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 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 Secondary infection by anaerobic bacteria possibly ensues a battle for oxygen in SARS-Cov2 infected patients: anaerobe-targeting antibiotics (like doxycycline/Metronidazole) to supplement Azithromycin in the treatment regimen of COVID19?

2020 ◽  
Author(s):  
Sandeep Chakraborty ◽  
Gautam Das
Keyword(s):  
Health Care ◽  
Treatment Regimen ◽  
Health Care Providers ◽  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
Anaerobic Bacteria ◽  
Care Providers ◽  
Rna Seq ◽  
Sequencing Data ◽  
Hemoglobin Degradation

The Covid19 pandemic [1], triggered by novel strain of a coronavirus SARS-Cov2 [2] first detected in Wuhan City, China, has spread globally like a wildfire [3], resulting in significant loss of life [4] and endangering health care providers and community health care workers [5]. Understanding and interpreting the underlying metagenome of this disease will help provide direction for the right treatment regimen.RNA-sequencing as a more sensitive and comprehensive diagnostic test:RNA-sequencing is a more sensitive and comprehensive test (albeit more time-consuming and expensive), providing information on a larger range of organisms (metagenomic profile) present in the patient sample in comparison to reverse transcription PCR or antibody-testing. For example in one study, Covid19 patients were tested for four bacterial species, including Mycoplasma, with negative results. However, the sequencing data clearly reveals the presence of Mycoplasma [6]. Another study of 2 patients in Wuhan [7] used the Metaphlan2 program to conclude that Capnocytophaga and Veillonella are the only bacterial species present in one patient, and found none in another, when this clearly was not the case [8].Other RNA-sequencing data submitted in NCBI has identified several potentially pathogenic bacteria in multiple patient samples from across the globe [6,9–12]. The obligate anaerobe Prevotella had signifi- cant abundance in one patient, over-expressing immune-suppression proteins [13]. While all studies reveal Prevotella in varying abundance, other bacteria (Lautropia, Cutibacterium, Haemophilus, Pseudomonas, Sphingomonas etc.) are also found in significant quantity to attract attention to secondary infections [6,12]. RNA-seq also reveals extremely low viral loads in many patients, explaining the high false negatives (8 times negative before a positive) [14] and failure to detect virus using RT-PCR in severely sick patients, who were CT+ve [15].Anaerobic bacteria hypothesis:Recent studies from Italy have suggested that Covid-19 does not lead to a ‘“typical” acute respiratory distress syndrome (ARDS)’ [16]. Furthermore, elevated D-dimer levels suggest hemoglobin degradation leading to coagulation [17,18].A simple hypothesis that emerges from RNA-seq data is over-representation of anaerobic bacteria in Covid19 patients, not found in BALF samples from normal patients (unpublished data), in a battle for oxygen. These bacteria express hemoglobin degrading proteins [19], heme-binding proteins sequestering heme after hemoglobin degradation [20], ‘plundering‘ iron, and thereby sequestering oxygen [21]. Hypoxia could also result from formate, the by-product of anaerobic respiration, which inhibits mitochondrial cytochrome oxidase, causing hypoxia at the cellular level [22].Our proposal for anaerobe-specific antibiotics as a therapy:We propose the use of anaerobe-specific antibiotics, like Metronidazole, in the treatment regimen to supple- ment the successfully used doxycycline/Azithromycin antibiotic [23], along with anti-coagulants [24].

scholarly journals Industry update for May 2019

2019 ◽  
Vol 10 (9) ◽  
pp. 555-561
Author(s):  
Louise Rosenmayr-Templeton
Keyword(s):  
Gene Therapy ◽  
Cost Effectiveness ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Clinical Results ◽  
The Other ◽  
Press Releases ◽  
The Us ◽  
True Meaning ◽  
Genetic Medicine

This industry update features a round-up of pharmaceutical news in May 2019 based on press releases and websites. The month was characterized by the achievement of significant milestones in gene therapy. The biggest of these was the US FDA’s approval of Zolgensma®. This medicine sums up the promise and price of genetic medicine. On one hand the clinical results show Zolgensma can dramatically improve the prognosis for infants with spinal muscular atrophy after just one administration, while on the other, it has been priced at around US$2.1 million. With more such therapies likely to reach the market, the debate on Zolgensma goes beyond cost, to overall affordability, the true meaning of cost–effectiveness and how to reward companies for effective, innovative medicines.

