Truncating mutations in filamin C (
) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and ...structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere structural integrity, and likely nuclear function. Our previous study showed that the transcriptional profiles of
homozygous deletions in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly comparable to the transcriptome profiles of hiPSC-CMs from patients with
truncating mutations. Therefore, in this study, we used CRISPR-Cas-engineered hiPSC-derived
knockout cardiac myocytes as a model of FLNC cardiomyopathy to determine pathogenic mechanisms and to examine structural changes caused by FLNC deficiency. RNA sequencing data indicated the significant upregulation of focal adhesion signaling and the dysregulation of thin filament genes in
-knockout (FLNC
) hiPSC-CMs compared to isogenic hiPSC-CMs. Furthermore, our findings suggest that the complete loss of FLNC in cardiomyocytes led to cytoskeletal defects and the activation of focal adhesion kinase. Pharmacological inhibition of PDGFRA signaling using crenolanib (an FDA-approved drug) reduced focal adhesion kinase activation and partially normalized the focal adhesion signaling pathway. The findings from this study suggest the opportunity in repurposing FDA-approved drug as a therapeutic strategy to treat FLNC cardiomyopathy.
Antimicrobial resistance (AMR) is a major concern facing global health today, with the greatest impact in developing countries where the burden of infectious diseases is much higher. The ...inappropriate prescribing and use of antibiotics are contributory factors to increasing antibiotic resistance. Antimicrobial stewardship programmes (AMS) are implemented to optimise use and promote behavioural change in the use of antimicrobials. AMS programmes have been widely employed and proven to improve antibiotic use in many high-income settings. However, strategies to contain antimicrobial resistance have yet to be successfully implemented in low-resource settings. A recent toolkit for AMS in low- and middle-income countries by the World Health Organisation (WHO) recognizes the importance of local context in the development of AMS programmes. This study employed a bottom-up approach to identify important local determinants of antimicrobial prescribing practices in a low-middle income setting, to inform the development of a local AMS programme. Analysis of prescribing practices and interviews with prescribers highlighted priorities for AMS, which include increasing awareness of antibiotic resistance, development and maintenance of guidelines for antibiotic use, monitoring and surveillance of antibiotic use, ensuring the quality of low-cost generic medicines, and improved laboratory services. The application of an established theoretical model for behaviour change guided the development of specific proposals for AMS. Finally, in a consultation with stakeholders, the feasibility of the plan was explored along with strategies for its implementation. This project provides an example of the design, and proposal for implementation of an AMS plan to improve antibiotic use in hospitals in low-middle income settings.
1 Centre for Molecular Microbiology and Infectious Diseases, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK
2 School of Geography, Archaeology and Palaeoecology, Queen's ...University Belfast, Belfast BT7 1NN, UK
3 Department of Genetics, Institute of Child Health, University College London, London WC1N 1EH, UK
4 Peter the Great Museum of Anthropology and Ethnography (Kunstkamera), 3 University Embankment, St Petersburg 199034, Russia
Correspondence G. Michael Taylor gm.taylor{at}ucl.ac.uk
Tuberculosis has plagued humankind since prehistoric times, as is evident from characteristic lesions on human skeletons dating back to the Neolithic period. The disease in man is due predominantly to infection with either Mycobacterium tuberculosis or Mycobacterium bovis , both members of the M. tuberculosis (MTB) complex. A number of studies have shown that when conditions permit, surviving mycobacterial DNA may be amplified from bone by PCR. Such ancient DNA (aDNA) analyses are subject to stringent tests of authenticity and, when feasible, are invariably limited by DNA fragmentation. Using PCRs based on single-nucleotide polymorphic loci and regions of difference (RDs) in the MTB complex, a study was made of five Iron Age individuals with spinal lesions recovered from the cemetery of Aymyrlyg, South Siberia. A sensitive screening PCR for MTB complex mycobacteria was positive in four out of the five cases. Genotyping evidence indicated that all four cases were due to infection with M. bovis rather than M. tuberculosis and the data were consistent with the proposed phylogenetic model of the MTB complex. This is believed to be the first report of M. bovis causing Pott's disease in archaeological human remains. The study shows that genotyping of ancestral strains of MTB complex mycobacteria from contexts of known date provides information which allows the phylogeny of the model to be tested. Moreover, it shows that loss of DNA from RD4, which defines classic M. bovis , had already occurred from the genome over 2000 years before the present.
Abbreviations: aDNA, ancient DNA; AMS, accelerator mass spectroscopy; BP, before the present; DR, direct repeat; MTB complex, Mycobacterium tuberculosis complex; RD, region of difference
Present address: Centre for Infectious Diseases and International Health, Windeyer Institute, University College London, 46 Cleveland Street, London W1T 4JF, UK.
