HD Model Research Articles

High Resolution Discharge Simulations Over Europe and the Baltic Sea Catchment

Regional coupled system models require a high-resolution discharge component to couple their atmosphere/land components to the ocean component and to adequately resolve smaller catchments and the day-to-day variability of discharge. As the currently coupled discharge models usually do not fulfill this requirement, we improved a well-established discharge model, the HD model, to be globally applicable at 5 Min. resolution to prepare high-resolution discharge simulations over Europe and the Baltic Sea catchment. Here, no river specific parameter adjustments were conducted so that the model is generally applicable for climate change studies and over ungauged catchments. For the validation of the 5 Min. HD (HD5) model, we drive it with prescribed fields of surface and subsurface runoff. As no large-scale observations of these variables exist, they need to be calculated by a land surface scheme or hydrology model using observed or re-analyzed meteorological data. In order to pay regard to uncertainties introduced by these calculations, three different methods and datasets were used to derive the required fields of surface and subsurface runoff for the forcing of the HD5 model. 10-years simulations (2000-2009) show that for many European rivers, where daily discharge observations were available for comparison, the HD5 model captures the main discharge peaks reasonably well. As direct anthropogenic impact on the discharge, such as by regulation or dams, is not regarded in the HD model, those effects generally cannot be simulated. Thus, discharges for many heavily regulated rivers in Scandinavia or for the rivers Volga and Don are not well represented by the model. The comparison of the simulated discharges obtained indicates that the HD5 model is suitable to evaluate the terrestrial hydrological cycle of climate models or land surface models, especially with regard to the separation of throughfall (rain or snow melt) into surface and subsurface runoff.

Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington\u2019s Disease: a Longitudinal PET Study

Impairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington’s Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [11C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (VT (IDIF)) and voxel-wise parametric VT (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [11C]ITDM VT (IDIF) quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [11C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [11C]ITDM PET imaging demonstrated higher [11C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.

Morphometric characteristics of the optical disc and thickness of retinal nerve fibre layer using Cirrus 5000 optical coherence tomography in healthy patients attending the National Institute of Ophthalmology

Abstract Objective To describe the morphometric characteristics and thickness of the retinal nerve fibre layer (CFNR) in healthy patients using optical coherence tomography (OCT). Methods A cross-sectional and descriptive study was conducted on a total of 184 eyes of 184 people of mestizo origin enrolled after a complete ophthalmological evaluation at the National Institute of Ophthalmology, Lima-Peru. The morphometric parameters of the optical disc and thickness of the CFNR were measured by OCT ZEISS Cirrus HD Model 5000. Megalopapilla was defined as: area of ​​the optical disc greater than 2.5 mm2 and area greater than the mean plus 2 standard deviations. Results The areas obtained were: optical disc of 2.21 ± 0.43 mm2, neuroretinal ring of 1.37 ± 0.25 mm2, 0.84 ± 0.48 mm2 cup; mean cup/disc ratio of 0.58 ± 0.16, vertical cup/disc ratio of 0.55 ± 0.15, and a CFNR thickness of 100.30 ± 8.54 μm. The prevalence of megalopapilla, being considered as a disc area greater than 2.5 mm2 and 3.07 mm2, was 24% and 4%, respectively. When comparing megalopapilla with normal discs, the area of ​​the ring (P = .08) and thickness of CFNR (P = .73) did not show statistically significant differences. Conclusion The mean disc area was 2.21 ± 0.43 mm2 with a CFNR thickness of 100.30 ± 8.54 μm. The prevalence of megalopapilla was 24% and 4%, considering a disc area greater than 2.5 mm2 and 3.07 mm2, respectively. These results show that the megalopapilla and normal discs are similar in terms of ring area and CFNR thickness.

Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of Huntington's disease

BackgroundHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG140 knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age. ObjectiveThis study was aimed at assessing the effects of exercise, in the form of treadmill running, and examining its impact on motor behavior and markers of metabolism in the CAG140 KI mouse model of HD after motor symptoms have emerged. MethodsCAG140 KI mice at 13–15 months of age were subjected to treadmill exercise 3 days per week for 1 h per day or remained sedentary. After 12 weeks of exercise brain tissues were analyzed for enzymatic activity including mitochondria Complexes I, II/III, and IV, transglutaminase, aconitase, pyruvate dehydrogenase, and phosphofructokinase1/2. In addition, the concentration was determined for nitrate/nitrite, pyruvate carboxylase, NAD+/NADH, and glutamate as well as the ratio of mitochondria and nuclear DNA. Motor behavior was tested using the rotarod. ResultsExercise resulted in increased [nitrite + nitrate] levels (surmised as nitric oxide), reduced transglutaminase activity, increased aconitase activity with increased tricarboxylic acid-generated reducing equivalents and mitochondrial oxidative phosphorylation complexes activity. Mitochondrial function was strengthened by increases in glycolysis, pyruvate dehydrogenase activity, and anaplerosis component represented by pyruvate carboxylase. ConclusionsThese changes in mitochondrial function were associated with improved motor performance on the rotarod test. These findings suggest that exercise may have beneficial effects on motor behavior by reversing deficits in mitochondrial function in a rodent model of HD.

The interplay between redox signalling and proteostasis in neurodegeneration: In vivo effects of a mitochondria-targeted antioxidant in Huntington's disease mice

Abnormal protein homeostasis (proteostasis), dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders, such as Huntington's (HD), Alzheimer's and Parkinson's diseases. It remains incompletely understood, however, how changes in redox signalling affect proteostasis mechanisms, including protein degradation pathways and unfolded protein responses (UPR). Here we address this open question by investigating the interplay between redox signalling and proteostasis in a mouse model of HD, and by examining the in vivo effects of the mitochondria-targeted antioxidant MitoQ. We performed behavioural tests in wild-type and R6/2 HD mice, examined markers of oxidative stress, UPR activation, and the status of key protein degradation pathways in brain and peripheral tissues. We show that R6/2 mice present widespread markers of oxidative stress, with tissue-specific changes in proteostasis that were more pronounced in the brain and muscle than in the liver. R6/2 mice presented increased levels of cytosolic and mitochondrial chaperones, particularly in muscle, indicating UPR activation. Treatment with MitoQ significantly ameliorated fine motor control of R6/2 mice, and reduced markers of oxidative damage in muscle. Additionally, MitoQ attenuated overactive autophagy induction in the R6/2 muscle, which has been associated with muscle wasting. Treatment with MitoQ did not alter autophagy markers in the brain, in agreement with its low brain bioavailability, which limits the risk of impairing neuronal protein clearance mechanisms. This study supports the hypotheses that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment in HD, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD.

Machine learning classification models for fetal skeletal development performance prediction using maternal bone metabolic proteins in goats.

BackgroundIn developing countries, maternal undernutrition is the major intrauterine environmental factor contributing to fetal development and adverse pregnancy outcomes. Maternal nutrition restriction (MNR) in gestation has proven to impact overall growth, bone development, and proliferation and metabolism of mesenchymal stem cells in offspring. However, the efficient method for elucidation of fetal bone development performance through maternal bone metabolic biochemical markers remains elusive.MethodsWe adapted goats to elucidate fetal bone development state with maternal serum bone metabolic proteins under malnutrition conditions in mid- and late-gestation stages. We used the experimental data to create 72 datasets by mixing different input features such as one-hot encoding of experimental conditions, metabolic original data, experimental-centered features and experimental condition probabilities. Seven Machine Learning methods have been used to predict six fetal bone parameters (weight, length, and diameter of femur/humerus).ResultsThe results indicated that MNR influences fetal bone development (femur and humerus) and fetal bone metabolic protein levels (C-terminal telopeptides of collagen I, CTx, in middle-gestation and N-terminal telopeptides of collagen I, NTx, in late-gestation), and maternal bone metabolites (low bone alkaline phosphatase, BALP, in middle-gestation and high BALP in late-gestation). The results show the importance of experimental conditions (ECs) encoding by mixing the information with the serum metabolic data. The best classification models obtained for femur weight (Fw) and length (FI), and humerus weight (Hw) are Support Vector Machines classifiers with the leave-one-out cross-validation accuracy of 1. The rest of the accuracies are 0.98, 0.946 and 0.696 for the diameter of femur (Fd), diameter and length of humerus (Hd, Hl), respectively. With the feature importance analysis, the moving averages mixed ECs are generally more important for the majority of the models. The moving average of parathyroid hormone (PTH) within nutritional conditions (MA-PTH-experim) is important for Fd, Hd and Hl prediction models but its removal for enhancing the Fw, Fl and Hw model performance. Further, using one feature models, it is possible to obtain even more accurate models compared with the feature importance analysis models. In conclusion, the machine learning is an efficient method to confirm the important role of PTH and BALP mixed with nutritional conditions for fetal bone growth performance of goats. All the Python scripts including results and comments are available into an open repository at https://gitlab.com/muntisa/goat-bones-machine-learning.