scholarly journals Strings Attached

2017 ◽  
Vol 139 (05) ◽  
pp. 32-37
Author(s):  
Tim Sprinkle
Keyword(s):  
Public Relations ◽  
Growth Potential ◽  
American Business ◽  
Us Economy ◽  
Foreign Government ◽  
The Us ◽  
The World ◽  
Us Government ◽  
International Investors ◽  
Different Parts

This article discusses reasons for various American startup companies to shift abroad for funding and production, and their impact on the American business scenarios. Founders are accepting funding from overseas investors, setting up supply chains in different parts of the world, servicing customers internationally, and even selling their businesses to foreign government-backed funds. Although the idea of losing American inventions and technologies to international investors and buyers is not generally good for public relations, the current landscape of global startup development has winners on both sides, and overseas involvement in US companies does not necessarily mean a net loss domestically. The US government must find a way to move the US economy forward, preventing predatory pricing and mercantilist practices by exporters while at the same time reaping the international flow of ideas and funds that power innovation. The experts believe that ignoring the rest of the world would not only limit the growth potential of US startups, but over time would reduce America’s global leadership in innovation.

scholarly journals Mountain stoneflies may tolerate warming streams: evidence from organismal physiology and gene expression

2019 ◽  
Author(s):  
Scott Hotaling ◽  
Alisha A. Shah ◽  
Kerry L. McGowan ◽  
Lusha M. Tronstad ◽  
J. Joseph Giersch ◽  
...  
Keyword(s):  
Thermal Stress ◽  
Constitutive Expression ◽  
High Elevation ◽  
Cellular Level ◽  
Cellular Stress Response ◽  
Mountain Stream ◽  
Sequencing Data ◽  
Stream Insects ◽  
Short Term Exposure ◽  
Genes Encoding

AbstractRapid glacier recession is altering the physical conditions of headwater streams. Stream temperatures are predicted to rise and become increasingly variable, putting entire meltwater-associated biological communities at risk of extinction. Thus, there is a pressing need to understand how thermal stress affects mountain stream insects, particularly where glaciers are likely to vanish on contemporary timescales. In this study, we tested the critical thermal maximum (CTMAX) of stonefly nymphs representing multiple species and a range of thermal regimes in the high Rocky Mountains, USA. We then collected RNA-sequencing data to assess how organismal thermal stress translated to the cellular level. Our focal species included the meltwater stonefly, Lednia tumana, which was recently listed under the U.S. Endangered Species Act due to climate-induced habitat loss. For all study species, critical thermal maxima (CTMAX > 20°C) far exceeded the stream temperatures mountain stoneflies experience (< 10°C). Moreover, while evidence for a cellular stress response was present, we also observed constitutive expression of genes encoding proteins known to underlie thermal stress (i.e., heat shock proteins) even at low temperatures that reflected natural conditions. We show that high-elevation aquatic insects may not be physiologically threatened by short-term exposure to warm temperatures and that longer term physiological responses or biotic factors (e.g., competition) may better explain their extreme distributions.

Somatic diseases and suicidal behaviour

2021 ◽  
pp. 321-332
Author(s):  
Elsebeth Stenager ◽  
Egon Stenager ◽  
Annette Erlangsen
Keyword(s):  
Mental Disorders ◽  
Suicidal Behaviour ◽  
Children And Youth ◽  
Medical Settings ◽  
Physical Conditions ◽  
Pain Syndromes ◽  
The Us ◽  
Somatic Disorders ◽  
Somatic Diseases ◽  
Different Parts

The association between somatic disorders and suicidal behaviour has been examined in many studies. Despite large variation in quality and study design, recent studies have improved our knowledge substantially, not only regarding the extent of risk but also factors influencing the risk. Most studies have been conducted in European countries, the US, Australia, Japan, and South Korea. A series of studies have examined suicide risk in relation to somatic disorders of older persons, while others addressed somatic disorders and attempted suicide in children and youth. Physical conditions may play an important role in medical settings, regardless of whether mental disorders are present or not, though especially when mental disorders are present. This chapter presents a review of present knowledge on suicide and suicidal behaviour in selected somatic disorders and pain syndromes, with a focus on studies from different parts of the world.

