Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Interferon-α plays a crucial role in the pathogenesis of systemic lupus erythematosus. Nevertheless, the different human cell types producing this cytokine as well as the stimuli inducing its production have not been completely characterized. So far, a subpopulation of dendritic cells activated by immune complexes has been identified as major producers of interferon-α in patients with lupus. However, those cells represent a minor population and some studies have reported the secretion of interferon-α by other cells. On the other hand, more than 50% of blood leukocytes are neutrophils and their functions are still not fully understood. Recent data suggest that neutrophils, though usually not considered interferon-α-producing cells, may represent an unexpected source of this cytokine in response to some lupus stimuli

Elimination of the Warburg effect in Chinese hamster ovary (CHO) cells improves cell phenotype as a protein production platform

Lactate is a common metabolite and is central to many important processes. One of its more prominent roles is in the Warburg effect, in which cancer cells exhibit high rates of glycolytic flux followed by secretion of lactate, even in the presence of oxygen. This fermentation of pyruvate to lactate via lactate dehydrogenase (Ldh) accompanies increased proliferation of cancer cells and several other types of rapidly proliferating cell types in immune cell activation and embryonic development. Aerobic glycolysis is also prominent in biotherapeutic protein production, where mammalian production cells often secrete high levels of lactate. The accumulation of lactate is deleterious for cell growth, viability, product formation, and quality, both directly via acidification of the media and indirectly through base addition to control culture pH. Despite a clear genetic target, efforts to eliminate lactate secretion via knockout of Ldh(s) in mammalian cells have been unsuccessful, pointing to the essentiality of Ldh mediated NAD regeneration. A wide variety of approaches have been utilized to limit lactate accumulation in culture, including knockdown or inhibition of Ldh, replacement of glucose with alternate sugars, controlled feeding strategies, and many others, however none have proven successful in eliminating the Warburg effect. We report the elimination of the Warburg effect in a CHO cell line by using CRISPR/Cas9-based engineering to simultaneously knockout enzymes responsible for lactate production and ancillary regulators. The resulting cell lines remain proliferative while consuming significantly less glucose and can be used to generate protein producing lines using standard industrial processes. In a pH-controlled fedbatch process, the Warburg null cells require minimal base addition to maintain a stable pH, allowing an extended growth phase. The knockout strategy was also successfully applied to a CHO cell line producing Rituximab, again resulting in a prolonged growth phase. Additionally, protein production was maintained, while product quality was improved with increased glycan galactosylation. Thus, CHO cells without the capacity of Warburg metabolism may be useful for engineering production cell lines with enhanced bioproduction traits

Neurological Symptoms in Patients with Biopsy Proven Celiac Disease

Abstract: In celiac disease (CD), the gut is the typical manifestation site but atypical neurological presentations are thought to occur in 6 to 10% with cerebellar ataxia being the most frequent symptom. Most studies in this field are focused on patients under primary neurological care. To exclude such an observation bias, patients with biopsy proven celiac disease were screened for neurological disease. A total of 72 patients with biopsy proven celiac disease (CD) (mean age 51 6 15 years, mean disease duration 8 6 11 years) were recruited through advertisements. All participants adhered to a gluten-free diet. Patients were interviewed following a standard questionnaire and examined clinically for neurological symptoms. Medical history revealed neurological disorders such as migraine (28%), carpal tunnel syndrome (20%), vestibular dysfunction (8%), seizures (6%), and myelitis (3%). Interestingly, 35% of patients with CD reported of a history of psychiatric disease including depression, personality changes, or even psychosis. Physical examination yielded stance and gait problems in about one third of patients that could be attributed to afferent ataxia in 26%, vestibular dysfunction in 6%, and cerebellar ataxia in 6%. Other motor features such as basal ganglia symptoms, pyramidal tract signs, tics, and myoclonus were infrequent. 35% of patients with CD showed deep sensory loss and reduced ankle reflexes in 14%. Gait disturbances in CD do not only result from cerebellar ataxia but also from proprioceptive or vestibular impairment. Neurological problems may even develop despite strict adherence to a gluten-free diet. 2009 Movement Disorder Societ

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

AUTOIMMUNITE HUMORALE ET CELLULAIRE DIRIGEE CONTRE LE NUCLEOSOME ET LA POLY (ADP-RIBOSE) POLYMERASE, ENZYME DE REPARATION DE L'ADN. IMPLICATIONS PHYSIOPATHOLOGIQUES DANS LA MALADIE LUPIQUE

