Funding Opportunity PA-18-722 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) is being issued by the NIH Adherence Network through the Office of Behavioral and Social Sciences Research (OBSSR) with participation from multiple NIH Institutes and Centers. This FOA calls for research grant applications that address patient adherence to treatment and prevention regimens to promote health outcomes. These adherence applications may address healthcare regimen initiation, implementation, and/or persistence by patients. Descriptive and intervention research may address adherence determinants at one or more levels of ecologic influence, including the patient, caregiver/family, provider and/or healthcare system, and community levels. Attention to scientific rigor in all applications is paramount, with emphasis on testing intervention mechanisms of action and use of appropriate sample sizes and valid outcome measures. The specific research interests of participating NIH Institutes and Centers are detailed within. This FOA accepts applications that either propose or do not propose a clinical trial(s).

Funding Opportunity PA-18-723 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) is being issued by the NIH Adherence Network through the Office of Behavioral and Social Sciences Research (OBSSR) with participation from multiple NIH Institutes and Centers. This FOA calls for research grant applications that address patient adherence to treatment and prevention regimens to promote health outcomes. These adherence applications may address healthcare regimen initiation, implementation, and/or persistence by patients. Descriptive and intervention research may address adherence determinants at one or more levels of ecologic influence, including the patient, caregiver/family, provider and/or healthcare system, and community levels. Attention to scientific rigor in all applications is paramount, with emphasis on testing intervention mechanisms of action and use of appropriate sample sizes and valid outcome measures. The specific research interests of participating NIH Institutes and Centers are detailed within. This FOA accepts applications that either propose or do not propose a clinical trial(s).

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Toward Decentralized Agrigenomic Surveillance? A Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Approach for Adaptable and Rapid Detection of User-Defined Fungal Pathogens in Potato Crops.

OMICS. 2018 Mar 27;:

Authors: Kambouris ME, Manoussopoulos Y, Kritikou S, Milioni A, Mantzoukas S, Velegraki A

Abstract
Agrigenomics is one of the emerging focus areas for omics sciences. Yet, agrigenomics differs from medical omics applications such as pharmacogenomics and precision medicine, by virtue of vastly distributed geography of applications at the intersection of agriculture, nutrition, and genomics research streams. Crucially, agrigenomics can address diagnostics and safety surveillance needs in remote and rural farming communities or decentralized food, crop, and environmental monitoring programs for prompt, selective, and differential identification of pathogens. A case in point is the potato crop that serves as a fundamental nutritional source worldwide. Decentralized potato crop and plant protection facilities are pivotal to minimize unnecessary, preemptive use of broad-spectrum fungicides, thus helping to curtail the costs, environmental burden, and the development of resistance in opportunistic human pathogenic fungi. We report here a polymerase chain reaction-restriction fragment length polymorphism approach that is sensitive and adaptable in detection and broad identification of fungal pathogens in potato crops, with a view to future decentralized agrigenomic surveillance programs. Notably, the fingerprinting patterns obtained by the method fully differentiated 12 fungal species examined in silico, with 10 of them also tested in vitro. The method can be scaled up through improvements in electrophoresis and enzyme panel for adaption to other crops and/or pathogens. We suggest that decentralized and integrated agrosurveillance programs and translational agrigenomic programs can inform future innovations in multidomain biosecurity, particularly across omics applications from agriculture and nutrition to clinical medicine and environmental biosafety.

PMID: 29584542 [PubMed - as supplied by publisher]

Related Articles

Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer.

J Cancer. 2018;9(6):1088-1095

Authors: Luo CH, Zhao M, Tang YX, Shahabi S, Fang KN, Chen Y, Tang Y, Chen XY, Wang J, Zhou HH

Abstract
Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations.

PMID: 29581788 [PubMed]

Related Articles

Pharmacoepidemiology in pediatrics: Needs, challenges and future directions for research.

Therapie. 2018 Feb 21;:

Authors: Osokogu OU, Verhamme K, Sturkenboom M, Kaguelidou F

Abstract
Despite international initiatives to promote clinical research in pediatrics, there are still many gaps of knowledge in the use of drugs to treat this specific population. When important information cannot be derived only from clinical trials, use of available observational research tools is required. In this paper, we provide an overview of the particular interest of pharmacoepidemiological research into the evaluation of drug effects in children and adolescents. We also sought to underline the unique challenges and specific needs regarding this research. Implementation of innovative methodologies and expansion of database networks to perform necessary studies could further improve performances of observational research.

PMID: 29580613 [PubMed - as supplied by publisher]

Related Articles

Drug evaluation in children 10years after the European pediatric regulation current challenges and perspectives.

Therapie. 2018 Feb 17;:

Authors: Élie V, Leroux S, Kaguelidou F, Jacqz-Aigrain E

Abstract
The European pediatric regulation, that entered into force in June 2007 with the objectives to improve the health of children in Europe, dramatically changed the regulatory environment of paediatric drug evaluation in Europe. The recent 10years European medicines agency (EMA) report showed that the number of paediatric trials increased and that 238 new medicines and indications for use in children were authorised in the EU. However, results remain constrated and futur developments require european collaborations beween all experts in developmental pharmacology, drug evaluation and trial conduct, training, all aspects already considered in different EU paediatric programs.

PMID: 29580612 [PubMed - as supplied by publisher]

Related Articles

Pharmacogenetics of oral antidiabetic therapy.

Pharmacogenomics. 2018 Mar 27;:

Authors: Ordelheide AM, de Angelis MH, Häring HU, Staiger H

Abstract
Type 2 diabetes prevalence is still on the rise worldwide. Antidiabetic drugs are widely prescribed to patients with Type 2 diabetes. Most patients start with metformin which is mostly well tolerated. However, a high percentage of patients fail to achieve glycemic control. The effectiveness of metformin as well as most other antidiabetic drugs depends among other factors on interindividual genetic differences that are up to now ignored in the treatment of Type 2 diabetes. Interestingly, many genes influencing the effectiveness of antidiabetic drugs are Type 2 diabetes risk genes making matters worse. Here, we shed light on these interindividual genetic differences.

PMID: 29580198 [PubMed - as supplied by publisher]

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Effect of hydrochlorothiazide on serum uric acid concentration: a genome-wide association study.

Pharmacogenomics. 2018 Mar 27;:

Authors: Ala-Mutka EM, Rimpelä JM, Fyhrquist F, Kontula KK, Hiltunen TP

Abstract
AIM: To recognize genetic associations of hydrochlorothiazide-induced change in serum uric acid (SUA) concentration.
PATIENTS & METHODS: We conducted a genome-wide association study on hydrochlorothiazide-induced change in SUA in 214 Finnish men from the GENRES study. Replication analyses were performed in 465 Finns from the LIFE study.
RESULTS: In GENRES, we identified 31 loci associated with hydrochlorothiazide-induced change in SUA at p < 5 × 10-5. rs1002976 near VEGFC associated with the change in GENRES and in LIFE. rs950569 near BRINP3 associated with the change in SUA in GENRES and LIFE. The analysis of previously reported SNPs and candidate genes provided some proof for PADI4 and ABCC4.
CONCLUSION: We report genetic markers that may predict the increase in SUA concentration during thiazide treatment.

PMID: 29580174 [PubMed - as supplied by publisher]

Related Articles

From Homer and Hippocrates to modern personalized medicine: is there a role for pharmacoepigenomics in the treatment of alcohol addiction?

Pharmacogenomics. 2018 Mar 27;:

Authors: Ragia G, Manolopoulos VG

Abstract
From the earliest times to the present, alcohol has evolved as part of life and culture. For most adults, moderate alcohol use is harmless, however, it lies at one end of a range that moves through alcohol abuse to alcohol addiction. Alcohol addiction is a serious and chronic psychiatric disorder that, on top of its heavy consequences on health, also brings significant social and economic losses to individuals and society at large. Pharmacotherapy of alcohol addiction exists, but its effectiveness varies significantly among individuals. Genomic and nongenomic factors are significant contributors to interindividual variation in the clinical presentation of alcohol problems and the response to a given treatment. In addition, emerging evidence suggests pharmacoepigenomics of alcohol addiction as a novel promising area for improvement of alcohol addiction management.

PMID: 29580163 [PubMed - as supplied by publisher]

Related Articles

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study.

J Mol Diagn. 2017 Jul;19(4):561-566

Authors: Rasmussen-Torvik LJ, Almoguera B, Doheny KF, Freimuth RR, Gordon AS, Hakonarson H, Hawkins JB, Husami A, Ivacic LC, Kullo IJ, Linderman MD, Manolio TA, Obeng AO, Pellegrino R, Prows CA, Ritchie MD, Smith ME, Stallings SC, Wolf WA, Zhang K, Scott SA

Abstract
There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

PMID: 28502727 [PubMed - indexed for MEDLINE]

Oral versus inhaled antibiotics for bronchiectasis.

Cochrane Database Syst Rev. 2018 Mar 27;3:CD012579

Authors: Spencer S, Felix LM, Milan SJ, Normansell R, Goeminne PC, Chalmers JD, Donovan T

Abstract
BACKGROUND: Bronchiectasis is a chronic inflammatory disease characterised by a recurrent cycle of respiratory bacterial infections associated with cough, sputum production and impaired quality of life. Antibiotics are the main therapeutic option for managing bronchiectasis exacerbations. Evidence suggests that inhaled antibiotics may be associated with more effective eradication of infective organisms and a lower risk of developing antibiotic resistance when compared with orally administered antibiotics. However, it is currently unclear whether antibiotics are more effective when administered orally or by inhalation.
OBJECTIVES: To determine the comparative efficacy and safety of oral versus inhaled antibiotics in the treatment of adults and children with bronchiectasis.
SEARCH METHODS: We identified studies through searches of the Cochrane Airways Group's Specialised Register (CAGR), which is maintained by the Information Specialist for the group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched ClinicalTrials.gov and the WHO trials portal. We searched all databases in March 2018 and imposed no restrictions on language of publication.
SELECTION CRITERIA: We planned to include studies which compared oral antibiotics with inhaled antibiotics. We would have considered short-term use (less than four weeks) for treating acute exacerbations separately from longer-term use as a prophylactic (4 weeks or more). We would have considered both intraclass and interclass comparisons. We planned to exclude studies if the participants received continuous or high-dose antibiotics immediately before the start of the trial, or if they have received a diagnosis of cystic fibrosis (CF), sarcoidosis, active allergic bronchopulmonary aspergillosis or active non-tuberculous Mycobacterial infection.
DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria to the searches and we planned for two authors to independently extract data, assess risk of bias and assess overall quality of the evidence using GRADE criteria. We also planned to obtain missing data from the authors where possible and to report results with 95% confidence intervals (CIs).
MAIN RESULTS: We identified 313 unique records through database searches and a further 21 records from trial registers. We excluded 307 on the basis of title and abstract alone and a further 27 after examining full-text reports. No studies were identified for inclusion in the review.
AUTHORS' CONCLUSIONS: There is currently no evidence indicating whether orally administered antibiotics are more beneficial compared to inhaled antibiotics. The recent ERS bronchiectasis guidelines provide a practical approach to the use of long-term antibiotics. New research is needed comparing inhaled versus oral antibiotic therapies for bronchiectasis patients with a history of frequent exacerbations, to establish which approach is the most effective in terms of exacerbation prevention, quality of life, treatment burden, and antibiotic resistance.

PMID: 29587336 [PubMed - as supplied by publisher]

Quality before Quantity: Inspecting CFTR.

