Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in PulseNet International. ...PNLA&C laboratories use common molecular techniques to track pathogens causing foodborne illness. We aimed to demonstrate the possibility and advantages of transitioning to whole genome sequencing (WGS) for surveillance within existing networks across a continent where S. sonnei is endemic.
We applied WGS to representative archive isolates of S. sonnei (n = 323) from laboratories in nine PNLA&C countries to generate a regional phylogenomic reference for S. sonnei and put this in the global context. We used this reference to contextualise 16 S. sonnei from three Argentinian outbreaks, using locally generated sequence data. Assembled genome sequences were used to predict antimicrobial resistance (AMR) phenotypes and identify AMR determinants.
S. sonnei isolates clustered in five Latin American sublineages in the global phylogeny, with many (46%, 149 of 323) belonging to previously undescribed sublineages. Predicted multidrug resistance was common (77%, 249 of 323), and clinically relevant differences in AMR were found among sublineages. The regional overview showed that Argentinian outbreak isolates belonged to distinct sublineages and had different epidemiologic origins.
Latin America contains novel genetic diversity of S. sonnei that is relevant on a global scale and commonly exhibits multidrug resistance. Retrospective passive surveillance with WGS has utility for informing treatment, identifying regionally epidemic sublineages and providing a framework for interpretation of prospective, locally sequenced outbreaks.
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Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations
. RMC-7977 is a highly selective inhibitor of the ...active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants
. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS
. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.
Essential Medical Genetics Tobias, Edward S; Connor, Michael; Smith, Malcolm Ferguson
2011, 2011., 2011/01/01, 2011-11-15, 2011-11-22, Volume:
22
eBook
Adopted at Cambridge UniversityEssential Medical Genetics provides students, clinicians, counsellors and scientists with the up-to-date information they need regarding the basic principles underlying ...medical genetics. It also provides guidance on how to apply current knowledge in clinical contexts, covering a wide variety of topics: from genome structure and function to mutations, screening and risk assessment for inherited disorders.This sixth edition has been substantially updated to include, for instance, the latest information on the Human Genome Project as well as several new molecular genetic and chromosome analysis techniques.In full colour throughout, it includes a number of brand new features, including: a large number of self-assessment questions; 'Essentials' chapter summaries; further reading suggestions; and case study scenarios introducing clinical situations. An invaluable new section gives illustrated practical advice regarding how to choose the best available online genetic databases and also, importantly, how to most easily and most efficiently use them, for a wide range of purposes.Essential Medical Geneticsis the perfect resource for a course on medical genetics, and is now accompanied by a regularly updated website and the FREE enhanced Wiley Desktop Edition (upon purchase of the book).The companion website at www.wiley.com/go/tobiasfeatures figures from the book in PowerPoint format and a link to the authors' website with regularly updated links to genetic databases and additional self-test questions.
Most tests of cognitive behavioral therapy (CBT) for youth anxiety disorders have shown beneficial effects, but these have been efficacy trials with recruited youths treated by researcher-employed ...therapists. One previous (nonrandomized) trial in community clinics found that CBT did not outperform usual care (UC). The present study used a more stringent effectiveness design to test CBT versus UC in youths referred to community clinics, with all treatment provided by therapists employed in the clinics.
A randomized controlled trial methodology was used. Therapists were randomized to training and supervision in the Coping Cat CBT program or UC. Forty-eight youths (56% girls, 8 to 15 years of age, 38% Caucasian, 33% Latino, 15% African-American) diagnosed with DSM-IV anxiety disorders were randomized to CBT or UC.
At the end of treatment more than half the youths no longer met criteria for their primary anxiety disorder, but the groups did not differ significantly on symptom (e.g., parent report, eta-square = 0.0001; child report, eta-square = 0.09; both differences favoring UC) or diagnostic (CBT, 66.7% without primary diagnosis; UC, 73.7%; odds ratio 0.71) outcomes. No differences were found with regard to outcomes of comorbid conditions, treatment duration, or costs. However, youths receiving CBT used fewer additional services than UC youths (χ(2)(1) = 8.82, p = .006).
CBT did not produce better clinical outcomes than usual community clinic care. This initial test involved a relatively modest sample size; more research is needed to clarify whether there are conditions under which CBT can produce better clinical outcomes than usual clinical care. CLINICAL TRIAL REGISTRY INFORMATION: Community Clinic Test of Youth Anxiety and Depression Study, URL: http://clinicaltrials.gov, unique identifier: NCT01005836.
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage ...analysis and identified an identical heterozygous mutation (617G → A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.NOTE: In the version of this article initially published, several contributing authors were listed collectively under the name The International FOP Research Consortium. In order to facilitate the electronic citation of author contributions, the authors have chosen to delete the Consortium name and replace it with the names of the individual consortium authors in alphabetical order. This error has been corrected in the HTML and PDF versions of the article.
The Close AGN Reference Survey (CARS) Smirnova-Pinchukova, I.; Husemann, B.; Davis, T. A. ...
Astronomy and astrophysics (Berlin),
03/2022, Volume:
659
Journal Article
Peer reviewed
Open access
Context.
Active galactic nuclei (AGN) are thought to be responsible for the suppression of star formation in massive ∼10
10
M
⊙
galaxies. While this process is a key feature in numerical ...simulations of galaxy formation, it has not been unambiguously confirmed in observational studies yet.
Aims.
The characterization of the star formation rate (SFR) in AGN host galaxies is challenging as AGN light contaminates most SFR tracers. Furthermore, the various SFR tracers are sensitive to different timescales of star formation from approximately a few to 100 Myr. We aim to obtain and compare SFR estimates from different tracers for AGN host galaxies in the Close AGN Reference Survey (CARS) to provide new observational insights into the recent SFR history of those systems.
Methods.
We constructed integrated panchromatic spectral energy distributions to measure the far infrared (FIR) luminosity as a tracer for the recent (< 100 Myr) SFR. In addition we used the integral-field unit observation of the CARS targets to employ the H
α
luminosity decontaminated by AGN excitation as a proxy for the current (< 5 Myr) SFR.
Results.
We find that significant differences in specific SFR of the AGN host galaxies as compared with the larger galaxy population disappear once cold gas mass, in addition to stellar mass, is used to predict the SFR for a specific AGN host. Only a tentative trend with the inclination of the host galaxy remains, such that SFR appears slightly lower than expected when the galaxies of unobscured AGN appear more edge-on along our line-of-sight, particular for dust-insensitive FIR-based SFRs. We identify individual galaxies with a significant difference in their SFR which can be related to a recent enhancement or decline in their SFR history that might be related to various processes including interactions, gas consumption, outflows, and AGN feedback.
Conclusions.
AGN can be present in various stages of galaxy evolution which makes it difficult to relate the SFR solely to the impact of the AGN. Our study shows that stellar mass alone is an insufficient parameter to estimate the expected SFR of an AGN host galaxy compared to the underlying non-AGN galaxy population. We do not find any strong evidence for a global positive or negative AGN feedback in the CARS sample. However, there is tentative evidence that (1) the relative orientation of the AGN engine with respect to the host galaxies might alter the efficiency of AGN feedback and that (2) the recent SFH is an additional tool to identify rapid changes in galaxy growth driven by the AGN or other processes.
The NuMI neutrino beam Adamson, P.; Andrews, R.; Augustine, D. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
01/2016, Volume:
806
Journal Article
Peer reviewed
Open access
This paper describes the hardware and operations of the Neutrinos at the Main Injector (NuMI) beam at Fermilab. It elaborates on the design considerations for the beam as a whole and for individual ...elements. The most important design details of individual components are described. Beam monitoring systems and procedures, including the tuning and alignment of the beam and NuMI long-term performance, are also discussed.
A role for altered iron metabolism in the pathogenesis of Alzheimer's disease has been suggested by several reports associating the cardinal neuropathologic lesions with markers of free ...radical-induced damage and redox-active iron. We hypothesized that the abnormal distribution of iron in Alzheimer brain might result from alterations in iron regulatory proteins (IRP) such as IRP-1 and IRP-2, the main control elements of cellular iron homeostasis. Here, we report that while IRP-1 is present at similar levels in both Alzheimer and control brain tissue, IRP-2 shows striking differences and is associated with intraneuronal lesions, including neurofibrillary tangles, senile plaque neurites and neuropil threads. Since IRP-2 colocalizes with redox-active iron, our results suggest that alterations in IRP-2 might be directly linked to impaired iron homeostasis in Alzheimer's disease.
Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all ...genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.
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