Cosmological simulations predict that the Universe contains a network of intergalactic gas filaments, within which galaxies form and evolve. However, the faintness of any emission from these ...filaments has limited tests of this prediction. We report the detection of rest-frame ultraviolet Lyman-α radiation from multiple filaments extending more than one megaparsec between galaxies within the SSA22 protocluster at a redshift of 3.1. Intense star formation and supermassive black-hole activity is occurring within the galaxies embedded in these structures, which are the likely sources of the elevated ionizing radiation powering the observed Lyman-α emission. Our observations map the gas in filamentary structures of the type thought to fuel the growth of galaxies and black holes in massive protoclusters.
Summary
Background In previous studies, etanercept significantly improved plaque psoriasis and was well tolerated.
Objectives To examine further the efficacy and safety of etanercept and to assess ...maintenance of treatment effect after dose reduction of etanercept.
Methods In this multicentre 24‐week study in the U.S.A., Canada and Western Europe, patients were at least 18 years old; had active, clinically stable plaque psoriasis involving at least 10% of body surface area; had a minimum Psoriasis Area and Severity Index (PASI) of 10 at screening; and had received or were a candidate to receive systemic psoriasis therapy or phototherapy. During the first 12 weeks of the study, patients were randomly assigned to receive by subcutaneous injection etanercept twice weekly (BIW) at a dose of 50 mg or 25 mg, or placebo BIW in a double‐blind fashion. During the second 12 weeks, all patients received etanercept 25 mg BIW. The primary endpoint was a 75% or greater improvement from baseline in PASI (PASI 75) at 12 weeks.
Results Five hundred and eighty‐three subjects were randomized and received at least one dose of study drug. At week 12, a PASI 75 was achieved by 49% of patients in the etanercept 50 mg BIW group, 34% in the 25 mg BIW group, and 3% in the placebo group (P < 0·0001 for each etanercept group compared with placebo). At week 24 (after 12 weeks of open‐label 25 mg etanercept BIW), a PASI 75 was achieved by 54% of patients whose dose was reduced from 50 mg BIW to 25 mg BIW, by 45% of patients in the continuous 25 mg BIW group, and by 28% in the group that received placebo followed by etanercept 25 mg BIW. Etanercept was well tolerated throughout the study.
Conclusions Etanercept provided clinically meaningful benefit to patients with chronic plaque psoriasis, with no apparent decrease in efficacy after dose reduction.
Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense ...transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring "genes" in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.
Photodynamic therapy (PDT) promotes cell death, and it has been successfully employed as a treatment resource for neuropathic complications of diabetes mellitus (T1DM) and hepatocellular carcinoma. ...The liver is the major organ involved in the regulation of energy homeostasis, and in pathological conditions such as T1DM, changes in liver metabolic pathways result in hyperglycemia, which is associated with multiple organic dysfunctions. In this context, it has been suggested that chlorophyll-a and its derivatives have anti-diabetic actions, such as reducing hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, but these effects have not yet been proven. Thus, the biological action of PDT with chlorophyll-a on hepatic parameters related to energy metabolism and oxidative stress in T1DM Wistar rats was investigated. Evaluation of the acute effects of this pigment was performed by incubation of isolated hepatocytes with chlorophyll-a and the chronic effects were evaluated by oral treatment with chlorophyll-based extract, with post-analysis of the intact liver by in situ perfusion. In both experimental protocols, chlorophyll-a decreased hepatic glucose release and glycogenolysis rate and stimulated the glycolytic pathway in DM/PDT. In addition, there was a reduction in hepatic oxidative stress, noticeable by decreased lipoperoxidation, reactive oxygen species, and carbonylated proteins in livers of chlorophyll-treated T1DM rats. These are indicators of the potential capacity of chlorophyll-a in improving the status of the diabetic liver.
Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic ...mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.