Dev Cell. 2018 Mar 26;44(6):655-656

Authors: Mou H

Abstract
CFTR biosynthesis is highly dynamic. In this issue of Developmental Cell, Okiyoneda et al. (2018) show that RFFL serves as a CFTR conformation scrutinizer at the plasma membrane. It recognizes misfolded CFTR proteins and marks them for degradation. This quality control mechanism may be explored to benefit cystic fibrosis patients.

PMID: 29587139 [PubMed - in process]

Evaluation of e-liquid toxicity using an open-source high-throughput screening assay.

PLoS Biol. 2018 Mar;16(3):e2003904

Authors: Sassano MF, Davis ES, Keating JE, Zorn BT, Kochar TK, Wolfgang MC, Glish GL, Tarran R

Abstract
The e-liquids used in electronic cigarettes (E-cigs) consist of propylene glycol (PG), vegetable glycerin (VG), nicotine, and chemical additives for flavoring. There are currently over 7,700 e-liquid flavors available, and while some have been tested for toxicity in the laboratory, most have not. Here, we developed a 3-phase, 384-well, plate-based, high-throughput screening (HTS) assay to rapidly triage and validate the toxicity of multiple e-liquids. Our data demonstrated that the PG/VG vehicle adversely affected cell viability and that a large number of e-liquids were more toxic than PG/VG. We also performed gas chromatography-mass spectrometry (GC-MS) analysis on all tested e-liquids. Subsequent nonmetric multidimensional scaling (NMDS) analysis revealed that e-liquids are an extremely heterogeneous group. Furthermore, these data indicated that (i) the more chemicals contained in an e-liquid, the more toxic it was likely to be and (ii) the presence of vanillin was associated with higher toxicity values. Further analysis of common constituents by electron ionization revealed that the concentration of cinnamaldehyde and vanillin, but not triacetin, correlated with toxicity. We have also developed a publicly available searchable website (www.eliquidinfo.org). Given the large numbers of available e-liquids, this website will serve as a resource to facilitate dissemination of this information. Our data suggest that an HTS approach to evaluate the toxicity of multiple e-liquids is feasible. Such an approach may serve as a roadmap to enable bodies such as the Food and Drug Administration (FDA) to better regulate e-liquid composition.

PMID: 29584716 [PubMed - in process]

Rural Residence and COPD Exacerbations: Analysis of the SPIROMICS Cohort.

Ann Am Thorac Soc. 2018 Mar 27;:

Authors: Burkes RM, Gassett AJ, Ceppe AS, Anderson W, O'Neal WK, Woodruff PG, Krishnan JA, Barr RG, Han MK, Martinez FJ, Comellas AP, Lambert AA, Kaufman JD, Dransfield MT, Wells JM, Kanner RE, Paine R, Bleecker ER, Paulin LM, Hansel NN, Drummond MB, SPIROMICS Investigators

Abstract
RATIONALE: Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear.
OBJECTIVE: To determine the independent association between rural residence and COPD-related outcomes including COPD exacerbations, airflow obstruction and symptom burden.
METHODS: A total of 1684 Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) participants with FEV1/FVC<0.70 had geocoding-defined rural-urban residence status determined (N=204 rural and N=1480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of home address to the block level at time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures.The primary outcome measures were exacerbations determined over the one-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. Odds ratio and incidence rate of exacerbations that required treatment with medications including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates.
RESULTS: Rural residence was independently associated with 70% increase in odds of total exacerbations [OR 1.70 (95% CI 1.13-2.56); p=0.012] and 46% higher incidence rate of total exacerbations [IRR 1.46 (95% CI 1.02-2.10); p=0.039]. There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation to analysis attenuated the association between rural residence and odds and incidence rate of total exacerbations [OR 1.52 (95% CI 1.00-2.32; p=0.05) and IRR 1.39 (95% CI 0.97 - 1.99); p=0.07]. There was no difference in symptoms or airflow obstruction between rural and urban participants.
CONCLUSIONS: Rural residence is independently associated with increased odds and incidence of total, but not severe COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of increased risk of COPD exacerbations in the rural population.

