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Cell Oct 2020Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes...
Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from over 12,000 genes across 32 normal human tissues. Tissue-specific or tissue-enriched proteins were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode tissue-specific proteins. Discordance of RNA and protein enrichment revealed potential sites of synthesis and action of secreted proteins. The tissue-specific distribution of proteins also provides an in-depth view of complex biological events that require the interplay of multiple tissues. Most importantly, our study demonstrated that protein tissue-enrichment information can explain phenotypes of genetic diseases, which cannot be obtained by transcript information alone. Overall, our results demonstrate how understanding protein levels can provide insights into regulation, secretome, metabolism, and human diseases.
Topics: Gene Expression; Gene Expression Profiling; Humans; Proteome; Proteomics; RNA; RNA, Messenger; Transcriptome
PubMed: 32916130
DOI: 10.1016/j.cell.2020.08.036 -
American Journal of Medical Genetics.... Dec 2020
Topics: Anticoagulants; Blood Coagulation; COVID-19; Humans; Post-Exposure Prophylaxis; Proteus Syndrome; COVID-19 Drug Treatment
PubMed: 32914583
DOI: 10.1002/ajmg.a.61861 -
JAMA Sep 2020Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.
OBJECTIVE
To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.
INTERVENTIONS
Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.
MAIN OUTCOMES AND MEASURES
The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.
RESULTS
Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.
CONCLUSIONS AND RELEVANCE
Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04292730.
Topics: Adenosine Monophosphate; Administration, Intravenous; Aged; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Administration Schedule; Female; Hospitalization; Humans; Male; Middle Aged; Odds Ratio; Pandemics; Patient Acuity; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32821939
DOI: 10.1001/jama.2020.16349 -
The FEBS Journal May 2021Mutations occurring during embryonic development affect only a subset of cells resulting in two or more distinct cell populations that are present at different levels,... (Review)
Review
Mutations occurring during embryonic development affect only a subset of cells resulting in two or more distinct cell populations that are present at different levels, also known as postzygotic mosaicism (PZM). Although PZM is a common biological phenomenon, it is often overlooked as a source of disease due to the challenges associated with its detection and characterization, especially for very low-frequency variants. Moreover, PZM can cause a different phenotype compared to constitutional mutations. Especially, lethal mutations in receptor tyrosine kinase (RTK) pathway genes, which exist only in a mosaic state, can have completely new clinical manifestations and can look very different from the associated monogenic disorder. However, some key questions are still not addressed, such as the level of mosaicism resulting in a pathogenic phenotype and how the clinical outcome changes with the development and age. Addressing these questions is not trivial as we require methods with the sensitivity to capture some of these variants hidden away in very few cells. Recent ultra-accurate deep-sequencing approaches can now identify these low-level mosaics and will be central to understand systemic and local effects of mosaicism in the RTK pathway. The main focus of this review is to highlight the importance of low-level mosaics and the need to include their detection in studies of genomic variation associated with disease.
Topics: Child; Class I Phosphatidylinositol 3-Kinases; Embryo, Mammalian; Fibrous Dysplasia, Polyostotic; Gene Expression; Genes, Lethal; Germ-Line Mutation; Humans; Infant; Infant, Newborn; Mosaicism; Phenotype; Proteus Syndrome; Receptor Protein-Tyrosine Kinases; Signal Transduction; Sturge-Weber Syndrome
PubMed: 32810928
DOI: 10.1111/febs.15528 -
Experimental and Therapeutic Medicine Sep 2020Proteus syndrome (PS) is an extremely rare and sporadic disorder characterized by asymmetric and/or disproportionate overgrowth of limbs, hamartomas, and vascular...
Proteus syndrome (PS) is an extremely rare and sporadic disorder characterized by asymmetric and/or disproportionate overgrowth of limbs, hamartomas, and vascular malformations. The onset of overgrowth usually involves the skin, bone, fat, and other connective tissues in a patchy or mosaic pattern. Partial gigantism of the affected limb or digit is a pathognomonic sign of PS. Thus far, only a few cases of PS have been recorded in the literature. In the present report, a case of PS in a 35-year old woman with classic cerebriform plantar hyperplasia and macrodactyly of the left foot was documented. The clinical and molecular characteristics and differential diagnosis of PS are also discussed in this report.
