scholarly journals Fetal hemoglobin that binds oxygen more strongly than adult hemoglobin saves children (and sickle-cell patients where it persists longer) from heme-binding (oxygen sequestering) proteins of anaerobic bacteria (Prevotella, et al) - thereby making SARS-Cov2 benign for them

2020 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Sickle Cell ◽  
Secondary Infection ◽  
Cardiac Injury ◽  
Anaerobic Bacteria ◽  
Fetal Hemoglobin ◽  
Ground Glass Opacity ◽  
Ground Glass ◽  
Heme Binding ◽  
Sequencing Data ◽  
Adult Hemoglobin

Here, I postulate (supported by sequencing data from patients) rationale behind two of the most critical (low SpO2 [1], need for ventilators) and baffling (doesnt effect children or malaria endemic regions [2]) effects observed in SARS-Cov2 [3–6]. In short, secondary infection with anaerobic bacteria [7–9] which express heme-expressing proteins, and can degrade and utilize hemoglobin as an effective heme source [10, 11] - causing oxygen levels (which binds to heme) to go down. Also, Prevotella is known to lower lymphocyte counts [12], increase IL-6 in plasma [13–15], cause ground glass opacity in lungs [16], and associated with cardiac injury [17] - all symptoms associated with Covid19.

scholarly journals San Diego county Nanopore SARS-Cov2 sequencing data shows metagenomic Prevotella, Haemophilus parainfluenzae, a lot of unknown species and chimeric reads

2020 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
San Diego ◽  
Secondary Infection ◽  
Elongation Factor ◽  
Ground Glass Opacity ◽  
Ground Glass ◽  
Dominant Factor ◽  
Sequencing Data ◽  
Haemophilus Parainfluenzae ◽  
Unknown Species ◽  
Highly Correlated

Prevotella was definitely a dominant factor in the the SARS-Cov2 [1,2] patient [3], playing a key role in immune suppression [4]. The same immune suppressive proteins from the same bacteria (elongation factor Tu) was also observed in low amounts in two other patients [5].Prevotella is known to cause ground glass opacity [6] being used to identify SARS-Cov2 patients [7]. It is also known to increase IL-6 in plasma [8–10], which is correlated with severity/fatalities [11]. In 2003 SARS- Cov1 outbreak, secondary infection and IL-6 was highly correlated with hospitalization and deaths [12].Metagenomic presence - known bacteria, and many (10% of reads) unknown speciesHere, sequencing data (Accid:SRR11347377, Reads=2.64million, Nanopore) from San Diego show Prevotella, Haemophilus parainfluenzae (which can have the same ground glass in CT [13]) and other bacteria in small amounts (SI/bacteria.fa, N=23). More intriguingly, there are significant amount of reads with no known matches (SI/nomatches.fa, N=200K, about 10%).Chimeric reads (10% of reads) involving SARS-Cov2Like previous, data (N=3) showing SARS-Cov2 integration in bacteria [14], there are a significant percentage of chimeric reads (SI/integrated.fa, N=250K, ∼10%) having both SARS-Cov2 and something else (sometimes known bacterial reads). Is this sequencing artifact - or is the virus infecting both bacterial and human cells (which would be a first) [15]? It would explain the long incubations and false negatives.

scholarly journals The usual anaerobic bacterial suspects extracted from a global metagenomic database of Covid19 patients from Peru, Cambodia, China, Brazil and the US - Prevotella, Veillonella, Capnocytophaga, Fusobacterium, Oribacterium and Bacteroides should be monitored for colonization

2020 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Anaerobic Bacteria ◽  
Anaerobic Respiration ◽  
Clinical Results ◽  
Cellular Level ◽  
Heme Binding ◽  
Sequencing Data ◽  
The Us ◽  
Hemoglobin Degradation ◽  
Mitochondrial Cytochrome Oxidase ◽  
Different Parts