PMID: 29584453 [PubMed - as supplied by publisher]

Related Articles

Genetic and pharmacological inhibition of Cdk1 provides neuroprotection towards ischemic neuronal death.

Cell Death Discov. 2018;4:43

Authors: Marlier Q, Jibassia F, Verteneuil S, Linden J, Kaldis P, Meijer L, Nguyen L, Vandenbosch R, Malgrange B

Abstract
Cell cycle proteins are mainly expressed by dividing cells. However, it is well established that these molecules play additional non-canonical activities in several cell death contexts. Increasing evidence shows expression of cell cycle regulating proteins in post-mitotic cells, including mature neurons, following neuronal insult. Several cyclin-dependent kinases (Cdks) have already been shown to mediate ischemic neuronal death but Cdk1, a major cell cycle G2/M regulator, has not been investigated in this context. We therefore examined the role of Cdk1 in neuronal cell death following cerebral ischemia, using both in vitro and in vivo genetic and pharmacological approaches. Exposure of primary cortical neurons cultures to 4 h of oxygen-glucose deprivation (OGD) resulted in neuronal cell death and induced Cdk1 expression. Neurons from Cdk1-cKO mice showed partial resistance to OGD-induced neuronal cell death. Addition of R-roscovitine to the culture medium conferred neuroprotection against OGD-induced neuronal death. Transient 1-h occlusion of the cerebral artery (MCAO) also leads to Cdk1 expression and activation. Cdk1-cKO mice displayed partial resistance to transient 1-h MCAO. Moreover, systemic delivery of R-roscovitine was neuroprotective following transient 1-h MCAO. This study demonstrates that promising neuroprotective therapies can be considered through inhibition of the cell cycle machinery and particularly through pharmacological inhibition of Cdk1.

PMID: 29581894 [PubMed]

Related Articles

Improving imputation in disease-relevant regions: lessons from cystic fibrosis.

NPJ Genom Med. 2018;3:8

Authors: Panjwani N, Xiao B, Xu L, Gong J, Keenan K, Lin F, He G, Baskurt Z, Kim S, Zhang L, Esmaeili M, Blackman S, Scherer SW, Corvol H, Drumm M, Knowles M, Cutting G, Rommens JM, Sun L, Strug LJ

Abstract
Does genotype imputation with public reference panels identify variants contributing to disease? Genotype imputation using the 1000 Genomes Project (1KG; 2504 individuals) displayed poor coverage at the causal cystic fibrosis (CF) transmembrane conductance regulator (CFTR) locus for the International CF Gene Modifier Consortium. Imputation with the larger Haplotype Reference Consortium (HRC; 32,470 individuals) displayed improved coverage but low sensitivity of variants clinically relevant for CF. A hybrid reference that combined whole genome sequencing (WGS) from 101 CF individuals with the 1KG imputed a greater number of single-nucleotide variants (SNVs) that would be analyzed in a genetic association study (r2 ≥ 0.3 and MAF ≥ 0.5%) than imputation with the HRC, while the HRC excelled in the lower frequency spectrum. Using the 1KG or HRC as reference panels missed the most common CF-causing variants or displayed low imputation accuracy. Designs that incorporate population-specific WGS can improve imputation accuracy at disease-specific loci, while imputation using public data sets can omit disease-relevant genotypes.

PMID: 29581887 [PubMed]

Related Articles

Structural mechanisms of CFTR function and dysfunction.

J Gen Physiol. 2018 Mar 26;:

Authors: Hwang TC, Yeh JT, Zhang J, Yu YC, Yeh HI, Destefano S

Abstract
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) chloride channel plays a critical role in regulating transepithelial movement of water and electrolyte in exocrine tissues. Malfunction of the channel because of mutations of the cftr gene results in CF, the most prevalent lethal genetic disease among Caucasians. Recently, the publication of atomic structures of CFTR in two distinct conformations provides, for the first time, a clear overview of the protein. However, given the highly dynamic nature of the interactions among CFTR's various domains, better understanding of the functional significance of these structures requires an integration of these new structural insights with previously established biochemical/biophysical studies, which is the goal of this review.

PMID: 29581173 [PubMed - as supplied by publisher]

Related Articles

Unconventional Secretion of Transmembrane Proteins.

Semin Cell Dev Biol. 2018 Mar 23;:

Authors: Gee HY, Kim J, Lee MG

Abstract
Over the past 20 years it has become evident that eukaryotic cells utilize both conventional and unconventional pathways to deliver proteins to their target sites. Most proteins with a signal peptide and/or a transmembrane domain are conventionally transported through the endoplasmic reticulum to the Golgi apparatus and then to the plasma membrane. However, an increasing number of both soluble cargos (Type I, II, and III) and integral membrane proteins (Type IV) have been found to reach the plasma membrane via unconventional protein secretion (UPS) pathways that bypass the Golgi apparatus under certain conditions, such as cellular stress or development. Well-known examples of transmembrane proteins that undergo Type IV UPS pathways are position-specific antigen subunit alpha 1 integrin, cystic fibrosis transmembrane conductance regulator, myeloproliferative leukemia virus oncogene, and pendrin. Although we collectively refer to all Golgi-bypassing routes as UPS, individual trafficking pathways are diverse compared to the conventional pathways, and the molecular mechanisms of UPS pathways are not yet completely defined. This review summarizes the intracellular trafficking pathways of UPS cargo proteins, particularly those with transmembrane domains, and discusses the molecular machinery involved in the UPS of transmembrane proteins.

PMID: 29580969 [PubMed - as supplied by publisher]

Related Articles

Sweat test for cystic fibrosis: Wearable sweat sensor vs. standard laboratory test.

J Cyst Fibros. 2018 Mar 23;:

Authors: Choi DH, Thaxton A, Jeong IC, Kim K, Sosnay PR, Cutting GR, Searson PC

Abstract
BACKGROUND: Sweat chloride testing for diagnosis of cystic fibrosis (CF) involves sweat induction, collection and handling, and measurement in an analytical lab. We have developed a wearable sensor with an integrated salt bridge for real-time measurement of sweat chloride concentration. Here, in a proof-of-concept study, we compare the performance of the sensor to current clinical practice in CF patients and healthy subjects.
METHOD: Sweat was induced on both forearms of 10 individuals with CF and 10 healthy subjects using pilocarpine iontophoresis. A Macroduct sweat collection device was attached to one arm and sweat was collected for 30 min and then sent for laboratory analysis. A sensor was attached to the other arm and the chloride ion concentration monitored in real time for 30 min using a Bluetooth transceiver and smart phone app.
RESULTS: Stable sweat chloride measurements were obtained within 15 min following sweat induction using the wearable sensor. We define the detection time as the time at which the standard deviation of the real-time chloride ion concentration remained below 2 mEq/L for 5 min. The sweat volume for sensor measurements at the detection time was 13.1 ± 11.4 μL (SD), in many cases lower than the minimum sweat volume of 15 μL for conventional testing. The mean difference between sweat chloride concentrations measured by the sensor and the conventional laboratory practice was 6.2 ± 9.5 mEq/L (SD), close to the arm-to-arm variation of about 3 mEq/L. The Pearson correlation coefficient between the two measurements was 0.97 highlighting the excellent agreement between the two methods.
CONCLUSION: A wearable sensor can be used to make real-time measurements of sweat chloride within 15 min following sweat induction, requiring a small sweat volume, and with excellent agreement to standard methods.

PMID: 29580829 [PubMed - as supplied by publisher]