Introduction
Primary succession on glacial forelands is increasingly relevant as rapid glacial retreat is exposing growing land areas to plant colonization. We investigated temporal trends, controls, ...and outcomes in floral succession on a subarctic glacial foreland. Specifically, we examined changes in community composition (mosses, low shrubs, forbs, trees, and graminoids) over long-term (decadal) and short-term (< 10 years) scales and attempted to identify the underlying processes responsible for the observed successional patterns.
Methods
The study area was the foreland of the Skaftafellsjӧkull, located in Vatnajӧkull National Park near the south coast of Iceland. We established nine transect lines at varying distances from the ice front representing surfaces of age ranging from less than one decade to over 100 years. Each transect consisted of five measurement stations of 1 m
2
where we measured vegetative cover (VC), species richness (SR), and species density (SD) and calculated species evenness (SE). Measurements were made initially in 2007 and repeated at the same geographic coordinates in 2014.
Results
VC increased with distance from the ice front from 16% to over 90%. SR and SD increased from the youngest pioneer community through a mid-successional stage corresponding to an age of over 60 but less than 100 years. Increased VC but declining SR, SD, and SE characterized the oldest (over 100 years) bryophyte-dominated surfaces. Species turnover, which involved forbs almost exclusively, increased moderately from early through mid-successional sites and declined on older sites. Comparison of the measurements made in 2014 to those made in 2007 demonstrates increased SR at mid-successional sites while SD remained relatively constant.
Conclusion
At a small scale, colonization is controlled by local factors such as microtopography and aspect, particularly in proximity to the glacier. At the landscape level, changes in VC and community structure are controlled by time and nutrient availability. Low nutrient levels and limited site availability favor bryophyte dominance on the oldest surfaces. The greatest community-level changes observed over the 7-year interval were increases in surface cover by mosses and low shrubs, particularly in mid-successional and older sites. These changes suggest that the community on the oldest surfaces has not yet reached equilibrium.
To test different forms of private insurance coverage as mediators for racial disparities in onset, persistent level, and acceleration of functional limitations among Medicare age-eligible Americans.
...Data come from 7 waves of the Health and Retirement Study (1996-2008). Onset and progression latent growth models were used to estimate racial differences in onset, level, and growth of functional limitations among a sample of 5,755 people aged 65 and older in 1996. Employer-provided insurance, spousal insurance, and market insurance were next added to the model to test how differences in private insurance mediated the racial gap in physical limitations.
In baseline models, African Americans had larger persistent level of limitations over time. Although employer-provided, spousal provided, and market insurances were directly associated with lower persistent levels of limitation, only differences in market insurance accounted for the racial disparities in persistent level of limitations.
Results suggest private insurance is important for reducing functional limitations, but market insurance is an important mediator of the persistently larger level of limitations observed among African Americans.
Purpose
To quantify the influence of RS assay on changing chemotherapy plans in a general practice setting using causal inference methods.
Methods
We surveyed 3880 newly diagnosed breast cancer ...patients in Los Angeles and Georgia in 2013–14. We used inverse propensity weighting and multiple imputations to derive complete information for each patient about treatment status with and without testing.
Results
A half of the 1545 women eligible for testing (ER+ or PR+, HER2−, and stage I–II) received RS. We estimate that 30% (95% confidence interval (CI) 10–49%) of patients would have changed their treatment selections after RS assay, with 10% (CI 0–20%) being encouraged to undergo chemotherapy and 20% (CI 10–30%) being discouraged from chemotherapy. The subgroups whose treatment selections would be changed the most by RS were patients with positive nodes (44%; CI 24–64%), larger tumor (43% for tumor size >2 cm; CI 23–62%), or younger age (41% for <50 years, CI 23–58%). The assay was associated with a net reduction in chemotherapy use by 10% (CI 4–16%). The reduction was much greater for women with positive nodes (31%; CI 21–41%), larger tumor (30% for tumor size >2 cm; CI 22–38%), or younger age (22% for <50 years; CI 9–35%).
Conclusion
RS substantially changed chemotherapy treatment selections with the largest influence among patients with less favorable pre-test prognosis. Whether this is optimal awaits the results of clinical trials addressing the utility of RS testing in selected subgroups.
There are minimal data in the literature regarding the lymphatic drainage of the conjunctiva and lower eyelid and the relationship with postoperative chemosis and edema.
Injection, microdissection, ...and histologic and radiologic studies were conducted on 12 hemifacial fresh cadaver specimens. Indocyanine green lymphography was conducted in five volunteers.