The Covid19 pandemic [1], triggered by novel strain of a coronavirus SARS-Cov2 [2] has spread globally like a wildfire [3] after being first detected in Wuhan.Previous studies from China, Brazil and the US:Previously, several sequencing datasets - some of them published [4–9], others having sequencing data sub- mitted in NCBI (with no associated publications) [10–13] - have revealed the metagenome in these patients from different parts of the world. The overwhelming presence of anaerobic bacteria (very low concentration of oxygen kills them) in these patients has led to the theory that antibiotics (like doxycycline/Metronidazole) targeting these specific organisms may provide better clinical results [14].Two more studies added - patients from Peru and Cambodia:Here, two more studies from Peru (Table 1) and Cambodia (Table 2) provide further corroboration to the anaerobic bacteria theory. These anaerobic bacteria have virtually colonized the metagenome - pushing other aerobic species out of the niche, disrupting the homeostasis. Around 30% and 23% of the reads from Peru and Cambodia are bacterial, respectively. This is not observed in other patients, even when having chronic issues [15].Common opportunistic anaerobic bacteria in this global metagenomic Covid19 datasetHere, I enumerate common opportunistic anaerobic bacteria present in this global metagenomic Covid19 dataset (Table 3). Any or multiple of these might become the main colonizer after SARS-Cov2 infection in Covid19. The trigger of such an event is still elusive. However, once this happens, some of these bacte- ria express hemoglobin degrading proteins [16], heme-binding proteins sequestering heme after hemoglobin degradation [17], ‘plundering‘ iron, and thereby sequestering oxygen [18]. Hypoxia could also result from formate, the by-product of anaerobic respiration, which inhibits mitochondrial cytochrome oxidase, causing hypoxia at the cellular level [19].

scholarly journals Paper Electrophoresis of Abnormal Hemoglobins and Its Clinical Applications

Blood ◽  
1954 ◽  
Vol 9 (9) ◽  
pp. 897-910 ◽  
Author(s):  
ARNO G. MOTULSKY ◽  
MILTON H. PAUL ◽  
E. L. DURRUM
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Fetal Hemoglobin ◽  
Paper Electrophoresis ◽  
Clinical Applications ◽  
Hemoglobin C ◽  
Hemoglobin Type ◽  
Cell Life ◽  
Practical Tool ◽  
Adult Hemoglobin

Abstract 1. Paper electrophoresis of abnormal hemoglobins is a simple and convenient technic for the study of the hereditary hemoglobinopathies. 2. A semiquantitative paper electrophoretic technic is described, which allows rather accurate quantitation of the various hemoglobin components by inspection alone. 3. For exact results, the more elaborate technics of elution or photoelectric scanning may be employed. The accuracy of these quantitative technics is illustrated by artificial mixture experiments. 4. The clinical applications of the method in the study of sickle cell disease and hemoglobin C abnormalities are discussed. Apart from the more common hemoglobin abnormalities (such as sickle cell trait, sickle cell anemia, C trait, sickle cell-hemoglobin C disease), a patient with 100 per cent hemoglobin C (homozygous hemoglobin C disease) and a Negro patient with sickle cell-thalassemia disease were discovered. Normal adult hemoglobin (hemoglobin A) was found in all other hereditary and acquired anemias studied. Slightly increased amounts of fetal hemoglobin were detected in cases of hereditary nonspherocytic hemolytic disease and aregenerative anemia. 5. This technic may be used for red cell life span determinations by serially following the disappearance of a certain hemoglobin type transfused into a patient with a different hemoglobin variety. Further applications of the technic are suggested. 6. The combination of the technics of paper electrophoresis and alkali denaturation offer an adequate, simple, and practical tool for diagnosis and investigation of hereditary hemoglobinopathies. 7. Identical apparatus and buffer may be used for serum protein electrophoresis.

scholarly journals Decreased IL-6 and NK Cells in Early-Stage Lung Adenocarcinoma Presenting as Ground-Glass Opacity

2021 ◽  
Vol 11 ◽  
Author(s):  
Pengfei Zhang ◽  
Boxue He ◽  
Qidong Cai ◽  
Guangxu Tu ◽  
Xiong Peng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Nk Cells ◽  
Nk Cell ◽  
Early Stage ◽  
Ground Glass Opacity ◽  
Tumor Infiltrating Lymphocytes ◽  
Ground Glass ◽  
Normal Lung ◽  
Sequencing Data ◽  
Primary Lung Adenocarcinoma

BackgroundLung ground-glass opacities (GGOs) are an early manifestation of lung adenocarcinoma. It is of great value to study the changes in the immune microenvironment of GGO to elucidate the occurrence and evolution of early lung adenocarcinoma. Although the changes of IL-6 and NK cells in lung adenocarcinoma have caught global attention, we have little appreciation for how IL-6 and NK cells in the lung GGO affect the progression of early lung adenocarcinoma.MethodsWe analyzed the RNA sequencing data of surgical specimens from 21 patients with GGO-featured primary lung adenocarcinoma and verified the changes in the expression of IL-6 and other important immune molecules in the TCGA and GEO databases. Next, we used flow cytometry to detect the protein expression levels of important Th1/Th2 cytokines in GGO and normal lung tissues and the changes in the composition ratio of tumor infiltrating lymphocytes (TILs). Then, we analyzed the effect of IL-6 on NK cells through organoid culture and immunofluorescence. Finally, we explored the changes of related molecules and pathway might be involved.ResultsIL-6 may play an important role in the tumor microenvironment of early lung adenocarcinoma. Further research confirmed that the decrease of IL-6 in GGO tissue is consistent with the changes in NK cells, and there seems to be a correlation between these two phenomena.ConclusionThe IL-6 expression status and NK cell levels of early lung adenocarcinoma as GGO are significantly reduced, and the stimulation of IL-6 can up-regulate or activate NK cells in GGO, providing new insights into the diagnosis and pathogenesis of early lung cancer.

scholarly journals Correlation of fetal hemoglobin in different cancer patients and sickle cell anaemia: A review

2021 ◽  
Vol 12 (1) ◽  
pp. 396-400
Author(s):  
Ayesha Shahid ◽  
Jan Peerzada Fawad ullah
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Cell Growth ◽  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Fetal Hemoglobin ◽  
Globin Chain ◽  
Adult Hemoglobin ◽  
Malignant Condition ◽  
Stem Cell Growth Factor

Fetal hemoglobin is the main hemoglobin during gestation period. But this globin chain is replaced and is taken over by adult hemoglobin. Sometimes this switch from fetal to adult fails to occur leading to production of fetal hemoglobin as in case of sickle cell anemia. It is also observed that fetal hemoglobin expression is also seen under malignant condition. In malignancy the spleen, liver as well as gut acquire its ability to produce fetal hemoglobin. Certain HbF cells inducing factor such as stem cell growth factor and interleukin -3 also promote HbF erythropoiesis. HbF cells are indicated as a biomarker of tumour cells implicated in many carcinomas observed by immunohisto chemical investigations.

scholarly journals Differences in Antigenic Specificity of Human Normal Adult, Fetal, and Sickle Cell Anemia Hemoglobin

Blood ◽  
1953 ◽  
Vol 8 (5) ◽  
pp. 422-433 ◽  
Author(s):  
MORRIS GOODMAN ◽  
DAN H. CAMPBELL
Keyword(s):  
Physicochemical Properties ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Normal Adult ◽  
Antigenic Specificity ◽  
Antigenic Determinants ◽  
Adult Hemoglobin

Abstract 1. Small differences in the antigenic structures of human normal adult hemoglobin and sickle cell anemia hemoglobin were found to exist. A difference in the serologic behavior of these two hemoglobins attributable to a factor other than that of antigenic specificity was also demonstrated. This factor is thought to pertain to differences in the physicochemical properties of the 2 hemoglobins. 2. Rabbit antiserums failed to show a difference in antigenic specificity, but with chicken antiserums a difference was clearly demonstrated when the in vitro reactions were performed under conditions which produced maximal precipitation. Results suggest that these 2 hemoglobins have a predominance of common antigenic determinants but a small number that are unique for each of the types. 3. Relatively large differences in specificity were found to exist between fetal hemoglobin and adult hemoglobin which suggest that only a few antigenic groups are shared in common by the 2 types. 4. The second, minor hemoglobin in patients with sickle cell anemia was shown to have an antigenic specificity that was either identical with or very similar to that of fetal hemoglobin.

