bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status
Authors: Adrogué Horacio J. , Awan Ahmed A. , Madias Nicolaos E. 
Published: February 2020

<b><i>Background:</i></b> We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation. <b><i>Methods:</i></b> We examined baseline total body water (TBW), Na<sup>+</sup> space, HCO<sub>3</sub><sup>–</sup> space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO<sub>3</sub> infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na<sup>+</sup> space that exceeds TBW uncovers nonosmotic sodium storage. <b><i>Results:</i></b> Na<sup>+</sup> space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na<sup>+</sup> space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = –0.01x + 1.4, <i>p</i>= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked. <b><i>Conclusions:</i></b> This study demonstrates that hypobicarbonatemic animals have a Na<sup>+</sup> space that exceeds TBW after an acute infusion of hypertonic NaHCO<sub>3</sub> indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na<sup>+</sup> space, these animals have a larger HCO<sub>3</sub><sup>–</sup> space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO<sub>3</sub><sup>–</sup> loading whenever initial [HCO<sub>3</sub><sup>–</sup>]<sub>e</sub> is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.
Deep Mutational Scan of an
SCN5A
Voltage Sensor
Authors: Glazer Andrew M. , Kroncke Brett M. , Matreyek Kenneth A. , Yang Tao , Wada Yuko , Shields Tiffany , Salem Joe-Elie , Fowler Douglas M. , Roden Dan M. 
Published: February 2020

Background:
Variants in ion channel genes have classically been studied in low throughput by patch clamping. Deep mutational scanning is a complementary approach that can simultaneously assess function of thousands of variants.

Methods:

We have developed and validated a method to perform a deep mutational scan of variants in
SCN5A
, which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of
SCN5A
in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells.

Results:
In preliminary experiments, challenge with 3 drugs (veratridine, brevetoxin, and ouabain) could discriminate wild-type channels from gain- and loss-of-function pathogenic variants. High-throughput sequencing of the pre- and postdrug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The deep mutational scan scores identified 40 putative gain-of-function and 33 putative loss-of-function variants. For 8 of 9 variants, patch clamping data were consistent with the scores.

Conclusions:

These experiments demonstrate the accuracy of a high-throughput in vitro scan of
SCN5A
variant function, which can be used to identify deleterious variants in
SCN5A
and other ion channel genes.