Mutant Huntingtin Affects Diabetes and Alzheimer's Markers in Human and Cell Models of Huntington's Disease.

A higher incidence of diabetes was observed among family members of individuals affected by Huntington’s Disease with no follow-up studies investigating the genetic nature of the observation. Using a genome-wide association study (GWAS), RNA sequencing (RNA-Seq) analysis and western blotting of Rattus norvegicus and human, we were able to identify that the gene family of sortilin receptors was affected in Huntington’s Disease patients. We observed that less than 5% of SNPs were of statistical significance and that sortilins and HLA/MHC gene expression or SNPs were associated with mutant huntingtin (mHTT). These results suggest that ST14A cells derived from R. norvegicus are a reliable model of HD, since sortilins were identified through analysis of the transcriptome in these cells. These findings help highlight the genes involved in mechanisms targeted by diabetes drugs, such as glucose transporters as well as proteins controlling insulin release related to mHTT. To the best of our knowledge, this is the first GWAS using RNA-Seq data from both ST14A rat HD cell model and human Huntington’s Disease.

Study on the Antihypertensive Mechanism of Astragalus membranaceus and Salvia miltiorrhiza Based on Intestinal Flora-Host Metabolism.

Our previous studies have shown that the combination of Astragalus membranaceus and Salvia miltiorrhiza (HD) had a good antihypertensive effect, but its potential mechanism remained unclear. This study aimed to investigate the role of intestinal flora and serum metabolism induced by HD against hypertension. 16 spontaneous hypertensive rats (SHRs) were divided into HD group (5.9 g/kg) and model group (M) (normal saline), with eight Wistar-Kyoto (WKY) rats as control group (W) (normal saline). Rats were fed by gavage once a day for 28 days. The changes of intestinal flora and serum metabolism were analyzed by 16S rDNA sequencing and LC-MS/MS assay. HD decreased blood pressure steadily, improved the structure and composition of imbalance flora in SHRs, increased the abundance and diversity of flora, and decreased flora Firmicutes to Bacteroidetes (F/B) ratio. Rumen bacterium NK4A214, Clostridium sp. MC 40 increased remarkably in M group. Akkermansia, Akkermansia muciniphila, and Lactobacillus intestinalis increased significantly in HD group, which were functionally related to the significant increase of Lachnoclostridium, Faecalibaculum, and Lactobacillus reuteri in W group, which were all probiotics producing butyric acid, lactic acid, and regulating inflammation and other antihypertensive related factors. HD also changed the serum metabolic pattern of SHRs. 16 potential biomarkers related to inflammation, vasodilation, steroid hormones, oxidative stress, and etc. changed significantly, mainly enriched in arachidonic acid metabolism, tryptophan metabolism, steroid hormone biosynthesis, and glutathione metabolism. The correlation analysis demonstrated that the dominant genius and species in three groups were highly correlated with steroid hormone biosynthesis, arachidonic acid metabolism, tryptophan metabolism, and vitamin B6 metabolism. Our research indicated that HD had a good antihypertensive effect, which may be driven by the protective intestinal flora and beneficial metabolites induced by it, and the metabolites were closely related to the changes of intestinal flora. It provided new insights for the antihypertensive mechanism of HD.