scholarly journals Studies on Abnormal Hemoglobins

Blood ◽  
1955 ◽  
Vol 10 (5) ◽  
pp. 405-415 ◽  
Author(s):  
KARL SINGER ◽  
LILY SINGER ◽  
SEYMOUR R. GOLDBERG
Keyword(s):  
Sickle Cell Disease ◽  
Genetic Control ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sickle Cell Trait ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Negro Population ◽  
Different Types ◽  
Adult Hemoglobin

Abstract (1) Four Negro patients with mild sickle cell-thalassemia disease (heterozygous for the genes for S hemoglobin and for thalassemia) are described. In contrast to reports in the literature, some of these patients are only mildly anemic, or not anemic at all. In three, the values for MCV and MCH are decreased, but in one, all hematologic indices are normal. All four individuals show leptocytosis and elevated reticulocyte levels. (2) Hemoglobin analyses, consisting of a combination of electrophoresis and the alkali denaturation technic, demonstrate the S + A + F pattern in three, and the S + A pattern in the fourth. These patterns are considered pathognomonic for sickle cell-thalassemia disease. They may be sharply differentiated from the S + F pattern, encountered in classical (homozygous) sickle cell anemia, and from the A + S pattern found in the heterozygous sickle cell trait. The various types of hemoglobin are reported in the sequence of their quantitative representation in the hemolysate. Hemoglobin analysis is indispensable for the recognition of the different types of sickle cell disease. (3) Evidence is cited that clinically almost asymptomatic sickle cell-thalassemia disease is probably not too rare in the American Negro population. (4) The genetic aspects of the production of fetal hemoglobin are discussed. It is postulated that the production of fetal hemoglobin is also under genetic control. The genes for fetal hemoglobin are not alleles of the genes for normal adult hemoglobin and are physiologically almost completely suppressed by the latter. Pathologic genes may render this suppression incomplete.

scholarly journals Insulin-like Growth Factor Binding Protein-3 (IGFBP3) Induces Fetal Hemoglobin in Hematopoietic Stem and Progenitor Cells from Patients with Sickle Cell Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 722-722
Author(s):  
Alireza Paikari ◽  
Tian Mi ◽  
Yankai Zhang ◽  
Evadnie Rampersaud ◽  
Guolian Kang ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Insulin Signaling ◽  
Research Funding ◽  
Fetal Hemoglobin ◽  
Whole Genome ◽  
Sequencing Data ◽  
Hematopoietic Stem ◽  
Gamma Globin ◽  
Stem And Progenitor Cells ◽  
Erythroid Maturation

