The CFTR variant profile of Hispanic patients with cystic fibrosis: Impact on access to effective screening, diagnosis, and personalized medicine.

J Genet Couns. 2020 Mar 30;:

Authors: Januska MN, Marx L, Walker PA, Berdella MN, Langfelder-Schwind E

Abstract
Hispanic patients comprise an appreciable and increasing proportion of patients with cystic fibrosis (CF) in the United States (US). Hispanic patients with CF are known to have increased morbidity and mortality compared to non-Hispanic white patients with CF, and ongoing investigations are underway to identify contributing factors amenable to intervention in order to address the disparate health outcomes. One contributing factor is the different CF transmembrane conductance regulator (CFTR) variant profile observed in Hispanic patients with CF. The most common CFTR variant, p.Phe508del (legacy name F508del), is proportionally underrepresented in Hispanic patients with CF. This difference has implications for prenatal screening, newborn screening (NBS), and CFTR variant-specific therapeutic options. In particular, the recent approval of a highly effective CFTR modulator for patients carrying at least one copy of F508del, elexacaftor/tezacaftor/ivacaftor triple combination therapy, underscores the potential for unequal access to personalized treatment for Hispanic patients with CF. We report the CFTR variant profiles of Hispanic patients with CF and non-CF Hispanic infants with a false-positive New York State CF NBS at a single center in New York City over a 5-year study period, as an opportunity to address the racial and ethnic disparities that currently exist in CF screening, diagnosis, and treatment. In addition to the previously documented disparate prevalence of the CFTR variant F508del in Hispanic patients, we observed two CFTR variants, p.His609Arg (legacy name H609R) and p.Thr1036Asn (legacy name T1036N), frequently identified in our Hispanic patients of Ecuadorian and Mexican ancestry, respectively, that are not well-described in the US population. The presence of population-specific and individually rare CFTR variants in Hispanic patients with CF further accentuates the disparity in health outcomes, as these CFTR variants are often absent from prenatal and NBS CFTR variant panels, potentially delaying diagnosis, and without an approved CFTR variant-specific therapy.

PMID: 32227567 [PubMed - as supplied by publisher]

Interventions for preventing and managing advanced liver disease in cystic fibrosis.

Cochrane Database Syst Rev. 2020 Mar 30;3:CD012056

Authors: Palaniappan SK, Than NN, Thein AW, van Mourik I

Abstract
BACKGROUND: Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. This is an updated version of a previously published review.
OBJECTIVES: To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 November 2019. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 01 January 2020.
SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both).
DATA COLLECTION AND ANALYSIS: Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review.
MAIN RESULTS: A comprehensive search of the literature did not identify any published eligible randomised controlled trials.
AUTHORS' CONCLUSIONS: In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis.

PMID: 32227478 [PubMed - in process]

Optical Nanosensors for in vivo Physiological Chloride Detection for Monitoring Cystic Fibrosis Treatment.

Anal Methods. 2020 Mar 21;12(11):1441-1448

Authors: Di W, Clark HA

Abstract
Personalized approaches for continuous monitoring of chloride levels are potentially valuable for evaluating the efficacy of new treatments of genetic disorders such as cystic fibrosis. In this report, we validated optode-based nanosensors for real-time chloride monitoring in the interstitial fluid of living animals. These nanosensors take advantage of a ratiometric sensing scheme which demonstrates reversible and selective chloride detection in the physiological range. We further investigate how skin pigmentation affects the sensor performance during in vivo fluorescence imaging. We successfully monitored endogenous chloride changes using nanosensors during pharmacological treatment in a cystic fibrosis mouse model. We believe this platform is a valuable tool for chloride detection which could assess the efficacy of new treatments for cystic fibrosis.

PMID: 32226484 [PubMed]

Exposure of Aspergillus fumigatus to Atorvastatin Leads to Altered Membrane Permeability and Induction of an Oxidative Stress Response.

