Non-cross-linking gold nanoparticle aggregation as a detection method for single-base substitutions

Aggregation of DNA-modified gold nanoparticles in a non-cross-linking configuration has extraordinary selectivity against terminal mismatch of the surface-bound duplex. In this paper, we demonstrate the utility of this selectivity for detection of single-base substitutions. The samples were prepared through standard protocols: DNA extraction, PCR amplification and single-base primer extension. Oligonucleotide-modified nanoparticles correctly responded to the unpurified products from the primer extension: aggregation for the full match and dispersion for all the mismatches. Applicability of this method to genomic DNA was tested with five human tumor cell lines, and verified by conventional technologies: mass spectrometry and direct sequencing. Unlike the existing methods for single-base substitution analysis, this method does not need specialized equipments, and opens up a new possibility of point-of-care diagnosis for single-nucleotide polymorphisms

Model-Free Idealization: Adaptive Integrated Approach for Idealization of Ion Channel Currents (AI2)

Single-channel electrophysiological recordings provide insights into transmembrane ion permeation and channel gating mechanisms. The first step in the analysis of the recorded currents involves an "idealization" process, in which noisy raw data are classified into two discrete levels corresponding to the open and closed states of channels. This provides valuable information on the gating kinetics of ion channels. However, the idealization step is often challenging in cases of currents with poor signal-to-noise ratios (SNR) and baseline drifts, especially when the gating model of the target channel is not identified. We report herein on a highly robust model-free idealization method for achieving this goal. The algorithm, called AI2 (Adaptive Integrated Approach for the Idealization of Ion Channel Currents), is composed of Kalman filter and Gaussian Mixture Model (GMM) clustering and functions without user input. AI2 automatically determines the noise reduction setting based on the degree of separation between the open and closed levels. We validated the method on pseudo-channel-current datasets which contain either computed or experimentally recorded noise. The AI2 algorithm was then tested on actual experimental data for biological channels including gramicidin A, a voltage-gated sodium channel, and other unidentified channels. We compared the idealization results with those obtained by the conventional methods, including the 50%-threshold-crossing method

Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness

Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs

Ancient Jomon genome sequence analysis sheds light on migration patterns of early East Asian populations

Anatomically modern humans reached East Asia more than 40,000 years ago. However, key questions still remain unanswered with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of the region may elucidate a more detailed picture of the peopling of East Eurasia. Here, we analyze the whole-genome sequence of a 2,500-year-old individual (IK002) from the main-island of Japan that is characterized with a typical Jomon culture. The phylogenetic analyses support multiple waves of migration, with IK002 forming a basal lineage to the East and Northeast Asian genomes examined, likely representing some of the earliest-wave migrants who went north from Southeast Asia to East Asia. Furthermore, IK002 shows strong genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration. This study highlights the power of ancient genomics to provide new insights into the complex history of human migration into East Eurasia

Genome-wide SNP analysis reveals population structure and demographic history of the ryukyu islanders in the southern part of the Japanese archipelago.

The Ryukyu Islands are located to the southwest of the Japanese archipelago. Archaeological evidence has revealed the existence of prehistoric cultural differentiation between the northern Ryukyu islands of Amami and Okinawa, and the southern Ryukyu islands of Miyako and Yaeyama. To examine a genetic subdivision in the Ryukyu Islands, we conducted genome-wide single nucleotide polymorphism typing of inhabitants from the Okinawa Islands, the Miyako Islands, and the Yaeyama Islands. Principal component and cluster analyses revealed genetic differentiation among the island groups, especially between Okinawa and Miyako. No genetic affinity was observed between aboriginal Taiwanese and any of the Ryukyu populations. The genetic differentiation observed between the inhabitants of the Okinawa Islands and the Miyako Islands is likely to have arisen due to genetic drift rather than admixture with people from neighboring regions. Based on the observed genetic differences, the divergence time between the inhabitants of Okinawa and Miyako islands was dated to the Holocene. These findings suggest that the Pleistocene inhabitants, whose bones have been found on the southern Ryukyu Islands, did not make a major genetic contribution, if any, to the present-day inhabitants of the southern Ryukyu Islands

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection