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Purpose: To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data.
Results: Among 550 patients (272 ACD, 278 Control), symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls (12 versus 14; p = 0.33) in unadjusted analyses, but statistically significant differences favoring ACD (19 versus 29; p < 0.001) in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses.
Conclusion: In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only.
Music is an effective means of stress-reduction. However, to date there has been no systematic comparison between musical and language-based means of stress reduction in an ambulatory setting. Furthermore, although the aim for listening to music appears to play a role in its effect, this has not yet been investigated thoroughly. We compared musical means, language-based means like guided relaxation or self-enhancement exercises, and a combination of both with respect to their potential to reduce perceived stress. Furthermore, we investigated whether the aim one wants to achieve by listening to these means had an impact on their effect. We tested 64 participants (age: M = 40.09 years; 18 female) for 3–10 days during their everyday life using an app containing three means: musical means, language-based means, and a combination of both. For the music and the combination conditions participants were asked to select an aim: relaxation or activation. We measured perceived stress, relaxation, activation, and electrical skin resistance (ESR) as a marker of sympathetic nervous system (SNS) activity before and after using the app. Participants were instructed to use the app as often as desired. Overall, perceived stress was reduced after using the app, while perceived relaxation and activation were increased. There were no differences between the three means regarding their effect on perceived stress and relaxation, but music led to a greater increase in ESR and perceived activation compared to the other means. There was a decrease in ESR only for music. Moreover, perceived stress was reduced and perceived relaxation was increased to greater extent if the aim “relaxation” had been selected. Perceived activation, however, showed a larger increase if the aim had been “activation,” which was even more marked in the case of music listening. Our results indicate that all three means reduced perceived stress and promoted feelings of relaxation and activation. For enhancing feelings of activation music seems to be more effective than the other means, which was reflected in increased SNS activity as well. Furthermore, the choice of an aim plays an important role for the reduction of stress, and promotion of relaxation and activation.
Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning.
Background: Transcatheter aortic valve replacement (TAVR) is a therapeutic option for patients with aortic valve stenosis at increased surgical risk. Telomeres are an established marker for cellular senescence and have served to evaluate cardiovascular diseases including severe aortic valve stenosis. In our study, we hypothesized that telomere length may be a predictor for outcome and associated with comorbidities in patients with TAVR.
Methods and results: We analyzed leucocyte telomere length from 155 patients who underwent TAVR and correlated the results with 1-year mortality and severe comorbidities. The cohort was subdivided into 3 groups according to telomere length. Although a trend for a positive correlation of telomere length with a lower EuroSCORE could be found, telomere length was not associated with survival, aortic valve opening area or cardiovascular comorbidities (peripheral, coronary or cerebrovascular disease). Interestingly, long telomeres were significantly correlated to a reduced left ventricular ejection fraction (LVEF).
Conclusion: In elderly patients with severe aortic valve stenosis, leucocyte telomere length did not predict post-procedural survival. The correlation between long telomere length and reduced LVEF in these patients deserves further attention.
Der Beitrag liest Hebbels Judith (1840) vor dem Hintergrund der politischen Ereignisse im postrevolutionären und postrestaurativen Europa, wobei das Interesse der imaginären Dimension der Politik gilt. Ausgehend von einer gespenstischen Hand im Theatertext und der jungfräulichen Titelfigur als Guillotine wiederholt das Drama die brutale Enthauptung, die Europa im ausgehenden 18. Jahrhundert erschütterte und eine kopflose Gemeinschaft hinterließ. Eine unheimliche Hand, die sich "aus der schwarzen Erde" ausstreckt, lässt den Theatertext zunächst nicht nur zwischen einer restaurativen und revolutionären Politik, sondern auch zwischen einer idealistisch-romantischen und realistischen Kunst oszillieren. Die dramatische Aufführungspraxis rechnet dabei zum einen mit der Romantik ab. Zum anderen lässt sich anhand von Modi des realistischen Darstellens auf der Theaterbühne beobachten, wie die restaurative Politik mit den Anfängen des realistischen Erzählens zusammenfällt.
