being located in S4 segments. Muscle paralysis probably results from the presence of a gating pore current associated with hypokalaemia for both mutations, possibly aggravated by external acidosis for the R1239H mutation.
image
Cholecystokinin selectively activates short axon cells to enhance inhibition of olfactory bulb output neurons
Authors: Liu Xiang , Liu Shaolin 
Published: March 2018

Key points
Cholecystokinin (CCK) via CCK‐B receptors significantly enhances the GABAA receptor‐mediated synaptic inhibition of principal olfactory bulb (OB) output neurons.
This CCK action requires action potentials in presynaptic neurons.
The enhanced inhibition of OB output neurons is a result of CCK‐elevated inhibitory input from the glomerular circuit.
CCK modulation of the glomerular circuit also leads to potentiated presynaptic inhibition of olfactory nerve terminals and postsynaptic inhibition of glomerular neurons.
Selective excitation of short axon cells underlies the CCK‐potentiated glomerular inhibition.
AbstractNeuropeptides such as cholecystokinin (CCK) are important for many brain functions, including sensory processing. CCK is predominantly present in a subpopulation of excitatory neurons and activation of CCK receptors is implicated in olfactory signal processing in the olfactory bulb (OB). However, the cellular and circuit mechanisms underlying the actions of CCK in the OB remain elusive. In the present study, we characterized the effects of CCK on synaptic inhibition of the principal OB output neurons mitral/tufted cells (MTCs) followed by mechanistic analyses at both circuit and cellular levels. First, we found that CCK via CCK‐B receptors enhances the GABAA receptor‐mediated spontaneous IPSCs in MTCs. Second, CCK does not affect the action potential independent miniature IPSCs in MTCs. Third, CCK potentiates glomerular inhibition resulting in increased GABAB receptor‐mediated presynaptic inhibition of olfactory nerve terminals and enhanced spontaneous IPSCs in MTCs and glomerular neurons. Fourth, CCK enhances miniature IPSCs in the excitatory external tufted cells, although neither in the inhibitory short axon cells (SACs) nor in periglomerular cells (PGCs). Finally, CCK excites all tested SACs and a very small minority of GABAergic neurons in the granule cell layer or in periglomerular cells, but not in deep SACs. These results demonstrate that CCK selectively activates SACs to engage the SAC‐formed interglomerular circuit and thus elevates inhibition broadly in the OB glomerular layer. This modulation may prevent the system from saturating in response to a high concentration of odourants or facilitate the detection of weak stimuli by increasing signal‐to‐noise ratio.
Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep
Authors: Bennet Laura , Galinsky Robert , Draghi Vittoria , Lear Christopher A. , Davidson Joanne O. , Unsworth Charles P. , Gunn Alistair J. 
Published: March 2018

Key points
We evaluated the effect of magnesium sulphate (MgSO4) on seizures induced by asphyxia in preterm fetal sheep.
MgSO4 did not prevent seizures, but significantly reduced the total duration, number of seizures, seizure amplitude and average seizure burden.
Saline‐asphyxia male fetuses had significantly more seizures than female fetuses, but male fetuses showed significantly greater reduction in seizures during MgSO4 infusion than female fetuses.
A circadian profile of seizure activity was observed in all fetuses, with peak seizures seen around 04.00–06.00 h on the first and second days after the end of asphyxia.
This study is the first to demonstrate that MgSO4 has utility as an anti‐seizure agent after hypoxia–ischaemia. More information is needed about the mechanisms mediating the effect of MgSO4 on seizures and sexual dimorphism, and the influence of circadian rhythms on seizure expression.
AbstractSeizures are common in newborns after asphyxia at birth and are often refractory to anti‐seizure agents. Magnesium sulphate (MgSO4) has anticonvulsant effects and is increasingly given to women in preterm labour for potential neuroprotection. There is limited information on its effects on perinatal seizures. We examined the hypothesis that MgSO4 infusion would reduce fetal seizures after asphyxia in utero. Preterm fetal sheep at 0.7 gestation (104 days, term = 147 days) were given intravenous infusions of either saline (n = 14) or MgSO4 (n = 12, 160 mg bolus + 48 mg h−1 infusion over 48 h). Fetuses underwent umbilical cord occlusion (UCO) for 25 min, 24 h after the start of infusion. The start time for seizures did not differ between groups, but MgSO4 significantly reduced the total number of seizures (P < 0.001), peak seizure amplitude (P < 0.05) and seizure burden (P < 0.005). Within the saline‐asphyxia group, male fetuses had significantly more seizures than females (P < 0.05). Within the MgSO4‐asphyxia group, although both sexes had fewer seizures than the saline‐asphyxia group, the greatest effect of MgSO4 was on male fetuses, with reduced numbers of seizures (P < 0.001) and seizure burden (P < 0.005). Only 1 out of 6 MgSO4 males had seizures on the second day post‐UCO compared to 5 out of 6 MgSO4 female fetuses (P = 0.08). Finally, seizures showed a circadian profile with peak seizures between 04.00 and 06.00 h on the first and second day post‐UCO. Collectively, these results suggest that MgSO4 may have utility in treating perinatal seizures and has sexually dimorphic effects.
Differential effects of vision upon the accuracy and precision of vestibular‐evoked balance responses
Authors: Mackenzie Stuart W. , Reynolds Raymond F. 
Published: March 2018

