ZusammenfassungIn den drei deutschen Stadtstaaten wurden mit Beginn der Schuljahre 2009/10 (Bremen) und 2010/11 (Berlin und Hamburg) Zwei-Wege-Modelle eingeführt, die in der Sekundarstufe nur noch ...Gymnasien und Gesamtschulen umfassen. Anhand von Daten der vom Institut zur Qualitätsentwicklung im Bildungswesen (IQB) in den Jahren 2009 und 2015 durchgeführten Schulleistungsstudien werden Unterschiede im Schulartbesuch zwischen Schülern mit und Schülern ohne Migrationshintergrund jeweils vor und nach Kontrolle von Indikatoren für Leistung und Sozialstatus untersucht, um zu prüfen, wie sie sich im Zuge der Schulstrukturreformen verändert haben. Es zeigt sich, dass Schüler mit Migrationshintergrund in mehrgliedrigen Schulsystemen vor allem an Haupt- und Realschulen und in den Zwei-Wege-Modellen dann an Gesamtschulen überrepräsentiert sind. In Berlin und Bremen hat ethnische Segregation zwischen Schularten abgenommen; in Hamburg zeigte sich keine signifikante Veränderung. Bei ähnlicher Leistung und ähnlichem Sozialstatus besuchen Schüler mit Migrationshintergrund häufiger das Gymnasium als Schüler ohne Migrationshintergrund. Diese Tendenz wurde in Berlin und Bremen erst in den Zwei-Wege-Modellen festgestellt und könnte zur Abnahme der Segregation beigetragen haben.
Variants in SCYL1 can cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). The encoded protein is involved in intracellular trafficking ...between Golgi and ER, specific mechanisms are still to be elucidated. We reprogrammed fibroblasts of a 2 years old male patient with CALFAN Syndrome due to a homozygous nonsense variant in SCYL1 (c.1882C > T; c.1882C > T/p.Gln628*; p.Gln628*) and generated DHMCi005-A using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen). Cells showed a normal karyotype. Pluripotency was proven using immunohistochemistry, RT-PCR, and flow cytometry. Differentiation into all germ layers was shown using the STEMdiff™ Trilineage Differentiation Kit (Stemcell Technologies).
Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of ...the clinical spectrum and genetic findings.
Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts.
Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro.
ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
Abstract Leucine aminoacyl tRNA‐synthetase 1 (LARS1)‐deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever‐associated acute liver failure (ALF), ...chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1‐deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro‐active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.
Phospholipidosis (PLD) is a lysosomal storage disorder induced by compounds, notably cationic amphiphilic drugs, which although reversible interferes with cellular phospholipids.The in silico method ...described utilizes the amphiphilic moment ΔΔG AM (kJ/mol) together with basic pK a values to assign PLD inducing potential to a compound. The new model was accurate and sensitive (85% and 82%, respectively) when compared to other data sets. Therefore, the parallel in vitro assay for PLD was discontinued. The data reinforce our view that the amphiphilic moment is far more informative for determining a compound's potential to induce PLD than the combined use of basic pK a and ClogP values.
The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia ...(PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin cbl C and methylenetetrahydrofolate reductase MTHFR deficiency), cystathionine β-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA N = 13, MMA N = 6, cblC deficiency N = 5, MTHFR deficiency N = 2 and CBS deficiency N = 1), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-β-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.
Recent studies suggest CD133, a surface protein widely used for isolation of colon cancer stem cells, to be associated with tumor angiogenesis and recurrence. We hypothesized that gene expression ...levels and germline variations in CD133 will predict clinical outcome in patients with metastatic colorectal cancer (mCRC), treated in first-line setting with 5-fluorouracil, oxaliplatin and bevacizumab (BV), and we investigated whether there is a correlation with gene expression levels of CD133, vascular endothelial growth factor (VEGF) and its receptors. We evaluated intra-tumoral gene expression levels by quantitative real-time (RT) PCR from 54 patients and three germline variants of the CD133 gene by PCR-restriction-fragment length polymorphism from 91 patients with genomic DNA. High gene expression levels of CD133 (>7.76) conferred a significantly greater tumor response (RR=86%) than patients with low expression levels (7.76, RR=38%, adjusted P=0.003), independent of VEGF or its receptor gene expression levels. Gene expression levels of CD133 were significantly associated with VEGF and its receptors messenger RNA levels (VEGFR-1 (P<0.01), -2 and -3, P<0.05). Combined analyses of two polymorphisms showed a significant association with progression-free survival (PFS) (18.5 months vs 9.8 months, P=0.004) in a multivariate analysis as an independent prognostic factor for PFS (adjusted P=0.002). These results suggest that CD133 is a predictive marker for standard first-line BV-based treatment in mCRC.