Der Artikel schlägt vor, die Frage nach dem Berühren indirekt, d.h. ausgehend von einer Unhaltbarkeit der Unbetroffenheit aufzugreifen. In 'Schiffbruch mit Zuschauer' diskutiert Hans Blumenberg den Verlust der Zuschauerposition als einen rezeptionsgeschichtlichen Umschlagpunkt. Entscheidend hierfür sind die von Jacob Burckhardt beschriebenen Aporien der Geschichtsschreibung im "Revolutionszeitalter". Ein Blick auf Burckhardts Metaphernkonstellationen kann zeigen, dass die beschriebene "Krisis" die Logik der großen historischen Instanzen gerade unberührt lässt. Demgegenüber lässt sich mit Blumenbergs bereits 1979 angekündigter 'Theorie der Unbegrifflichkeit' eine Variante möglichen Distanzverlusts erschließen, die sich keinem hintergründigen Spiel historisch wirksamer Kräfte, sondern der immanenten – und darin keineswegs ahistorischen – Destruktion der Leistung des Begriffs verdankt. Unter dem Titel der Berührbarkeit wird die Wiederkehr des Sinnlichen zunächst als eine Krise methodischer Sicherungen reformulierbar.
Der Artikel arbeitet an Platons Gastmahl ein semantisches Netz rund um das Konzept des 'Berührens' heraus. Dabei bildet das Verb ἅπτομαι ein zentrales Relais, das zwischen dem vieldiskutierten 'philosophischen Gehalt' des Textes und der in ihrem performativen Beitrag meist unterschätzten Rahmenhandlung vermittelt. Im Nachvollzug der Konstellationen des Berührens zeigt sich, dass dem Berühren, als Berühren, nicht begrifflich beizukommen ist – es entzieht sich dem aneignenden Zugriff. Berühren ist eben nicht Begriff. Deshalb muss sich das Gastmahl der Berührung auf andere Weise nähern, nämlich berührend – wofür die narratologische Konstruktion des Textes von entscheidender Wichtigkeit ist. Er praktiziert Philo-Logie, d.h. nutzt die Macht der Worte, die genau daraus entsteht, dass sie in einer sehr präzisen Weise zwischen den Beteiligten aus einer konstitutiven Distanz heraus wirken.
Philologie der Hand
(2019)
Mit größter Selbstverständlichkeit spricht die Wissensgeschichte der Philologie von einer "Philologie des Ohrs" und einer "Philologie des Auges". Während sich die Ohrenphilologie in der Tradition des Phono(logo)zentrismus eingerichtet hat, beruft sich die Augenphilologie darauf, dass Literatur als Schrifttum zunächst optisch wahrgenommen werden müsse, bevor aus gesehenen Texten auch gelesene würden. Wie verkürzt beide Schulen argumentieren, zeigt sich nicht nur an Schriftsystemen, die den Tastsinn adressieren, oder an Sprachformen, die sich wesentlich auf die Handgeste stützen. Ein näherer Blick auf die Geschichte der Literatur enthüllt, dass die vermeintlich klare Aufteilung des philologischen Territoriums zwischen Akustik und Optik deutlich komplexer ist, denn die Dyade Auge-Ohr unterliegt permanenten Triangulierungen durch die Hand. Der Beitrag zeichnet diese Dreiecksbeziehungen mit ‚Blick‘ auf drei vernachlässigte Paradigmen der Moderne nach: Die Poetik der Geste, die Poetik des Werkzeugs und die Poetik der Berührung. Im Zentrum stehen dabei Konzepte des russischen Formalismus, der konstruktivistischen Produktionsliteratur, der symbolistischen Lautlehre und der futuristischen Haptologie.
