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Recent phylogenomic studies have failed to conclusively resolve certain branches of the placental mammalian tree, despite the evolutionary analysis of genomic data from 32 species. Previous analyses of single genes and retroposon insertion data yielded support for different phylogenetic scenarios for the most basal divergences. The results indicated that some mammalian divergences were best interpreted not as a single bifurcating tree, but as an evolutionary network. In these studies the relationships among some orders of the super-clade Laurasiatheria were poorly supported, albeit not studied in detail. Therefore, 4775 protein-coding genes (6,196,263 nucleotides) were collected and aligned in order to analyze the evolution of this clade. Additionally, over 200,000 introns were screened in silico, resulting in 32 phylogenetically informative long interspersed nuclear elements (LINE) insertion events.
The present study shows that the genome evolution of Laurasiatheria may best be understood as an evolutionary network. Thus, contrary to the common expectation to resolve major evolutionary events as a bifurcating tree, genome analyses unveil complex speciation processes even in deep mammalian divergences. We exemplify this on a subset of 1159 suitable genes that have individual histories, most likely due to incomplete lineage sorting or introgression, processes that can make the genealogy of mammalian genomes complex.
These unexpected results have major implications for the understanding of evolution in general, because the evolution of even some higher level taxa such as mammalian orders may sometimes not be interpreted as a simple bifurcating pattern.
Viewing of ambiguous stimuli can lead to bistable perception alternating between the possible percepts. During continuous presentation of ambiguous stimuli, percept changes occur as single events, whereas during intermittent presentation of ambiguous stimuli, percept changes occur at more or less regular intervals either as single events or bursts. Response patterns can be highly variable and have been reported to show systematic differences between patients with schizophrenia and healthy controls. Existing models of bistable perception often use detailed assumptions and large parameter sets which make parameter estimation challenging. Here we propose a parsimonious stochastic model that provides a link between empirical data analysis of the observed response patterns and detailed models of underlying neuronal processes. Firstly, we use a Hidden Markov Model (HMM) for the times between percept changes, which assumes one single state in continuous presentation and a stable and an unstable state in intermittent presentation. The HMM captures the observed differences between patients with schizophrenia and healthy controls, but remains descriptive. Therefore, we secondly propose a hierarchical Brownian model (HBM), which produces similar response patterns but also provides a relation to potential underlying mechanisms. The main idea is that neuronal activity is described as an activity difference between two competing neuronal populations reflected in Brownian motions with drift. This differential activity generates switching between the two conflicting percepts and between stable and unstable states with similar mechanisms on different neuronal levels. With only a small number of parameters, the HBM can be fitted closely to a high variety of response patterns and captures group differences between healthy controls and patients with schizophrenia. At the same time, it provides a link to mechanistic models of bistable perception, linking the group differences to potential underlying mechanisms.
Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs—elicited by the loss of Rag GTPases—inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was a genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult patients (median age: 42 years) with B-cell precursor ALL (BCP-ALL) were classified as having Ph-like ALL using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and KMT2A-rearrangements. IGH-CRLF2 rearrangements (6/16; P=0.002) and mutations in JAK2 (7/16; P<0.001) were found exclusively in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated in German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% among both Ph-like ALL patients (n=19) and the “remaining BCP-ALL” cases (n=40), i.e. patients negative for BCR-ABL1 and KMT2A-rearrangements and the Ph-like subtype. Significantly fewer Ph-like ALL patients reached molecular complete remission (33% versus 79%; P=0.02) and had a lower probability of continuous complete remission (26% versus 60%; P=0.03) and overall survival (22% versus 64%; P=0.006) at 5 years compared to the remaining BCP-ALL patients. The profile of genetic lesions in adults with Ph-like ALL, including older adults, resembles that of pediatric Ph-like ALL and differs from the profile in the remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.
Objective: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). Methods: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. Results: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery. Conclusions: The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT.
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
(2019)
Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability.
Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies.
Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type.
Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Aim: It can be challenging to distinguish COVID-19 in children from other common infections. We set out to determine the rate at which children consulting a primary care paediatrician with an acute infection are infected with SARS-CoV-2 and to compare distinct findings. Method: In seven out-patient clinics, children aged 0–13 years with any new respiratory or gastrointestinal symptoms and presumed infection were invited to be tested for SARS-CoV-2. Factors that were correlated with testing positive were determined. Samples were collected from 25 January 2021 to 01 April 2021. Results: Seven hundred and eighty-three children participated in the study (median age 3 years and 0 months, range 1 month to 12 years and 11 months). Three hundred and fifty-eight were female (45.7%). SARS-CoV-2 RNA was detected in 19 (2.4%). The most common symptoms in children with as well as without detectable SARS-CoV-2 RNA were rhinitis, fever and cough. Known recent exposure to a case of COVID-19 was significantly correlated with testing positive, but symptoms or clinical findings were not. Conclusion: COVID-19 among the children with symptoms of an acute infection was uncommon, and the clinical presentation did not differ significantly between children with and without evidence of an infection with SARS-CoV-2.
