Developmentally Regulated, Alternative RNA Splicing-generated Pectoral Muscle-specific Troponin T Isoforms and Role of the NH2-terminal Hypervariable Region in the Tolerance to Acidosis

Expression of multiple protein 4.1 isoforms in erythroid progenitors and in a variety of nonerythroid tissues results from alternative pre- mRNA splicing. In 4.1 pre-mRNA, several translation initiation sites are present; synthesis of isoforms larger than 80 kD occurs when an upstream 5′ AUG is spliced in, whereas the 80-kD mature erythroid isoform is produced when the upstream AUG is spliced out and translation is initiated at the downstream AUG. During erythropoiesis, this splicing switch is developmentally regulated. We studied this developmental switch in hereditary elliptocytosis 4.1Alg, in which a DNA rearrangement involving the exon containing the downstream AUG results in loss of coding capacity for the 80-kD 4.1, leading to mature red blood cells deficient in 4.1 with decreased membrane mechanical stability. Analysis of erythroblast RNA by reverse transcriptase- polymerase chain reaction showed that, although it retained the upstream AUG, its coding region was approximately 2.2 kb, compared with approximately 2.5 kb of normal 4.1 mRNA, because of the deletion of exons, including the one that codes for the downstream AUG. Immunofluorescent microscopy and Western blot analysis documented protein 4.1 expression in HE 4.1Alg erythroblasts. These studies emphasize the crucial role of differentiation-regulated RNA splicing because, within the same erythroid tissue, the HE 4.1Alg phenotype did not appear until after the differentiation-associated splicing event.

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Through thick and thin: Diagnosis of transthyretin cardiac amyloidosis through non-invasive multimodality imaging

Proceedings of Singapore Healthcare ◽

10.1177/20101058211006146 ◽

2021 ◽

pp. 201010582110061

Author(s):

Raja Ezman Raja Shariff ◽

Hafisyatul Aiza Zainal Abidin ◽

Sazzli Kasim

Keyword(s):

Cardiac Amyloidosis ◽

Troponin T ◽

Multimodality Imaging ◽

High Sensitivity ◽

Dark Blood ◽

Non Invasive ◽

Doppler Study ◽

Alternative Means ◽

High Sensitivity Troponin T

Cardiac amyloidosis is a severely underdiagnosed cause of heart failure with preserved ejection fraction. We report a case of highly probable transthyretin (ATTR) cardiac amyloidosis (ATTR-CA) diagnosed through the assistance of non-invasive multimodality imaging. An 81-year-old man presented with worsening dyspnoea, reduced effort tolerance and limb swelling. Examination and bedside investigations demonstrated congestive cardiac failure. On arrival, N-terminal-pro B-type natriuretic peptide was 2400 ng/L, and high-sensitivity troponin T was 78 mmol/L. Echocardiography showed severe left and right ventricular hypertrophy, and a Doppler study revealed diastolic dysfunction. Cardiac magnetic resonance imaging revealed on non-conventional dark blood sequence an abnormal inversion time for nulling myocardium suggestive of infiltrative disease, including amyloidosis. The patient was referred for nuclear-based studies involving technetium-99m pyrophosphate which demonstrated changes highly diagnostic of ATTR-CA. Early diagnosis of ATTR-CA remains paramount due to the increasing availability of disease-modifying therapies. Current guidelines recognise the role of multimodality imaging in confidently recognising the disease without the need for histological evidence in the appropriate context, providing an alternative means of diagnosis.

