The vast majority of genome-wide association study (GWAS) risk loci fall in non-coding regions of the genome. One possible hypothesis is that these GWAS risk loci alter the individual’s disease risk ...through their effect on gene expression in different tissues. In order to understand the mechanisms driving a GWAS risk locus, it is helpful to determine which gene is affected in specific tissue types. For example, the relevant gene and tissue could play a role in the disease mechanism if the same variant responsible for a GWAS locus also affects gene expression. Identifying whether or not the same variant is causal in both GWASs and expression quantitative trail locus (eQTL) studies is challenging because of the uncertainty induced by linkage disequilibrium and the fact that some loci harbor multiple causal variants. However, current methods that address this problem assume that each locus contains a single causal variant. In this paper, we present eCAVIAR, a probabilistic method that has several key advantages over existing methods. First, our method can account for more than one causal variant in any given locus. Second, it can leverage summary statistics without accessing the individual genotype data. We use both simulated and real datasets to demonstrate the utility of our method. Using publicly available eQTL data on 45 different tissues, we demonstrate that eCAVIAR can prioritize likely relevant tissues and target genes for a set of glucose- and insulin-related trait loci.
This study focuses on different iron regulation mechanisms of glioblastoma (GBM) cancer stem‐like cells (CSCs) and non‐stem tumor cells (NSTCs) using multiple approaches: cell viability, density, and ...magnetophoresis. GBM CSCs and NSTCs were exposed to elevated iron concentration, and their magnetic susceptibility was measured using single cell magnetophoresis (SCM), which tracks the magnetic and settling velocities of thousands of individual cells passing through the magnetic field with a constant energy gradient. Our results consistently demonstrate that GBM NSTCs have higher magnetic susceptibility distribution at increased iron concentration compared with CSCs, and we speculate that it is because CSCs have the ability to store a high amount of iron in ferritin, whereas the free iron ions inside the NSTCs lead to higher magnetic susceptibility and reduced cell viability and growth. Further, their difference in magnetic susceptibility has led us to pursue a separate experiment using a quadrupole magnetic separator (QMS), a novel microfluidic device that uses a concentric channel and permanent magnets in a special configuration to separate samples based on their magnetic susceptibilities. GBM CSCs and NSTCs were exposed to elevated iron concentration, stained with two different trackers, mixed and introduced into QMS; subsequently, the separated fractions were analyzed by fluorescent microscopy. The separation results portray a successful label‐less magnetic separation of the two populations.
This study explores the iron regulation mechanism of the glioblastoma (GBM) cancer stem cells (CSCs) and non‐stem tumor cells (NSTCs), yielding various questions regarding the iron‐storage methods of these cancer cells as well as feasibility to magnetically separate unlabeled, iron‐rich GBM CSCs and NSTCs using a novel magnetic separation system, a quadrupole magnetic sorter.
In standard genome-wide association studies (GWAS), the standard association test is underpowered to detect associations between loci with multiple causal variants with small effect sizes. We propose ...a statistical method, Model-based Association test Reflecting causal Status (MARS), that finds associations between variants in risk loci and a phenotype, considering the causal status of variants, only requiring the existing summary statistics to detect associated risk loci. Utilizing extensive simulated data and real data, we show that MARS increases the power of detecting true associated risk loci compared to previous approaches that consider multiple variants, while controlling the type I error.
Oxygen intrusion into the anode chamber through proton exchange membrane can result in positive redox conditions in fed-batch, two chamber MFCs at the end of a cycle when the substrate is depleted. A ...slight increase in dissolved oxygen to 0.3 mg/L during MFC operation was not found to adversely affect power generation over subsequent cycles if sufficient substrate (acetate) was provided. Purging the anode chamber with air or pure oxygen for up to 10 days and 10 hrs also did not affect power generation, as power rapidly returned to previous levels when the chamber was sparged with nitrogen gas. When MFCs are connected in series, voltage reversal can occur resulting in a positive voltage applied to the anode biofilm. To investigate if this adversely affected the bacteria, voltages of 1, 2, 3, 4, and 9 V, were applied for 1 hr to the MFC before reconnecting it back to a fixed external load (1,000 Omega). A voltage of <2 V did not affect power generation. However, applying 3 V resulted in a 15 h lag phase before recovery, and 9 V produced a 60 h lag phase suggesting substantial damage to the bacteria that required re-growth of bacteria in the biofilm. These results indicate that charge reversal will be a more serious problem than oxygen intrusion into the anode chamber for sustained performance of MFCs.
Researchers have long studied the regulatory processes of genes to uncover their functions. Gene regulatory network analysis is one of the popular approaches for understanding these processes, ...requiring accurate identification of interactions among the genes to establish the gene regulatory network. Advances in genome-wide association studies and expression quantitative trait loci studies have led to a wealth of genomic data, facilitating more accurate inference of gene-gene interactions. However, unknown confounding factors may influence these interactions, making their interpretation complicated. Mendelian randomization (MR) has emerged as a valuable tool for causal inference in genetics, addressing confounding effects by estimating causal relationships using instrumental variables. In this paper, we propose a new statistical method, MR-GGI, for accurately inferring gene-gene interactions using Mendelian randomization.
MR-GGI applies one gene as the exposure and another as the outcome, using causal cis-single-nucleotide polymorphisms as instrumental variables in the inverse-variance weighted MR model. Through simulations, we have demonstrated MR-GGI's ability to control type 1 error and maintain statistical power despite confounding effects. MR-GGI performed the best when compared to other methods using the F1 score on the DREAM5 dataset. Additionally, when applied to yeast genomic data, MR-GGI successfully identified six clusters. Through gene ontology analysis, we have confirmed that each cluster in our study performs distinct functional roles by gathering genes with specific functions.