Comparison of subgrid-scale models for large-eddy simulation of hydrodynamic and magnetohydrodynamic channel flows

Purpose This paper aims to address the performance of different subgrid-scale models (SGS) for hydro- (HD) and magnetohydrodynamic (MHD) channel flows within a collocated finite-volume scheme. Design/methodology/approach First, the SGS energy transfer is analyzed by a priori tests using fully resolved DNS data. Here, the focus lies on the influence of the magnetic field on the SGS energy transport. Second, the authors performed a series of 18 a posteriori model tests, using different grid resolutions and SGS models for HD and MHD channel flows. Findings From the a priori analysis, the authors observe a quantitative reduction of the SGS energy transport because of the action of the magnetic field depending on its orientation. The a posteriori model tests show a clear improvement because of the use of mixed-models within the numerical scheme. Originality/value This study demonstrates the necessity of improved SGS modeling strategies for magnetohydrodynamic channel flows within a collocated finite-volume scheme.

Toward Core-Free Pavement Compaction Evaluation: An Innovative Method Relating Asphalt Permittivity to Density

Asphalt pavement compaction quality control and quality assurance (QC/QA) are traditionally based on destructive drilled cores and/or nuclear gauge results, which both are spot measurements representing significantly less than 1 percent of the in-service pavement. Ground penetrating radar (GPR) is emerging as a tool that can be used for nondestructive continuous assessment of asphalt pavement compaction quality through measuring the pavement dielectric constant. Previous studies have established that asphalt pavement dielectric constant measurements are inversely proportional to the air void content for a given asphalt mixture. However, field cores are currently required to calibrate the measured dielectric constant to the pavement density. In this paper, a method is proposed to eliminate the need for field calibration cores by measuring the dielectric constant of asphalt specimens compacted to various air void contents. This can be accomplished with a superpave gyratory compactor (SGC), which is routinely used in the pavement industry to fabricate 6 in. (15.2 cm.) diameter specimens. However, this poses difficulties with the GPR antenna height, direct coupling, and the Fresnel zone in relation to the asphalt specimen dimension limitation. These challenges are overcome by employing a plastic spacer with a known dielectric constant between the SGC specimen and the antenna. The purpose of the spacer is to reduce GPR wave speed so that the signal reflected from the specimen is separated from the direct coupling effects at an antenna height where the Fresnel zone of the GPR is not affected by the specimen dimension. The specimen dielectric constant can then be measured using the reflection coefficient-based surface reflection method (SR) or the pulse velocity-based time-of-flight method (TOF). Also, The Hoegh–Dai model (HD model) is demonstrated to reasonably predict pavement density based on the results of field measurements and corresponding core validation, especially as compared to the conventional exponential model. Results are presented from multiple days of paving on one project, as well as a single paving day on a project with significantly different mix properties. The agreement between the HD model, coreless prediction, and field cores shows the promise for implementation of dielectric-based asphalt compaction evaluation without the need for destructive field core calibration.

Wheat wounding-responsive HD-Zip IV transcription factor GL7 is predominantly expressed in grain and activates genes encoding defensins.

