-
Stem Cell Research Jun 2024Lysosomes play crucial roles in regulating cell metabolism, and K channels are critical for controlling various aspects of lysosomal function. Additionally, lysosomal...
Lysosomes play crucial roles in regulating cell metabolism, and K channels are critical for controlling various aspects of lysosomal function. Additionally, lysosomal activity is essential for maintaining the quiescence of hematopoietic stem cells (HSCs) under both steady-state and stress conditions. Tmem175 is a lysosomal potassium channel protein. To further investigate the role of K channels in HSCs, our study employed knockout mice to examine the function of Tmem175. Our research findings demonstrate that the deletion of Tmem175 does not disrupt the functionality of HSCs in both stable and stressed conditions, including irradiation and intraperitoneal 5-FU injections. However, we did observe that the absence of Tmem175 impairs the long-term differentiation capacity of HSCs into myeloid differentiated subpopulation cells(In this paper, it is referred to simply as M cells)in HSC transplantation test, while promoting their differentiation into T cells. This suggests that Tmem175 plays a role in the lineage differentiation of HSCs without being essential for their self-renewal or long-term regenerative capabilities.
PubMed: 38878670
DOI: 10.1016/j.scr.2024.103469 -
The Journal of Biological Chemistry Jun 2024The voltage-gated potassium ion channel K11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause Long QT Syndrome...
The voltage-gated potassium ion channel K11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause Long QT Syndrome (LQTS), which is associated with fatal arrhythmias. Approximately 90% of LQTS-associated variants cause intracellular protein transport (trafficking) dysfunction, which pharmacological chaperones like E-4031 can rescue. Protein folding and trafficking decisions are regulated by chaperones, protein quality control factors, and trafficking machinery comprising the cellular proteostasis network. Here, we test whether trafficking dysfunction is associated with alterations in the proteostasis network of pathogenic Kv11.1 variants and whether pharmacological chaperones can normalize the proteostasis network of responsive variants. We used affinity-purification coupled with tandem mass tag-based quantitative mass spectrometry to assess protein interaction changes of wild-type (WT) K11.1 or trafficking-deficient channel variants in the presence or absence of E4031. We identified 572 core K11.1 protein interactors. Trafficking-deficient variants K11.1-G601S and K11.1-G601S-G965* had significantly increased interactions with proteins responsible for folding, trafficking, and degradation compared to WT. We confirmed previous findings that the proteasome is critical for K11.1 degradation. Our report provides the first comprehensive characterization of protein quality control mechanisms of K11.1. We find extensive interactome remodeling associated with trafficking-deficient K11.1 variants, and with pharmacological chaperone rescue of K11.1 cell surface expression. The identified protein interactions could be targeted therapeutically to improve K11.1 trafficking and treat Long QT Syndrome.
PubMed: 38876300
DOI: 10.1016/j.jbc.2024.107465 -
Molecular Biology Reports Jun 2024The diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin...
BACKGROUND
The diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin production and secretion; low birthweight infants may have a reduced response to insulin. We report a novel missense ABCC8 variant associated with a clinical phenotype compatible with transient neonatal diabetes mellitus (TNDM) in a fetal growth restricted preterm infant.
METHODS AND RESULTS
A preterm growth restricted infant experienced hyperglycemia from the first day of life, requiring insulin therapy on the 13th and 15th day of life and leading to the diagnosis of TNDM. Glycemic values normalized from the 35th day of life onwards. Genetic screening was performed by next generation sequencing, using a Clinical Exon panel of 4800 genes, filtered for those associated with the clinical presentation and by means of methylation-specific multiplex ligation-dependent probe amplification analysis to identify chromosomal aberrations at 6q24. Genetic tests excluded defects at 6q24 and were negative for KCNJ11, SLC2A2 (GLUT-2) and HNF1B, but revealed the presence of the heterozygous missense variant c.2959T > C (p.Ser987Pro) in ABCC8 gene. The presence of the variant was excluded in parents' DNA and the proband variant was then considered de novo.
