Physiol Rep. 2021 Sep;9(17):e15023. doi: 10.14814/phy2.15023.

ABSTRACT

Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). In the lungs, this manifests as immune cell infiltration and bacterial infections, leading to tissue destruction. Previous work has determined that acute bacterial sphingomyelinase (SMase) decreases CFTR function in bronchial epithelial cells from individuals without CF (nHBEs) and with CF (cfHBEs, homozygous ΔF508-CFTR mutation). This study focuses on exploring the mechanisms underlying this effect. SMase increased the abundance of dihydroceramides, a result mimicked by blockade of ceramidase enzyme using ceranib-1, which also decreased CFTR function. The SMase-mediated inhibitory mechanism did not involve the reduction of cellular CFTR abundance or removal of CFTR from the apical surface, nor did it involve the activation of 5' adenosine monophosphate-activated protein kinase. In order to determine the pathological relevance of these sphingolipid imbalances, we evaluated the sphingolipid profiles of cfHBEs and cfHNEs (nasal) as compared to non-CF controls. Sphingomyelins, ceramides, and dihydroceramides were largely increased in CF cells. Correction of ΔF508-CFTR trafficking with VX445 + VX661 decreased some sphingomyelins and all ceramides, but exacerbated increases in dihydroceramides. Additional treatment with the CFTR potentiator VX770 did not affect these changes, suggesting rescue of misfolded CFTR was sufficient. We furthermore determined that cfHBEs express more acid-SMase protein than nHBEs. Lastly, we determined that airway-like neutrophils, which are increased in the CF lung, secrete acid-SMase. Identifying the mechanism of SMase-mediated inhibition of CFTR will be important, given the imbalance of sphingolipids in CF cells and the secretion of acid-SMase from cell types relevant to CF.

PMID:34514718 | DOI:10.14814/phy2.15023

JAC Antimicrob Resist. 2021 Sep 4;3(3):dlab126. doi: 10.1093/jacamr/dlab126. eCollection 2021 Sep.

ABSTRACT

OBJECTIVES: To evaluate the antimicrobial susceptibility patterns of Pseudomonas aeruginosa isolates collected from the lower respiratory tract of cystic fibrosis (CF) patients.

METHODS: We susceptibility tested 273 contemporary P. aeruginosa isolates from 39 hospitals worldwide (17 countries) by the reference broth microdilution method.

RESULTS: Ceftazidime/avibactam [MIC50/90, 2/8 mg/L; 96.0% susceptible (S)] was the most active agent, followed by ceftolozane/tazobactam (MIC50/90, 1/4 mg/L; 90.5% S), ceftazidime (MIC50/90, 2/>32 mg/L; 80.6% S), piperacillin/tazobactam (MIC50/90, 4/128 mg/L; 80.2% S) and tobramycin (MIC50/90, 2/>16 mg/L; 76.6% S). Ceftazidime/avibactam retained activity against P. aeruginosa isolates non-susceptible to meropenem (86.5% S to ceftazidime/avibactam), piperacillin/tazobactam (85.2% S to ceftazidime/avibactam) or ceftazidime (79.2% S to ceftazidime/avibactam). MDR phenotype was observed among 36.3% of isolates, and 88.9% and 73.7% of MDR isolates were susceptible to ceftazidime/avibactam and ceftolozane/tazobactam, respectively. Against isolates non-susceptible to meropenem, piperacillin/tazobactam and ceftazidime, susceptibility rates were 78.9% for ceftazidime/avibactam and 47.4% for ceftolozane/tazobactam. Ceftazidime/avibactam was active against 65.4% of ceftolozane/tazobactam-non-susceptible isolates and ceftolozane/tazobactam was active against 18.2% of ceftazidime/avibactam-non-susceptible isolates.

CONCLUSIONS: Ceftazidime/avibactam and ceftolozane/tazobactam exhibited potent and broad-spectrum activity against P. aeruginosa isolated from CF patients worldwide, but higher susceptibility rates for ceftazidime/avibactam compared with ceftolozane/tazobactam were observed among the resistant subsets. Ceftazidime/avibactam and ceftolozane/tazobactam represent valuable options to treat CF pulmonary exacerbations caused by P. aeruginosa.

PMID:34514403 | PMC:PMC8417452 | DOI:10.1093/jacamr/dlab126

Front Cell Infect Microbiol. 2021 Aug 27;11:724569. doi: 10.3389/fcimb.2021.724569. eCollection 2021.