Key points
Effective balance control requires the transformation of vestibular signals from head‐ to foot‐centred coordinates in order to move the body in an appropriate direction.
This transformation process has previously been studied by analysing the directional accuracy of the averaged sway response to multiple electrical vestibular stimuli (EVS).
Here we studied trial‐by‐trial variability of EVS responses to measure any changes in directional precision which may be masked by the averaging process.
We found that vision increased directional variability without influencing the mean sway direction, demonstrating that response accuracy and precision are dissociable.
These results emphasise the importance of single trial analysis in determining the efficacy of vestibular control of balance.
AbstractVestibular information must be transformed from head‐ to‐foot‐centred coordinates for balance control. This transformation process has previously been investigated using electrical vestibular stimulation (EVS), which evokes a sway response fixed in head coordinates. The craniocentric nature of the response has been demonstrated by analysing average responses to multiple stimuli. This approach misses any trial‐by‐trial variability which would reflect poor balance control. Here we performed single‐trial analysis to measure this directional variability (precision), and compared this to mean performance (accuracy). We determined the effect of vision upon both parameters. Standing volunteers adopted various head orientations (0, ±30 and ±60 deg yaw) while EVS‐evoked response direction was determined from ground reaction force vectors. As previously reported, mean force direction was orientated towards the anodal ear, and rotated in line with head yaw. Although vision caused a ∼50% reduction in response magnitude, it had no influence on the direction of the mean sway response, indicating that accuracy was unaffected. However, individual trial analysis revealed up to 30% increases in directional variability with the eyes open. This increase was inversely correlated with the size of the force response. The paradoxical observation that vision reduces the precision of the balance response may be explained by a multi‐sensory integration process. As additional veridical sensory information becomes available, this lessens the relative contribution of vestibular input, causing a simultaneous reduction in both the magnitude and the precision of the response to EVS. Our novel approach demonstrates the importance of single‐trial analysis in revealing the efficacy of vestibular reflexes.
Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics
Authors: Beattie Kylie A. , Hill Adam P. , Bardenet Rémi , Cui Yi , Vandenberg Jamie I. , Gavaghan David J. , de Boer Teun P. , Mirams Gary R. 
Published: March 2018

Key points
Ion current kinetics are commonly represented by current–voltage relationships, time constant–voltage relationships and subsequently mathematical models fitted to these. These experiments take substantial time, which means they are rarely performed in the same cell.
Rather than traditional square‐wave voltage clamps, we fitted a model to the current evoked by a novel sum‐of‐sinusoids voltage clamp that was only 8 s long.
Short protocols that can be performed multiple times within a single cell will offer many new opportunities to measure how ion current kinetics are affected by changing conditions.
The new model predicts the current under traditional square‐wave protocols well, with better predictions of underlying currents than literature models. The current under a novel physiologically relevant series of action potential clamps is predicted extremely well.
The short sinusoidal protocols allow a model to be fully fitted to individual cells, allowing us to examine cell–cell variability in current kinetics for the first time.
AbstractUnderstanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics – the voltage‐dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fitted a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells overexpressing hERG1a. The model was then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprising a collection of physiologically relevant action potentials. We demonstrate that we can make predictive cell‐specific models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell–cell variability in current kinetics. Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches.
Activity‐dependent synaptic integration and modulation of bilateral excitatory inputs in an auditory coincidence detection circuit
Authors: Lu Yong , Liu Yuwei , Curry Rebecca J. 
Published: March 2018

Key points
Binaural excitatory inputs to coincidence detection neurons in nucleus laminaris (NL) play essential roles in interaural time difference coding for sound localization.
Here, we show that the two excitatory inputs are physiologically nearly completely segregated. Synaptic integration shows linear summation of EPSPs, ensuring high efficiency of coincidence detection of the bilateral excitatory inputs.
We further show that the two excitatory inputs to single NL neurons are symmetrical in synaptic strength, kinetics and short‐term plasticity.
Modulation of the EPSCs by metabotropic glutamate receptors (mGluRs) is identical between the two excitatory inputs, maintaining balanced bilateral excitation under neuromodulatory conditions.
Unilateral hearing deprivation reduces synaptic excitation and paradoxically strengthens mGluR modulation of EPSCs, suggesting activity‐dependent anti‐homeostatic regulation, a novel synaptic plasticity in response to sensory manipulations.
AbstractNeurons in the avian nucleus laminaris (NL) receive bilateral excitatory inputs from the cochlear nucleus magnocellularis, via morphologically symmetrical dorsal (ipsilateral) and ventral (contralateral) dendrites. Using in vitro whole‐cell patch recordings in chicken brainstem slices, we investigated synaptic integration and modulation of the bilateral inputs to NL under normal and hearing deprivation conditions. We found that the two excitatory inputs onto single NL neurons were nearly completely segregated, and integration of the two inputs was linear for EPSPs. The two inputs had similar synaptic strength, kinetics and short‐term plasticity. EPSCs in low but not middle and high frequency neurons were suppressed by activation of group I and II metabotropic glutamate receptors (mGluR I and II), with similar modulatory strength between the ipsilateral and contralateral inputs. Unilateral hearing deprivation by cochlea removal reduced the excitatory transmission on the deprived dendritic domain of NL. Interestingly, EPSCs evoked at the deprived domain were modulated more strongly by mGluR II than at the counterpart domain that received intact input in low frequency neurons, suggesting anti‐homeostatic regulation. This was supported by a stronger expression of mGluR II protein on the deprived neuropils of NL. Under mGluR II modulation, EPSCs on the deprived input show transient synaptic facilitation, forming a striking contrast with normal hearing conditions under which pure synaptic depression is observed. These results demonstrate physiological symmetry and thus balanced bilateral excitatory inputs to NL neurons. The activity‐dependent anti‐homeostatic plasticity of mGluR modulation constitutes a novel mechanism regulating synaptic transmission in response to sensory input manipulations.
Deaminase-Dead Mouse APOBEC3 Is an
In Vivo
Retroviral Restriction Factor
Authors: Stavrou Spyridon , Zhao Wenming , Blouch Kristin , Ross Susan R. 
Published: March 2018

ABSTRACT

The apolipoprotein B editing complex 3 (APOBEC3) proteins are potent retroviral restriction factors that are under strong positive selection, both in terms of gene copy number and sequence diversity. A common feature of all the members of the APOBEC3 family is the presence of one or two cytidine deamination domains, essential for cytidine deamination of retroviral reverse transcripts as well as packaging into virions. Several studies have indicated that human and mouse APOBEC3 proteins restrict retrovirus infection via cytidine deaminase (CD)-dependent and -independent means. To understand the relative contribution of CD-independent restriction
in vivo
, we created strains of transgenic mice on an APOBEC3 knockout background that express a deaminase-dead mouse APOBEC3 due to point mutations in both CD domains (E73Q/E253Q). Here, we show that the CD-dead APOBEC3 can restrict murine retroviruses
in vivo
. Moreover, unlike the wild-type protein, the mutant APOBEC3 is not packaged into virions but acts only as a cell-intrinsic restriction factor that blocks reverse transcription by incoming viruses. Finally, we show that wild-type and CD-dead mouse APOBEC3 can bind to murine leukemia virus (MLV) reverse transcriptase. Our findings suggest that the mouse APOBEC3 cytidine deaminase activity is not required for retrovirus restriction.

IMPORTANCE
APOBEC3 proteins are important host cellular restriction factors essential for restricting retrovirus infection by causing mutations in the virus genome and by blocking reverse transcription. While both methods of restriction function
in vitro
, little is known about their role during
in vivo
infection. By developing transgenic mice with mutations in the cytidine deamination domains needed for enzymatic activity and interaction with viral RNA, we show that APOBEC3 proteins can still restrict
in vivo
infection by interacting with reverse transcriptase and blocking its activity. These studies demonstrate that APOBEC3 proteins have evolved multiple means for blocking retrovirus infection and that all of these means function
in vivo
.
Transmission, Human Population, and Pathogenicity: the Ebola Case in Point
Authors: Delgado Rafael , Simón Fernando 
Published: March 2018

ABSTRACTThe 2013–2016 Ebola outbreak in West Africa has been the largest ever of a known disease in a new context that produced an unprecedented impact and is changing the international approach to responding to public health emergencies. The unprecedented scale of the outbreak, the use of advanced technology for detecting and characterizing the infectious agent, along with the opportunity to treat patients in modern facilities have greatly increased our knowledge of the disease and its transmission. Also, for the first time, an important international effort has been deployed to control the spread of the epidemic by providing care to patients and by adopting basic measures of public health control. Apart from supportive treatment and intensive therapy with fluids and electrolytes, no new compounds have been proved to be clinically effective to treat Ebola virus disease; however, a specific vaccine has shown significant protection in clinical trials in Guinea, opening an expectation for controlling future outbreaks.
Global Regulation by CsrA and Its RNA Antagonists
Authors: Romeo Tony , Babitzke Paul 
Published: March 2018

