Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and ...immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the
Fused in Sarcoma
gene (
FUS
) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22–46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the “stereotypic” form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the
FUS
gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in
FUS
in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive ‘stereotypic’ picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the
FUS
gene cause some cases of FTLD remains unresolved.
ABSTRACT We report the All-Sky Automated Survey for SuperNovae discovery of the tidal disruption event (TDE) ASASSN-23bd (AT 2023clx) in NGC 3799, a LINER galaxy with no evidence of strong active ...galactic nucleus (AGN) activity over the past decade. With a redshift of z = 0.01107 and a peak ultraviolet (UV)/optical luminosity of (5.4 ± 0.4) × 1042 erg s−1, ASASSN-23bd is the lowest-redshift and least-luminous TDE discovered to date. Spectroscopically, ASASSN-23bd shows H α and He i emission throughout its spectral time series, there are no coronal lines in its near-infrared spectrum, and the UV spectrum shows nitrogen lines without the strong carbon and magnesium lines typically seen for AGN. Fits to the rising ASAS-SN light curve show that ASASSN-23bd started to brighten on MJD 59988$^{+1}_{-1}$, ∼9 d before discovery, with a nearly linear rise in flux, peaking in the g band on MJD $60 \, 000^{+3}_{-3}$. Scaling relations and TDE light curve modelling find a black hole mass of ∼106 M⊙, which is on the lower end of supermassive black hole masses. ASASSN-23bd is a dim X-ray source, with an upper limit of $L_{0.3-10\, \mathrm{keV}} \lt 1.0\times 10^{40}$ erg s−1 from stacking all Swift observations prior to MJD 60061, but with soft (∼0.1 keV) thermal emission with a luminosity of $L_{0.3-2 \, \mathrm{keV}}\sim 4\times 10^{39}$ erg s−1 in XMM-Newton observations on MJD 60095. The rapid (t < 15 d) light curve rise, low UV/optical luminosity, and a luminosity decline over 40 d of ΔL40 ≈ −0.7 dex make ASASSN-23bd one of the dimmest TDEs to date and a member of the growing ‘Low Luminosity and Fast’ class of TDEs.
Background Evidence is needed for the best long‐term diet for weight loss, and improvement in cardiac risk and disease in obese adults.
Methods We systematically reviewed randomized controlled ...trials (RCTs) in any language. We searched 13 databases and handsearched journals. Trials lasted 1 year or more. One investigator extracted the data and a second checked data extraction. Trial quality was assessed.
Results Low fat diets (LFDs) produced significant weight losses up to 36 months (−3.55 kg; 95% CI, −4.54 to −2.55 kg). Blood pressure, lipids and fasting plasma glucose improved with these diets after 12 months. Four studies found that LFDs may prevent type 2 diabetes and reduce antihypertensive medication for up to 3 years. A very low calorie diet (VLCD, <4.2 MJ day−1) was associated with the most weight loss after 12 months (−13.40 kg; 95% CI, −18.43 to −8.37 kg) in one small study with beneficial effects on asthma. There was no evidence that low carbohydrate protein sparing modified fasts (PSMFs) were associated with greater long‐term weight loss than low calorie diets (LCDs, 4.2–6.7 MJ day−1) or VLCDs. PSMFs were, however, associated with greater lowering of fasting plasma glucose and HbA1c than LCDs.
Conclusions Little evidence supports the use of diets other than LFDs for weight reduction. With the increasing prevalence of morbid obesity, long‐term follow‐up in RCTs is needed to evaluate the effect of LCDs, VLCDs and PSMFs more fully.
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•Two new series 6a-g and 7a-f and cyclized analogues pyrazolo-2-quinolones 7a-f have been designed and synthesized.•In vitro cytotoxic activity of the new compounds against 60 cancer ...cell lines.•Compounds 6c, 6d, 6e, 6f, 7b, 7e and 7f were further examined against CCRF-CEM and MOLT-4 leukemia cell lines.•Compound 7f was the most active compound with IC50 = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively.•Compound 7f showed comparable inhibitory effect to erlotinib on the EGFR TK.•Docking studies of the most active compounds were done against 3D crystal structure of EGFR.