ABSTRACT

Hallmarks of cystic fibrosis (CF) are increased viscosity of mucus and impaired mucociliary clearance within the airways due to mutations of the cystic fibrosis conductance regulator gene. This facilitates the colonization of the lung by microbial pathogens and the concomitant establishment of chronic infections leading to tissue damage, reduced lung function, and decreased life expectancy. Although the interplay between key CF pathogens plays a major role during disease progression, the pathophysiology of the microbial community in CF lungs remains poorly understood. Particular challenges in the analysis of the microbial population present in CF sputum is (I) the inhomogeneous, viscous, and slimy consistence of CF sputum, and (II) the high number of human proteins masking comparably low abundant microbial proteins. To address these challenges, we used 21 CF sputum samples to develop a reliable, reproducible and widely applicable protocol for sputum processing, microbial enrichment, cell disruption, protein extraction and subsequent metaproteomic analyses. As a proof of concept, we selected three sputum samples for detailed metaproteome analyses and complemented and validated metaproteome data by 16S sequencing, metabolomic as well as microscopic analyses. Applying our protocol, the number of bacterial proteins/protein groups increased from 199-425 to 392-868 in enriched samples compared to nonenriched controls. These early microbial metaproteome data suggest that the arginine deiminase pathway and multiple proteases and peptidases identified from various bacterial genera could so far be underappreciated in their contribution to the CF pathophysiology. By providing a standardized and effective protocol for sputum processing and microbial enrichment, our study represents an important basis for future studies investigating the physiology of microbial pathogens in CF in vivo - an important prerequisite for the development of novel antimicrobial therapies to combat chronic recurrent airway infection in CF.

PMID:34513734 | PMC:PMC8432295 | DOI:10.3389/fcimb.2021.724569

Cureus. 2021 Sep 3;13(9):e17678. doi: 10.7759/cureus.17678. eCollection 2021 Sep.

ABSTRACT

Propofol and midazolam are commonly used drugs in procedural sedation. Midazolam is widely used for its five principal pharmacologic effects: anxiolysis, sedation and hypnosis, anticonvulsant actions, spinal cord-mediated skeletal muscle relaxation, and anterograde amnesia. Increased talkativeness, emotional release, excitement, and excessive movement are the common paradoxical reactions to all kinds of benzodiazepines, which are reported since the introduction of chlordiazepoxide (Librium), the first benzodiazepine in 1955. In the United States, sedation with a combination of midazolam with opioids accounts for approximately 75% of routine procedural sedations. Most cases are distinctive. However, some data indicate that these reactions are due to serotonin imbalance, a central cholinergic effect, or a reflection of genetically determined variability in benzodiazepine receptor density or affinity (isoreceptors) throughout the brain. The idea of isoreceptors is comparable to that of isoenzymes like genetic variants of pseudocholinesterase. We report a case in which midazolam administration resulted in paradoxical reactions, which manifested as profound delirium with extrapyramidal symptoms after cessation of propofol sedation in a term parturient during cesarean section. This case report describes paradoxical reactions to benzodiazepines in a term parturient promptly reversed with a small dose of flumazenil. Even though paradoxical reactions to benzodiazepines have low prevalence and are not life-threatening, they have to be treated promptly with flumazenil. Therefore, anesthesiologists performing procedural sedation should be aware of untoward reactions and be prepared to manage them promptly.

PMID:34513535 | PMC:PMC8415540 | DOI:10.7759/cureus.17678

Cureus. 2021 Jul 29;13(7):e16723. doi: 10.7759/cureus.16723. eCollection 2021 Jul.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease primarily affecting the respiratory system and gastrointestinal system. The life expectancy of patients with CF has significantly improved due to medical advancement and the effective use of screening techniques. However, new challenges have emerged. Particularly those involving cardiovascular pathology. This study aims to provide a better understanding of the different mechanisms that cause cardiovascular complications in patients with CF, which would help find an efficient treatment that not only prolongs survival but also improves their quality of life. This study extensively reviews different theories such as right ventricular hypertrophy due to lung pathology, ventricular interdependence, the association of nutritional deficiencies and severe cystic fibrosis transmembrane conductance regulator (CFTR) genotypes with myocardial fibrosis, effects of hypoxia, recurrent infections, and systemic inflammation of the heart and blood vessels that explain the direct or indirect involvement of the cardiovascular system in CF. For this review, 258 articles were retrieved from PubMed and Google Scholar. Out of which, a total of 12 high-quality articles were selected using appropriate quality assessment tools and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The result of this study suggests that early detection of cardiovascular dysfunction can improve the survival rate of the patient. Furthermore, this study could aid future researchers in the exploration of various best screening modality techniques for the early detection of cardiovascular dysfunction.