J Fungi (Basel). 2020 Mar 26;6(2):

Authors: Ajdidi A, Sheehan G, Kavanagh K

Abstract
Aspergillus fumigatus is a serious cause of disease in immune-deficient patients and in those with pulmonary malfunction (e.g., cystic fibrosis (CF), asthma). Atorvastatin is a member of the statin drug family, which are the main therapeutic agents used to decrease high serum cholesterol levels by inhibiting (HMG-CoA) reductase enzyme. The aim of the work presented here was to analyse the antifungal activity of atorvastatin and assess its effect on the virulence of A. fumigatus. Atorvastatin demonstrated strong antifungal activity and reduced the growth and viability of A. fumigatus. Exposure of A. fumigatus to atorvastatin led to a reduction in ergosterol content and increased membrane permeability, as evidenced by the release of protein, amino acids and gliotoxin. Proteomic analysis revealed an increased abundance of proteins associated with an oxidative stress response, such as the glutathione s-transferase family protein (+8.43-fold), heat shock protein Hsp30/Hsp42 (+2.02-fold) and 5-demethoxyubiquinone hydroxylase, mitochondrial (+1.73-fold), as well as secondary metabolites such as isocyanide synthase A icsA (+8.52-fold) and non-ribosomal peptide synthetase fmpE (+3.06-fold). The results presented here indicate that atorvastatin has strong antifungal properties and may have potential application in the treatment of A. fumigatus infections alone or in combination with existing antifungal agents.

PMID: 32225059 [PubMed]

Extracellular Vesicle-Mediated siRNA Delivery, Protein Delivery, and CFTR Complementation in Well-Differentiated Human Airway Epithelial Cells.

Genes (Basel). 2020 Mar 26;11(4):

Authors: Singh BK, Cooney AL, Krishnamurthy S, Sinn PL

Abstract
Extracellular vesicles (EVs) are a class of naturally occurring secreted cellular bodies that are involved in long distance cell-to-cell communication. Proteins, lipids, mRNA, and miRNA can be packaged into these vesicles and released from the cell. This information is then delivered to target cells. Since EVs are naturally adapted molecular messengers, they have emerged as an innovative, inexpensive, and robust method to deliver therapeutic cargo in vitro and in vivo. Well-differentiated primary cultures of human airway epithelial cells (HAE) are refractory to standard transfection techniques. Indeed, common strategies used to overexpress or knockdown gene expression in immortalized cell lines simply have no detectable effect in HAE. Here we use EVs to efficiently deliver siRNA or protein to HAE. Furthermore, EVs can deliver CFTR protein to cystic fibrosis donor cells and functionally correct the Cl- channel defect in vitro. EV-mediated delivery of siRNA or proteins to HAE provides a powerful genetic tool in a model system that closely recapitulates the in vivo airways.

PMID: 32224868 [PubMed - in process]

Generation of an induced pluripotent stem cell line (MHHi018-A) from a patient with Cystic Fibrosis carrying p.Asn1303Lys (N1303K) mutation.

Stem Cell Res. 2020 Mar 25;44:101744

Authors: Merkert S, Schubert M, Haase A, Janssens HM, Scholte B, Lachmann N, Göhring G, Martin U

Abstract
Cystic Fibrosis (CF) is a genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which encodes for a chloride ion channel regulating the balance of salt and water across secretory epithelia. Here we generated an iPSC line from a CF patient homozygous for the p.Asn1303Lys mutation, a Class II folding defect mutation. This iPSC line provides a useful resource for disease modeling and to investigate the pharmacological response to CFTR modulators in iPSC derived epithelia.

PMID: 32220772 [PubMed - as supplied by publisher]

Early Pulmonary Function and Mid Term Outcome in Lung Transplantation after Ex Vivo Lung Perfusion- a single-center, retrospective, observational, cohort study.

Transpl Int. 2020 Mar 26;:

Authors: Fumagalli J, Rosso L, Gori F, Morlacchi LC, Rossetti V, Tarsia P, Blasi F, Righi I, Mendogni P, Palleschi A, Tosi D, Bonitta G, Nosotti M, Benazzi E, Scaravilli V, Valenza F, Grasselli G, Zanella A

Abstract
BACKGROUND: Outcomes after transplantation of lungs (LuTX) treated with Ex-Vivo Lung Perfusion (EVLP) are debated.
METHODS: In a single-center 8-years retrospective analysis we compared: donors' and recipients' characteristics, gas exchange and lung mechanics at ICU admission, 3, 6 and 12 months, and patients survival of LuTX from Standard donors compared to EVLP treated grafts.
RESULTS: 193 LuTX were performed. Thirty-one LuTX, out of 50 EVLP procedures, were carried-out: 7 from non-heart-beating and 24 from extended criteria brain-dead donors. Recipients' characteristics were similar. At ICU admission, compared to Standard donors, EVLP patients had worse PaO2 /FiO2 (276 [206;374] vs. 204 [133;245] mmHg, p<0.05), more frequent extracorporeal support (18 vs. 32%, p=0.053) and longer mechanical ventilation duration (28-days ventilator-free days: 27 [24; 28] vs. 26 [19;27], p<0.05). ICU length of stay (4 [2;9] vs. 6 [3;12] days, p=0.208), 28-days survival (99 vs. 97%, p=0.735) and 1-year respiratory function were similar between groups. Log-rank analysis (median follow-up 2.5 years) demonstrated similar patients survival (p=0.439) and time free of chronic lung allograft disease (p=0.484).
CONCLUSIONS: The EVLP program increased by 16% the number of LuTX. Compared to Standard donors, EVLP patients had worse respiratory function immediately after LuTX but similar early and mid-term outcomes.

PMID: 32219887 [PubMed - as supplied by publisher]

Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity.

JAMA Netw Open. 2020 Mar 02;3(3):e201737

Authors: Farooq F, Mogayzel PJ, Lanzkron S, Haywood C, Strouse JJ

Abstract
Importance: Sickle cell disease (SCD) and cystic fibrosis (CF) are severe autosomal recessive disorders associated with intermittent disease exacerbations that require hospitalizations, progressive chronic organ injury, and substantial premature mortality. Research funding is a limited resource and may contribute to health care disparities, especially for rare diseases that disproportionally affect economically disadvantaged groups.
Objective: To compare disease-specific funding between SCD and CF and the association between funding and research productivity.
Design, Setting, and Participants: This cross-sectional study examined federal and foundation funding, publications indexed in PubMed, clinical trials registered in ClinicalTrials.gov, and new drug approvals from January 1, 2008, to December 31, 2018, in an estimated US population of approximately 90 000 individuals with SCD and approximately 30 000 individuals with CF.
Main Outcomes and Measures: Federal and foundation funding, publications indexed in PubMed, clinical trial registrations, and new drug approvals.
Results: From 2008 through 2018, federal funding was greater per person with CF compared with SCD (mean [SD], $2807 [$175] vs $812 [$147]; P < .001). Foundation expenditures were greater for CF than for SCD (mean [SD], $7690 [$3974] vs $102 [$13.7]; P < .001). Significantly more research articles (mean [SD], 1594 [225] vs 926 [157]; P < .001) and US Food and Drug Administration drug approvals (4 vs 1) were found for CF compared with SCD, but the total number of clinical trials was similar (mean [SD], 27.3 [6.9] vs 23.8 [6.3]; P = .22).
Conclusions and Relevance: The findings show that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD. Increased federal and foundation funding is needed for SCD and other diseases that disproportionately affect economically disadvantaged groups to address health care disparities.

PMID: 32219405 [PubMed - as supplied by publisher]

STAPHYLOCOCCUS AUREUS ENTEROTOXINS IN PEOPLE WITH CYSTIC FIBROSIS (CF).

Ulster Med J. 2020 Jan;89(1):38-39

Authors: Wen H, McCaughan J, Schock BC, Reid A, Rendall JC, Elborn JS, Downey DG, Ennis M, Moore JE

PMID: 32218627 [PubMed - as supplied by publisher]

Who's at The Door? - Surface Contamination of Door Frames in a Single-Bedded In-Patient Adult Cystic Fibrosis (CF) Unit.