These findings demonstrate that MR-GGI accurately inferences gene-gene interactions despite the confounding effects in real biological environments.
This experimental study reports on forced convective heat transfer in a highly porous cellular material, wire-woven bulk Kagome (WBK), made of aluminum (Al) helix wires forming Kagome-like unit cells ...that are distributed periodically and sandwiched between two solid Al facesheets. Due to the topological anisotropy of the WBK, two orientations, the most open and closed orientations, were selected for pressure drop and heat transfer measurements. For the range of Reynolds numbers (
Re) considered, the pressure drop in the WBK was found to be skin friction dominated at low
Re (laminar flow regime; no orientation effect on pressure drop) and form dominated at high
Re (transition from laminar to turbulent flow regime; slightly higher pressure drop in the most closed orientation). For heat transfer across the WBK, the Nusselt number in the most closed orientation was consistently higher than that in the most open orientation, attributable mainly to the difference in the open area ratio of the two orientations.
Neural circuit assembly requires selection of specific cell fates, axonal trajectories, and synaptic targets. By analyzing the function of a secreted semaphorin, Sema-2b, in Drosophila olfactory ...receptor neuron (ORN) development, we identified multiple molecular and cellular mechanisms that link these events. Notch signaling limits Sema-2b expression to ventromedial ORN classes, within which Sema-2b cell-autonomously sensitizes ORN axons to external semaphorins. Central-brain-derived Sema-2a and Sema-2b attract Sema-2b-expressing axons to the ventromedial trajectory. In addition, Sema-2b/PlexB-mediated axon-axon interactions consolidate this trajectory choice and promote ventromedial axon-bundle formation. Selecting the correct developmental trajectory is ultimately essential for proper target choice. These findings demonstrate that Sema-2b couples ORN axon guidance to postsynaptic target neuron dendrite patterning well before the final target selection phase, and exemplify how a single guidance molecule can drive consecutive stages of neural circuit assembly with the help of sophisticated spatial and temporal regulation.
•Notch signaling represses Sema-2b expression in specific ORNs•Axonal Sema-2b acts cell-autonomously to sensitize ORN axons to external semaphorins•Central brain semaphorins and axon-axon interactions direct trajectory choice•Early axon trajectory choice constrains final glomerular target selection
Joo et al. find that Notch signaling represses secreted Sema-2b to control a binary trajectory choice in olfactory axons, and that Sema-2b acts both cell-autonomously and nonautonomously to connect multiple phases of olfactory circuit wiring.
The impressive maneuverability demonstrated by birds has so far eluded comparably sized uncrewed aerial vehicles (UAVs). Modern studies have shown that birds’ ability to change the shape of their ...wings and tail in flight, known as morphing, allows birds to actively control their longitudinal and lateral flight characteristics. These advances in our understanding of avian flight paired with advances in UAV manufacturing capabilities and applications has, in part, led to a growing field of researchers studying and developing avian-inspired morphing aircraft. Because avian-inspired morphing bridges at least two distinct fields (biology and engineering), it becomes challenging to compare and contrast the current state of knowledge. Here, we have compiled and reviewed the literature on flight control and stability of avian-inspired morphing UAVs and birds to incorporate both an engineering and a biological perspective. We focused our survey on the longitudinal and lateral control provided by wing morphing (sweep, dihedral, twist, and camber) and tail morphing (incidence, spread, and rotation). In this work, we discussed each degree of freedom individually while highlighting some potential implications of coupled morphing designs. Our survey revealed that wing morphing can be used to tailor lift distributions through morphing mechanisms such as sweep, twist, and camber, and produce lateral control through asymmetric morphing mechanisms. Tail morphing contributes to pitching moment generation through tail spread and incidence, with tail rotation allowing for lateral moment control. The coupled effects of wing–tail morphing represent an emerging area of study that shows promise in maximizing the control of its morphing components. By contrasting the existing studies, we identified multiple novel avian flight control methodologies that engineering studies could validate and incorporate to enhance maneuverability. In addition, we discussed specific situations where avian-inspired UAVs can provide new insights to researchers studying bird flight. Collectively, our results serve a dual purpose: to provide testable hypotheses of flight control mechanisms that birds may use in flight as well as to support the design of highly maneuverable and multi-functional UAV designs.
The efficacy of empirical non-carbapenem antibiotics for extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia (ESBL-B) is still inconclusive. We conducted a multicenter ...retrospective cohort study to evaluate the efficacy of empirical non-carbapenem antibiotics for treating ESBL-B. Electronic medical records of individuals who were diagnosed with ESBL-B were reviewed between January 2010 and December 2014 at four university hospitals in Korea. Patients were classified into non-carbapenem and carbapenem groups according to the empirical antibiotic regimen. Patients treated with appropriate empirical antibiotics and who subsequently received carbapenems as definitive therapy were included in the analysis. The inverse probability of treatment weights, a statistical method that adjusts baseline statistics by giving weights based on propensity score, was used. During the study period, 232 adequately treated patients with ESBL-B were included in the analysis: 49 patients in the non-carbapenem group and 183 in the carbapenem group. The baseline characteristics and severity of infection were similar after propensity score weighting. The 30-day mortality rates for the two groups were not statistically significantly different (non-carbapenems 6.3% and carbapenems 11.4%;
P
= 0.42). In a multivariate analysis, empirical treatment with non-carbapenem antibiotics was not associated with 30-day all-cause mortality (HR 1.02, 95% CI 0.99–1.06,
P
= 0.14). In a subgroup analysis, empirical treatment with piperacillin-tazobactam was also not associated with 30-day all-cause mortality (HR 1.21, 95% CI 0.37–4.00,
P
= 0.75). Appropriate non-carbapenems were not inferior to carbapenems as initial empirical therapy for ESBL-B.
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