PMID:34513358 | PMC:PMC8405250 | DOI:10.7759/cureus.16723

Gastroenterol Res Pract. 2021 Aug 31;2021:5536563. doi: 10.1155/2021/5536563. eCollection 2021.

ABSTRACT

Inflammatory bowel disease includes ulcerative colitis (UC) and Crohn's disease (CD) of unknown etiology. The expression of ATP-binding cassette (ABC) family proteins has been associated with drug resistance and development of UC. The cystic fibrosis transmembrane conductance regulator (CFTR) or also known as ABCC7 is involved in the inflammatory chronic response. The aim of this study was to evaluate the role of ABCC7/CFTR in UC patients and normal controls without inflammation. This is an exploratory, observational, and cross-sectional study that included a total of 62 patients with UC and normal controls. Gene expression of CFTR was measured by RT-PCR, and protein expression of CFTR was determined by western blot analysis. We found a significant downregulation of the CFTR gene expression in patients with active UC compared to normal controls without inflammation (P < 0.004); even the gene expression of CFTR was decreased in remission UC patients compared to normal controls without inflammation (P = 0.04). The CFTR gene expression was associated with the clinical course of UC and the protein expression of CFTR was decreased in active UC patients compared to normal controls without inflammation suggesting that this molecule might play a role in the inflammation in UC patients.

PMID:34512749 | PMC:PMC8426104 | DOI:10.1155/2021/5536563

Front Pharmacol. 2021 Aug 27;12:737252. doi: 10.3389/fphar.2021.737252. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen causing life-threatening infections in cystic fibrosis patients and immunocompromised individuals, and it is a leading cause of nosocomial infections associated with significant morbidity and mortality. Treatment of P. aeruginosa infections is challenging due to the antibiotic resistance to most of the conventional antibiotics. Development of alternative therapeutic options is urgently demanded for the patients who have antibiotic-resistant infections. Traditional Chinese medicine (TCM) has a clinical history of thousands of years for prevention and treatment of infectious diseases in China, taking advantages of improving clinical outcomes, producing less side effects, inhibiting pathogen, and modulating host immunity. Recent research has revealed a variety of natural products derived from TCM showing significant antimicrobial effects on antibiotic-resistant strains of P. aeruginosa alone or combined with antibiotics in vitro or in animal models, suggesting that TCM is a promising complementary and alternative therapeutic approach for treatment of chronic P. aeruginosa infections. This review summarizes the recent findings attempting to dissect the mechanisms of TCM combating P. aeruginosa infections and highlights the molecular targets of TCM on P. aeruginosa and host.

PMID:34512364 | PMC:PMC8429605 | DOI:10.3389/fphar.2021.737252

J Cyst Fibros. 2021 Sep 9:S1569-1993(21)01360-6. doi: 10.1016/j.jcf.2021.08.019. Online ahead of print.

ABSTRACT

BACKGROUND: Culture conditions sometimes make it difficult to detect non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus, an emerging cystic fibrosis (CF) pathogen. The diagnosis of NTM positive cases not detected by classical culture methods might benefit from the development of a serological assay.

METHODS: As part of a diagnostic accuracy study, a total of 173 sera CF-patients, including 33 patients with M. abscessus positive cultures, and 31 non-CF healthy controls (HC) were evaluated. Four M. abscessus antigens were used separately, comprising two surface extracts (Interphase (INP) and a TLR2 positive extract (TLR2eF)) and two recombinant proteins (rMAB_2545c and rMAB_0555 also known as the phospholipase C (rPLC)).

RESULTS: TLR2eF and rPLC were the most efficient antigens to discriminate NTM-culture positive CF-patients from NTM-culture negative CF-patients. The best clinical values were obtained for the detection of M. abscessus-culture positive CF-patients; with sensitivities for the TLR2eF and rPLC of 81.2% (95% CI:65.7-92.3%) and 87.9% (95% CI:71.9-95.6%) respectively, and specificities of 88.9% (95% CI:85.3-94.8%) and 84.8% (95% CI:80.6-91.5%) respectively. When considering as positive all sera, giving a positive response in at least one of the two tests, and, as negative, all sera negative for both tests, we obtained a sensitivity of 93.9% and a specificity of 80.7% for the detection of M. abscessus-culture positive CF-patients.

