Phage Immunoprecipitation-Sequencing Reveals CDHR5 Autoantibodies in Select Patients With Interstitial Lung Disease.

OBJECTIVE: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. METHODS: We use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP-Seq. We next developed a radio-labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort. RESULTS: PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free-survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD. CONCLUSION: We used PhIP-Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5-IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity.

Chloroplast biogenesis involves spatial coordination of nuclear and organellar gene expression in Chlamydomonas.

The localization of translation can direct the polypeptide product to the proper intracellular compartment. Our results reveal translation by cytosolic ribosomes on a domain of the chloroplast envelope in the unicellular green alga Chlamydomonas (Chlamydomonas reinhardtii). We show that this envelope domain of isolated chloroplasts retains translationally active ribosomes and mRNAs encoding chloroplast proteins. This domain is aligned with localized translation by chloroplast ribosomes in the translation zone, a chloroplast compartment where photosystem subunits encoded by the plastid genome are synthesized and assembled. Roles of localized translation in directing newly synthesized subunits of photosynthesis complexes to discrete regions within the chloroplast for their assembly are suggested by differences in localization on the chloroplast of mRNAs encoding either subunit of the light-harvesting complex II or the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. Transcription of the chloroplast genome is spatially coordinated with translation, as revealed by our demonstration of a subpopulation of transcriptionally active chloroplast nucleoids at the translation zone. We propose that the expression of chloroplast proteins by the nuclear-cytosolic and organellar genetic systems is organized in spatially aligned subcompartments of the cytoplasm and chloroplast to facilitate the biogenesis of the photosynthetic complexes.

Activated STING in the thymus alters T cell development and selection leading to autoimmunity.

Classifying systemic inflammatory disorders as autoinflammatory or autoimmune provides insight into disease pathogenesis and whether treatment should target innate molecules and their signaling pathways or the adaptive immune response. COPA syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Studies show constitutive activation of the innate immune molecule STING is centrally involved in disease. However, the mechanisms by which STING results in loss of T cell tolerance and autoimmunity in COPA syndrome or more common autoimmune diseases is not understood. Using CopaE241K/+ mice, we uncovered a functional role for STING in the thymus. Single cell data of human thymus demonstrates STING is highly expressed in medullary thymic epithelial cells (mTECs) involved in processing and presenting self-antigens to thymocytes. In CopaE241K/+ mice, activated STING in mTECs triggered interferon signaling, impaired macroautophagy and caused a defect in negative selection of T cells. Wild-type mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings important for settings that activate thymic STING.

PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease.

Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NFκB signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.

Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies.

Interstitial lung diseases (ILD) are heterogeneous conditions that may lead to progressive fibrosis and death of affected individuals. Despite diversity in clinical manifestations, enlargement of lung-associated lymph nodes (LLN) in fibrotic ILD patients predicts worse survival. Herein, we revealed a common adaptive immune landscape in LLNs of all ILD patients, characterized by highly activated germinal centers and antigen-activated T cells including regulatory T cells (Tregs). In support of these findings, we identified serum reactivity to 17 candidate auto-antigens in ILD patients through a proteome-wide screening using phage immunoprecipitation sequencing. Autoantibody responses to actin binding LIM protein 1 (ABLIM1), a protein highly expressed in aberrant basaloid cells of fibrotic lungs, were correlated with LLN frequencies of T follicular helper cells and Tregs in ILD patients. Together, we demonstrate that end-stage ILD patients have converging immune mechanisms, in part driven by antigen-specific immune responses, which may contribute to disease progression.

Social participation and mild cognitive impairment in low- and middle-income countries.

Social participation may theoretically decrease risk for mild cognitive impairment (MCI). However, to date, no study has specifically investigated the association between social participation and MCI in LMICs, while the mediating role of loneliness is unknown. Thus, we investigated this association in a sample of adults aged ≥50 years from six low- and middle-income countries (LMICs; China, Ghana, India, Mexico, Russia, South Africa) using nationally representative datasets. We analyzed cross-sectional, community-based data from the Study on Global Ageing and Adult Health. A social participation score (range 0-10 with higher scores corresponding to greater levels of social participation) was created based on nine questions about involvement in community activities in the last 12 months. The National Institute on Ageing-Alzheimer's Association criteria were used to define MCI. Multivariable logistic regression and mediation analysis was performed. The analytical sample consisted of 32,715 individuals aged ≥50 years with preserved functional abilities [mean (SD) age 62.1 (15.6) years; 51.7% females]. In the overall sample, after adjustment for potential confounders, a one-unit increase in the social participation score was associated with a 13% decrease in odds for MCI (OR = 0.87; 95%CI = 0.82-0.93). Loneliness only explained 3.0% of the association. Greater levels of social participation were associated with a reduced odds for MCI, and this was not largely explained by loneliness. It may be prudent to implement interventions in LMICs to increase levels of social participation to aid in the prevention of MCI and ultimately dementia.

