Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation.

Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca2+ rise that controls motility. The mechanisms underlying such ultra-sensitivity are ill-defined. Here, we determine by mass spectrometry the copy number of nineteen chemosensory signaling proteins in sperm flagella from the sea urchin Arbacia punctulata. Proteins are up to 1,000-fold more abundant than the free cellular messengers cAMP, cGMP, H+ , and Ca2+ . Opto-chemical techniques show that high protein concentrations kinetically compartmentalize the flagellum: Within milliseconds, cGMP is relayed from the receptor guanylate cyclase to a cGMP-gated channel that serves as a perfect chemo-electrical transducer. cGMP is rapidly hydrolyzed, possibly via "substrate channeling" from the channel to the phosphodiesterase PDE5. The channel/PDE5 tandem encodes cGMP turnover rates rather than concentrations. The rate-detection mechanism allows continuous stimulus sampling over a wide dynamic range. The textbook notion of signal amplification-few enzyme molecules process many messenger molecules-does not hold for sperm flagella. Instead, high protein concentrations ascertain messenger detection. Similar mechanisms may occur in other small compartments like primary cilia or dendritic spines.

A family of hyperpolarization-activated channels selective for protons.

Proton (H+) channels are special: They select protons against other ions that are up to a millionfold more abundant. Only a few proton channels have been identified so far. Here, we identify a family of voltage-gated "pacemaker" channels, HCNL1, that are exquisitely selective for protons. HCNL1 activates during hyperpolarization and conducts protons into the cytosol. Surprisingly, protons permeate through the channel's voltage-sensing domain, whereas the pore domain is nonfunctional. Key to proton permeation is a methionine residue that interrupts the series of regularly spaced arginine residues in the S4 voltage sensor. HCNL1 forms a tetramer and thus contains four proton pores. Unlike classic HCN channels, HCNL1 is not gated by cyclic nucleotides. The channel is present in zebrafish sperm and carries a proton inward current that acidifies the cytosol. Our results suggest that protons rather than cyclic nucleotides serve as cellular messengers in zebrafish sperm. Through small modifications in two key functional domains, HCNL1 evolutionarily adapted to a low-Na+ freshwater environment to conserve sperm's ability to depolarize.

Reconstruction of the birth of a male sex chromosome present in Atlantic herring.

The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene BMPR1BBY encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca2+ channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an ∼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.

Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis.

The fate of infected macrophages has an essential role in protection against Mycobacterium tuberculosis by regulating innate and adaptive immunity. M. tuberculosis exploits cell necrosis to exit from macrophages and spread. In contrast, apoptosis, which is characterized by an intact plasma membrane, is an innate mechanism that results in lower bacterial viability. Virulent M. tuberculosis inhibits apoptosis and promotes necrotic cell death by inhibiting production of prostaglandin E(2). Here we show that by activating the 5-lipoxygenase pathway, M. tuberculosis not only inhibited apoptosis but also prevented cross-presentation of its antigens by dendritic cells, which impeded the initiation of T cell immunity. Our results explain why T cell priming in response to M. tuberculosis is delayed and emphasize the importance of early immunity.

Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair.

Induction of macrophage necrosis is a strategy used by virulent Mycobacterium tuberculosis (Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross-priming by antigen-presenting cells. Here we show that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions, a process crucial for preventing necrosis and promoting apoptosis, required translocation of lysosomal and Golgi apparatus-derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E(2) (PGE(2)), which regulates synaptotagmin 7 (Syt-7), the calcium sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A(4) (LXA(4)), which blocks PGE(2) biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.

Combining segmental bulk- and single-cell RNA-sequencing to define the chondrocyte gene expression signature in the murine knee joint.