Histology identified lymphatic vessels superficial and deep to the orbicularis oculi. Cadaveric dissection, injection, and radiographic studies identified interconnecting superficial and deep facial lymphatic systems and a conjunctival lymphatic network draining through the tarsal plate to the deep lymphatic system. The superficial lymphatic collectors traveled in subcutaneous fat within the lateral orbital and nasolabial fat compartments. The lateral deep lymphatic collectors traveled beneath orbicularis oculi, then through the superficial orbicularis retaining ligament, and into the sub-orbicularis oculi fat in the roof of the prezygomatic space. These vessels descended to preperiosteal fat at the level of zygomaticocutaneous ligaments to travel adjacent to the facial nerve into preauricular nodes. Indocyanine green lymphography identified correlating draining pathways laterally to the parotid nodes and medially to submandibular nodes.
The authors have found that the lower eyelid and conjunctiva are drained by interconnecting superficial and deep lymphatic systems of the face. The superficial system is vulnerable to damage in incisions and dissection in the infraorbital area. The deep system is vulnerable to damage in dissection around the orbicularis retaining ligament and the zygomaticocutaneous ligaments. The authors suggest that concurrent damage to both the superficial and deep lymphatic systems, especially laterally, may be responsible for postoperative chemosis and edema.
Forest dynamics and tree species composition vary substantially between Paleotropical and Neotropical forests, but these broad biogeographic regions are treated uniformly in many land models. To ...assess whether these regional differences translate into variation in productivity and carbon (C) storage, we compiled a database of climate, tree stem growth, litterfall, aboveground net primary production (ANPP), and aboveground biomass across tropical rainforest sites spanning 33 countries throughout Central and South America, Asia, and Australasia, but excluding Africa due to a paucity of available data. Though the sum of litterfall and stem growth (ANPP) did not differ between regions, both stem growth and the ratio of stem growth to litterfall were higher in Paleotropical forests compared to Neotropical forests across the full observed range of ANPP. Greater C allocation to woody growth likely explains the much larger aboveground biomass estimates in Paleotropical forests (∼29%, or ∼80 Mg DW/ha, greater than in the Neotropics). Climate was similar in Paleo- and Neotropical forests, thus the observed differences in C likely reflect differences in the evolutionary history of species and forest structure and function between regions. Our analysis suggests that Paleotropical forests, which can be dominated by tall-statured Dipterocarpaceae species, may be disproportionate hotspots for aboveground C storage. Land models typically treat these distinct tropical forests with differential structures as a single functional unit, but our findings suggest that this may overlook critical biogeographic variation in C storage potential among regions.
Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence ...of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C→T) and 1,298 (A→C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07-0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20-1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.
•We propose a new algorithm for correcting susceptibility distortions in high-resolution fMRI scans, using a T1 weighted image and two inverse phase-encoding EPI images.•The robustness of the ...proposed algorithm is increased by using regularization parameters that are automatically selected via Bayesian optimization.•Compared with two state-of-the-art methods (TOPUP and HySCO), the proposed method runs significantly faster while achieving a similar correction accuracy.•It also provides a better alignment of the BOLD responses to the T1w image, and produces less image blur compared to the existing methods.•The proposed method is suitable for several high-resolution fMRI applications, including retinotopic mapping and BOLD localization.
Functional magnetic resonance imaging (fMRI) enables non-invasive examination of both the structure and the function of the human brain. The prevalence of high spatial-resolution (sub-millimeter) fMRI has triggered new research on the intra-cortex, such as cortical columns and cortical layers. At present, echo-planar imaging (EPI) is used exclusively to acquire fMRI data; however, susceptibility artifacts are unavoidable. These distortions are especially severe in high spatial-resolution images and can lead to misrepresentation of brain function in fMRI experiments.
This paper presents a new method for correcting susceptibility artifacts by combining a T1-weighted (T1w) image and inverse phase-encoding (PE) based registration. The latter uses two EPI images acquired using identical sequences but with inverse-PE directions. In the proposed method, the T1w image is used to regularize the registration, and to select the regularization parameters automatically. The motivation is that the T1w image is considered to reflect the anatomical structure of the brain.
Our proposed method is evaluated on two sub-millimeter EPI-fMRI datasets, acquired using 3T and 7T scanners. Experiments show that the proposed method provides improved corrections that are well-aligned to the T1w image.
The proposed method provides more robust and sharper corrections and runs faster compared with two other state-of-the-art inverse-PE based correction methods, i.e. HySCO and TOPUP.
The proposed correction method used the T1w image as a reference in the inverse-PE registration. Results show its promising performance. Our proposed method is timely, as sub-millimeter fMRI has become increasingly popular.
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