The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental ...architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.
Lung cancer currently causes the majority of cancer-related deaths worldwide and new treatments are in high demand. Gene therapy could be a promising treatment but currently lacks sufficient ...efficiency for clinical use, primarily due to limited cellular and nuclear DNA delivery. In the present study, we investigated whether it was possible to exploit the endogenous nuclear-shuttling activity by the nuclear factor kappa B (NFκB) system, which is highly prominent in many cancers as well as lung cancer. We observed that insertion of a DNA nuclear-targeting sequence (DTS) recognized by NFκB could improve plasmid nuclear delivery and enhance the therapeutic effect of a validated transcriptionally cancer-targeted suicide gene therapy system. A clear correlation between the number of inserted NFκB-binding sites and the therapeutic effect of the suicide system was observed in both small cell lung cancer (SCLC) and non-SCLC cell lines. The effect was observed to be due to elevated nuclear translocation of the suicide gene-encoding plasmids. The results show that a significant improvement of gene therapeutic efficiency can be obtained by increasing the intracellular trafficking of therapeutic DNA. This is to our knowledge the first time a DTS strategy has been implemented for suicide gene therapy.
SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) ...within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.
Abstract Large conductance calcium-activated potassium (BKCa ) channels are membrane proteins contributing to electrical propagation through neurons. Calcitonin gene-related peptide (CGRP) is a ...neuropeptide found in the trigeminovascular system (TGVS). Both BKCa channels and CGRP are involved in migraine pathophysiology. Here we study the expression and localization of BKCa channels and CGRP in the rat trigeminal ganglion (TG) and the trigeminal nucleus caudalis (TNC) as these structures are involved in migraine pain. Also the effect of the BKCa channel blocker iberiotoxin and the BKCa channel opener NS11021 on CGRP release from isolated TG and TNC was investigated. By RT-PCR, BKCa channel mRNA was detected in the TG and the TNC. A significant difference in BKCa channel mRNA transcript levels were found using qPCR between the TNC as compared to the TG. The BKCa channel protein was more expressed in the TNC as compared to the TG shown by western blotting. Immunohistochemistry identified BKCa channels in the nerve cell bodies of the TG and the TNC. The β2- and β4-subunit proteins were found in the TG and the TNC. They were both more expressed in the TNC as compared to TG shown by western blotting. In isolated TNC, the BKCa channel blocker iberiotoxin induced a concentration-dependent release of CGRP that was attenuated by the BKCa channel opener NS11021. No effect on basal CGRP release was found by NS11021 in isolated TG or TNC or by iberiotoxin in TG. In conclusion, we found both BKCa channel mRNA and protein expression in the TG and the TNC. The BKCa channel protein and the modulatory β2- and β4-subunt proteins were more expressed in the TNC than in the TG. Iberiotoxin induced an increase in CGRP release from the TNC that was attenuated by NS11021. Thus, BKCa channels might have a role in trigeminovascular pain transmission.
SUMMARY
Plant species with large genomes tend to be excluded from climatically more extreme environments with a shorter growing season. Species that occupy such environments are assumed to be under ...natural selection for more rapid growth and smaller genome size (GS). However, evidence for this is available only for temperate organisms. Here, we study the evolution of GS in two subfamilies of the tropical family Zingiberaceae to find out whether species with larger genomes are confined to environments where the vegetative season is longer. We tested our hypothesis on 337 ginger species from regions with contrasting climates by correlating their GS with an array of plant traits and environmental variables. We revealed 16‐fold variation in GS which was tightly related to shoot seasonality. Negative correlations of GS with latitude, temperature and precipitation emerged in the subfamily Zingiberoidae, demonstrating that species with larger GS are excluded from areas with a shorter growing season. In the subfamily Alpinioideae, GS turned out to be correlated with the type of stem and light requirements and its members cope with seasonality mainly by adaptation to shady and moist habitats. The Ornstein–Uhlenbeck models suggested that evolution in regions with humid climates favoured larger GS than in drier regions. Our results indicate that climate seasonality exerts an upper constraint on GS not only in temperate regions but also in the tropics, unless species with large genomes find alternative ways to escape from that constraint.