OBJECTIVE: Due to the small size of the murine knee joint, extracting the chondrocyte transcriptome from articular cartilage (AC) is a major technical challenge. In this study, we demonstrate a new pragmatic approach of combining bulk RNA-sequencing (RNA-seq) and single cell (sc)RNA-seq to address this problem. DESIGN: We propose a new cutting strategy for the murine femur which produces three segments with a predictable mixed cell population, where one segment contains AC and growth plate (GP) chondrocytes, another GP chondrocytes, and the last segment only bone and bone marrow. We analysed the bulk RNA-seq of the different segments to find distinct genes between the segments. The segment containing AC chondrocytes was digested and analysed via scRNA-seq. RESULTS: Differential expression analysis using bulk RNA-seq identified 350 candidate chondrocyte gene in the AC segment. Gene set enrichment analysis of these genes revealed biological processes related- and non-related to chondrocytes, including, cartilage development (adj. P-value: 3.45E-17) and endochondral bone growth (adj. P-value 1.22E-4), respectively. ScRNA-seq of the AC segment found a cluster of 131 cells containing mainly chondrocytes. This cluster had 759 differentially expressed genes which enriched for extracellular matrix organisation (adj. P-value 7.76E-40) and other joint development processes. The intersection of the gene sets of bulk- and scRNA-seq contained 75 genes. CONCLUSIONS: Based on our results, we conclude that the combination of the two RNA-seq methods is necessary to precisely delineate the chondrocyte transcriptome and to study the disease phenotypes of chondrocytes in murine OA models in the future.

Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells.

Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracycline-controlled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.

Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations.

The nonlysosomal glucosylceramidase ß2 (GBA2) catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Mutations in the human GBA2 gene have been associated with hereditary spastic paraplegia (HSP), autosomal-recessive cerebellar ataxia (ARCA), and the Marinesco-Sjögren-like syndrome. However, the underlying molecular mechanisms are ill-defined. Here, using biochemistry, immunohistochemistry, structural modeling, and mouse genetics, we demonstrate that all but one of the spastic gait locus #46 (SPG46)-connected mutations cause a loss of GBA2 activity. We demonstrate that GBA2 proteins form oligomeric complexes and that protein-protein interactions are perturbed by some of these mutations. To study the pathogenesis of GBA2-related HSP and ARCA in vivo, we investigated GBA2-KO mice as a mammalian model system. However, these mice exhibited a high phenotypic variance and did not fully resemble the human phenotype, suggesting that mouse and human GBA2 differ in function. Whereas some GBA2-KO mice displayed a strong locomotor defect, others displayed only mild alterations of the gait pattern and no signs of cerebellar defects. On a cellular level, inhibition of GBA2 activity in isolated cerebellar neurons dramatically affected F-actin dynamics and reduced neurite outgrowth, which has been associated with the development of neurological disorders. Our results shed light on the molecular mechanism underlying the pathogenesis of GBA2-related HSP and ARCA and reveal species-specific differences in GBA2 function in vivo.

Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence.

Macrophages infected with attenuated Mycobacterium tuberculosis strain H37Ra become apoptotic, which limits bacterial replication and facilitates antigen presentation. Here we demonstrate that cells infected with H37Ra became apoptotic after the formation of an apoptotic envelope on their surface was complete. This process required exposure of phosphatidylserine on the cell surface, followed by deposition of the phospholipid-binding protein annexin-1 and then transglutaminase-mediated crosslinking of annexin-1 through its amino-terminal domain. In macrophages infected with the virulent strain H37Rv, in contrast, the amino-terminal domain of annexin-1 was removed by proteolysis, thus preventing completion of the apoptotic envelope, which resulted in macrophage death by necrosis. Virulent M. tuberculosis therefore avoids the host defense system by blocking formation of the apoptotic envelope, which leads to macrophage necrosis and dissemination of infection in the lung.

Monitoring of Thyroid Malfunction and Therapies in Pregnancy and the Postpartum Period: A Systematic Updated Critical Review of the Literature.

PURPOSE: From the very beginning of pregnancy, the maternal thyroid has to adapt to increased thyroid hormone secretion of up to 50%. This is paralleled by changes in thyroid-stimulating hormone secretion and by the thyroid-topic action of human chorionic gonadotropin. Thus, hypothyroidism and hyperthyroidism may occur. Many women exhibit preexisting thyroid diseases. This review tries to add the most recently published approaches to diagnosing thyroid malfunction in pregnancy to existing guidelines. METHODS: Different literature-based approaches to diagnosing thyroid malfunction during pregnancy and the postpartum period were applied. To diagnose thyroid malfunction in pregnancy, trimester-specific reference ranges for thyroid-stimulating hormone and T4 are used. RESULTS: Definitions of thyroid malfunction are given. Treatment schedules for various thyroid diseases were reviewed and, on the basis of recent findings, were revised where necessary. For a daily clinical workup, this outline not only suggests diagnostic and therapeutic steps but also refers to frequent pitfalls and misinterpretations of laboratory data. CONCLUSIONS: Although the body of knowledge is increasing rapidly, the authors believe that this review is able to present new ideas concerning diagnostic and therapeutic tools for thyroid malfunction in pregnancy and the postpartum period. Nevertheless, there seems to remain room for individual approaches based on the personal experience of physicians who deal with these issues regularly.

Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis is an extremely successful pathogen, and its success is widely attributed to its ability to manipulate the intracellular environment of macrophages. A central phenomenon of tuberculosis pathology enabling immune evasion is the capacity of virulent M. tuberculosis (H37Rv) to induce macrophage necrosis, which facilitates the escape of the mycobacteria from the macrophage and spread of infection. In contrast, avirulent M. tuberculosis (H37Ra) induces macrophage apoptosis, which permits Ag presentation and activation of adaptive immunity. Previously, we found that H37Rv induces plasma membrane microdisruptions, leading to necrosis in the absence of plasma membrane repair. In contrast, H37Ra permits plasma membrane repair, which changes the host cell death modality to apoptosis, suggesting that membrane repair is critical for sequestering the pathogen in apoptotic vesicles. However, mechanisms of plasma membrane repair induced in response to M. tuberculosis infection remain unknown. Plasma membrane repair is known to induce a Ca2+-mediated signaling, which recruits lysosomes to the area of damaged plasma membrane sites for its resealing. In this study, we found that the small GTPase Arl8b is required for plasma membrane repair by controlling the exocytosis of lysosomes in cell lines and in human primary macrophages. Importantly, we found that the Arl8b secretion pathway is crucial to control the type of cell death of the M. tuberculosis-infected macrophages. Indeed, Arl8b-depleted macrophages infected with avirulent H37Ra undergo necrotic instead of apoptotic cell death. These findings suggest that membrane repair mediated by Arl8b may be an important mechanism distinguishing avirulent from virulent M. tuberculosis-induced necrotic cell death.

Identification of a feedback loop involving ß-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.

The lysosomal acid ß-glucosidase GBA1 and the non-lysosomal ß-glucosidase GBA2 degrade glucosylceramide (GlcCer) to glucose and ceramide in different cellular compartments. Loss of GBA2 activity and the resulting accumulation of GlcCer results in male infertility, whereas mutations in the GBA1 gene and loss of GBA1 activity cause the lipid-storage disorder Gaucher disease. However, the role of GBA2 in Gaucher disease pathology and its relationship to GBA1 is not well understood. Here, we report a GBA1-dependent down-regulation of GBA2 activity in patients with Gaucher disease. Using an experimental approach combining cell biology, biochemistry, and mass spectrometry, we show that sphingosine, the cytotoxic metabolite accumulating in Gaucher cells through the action of GBA2, directly binds to GBA2 and inhibits its activity. We propose a negative feedback loop, in which sphingosine inhibits GBA2 activity in Gaucher cells, preventing further sphingosine accumulation and, thereby, cytotoxicity. Our findings add a new chapter to the understanding of the complex molecular mechanism underlying Gaucher disease and the regulation of ß-glucosidase activity in general.

Impact of Acute Intestinal Ischemia and Reperfusion Injury on Hemodynamics and Remote Organs in a Rat Model.

BACKGROUND: Acute mesenteric ischemia following cardiovascular surgery is a rare but fatal complication. We established a new rat model for hemodynamic monitoring during mesenteric ischemia/reperfusion (I/R) and evaluated the impact of mesenteric I/R on hemodynamics and remote organ injury. METHODS: Mesenteric I/R was induced in male Wistar rats by superior mesenteric artery occlusion for 90 minutes, followed by 120 minutes of reperfusion. Before I/R, ventilation and hemodynamic monitoring including mean arterial blood pressure (MAP) and cardiac output (CO) were established. During reperfusion Geloplasma (I/R + Geloplasma, N = 6) and Ringer's solution (I/R + Ringer, N = 6) were titrated according to CO and compared with I/R without volume resuscitation (I/R only, N = 6) and a sham group (sham, N = 6). Blood samples were regularly taken for serum marker measurements. After reperfusion organs were harvested for histology studies. RESULTS: After acute mesenteric I/R, MAP and CO decreased (p < 0.01) while systemic and pulmonary vascular resistance increased (p < 0.01) continuously in the I/R group. Volume substitution according to CO initially stabilized hemodynamic parameters, but CO declined independently in the late stage. Compared with the I/R + Ringer group, the I/R + Geloplasma group required less volume for resuscitation (p < 0.01), experienced less metabolic acidosis. I/R groups had more organ injuries, more neutrophils sequestration, and higher creatine phosphokinase-MB levels than sham group. CONCLUSION: A new model for CO monitoring after mesenteric I/R injury demonstrated severe hypovolemic shock during reperfusion followed by remote myocardial and lung injury. Far less colloid volume is needed for hemodynamic stabilization after I/R compared with crystalloid volume.