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Role of Alternative Splicing in Regulating Host Response to Viral Infection

Cells ◽

10.3390/cells10071720 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1720

Author(s):

Kuo-Chieh Liao ◽

Mariano A. Garcia-Blanco

Keyword(s):

Innate Immunity ◽

Alternative Splicing ◽

Immune Responses ◽

Viral Infection ◽

Rna Splicing ◽

Type I ◽

Host Immune Responses ◽

Transcriptional Regulatory Mechanisms ◽

Host Virus Interactions

The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the functional significance of alternative splicing in innate immune responses to viral infection. We describe how several central components of the Type I and III interferon pathways encode spliced isoforms to regulate IFN activation and function. Additionally, the functional roles of splicing factors and modulators in antiviral immunity are discussed. Lastly, we discuss how cell death pathways are regulated by alternative splicing as well as the potential role of this regulation on host immunity and viral infection. Altogether, these studies highlight the importance of RNA splicing in regulating host–virus interactions and suggest a role in downregulating antiviral innate immunity; this may be critical to prevent pathological inflammation.

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COVID-19 cardiac injury and the use of colchicine

BMJ Case Reports ◽

10.1136/bcr-2020-241047 ◽

2021 ◽

Vol 14 (2) ◽

pp. e241047

Author(s):

Vanesa Anton-Vazquez ◽

Laura Byrne ◽

Lisa Anderson ◽

Lisa Hamzah

Keyword(s):

Sinus Tachycardia ◽

Inflammatory Responses ◽

Troponin T ◽

Systolic Function ◽

Cardiac Injury ◽

T Wave ◽

Wave Inversion ◽

Ventricular Extrasystoles

We report a case of cardiac injury in a 46-year-old man affected by COVID-19. The patient presented with shortness of breath and fever. ECG revealed sinus tachycardia with ventricular extrasystoles and T-wave inversion in anterior leads. Troponin T and N-terminal pro B-type natriuretic peptide were elevated. Transthoracic echocardiography showed severely reduced systolic function with an estimated left ventricle ejection fraction of 30%. A nasopharingeal swab was positive for SARS-CoV-2. On day 6, 11 days after onset of symptoms, the patient deteriorated clinically with new chest pain and type 1 respiratory failure. Treatment with colchicine 0.5 mg 8-hourly resulted in rapid clinical resolution. This case report highlights how cardiac injury can dominate the clinical picture in COVID-19 infection. The role of colchicine therapy should be further studied to determine its usefulness in reducing myocardial and possibly lung parenchymal inflammatory responses.

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Identification and developmental regulation of a neuron-specific subunit of cytoplasmic dynein.

Molecular Biology of the Cell ◽

10.1091/mbc.7.2.331 ◽

1996 ◽

Vol 7 (2) ◽

pp. 331-343 ◽

Cited By ~ 45

Author(s):

K K Pfister ◽

M W Salata ◽

J F Dillman ◽

E Torre ◽

R J Lye

Keyword(s):

Axonal Transport ◽

Developmental Regulation ◽

Cytoplasmic Dynein ◽

Retrograde Axonal Transport ◽

Protein Isoforms ◽

Cultured Neurons ◽

Developmentally Regulated ◽

Time Period ◽

Intermediate Chains

Cytoplasmic dynein is the microtubule minus-end-directed motor for the retrograde axonal transport of membranous organelles. Because of its similarity to the intermediate chains of flagellar dynein, the 74-kDa intermediate chain (IC74) subunit of dynein is thought to be involved in binding dynein to its membranous organelle cargo. Previously, we identified six isoforms of the IC74 cytoplasmic dynein subunit in the brain. We further demonstrated that cultured glia and neurons expressed different dynein IC74 isoforms and phospho-isoforms. Two isoforms were observed when dynein from glia was analyzed. When dynein from cultured neurons was analyzed, six IC74 isoforms were observed, although the relative amounts of the dynein isoforms from cultured neurons differed from those found in dynein from brain. To better understand the role of the neuronal IC74 isoforms and identify neuron-specific IC74 dynein subunits, the expression of the IC74 protein isoforms and mRNAs of various tissues were compared. As a result of this comparison, the identity of each of the isoform spots observed on two-dimensional gels was correlated with the products of each of the IC74 mRNAs. We also found that between the fifteenth day of gestation (E15) and the fifth day after birth (P5), the relative expression of the IC74 protein isoforms changes, demonstrating that the expression of IC74 isoforms is developmentally regulated in brain. During this time period, there is relatively little change in the abundance of the various IC74 mRNAs. The E15 to P5 time period is one of rapid process extension and initial pattern formation in the rat brain. This result indicates that the changes in neuronal IC74 isoforms coincide with neuronal differentiation, in particular the extension of processes. This suggests a role for the neuronal IC74 isoforms in the establishment or regulation of retrograde axonal transport.