CONCLUSION: High antibody titers against TLR2eF and rPLC were obtained in M. abscessus-culture positive CF-patients, allowing us to consider these serological markers as potential tools in the detection of CF-patients infected with M. abscessus.

PMID:34511392 | DOI:10.1016/j.jcf.2021.08.019

J Cyst Fibros. 2021 Sep 9:S1569-1993(21)01373-4. doi: 10.1016/j.jcf.2021.08.032. Online ahead of print.

NO ABSTRACT

PMID:34511391 | DOI:10.1016/j.jcf.2021.08.032

J Cyst Fibros. 2021 Sep 9:S1569-1993(21)01362-X. doi: 10.1016/j.jcf.2021.08.021. Online ahead of print.

NO ABSTRACT

PMID:34511390 | DOI:10.1016/j.jcf.2021.08.021

BMC Bioinformatics. 2021 Sep 11;22(1):435. doi: 10.1186/s12859-021-04341-y.

ABSTRACT

BACKGROUND: Proteins are integral part of all living beings, which are building blocks of many amino acids. To be functionally active, amino acids chain folds up in a complex way to give each protein a unique 3D shape, where a minor error may cause misfolded structure. Genetic disorder diseases i.e. Alzheimer, Parkinson, etc. arise due to misfolding in protein sequences. Thus, identifying patterns of amino acids is important for inferring protein associated genetic diseases. Recent studies in predicting amino acids patterns focused on only simple protein misfolded disease i.e. Chromaffin Tumor, by association rule mining. However, more complex diseases are yet to be attempted. Moreover, association rules obtained by these studies were not verified by usefulness measuring tools.

RESULTS: In this work, we analyzed protein sequences associated with complex protein misfolded diseases (i.e. Sickle Cell Anemia, Breast Cancer, Cystic Fibrosis, Nephrogenic Diabetes Insipidus, and Retinitis Pigmentosa 4) by association rule mining technique and objective interestingness measuring tools. Experimental results show the effectiveness of our method.

CONCLUSION: Adopting quantitative experimental methods, this work can form more reliable, useful and strong association rules i. e. dominating patterns of amino acid of complex protein misfolded diseases. Thus, in addition to usual applications, the identified patterns can be more useful in discovering medicines for protein misfolded diseases and thereby may open up new opportunities in medical science to handle genetic disorder diseases.

PMID:34511072 | DOI:10.1186/s12859-021-04341-y

Proteomics Clin Appl. 2021 Sep 12:e2100062. doi: 10.1002/prca.202100062. Online ahead of print.

ABSTRACT

PURPOSE: Comparative genomics and phenotypic assays have shown that antibiotic resistance profiles differ among clinical isolates of Pseudomonas aeruginosa and that genotype-phenotype associations are difficult to establish for resistance phenotypes based on these comparisons alone.

EXPERIMENTAL DESIGN: Here, we used label-free quantitative proteomics to compare two isolates of the Liverpool Epidemic Strain (LES) of P. aeruginosa, LESlike1 and LESB58, and the common laboratory strain P. aeruginosa PAO1 to more accurately predict functional differences between strains.

RESULTS: Our results show that the proteomes of the LES isolates are more similar to each other than to PAO1; however, a number of differences were observed in the abundance of proteins involved in quorum sensing, virulence, and antibiotic resistance, including in the comparison of LESlike1 and LESB58. Additionally, the proteomic data revealed a higher abundance of proteins involved in polymyxin and aminoglycoside resistance in LESlike1. Minimum inhibitory concentration assays showed that LESlike1 had up to 128-fold higher resistance to antibiotics from these classes.

CONCLUSIONS: These findings provide an example of the ability of proteomic data to complement genotypic and phenotypic studies to understand resistance in clinical isolates.

CLINICAL RELEVANCE: P. aeruginosa is a predominant pathogen in chronic lung infections in individuals with cystic fibrosis (CF). LES isolates are capable of transferring between CF patients and have been associated with increased hospital visits and antibiotic treatments. This article is protected by copyright. All rights reserved.

PMID:34510773 | DOI:10.1002/prca.202100062

Am J Surg Pathol. 2021 Sep 13. doi: 10.1097/PAS.0000000000001803. Online ahead of print.

ABSTRACT

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed. Microscopic differences between the gallbladder and extrahepatic bile ducts in cystic fibrosis and sporadic biliary atresia were unequivocal, despite some histologic overlap; no erosive or fibro-obliterative lesions typical of biliary atresia were seen. Common in liver, biopsies were small duct cholangiopathy with intense focal cholangiolitis and massive accumulation of ceroid pigment within damaged cholangiocytes, and in portal macrophages, portal fibrosis, and unequivocal features of large duct obstruction were inconspicuous compared with biliary atresia. Plugs of bile in small ducts tended to be pale and strongly periodic acid-Schiff-reactive in cystic fibrosis. Distinguishing the liver lesion from that of biliary atresia is challenging but possible. Liver biopsies from 2 additional infants with cystic fibrosis and prolonged jaundice that spontaneously resolved showed a similar small duct cholangiopathy. Small gallbladders and extrahepatic ducts challenge surgical judgment as findings in liver biopsies challenge the pathologist. The decision to perform a Kasai procedure is reasonable when mimicry of biliary atresia is grossly complete. We hypothesize that a disorder of bile volume/flow during development and/or early infancy linked to the CFTR mutation alone or in combination with the stresses of neonatal intensive care causes destructive cholangiolitis and intrahepatic reduction of bile flow with secondary hypoplasia of extrahepatic biliary structures.

PMID:34510112 | DOI:10.1097/PAS.0000000000001803

Sci Rep. 2021 Sep 10;11(1):18042. doi: 10.1038/s41598-021-97197-4.

ABSTRACT

Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl transferases PptAb from Mycobacterium abscessus and PcpS from Pseudomonas aeruginosa, two pathogenic bacteria associated with cystic fibrosis and bronchiectasis, respectively. Compound 8918 exhibits inhibitory activity against PptAb but displays no activity against PcpS in vitro, while no antimicrobial activity against Mycobacterium abscessus or Pseudomonas aeruginosa could be detected. X-ray crystallographic analysis of 8918 bound to PptAb-CoA alone and in complex with an acyl carrier protein domain in addition to the crystal structure of PcpS in complex with CoA revealed the structural basis for the inhibition mechanism of PptAb by 8918 and its ineffectiveness against PcpS. Finally, in crystallo screening of potent inhibitors from the National Cancer Institute library identified a hydroxypyrimidinethione derivative that binds PptAb. Both compounds could serve as scaffolds for the future development of phosphopantetheinyl transferases inhibitors.

PMID:34508141 | DOI:10.1038/s41598-021-97197-4

J Cyst Fibros. 2021 Sep 7:S1569-1993(21)01366-7. doi: 10.1016/j.jcf.2021.08.025. Online ahead of print.

NO ABSTRACT

PMID:34507897 | DOI:10.1016/j.jcf.2021.08.025

Med Clin (Barc). 2021 Sep 7:S0025-7753(21)00441-3. doi: 10.1016/j.medcli.2021.06.025. Online ahead of print.

ABSTRACT

INTRODUCTION: This systematic review aims to analyze the validity and reliability of available tools to assess health-related quality of life (HRQoL) and exercise tolerance in children and adolescents with cystic fibrosis (CF).

MATERIALS AND METHODS: A review of observational studies studying the validity and reliability of the tools was conducted. The COSMIN (COnsesus-based Standards for the selection of health Measurements INstruments) guide was followed to analyze the quality of these tools.

RESULTS: A total of 18 studies were selected. Of the eight HRQoL tools, five generic and three specific, analyzed in 14 studies, the Cystic Fibrosis Questionnaire-Revised (CFQ-R) presents the best properties. Of the four tools analyzed to assess exercise tolerance, cycle ergometry and the modified shuttle test are the most valid and reliable.

CONCLUSIONS: The CFQ-R, cycloergometry and the modified shuttle test have the best properties for the assessment of children with CF, but more studies are needed.

PMID:34507821 | DOI:10.1016/j.medcli.2021.06.025

Chest. 2021 Sep 7:S0012-3692(21)03846-0. doi: 10.1016/j.chest.2021.08.073. Online ahead of print.