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Neutrophil extracellular traps (NET): not only antimicrobial but also modulators of innate and adaptive immunities in inflammatory autoimmune diseases

Polymorphonuclear neutrophils (PMN) represent one of the first lines of defence against invading pathogens and are the most abundant leucocytes in the circulation. Generally described as pro-inflammatory cells, recent data suggest that PMN also have immunomodulatory capacities. In response to certain stimuli, activated PMN expel neutrophil extracellular traps (NET), structures made of DNA and associated proteins. Although originally described as an innate immune mechanism fighting bacterial infection, NET formation (or probably rather an excess of NET together with impaired clearance of NET) may be deleterious. Indeed, NET have been implicated in the development of several inflammatory and autoimmune diseases as rheumatoid arthritis or systemic lupus erythematosus, as well as fibrosis or cancer. They have been suggested as a source of (neo)autoantigens or regulatory proteins like proteases or to act as a physical barrier. Different mechanisms of NET formation have been described, leading to PMN death or not, depending on the stimulus. Interestingly, NET may be both pro-inflammatory and anti-inflammatory and this probably partly depends on the mechanism, and thus the stimuli, triggering NET formation. Within this review, we will describe the pro-inflammatory and anti-inflammatory activities of NET and especially how NET may modulate immune responses

Polymorphonuclear Neutrophils in Rheumatoid Arthritis and Systemic Lupus Erythematosus: More Complicated Than Anticipated

Polymorphonuclear neutrophils (PMN) are the most abundant leucocytes in the circulation in humans. They represent a heterogeneous population exerting diverse functions through several activities. Usually described as typical pro-inflammatory cells, immunomodulatory properties of PMNs have been reported. Among others, once activated and depending on the stimulus, PMNs expel neutrophil extracellular traps (NET) in the extracellular space. NETs are complexes made of DNA and granule proteins representing an innate immune mechanism fighting infections. Nevertheless, an excess of NET formation might be involved in the development of inflammatory or autoimmune responses. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two chronic, inflammatory, autoimmune diseases of unknown etiology and affecting mostly women. Several abnormal or non-classical functions of PMNs or PMN sub-populations have been described in SLE and RA. Particularly, NETs have been suggested to trigger pro-inflammatory responses by exposing pro-inflammatory mediators. Likewise, NETs may be the targets of autoantibodies or even might trigger the development of autoantibodies by exposing autoantigens. In the present review, we will summarize heterogeneous properties of human PMNs and we will discuss recent evidence linking PMNs and NETs to the pathogenesis of both SLE and RA

Presence Promotes Performance on a Virtual Spatial Cognition Task: Impact of Human Factors on Virtual Reality Assessment

The use of virtual reality in spatial cognition evaluation has been growing rapidly, mainly because of its potential applications in the training and diagnosis of cognitive impairment and its ability to blend experimental control and ecological validity. However, there are still many gray areas on virtual reality, notably on the sense of presence and its complex relationship to task performance. Performance in VR is often suggested to be influenced by other human factors including, amongst others, cybersickness, gender, video game experience, and field dependence. Would an individual experiencing more presence systematically show better performance? This study aimed to be part of a framework of virtual reality as this question is fundamental for rigorous assessment and diagnostics, and particularly in the spatial cognition field. Forty-eight healthy young subjects were recruited to take part in a virtual spatial cognition evaluation. Spatial cognition performance, along with their level of presence, cybersickness, video game experience, gender and field dependence, were measured. Matrix correlations were used, along with linear regressions and mediation analysis. Results show that presence promoted performance on the spatial cognition evaluation, while cybersickness symptoms hindered it, notably among women. The presence—performance relationship was not mediated by other human factors. Video game experience significantly predicted both sense of presence and cybersickness, the latter two being negatively correlated. Even if women experienced more negative symptoms than men, gender appears less informative than cybersickness and video game experience. Field dependence was not associated with any other variable. Results are discussed by confronting two theories of cognition (representational vs. ecological), highlighting that virtual reality is not a simple transposition of reality but truly a new paradigm with its own biases favoring some individuals more than others, and that some human factors have to be controlled for rigorous uses of virtual environments, particularly for spatial cognition evaluation