Untersuchungen zur Induktion regulatorischer T-Zellen durch die transmembranen Hüllproteine von HIV-1 und anderer Retroviren

Infektionen mit HIV, FIV und anderen Retroviren haben häufig eine Immundefizienz zur Folge. Der Mechanismus dieser Immundefizienz ist weitestgehend unbekannt und vom besonderen Interesse für die HIV-Forschung. Erste Daten zeigten, dass ein hoch konservierter Bereich des transmembranen Hüllproteins gp41, die immunsuppressive Domäne (Isu-Domäne), in vitro immunsuppressive Eigenschaften aufweist. Der Einfluss dieser Domäne von gp41 auf die Cytokinmodulation und die Aktivierung der regulatorischen T-Zellen (Tregs), wurde deshalb in dieser Arbeit genauer untersucht. Zur Charakterisierung der Wirkung der HIV-1 Isu-Domäne wurden synthetische Peptide, die die Sequenz der HIV-1 Isu-Domäne enthalten, zu Isu-Homopolymeren gekoppelt und das rekombinante HERV-K TM wurde aus Hefezellen exprimiert. Nachdem in einer Mikroarray Analyse in humanen PBMCs nach der Inkubation mit dem Isu-Homopolymer bzw. HERV-K TM etwa 440 Gene überexprimiert gefunden worden waren, darunter die Cytokine IL-6, IL-10, INF-1α aber auch andere Proteine wie MMP-1, MMP-12 und TREM-1, wurden deren Expression in Kinetiken mittels real time RT-PCR und ELISA Analyse untersucht. Die Inkubation von PBMCs mit dem Isu-Homopolymer und dem HERV-K TM führte zu einer erhöhten Genexpression von IL-10 zwischen 6 und 10 Stunden, während eine Freisetzung von IL-10 Protein zwischen 10 und 24 Stunden beobachtet wurde. Eine direkte Übereinstimmung der IL-10 Genexpression und der gemessenen IL-10 Menge im Überstand konnte nachgewiesen werden. Die Mikroarray Analyse zeigte für IL-6 die stärkste Überexprimierung aller untersuchten Gene. Dies konnte im Rahmen der Kineitk bestätigt werden, bei der bereits 4 Stunden nach Inkubation eine signifikante Hochregulierung des IL-6 Transkripts detektiert wurde. Die Untersuchung des Cytokins INF-1α zeigten in einer Kinetik ebenfalls eine Hochregulierung des Gens. Die Rolle der Tregs bei der Immunpathogenese der retroviralen Infektion ist noch weitestgehend unbekannt. Unter anderem konnte eine Aktivierung der Tregs sowohl in HIV-infzierten Menschen als auch in FIV-infizierten Katzen gezeigt werden. In dieser Arbeit konnte eine signifikante FoxP3 Hochregulierung als Marker der Aktivierung von Tregs zwischen 6 und 12 Stunden nach Inkubation von PBMCs mit Isu-Homopolymeren bzw. mit HERV-K TM beobachtet werden. Außerdem wurde die Zahl der CD4+CD25+FoxP3+ T-Zellen nach 24 Stunden und 72 Stunden mittels Durchflusszytometrie bestimmt. Dabei konnte ein signifikanter Anstieg der Tregs bestätigt werden, die mit den Daten der Expressionsanalyse von FoxP3 übereinstimmen. Die Ergebnisse zeigen, dass die HIV-1 Isu-Domäne in vitro an der Aktivierung immunsuppressiver Mechanismen beteiligt ist

Application of GM (1,1) and EXGM (1,1) forecasting models to Turkey's research and development expenditures

Disiplinler arası bir bilim alanı olan Gri sistem Teorisi az sayıda veri kullanarak bilinmeyen sistemlerin davranışını tahmin etmektedir ve birçok alana başarı ile uygulanmıştır. Bu çalışmada ise Gri Sistem Teorisi Türkiye’nin Araştırma ve Geliştirme (Ar-Ge) harcamalarını tahmin etmek için kullanılmıştır. 2011-2020 yılları arasındaki Ar-Ge harcamaları verileri Türkiye İstatistik Kurumu’ndan alınarak 2021-2030 yıllarının tahmini Standart Gri Model (GM (1,1)) ve Üstel Gri Model (EXGM (1,1)) kullanılarak yapılmıştır. Her iki modelin tahmin değerlerindeki hata ve korelasyon sonuçları karşılaştırılmıştır. 2011-2020 yılları arasındaki verileri kullanarak, gerçek ve tahmin değeri arasındaki yüzde bağıl hata (RPE) ve ortalama yüzde bağıl hata (MAPE) belirlenmiştir.Grey system theory, which is an interdisciplinary field of science, predicts the behaviour of unknown systems using a small amount of data and has been successfully applied to many fields. In this study, the Grey System Theory is used to estimate Turkey's Research and Development (R&D) expenditures. Turkey's R&D expenditure datas were taken from the Turkish Statistical Institute for the years 2011-2020 and estimated for the years 2021-2030 using Standard Gray Model (GM (1,1)) and Exponential Gray Model (EXGM (1,1)). The error and correlation results in the prediction values of both models were compared. The percentage relative error (RPE) between the actual and predicted values and mean absolute percentage error (MAPE) were determined using the data from 2011-2020