ABSTRACT

Cystic fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of the disease. We present an ethical dilemma involving an 11-year-old child with CF and end stage lung disease. Shortly after starting treatment with Elexacaftor-Tezacaftor-Ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other is limited. A survey of CF center team members was conducted for the purpose of this manuscript. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared to other team members, are more likely to provide a specific recommendation vs. to present the information and let the family decide (odds ratio (95% confidence interval)=4.0 (1.2-12.8), p=0.021). A shared decision-making model, stressing our moral obligation as clinicians to respect autonomy by appreciating family values while offering to participate in the decision-making process and ensuring non-maleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. Current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making which is focused on respecting autonomy is our preferred approach in these situations.

PMID:34506793 | DOI:10.1016/j.chest.2021.08.073

Lancet Infect Dis. 2021 Sep 7:S1473-3099(21)00122-5. doi: 10.1016/S1473-3099(21)00122-5. Online ahead of print.

ABSTRACT

Standard doses of antibiotics do not efficiently treat chronic infections of the soft tissue and bone. In this Personal View, we advocate for improving treatment of these infections by taking the infectious microenvironment into account. The infectious microenvironment can cause sensitive bacteria to lose their susceptibility to antibiotics that are effective in standard laboratory susceptibility testing. We propose that bacteria behave substantially different in standard laboratory conditions than they do in actual infections. The infectious microenvironment could impose changes in growth and metabolic activity that result in increased protection against antibiotics. Therefore, we advocate that improved antibiotic treatment of chronic infection is achievable when antibiotics are recommended on the basis of susceptibility testing in relevant in vitro conditions that resemble actual infectious microenvironments. We recommend establishing knowledge of the relevant conditions of the chemical and physical composition of the infectious microenvironment. Recent advances in RNA sequencing, metabolomics, and microscopy have made it possible for the characterisation of the microenvironment of infections and to validate the clinical relevance of in vitro conditions to actual infections.

PMID:34506737 | DOI:10.1016/S1473-3099(21)00122-5

Biol Chem. 2021 Sep 10. doi: 10.1515/hsz-2021-0243. Online ahead of print.

ABSTRACT

The gold standard for the diagnosis of bacterial infections in clinical samples is based on culture tests that are time-consuming and labor-intense. For these reasons, an extraordinary effort has been made to identify biomarkers as the tools for sensitive, rapid and accurate identification of pathogenic microorganisms. Moreover, biomarkers have been tested to distinguish colonization from infection, monitor disease progression, determine the clinical status of patients or predict clinical outcomes. This mini-review describes Pseudomonas aeruginosa and Staphylococcus aureus biomarkers, which contribute to pathogenesis and have been used in culture-independent bacterial identification directly from patient samples.

PMID:34505460 | DOI:10.1515/hsz-2021-0243

Hum Mol Genet. 2021 Sep 9:ddab260. doi: 10.1093/hmg/ddab260. Online ahead of print.

ABSTRACT

Limb-girdle muscular dystrophy 3 (LGMDR3) is caused by mutations in the SGCA gene coding for α-sarcoglycan (SG). Together with β- γ- and δ-SG, α-SG forms a tetramer embedded in the dystrophin associated protein complex (DAPC) crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded, even though potentially functional α-SG. These mutants are prematurely discarded by the cell quality control. Lacking one subunit, the SG-complex is disrupted. The resulting loss of function leads to sarcolemma instability, muscle fiber damage and progressive limb muscle weakness. LGMDR3 is severely disabling and, unfortunately, still incurable. Here we propose the use of small molecules, belonging to the class of cystic fibrosis transmembrane regulator (CFTR) correctors, for recovering mutants of α-SG defective in folding and trafficking. Specifically, CFTR corrector C17 successfully rerouted the SG-complex containing the human R98H-α-SG to the sarcolemma of hind-limb muscles of a novel LGMDR3 murine model. Notably, the muscle force of the treated model animals was fully recovered. To our knowledge, this is the first time that a compound designated for cystic fibrosis (CF) is successfully tested in a muscular dystrophy and may represent a novel paradigm of treatment for LGMDR3 as well as different other indications in which a potentially functional protein is prematurely discarded as folding-defective. Furthermore, the use of small molecules for recovering the endogenous mutated SG has an evident advantage over complex procedures such as gene or cell transfer.

PMID:34505136 | DOI:10.1093/hmg/ddab260