Accumulation of glucosylceramide in the absence of the beta-glucosidase GBA2 alters cytoskeletal dynamics.

Glycosphingolipids are key elements of cellular membranes, thereby, controlling a variety of cellular functions. Accumulation of the simple glycosphingolipid glucosylceramide results in life-threatening lipid storage-diseases or in male infertility. How glucosylceramide regulates cellular processes is ill defined. Here, we reveal that glucosylceramide accumulation in GBA2 knockout-mice alters cytoskeletal dynamics due to a more ordered lipid organization in the plasma membrane. In dermal fibroblasts, accumulation of glucosylceramide augments actin polymerization and promotes microtubules persistence, resulting in a higher number of filopodia and lamellipodia and longer microtubules. Similar cytoskeletal defects were observed in male germ and Sertoli cells from GBA2 knockout-mice. In particular, the organization of F-actin structures in the ectoplasmic specialization and microtubules in the sperm manchette is affected. Thus, glucosylceramide regulates cytoskeletal dynamics, providing mechanistic insights into how glucosylceramide controls signaling pathways not only during sperm development, but also in other cell types.

[Which factors are associated with the use of potentially inadequate medications (PIM) in the elderly? : Results from the German health interview and examination survey (DEGS1)]. / Welche Faktoren begünstigen die Anwendung potenziell ungeeigneter Medikamente bei älteren Menschen? : Ergebnisse aus der Studie zur Gesundheit Erwachsener in Deutschland (DEGS1).

BACKGROUND: Recent studies demonstrate a relationship between the prescription of potentially inappropriate medications (PIM) for patients 65 years or older and an increased risk for adverse events, in particular hospitalisations. The RKI conducted DEGS1-Survey ("German health interview and examination survey for adults") provides a representative sample of the target population to identify determinants for PIM use. OBJECTIVE: The aim of this study was to determine characteristics of older persons in Germany, who currently use PIM, and if there are subpopulations among older persons with a particularly high PIM use. METHODS: Within the DEGS1-Survey a total of 175 variables regarding health and social aspects were documented from 1392 community-dwelling persons between 65 and 79 years of age, and medication intake during the last seven days was recorded. PIM drugs were identified according to the PRISCUS list. Associations between PIM use and variables recorded were evaluated by means of multivariate statistical models. RESULTS: Within seven days before the survey PIM drugs were used by 13.0% (95%-CI: 10.7-15.6) of the respondents. The following factors significantly increase the risk for receiving a PIM: number of drugs taken in the last seven days; number of visits to different physician specialists during the last 12 months; sleep disorders; psychiatric condition, and diseases affecting the musculoskeletal system. The majority of PIMs were antidepressants and anxiolytics/sedatives. Elderly women with depression, sleep disorders, and a need for analgesics are particularly affected by increased PIM use. They deserve special attention in this regard.

Oxygen uptake prediction in rivers and streams: A stochastic approach.

Dissolved oxygen fluctuations in a river over a short period of time were assumed to be caused by the microbial growth dynamics, and a stochastic model was built for oxygen uptake. As a case study, biochemical oxygen demand (BOD) was measured in water from the Ura River, Oita River, and Otozu River flowing through the urban district of Oita, Japan. Water samples were taken from each river and partitioned into BOD bottles. BOD was measured in five of these bottles on each of nine days. The experimental results show that the average daily BOD decreased exponentially as expressed by the Streeter-Phelps equation. A wide range of the measured five daily BOD-values was expressed by the difference between the maximum and minimum BOD-values on each day for each river. After the first few days the range became smaller. The proposed stochastic model describes the observed experimental fluctuation of BOD over time. Eighty to ninety percent of the experimental BOD plots are within the 80% probability range given by the model. The uncertainty of BOD prediction can be expressed by the error which is the non-dimensional ratio of the range to the median. Modeled and experimental results reveal that the error is about 0.5-1 (50-100% of expected value) after a few days. This suggests that the BOD predicted by deterministic water quality models can include uncertainty, i.e. the actual BOD can be a quarter or double of the simulated value, for the time scale of a few days. For a longer period, e.g. more than a week, the error can become even more significant.