Several classes of transcription factors are involved in the activation of defensins. A new type of the transcription factor responsible for the regulation of wheat grain specific defensins was characterised in this work. HD-Zip class IV transcription factors constitute a family of multidomain proteins. A full-length cDNA of HD-Zip IV, designated TaGL7 was isolated from the developing grain of bread wheat, using a specific DNA sequence as bait in the Y1H screen. 3D models of TaGL7 HD complexed with DNA cis-elements rationalised differences that underlined accommodations of binding and non-binding DNA, while the START-like domain model predicted binding of lipidic molecules inside a concave hydrophobic cavity. The 3'-untranslated region of TaGL7 was used as a probe to isolate the genomic clone of TdGL7 from a BAC library prepared from durum wheat. The spatial and temporal activity of the TdGL7 promoter was tested in transgenic wheat, barley and rice. TdGL7 was expressed mostly in ovary at fertilisation and its promoter was active in a liquid endosperm during cellularisation and later in the endosperm transfer cells, aleurone, and starchy endosperm. The pattern of TdGL7 expression resembled that of genes that encode grain-specific lipid transfer proteins, particularly defensins. In addition, GL7 expression was upregulated by mechanical wounding, similarly to defensin genes. Co-bombardment of cultured wheat cells with TdGL7 driven by constitutive promoter and seven grain or root specific defensin promoters fused to GUS gene, revealed activation of four promoters. The data confirmed the previously proposed role of HD-Zip IV transcription factors in the regulation of genes that encode lipid transfer proteins involved in lipid transport and defence. The TdGL7 promoter could be used to engineer cereal grains with enhanced resistance to insects and fungal infections.

Simulation of Storm Surges in the South Central Coast of Vietnam Under Climate Change

The research was supported by National Research Project Program of Vietnam: science and technology in response to climate change, natural resources and environmental management in the 2016-2020 period (program number: BĐKH/16-20), Developing a sustainable socio-economic model adapting to extreme natural disasters under climate change in the South Central region of Viet Nam. A case study of Ninh Thuan province (grant number: BĐKH.04/16-20). Abstract This paper presents the results of storm surge simulation in the South Central region of Vietnam using the Mike 21-FM HD model. Wind pressure fields of typical storms were first identified in period of 1986-2005 using the parametric wind field model. Storm surge risk was then simulated based on the rare 10, 50 and 100-year frequency corresponding to 2030, 2050, and 2100 scenarios. Storm surge model was finally calibrated and validated using the level of water measured in the November 2009 Typhoon Mirinae and October 2013 Typhoon Nari. The results show that storm surges were consistent with water level variation and amplitude; the maximum and minimum storm surges were 2.34m in the Binh Thuan coastal area and 0.78m in the Khanh Hoa coastal area, respectively. The results of this study demonstrated the use of MIKE 21-FM HD model for the simulation of storm surges in the future plays an important role in damage risk reduction caused by storm surges. Keywords: storm surge simulation, climate change, Mike 21-FM HD model, South Central coast of Vietnam. DOI : 10.7176/JEES/9-6-08 Publication date :June 30 th 2019

Cysteamine Protects Neurons from Mutant Huntingtin Toxicity.

The potential benefit of cysteamine for Huntington's disease has been demonstrated in HD animal models. Cysteamine and its derivate cystamine were shown to reduce neuropathology and prolong lifespan. Human studies have demonstrated safety, and suggestive results regarding efficacy. Despite all the studies available in vivo, there are only few in vitro studies, and the mechanism of action of cysteamine remains unclear. The objective of this study is to assess the capacity of cysteamine for neuroprotection against mutant Huntingtin in vitro using cellular models of HD, and to provide initial data regarding mechanism of action. We tested the neuroprotective properties of cysteamine in vitro in our primary neuron and iPSC models of HD. Cysteamine showed a strong neuroprotective effect (EC50 = 7.1 nM) against mutant Htt-(aa-1-586 82Q) toxicity, in a nuclear condensation cell toxicity assay. Cysteamine also rescued mitochondrial changes induced by mutant Htt. Modulation of the levels of cysteine or glutathione failed to protect neurons, suggesting that cysteamine neuroprotection is not mediated through cysteine metabolism. Taurine and Hypotaurine, which are metabolites of cysteamine can protect neurons against Htt toxicity, but the inhibition of the enzyme converting cysteamine to hypotaurine does not block either protective activity, suggesting independent protective pathways. Cysteamine has been suggested to activate BDNF secretion; however, cysteamine protection was not blocked by BDNF pathway antagonists. Cysteamine was strongly neuroprotective with relatively high potency. We demonstrated that the main neuroprotective pathways that have been proposed to be the mechanism of protection by cysteamine can all be blocked and still not prevent the neuroprotective effect. The results suggest the involvement of other yet-to-be-determined neuroprotective pathways.