Ulster Med J. 2020 Jan;89(1):17-20

Authors: Furukawa M, McCaughan J, Stirling J, Millar BC, Addy C, Caskey S, Goldsmith CE, Rendall JC, Misawa N, Downey DG, Moore JE

Abstract
The Gram-negative bacterium, Pseudomonas aeruginosa, is a major respiratory pathogen in patients with cystic fibrosis (CF), with an associated increase in morbidity and mortality. Consequently, infection prevention and control (IPC) plays an important role within health care in order to minimize the risk of cross-infection of this organism amongst patients and the hospital environment. It was the aim of this study to examine bacterial contamination of the health estate of CF in-patients' single-bedded rooms and related environments (n=40). Twelve bacterial genera were identified, six being Gram-positive (Brevibacterium, Dermacoccus, Micrococcus, Rothia, Staphylococcus and Streptococcus), and six being Gram-negative (Acinetobacter, Citrobacter, Klebsiella, Moraxella, Pantoea and Pseudoxanthomonas). None of the organisms identified were considered of particular clinical significance to CF patients. The CF lung and associated sputa may be important reservoirs of Pseudomonas aeruginosa, with potential for spill-over into the health care estate. In the aftermath of the Pseudomonas neonatal outbreak at Altnagelvin and the Royal Jubilee Maternity Hospitals, where there was heightened IPC awareness regarding the presence of this bacterium, it is encouraging to note its absence from the CF-health care estate examined.

PMID: 32218622 [PubMed - as supplied by publisher]

Complete Genome Sequences of Clinical Pandoraea fibrosis Isolates.

Microbiol Resour Announc. 2020 Mar 26;9(13):

Authors: Pitt ME, Nguyen SH, Duarte TPS, Roddam LF, Blaskovich MAT, Cooper MA, Coin LJM

Abstract
Pandoraea fibrosis is a newly identified Gram-negative bacterial species that was isolated from the respiratory tract of an Australian cystic fibrosis patient. The complete assembled genome sequences of two consecutive isolates (second isolate collected 11 months after antibiotic treatment) from the same individual are presented here.

PMID: 32217674 [PubMed - as supplied by publisher]

Confidence and skills for cystic fibrosis end-of-life care.

BMJ Support Palliat Care. 2020 Mar 26;:

Authors: Harris-Skillman E, Chapman S, Lowney A, Miller M, Flight W

Abstract
OBJECTIVES: Optimal cystic fibrosis (CF) end-of-life care (EOLC) is a challenge. There is little formal guidance about who should deliver this and how CF multi-disciplinary teams should interact with specialist palliative care. We assessed the knowledge, experience and preparedness of both CF and palliative care professionals for CF EOLC.
METHODS: An electronic questionnaire was distributed to all members of the Oxford adult CF and palliative care teams.
RESULTS: 35 of a possible 63 members responded (19 CF team; 16 palliative care). Levels of preparedness were low in both groups. Only 11% of CF and 19% of palliative care team members felt fully prepared for EOLC in adult CF. 58% of CF members had no (21%) or minimal (37%) general palliative care training. Similarly, 69% of the palliative care team had no CF-specific training. All respondents desired additional education. CF team members preferred further education in general EOLC while palliative care team members emphasised a need for more CF-specific knowledge.
CONCLUSIONS: Few members of either the CF or palliative care teams felt fully prepared to deliver CF EOLC and many desired additional educations. They expressed complementary knowledge gaps, which suggests both could benefit from increased collaboration and sharing of specialist knowledge.

PMID: 32217617 [PubMed - as supplied by publisher]

Utility and validity of dynamic chest radiography in cystic fibrosis (dynamic CF): an observational, non-controlled, non-randomised, single-centre, prospective study.