Abstract Background: Fetal hemoglobin (HbF, α2g2) induction is known to reduce the clinical complications of sickle cell anemia (SCA). Progress in identifying novel HbF inducing strategies has been slowed by an incomplete understanding of gamma-globin regulation. We have used natural genetic variation to identify novel genes and pathways associated with HbF levels in patients with SCA, beginning with whole exome sequencing (WES). This approach identified FOXO3, a transcription factor important for insulin signaling and erythroid maturation, among other functions, as a positive regulator of HbF. We then confirmed the role of FOXO3 in HbF regulation with functional studies in erythroid culture (Zhang, Blood 2018). To overcome the limitations of WES, namely the absence of regulatory and promotor sequencing data, we performed whole genome sequencing (WGS) on 658 pediatric SCA patients, and analyzed the data for common variants predictive of HbF levels. Methods : WGS was performed on a cohort of 658 pediatric patients with HbSS and HbSβ0 with IRB approval from Texas Children's Hospital, and from St Jude Children's Research Hospital, as part of the Sickle Cell Clinical Research and Intervention Program (Hankins et al 2018). Baseline HbF levels, not on hydroxyurea therapy, was measured by HPLC. Subjects were between 6 months and 21 years of age from both institutions; 52% were male. We used mixed linear regression models to screen for variants associated with transformed HbF values, and performed ridge regression with 10-fold cross-validation to confirm associations after adjustment for HBG and BCL11A-associated variants, age, sex, and race (determined by principal components analysis). Hematopoietic stem and progenitor cells (HSPCs) from 3 patients (all HbSS) were treated with recombinant human IGFBP3 (1µg/ml) beginning on day 7 of two-phase culture. Effects of IGFBP3 on gamma-globin expression were evaluated by RT-qPCR, and on HbF levels by HPLC, on days 14 and 21 of culture. The effects of IGFBP3 on known modifiers of HbF and the FOXO3 pathway were assessed by RT-qPCR and western blot on day 21 of culture. Erythroid maturation was assessed by flow cytometry using anti-CD71, GPA, and Band3 on day 21 of culture. Results: Our whole genome sequencing data identified a strong association between all 11 variants 200 kb upstream of IGFBP3 and baseline HbF levels (p<1x10-9). The association of IGFBP3 variants with HbF remained after correcting for HBG and BCL11A variants in addition to patient age, sex, and race (p<0.001). Eleven SNPs were tested, and corrected for multiple testing. Mean HbF levels for patients heterozygous for an IGFBP3 variant predicted to alter IGFBP3 levels as determined by NESDA conditional eQTL catalog (Jenson et al, 2017) were 43% higher compared to patients without a variant (t-test p<0.0002). In erythroblasts treated with IGFBP3, gamma globin expression doubled compared to untreated (p=0.01). %HbF in IGFBP3 treated cells at day 21 of culture was the same as on day 14, while the HbF of untreated cells declined (Figure 1). IGFBP3 did not alter expression of known gamma globin regulators BCL11A, KLF1, and MYB, nor did it alter erythroid maturation as measured by flow cytometry with anti-CD71, GPA, and Band3, and morphologic examination. Conclusions: WGS analysis identified variants in the regulatory region of IGFBP3 as associated with higher levels of HbF. Addition of exogenous human recombinant IGFBP3 to HSPCs prevented the physiologic decline of HbF, resulting in higher %HbF levels in erythroblasts, functionally confirming the association. Exogenous IGFBP3 did not arrest maturation, supporting our hypothesis that IGFBP3 affects HbF production directly via gamma globin induction, rather than through manipulation of maturation. IGFBP3 did not alter expression of known regulators of HbF (BCL11A, KLF1, and MYB). These findings are compatible with our prior data identifying FOXO3 as a positive regulator of gamma globin, and our use of metformin as a HbF inducer in an ongoing clinical trial. Metformin increases IGFBP3 levels, and it has been shown that increases in IGFBP3 lead to activation of FOXO3 through the insulin signaling pathway. We therefore conclude that the insulin signaling pathway plays a significant role in gamma-globin regulation and is an important therapeutic target for HbF induction in patients with SCA. Disclosures Hankins: Global Blood Therapeutics: Research Funding; bluebird bio: Consultancy; Novartis: Research Funding; NCQA: Consultancy. Estepp:Global Blood Therapeutics: Consultancy, Research Funding; NHLBI: Research Funding; Daiichi Sankyo: Consultancy; ASH Scholar: Research Funding.

COVID-19: Update on Pathogenesis and Treatment Strategies

2020 ◽  
Vol 16 (1) ◽  
pp. 1-5
Author(s):  
Rakesh K. Chauhan ◽  
Pramod K. Sharma ◽  
Shikha Srivastava
Keyword(s):  
Monoclonal Antibody ◽  
Plasma Membrane ◽  
Human Monoclonal Antibody ◽  
Cardiac Injury ◽  
Treatment Strategies ◽  
Severe Pneumonia ◽  
Ground Glass Opacity ◽  
Golgi Membrane ◽  
Virus Particles ◽  
Global Pandemic

COVID-19 (Coronavirus disease) is the most contagious virus, which has been characterized as a global pandemic by WHO. The pathological cycle of COVID-19 virus can be specified as RNAaemia, severe pneumonia, along with the Ground-glass opacity (GGO), and acute cardiac injury. The S protein of Coronavirus has been reported to be involved in the entry of the virus into the host cell, which can be accomplished by direct membrane fusion between the virus and plasma membrane. In the endoplasmic reticulum or Golgi membrane, the newly formed enveloped glycoproteins are introduced. The spread of disease occurs due to contact and droplets unleashed by the vesicles holding the virus particles combined with the plasma membrane to the virus released by the host. The present manuscript describes the pathogenesis of COVID-19 and various treatment strategies that include drugs such as chloroquine and hydroxychloroquine, an anti-malarial drug, antibodies: SARS-CoV-specific human monoclonal antibody CR3022 and plasma treatment facilitate the therapeutic effect.

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