Focused ultrasound-induced blood brain-barrier opening enhanced vascular permeability for GDNF delivery in Huntington's disease mouse model

BackgroundHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene encoding the huntingtin (Htt) protein, which results in a protein containing an abnormally expanded polyglutamine (polyQ) sequence. The expanded polyQ in the Htt protein is toxic to brain cells. No therapy exists to delay disease progression. MethodsThis study describes a gene-liposome system that synergistically applied focused ultrasound (FUS)-blood-brain barrier (BBB) opening for rescuing motor and neuropathological impairments when administered from pre to post-symptomatic transgenic mouse models of HD. DPPC liposomes (LPs) are designed to carry glia cell line-derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex. Pulsed FUS exposure with microbubbles (MBs) was used to induce BBB opening for non-viral, non-invasive, and targeted gene delivery into the central nervous system (CNS) for therapeutic purposes. ResultsFUS-gene therapy significantly improved motor performance with GDNFp-LPs + FUS treated HD mice equilibrating longer periods in the animal behavior. Reflecting the improvements observed in motor function, GDNF overexpression results in significantly decreased formation of polyglutamine-expanded aggregates, reduced oxidative stress and apoptosis, promoted neurite outgrowth, and improved neuronal survival. Immunoblotting and histological staining further confirmed the neuroprotective effect from delivery of GDNF genes to neuronal cells. ConclusionsThis study suggests that the GDNFp-LPs plus FUS sonication can provide an effective gene therapy to achieve local extravasation and triggered gene delivery for non-invasive in vivo treatment of CNS diseases.

Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to improved Huntington\u2019s pathology in zQ175 mice

Huntington’s disease (HD) is a neurodegenerative disorder caused by a genetic abnormality in the huntingtin gene that leads to a polyglutamine repeat expansion of the huntingtin protein. The cleaved polyglutamine expansion of mutant huntingtin (mHTT) protein can form aggregates strongly correlated with HD progression. We have previously shown that the inhibition of mGluR5 using CTEP, a selective negative allosteric mGluR5 modulator, can delay disease progression and reduce in mHTT aggregates in the zQ175 mouse model of HD. This was paralleled by enhanced catalytic activity of Unc-51-like kinase 1 (ULK1), a kinase modulated by mammalian target of rapamycin (mTOR) and key regulator of autophagy initiation. In the present study, we show that CTEP can correct aberrant phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling detected in zQ175 mice that may underlie the enhanced ULK1 activity and activation of autophagy. We also show that CTEP can facilitate cAMP response element-binding protein (CREB)-mediated expression of brain-derived neurotrophic factor (BDNF) to foster neuronal survival and reduce apoptosis. Taken together, our findings provide the molecular evidence for how targeting mGluR5 using a well-tolerated selective NAM can mitigate two critical mechanisms of neurodegeneration, autophagy and apoptosis.

Genistein induces degradation of mutant huntingtin in fibroblasts from Huntington\u2019s disease patients

Mutations in the HTT gene, consisting of expansion of CAG triplets, cause the Huntington’s disease (HD), one of the major neurodegenerative disorders. Formation of aggregates of mutant huntingtin (mHTT, the product of the mutant HTT gene) leads to cellular dysfunctions, and subsequent neurodegeneration which manifest clinically as motor abnormalities and cognitive deficits. We recently used immortalized HEK-293 cells expressing the 1st exon of the mutant HTT gene as a cellular model of HD, and showed that the stimulation of autophagy by genistein corrected the mutant phenotype. However, effects of genistein on HD patient-derived cells remained unknown. In this report, we demonstrated that genistein also instigated degradation of mHTT in fibroblasts derived from HD patients. This was assessed as a significant decrease in the levels of HTT in HD fibroblasts measured by Western-blotting, and the disappearance of intracellular mHTT aggregates in cells observed by fluorescent microscopy. Fibroblasts derived from control persons were not affected by genistein treatment. These results indicate that genistein can improve HD phenotype in patient-derived cells, and substantiates the need for further studies of this isoflavone as a potential therapeutic agent.