BMJ Open Respir Res. 2020 Mar;7(1):

Authors: FitzMaurice TS, McNamara PS, Nazareth D, McCann C, Bedi R, Shaw M, Walshaw M

Abstract
INTRODUCTION: Dynamic chest radiography (DCR) uses novel, low-dose radiographic technology to capture images of the thoracic cavity while in motion. Pulmonary function testing is important in cystic fibrosis (CF). The tolerability, rapid acquisition and lower radiation and cost compared with CT imaging may make DCR a useful adjunct to current standards of care.
METHODS AND ANALYSIS: This is an observational, non-controlled, non-randomised, single-centre, prospective study. This study is conducted at the Liverpool Heart and Chest Hospital (LHCH) adult CF unit. Participants are adults with CF. This study reviews DCR taken during routine CF Annual Review (n=150), validates DCR-derived lung volumes against whole body plethysmography (n=20) and examines DCR at the start and end of pulmonary exacerbations of CF (n=20). The primary objectives of this study are to examine if DCR provides lung function information that correlates with PFT, and lung volumes that correlate whole body plethysmography.
ETHICS AND DISSEMINATION: This study has received the following approvals: HRA REC (11 December 2019) and LHCH R&I (11 October 2019). Results are made available to people with CF, the funders and other researchers. Processed, anonymised data are available from the research team on request.
TRIAL REGISTRATION NUMBER: ISRCTN 64994816.

PMID: 32217535 [PubMed - as supplied by publisher]

Lung clearance index evaluation in detecting nocturnal hypoxemia in cystic fibrosis patients: Toward a new diagnostic tool.

Respir Med. 2020 Apr;164:105906

Authors: Papale M, Parisi GF, Spicuzza L, Licari A, Bongiovanni A, Mulè E, Rotolo N, Manti S, Leonardi S

Abstract
BACKGROUND: Nocturnal hypoxemia adversely affects outcomes in patients with cystic fibrosis (CF). Although an early detection of this abnormality may be desirable, still its predictability remains uncertain. The Lung Clearance Index (LCI) is a measure of lung ventilation distribution obtained from a multiple-breath washout technique (MBW), recently implemented in patients with CF. This study aimed to establish whether the LCI predicts nocturnal hypoxemia in patients with stable CF, with mild to moderate disease, and normal diurnal gas exchange.
METHODS: 31 stable patients (15 males, mean age 17.4 ± 5.2 years) with mild to moderate CF, normoxic when awake, were enrolled. In all patients we performed nocturnal cardio-respiratory polygraphy, lung function measurement, and MBW test to derive LCI values.
RESULTS: LCI was abnormal in most of the patients and inversely correlated with mean nocturnal SpO2 (r = -0.880 p < 0.01). A receiver operating characteristic (ROC) analysis, performed to assess whether LCI predicted nocturnal hypoxemia, revealed a high predictive accuracy of LCI for nocturnal desaturation (AUC = 0.96; Youden index = 0.79). Forced expiratory volume in 1 s (FEV1) was predictive only in patients with more severe airway obstruction, with a moderate degree of accuracy (AUC 0.71).
CONCLUSIONS: The LCI showed a high effectiveness in predicting nocturnal hypoxemia in stable patients with CF, particularly when compared with a traditional parameter of lung function such as FEV1.

PMID: 32217291 [PubMed - as supplied by publisher]

Top-ten tips for managing nutritional issues and gastrointestinal symptoms in children with neurological impairment.

Ital J Pediatr. 2020 Mar 27;46(1):35

Authors: Dipasquale V, Gottrand F, Sullivan PB, Romano C

Abstract
The prevalence of children with neurological impairment (NI) presenting feeding difficulties and gastrointestinal symptoms is rising. The most recent guidelines recommend early nutritional assessment and intervention in order to prevent undernutrition and growth failure, along with the proper diagnosis and treatment of some frequent gastrointestinal symptoms, such as gastroesophageal reflux disease (GERD) and constipation, which can further worsen the feeding process and nutritional status. Nonetheless, the nutritional issues and growth deficits of children with NI are often considered to be of low priority or under recognised by healthcare providers. The present article proposes ten top tips that highlight the major points along the nutritional management pathway of NI children. The implementation of these tips in all healthcare settings could potentially improve patient outcomes and reduce morbidity and mortality.