PubMed: 32765766
DOI: 10.3892/etm.2020.8986 -
Microbial Pathogenesis Oct 2020In order to investigate enterobacteria presence involved in the secondary infections in Porcine Reproductive and Respiratory Syndrome (PRRS) pigs with different viral...
In order to investigate enterobacteria presence involved in the secondary infections in Porcine Reproductive and Respiratory Syndrome (PRRS) pigs with different viral co-infections, we identified enterobacteria for guiding clinical treatment. Twenty-one diseased pigs were diagnosed with the PRRS virus (PRRSV) and other 7 virus primers by PCR/RT-PCR in the lung and spleen samples. Enterobacteria were isolated using MacConkey agar from 5 visceral samples of PRRS pigs, and identified by 16S rDNA sequencing. PRRSV was positive in 100% of the lung samples and 81.0% of the spleen samples. Seven diseased pigs were diagnosed with only PRRSV infection (33.3%), 7 pigs with PRRSV and 1 or 2 other viruses (33.3%) and 7 pigs with PRRSV and more than 2 types of other viruses (33.3%). PRRSV was more inclined to co-infect pigs with porcine group A rotavirus (PARV) with the co-infection rate of 52.4% (11/21). Approximately 13 types of bacteria were successfully isolated from lung, spleen, liver, kidney and lymph node samples of different PRRS pigs. Enterobacteria were isolated in 100% of lung, liver and lymph samples from pigs infected with PRRSV alone. However, the isolation rates were significantly decreased in the more than 3 viruses co-infection group. Escherichia coli was the most prevalent bacterium, followed by Morganella, Proteus, Shigella, Salmonella, Klebsiella and Aeromonas. Most of the isolated enterobacteria were opportunistic pathogens. Therefore, timely combination with antimicrobial agents is necessary for effective treatment of PRRS-infected pigs.
Topics: Animals; Coinfection; Enterobacteriaceae; Porcine Reproductive and Respiratory Syndrome; Porcine respiratory and reproductive syndrome virus; Swine; Viscera
PubMed: 32659314
DOI: 10.1016/j.micpath.2020.104385 -
Scientific Reports Jul 2020Escherichia coli is the dominant bacterial cause of UTI among the uropathogens in both developed and developing countries. This study is to investigate the effect of...
Escherichia coli is the dominant bacterial cause of UTI among the uropathogens in both developed and developing countries. This study is to investigate the effect of Acacia nilotica aqueous extract on the survival and biofilm of isolated pathogens to reduce UTIs diseases. A total of 170 urine samples were collected from Luxor general hospital and private medical analysis laboratories in Luxor providence, Egypt. Samples were screened for the incidence of uropathogens by biochemical tests, antibiotics susceptibility, detection of virulence, and antibiotic-resistant genes by multiplex PCR, biofilm formation, and time-killing assay. Escherichia coli is by far the most prevalent causative agent with the percentage of 73.7% followed by Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeuroginosa, and Acinetobacter baumanii. Isolates were multidrug-resistant containing bla, bla, bla, qnrs, and aac(3)-Ia resistant genes. All isolates were sensitive to 15-16.7 mg ml of Acacia nilotica aqueous extract. Time killing assay confirmed the bactericidal effect of the extract over time (20-24 h). A high percentage of 3-Cyclohexane-1-Carboxaldehyde, 2,6,6-trimethyl (23.5%); á-Selinene (15.12%); Oleic Acid (14.52%); Globulol (11.35%) were detected among 19 bioactive phytochemical compounds in the aqueous extract of A. nilotica over the GC-mass spectra analysis. The plant extract reduced significantly the biofilm activity of E. coli, K. pneumoniae, P. mirabilis, and P. aeuroginosa by 62.6, 59. 03, 48.9 and 39.2%, respectively. The challenge to improve the production of A. nilotica phytochemicals is considered a very low price for the return.