Aim: It can be challenging to distinguish COVID-19 in children from other common infections. We set out to determine the rate at which children consulting a primary care paediatrician with an acute infection are infected with SARS-CoV-2 and to compare distinct findings. Method: In seven out-patient clinics, children aged 0–13 years with any new respiratory or gastrointestinal symptoms and presumed infection were invited to be tested for SARS-CoV-2. Factors that were correlated with testing positive were determined. Samples were collected from 25 January 2021 to 01 April 2021. Results: Seven hundred and eighty-three children participated in the study (median age 3 years and 0 months, range 1 month to 12 years and 11 months). Three hundred and fifty-eight were female (45.7%). SARS-CoV-2 RNA was detected in 19 (2.4%). The most common symptoms in children with as well as without detectable SARS-CoV-2 RNA were rhinitis, fever and cough. Known recent exposure to a case of COVID-19 was significantly correlated with testing positive, but symptoms or clinical findings were not. Conclusion: COVID-19 among the children with symptoms of an acute infection was uncommon, and the clinical presentation did not differ significantly between children with and without evidence of an infection with SARS-CoV-2.
Die EU verabschiedete am 21. Mai 1992 die Richtlinie zur Erhaltung der natürlichen Lebensräume sowie der wildlebenden Tiere und Pflanzen, die sogenannte Fauna-Flora-Habitat-Richtlinie (FFH-Richtlinie). Die Mitgliedsstaaten sind seitdem verpflichtet, ein europaweites Netz von besonderen Schutzgebieten zur Erhaltung der biologischen Vielfalt und zur Förderung einer nachhaltigen Entwicklung aufzubauen. In dieses Natura 2000 genannte Netz sind auch die auf der Grundlage der seit 1979 geltenden EU-Vogelschutzrichtlinie gemeldeten Europäischen Vogelschutzgebiete (EU SPA) integriert. Die reichhaltige Naturausstattung Sachsen-Anhalts ermöglichte die Auswahl von 265 FFH-Gebieten und 32 Vogelschutzgebieten (EU SPA). Die Gebiete wurden als „Gebiete von gemeinschaftlicher Bedeutung der kontinentalen und der atlantischen biogeographischen Region“ im Amtsblatt der EU vom 15.01.2008 veröffentlicht. Nach den Vorgaben der FFH- und Vogelschutzrichtlinie sind die Natura 2000-Gebiete nun als besondere Schutzgebiete national zu sichern. Darüber hinaus sind in den besonderen Schutzgebieten geeignete Maßnahmen zu treffen, um die Verschlechterung der natürlichen Lebensräume und der Habitate der Arten, für die die Gebiete ausgewiesen worden sind, zu vermeiden (vgl. Art. 6, Abs. 2 FFH Richtlinie). Alle erforderlichen Maßnahmen sind an den Ansprüchen der in den jeweiligen Gebieten vorkommenden Lebensraumtypen und Arten auszurichten.
Mit dem vorliegenden Sonderheft wird beispielhaft der Verfahrensweg der Ausweisung des Naturschutzgebietes Aland-Elbe-Niederung zur Umsetzung von Natura 2000 im Land Sachsen-Anhalt dokumentiert. Neben der Darstellung der naturräumlichen Situation des Gebietes und seiner naturschutzfachlichen Bedeutung werden insbes. Inhalt und Ablauf des Verwaltungsverfahrens sowie die Lösung der vielfältigen Nutzungskonflikte dargestellt. Dem Heft liegt eine beidseitig bedruckte Schutzgebietskarte des Landes Sachsen-Anhalt im Maßstab 1:250.000 bei. Auf einer Seite sind Schutzgebiete nach internationalem Recht dargestellt. Die zweite Seite der Karte liefert eine aktuelle Zusammenstellung (Stand 31.12.2009) der nach Landesnaturschutzrecht geschützten Gebiete und Objekte. Ein Beiheft mit Namen, Bezeichnung und Größe aller Gebiete komplettiert die Ausgabe.