Comparison of subclinical neuronal injury by measuringneuron-specific enolase in patients with severeaortic stenosis treated with transcatheter aortic valvereplacement or sutureless aortic valve replacement

Aim: Severe aortic valve stenosis (SAVS) which causes angina pectoris, syncope, arrhythmias, and sudden cardiac death, may be treated with transcatheter aortic valve replacement (TAVR) or sutureless aortic valve replacement (SU-AVR). We aimed to predict subclinical neuronal injury (SNI) by measuring neuron-specific enolase (NSE) in patients who underwent the TAVR and the SU-AVR. Materials and Methods: This clinical trial was carried out between January 2015 and January 2017. A total of 53 patients who had severe aortic valve stenosis (SAVS) and underwent TAVR and SU-AVR were included. The Serum NSE level was measured just before and 24 hours after the procedure. Demographic variables, neurologic assessment findings, clinical and echocardiographic data, carotid ultrasounds reports, and laboratory findings were recorded. Results: A total of 53 patients were included the study. The mean age was 78.4±8.6 and 20 were man (37.7%). The mean age of the TAVR group was significantly higher than the SU-AVR group (82.9±4.7 vs 71.5±8.7, p<0.001). The NSE level was significantly higher in the SUAVR group compared to the TAVR group after the procedure (21.15±10.25 vs 35.32±12.64, p<0.001). Differences between before and after the procedure the National Institutes of Health Stroke Scale (NIHSS), demographic and echocardiographic variables were similar between the two groups. Conclusion: Serum NSE level was significantly higher in the SU-AVR group than the TAVR group Therefore, we may consider the SNI rate is higher as well. In patients who are at higher risk for neurological damage or have neurologic disease, TAVR may be a better treatment option instead of SUAVR

Validation of novel multiplex technologies

The parallel analysis of multiple factors, such as cytokines, from small sample size is an interesting approach for assessment of in vivo activation signatures and functionality after ex vivo stimulation. One interesting application is for therapy monitoring, such as safety data, pharmacodynamics, evidences for mode-of-action and side effects, particularly useful for accompanying early phase clinical trials. There are different platforms for Multiplex analysis of ligands available. We compared in this study the performance of three different platforms (Luminex Bio-Plex® 200, MesoScale Discovery®, Ella®) which use different ways of achieving parallel measurements of biomarkers from small liquid sample size. We show examples of in house assessment of intra- and inter-assay variations, determination of range and recovery for classical immunological serum markers and discuss advantages and disadvantages for these three platforms in relation to the question addressed

Intramuscular and intratendinous placenta‐derived mesenchymal stromal‐like cell treatment of a chronic quadriceps tendon rupture