Körper und ihre Sinneswahrnehmung gehören zu den Voraussetzungen von Literatur und, Philosophie; die Bestimmung ihrer Funktion zählt zugleich zu einer der schwierigsten und umstrittensten Aufgaben dieser Künste und Disziplinen. Der Komplex um das Berühren, zu dem Haptik, Taktilität und Gefühl, Motorik, Sensorik und Affektivität gleichermaßen gehören, ist in der Körper- und Sinnesgeschichte notorisch von Vernachlässigung bedroht, hat in den Kultur- und Medienwissenschaften aber zuletzt neue Aufmerksamkeit erfahren. Philologische Ansätze befinden sich derzeit noch am Rand dieser Debatten, obwohl ihre Begriffe und Verfahren sogar als besonders 'berührungsaffin' gelten können. Genaue philologische Lektüren bieten die Möglichkeit, das je singuläre Verhältnis von Affektion und Sinnlichkeit und die Bedeutung des Tastsinns im Zusammenspiel mit anderen Sinnen zu erfassen. Philologische Verfahren können das metaphorische Potenzial des Berührens ebenso ausloten wie sein Verhältnis zum 'Realen'. Die Beiträge dieses Bandes zur europäischen Literatur, aber auch zur Philosophie von der Antike bis ins späte 20. Jahrhundert untersuchen das Berühren als relationale Figur, in der poetische Gestaltung und Materialität, Bildlichkeit und Buchstäblichkeit, Begreifen und Ergreifen, Anschauung und Affizierung in Beziehung treten. Im Zentrum stehen Fragen nach dem Verhältnis von Gemeinschaft und Individualität, von Literatur und Philosophie sowie nach der Funktion von Ansteckungs- und Distanzierungsverfahren in diesen Zusammenhängen. Dabei geraten gerade auch Wahrnehmungsräume in den Blick, die zumeist unter dem Primat des Visuellen verhandelt wurden. In Re- und Gegenlektüren schlagen die Beiträge eine Ausweitung der Sinnesbezüge vor.
In the mouse, most mature olfactory sensory neurons (OSNs) express one allele of one gene from the repertoire of ~1100 odorant receptor (OR) genes, which encode G-protein coupled receptors (GPCRs). Axons of OSNs that express a given OR coalesce into homogeneous glomeruli, which reside at conserved positions in the olfactory bulb. ORs are intimately involved in ensuring the expression of one OR per OSN and the coalescence of OSN axons into glomeruli. But the mechanisms whereby ORs accomplish these diverse functions remain poorly understood. An experimental approach that has been informative is to substitute an OR genetically with another GPCR that is normally not expressed in OSNs, in order to determine in which aspects this GPCR can serve as surrogate OR in mouse OSNs. Thus far only the β2-adrenergic receptor (β2AR, Ardb2) has been shown to be able to serve as surrogate OR in OSNs; the β2AR could substitute for the M71 OR in all aspects examined. Can other non-olfactory GPCRs function equally well as surrogate ORs in OSNs? Here, we have generated and characterized two novel gene-targeted mouse strains in which the mouse melanocortin 4 receptor (Mc4r) or the mouse dopamine receptor D1 (Drd1a) is coexpressed with tauGFP in OSNs that express the OR locus M71. These alleles and strains are abbreviated as Mc4r→M71-GFP and Drd1a→M71-GFP. We detected strong Mc4r or Drd1a immunoreactivity in axons and dendritic knobs and cilia of OSNs that express Mc4r or Drd1a from the M71 locus. These OSNs responded physiologically to cognate agonists for Mc4r (Ro27-3225) or Drd1a (SKF81297), and not to the M71 ligand acetophenone. Axons of OSNs expressing Mc4r→M71-GFP coalesced into glomeruli. Axons of OSNs expressing Drd1a→M71-GFP converged onto restricted areas of the olfactory bulb but did not coalesce into glomeruli. Thus, OR functions in OSNs can be substituted by Mc4r or Drd1a, but not as well as by β2AR. We attribute the weak performance of Drd1a as surrogate OR to poor OSN maturation.