scholarly journals Nitrosative stress sensing inPorphyromonas gingivalis: structure of and heme binding by the transcriptional regulator HcpR

2019 ◽  
Vol 75 (4) ◽  
pp. 437-450 ◽  
Author(s):  
B. Ross Belvin ◽  
Faik N. Musayev ◽  
John Burgner ◽  
J. Neel Scarsdale ◽  
Carlos R. Escalante ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Gas Sensing ◽  
Anaerobic Bacteria ◽  
Heme Iron ◽  
Heme Binding ◽  
X Ray ◽  
X Ray Scattering ◽  
Stress Sensing ◽  
High Degree

Although the HcpR regulator plays a vital step in initiation of the nitrosative stress response in many Gram-negative anaerobic bacteria, the molecular mechanisms that it uses to mediate gas sensing are not well understood. Here, a 2.6 Å resolution crystal structure of the N-terminal sensing domain of the anaerobic periodontopathogenPorphyromonas gingivalisHcpR is presented. The protein has classical features of the regulators belonging to the FNR-CRP family and contains a hydrophobic pocket in its N-terminal sensing domain. It is shown that heme bound to HcpR exhibits heme iron as a hexacoordinate system in the absence of nitric oxide (NO) and that upon nitrosylation it transitions to a pentacoordinate system. Finally, small-angle X-ray scattering experiments on full-length HcpR reveal that the C-terminal DNA-binding domain of HcpR has a high degree of interdomain flexibility.

scholarly journals Quantification of labile heme in live malaria parasites using a genetically encoded biosensor

2017 ◽  
Vol 114 (11) ◽  
pp. E2068-E2076 ◽  
Author(s):  
James R. Abshire ◽  
Christopher J. Rowlands ◽  
Suresh M. Ganesan ◽  
Peter T. C. So ◽  
Jacquin C. Niles
Keyword(s):  
Blood Cells ◽  
Antimalarial Activity ◽  
Cellular Damage ◽  
Malarial Parasite ◽  
Redox Activity ◽  
Parasite Development ◽  
Heme Binding ◽  
Environmental Perturbations ◽  
Hemoglobin Degradation ◽  
Relevant Component

Heme is ubiquitous, yet relatively little is known about the maintenance of labile pools of this cofactor, which likely ensures its timely bioavailability for proper cellular function. Quantitative analysis of labile heme is of fundamental importance to understanding how nature preserves access to the diverse chemistry heme enables, while minimizing cellular damage caused by its redox activity. Here, we have developed and characterized a protein-based sensor that undergoes fluorescence quenching upon heme binding. By genetically encoding this sensor in the human malarial parasite, Plasmodium falciparum, we have quantified cytosolic labile heme levels in intact, blood-stage parasites. Our findings indicate that a labile heme pool (∼1.6 µM) is stably maintained throughout parasite development within red blood cells, even during a period coincident with extensive hemoglobin degradation by the parasite. We also find that the heme-binding antimalarial drug chloroquine specifically increases labile cytosolic heme, indicative of dysregulation of this homeostatic pool that may be a relevant component of the antimalarial activity of this compound class. We propose that use of this technology under various environmental perturbations in P. falciparum can yield quantitative insights into fundamental heme biology.