Background: Quadriceps tendon ruptures (QTRs) are rare but debilitating injuries, often associated with chronic metabolic conditions or long-term steroid treatment. While the surgical treatment for acute QTRs is described thoroughly, no common strategy exists for the often frustrating treatment of chronic, reoccurring QTRs. The pro-angiogenic and immunomodulatory properties of placenta-derived adherent mesenchymal stromal-like (PLX-PAD) cells have been described to protect musculoskeletal tissues from inflammation and catabolic cytokine migration, yet little is known about the regenerative potential of PLX-PAD cells in repetitively damaged tendon tissue. Case: We report the case of an 80-year-old male patient with a chronic three-time QTR of his right knee. The quadriceps tendon was reconstructed applying a conventional suture anchor repair procedure combined with a synthetic mesh augmentation and additional intramuscular and intratendineous PLX-PAD cell injections as an individualized treatment approach. No adverse events were reported, and excellent radiological and functional outcomes with a passive range of motion of 0/0/120 degrees knee extension-flexion were observed at the 12 month follow-up. Gait analysis confirmed restoration of joint motion, including gait speed, deficit in step length, and knee extensor muscle strength (pre-surgery: 0.98 m/s, 40 cm, 42.4 +/- 12.4 N; 9 months post-surgery: 1.07 m/s, 0 cm, 10.4 +/- 18.9 N) as well as hyperextension throughout stance and late swing phases (pre-surgery: -11.2 +/- 0.9 degrees; 9 months post-surgery: -2.7 +/- 1.6 degrees). Postoperative lymphocyte and cytokine analyses from the patient's peripheral blood serum suggested a systemic short-term immunoregulatory reaction with postoperatively increased interleukin (IL)-6 (pre-surgery: 0.79 pg/mL; day 1: 139.97 pg/mL; day 5: 5.58 pg/mL; 9 months: 1.76 pg/mL) and IL-10 (pre-surgery: 0.9 pg/mL; day 1: 1.21 pg/ mL; day 5: 0.3 pg/mL; 9 months: 0.34 pg/mL) levels that decreased again over time. Conclusions: Herein, we demonstrate a successfully treated chronic QTR with a synergistic surgical and biological reconstructive treatment approach. This local add-on treatment with PLX-PAD cells may be considered in specific cases of chronic QTRs, not susceptible to traditional suture anchor procedures and which exhibit a high risk of treatment failure. Further scientific engagement is warranted to explore underlying immunomodulatory mechanisms of action behind PLX-PAD cell treatment for tendon injuries

Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS: The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine

Grey modeling method for estimating time series

Gri sistem teorisi bilinmeyen sistemlerin davranışını az sayıda veri ile tahmin etmektedir. Gri tahmin teorisi disiplinler arası bir bilimsel alandır ve son otuz yılda kısmen bilinmeyen parametrelere sahip birçok sisteme uygulanmıştır. Bu çalışmada ise Türkiye' nin 2011-2020 yılları arasındaki Ar-Ge ve eğitim harcamaları verileri ve 2010-2019 yılları arasındaki elektrik üretimi verileri Türkiye İstatistik Kurumu' ndan alınmıştır. Ar-Ge ve eğitim harcamaları 2021-2030 yılları için ve elektrik üretimi 2020-2029 yılları için Standart Gri Model (GM (1,1)), Yeni Gri Model (NGM (1,1)) ve Üstel Gri Model (EXGM (1,1)) kullanılarak tahmin edilmiştir. Her üç modelin sonuçları karşılaştırılmıştır. Gerçek ve tahmin değeri arasındaki yüzde bağıl hata (RPE) ve ortalama yüzde bağıl hata (MAPE) belirlenmiştir. Gerçek değer ve tahmin değerleri arasındaki korelasyon incelenmiştir. MAPE değeri Ar-Ge harcamaları için GM (1,1) ile %2.95, NGM (1,1) ile %14,01 ve EXGM (1,1) ile % 1.48 olarak hesaplanmıştır. Eğitim harcamaları için GM (1,1) ile %3.32, NGM (1,1) ile %8.66 ve EXGM (1,1) ile % 3.09 olarak hesaplanmıştır. Elektrik üretimi için GM (1,1) ile %1.58, NGM (1,1) ile %6,67 ve EXGM (1,1) ile % 1.36 olarak hesaplanmıştır. Gerçek değer ve tahmini değerin arasındaki korelasyonu gösteren R2 değerleri sıra ile Ar-Ge harcamaları için GM(1,1) ile 0.9974, NGM (1,1) ile 0.9821 ve EXGM (1,1) ile 0,9985 olarak hesaplanmıştır. Eğitim harcamaları için GM(1,1) ile 0.9845, NGM (1,1) ile 0.9619 ve EXGM (1,1) ile 0,9846 olarak hesaplanmıştır. Elektrik üretimi için GM(1,1) ile 0.9734, NGM (1,1) ile 0.6462 ve EXGM (1,1) ile 0,9753 olarak hesaplanmıştır. Sonuç olarak GM (1,1), NGM (1,1) ve EXGM (1,1) yöntemleri ile yapılan tahmin değerlerinin hata ve korelasyon sonuçları incelendiğinde tüm uygulamalarda EXGM (1,1) yönteminin daha iyi sonuç verdiği görülmektedir. Önümüzdeki 10 yıl içerisinde Ülkemizin Ar-Ge ve eğitim harcamalarının ve elektrik üretiminin üstel bir şekilde artacağı öngörülmektedir.Grey systems theory predicts the behavior of unknown systems with little data. Grey prediction theory is an interdisciplinary scientific field and has been applied to many systems with partially unknown parameters over the past three decades. In this study, Turkey's R&D and education expenditures data between 2011-2020 and electricity production data between 2010-2019 were taken from the Turkish Statistical Institute. R&D and education expenditures for the years 2021-2030 and electricity production for the years 2020-2029 were estimated by using Standard Grey Model (GM (1,1)), Novel Grey Model (NGM(1,1)) and Exponential Grey Model (EXGM (1,1)). The results of all three models were compared. The percentage relative error (RPE) between the actual and predicted values and mean absolute percentage error (MAPE) were determined. The correlation between the actual value and the predicted value was examined. The MAPE value for R&D expenditures was calculated as 2.95% with GM (1,1), 14.01% with NGM (1,1) and 1.48% with EXGM (1,1), respectively. It was calculated as 3.32% with GM (1,1), 8.66% with NGM (1,1) and 3.09% with EXGM (1,1) for education expenditures. It was calculated as 1.58% with GM (1.1), 8.66% with NGM (1,1) and 1.36% with EXGM (1,1) for electricity production. R2 values, which show the correlation between actual value and estimated value were calculated as 0,9974 with GM (1,1), 0,9821 with NGM (1,1) and 0,9985 with EXGM (1,1) for R&D expenditures. It was calculated as 0,9845 with GM(1,1), 0,9619 with NGM (1,1) and 0,9846 with EXGM (1,1) for education expenditures. For electricity production, it was calculated as 0,9734 with GM (1,1), 0,9619 with NGM (1,1) and 0,9753 with EXGM (1,1). As a result, when the error and correlation results of the estimation values obtained from GM (1,1), NGM (1,1) and EXGM (1,1) methods are examined, it was seen that the EXGM (1.1) method gives better results in all applications. It was predicted that our country's R&D and education expenditures and electricity production will increase exponentially in the next 10 years