PMID: 32216797 [PubMed - as supplied by publisher]

[Correlation between CFTR 5T polymorphisms and the risk of congenital bilateral absence of the vas deferens].

Zhonghua Nan Ke Xue. 2019 Mar;25(3):231-237

Authors: Zhao GG, Sun HB, Zhi HJ, Wang F, Wu QY, Xia XY, Xu XF

Abstract
Objective: To investigate the association between the 5T site polymorphism of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and the risk of congenital bilateral absence of the vas deferens (CBAVD).
METHODS: This case-control study included 40 male patients with isolated CBAVD in the experimental group and 104 healthy men as controls. We used the Sanger sequencing method to encode the CFTR gene intron 9 (TG) m-n(T) and type the haplotypes, followed by a review and meta-analysis of the data obtained from the experiment and relevant literature from the PubMed, Web of science, Medline, CNKI and an exploration of the correlation between 5T mutation and the risk of CBAVD.
RESULTS: Sanger sequencing revealed 6 genotypes in the CBAVD patients, including TG11-5T, TG12-5T, TG13-5T, TG11-7T, TG12-7T and TG11-9T, and 7 in the healthy controls, which were TG11-5T, TG12-5T, TG10-7T, TG11-7T, TG12-7T, TG13-7T and TG11-9T. Compared with the controls, the CBAVD patients showed obviously increased rates of the TG12-5T haplotype (4.81% ［10/208］ vs 16.25% ［13/80］) and the TG13-5T haplotype (0% vs 7.5% ［6/80］), but no significant difference in the TG11-5T haplotype (1.92% ［4/208］ vs 2.50% ［2/80］). There was a statistically significant difference between the experimental and control groups in the TG12_13-5T haplotype (OR = 7.40, 95% CI: 4.83－11.34, P < 0.01). The TG12_13-5T haplotype was found to be highly correlated with CBAVD.
CONCLUSIONS: The haplotype of TG12_13-5T increases the risk of CBAVD in men, which has provided a theoretical basis for male reproduction.

PMID: 32216241 [PubMed - in process]

[Protective effect of Yishen Tongluo Recipe against benzo(a)pyrene-induced sperm DNA methylation changes in male rats].

Zhonghua Nan Ke Xue. 2019 Feb;25(2):154-159

Authors: Sun ZX, Zhang CM, Li PC, Chen JS, Wang ZL, Men B

Abstract
Objective: To explore the protective effect of Yishen Tongluo Recipe (YTR) against aberrant sperm DNA methylation in male rats exposed to benzo(a)pyrene (BaP).
METHODS: Thirty male SD rats of the SPF grade were randomly divided into three groups of equal number: solvent control, BaP exposure and YTR intervention. The animals of the solvent control group were injected intraperitoneally with 0.5% DMSO while those of the other two groups with BaP at 0.1 mg/kg/d, all for 60 days, and at 31 days of BaP exposure, those of the YTR group were treated intragastrically with YTR for 30 days. Then, the left epididymides were harvested from all the rats and sperm suspensions collected and centrifuged for extraction of sperm DNA. The methylated DNA immunoprecipitation sequencing (MeDIP-seq) technique was used to detect the whole-genome DNA methylation in different groups.
RESULTS: Exposure to BaP induced the up-regulation of 828 genes encoding mRNA in the sperm DNA, while YTR intervention produced a significant protective effect on the transforming growth factor β3 (TGF-β3), cystic fibrosis transmembrane conductance regulator (CFTR) and recombination activating gene 1 (RAG1), and down-regulated the expressions of 3 227 genes. BaP exposure also caused the up-regulation of 783 genes encoding lncRNA in the sperm DNA, and YTR treatment exhibited an evident protective effect on 62 of the up-regulated genes, induced the down-regulation of 3 378 genes, and showed a protective effect on 56 of the down-regulated genes.
CONCLUSIONS: YTR has a protective effect against aberrant sperm DNA methylation in male rats exposed to BaP, which may be associated with lncRNA.