Before using low‐quality wood chips for gasification on the small and medium scale (30–500 kWel), mechanical fuel pretreatment has to be employed to ensure the required fuel characteristics ...concerning particle size distribution and moisture. Two different low‐quality wood assortments (calamity wood and roadside maintenance wood) were subjected to three different mechanical fuel pretreatment strategies and a detailed analysis was realized along the supply chains. The results reveal the enrichment in elements characteristic of soil contamination in the removed fine fraction. Gasification tests were successfully performed with the upgraded low‐quality fuels in field trials and indicated comparable electrical efficiencies but higher supervision effort during plant operation.
If low‐quality wood fuels are used, screening and drying can ensure the fuel quality required for gasification on the small and medium scale (30–500 kWel). Calamity wood and roadside maintenance wood were subjected to drying and screening in three different supply chains. Fuel upgrading was accompanied by detailed analysis and successfully performed gasification field trials.
Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such ...T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and HLA-C 04:01 and were associated with responses to ICI therapy. Patients with CD8
+
T cell responses to these epitopes had improved overall and progression-free survival. T cells specific for such epitopes could eliminate HLA class I-matched NSCLC cells ex vivo and were enriched in patient lung tumors. The identification of novel lung cancer HLA-associated epitopes that correlate with improved ICI-dependent treatment outcomes suggests that keratinocyte-specific proteins are important tumor-associated antigens in NSCLC. These findings improve our understanding of the mechanisms of ICI therapy and may help support the development of vaccination strategies to improve ICI-based treatment of these tumors.
Vast areas of the terrestrial Subarctic and Arctic are underlain by permafrost. Landscape evolution is therefore largely controlled by climate-driven periglacial processes. The response of the frozen ...ground to late Quaternary warm and cold stages is preserved in permafrost sequences, and deducible by multi-proxy palaeoenvironmental approaches. Here, we analyse radiocarbon-dated mid-Wisconsin Interstadial and Holocene lacustrine deposits preserved in the Kit-1 pingo permafrost sequence combined with water and surface sediment samples from nine modern water bodies on Seward Peninsula (NW Alaska) to reconstruct thermokarst dynamics and determine major abiotic factors that controlled the aquatic ecosystem variability. Our methods comprise taxonomical diatom analyses as well as Detrended Correspondence Analysis (DCA) and Redundancy Analysis (RDA). Our results show, that the fossil diatom record reflects thermokarst lake succession since about 4214Ckyr BP. Different thermokarst lake stages during the mid-Wisconsin Interstadial, the late Wisconsin and the early Holocene are mirrored by changes in diatom abundance, diversity, and ecology. We interpret the taxonomical changes in the fossil diatom assemblages in combination with both modern diatom data from surrounding ponds and existing micropalaeontological, sedimentological and mineralogical data from the pingo sequence. A diatom-based quantitative reconstruction of lake water рН indicates changing lake environments during mid-Wisconsin to early Holocene stages. Mineralogical analyses indicate presence of tephra fallout and its impact on fossil diatom communities. Our comparison of modern and fossil diatom communities shows the highest floristic similarity of modern polygon ponds to the corresponding initial (shallow water) development stages of thermokarst lakes. We conclude, that mid-Wisconsin thermokarst processes in the study area could establish during relatively warm interstadial climate conditions accompanied by increased precipitation due to approaching coasts, while still high continentality and hence high seasonal temperature gradients led to warm summers in the central part of Beringia.
•We present palaeolake archive from remote pingo deposites in western Alaska•Diatoms reveal climate conditions enabling thermokarst 42,000years ago•Climate and volcanic tephra events had significant impact on the palaeoecology•High precipitation and seasonal temperature gradients enabled glacial thermokarst
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