An evaluation of image reproduction algorithms for high contrast scenes on large and small screen display devices

Rendering high contrast scenes on display devices with limited dynamic range is a challenging task. Two groups of algorithms have emerged to take up this challenge: tone mapping operators (TMOs) and more recently exposure fusion (EF) techniques. While several formal evaluation studies comparing TMOs exist, no formal evaluation has yet been performed that compares EF techniques with each other or compares them against TMOs. Moreover, with the advancements in hand-held devices and programmable digital cameras it became possible to directly capture and view high dynamic range (HDR) content on these devices which are characterized by their small screens. However, currently very little is known about how to best visualize a high contrast scene on a small screen. Thus the primary goal of this paper is to provide answers to both of these questions by conducting a series of rigorous psychophysical experiments. Our results suggest that the best tone mapping algorithms are generally superior to EF algorithms except for the reproduction of colors. Furthermore, contrary to some previous work, we find that the differences between algorithms are barely perceptible on small screens and therefore one can opt for a simpler solution than a more complex and accurate one

The relationships of motor-evoked potentials to hand dexterity, motor function, and spasticity in chronic stroke patients: A transcranial magnetic stimulation study

The standardization of patient evaluation and monitoring methods has a special importance in evaluating the effectiveness of therapeutic methods using drugs or rehabilitative techniques in stroke rehabilitation. The aim of this study was to investigate the relationships between clinical instruments and transcranial magnetic stimulation (TMS)-evoked neurophysiological parameters in stroke patients. This study included 22 chronic post-stroke patients who were clinically assessed using the Motricity Index (MI), finger-tapping test (FTT), Motor Activity Log (MAL) 28, Brunnstrom motor staging and Ashworth Scale (ASH). Motor-evoked potential (MEP) latency and amplitude, resting motor threshold (rMT) and central motor conduction time (CMCT) were measured with TMS. Shorter MEP-latency, shorter CMCT, higher motor-evoked potential amplitude, and diminished rMT exhibited significant correlations with clinical measures evaluating motor stage, dexterity, and daily life functionality. rMT exhibited a negative correlation with hand and lower extremity Brunnstrom stages (r = -0.64, r = -0.51, respectively), MI score (r = -0.48), FTT score (r = -0.69), and also with amount of use scale and quality of movement scale of MAL 28 scores (r = -0.61, r = -0.62, respectively). Higher MEP amplitude and diminished rMT showed positive correlations with reduced ASH score (r = -0.65, r = 0.44, respectively). The TMS-evoked neurophysiologic parameters including MEP latency, amplitude, rMT and CMCT generally have positive correlation with clinical measures which evaluate motor stage, dexterity and daily life functionality. Additionally, spasticity has also remarkable relationships with MEP amplitude and rMT. These results suggest that TMS-evoked neurophysiological parameters were useful measures for monitoring post-stroke patients