PMID: 32216203 [PubMed - in process]

Maturity-onset diabetes of the young: Different diabetes in an infant with cystic fibrosis.

Pediatr Pulmonol. 2020 Mar 26;:

Authors: Hangül M, Erdoğan M, Hatipoğlu N, Köse M

Abstract
Cystic fibrosis (CF) is one of the most common autosomal recessive and multisystemic diseases. CF affects many systems. One of these systems is the endocrine and exocrine functions of the pancreas, causing cystic fibrosis-related diabetes, which is extremely complex and has unique pathogenesis. Maturity-onset diabetes of the young (MODY) is a rare type of diabetes with autosomal dominant inheritance and is not expected in patients with CF. In this study, we present MODY due to a novel glucokinase gene mutation, which is an unexpected form of diabetes in patients with CF. This is previously unreported in the literature.

PMID: 32216090 [PubMed - as supplied by publisher]

c-di-GMP modulates type IV MSHA pilus retraction and surface attachment in Vibrio cholerae.

Nat Commun. 2020 Mar 25;11(1):1549

Authors: Floyd KA, Lee CK, Xian W, Nametalla M, Valentine A, Crair B, Zhu S, Hughes HQ, Chlebek JL, Wu DC, Hwan Park J, Farhat AM, Lomba CJ, Ellison CK, Brun YV, Campos-Gomez J, Dalia AB, Liu J, Biais N, Wong GCL, Yildiz FH

Abstract
Biofilm formation by Vibrio cholerae facilitates environmental persistence, and hyperinfectivity within the host. Biofilm formation is regulated by 3',5'-cyclic diguanylate (c-di-GMP) and requires production of the type IV mannose-sensitive hemagglutinin (MSHA) pilus. Here, we show that the MSHA pilus is a dynamic extendable and retractable system, and its activity is directly controlled by c-di-GMP. The interaction between c-di-GMP and the ATPase MshE promotes pilus extension, whereas low levels of c-di-GMP correlate with enhanced retraction. Loss of retraction facilitated by the ATPase PilT increases near-surface roaming motility, and impairs initial surface attachment. However, prolonged retraction upon surface attachment results in reduced MSHA-mediated surface anchoring and increased levels of detachment. Our results indicate that c-di-GMP directly controls MshE activity, thus regulating MSHA pilus extension and retraction dynamics, and modulating V. cholerae surface attachment and colonization.

PMID: 32214098 [PubMed - in process]

Differences in cystic fibrosis-associated Burkholderia spp. bacteria metabolomes after exposure to the antibiotic trimethoprim.

ACS Infect Dis. 2020 Mar 26;:

Authors: McAvoy AC, Jaiyesimi O, Threatt PH, Seladi T, Goldberg JB, da Silva RR, Garg N

Abstract
The Burkholderia cepacia complex is a group of closely related bacterial species with large genomes that infect immunocompromised individuals and those living with cystic fibrosis. Some of these species are found more frequently and cause more severe disease than others, yet metabolomic differences between these have not been described. Furthermore, our understanding of how these species respond to antibiotics is limited. We investigated the metabolomics differences between three most prevalent Burkholderia spp. associated with cystic fibrosis; B. cenocepacia, B. multivorans, and B. dolosa in the presence and absence of the antibiotic trimethoprim. Using a combination of supervised and unsupervised metabolomics data visualization and analysis tools, we describe the overall differences between strains of the same species and between species. Specifically, we report for the first time, the role of the pyomelanin pathway in the metabolism of trimethoprim. We also report differences in detection of known secondary metabolites such as fragin, ornibactin, and N-acylhomoserine lactones and their analogs in closely related strains. Furthermore, we highlight the potential for the discovery of new secondary metabolites in clinical strains of Burkholderia sp. The metabolomics differences described in this study highlight the personalized nature of closely related Burkholderia strains.

PMID: 32212725 [PubMed - as supplied by publisher]