Gene targeting in embryonic stem (ES) cells remains best practice for introducing complex mutations into the mouse germline. One aspect in this multistep process that has not been streamlined with regard to the logistics and ethics of mouse breeding is the efficiency of germline transmission: the transmission of the ES cell-derived genome through the germline of chimeras to their offspring. A method whereby male chimeras transmit exclusively the genome of the injected ES cells to their offspring has been developed. The new technology, referred to as goGermline, entails injecting ES cells into blastocysts produced by superovulated homozygous Tsc22d3 floxed females mated with homozygous ROSA26-Cre males. This cross produces males that are sterile due to a complete cell-autonomous defect in spermatogenesis. The resulting male chimeras can be sterile but when fertile, they transmit the ES cell-derived genome to 100% of their offspring. The method was validated extensively and in two laboratories for gene-targeted ES clones that were derived from the commonly used parental ES cell lines Bruce4, E14, and JM8A3. The complete elimination of the collateral birth of undesired, non-ES cell-derived offspring in goGermline technology fulfills the reduction imperative of the 3R principle of humane experimental technique with animals. genesis 54:326-333, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.
Extraembryonic endoderm stem (XEN) cell lines can be derived and maintained in vitro and reflect the primitive endoderm lineage. Platelet-derived growth factor receptor alpha (PDGFRA) is thought to be essential for the derivation and maintenance of mouse XEN cell lines. Here, we have re-evaluated this requirement for PDGFRA. We derived multiple PDGFRA-deficient XEN cell lines from postimplantation and preimplantation embryos of a PDGFRA-GFP knockout strain. We also converted PDGFRA-deficient embryonic stem cell lines into XEN cell lines chemically by transient culturing with retinoic acid and Activin A. We confirmed the XEN profile of our 12 PDGFRA-deficient cell lines by immunofluorescence with various markers, by NanoString gene expression analyses, and by their contribution to the extraembryonic endoderm of chimeric embryos produced by injecting these cells into blastocysts. Thus, PDGFRA is not essential for the derivation and maintenance of XEN cell lines.
Efficient derivation of extraembryonic endoderm stem cell lines from mouse postimplantation embryos
(2016)
Various types of stem cell lines have been derived from preimplantation or postimplantation mouse embryos: embryonic stem cell lines, epiblast stem cell lines, and trophoblast stem cell lines. It is not known if extraembryonic endoderm stem (XEN) cell lines can be derived from postimplantation mouse embryos. Here, we report the derivation of 77 XEN cell lines from 85 postimplantation embryos at embryonic day E5.5 or E6.5, in parallel to the derivation of 41 XEN lines from 69 preimplantation embryos at the blastocyst stage. We attain a success rate of 100% of XEN cell line derivation with our E5.5 whole-embryo and E6.5 disaggregated-embryo methods. Immunofluorescence and NanoString gene expression analyses indicate that the XEN cell lines that we derived from postimplantation embryos (post-XEN) are very similar to the XEN cell lines that we derived from preimplantation embryos (pre-XEN) using a conventional method. After injection into blastocysts, post-XEN cells contribute to extraembryonic endoderm in chimeras at E6.5 and E7.5.
Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
Global response of diacylglycerol kinase towards substrate binding observed by 2D and 3D MAS NMR
(2019)
Escherichia coli diacylglycerol kinase (DGK) is an integral membrane protein, which catalyses the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatic acid (PA). It is a unique trimeric enzyme, which does not share sequence homology with typical kinases. It exhibits a notable complexity in structure and function despite of its small size. Here, chemical shift assignment of wild-type DGK within lipid bilayers was carried out based on 3D MAS NMR, utilizing manual and automatic analysis protocols. Upon nucleotide binding, extensive chemical shift perturbations could be observed. These data provide evidence for a symmetric DGK trimer with all of its three active sites concurrently occupied. Additionally, we could detect that the nucleotide substrate induces a substantial conformational change, most likely directing DGK into its catalytic active form. Furthermore, functionally relevant interprotomer interactions are identified by DNP-enhanced MAS NMR in combination with site-directed mutagenesis and functional assays.
