Monkey hybrid stem cells develop cellular features of Huntington's disease

<p>Abstract</p> <p>Background</p> <p>Pluripotent stem cells that are capable of differentiating into different cell types and develop robust hallmark cellular features are useful tools for clarifying the impact of developmental events on neurodegenerative diseases such as Huntington's disease. Additionally, a Huntington's cell model that develops robust pathological features of Huntington's disease would be valuable for drug discovery research.</p> <p>Results</p> <p>To test this hypothesis, a pluripotent Huntington's disease monkey hybrid cell line (TrES1) was established from a tetraploid Huntington's disease monkey blastocyst generated by the fusion of transgenic Huntington's monkey skin fibroblast and a wild-type non-transgenic monkey oocyte. The TrES1 developed key Huntington's disease cellular pathological features that paralleled neural development. It expressed mutant huntingtin and stem cell markers, was capable of differentiating to neural cells, and developed teratoma in severely compromised immune deficient (SCID) mice. Interestingly, the expression of mutant htt, the accumulation of oligomeric mutant htt and the formation of intranuclear inclusions paralleled neural development <it>in vitro </it>, and even mutant htt was ubiquitously expressed. This suggests the development of Huntington's disease cellular features is influenced by neural developmental events.</p> <p>Conclusions</p> <p>Huntington's disease cellular features is influenced by neural developmental events. These results are the first to demonstrate that a pluripotent stem cell line is able to mimic Huntington's disease progression that parallels neural development, which could be a useful cell model for investigating the developmental impact on Huntington's disease pathogenesis.</p

The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19

Differences in efficacy of monepantel, derquantel and abamectin against multi-resistant nematodes of sheep

Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%)

New approaches to high-resolution mapping of marine vertical structures

Vertical walls in marine environments can harbour high biodiversity and provide natural protection from bottom-trawling activities. However, traditional mapping techniques are usually restricted to down-looking approaches which cannot adequately replicate their 3D structure. We combined sideways-looking multibeam echosounder (MBES) data from an AUV, forward-looking MBES data from ROVs and ROV-acquired videos to examine walls from Rockall Bank and Whittard Canyon, Northeast Atlantic. High-resolution 3D point clouds were extracted from each sonar dataset and structure from motion photogrammetry (SfM) was applied to recreate 3D representations of video transects along the walls. With these reconstructions, it was possible to interact with extensive sections of video footage and precisely position individuals. Terrain variables were derived on scales comparable to those experienced by megabenthic individuals. These were used to show differences in environmental conditions between observed and background locations as well as explain spatial patterns in ecological characteristics. In addition, since the SfM 3D reconstructions retained colours, they were employed to separate and quantify live coral colonies versus dead framework. The combination of these new technologies allows us, for the first time, to map the physical 3D structure of previously inaccessible habitats and demonstrates the complexity and importance of vertical structures

Measures in Visualization Space

Postponed access: the file will be available after 2021-08-12Measurement is an integral part of modern science, providing the fundamental means for evaluation, comparison, and prediction. In the context of visualization, several different types of measures have been proposed, ranging from approaches that evaluate particular aspects of visualization techniques, their perceptual characteristics, and even economic factors. Furthermore, there are approaches that attempt to provide means for measuring general properties of the visualization process as a whole. Measures can be quantitative or qualitative, and one of the primary goals is to provide objective means for reasoning about visualizations and their effectiveness. As such, they play a central role in the development of scientific theories for visualization. In this chapter, we provide an overview of the current state of the art, survey and classify different types of visualization measures, characterize their strengths and drawbacks, and provide an outline of open challenges for future research.acceptedVersio

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Insecticide resistance in Anopheles gambiae from south-western Chad, Central Africa

<p>Abstract</p> <p>Background</p> <p>Indoor residual spraying and insecticide-treated nets (ITN) are essential components of malaria vector control in Africa. Pyrethroids are the only recommended compounds for nets treatment because they are fast-acting insecticides with low mammalian toxicity. However, there is growing concern that pyrethroid resistance may threaten the sustainability of ITN scaling-up programmes. Here, insecticide susceptibility was investigated in <it>Anopheles gambiae </it>sensu lato from an area of large scale ITN distribution programme in south-western Chad.</p> <p>Methods</p> <p>Susceptibility to 4% DDT, 0.05% deltamethrin, 0.75% permethrin, 0.1% bendiocarb and 5% malathion was assessed using the WHO standard procedures for adult mosquitoes. Tests were carried out with two to four days-old, non-engorged female mosquitoes. The <it>An. gambiae </it>Kisumu strain was used as a reference. Knockdown effect was recorded every 5 min and mortality scored 24 h after exposure. Mosquitoes were identified to species and molecular form by PCR-RFLP and genotypes at the <it>kdr </it>locus were determined in surviving specimens by Hot Oligonucleotide Ligation Assay (HOLA).</p> <p>Results</p> <p>During this survey, full susceptibility to malathion was recorded in all samples. Reduced susceptibility to bendiocarb (mortality rate of 96.1%) was found in one sample out of nine assayed. Increased tolerance to pyrethroids was detected in most samples (8/9) with mortality rates ranging from 70.2 to 96.6% for deltamethrin and from 26.7 to 96.3% for permethrin. Pyrethroid tolerance was not associated with a significant increase of knock-down times. <it>Anopheles arabiensis </it>was the predominant species of the <it>An. gambiae </it>complex in the study area, representing 75 to 100% of the samples. Screening for <it>kdr </it>mutations detected the L1014F mutation in 88.6% (N = 35) of surviving <it>An</it>. <it>gambiae </it>sensu stricto S form mosquitoes. All surviving <it>An. arabiensis </it>(N = 49) and M form <it>An</it>. <it>gambiae </it>s.s. (N = 1) carried the susceptible allele.</p> <p>Conclusion</p> <p>This first investigation of malaria vector susceptibility to insecticides in Chad revealed variable levels of resistance to pyrethroid insecticides (permethrin and deltamethrin) in most <it>An</it>. <it>gambiae </it>s.l. populations. Resistance was associated with the L1014F <it>kdr </it>mutation in the S form of <it>An. gambiae </it>s.s.. Alternative mechanisms, probably of metabolic origin are involved in <it>An. arabiensis</it>. These results emphasize the crucial need for insecticide resistance monitoring and in-depth investigation of resistance mechanisms in malaria vectors in Chad. The impact of reduced susceptibility to pyrethroids on ITN efficacy should be further assessed.</p