Die Altinyayla Ovasi. Das Umland von Kusakli-Sarissa. Entwicklung und Ressourcennutzung der Kulturlandschaft in einer Zentralanatolischen Siedlungskammer.

Die Arbeit beschäftigt sich mit der Siedlungsgenese innerhalb der Altinyayla Ovasi, einer zentralanatolischen Siedlungskammer, des sich im Laufe des Holozäns entwickelnden Klimas und einigen Überlegungen zur möglichen Wirtschaftsweise am Beispiel des hethitischen Sarissas, dem Ausgangspunkt oder Schlüsselort zur Bearbeitung des Hochtals. Die Arbeit verfolgt u.a. die Fragestellung, ob in der Altınyayla Ovası, in einer Höhenlagen der Gebirgslandschaft Zentralanatoliens, eine autarke Versorgung einer spätbronzezeitlichen Stadt wie Sarissa möglich war

Assessing and improving the validity of COVID-19 autopsy studies - A multicentre approach to establish essential standards for immunohistochemical and ultrastructural analyses

Background Autopsy studies have provided valuable insights into the pathophysiology of COVID-19. Controversies remain about whether the clinical presentation is due to direct organ damage by SARS-CoV-2 or secondary effects, such as overshooting immune response. SARS-CoV-2 detection in tissues by RT-qPCR and immunohistochemistry (IHC) or electron microscopy (EM) can help answer these questions, but a comprehensive evaluation of these applications is missing. Methods We assessed publications using IHC and EM for SARS-CoV-2 detection in autopsy tissues. We systematically evaluated commercially available antibodies against the SARS-CoV-2 proteins in cultured cell lines and COVID-19 autopsy tissues. In a multicentre study, we evaluated specificity, reproducibility, and inter-observer variability of SARS-CoV-2 IHC. We correlated RT-qPCR viral tissue loads with semiquantitative IHC scoring. We used qualitative and quantitative EM analyses to refine criteria for ultrastructural identification of SARS-CoV-2. Findings Publications show high variability in detection and interpretation of SARS-CoV-2 abundance in autopsy tissues by IHC or EM. We show that IHC using antibodies against SARS-CoV-2 nucleocapsid yields the highest sensitivity and specificity. We found a positive correlation between presence of viral proteins by IHC and RT-qPCR-determined SARS-CoV-2 viral RNA load (N= 35; r=-0.83, p-value <0.0001). For EM, we refined criteria for virus identification and provide recommendations for optimized sampling and analysis. 135 of 144 publications misinterpret cellular structures as virus using EM or show only insufficient data. We provide publicly accessible digitized EM sections as a reference and for training purposes. Interpretation Since detection of SARS-CoV-2 in human autopsy tissues by IHC and EM is difficult and frequently incorrect, we propose criteria for a re-evaluation of available data and guidance for further investigations of direct organ effects by SARS-CoV-2. Funding German Federal Ministry of Health, German Federal Ministry of Education and Research, Berlin University Alliance, German Research Foundation, German Center for Infectious Research.Peer Reviewe

Die Altinyayla Ovasi. Das Umland von Kusakli-Sarissa. Entwicklung und Ressourcennutzung der Kulturlandschaft in einer Zentralanatolischen Siedlungskammer.

Die Arbeit beschäftigt sich mit der Siedlungsgenese innerhalb der Altinyayla Ovasi, einer zentralanatolischen Siedlungskammer, des sich im Laufe des Holozäns entwickelnden Klimas und einigen Überlegungen zur möglichen Wirtschaftsweise am Beispiel des hethitischen Sarissas, dem Ausgangspunkt oder Schlüsselort zur Bearbeitung des Hochtals. Die Arbeit verfolgt u.a. die Fragestellung, ob in der Altınyayla Ovası, in einer Höhenlagen der Gebirgslandschaft Zentralanatoliens, eine autarke Versorgung einer spätbronzezeitlichen Stadt wie Sarissa möglich war

Comparison of fast multi-slice and standard segmented techniques for detection of late gadolinium enhancement in ischemic and non-ischemic cardiomyopathy – a prospective clinical cardiovascular magnetic resonance trial

Abstract Background Segmented phase-sensitive inversion recovery (PSIR) cardiovascular magnetic resonance (CMR) sequences are reference standard for non-invasive evaluation of myocardial fibrosis using late gadolinium enhancement (LGE). Several multi-slice LGE sequences have been introduced for faster acquisition in patients with arrhythmia and insufficient breathhold capability. The aim of this study was to assess the accuracy of several multi-slice LGE sequences to detect and quantify myocardial fibrosis in patients with ischemic and non-ischemic myocardial disease. Methods Patients with known or suspected LGE due to chronic infarction, inflammatory myocardial disease and hypertrophic cardiomyopathy (HCM) were prospectively recruited. LGE images were acquired 10–20 min after administration of 0.2 mmol/kg gadolinium-based contrast agent. Three different LGE sequences were acquired: a segmented, single-slice/single-breath-hold fast low angle shot PSIR sequence (FLASH-PSIR), a multi-slice balanced steady-state free precession inversion recovery sequence (bSSFP-IR) and a multi-slice bSSFP-PSIR sequence during breathhold and free breathing. Image quality was evaluated with a 4-point scoring system. Contrast-to-noise ratios (CNR) and acquisition time were evaluated. LGE was quantitatively assessed using a semi-automated threshold method. Differences in size of fibrosis were analyzed using Bland-Altman analysis. Results Three hundred twelve patients were enrolled (n = 212 chronic infarction, n = 47 inflammatory myocardial disease, n = 53 HCM) Of which 201 patients (67,4%) had detectable LGE (n = 143 with chronic infarction, n = 27 with inflammatory heart disease and n = 31 with HCM). Image quality and CNR were best on multi-slice bSSFP-PSIR. Acquisition times were significantly shorter for all multi-slice sequences (bSSFP-IR: 23.4 ± 7.2 s; bSSFP-PSIR: 21.9 ± 6.4 s) as compared to FLASH-PSIR (361.5 ± 95.33 s). There was no significant difference of mean LGE size for all sequences in all study groups (FLASH-PSIR: 8.96 ± 10.64 g; bSSFP-IR: 8.69 ± 10.75 g; bSSFP-PSIR: 9.05 ± 10.84 g; bSSFP-PSIR free breathing: 8.85 ± 10.71 g, p > 0.05). LGE size was not affected by arrhythmia or absence of breathhold on multi-slice LGE sequences. Conclusions Fast multi-slice and standard segmented LGE sequences are equivalent techniques for the assessment of myocardial fibrosis, independent of an ischemic or non-ischemic etiology. Even in patients with arrhythmia and insufficient breathhold capability, multi-slice sequences yield excellent image quality at significantly reduced scan time and may be used as standard LGE approach. Trial registration ISRCTN48802295 (retrospectively registered)

The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells

Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4–previously identified as a water-soluble Ras inhibitor– targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity