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CRISPR/Cas13-Based Methods for Ultrasensitive and Specific Diagnosis regarding microRNAs.
The results suggest that the two groups of NSIAD mutations represent two distinct molecular mechanisms of constitutive activation in GPCRs.An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Investigations into the nature of platelet functional variety and consequences for homeostasis require new methods for resolving single platelet phenotypes. Here we combine droplet microfluidics with flow cytometry for high throughput single platelet function analysis. A large-scale sensitivity continuum was shown to be a general feature of human platelets from individual donors, with hypersensitive platelets coordinating significant sensitivity gains in bulk platelet populations and shown to direct aggregation in droplet-confined minimal platelet systems. buy NVP-BGT226 Sensitivity gains scaled with agonist potency (convulxin > TRAP-14>ADP) and reduced the collagen and thrombin activation threshold required for platelet population polarization into pro-aggregatory and pro-coagulant states. The heterotypic platelet response results from an intrinsic behavioural program. The method and findings invite future discoveries into the nature of hypersensitive platelets and how community effects produce population level responses in health and disease.Photoacoustic endoscopy (PAE) is a method of in-vivo imaging that uses tissue absorption properties. In PAE, the main tools used to detect the acoustic signal are mechanical ultrasound transducers, which require direct contact and which are difficult to miniaturize. All-optic photoacoustic sensors can challenge this issue as they can provide contact-free sensing. Here, we demonstrate sensing of photo-acoustic signals through a multimode fiber (MMF) which can provide an ultra-thin endoscopic photoacoustic sensor. Furthermore, we show the advantage of using the optical-flow method for speckle sensing and extract the photoacoustic signal despite the mode-mixing along the MMF. Moreover, it is demonstrated for the first time that the speckle reconstruction method can be used without the need for imaging of the speckles as this enables the use of multimode fibers for the speckle method.Purpose Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P less then 10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.Purpose Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. Methods We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. Results We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. Conclusions We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The biological processes that are associated with the physiological fitness state of a cell comprise a diverse set of molecular events. Reactive oxygen species (ROS), mitochondrial dysfunction, telomere shortening, genomic instability, epigenetic changes, protein aggregation, and down-regulation of quality control mechanisms are all hallmarks of cellular decline. Stress-related and decline-related changes can be assayed, but usually through means that are highly disruptive to living cells and tissues. Biomarkers for organismal decline and aging are urgently needed for diagnostic and drug development. Our goal in this study is to provide a proof-of-concept for a non-invasive assay of global molecular events in the cytoplasm of living animals. We show that Microwave Dielectric Spectroscopy (MDS) can be used to determine the hydration state of the intracellular environment in live C. elegans worms. MDS spectra were correlative with altered states in the cellular protein folding environment known to be associated with previously described mutations in the C.
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