The imposex phenomenon in female prosobranch gastropods provides one of the best documented examples of endocrine disruption in wildlife. While many field studies have demonstrated the negative ...impact of tributyltin (TBT) upon female gastropods, the mechanism(s) underlying imposex development has not yet been fully clarified. Over the years several hypotheses have been raised to determine the biochemical and molecular determinants of this process. Nevertheless, the interplay between the different suggested pathways (neuroendocrine, steroid and retinoid) is still unknown. Hence, through a combination of exposure experiments, we show that the 9-
cis-retinoic acid (9cisRA), the proposed natural ligand of the retinoic X receptor (RXR), induces imposex in females of
Nucella lapillus to the same degree as tributyltin, when administered at similar concentrations (1
μg/g body weight). Methoprene acid, a selective ligand for RXR, also induces imposex, albeit to a lower degree than that of the positive control. In contrast, testosterone significantly induced imposex, but had no effect on female penis induction, while the neuropeptide APGWamide had no effect on imposex development. These results clearly demonstrate that imposex induction in
N. lapillus is mediated through the modulation of the RXR signalling pathways. In addition to the effects reported in female dogwhelks, both TBT and RA significantly increased male penis length, thus suggesting that TBT may also impact male secondary sex organs through the RXR signalling pathways. As a step for future studies, we have cloned the orthologue of
N. lapillus RXR and provide experimental evidence that it binds 9cisRA. Finally, the basal expression level of RXR in several tissues of
N. lapillus was determined through real-time PCR, thus showing that RXR is ubiquitously expressed in mollusc tissues, with the highest expression levels being recorded in female and male gonads. The mechanistic impacts of the overall findings to the imposex process are discussed.
Supramolecular assembly can yield ordered structures by taking advantage of the cumulative effect of multiple non-covalent interactions between adjacent molecules. The thermodynamic origin of many ...self-assembled structures in water is the balance between the hydrophilic and hydrophobic segments of the molecule. Here, we show that this approach can be generalized to use solvophobic and solvophilic segments of fully hydrophobic alkylated fullerene molecules. Addition of n-alkanes results in their assembly--due to the antipathy of C60 towards n-alkanes--into micelles and hexagonally packed gel-fibres containing insulated C60 nanowires. The addition of pristine C60 instead directs the assembly into lamellar mesophases by increasing the proportion of π-conjugated material in the mixture. The assembled structures contain a large fraction of optoelectronically active material and exhibit comparably high photoconductivities. This method is shown to be applicable to several alkyl-π-conjugated molecules, and can be used to construct organized functional materials with π-conjugated sections.
Inactivity causes muscle atrophy and capillary regression in skeletal muscle. Chlorogenic acid has an antioxidant capacity and may prevent capillary regression. Therefore, the protective effects of ...chlorogenic acid on inactivity-induced capillary regression in rat soleus muscle were investigated. Twenty male Wistar rats were randomly divided into four groups: control (CON), chlorogenic acid supplementation (CGA), 2-week hindlimb unloading (HU), 2-week hindlimb unloading plus chlorogenic acid supplementation (HU+CGA). The rats in CGA and HU+CGA groups were orally administrated chlorogenic acid (850 mg/kg/day). Unloading resulted in a decrease in capillary number, oxidative capacity, and an increase in oxidative stress of the soleus muscle, whereas chlorogenic acid supplementation prevented capillary and metabolic changes resulting from unloading by reducing oxidative stress. In conclusion, chlorogenic acid supplementation may qualify as an effective treatment to reduce capillary regression in skeletal muscle caused by disuse muscle atrophy.
Display omitted
The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide ...analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.
Abstract
We present observations of a giant Ly
α
blob (LAB) in the SSA22 protocluster at
z
= 3.1, SSA22-LAB1, taken with the Atacama Large Millimeter/submillimeter Array. Dust continuum, along with C
...ii
158
μ
m and CO(4–3) line emission have been detected in LAB1, showing complex morphology and kinematics across a ∼100 kpc central region. Seven galaxies at
z
= 3.0987–3.1016 in the surroundings are identified in C
ii
and dust continuum emission, with two of them potential companions or tidal structures associated with the most massive galaxies. Spatially resolved C
ii
and infrared luminosity ratios for the widely distributed media (
L
Cɪɪ
/
L
IR
≈ 10
−2
−10
−3
) suggest that the observed extended interstellar media are likely to have originated from star formation activity and the contribution from shocked gas is probably not dominant. LAB1 is found to harbor a total molecular gas mass
M
mol
= (8.7 ± 2.0) × 10
10
M
⊙
, concentrated in the core region of the Ly
α
-emitting area. While (primarily obscured) star formation activity in the LAB1 core is one of the most plausible power sources for the Ly
α
emission, multiple major mergers found in the core may also play a role in making LAB1 exceptionally bright and extended in Ly
α
as a result of cooling radiation induced by gravitational interactions.
PDF