CONCLUSIONS
In our infant, the persistence of hyperglycemia beyond 3 weeks of life led us to the diagnosis of TNDM and to hypothesize a possible genetic cause. The genetic variant we found could be, most likely, the main cause of both FGR and TNDM.
Topics: Humans; Fetal Growth Retardation; Mutation, Missense; Sulfonylurea Receptors; Infant, Newborn; Diabetes Mellitus; Female; Male; Infant, Premature; Insulin; Infant, Newborn, Diseases
PubMed: 38874636
DOI: 10.1007/s11033-024-09668-2 -
MBio Jun 2024Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the family of the order. LCMV is associated with...
Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in immunocompromised populations and, as the prototypical arenavirus member, acts as a model for the many highly pathogenic members of the family, such as Junín, Lassa, and Lujo viruses, all of which are associated with devastating hemorrhagic fevers. To enter cells, the LCMV envelope fuses with late endosomal membranes, for which two established requirements are low pH and interaction between the LCMV glycoprotein (GP) spike and secondary receptor CD164. LCMV subsequently uncoats, where the RNA genome-associated nucleoprotein (NP) separates from the Z protein matrix layer, releasing the viral genome into the cytosol. To further examine LCMV endosome escape, we performed an siRNA screen which identified host cell potassium ion (K) channels as important for LCMV infection, with pharmacological inhibition confirming K channel involvement during the LCMV entry phase completely abrogating productive infection. To better understand the K-mediated block in infection, we tracked incoming virions along their entry pathway under physiological conditions, where uncoating was signified by separation of NP and Z proteins. In contrast, K channel blockade prevented uncoating, trapping virions within Rab7 and CD164-positive endosomes, identifying K as a third LCMV entry requirement. K did not increase GP-CD164 binding or alter GP-CD164-dependent fusion. Thus, we propose that K mediates uncoating by modulating NP-Z interactions within the virion interior. These results suggest K channels represent a potential anti-arenaviral target.IMPORTANCEArenaviruses can cause fatal human disease for which approved preventative or therapeutic options are not available. Here, using the prototypical LCMV, we identified K channels as critical for arenavirus infection, playing a vital role during the entry phase of the infection cycle. We showed that blocking K channel function resulted in entrapment of LCMV particles within late endosomal compartments, thus preventing productive replication. Our data suggest K is required for LCMV uncoating and genome release by modulating interactions between the viral nucleoprotein and the matrix protein layer inside the virus particle.
PubMed: 38874413
DOI: 10.1128/mbio.01684-23 -
Frontiers in Genetics 2024Long QT syndrome (LQTS) is an inherited malignant arrhythmia syndrome that poses a risk of sudden death. Variants in the Potassium Voltage-Gated Channel Subfamily H...
BACKGROUND
Long QT syndrome (LQTS) is an inherited malignant arrhythmia syndrome that poses a risk of sudden death. Variants in the Potassium Voltage-Gated Channel Subfamily H Member 2 () gene are known to cause Long QT syndrome through an autosomal dominant inheritance pattern. However, as of now, there have been no reports of any variant leading to Long QT syndrome exhibiting incomplete penetrance that is influenced by gender.
METHODS
Whole-exome sequencing (WES) was conducted on the proband to identify pathogenic variants. Subsequently, Sanger sequencing was employed to validate the identified likely pathogenic variants in all family members.
RESULTS
We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel missense variant (p.Val630Gly, c.1889 T>G) as the causative factor for the family's phenotype. Within this family, all three male carriers of the variant carriers exhibited the Long QT syndrome phenotype: one experienced sudden death during sleep, another received an implantable cardioverter defibrillator (ICD), and a younger man displayed a prolonged QTc interval without any instances of syncope or malignant arrhythmia to date. Interestingly, the middle-aged female carrier showed no Long QT Syndrome phenotype. However, her offspring, diagnosed with Turner syndrome (45, X) and also a carrier of this variant, experienced frequent syncope starting at 12 years old and was diagnosed with Long QT syndrome, leading to an ICD implantation when she was 15 years old. These observations suggest that the manifestation of Long QT syndrome associated with this KCNH2 variant exhibits incomplete penetrance influenced by gender within this family, indicating potential protective mechanisms against the syndrome in females affected by this variant.