[CRISPR-Cas system as molecular scissors for gene therapy]. / CRISPR-Cas-System als molekulare Schere für Gentherapie.

Since the discovery of the CRISPR-Cas system as the adaptive immune system of prokaryotes, the underlying mechanism has proven to be a precise molecular tool for the targeted editing of genetic information in various cell types. By using the CRISPR-Cas9 system DNA sequences can be cut out at any site in the genome and changed in a sequence-specific manner. In the long term this provides the opportunity to cure diseases caused by gene mutations.

Beneficial effects of levosimendan on survival in patients undergoing extracorporeal membrane oxygenation after cardiovascular surgery.

BACKGROUND: The impact of levosimendan treatment on clinical outcome in patients undergoing extracorporeal membrane oxygenation (ECMO) support after cardiovascular surgery is unknown. We hypothesized that the beneficial effects of levosimendan might improve survival when adequate end-organ perfusion is ensured by concomitant ECMO therapy. We therefore studied the impact of levosimendan treatment on survival and failure of ECMO weaning in patients after cardiovascular surgery. METHODS: We enrolled a total of 240 patients undergoing veno-arterial ECMO therapy after cardiovascular surgery at a university-affiliated tertiary care centre into our observational single-centre registry. RESULTS: During a median follow-up period of 37 months (interquartile range 19-67 months), 65% of patients died. Seventy-five per cent of patients received levosimendan treatment within the first 24 h after initiation of ECMO therapy. Cox regression analysis showed an association between levosimendan treatment and successful ECMO weaning [adjusted hazard ratio (HR) 0.41; 95% confience interval (CI) 0.22-0.80; P=0.008], 30 day mortality (adjusted HR 0.52; 95% CI 0.30-0.89; P=0.016), and long-term mortality (adjusted HR 0.64; 95% CI 0.42-0.98; P=0.04). CONCLUSIONS: These data suggest an association between levosimendan treatment and improved short- and long-term survival in patients undergoing ECMO support after cardiovascular surgery.

Predictors of aortic pulse wave velocity in the elderly with severe aortic stenosis.

UNLABELLED: Predictors of aortic pulse wave velocity (AoPWV) were not previously studied in the elderly with severe aortic stenosis (AS). We aimed to compare the AoPWV in these patients with matched controls and to study the predictors of AoPWV in this population. We measured the AoPWV during cardiac catheterisation in 40 patients with severe AS and 20 matched controls. AoPWV in both groups was similar (p = 0.198) and lied within normal reference value for age in 68 % of elderly with severe AS. Central systolic blood pressure (SBP) (adjusted ß = 0.45, p = 0.001) and glomerular filtration rate (GFR) (adjusted ß = -0.29, p = 0.023) were the only independent predictors of AoPWV in AS group. Central SBP >140 mmHg was the best predictor of abnormal AoPWV (≥14.6 m/s) with 100 % sensitivity and 70 % specificity, p < 0.001. CONCLUSION: AoPWV is not increased in the elderly with severe AS compared to controls, and lies within the reference value for age in the majority of these patients. Central SBP >140 mmHg best predicts abnormal AoPWV in the elderly with severe AS.

[Role of non-coding regulatory ribonucleic acids in chronic inflammatory diseases]. / Rolle nicht kodierender regulatorischer Ribonukleinsäuren bei chronisch entzündlichen Erkrankungen.

Non-coding regulatory ribonucleic acids (RNA), including microRNA, long non-coding RNA and circular RNA, can influence the expression of genes mediating inflammatory processes and therefore affect the course and progression of chronic inflammatory diseases. Recent studies using antisense oligonucleotides suggest that such non-coding regulatory RNAs are suitable as novel therapeutic target molecules for the treatment of inflammatory rheumatic diseases.