Two new series of diethyl 2-2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC50 = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC50 = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds’ activity.
IMPORTANCE: Based on studies with relatively small sample size, fragility fractures are commonly reported in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD). OBJECTIVE: To ...determine the fracture burden and growth impairment in a large contemporary cohort of boys with DMD in the United Kingdom and in relation to GC regimen. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of fracture morbidity and growth from 832 boys with DMD in the UK NorthStar database (2006-2015), which systematically captures information from 23 participating centers. A total of 564 boys had more than 1 visit. No numbers of boys who refused were collected, but informal data from 2 centers in London and from Scotland show that refusal is very low. Data were analyzed between October 2006 and October 2015. MAIN OUTCOMES AND MEASURES: Fracture incidence rate per 10 000 person-years was determined. Cox regression analysis was used to identify factors associated with first fracture. RESULTS: Median age at baseline was 6.9 years (interquartile range, 4.9-7.2 years). At baseline, new fractures were reported in 7 of 564 participants (1.2%). During a median follow-up of 4 years (interquartile range, 2.0-6.0 years), incident fractures were reported in 156 of 564 participants (27.7%), corresponding to an overall fracture incidence rate of 682 per 10 000 person-years (95% CI, 579-798). The highest fracture incidence rate was observed in those treated with daily deflazacort at 1367 per 10 000 person-years (95% CI, 796-2188). After adjusting for age at last visit, mean hydrocortisone equivalent exposure, mobility status, and bisphosphonate use prior to first fracture, boys treated with daily deflazacort had a 18.6-fold increase risk for first fracture (95% CI, 1.7-208.6; P = .02). Using adjusted regression models, change in height standard deviation scores was −1.6 SD lower (95% CI, −3.0 to −0.1; P = .03) in those treated with daily deflazacort compared with GC-naive boys, whereas there were no statistical differences in the other GC regimen. CONCLUSIONS AND RELEVANCE: In this large group of boys with DMD with longitudinal data, we document a high fracture burden. Boys treated with daily deflazacort had the highest fracture incidence rate and the greatest degree of linear growth failure. Clinical trials of primary bone protective therapies and strategies to improve growth in boys with DMD are urgently needed, but stratification based on GC regimen may be necessary.
Galaxy and Mass Assembly (GAMA) is a project to study galaxy formation and evolution, combining imaging data from ultraviolet to radio with spectroscopic data from the AAOmega spectrograph on the ...Anglo-Australian Telescope. Using data from Phase 1 of GAMA, taken over three observing seasons, and correcting for various minor sources of incompleteness, we calculate galaxy luminosity functions (LFs) and their evolution in the ugriz passbands.
At low redshift, z < 0.1, we find that blue galaxies, defined according to a magnitude-dependent but non-evolving colour cut, are reasonably well fitted over a range of more than 10 magnitudes by simple Schechter functions in all bands. Red galaxies, and the combined blue plus red sample, require double power-law Schechter functions to fit a dip in their LF faintwards of the characteristic magnitude M* before a steepening faint end. This upturn is at least partly due to dust-reddened disc galaxies.
We measure the evolution of the galaxy LF over the redshift range 0.002 < z < 0.5 both by using a parametric fit and by measuring binned LFs in redshift slices. The characteristic luminosity L* is found to increase with redshift in all bands, with red galaxies showing stronger luminosity evolution than blue galaxies. The comoving number density of blue galaxies increases with redshift, while that of red galaxies decreases, consistent with prevailing movement from blue cloud to red sequence. As well as being more numerous at higher redshift, blue galaxies also dominate the overall luminosity density beyond redshifts z≃ 0.2. At lower redshifts, the luminosity density is dominated by red galaxies in the riz bands, and by blue galaxies in u and g.
Identification of water in our Solar System is a key point to understanding the formation and evolution of planetary bodies as well as for astrobiological studies. Scientists identified hydrated ...minerals as a prime source of H2O in our Solar System. Minerals such as clays, serpentines and other phyllosilicates were discovered by orbiter and lander spacecraft and ground observations on a large variety of rocky surfaces from Mars to small asteroids using InfraRed (IR) spectroscopy as primary technique. It has already been observed that in the presence of large amounts of hydrated minerals in mixtures with anhydrous minerals, the IR spectra can be dominated by the features of hydrated minerals. However, it is still poorly studied how the IR spectra change in presence of different grain size of the two components.
The goal of this study was to investigate the infrared spectroscopic features of anhydrous mineral spectra in presence of low amounts of small grain size hydrated hyperfine particles. We prepared several mixtures using 1 wt% and 5 wt% of very small grain size (< 10 μm) hydrated minerals and 95 wt% and 99 wt% of larger grain size (200–500 μm) anhydrous minerals. We measured the IR reflectance spectrum of these mixtures in the range 8000–400 cm−1 (1.25–25 μm). Results presented here show how the presence of a very limited amount of hydrated minerals with grain size one order of magnitude smaller than the anhydrous component is sufficient to change the IR spectrum, especially in the Near-InfraRed (NIR) region where some of the major hydrated features manifest. On the contrary, the Mid-InfraRed (MIR) part of the spectrum (also identified as thermal infrared) is definitely less affected and anhydrous mineral features continue to be dominant with slight modifications. This result is of pivotal importance for correctly interpreting the IR reflectance observations of planetary bodies such as Mars or asteroids where a mixing of anhydrous and hydrated minerals can be observed. The presence of strong spectroscopic features due to hydrated minerals can be misinterpreted as a large abundance of this material instead of a spectroscopic effect.
•We mixed 1 wt% of hyperfine <10 μm hydrated minerals with bigger anhydrous minerals.•Near Infrared range shows notable changes due to the addition of hydrated minerals.•The hydrated OH/H2O feature at 2.7 μm appear to be dominant in the anhydrous spectra.•Mid Infrared range is less affected and anhydrous mineral features are dominant.•These results can affect interpretation of planetary remote sensing infrared data.
The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are ...reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and
222
Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background (
∼
17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected
222
Rn activity concentration in XENONnT is determined to be 4.2 (
-
0.7
+
0.5
)
μ
Bq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The permanganate-mediated oxidative cyclization of a series of 2-methylenehept-5-eneoates bearing different chiral auxiliaries was investigated, leading to the discovery of trans-2-tritylcyclohexanol ...(TTC) as a highly effective chiral controller for the formation of the 2,5-substituted THF diol product with high diastereoselectivity (dr ∼97:3). Chiral resolution of (±)-TTC, prepared in one step from cyclohexene oxide, afforded (−)-(1S,2R)-TTC (er >99:1), which was applied to the synthesis of (+)-trans-(2S,5S)-linalool oxide.
Abstract Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Recent studies suggest that apoptotic mechanisms may ...partially contribute to the pathogenesis of this disorder. Cathepsin D is the predominant lysosomal protease and is abundantly expressed in the brain. It plays an important role in regulation of cellular apoptosis and has been shown to mediate apoptosis induced by cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ. In this study, we examined the expression levels of cathepsin D in the autistic brain. We found that cathepsin D protein expression was significantly increased in the frontal cortex, in pyramidal and granule cells of the hippocampus, and in cerebellar neurons in autistic subjects as compared to controls. In addition, we found that the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, while caspase-3, a critical executioner of apoptosis, was increased in the cerebellum of autistic subjects. Previously our studies have shown that Bcl-2 expression is decreased and the BDNF-Akt-Bcl-2 pathway is compromised in the frontal cortex of autistic subjects, which suggested that increased apoptosis may be involved in the pathogenesis of autism. Our current finding of decreased Bcl-2 and increased capase-3 in the cerebellum of autistic subjects further supports this suggestion. In addition, the finding of increased cathepsin D in the cerebellum of autistic subjects suggests that, through its regulation of apoptosis, the altered activities of cathepsin D in the autistic brain may play an important role in the pathogenesis of autism.
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