Significance Statement
The question of how species can adapt to periods of drought and drought stress is of great relevance in the current period of climate change and it is also worth asking whether mechanisms of adaptation are similar in different parts of the world. Here, we focused on the poorly understood but complex biomes like monsoon forest, tropical dry forest and tropical rainforest, while using the economically important family Zingiberaceae as a model group.
The breakup of Africa from South America is associated with the emplacement of the Paraná-Etendeka flood basalt province from around 134 Ma and the Tristan da Cunha plume. Yet many additional ...volcanic events occur that are younger than the main pulse of the Paraná-Etendeka and straddle the rift to drift phases of the main breakup. This contribution reports on new geochronological constraints from the Angolan part of the African Margin. Three coastal and one inland section have been sampled stretching across some 400 Km, with 39Ar/40Ar, U-Pb and Palaeontology used to provide age constraints. Ages from the new data range from ~100 to 81 Ma, with three main events (cr. 100, 91 and 82–81 Ma). Volcanic events are occurring within the Early to Late Cretaceous, along this part of the margin with a general younging towards Namibia. With the constraints of additional age information both onshore and offshore Angola, a clear younging trend at the early stages of rift to drift is recorded in the volcanic events that unzip from North to South. Similar age volcanic events are reported from the Brazilian side of the conjugate margin, and highlight the need to fully incorporate these relatively low volume volcanic pulses into the plate tectonic breakup models of the South Atlantic Margin.
It is well described that patients with pulmonary arteriovenous malformations (PAVMs) and Hereditary Hemorrhagic Telangiectasia (HHT) have an increased risk of cerebral abscess (CA). However, as both ...CA and HHT are rare, the proportion of patients with CA who are diagnosed with HHT has not been previously described. A retrospective study was carried out of all patients treated surgically for CA between January 1995 and September 2014 at the Department of Neurosurgery, Odense University Hospital. The cases were then cross-referenced with the Danish HHT database. Eighty patients aged 5–79 years were included. The incidence of CA was 0.33/100,000/year. Two patients (2.5%) were registered as having HHT. Bacterial pathogens were identified in 70% of all cases, most frequently streptococci species (46.3%). The most common predisposing condition was odontogenic infection (20%), followed by post-operative infection (13.8%) and post-trauma (6.3%). Patients undergoing a full diagnostic program to determine predisposing conditions causing CA increased over the 20-year period from 11.8% to 65.2%. The 3-month and 1-year mortality rates were 7.5% and 11.25%, respectively. There is an overrepresentation of HHT patients in a cohort of patients with CA, and HHT should be investigated as the cause of the CA if no other apparent cause can be identified.
Research on gingers and their traditional uses by three different indigenous ethnic groups at Lore Lindu National Park, Central Sulawesi, Indonesia was carried out from February to June 2018. The ...objectives of the research was to gain information about the diversity of the family Zingiberaceae and its traditional uses by the Topo Baria, Toi Toro Muma and To Kaili Ledo people. Key informants were traditional healers (sando), traditional leaders (adat), community leaders, village leaders, religion leaders, government officers and crafts-people. The interviews were recorded using audio recorders and notebooks. Samples of plants were collected and photographed while recording the information. Response was obtained by "Snowball technique". A total of 24 species of Zingiberaceae were used of which 19 were determined to species level. Eight species were collected from natural forest, while 14 were recorded from agricultural habitat. Four of the species were endemic to Sulawesi (Alpinia eremochlamys, A. rubricaulis, Etlingera acanthodes and E. flexuosa). Fourteen species were not native to Sulawesi but widely cultivated in the region. The information about the uses by the Topo Baria was not adequate whereas the contrary the Toi Toro Muma and To Kaili Ledo used several species for various daily purposes, such as medicine, spice, cosmetics, ornamentals, or to be eat freshly.
Introduction
The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of ...adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between “gross total removal” and “subtotal removal,” while the latter comprises a five-tiered differentiation of the surgeon’s impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with
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Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas.
Objective
To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of
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Ga DOTATOC PET, we propose “Copenhagen Grading” for meningiomas.
Results
Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen.
Conclusion
Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation.
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