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"Shaw"
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Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Kv3 channels have distinctive gating kinetics tailored for rapid repolarization in fast-spiking neurons. Malfunction of this process due to genetic variants in the
KCNC1
gene causes severe epileptic disorders, yet the structural determinants for the unusual gating properties remain elusive. Here, we present cryo-electron microscopy structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic tetramerization domain T1 which facilitates interactions with C-terminal axonal targeting motif and key components of the gating machinery. Additional interactions between S1/S2 linker and turret domain strengthen the interface between voltage sensor and pore domain. Supported by molecular dynamics simulations, electrophysiological and mutational analyses, we identify several residues in the S4/S5 linker which influence the gating kinetics and an electrostatic interaction between acidic residues in α6 of T1 and R449 in the pore-flanking S6T helices. These findings provide insights into gating control and disease mechanisms and may guide strategies for the design of pharmaceutical drugs targeting Kv3 channels.
Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.
Journal Article
Scaling CO 2 –brine mixing in permeable media via analogue models
Supercritical${\\rm CO}_2$injection and dissolution into deep brine aquifers allow its sequestration within geological formations. After injection,${\\rm CO}_{2}$gas phase is buoyancy-driven over the denser aqueous brine, reaching an apparent gravitational stable distribution. However,${\\rm CO}_2$dissolution in brine propels convection since the mixture is even denser than the underlying brine. This process still needs to be characterised comprehensively. Here, we investigate the irreversible mixing of dissolved${\\rm CO}_2$in brine through laboratory-scale numerical experiments utilising the Hele-Shaw model (Letelier et al. , J. Fluid Mech. , vol. 864, 2019, pp. 746–767) and a fully miscible two-fluid system. In this scenario, mixing the less dense fluid – mimicking${\\rm CO}_{2}$gas phase – with the heavier fluid – representing aqueous brine – catalyses cabbeling-powered convection. Our numerical simulations recover the laboratory results in porous media by Neufeld et al. ( Geophys. Res. Lett. , vol. 37, issue 22, 2010, L22404) and may explain the scaling law obtained by Backhaus et al. ( Phys. Rev. Lett. , vol. 106, issue 10, 2011, 104501) in Hele-Shaw cells. More remarkably, we show that the mass flux between the two analogue fluids, characterised by the Sherwood number$ {{Sh}}$, obeys the universal scaling law$ {{Sh}}\\sim {{Ra}}\\, \\vartheta _{scalar}$, with$ {{Ra}}$the Rayleigh number and$\\vartheta _{scalar}$the mean scalar dissipation rate. This paper sheds light on the fluid dynamics and solubility trapping in geological carbon sequestration.
Journal Article
Bernard Shaw, W.T. Stead, and the new journalism : Whitechapel, Parnell, Titanic and the Great War
This book explores Bernard Shaw's journalism from the mid-1880s through the Great War, a period in which Shaw contributed some of the most powerful and socially relevant journalism the western world has experienced. In approaching Shaw's journalism, the promoter and abuser of the New Journalism, W. T. Stead, is contrasted to Shaw, as Shaw countered the sensational news copy Stead and his disciples generated. To understand Shaw's brand of New Journalism, his responses to the popular press? portrayals of high profile historical crises are examined, while other examples prompting Shaw's journalism over the period are cited for depth: the 1888 Whitechapel murders, the 1890-91 O'Shea divorce scandal that fell Charles Stewart Parnell, peace crusades within militarism, the catastrophic Titanic sinking, and the Great War. Through Shaw's journalism that undermined the popular press' shock efforts that prevented rational thought, Shaw endeavored to promote clear thinking through the immediacy of his critical journalism. Arguably, Shaw saved the free press.
BOOK
جورج برنارد شو يفصح عن نفسه
الكتاب يتناول سيرة حياة جورج برنارد شو ؛ لابد من استحضار محطة بارزة في مسيرة شو، إذ إنه رفض تسلم جائزة نوبل في أول مرة فاز بها عام 1925، ليعود ويقبلها في العام التالي، وفي أول مرة، قال شو : \"إنني أغفر لنوبل أنه اخترع الديناميت ولكنني لا أغفر له أنه أنشأ جائزة نوبل\"، ويعتبر شو أول من رفض الجائزة منذ إنشائها عام 1901، وقد قال حينها : \"هذه الجائزة أشبه بطوق نجاة يلقى به إلى شخص وصل فعلا إلى بر الأمان ولم يعد معرضا للخطر\"، في عام 1926 قبل شو الجائزة، بعدما أقنعته زوجته بأنها شرف لأيرلندا، لكنه ظل مصرا على رفض الحصول على قيمتها المادية، وطلب أن تستخدم في ترجمة أعمال زميله الكاتب المسرحي \"أوجست ستريندبرج\" من السويدية إلى الإنكليزية، \"سيرة لواحد من أهم كتاب القرن العشرين ممن تركوا أثرا بالغا في الفن المسرحي العالمي خلده بين كبار المسرحيين عبر التاريخ، ولا تزال أعماله تلقى اهتماما كبيرا حول العالم من عشاق هذا الفن، وتبرز أهمية هذه السيرة كون الكاتب قد وضع فيها خلاصة تجربته في الحياة والكتابة وأنهاها قبل عامين فقط من وفاته، ما يجعلها المصدر الأهم في مراجعة التجربة الذاتية لكاتب طبع أدبه وأخلاقياته ومواقفه الكبيرة ختما عميقا في أرض الفنون والآداب.\"
BOOK
A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy
Anna-Elina Lehesjoki and colleagues report exome sequencing of 84 cases of progressive myoclonus epilepsy (PME) and targeted resequencing of an additional 28 cases. They identify
de novo
mutations in
KCNC1
in 13 cases and mutations in genes not previously associated with PME, including
PRNP
,
SACS
and
TBC1D24
, in additional cases.
Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent
de novo
mutation, c.959G>A (p.Arg320His), in
KCNC1
was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation.
KCNC1
encodes K
V
3.1, a subunit of the K
V
3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (
NEU1
,
NHLRC1
,
AFG3L2
,
EPM2A
,
CLN6
and
SERPINI1
). Identification of mutations in
PRNP
,
SACS
and
TBC1D24
expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of
de novo
mutations in this disease entity.
Journal Article