Multiple water band detections in the CARMENES near-infrared transmission spectrum of HD 189733 b

Aims. We explore the capabilities of CARMENES for characterising hot-Jupiter atmospheres by targeting multiple water bands, in particular, those at 1.15 and 1.4 μm. Hubble Space Telescope observations suggest that this wavelength region is relevant for distinguishing between hazy and/or cloudy and clear atmospheres. Methods. We observed one transit of the hot Jupiter HD 189733 b with CARMENES. Telluric and stellar absorption lines were removed using SYSREM, which performs a principal component analysis including proper error propagation. The residual spectra were analysed for water absorption with cross-correlation techniques using synthetic atmospheric absorption models. Results. We report a cross-correlation peak at a signal-to-noise ratio (S/N) of 6.6, revealing the presence of water in the transmission spectrum of HD 189733 b. The absorption signal appeared slightly blueshifted at –3.9 ± 1.3 km s−1. We measured the individual cross-correlation signals of the water bands at 1.15 and 1.4 μm, finding cross-correlation peaks at S/N of 4.9 and 4.4, respectively. The 1.4 μm feature is consistent with that observed with the Hubble Space Telescope. Conclusions. The water bands studied in this work have been mainly observed in a handful of planets from space. Being able also to detect them individually from the ground at higher spectral resolution can provide insightful information to constrain the properties of exoplanet atmospheres. Although the current multi-band detections can not yet constrain atmospheric haze models for HD 189733 b, future observations at higher S/N could provide an alternative way to achieve this aim.

Simultaneous Spectral Energy Distribution and Near-infrared Interferometry Modeling of HD 142666

Abstract We present comprehensive models of the Herbig Ae star, HD 142666, which aim to simultaneously explain its spectral energy distribution (SED) and near-infrared (NIR) interferometry. Our new submilliarcsecond resolution CHARA (CLASSIC and CLIMB) interferometric observations, supplemented with archival shorter baseline data from VLTI/PIONIER and the Keck Interferometer, are modeled using centrosymmetric geometric models and an axisymmetric radiative transfer code. CHARA’s 330 m baselines enable us to place strong constraints on the viewing geometry, revealing a disk inclined at 58° from face-on with a 160° major axis position angle. Disk models imposing vertical hydrostatic equilibrium provide poor fits to the SED. Models accounting for disk scale height inflation, possibly induced by turbulence associated with magnetorotational instabilities, and invoking grain growth to ≳1 μm size in the disk rim are required to simultaneously reproduce the SED and measured visibility profile. However, visibility residuals for our best model fits to the SED indicate the presence of unexplained NIR emission, particularly along the apparent disk minor axis, while closure phase residuals indicate a more centrosymmetric emitting region. In addition, our inferred 58° disk inclination is inconsistent with a disk-based origin for the UX Ori-type variability exhibited by HD 142666. Additional complexity, unaccounted for in our models, is clearly present in the NIR-emitting region. We propose that the disk is likely inclined toward a more edge-on orientation and/or an optically thick outflow component also contributes to the NIR circumstellar flux.

A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies.

ABSTRACTHuntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions.This article has an associated First Person interview with the first author of the paper.

Validation of two parameter function height diameter models

Eleven nonlinear height diameter models were fitted and developed for Pinus trees based on individual tree height and diameter at breast height data (n=300) collected from block Langate of Kashmir province in India. Fitting of height diameter models using non-linear least square regression showed that all the parameters across all models were significant. In order to test the predictive performance of the models 10- folded cross-validation technique was used in this study. Comparison of AIC, RMSE, ME and Ad-R 2 values for the training and validation data showed that most of the non-linear HD models capture the height diameter relationships for Pinus trees. Validation results suggest that Naslund -2 HD model provide the best height predictions in case of Pinus tree.