A Review of the Emerging White Chick Hatchery Disease.

White chick hatchery disease is an emerging disease of broiler chicks with which the virus, chicken astrovirus, has been associated. Adult birds typically show no obvious clinical signs of infection, although some broiler breeder flocks have experienced slight egg drops. Substantial decreases in hatching are experienced over a two-week period, with an increase in mid-to-late embryo deaths, chicks too weak to hatch and pale, runted chicks with high mortality. Chicken astrovirus is an enteric virus, and strains are typically transmitted horizontally within flocks via the faecal-oral route; however, dead-in-shell embryos and weak, pale hatchlings indicate vertical transmission of the strains associated with white chick hatchery disease. Hatch levels are typically restored after two weeks when seroconversion of the hens to chicken astrovirus has occurred. Currently, there are no commercial vaccines available for the virus; therefore, the only means of protection is by good levels of biosecurity. This review aims to outline the current understanding regarding white chick hatchery disease in broiler chick flocks suffering from severe early mortality and increased embryo death in countries worldwide.

Ejaculation Disorders in Male Patients with Cancer: A Systematic Review and Meta-Analysis of Prevalence.

PURPOSE: Ejaculatory dysfunction (EjD) and erectile dysfunction after cancer treatment are clinically important complications, but their exact prevalence by various kinds of cancer site and type of treatment is unknown. The aim of this systematic review and meta-analysis was to examine the available evidence and provide pooled estimates for prevalence of EjD and erectile dysfunction in relation to all cancer sites and identify characteristics associated with EjD in cancer patients. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of cross-sectional and case-control studies. We searched 4 electronic databases (Medline®, CINAHL, PsychInfo and Embase®) until July 22, 2020. All retrospective or prospective studies reporting the prevalence of EjD in male patients with cancer were included in this review. A random effects meta-analysis was conducted calculating prevalence proportions with 95% confidence intervals. Prevalence proportions were calculated for the incidences of EjD by cancer site and type of treatment. RESULTS: A total of 64 studies (a total of 10,057 participants) were included for analysis. The most common cancer sites were bladder, colon, testis and rectum. The prevalence rates of EjD after surgical intervention ranged from 14.5% (95% CI 2.2-56.3) in colon cancer to 53.0% (95% CI 23.3-80.7) in bladder cancer. The prevalence rates of erectile dysfunction ranged from 6.8% (95% CI 0.8-39.1) in bladder cancer to 68.7% (95% CI 55.2-79.6) in cancer of the rectum. CONCLUSIONS: In a large study-level meta-analysis, we looked at a high prevalence of EjD and erectile dysfunction at various cancer sites and across different treatment types. Prospective studies of EjD and erectile dysfunction after various kinds of cancer treatments are warranted.

Characterization of the substrate binding site of an iron detoxifying membrane transporter from Plasmodium falciparum.

BACKGROUND: Plasmodium species are entirely dependent upon their host as a source of essential iron. Although it is an indispensable micronutrient, oxidation of excess ferrous iron to the ferric state in the cell cytoplasm can produce reactive oxygen species that are cytotoxic. The malaria parasite must therefore carefully regulate the processes involved in iron acquisition and storage. A 273 amino acid membrane transporter that is a member of the vacuolar iron transporter (VIT) family and an orthologue of the yeast Ca2+-sensitive cross complementer (CCC1) protein plays a major role in cytosolic iron detoxification of Plasmodium species and functions in transport of ferrous iron ions into the endoplasmic reticulum for storage. While this transporter, termed PfVIT, is not critical for viability of the parasite evidence from studies of mice infected with VIT-deficient Plasmodium suggests it could still provide an efficient target for chemoprophylactic treatment of malaria. Individual amino acid residues that constitute the Fe2+ binding site of the protein were identified to better understand the structural basis of substrate recognition and binding by PfVIT. METHODS: Using the crystal structure of a recently published plant VIT as a template, a high-quality homology model of PfVIT was constructed to identify the amino acid composition of the transporter's substrate binding site and to act as a guide for subsequent mutagenesis studies. To test the effect of mutation of the substrate binding-site residues on PfVIT function a yeast complementation assay assessed the ability of overexpressed, recombinant wild type and mutant PfVIT to rescue an iron-sensitive deletion strain (ccc1∆) of Saccharomyces cerevisiae yeast from the toxic effects of a high concentration of extracellular iron. RESULTS: The combined in silico and mutagenesis approach identified a methionine residue located within the cytoplasmic metal binding domain of the transporter as essential for PfVIT function and provided insight into the structural basis for the Fe2+-selectivity of the protein. CONCLUSION: The structural model of the metal binding site of PfVIT opens the door for rational design of therapeutics to interfere with iron homeostasis within the malaria parasite.

Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia.

BACKGROUND: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. METHODS: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. RESULTS: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. CONCLUSIONS: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.

The phenotype associated with variants in TANGO2 may be explained by a dual role of the protein in ER-to-Golgi transport and at the mitochondria.

TANGO2 variants result in a complex disease phenotype consisting of recurrent crisis-induced rhabdomyolysis, encephalopathy, seizures, lactic acidosis, hypoglycemia, and cardiac arrhythmias. Although first described in a fruit fly model as a protein necessary for some aspect of Golgi function and organization, its role in the cell at a fundamental level has not been addressed. Such studies are necessary to better counsel families regarding treatment options and nutrition management to mitigate the metabolic aspects of the disease. The few studies performed to address the pathway(s) in which TANGO2 functions have led to enigmatic results, with some suggesting defects in membrane traffic while others suggest unknown mitochondrial defects. Here, we have performed a robust membrane trafficking assay on fibroblasts derived from three different individuals harboring TANGO2 variants and show that there is a significant delay in the movement of cargo between the endoplasmic reticulum and the Golgi. Importantly, this delay was attributed to a defect in TANGO2 function. We further show that a portion of TANGO2 protein localizes to the mitochondria through a necessary but not sufficient stretch of amino acids at the amino terminus of the protein. Fibroblasts from affected individuals also displayed changes in mitochondrial morphology. We conclude that TANGO2 functions in both membrane trafficking and in some as yet undetermined role in mitochondria physiology. The phenotype of affected individuals can be partially explained by this dual involvement of the protein.

Multi-tissue patterning drives anterior morphogenesis of the C. elegans embryo.

Complex structures derived from multiple tissue types are challenging to study in vivo, and our knowledge of how cells from different tissues are coordinated is limited. Model organisms have proven invaluable for improving our understanding of how chemical and mechanical cues between cells from two different tissues can govern specific morphogenetic events. Here we used Caenorhabditis elegans as a model system to show how cells from three different tissues are coordinated to give rise to the anterior lumen. While some aspects of pharyngeal morphogenesis have been well-described, it is less clear how cells from the pharynx, epidermis and neuroblasts coordinate to define the location of the anterior lumen and supporting structures. Using various microscopy and software approaches, we define the movements and patterns of these cells during anterior morphogenesis. Projections from the anterior-most pharyngeal cells (arcade cells) provide the first visible markers for the location of the future lumen, and facilitate patterning of the surrounding neuroblasts. These neuroblast patterns control the rate of migration of the anterior epidermal cells, whereas the epidermal cells ultimately reinforce and control the position of the future lumen, as they must join with the pharyngeal cells for their epithelialization. Our studies are the first to characterize anterior morphogenesis in C. elegans in detail and should lay the framework for identifying how these different patterns are controlled at the molecular level.

A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome.

Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon-driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.

A Defect in Thymic Tolerance Causes T Cell-Mediated Autoimmunity in a Murine Model of COPA Syndrome.

COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit α (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.

Photosystem Biogenesis Is Localized to the Translation Zone in the Chloroplast of Chlamydomonas.

Intracellular processes can be localized for efficiency or regulation. For example, localized mRNA translation by chloroplastic ribosomes occurs in the biogenesis of PSII, one of the two photosystems of the photosynthetic electron transport chain in the chloroplasts of plants and algae. The biogenesis of PSI and PSII requires the synthesis and assembly of their constituent polypeptide subunits, pigments, and cofactors. Although these biosynthetic pathways are well characterized, less is known about when and where they occur in developing chloroplasts. Here, we used fluorescence microscopy in the unicellular alga Chlamydomonas reinhardtii to reveal spatiotemporal organization in photosystem biogenesis. We focused on translation by chloroplastic ribosomes and chlorophyll biosynthesis in two developmental contexts of active photosystem biogenesis: (1) growth of the mature chloroplast and (2) greening of a nonphotosynthetic chloroplast. The results reveal that a translation zone is the primary location of the biogenesis of PSI and PSII. This discretely localized region within the chloroplast contrasts with the distributions of photosystems throughout this organelle and, therefore, is likely a hub where anabolic pathways converge for photosystem biogenesis.plantcell;31/12/3057/FX1F1fx1.

Solid-phase synthesis and structural characterisation of phosphoroselenolate-modified DNA: a backbone analogue which does not impose conformational bias and facilitates SAD X-ray crystallography.

Oligodeoxynucleotides incorporating internucleotide phosphoroselenolate linkages have been prepared under solid-phase synthesis conditions using dimer phosphoramidites. These dimers were constructed following the high yielding Michaelis-Arbuzov (M-A) reaction of nucleoside H-phosphonate derivatives with 5'-deoxythymidine-5'-selenocyanate and subsequent phosphitylation. Efficient coupling of the dimer phosphoramidites to solid-supported substrates was observed under both manual and automated conditions and required only minor modifications to the standard DNA synthesis cycle. In a further demonstration of the utility of M-A chemistry, the support-bound selenonucleoside was reacted with an H-phosphonate and then chain extended using phosphoramidite chemistry. Following initial unmasking of methyl-protected phosphoroselenolate diesters, pure oligodeoxynucleotides were isolated using standard deprotection and purification procedures and subsequently characterised by mass spectrometry and circular dichroism. The CD spectra of both modified and native duplexes derived from self-complementary sequences with A-form, B-form or mixed conformational preferences were essentially superimposable. These sequences were also used to study the effect of the modification upon duplex stability which showed context-dependent destabilisation (-0.4 to -3.1 °C per phosphoroselenolate) when introduced at the 5'-termini of A-form or mixed duplexes or at juxtaposed central loci within a B-form duplex (-1.0 °C per modification). As found with other nucleic acids incorporating selenium, expeditious crystallisation of a modified decanucleotide A-form duplex was observed and the structure solved to a resolution of 1.45 Å. The DNA structure adjacent to the modification was not significantly perturbed. The phosphoroselenolate linkage was found to impart resistance to nuclease activity.

Optimal position of lipped acetabular liners to improve stability in total hip arthroplasty-an intraoperative in vivo study.

BACKGROUND: Lipped or elevated acetabular liners are frequently used in total hip arthroplasty to improve stability. However, the optimal position of the lip is not known. The purpose of this study was to determine the optimal position of lipped acetabular liners in total hip arthroplasty performed with a posterior approach. METHODS: In 14 hips, lipped trial liners were placed intraoperatively in various positions around the posterior clock-face of the implanted acetabular shell component. For each liner position, stability of the hip was tested at maximal hip flexion with gradually increasing internal rotation until subluxation occurred, at which point the position of the hip was measured using smartphone accelerometer-based goniometers. Smartphone goniometers were first validated against a computer-assisted navigation system. Post-operative radiographs were analyzed for cup inclination angle, cup anteversion angle, and femoral offset. RESULTS: Mean cup inclination angle in our series was 31° ± 6°. The most common liner position that imparted the greatest stability to posterior subluxation was posteriorly and inferiorly (4 o'clock position for left hip, or 8 o'clock position for right hip). The range for most stable liner position for different patients varied from postero-superior (11 o'clock/1 o'clock position) to directly inferior (6 o'clock position). Comparing a non-lipped liner to a lipped liner placed in the optimal position, the average difference in internal rotation gained before dislocation was 23°. There was no association between cup inclination or anteversion angle with liner position of greatest stability. CONCLUSION: In hip replacements performed through a posterior approach and with mean cup inclination angle of 31° ± 6°, placing the lip of the elevated liner in the postero-inferior quadrant may impart more stability than in the postero-superior quadrant.

Analysis of pulmonary features and treatment approaches in the COPA syndrome.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.

Clamping down on drugs: the Escherichia coli multidrug efflux protein MdtM.

Multidrug resistance is principally a consequence of the active transport of drugs out of the cell by proteins that are integral membrane transporters. In the following review, we present a synthesis of current understanding of the Escherichia coli multidrug resistance transporter, MdtM, a 410 amino acid residue protein that belongs to the large and ubiquitous major facilitator superfamily (MFS).