Background: The clinical presentation of gastroesophageal reflux disease (GERD) shows a large symptom variation also in different intensities among patients. As several studies have shown, there is a large overlap in the symptomatic spectrum between proven GERD and other disorders such as dyspepsia, functional heartburn and/or somatoform disorders.
Aim: To prospectively evaluate the GERD patients with and without somatoform disorders before and after laparoscopic antireflux surgery.
Methods: In a tertiary referral center for foregut surgery over a period of 3 years patients with GERD, qualifying for the indication of laparoscopic antireflux surgery, were investigated prospectively regarding their symptomatic spectrum in order to identify GERD and associated somatoform disorders. Assessment of symptoms was performed by an instrument for the evaluation of somatoform disorders [Somatoform Symptom Index (SSI) > 17]. Quality of life was evaluated by Gastrointestinal Quality of Life Index (GIQLI).
Results: In 123 patients an indication for laparoscopic antireflux surgery was established and in 43 patients further medical therapy was suggested. The portion of somatoform tendencies in the total patient population was 20.48% (34 patients). Patients with a positive SSI had a preoperative GIQLI of 77 (32-111). Patients with a normal SSI had a GIQLI of 105 (29-140) (P < 0.0001). In patients with GERD the quality of life could be normalized from preoperative reduced values of GIQLI 102 (47-140) to postoperative values of 117 (44-144). In patients with GERD and somatoform disorders, the GIQLI was improved from preoperative GIQLI 75 (47-111) to postoperative 95 (44-122) (P < 0.0043).
Conclusion: Patients with GERD and associated somatoform disorders have significantly worse levels of quality of life. The latter patients can also benefit from laparoscopic fundoplication, however they will not reach a normal level.
Background: We evaluated the Kidney Donor Risk Index (KDRI) scoring system for kidney transplantation in the Eurotransplant Senior Program (ESP) that allocates kidneys from older donors to older recipients (≥65 years).
Material and methods: We retrospectively analyzed data of 37 kidney transplant recipients and 36 kidney donors who participated in kidney transplantation program according to the ESP at our center from January 2004 until December 2013.
Results: Mean recipient and donor age was 67.9±2.6 and 70.5±4.0 years respectively. The mean KDRI score was 1.7±0.27. Uncensored graft survival after 1 year and 5 years was 64.2% and 53.7% respectively. Subgroup analysis showed that in kidney transplantation with KDRI >1.83, graft survival was significantly reduced compared to lower KDRI subgroups. KDRI was significantly correlated with serum creatinine level at discharge (r=0.4).
Conclusions: ESP kidneys represent a group of high-risk grafts with high KDRI scores. Higher KDRI scores in ESP kidneys was associated with reduced postoperative short-term and long-term graft outcomes. KDRI might be useful in decision-making for selecting donors for ESP kidney transplantation.
Global impact models represent process-level understanding of how natural and human systems may be affected by climate change. Their projections are used in integrated assessments of climate change. Here we test, for the first time, systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions. Using the 2003 European heat wave and drought as a historical analogue for comparable events in the future, we find that a majority of models underestimate the extremeness of impacts in important sectors such as agriculture, terrestrial ecosystems, and heat-related human mortality, while impacts on water resources and hydropower are overestimated in some river basins; and the spread across models is often large. This has important implications for economic assessments of climate change impacts that rely on these models. It also means that societal risks from future extreme events may be greater than previously thought.
The TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to decrease glycolysis, to activate the pentose phosphate pathway, and to provide protection against oxidative damage. Hypoxic regions are considered characteristic of glioblastoma and linked with resistance to current treatment strategies. Here, we established that LNT-229 glioma cell lines stably expressed shRNA constructs targeting TIGAR, and exposed them to hypoxia, irradiation and temozolomide. The disruption of TIGAR enhanced levels of reactive oxygen species and cell death under hypoxic conditions, as well as the effectiveness of irradiation and temozolomide. In addition, TIGAR was upregulated by HIF-1α. As a component of a complex network, TIGAR contributes to the metabolic adjustments that arise from either spontaneous or therapy-induced changes in tumor microenvironment.
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.