Effects of Cold and Heat Stress on the Chemistry and Cell Structure of Peanut Seeds1

1997 ◽  
Vol 24 (1) ◽  
pp. 32-37 ◽  
Author(s):  
J. A. Singleton ◽  
H. E. Pattee
Keyword(s):  
Heat Stress ◽  
Cell Structure ◽  
Specific Conductivity ◽  
Anaerobic Respiration ◽  
Headspace Analysis ◽  
The United States ◽  
Frost Damage ◽  
Cellular Level ◽  
Peanut Seed ◽  
Irregular Cell

Abstract Frost damage and/or cold stress to crops in the United States runs more than $1 billion per year. In North Carolina during 1983, about 30,000 t of peanuts valued at $16 million were diverted from the edible market due to freeze damage. It is difficult to distinguish if a lot of peanut seed has been exposed to cold or heat stress because in both cases anaerobic respiration predominates. This research was undertaken to distinguish between cold and heat stresses at the cellular level on peanut seed by using dynamic headspace analysis, specific conductivity of the seed leachate, ion chromatography for cations and organic acids, ninhydrin detection for amino acids, and light microscopic techniques. Acetaldehyde, ethanol, and ethyl acetate are produced by both stress conditions. Two isomers of 2,3-butanediol and short-chain acids were identified from cold-stressed seed. These isomers were not found in heat-stressed peanut tissues and can be used to differentiate between the two environmental stresses. Specific conductivity of the leachate was higher from cold-stressed seed than from normal or heat-stressed seed, due to a higher efflux of potassium and acetic acid from the cells. Plasmolysis of the cold-stressed seed cells was consistently observed. Aleurone grains appeared to be larger, more dispersed, and tended to migrate towards the cell wall in the heat-treated samples, whereas the aleurone grains in the cold-stressed samples were smaller and more concentrated at the center of the cell. Irregular cell shape was common to both stresses.

Totality of evidence in development of the bevacizumab biosimilar ABP 215: Central and investigator evaluation of efficacy from the MAPLE study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20708-e20708
Author(s):  
Michael Thomas ◽  
Nick Thatcher ◽  
Jerome H Goldschmidt ◽  
Yuichiro Ohe ◽  
Helen McBride ◽  
...  
Keyword(s):  
Risk Ratio ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Double Blind Study ◽  
Double Blind ◽  
Free Survival ◽  
The Us ◽  
Duration Of Response ◽  
Totality Of Evidence

e20708 Background: ABP 215 (MVASI™ [bevacizumab]) is the first biosimilar to Avastin (bevacizumab) approved in the US and EU. This phase 3, double-blind study compared efficacy of ABP 215 with bevacizumab reference product (RP) in patients with advanced non-squamous NSCLC. Here we report the totality of evidence supporting similarity between ABP 215 and RP, including preclinical VEGF-A isoform binding relevant to the mechanism of action across indications, and clinical results of central and investigator evaluation of tumor response. Methods: VEGF-A kinetic parameters were compared for common isoforms 121, 165 and 189. Patients were randomized 1:1 to ABP 215 or RP 15 mg/kg Q3Wx6 cycles. All patients received carboplatin and paclitaxel Q3W for up to 6 cycles. Disease assessments (CT/MRI) were performed at screening, weeks 7, 13, 19, and Q9W thereafter by the investigator and, independently, by central, blinded radiologists. Efficacy was based on objective tumor assessments according to RECIST 1.1. Copies of all radiographs were submitted for central analysis. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% CI of the risk ratio was within the margin of 0.67-1.5. Additional efficacy analyses included duration of response (DOR) and progression-free survival (PFS). Results: Binding to all 3 isoforms was similar for ABP 215 and RP. In the MAPLE study, 642 patients (ABP 215, 328; RP, 314) were randomized. Based on central analysis, ORR was achieved in 128 (39.0%) patients in the ABP 215 and 131 (41.7%) in the RP groups, (ORR risk ratio: 0.93 [90% CI: 0.80, 1.09]). Based on investigator analysis, ORR was achieved in 157 (47.9%) patients in the ABP 215 and 151 (48.1%) in the RP groups (ORR risk ratio: 1.01 [90% CI: 0.88, 1.16]). Hazard ratio (HR, ABP 215 vs RP) for DOR was 1.08 (95% CI, 0.76, 1.54) and 0.76 (95% CI, 0.48, 1.23) per investigator and central assessment. PFS HR was 1.10 (90% CI, 0.92, 1.33) and 1.03 (90% CI, 0.83, 1.29) per investigator and central assessment. Conclusions: These results further confirm the similarity of ABP 215 and RP and support extrapolation to all available bevacizumab indications. Clinical trial information: NCT01966003.

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