CONCLUSION
Our investigation has led to the identification of a novel pathogenic variant responsible for Long QT syndrome within a familial context characterized by gender-selective, incomplete penetrance. This discovery highlights a unique pathogenic inheritance pattern for the gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.
PubMed: 38873110
DOI: 10.3389/fgene.2024.1409459 -
Anatolian Journal of Cardiology Jun 2024Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant...
Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant subset of hypertensive disorders characterized by genetic mutations that disrupt the normal physiological mechanisms of blood pressure regulation. This review focuses on elucidating the germline mutations affecting RAAS pathways that lead to distinct forms of heritable hypertension. By understanding the pathophysiological basis of conditions such as Gordon's syndrome, Liddle syndrome, congenital adrenal hyperplasia, and familial hyperaldosteronism types, this review aims to highlight the unique clinical features, diagnostic challenges, and therapeutic implications associated with these disorders. Recognizing specific clinical presentations and family histories indicative of monogenic hypertension is crucial for diagnosis, particularly as it often manifests as early-onset hypertension, abnormalities in potassium and blood pH, and occasionally, abnormal sexual development or related syndromes. Therefore, employing a targeted diagnostic approach through next-generation sequencing is essential to pinpoint the responsible genetic mutations, enabling accurate and individualized treatment plans. The critical importance of certain readily available specific channel blockers, such as thiazides or low-dose corticosteroids, in managing these disorders must be emphasized, as they play a key role in preventing serious complications, including cerebrovascular events. As advancements in genetic and molecular sciences continue to evolve, a deeper comprehension of the mechanisms underlying RAAS-related monogenic hypertension promises to revolutionize the management of this complex disorder, offering hope for more effective and individualized treatment options.
PubMed: 38872497
DOI: 10.14744/AnatolJCardiol.2024.4480 -
Cardiology in Review Jun 2024Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice projected to affect 12.1 million individuals by the year 2030. Patients...
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice projected to affect 12.1 million individuals by the year 2030. Patients who are diagnosed with AF have an increased risk of morbidity and mortality. Although catheter ablation is a class I treatment recommendation in patients with symptomatic paroxysmal AF, antiarrhythmic medications (AAM) continue to be the mainstay of treatment in limited resource settings not offering ablation procedures. Currently, the most used AAMs are those which block either the sodium or potassium channels. We hypothesized that the use of selective dual AAM (sodium and potassium channel blockers) (DAAM) improves the chance of maintaining sinus rhythm and decreases the need for catheter ablation when compared with single AAM (SAAM). This retrospective observational study was conducted in 150 patients with paroxysmal AF over 5 years at Richmond University Medical Center in Staten Island, New York. The following data were collected: age, sex, comorbidities, electrocardiogram findings, ejection fraction by echocardiography, classes of AAM, duration, and response to treatments. The primary endpoint included the absence of symptoms and maintenance of sinus rhythm. The secondary endpoint included the requirement of electrical cardioversion or catheter ablation. A total of 86 patients met the inclusion criteria in our analysis. The average age of the patients was 71.06 years (SD = 7.66). About 45 patients were given DAAM of either amiodarone + flecainide or dronedarone + flecainide and were treated for an average of 15.4 months, followed by catheter ablation, if needed. Also, 41 patients received a SAAM followed by catheter ablation, if needed. A Mann-Whitney test indicated that electrical cardioversion and catheter ablation were greater for the SAAM group (Md = 1) than for the DAAM group (Md = 0) (U = 294.00, P value <0.001; U = 507.00, P value <0.001, respectively). No pro-arrhythmic side effects or death were encountered in either group. Treatment of paroxysmal AF with DAAM is effective compared with SAAM and is less likely to need catheter ablation or electrical cardioversion. Well-designed prospective studies are needed to further explore the use of DAAM in the management of paroxysmal AF and its clinical impact in limited resource settings.