ABSTRACT

The sequence-specific RNA binding protein CsrA is employed by diverse bacteria in the posttranscriptional regulation of gene expression. Its binding interactions with RNA have been documented at atomic resolution and shown to alter RNA secondary structure, RNA stability, translation, and/or Rho-mediated transcription termination through a growing number of molecular mechanisms. In
Gammaproteobacteria
, small regulatory RNAs (sRNAs) that contain multiple CsrA binding sites compete with mRNA for binding to CsrA, thereby sequestering and antagonizing this protein. Both the synthesis and turnover of these sRNAs are regulated, allowing CsrA activity to be rapidly and efficiently adjusted in response to nutritional conditions and stresses. Feedback loops between the Csr regulatory components improve the dynamics of signal response by the Csr system. The Csr system of
Escherichia coli
is intimately interconnected with other global regulatory systems, permitting it to contribute to regulation by those systems. In some species, a protein antagonist of CsrA functions as part of a checkpoint for flagellum biosynthesis. In other species, a protein antagonist participates in a mechanism in which a type III secretion system is used for sensing interactions with host cells. Recent transcriptomics studies reveal vast effects of CsrA on gene expression through direct binding to hundreds of mRNAs, and indirectly through its effects on the expression of dozens of transcription factors. CsrA binding to base-pairing sRNAs and novel mRNA segments, such as the 3′ untranslated region and deep within coding regions, predict its participation in yet-to-be-discovered regulatory mechanisms.
Bacterial Iron Homeostasis Regulation by sRNAs
Authors: Chareyre Sylvia , Mandin Pierre 
Published: March 2018

ABSTRACT

While iron is essential to sustain growth, its excess can be detrimental to the cell by generating highly toxic reactive oxygen species. Regulation of iron homeostasis thus plays a vital role in almost all living organisms. During the last 15 years, the small RNA (sRNA) RyhB has been shown to be a key actor of iron homeostasis regulation in bacteria. Through multiple molecular mechanisms, RyhB represses expendable iron-utilizing proteins, promotes siderophore production, and coordinates Fe-S cluster cofactor biogenesis, thereby establishing a so-called iron-sparing response. In this review, we will summarize knowledge on how sRNAs control iron homeostasis mainly through studies on RyhB in
Escherichia coli
. The parallel roles and modes of action of other sRNAs in different bacteria will also be described. Finally, we will discuss what questions remain to be answered concerning this important stress response regulation by sRNAs.
Carbohydrate Utilization in Bacteria: Making the Most Out of Sugars with the Help of Small Regulatory RNAs
Authors: Durica-Mitic* Svetlana , Göpel* Yvonne , Görke Boris 
Published: March 2018

ABSTRACT

Survival of bacteria in ever-changing habitats with fluctuating nutrient supplies requires rapid adaptation of their metabolic capabilities. To this end, carbohydrate metabolism is governed by complex regulatory networks including posttranscriptional mechanisms that involve small regulatory RNAs (sRNAs) and RNA-binding proteins. sRNAs limit the response to substrate availability and set the threshold or time required for induction and repression of carbohydrate utilization systems. Carbon catabolite repression (CCR) also involves sRNAs. In
Enterobacteriaceae
, sRNA Spot 42 cooperates with the transcriptional regulator cyclic AMP (cAMP)-receptor protein (CRP) to repress secondary carbohydrate utilization genes when a preferred sugar is consumed. In pseudomonads, CCR operates entirely at the posttranscriptional level, involving RNA-binding protein Hfq and decoy sRNA CrcZ. Moreover, sRNAs coordinate fluxes through central carbohydrate metabolic pathways with carbohydrate availability. In Gram-negative bacteria, the interplay between RNA-binding protein CsrA and its cognate sRNAs regulates glycolysis and gluconeogenesis in response to signals derived from metabolism. Spot 42 and cAMP-CRP jointly downregulate tricarboxylic acid cycle activity when glycolytic carbon sources are ample. In addition, bacteria use sRNAs to reprogram carbohydrate metabolism in response to anaerobiosis and iron limitation. Finally, sRNAs also provide homeostasis of essential anabolic pathways, as exemplified by the hexosamine pathway providing cell envelope precursors. In this review, we discuss the manifold roles of bacterial sRNAs in regulation of carbon source uptake and utilization, substrate prioritization, and metabolism.