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The role of phosphorylation of troponin T and I by protein kinase a or c -dependent pathway in the myofilament Ca2+-sensitizing effects of MCI-154 and levosimendan

Journal of Cardiac Failure ◽

10.1016/s1071-9164(98)90440-7 ◽

1998 ◽

Vol 4 (3) ◽

pp. 102

Author(s):

Yoshimi Kitada ◽

R.John Solaro

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Troponin T ◽

Dependent Pathway ◽

Kinase A

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Why developmental niche construction is not selective niche construction: and why it matters

Interface Focus ◽

10.1098/rsfs.2016.0157 ◽

2017 ◽

Vol 7 (5) ◽

pp. 20160157 ◽

Cited By ~ 25

Author(s):

Karola Stotz

Keyword(s):

Niche Construction ◽

Active Role ◽

Evolutionary Significance ◽

Heritable Variation ◽

Developmentally Regulated ◽

Diverse Range ◽

Developmental Niche ◽

Constructed Environment ◽

Selective Environment

In the last decade, niche construction has been heralded as the neglected process in evolution. But niche construction is just one way in which the organism's interaction with and construction of the environment can have potential evolutionary significance. The constructed environment does not just select for , it also produces new variation. Nearly 3 decades ago, and in parallel with Odling-Smee's article ‘Niche-constructing phenotypes', West and King introduced the ‘ontogenetic niche’ to give the phenomena of exo genetic inheritance a formal name. Since then, a range of fields in the life sciences and medicine has amassed evidence that parents influence their offspring by means other than DNA (parental effects), and proposed mechanisms for how heritable variation can be environmentally induced and developmentally regulated. The concept of ‘developmental niche construction’ (DNC) elucidates how a diverse range of mechanisms contributes to the transgenerational transfer of developmental resources. My most central of claims is that whereas the selective niche of niche construction theory is primarily used to explain the active role of the organism in its selective environment, DNC is meant to indicate the active role of the organism in its developmental environment. The paper highlights the differences between the construction of the selective and the developmental niche, and explores the overall significance of DNC for evolutionary theory.

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The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

Cancers ◽

10.3390/cancers14020332 ◽

2022 ◽

Vol 14 (2) ◽

pp. 332

Author(s):

Yan Zhao ◽

Hongling Peng

Keyword(s):

Bone Marrow ◽

Pluripotent Stem Cells ◽

Rna Splicing ◽

Messenger Rna ◽

Hematologic Malignancies ◽

Cellular Processes ◽

Proliferation And Differentiation ◽

Regulatory Functions ◽

Increased Susceptibility

Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents. Therefore, this review elaborates on the biological characteristics and normal hematopoietic regulatory functions of m6A methylation modifications and their role in the pathogenesis of hematologic malignancies.

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Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

American Journal of Nephrology ◽

10.1159/000489606 ◽

2018 ◽

Vol 47 (5) ◽

pp. 361-371 ◽

Cited By ~ 7

Author(s):

Qing Kuang ◽

Ning Xue ◽

Jing Chen ◽

Ziyan Shen ◽

Xiaomeng Cui ◽

...

Keyword(s):

Renal Function ◽

Hydrogen Sulfide ◽

Cardiac Dysfunction ◽

Mononuclear Cells ◽

Troponin T ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Mrna Levels ◽

Ventricular Ejection Fraction

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H2S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative correlation between plasma H2S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD patients.

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