PubMed: 38869272
DOI: 10.1097/CRD.0000000000000738 -
Advanced Science (Weinheim,... Jun 2024The water evaporation rate of 3D solar evaporator heavily relies on the water transport height of the evaporator. In this work, a 3D solar evaporator featuring a soil...
The water evaporation rate of 3D solar evaporator heavily relies on the water transport height of the evaporator. In this work, a 3D solar evaporator featuring a soil capillary-like structure is designed by surface coating native balsa wood using potassium hydroxide activated carbon (KAC). This KAC-coated wood evaporator can transport water up to 32 cm, surpassing that of native wood by ≈8 times. Moreover, under 1 kW m solar radiation without wind, the KAC-coated wood evaporator exhibits a remarkable water evaporation rate of 25.3 kg m h, ranking among the highest compared with other reported evaporators. The exceptional water transport capabilities of the KAC-coated wood should be attributed to the black and hydrophilic KAC film, which creates a porous network resembling a soil capillary structure to facilitate efficient water transport. In the porous network of coated KAC film, the small internal pores play a pivotal role in achieving rapid capillary condensation, while the larger interstitial channels store condensed water, further promoting water transport up more and micropore capillary condensation. Moreover, this innovative design demonstrates efficacy in retarding phenol from wastewater through absorption onto the coated KAC film, thus presenting a new avenue for high-efficiency clean water production.
PubMed: 38867648
DOI: 10.1002/advs.202402583 -
Biological Research Jun 2024Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is...
BACKGROUND
Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K stimulation in brain slices.
RESULTS
Focal high-K stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus.
CONCLUSIONS
Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.
Topics: Animals; Astrocytes; Connexins; Cortical Spreading Depression; Synaptic Transmission; Connexin 43; Male; Nerve Tissue Proteins; Cerebral Cortex; Neurons; Hippocampus; Rats, Sprague-Dawley; Rats; Potassium
PubMed: 38867288
DOI: 10.1186/s40659-024-00519-9 -
Proceedings of the National Academy of... Jun 2024The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential...
The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP] in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]. Notably, diastolic [ATP] was <1 mM, which is eightfold to 10-fold lower than previously estimated. Accordingly, ATP-sensitive K (K) channels were active at physiological [ATP]. Cells exhibited two distinct types of ATP fluctuations during an action potential: net increases (Mode 1) or decreases (Mode 2) in [ATP]. Mode 1 [ATP] increases necessitated Ca entry and release from the sarcoplasmic reticulum (SR) and were associated with increases in mitochondrial Ca. By contrast, decreases in mitochondrial Ca accompanied Mode 2 [ATP] decreases. Down-regulation of the protein mitofusin 2 reduced the magnitude of [ATP] fluctuations, indicating that SR-mitochondrial coupling plays a crucial role in the dynamic control of ATP levels. Activation of β-adrenergic receptors decreased [ATP], underscoring the energetic impact of this signaling pathway. Finally, our work suggests that cross-bridge cycling is the largest consumer of ATP in a ventricular myocyte during an action potential. These findings provide insights into the energetic demands of EC coupling and highlight the dynamic nature of ATP concentrations in cardiac muscle.
Topics: Myocytes, Cardiac; Adenosine Triphosphate; Excitation Contraction Coupling; Animals; Calcium; Heart Ventricles; Action Potentials; Sarcoplasmic Reticulum; Heart Rate; Humans; KATP Channels; Myocardial Contraction; Mice
PubMed: 38865270
DOI: 10.1073/pnas.2318535121