Synthesis, identification and structure-activity relationship analysis of GATA4 and NKX2-5 protein-protein interaction modulators

Transcription factors GATA4 and NKX2-5 directly interact and synergistically activate several cardiac genes and stretch-induced cardiomyocyte hypertrophy. Previously, we identified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcriptional synergy. Here, the chemical space around the molecular structure of 1 was explored by synthesizing and characterizing 220 derivatives and structurally related compounds. In addition to the synergistic transcriptional activation, selected compounds were evaluated for their effects on transcriptional activities of GATA4 and NKX2-5 individually as well as potential cytotoxicity. The structure-activity relationship (SAR) analysis revealed that the aromatic isoxazole substituent in the southern part regulates the inhibition of GATA4-NKX2-5 transcriptional synergy. Moreover, inhibition of GATA4 transcriptional activity correlated with the reduced cell viability. In summary, comprehensive SAR analysis accompanied by data analysis successfully identified potent and selective inhibitors of GATA4-NKX2-5 transcriptional synergy and revealed structural features important for it.Peer reviewe

Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity

textabstractBackground: To examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum. Methods: In this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1-5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia. Results: Fifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor. Conclusion: Higher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy

Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress

Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12–18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of –20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high–frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm. Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents

Development of Secondary Woodland in Oak Wood Pastures Reduces the Richness of Rare Epiphytic Lichens

Wooded pastures with ancient trees were formerly abundant throughout Europe, but during the last century, grazing has largely been abandoned often resulting in dense forests. Ancient trees constitute habitat for many declining and threatened species, but the effects of secondary woodland on the biodiversity associated with these trees are largely unknown. We tested for difference in species richness, occurrence, and abundance of a set of nationally and regionally red-listed epiphytic lichens between ancient oaks located in secondary woodland and ancient oaks located in open conditions. We refined the test of the effect of secondary woodland by also including other explanatory variables. Species occurrence and abundance were modelled jointly using overdispersed zero-inflated Poisson models. The richness of the red-listed lichens on ancient oaks in secondary woodland was half of that compared with oaks growing in open conditions. The species-level analyses revealed that this was mainly the result of lower occupancy of two of the study species. The tree-level abundance of one species was also lower in secondary woodland. Potential explanations for this pattern are that the study lichens are adapted to desiccating conditions enhancing their population persistence by low competition or that open, windy conditions enhance their colonisation rate. This means that the development of secondary woodland is a threat to red-listed epiphytic lichens. We therefore suggest that woody vegetation is cleared and grazing resumed in abandoned oak pastures. Importantly, this will also benefit the vitality of the oaks

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

TRY plant trait database - enhanced coverage and open access

Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives