In two trials in patients with moderate-to-severe plaque psoriasis, the anti–interleukin-17A monoclonal antibody secukinumab was more effective than placebo and etanercept. Infectious complications ...occurred more often with secukinumab than with placebo.
Psoriasis is a chronic, immune-mediated inflammatory skin disease that is associated with substantial impairment of physical and psychological quality of life.
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Our understanding of the pathogenesis of psoriasis was advanced by the discovery of the class of type 17 helper T (Th17) cells, which regulates innate and adaptive immunity. The proinflammatory cytokine interleukin-17A is the primary effector of Th17 cells, but it is also produced by other cell types in psoriatic lesions, including γδ T cells, neutrophils, and possibly mast cells.
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Interleukin-17A stimulates keratinocytes to secrete chemokines and other proinflammatory mediators that recruit additional inflammatory cells, including neutrophils, . . .
L-Histidine Decarboxylase and Tourette's Syndrome Ercan-Sencicek, A. Gulhan; Stillman, Althea A; Ghosh, Ananda K ...
Nature reviews. Neuroscience,
05/2010, Letnik:
362, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Susceptibility to Tourette's syndrome is known to have a genetic influence. This study, of a nonconsanguineous family in which the father and his eight children are affected by the disorder, ...implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder.
This study of a nonconsanguineous family in which the father and his eight children are affected by Tourette's syndrome implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder.
Tourette's syndrome is characterized by childhood onset, waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical–striatal–thalamic–cortical circuitry.
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Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive–compulsive disorder and attention deficit–hyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority.
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The large genetic contribution to Tourette's syndrome is well established. . . .
The molecular mechanisms of toxicity of chemically modified phosphorothioate antisense oligonucleotides (PS-ASOs) are not fully understood. Here, we report that toxic gapmer PS-ASOs containing ...modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2'-O-methoxyethyl (2'-MOE) bind many cellular proteins with high avidity, altering their function, localization and stability. We show that RNase H1-dependent delocalization of paraspeckle proteins to nucleoli is an early event in PS-ASO toxicity, followed by nucleolar stress, p53 activation and apoptotic cell death. Introduction of a single 2'-O-methyl (2'-OMe) modification at gap position 2 reduced protein-binding, substantially decreasing hepatotoxicity and improving the therapeutic index with minimal impairment of antisense activity. We validated the ability of this modification to generally mitigate PS-ASO toxicity with more than 300 sequences. Our findings will guide the design of PS-ASOs with optimal therapeutic profiles.
AbstractObjectiveTo analyse the transmission dynamics of the monkeypox outbreak in the UK, declared a Public Health Emergency of International Concern in July 2022.DesignContact tracing study, ...linking data on case-contact pairs and on probable exposure dates.SettingCase questionnaires from the UK Health Security Agency (UKHSA), United Kingdom.Participants2746 people with polymerase chain reaction confirmed monkeypox virus in the UK between 6 May and 1 August 2022.Main outcome measuresThe incubation period and serial interval of a monkeypox infection using two bayesian time delay models—one corrected for interval censoring (ICC—interval censoring corrected) and one corrected for interval censoring, right truncation, and epidemic phase bias (ICRTC—interval censoring right truncation corrected). Growth rates of cases by reporting date, when monkeypox virus was confirmed and reported to UKHSA, were estimated using generalised additive models.ResultsThe mean age of participants was 37.8 years and 95% reported being gay, bisexual, and other men who have sex with men (1160 out of 1213 reporting). The mean incubation period was estimated to be 7.6 days (95% credible interval 6.5 to 9.9) using the ICC model and 7.8 days (6.6 to 9.2) using the ICRTC model. The estimated mean serial interval was 8.0 days (95% credible interval 6.5 to 9.8) using the ICC model and 9.5 days (7.4 to 12.3) using the ICRTC model. Although the mean serial interval was longer than the incubation period for both models, short serial intervals were more common than short incubation periods, with the 25th centile and the median of the serial interval shorter than the incubation period. For the ICC and ICRTC models, the corresponding estimates ranged from 1.8 days (95% credible interval 1.5 to 1.8) to 1.6 days (1.4 to 1.6) shorter at the 25th centile and 1.6 days (1.5 to 1.7) to 0.8 days (0.3 to 1.2) shorter at the median. 10 out of 13 linked patients had documented pre-symptomatic transmission. Doubling times of cases declined from 9.07 days (95% confidence interval 12.63 to 7.08) on the 6 May, when the first case of monkeypox was reported in the UK, to a halving time of 29 days (95% confidence interval 38.02 to 23.44) on 1 August.ConclusionsAnalysis of the instantaneous growth rate of monkeypox incidence indicates that the epidemic peaked in the UK as of 9 July and then started to decline. Short serial intervals were more common than short incubation periods suggesting considerable pre-symptomatic transmission, which was validated through linked patient level records. For patients who could be linked through personally identifiable data, four days was the maximum time that transmission was detected before symptoms manifested. An isolation period of 16 to 23 days would be required to detect 95% of people with a potential infection. The 95th centile of the serial interval was between 23 and 41 days, suggesting long infectious periods.
Useful materials must satisfy multiple objectives, where the optimization of one objective is often at the expense of another. The Pareto front reports the optimal trade-offs between these ...conflicting objectives. Here we use a self-driving laboratory, Ada, to define the Pareto front of conductivities and processing temperatures for palladium films formed by combustion synthesis. Ada discovers new synthesis conditions that yield metallic films at lower processing temperatures (below 200 °C) relative to the prior art for this technique (250 °C). This temperature difference makes possible the coating of different commodity plastic materials (e.g., Nafion, polyethersulfone). These combustion synthesis conditions enable us to to spray coat uniform palladium films with moderate conductivity (1.1 × 10
S m
) at 191 °C. Spray coating at 226 °C yields films with conductivities (2.0 × 10
S m
) comparable to those of sputtered films (2.0 to 5.8 × 10
S m
). This work shows how a self-driving laboratoy can discover materials that provide optimal trade-offs between conflicting objectives.
Ocean warming and acidification threaten the future growth of coral reefs. This is because the calcifying coral reef taxa that construct the calcium carbonate frameworks and cement the reef together ...are highly sensitive to ocean warming and acidification. However, the global-scale effects of ocean warming and acidification on rates of coral reef net carbonate production remain poorly constrained despite a wealth of studies assessing their effects on the calcification of individual organisms. Here, we present global estimates of projected future changes in coral reef net carbonate production under ocean warming and acidification. We apply a meta-analysis of responses of coral reef taxa calcification and bioerosion rates to predicted changes in coral cover driven by climate change to estimate the net carbonate production rates of 183 reefs worldwide by 2050 and 2100. We forecast mean global reef net carbonate production under representative concentration pathways (RCP) 2.6, 4.5, and 8.5 will decline by 76, 149, and 156%, respectively, by 2100. While 63% of reefs are projected to continue to accrete by 2100 under RCP2.6, 94% will be eroding by 2050 under RCP8.5, and no reefs will continue to accrete at rates matching projected sea level rise under RCP4.5 or 8.5 by 2100. Projected reduced coral cover due to bleaching events predominately drives these declines rather than the direct physiological impacts of ocean warming and acidification on calcification or bioerosion. Presently degraded reefs were also more sensitive in our analysis. These findings highlight the low likelihood that the world's coral reefs will maintain their functional roles without near-term stabilization of atmospheric CO
emissions.
Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger ...than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (ETV6) with neurotrophic tyrosine kinase receptor, type 3 (NTRK3) and fusion of acylglycerol kinase (AGK) with BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. Fusion oncogenes were less prevalent in tumors from a cohort of children with pediatric thyroid cancers that had not been exposed to radiation but were from the same geographical regions. Radiation-induced thyroid cancers provide a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.
Early assessments of the growth rate of COVID-19 were subject to significant uncertainty, as expected with limited data and difficulties in case ascertainment, but as cases were recorded in multiple ...countries, more robust inferences could be made. Using multiple countries, data streams and methods, we estimated that, when unconstrained, European COVID-19 confirmed cases doubled on average every 3 days (range 2.2-4.3 days) and Italian hospital and intensive care unit admissions every 2-3 days; values that are significantly lower than the 5-7 days dominating the early published literature. Furthermore, we showed that the impact of physical distancing interventions was typically not seen until at least 9 days after implementation, during which time confirmed cases could grow eightfold. We argue that such temporal patterns are more critical than precise estimates of the time-insensitive basic reproduction number
for initiating interventions, and that the combination of fast growth and long detection delays explains the struggle in countries' outbreak response better than large values of
alone. One year on from first reporting these results, reproduction numbers continue to dominate the media and public discourse, but robust estimates of unconstrained growth remain essential for planning worst-case scenarios, and detection delays are still key in informing the relaxation and re-implementation of interventions. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.
ABSTRACT We present the sixth catalog of Kepler candidate planets based on nearly four years of high precision photometry. This catalog builds on the legacy of previous catalogs released by the ...Kepler project and includes 1493 new Kepler Objects of Interest (KOIs) of which 554 are planet candidates, and 131 of these candidates have best-fit radii . This brings the total number of KOIs and planet candidates to 7348 and 4175 respectively. We suspect that many of these new candidates at the low signal-to-noise ratio limit may be false alarms created by instrumental noise, and discuss our efforts to identify such objects. We re-evaluate all previously published KOIs with orbital periods of days to provide a consistently vetted sample that can be used to improve planet occurrence rate calculations. We discuss the performance of our planet detection algorithms, and the consistency of our vetting products. The full catalog is publicly available at the NASA Exoplanet Archive.
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