Topics: Acacia; Acinetobacter Infections; Acinetobacter baumannii; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biofilms; Child; Drug Resistance, Multiple, Bacterial; Escherichia coli Infections; Female; Gas Chromatography-Mass Spectrometry; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Plant Extracts; Proteus Infections; Proteus mirabilis; Pseudomonas Infections; Urinary Tract Infections; Uropathogenic Escherichia coli; Young Adult
PubMed: 32636429
DOI: 10.1038/s41598-020-67732-w -
International Journal of Surgery Case... 2020Proteus Syndrome is a very rare syndrome, where only 200 cases has been reported so far.
INTRODUCTION
Proteus Syndrome is a very rare syndrome, where only 200 cases has been reported so far.
PRESENTATION OF CASE
We were presented with a 45 year male with features of chronic Intestinal Obstruction. On Examination he had a giant right middle finger (Fig. 1), giant left forearm, with amputated left hand, and massive abdominal distension with tenderness in upper abdomen.
DISCUSSION
Proteus Syndrome (PS) is a very rare syndrome, diagnosis of which is based on Biescker's criteria, either one finding from Criteria A, or two from B, or three from C. Confirmation of the disease is by finding genetic variation in the AKT1 gene. In addition to the presence to some of the criteria in our patient, he also had numerous intestinal lipomatosis, involving almost most of his small intestine. This in addition to high riding caecum and a narrow long mesentery which contributed to the development of small Bowel volvulus.
CONCLUSION
PS should be suspected whenever we encounter patients with macrodactyly and this should alert us to the possibility of other congenital anomalies.
PubMed: 32563816
DOI: 10.1016/j.ijscr.2020.06.052 -
Cold Spring Harbor Molecular Case... Jun 2020Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively...
Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in , a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 yr of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in .
Topics: Alleles; Allelic Imbalance; Amino Acid Substitution; Cervical Vertebrae; Genetic Association Studies; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant; Magnetic Resonance Imaging; Male; Medical History Taking; Mutation; Phenotype; Proteus Syndrome; Proto-Oncogene Proteins c-akt; Radiography; Symptom Assessment
PubMed: 32327430
DOI: 10.1101/mcs.a005181 -
Journal of the American Academy of... Feb 2021Proteus syndrome is an overgrowth disorder caused by a mosaic activating AKT1 variant. Hair abnormalities in Proteus syndrome have rarely been reported, and frequencies... (Observational Study)
Observational Study
BACKGROUND
Proteus syndrome is an overgrowth disorder caused by a mosaic activating AKT1 variant. Hair abnormalities in Proteus syndrome have rarely been reported, and frequencies of such findings have not been elucidated.
OBJECTIVE
To define the types and frequencies of hair findings in individuals with Proteus syndrome.
METHODS
A cross-sectional study was conducted of individuals with clinical features of Proteus syndrome and a confirmed pathogenic variant in AKT1 evaluated between November 1996 and June 2019 at the National Institutes of Health Clinical Center. Medical records were reviewed for patterning, density, and color of hair on the body and scalp.
RESULTS
Of 45 individuals evaluated, 29 (64%) had asymmetric hypertrichosis on the body. This included unilateral blaschkoid hypertrichotic patches overlying normal skin or epidermal nevi in 16 (36%), unilateral nonblaschkoid hypertrichotic patches in 11 (24%), and unilateral limb hypertrichosis in 10 (22%). Diffuse, scattered, or patchy changes in scalp hair density or color were present in 11 individuals (24%).
LIMITATIONS
The retrospective, observational design, and limited longitudinal follow-up.
CONCLUSIONS
Asymmetric variations in hair distribution, thickness, length, and color contribute to the overall mosaic appearance of the skin in Proteus syndrome, an observation that provides novel insights into the role of phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling in skin appendage development.
Topics: Adolescent; Adult; Child; Child, Preschool; Cross-Sectional Studies; DNA Mutational Analysis; Female; Hair Follicle; Humans; Hypertrichosis; Male; Mosaicism; Mutation; Phosphatidylinositol 3-Kinases; Prevalence; Proteus Syndrome; Proto-Oncogene Proteins c-akt; Retrospective Studies; Signal Transduction; Young Adult
PubMed: 32035943
DOI: 10.1016/j.jaad.2020.01.078