Abstract
The unipolar saturation current limit (
$${I}_{sat}$$
I
sat
) gives an upper limit to the corona current that can be obtained from a unipolar corona discharge. Therefore, it implies a ...theoretical limit to the performance of unipolar corona discharge devices. However, it has not been widely used in practice because it is difficult to deal with complex discharge configurations in an analytical way. This study aims to establish and validate a numerical methodology to evaluate the maximum current, which numerically imitates the unipolar saturation current limit. It was shown that the maximum current has the same mathematical definition as the unipolar saturation current. For validation, the maximum current was compared with an analytical solution of the Poisson equation for the coaxial cylinders configuration. The differences between the maximum current and unipolar saturation current limit for the coaxial cylinders, pin-to-plane, and single wire-to-plane configurations were discussed in terms of the assumptions used in the semi-analytical derivation of the unipolar saturation current limit. The validated methodology was applied to a multiple wire-to-plane configuration, for which a semi-analytical expression of the unipolar saturation current limit has not yet been developed. The effects of geometric and operation parameters on the maximum currents of the multiple wire-to-plane configuration were analyzed. The results were regressed into a single formula.
The role of B cells in the tumor microenvironment and B-cell-mediated antitumor immune responses remains relatively understudied. Recent seminal studies have discovered that B cells and associated ...tertiary lymphoid structures correlate with responses to checkpoint blockade immunotherapy and are prognostic for overall survival of cancer patients. B-cell subsets have remarkable functional diversity and include professional antigen-presenting cells, regulatory cells, memory populations, and antibody-producing plasma cells. Importantly, secreted antibodies can independently activate innate immune responses and induce the cancer immunity cycle. Thus, B cells and B-cell-mediated antibody responses comprise the largely underappreciated second arm of the adaptive immune system and certainly deserve further attention in the field of oncology. Here, we review the known functions of B cells in the tumor microenvironment, the contribution of B cells to the antitumor activity of immunotherapies, and the role of B cells in the overall survival of cancer patients.
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)-associated HNSCCs have better overall ...survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has ...been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.
Through the previously reported the quantum-identity, the light-model, and the T(temperature)·S(entropy) energy, the implied meaning of temperature and entropy, respectively, which it was difficult ...to intuitively recognize, was clearly defined. In order to minimize possible errors at this time, the interrelationship of the SI base unit, which is the smallest unit, and the T(temperature)·S(entropy) unit integration was used. In the process of converting to Planck units, each unit (criterion) for entropy and temperature was calculated, and their physical and chemical meanings were compared and reinterpreted. Thus, the unit of entropy is related to the Boltzmann constant, and the temperature is the oscillation of pure mass units. Therefore, the intuitive recognition of physical and chemical factors based on the unit of meter(m)-time(s) is considered sufficient as an initiator to move closer to new science beyond the current limited application.
Abstract
Summary
Mislabeling in the process of next generation sequencing is a frequent problem that can cause an entire genomic analysis to fail, and a regular cohort-level checkup is needed to ...ensure that it has not occurred. We developed a new, automated tool (BAMixChecker) that accurately detects sample mismatches from a given BAM file cohort with minimal user intervention. BAMixChecker uses a flexible, data-specific set of single-nucleotide polymorphisms and detects orphan (unpaired) and swapped (mispaired) samples based on genotype-concordance score and entropy-based file name analysis. BAMixChecker shows ∼100% accuracy in real WES, RNA-Seq and targeted sequencing data cohorts, even for small panels (<50 genes). BAMixChecker provides an HTML-style report that graphically outlines the sample matching status in tables and heatmaps, with which users can quickly inspect any mismatch events.
Availability and implementation
BAMixChecker is available at https://github.com/heinc1010/BAMixChecker
Supplementary information
Supplementary data are available at Bioinformatics online.
Aberrant mutations in KRAS play a critical role in tumor initiation and progression, and are a negative prognosis factor in lung adenocarcinoma (LUAD).
Using genomic analysis for K-Ras isoforms ...(K-Ras4A and K-Ras4B) and large-scale multi-omics data, we inspected the overall survival (OS) and disease-free survival (DFS) of LUAD patients based on the abundance of transcript variants by analyzing RNA expression and somatic mutation data from The Cancer Genome Atlas (n = 516). The expression of the minor transcript K-Ras4A and its proportion were positively correlated with the presence of KRAS mutations in LUAD. We found that both K-Ras4A abundance measures (expression and proportion) have a strong association with poor OS (p = 0.0149 and p = 3.18E-3, respectively) and DFS (p = 3.03E-4 and p = 0.0237, respectively), but only in patients harboring KRAS mutations. A Cox regression analysis showed significant results in groups with low expression (hazard ratio (HR) = 2.533, 95% confidence interval (CI) = 1.380-4.651, p = 2.72E-3) and low proportion (HR = 2.549, 95% CI = 1.387-4.684, p = 2.58E-3) of K-Ras4A.
Based on the above results, we report the possible use of abundance measures for K-Ras4A for predicting the survival of LUAD patients with KRAS mutations.
Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in ...MTOR account for 15%–25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×–20,012×) of five important mTOR pathway genes—PIK3CA, PIK3R2, AKT3, TSC1, and TSC2—by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T p.Arg22Trp and c.610C>T p.Arg204Cys) and TSC2 (c.4639G>A p.Val1547Ile), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.
Acetone-butanol-ethanol (ABE) fermentation by the anaerobic bacterium Clostridium acetobutylicum has been considered a promising process of industrial biofuel production. Phosphotransbutyrylase ...(phosphate butyryltransferase, PTB) plays a crucial role in butyrate metabolism by catalyzing the reversible conversion of butyryl-CoA into butyryl phosphate. Here, we report the crystal structure of PTB from the Clostridial host for ABE fermentation, C. acetobutylicum, (CaPTB) at a 2.9 A resolution. The overall structure of the CaPTB monomer is quite similar to those of other acyltransferases, with some regional structural differences. The monomeric structure of CaPTB consists of two distinct domains, the N- and C-terminal domains. The active site cleft was formed at the interface between the two domains. Interestingly, the crystal structure of CaPTB contained eight molecules per asymmetric unit, forming an octamer, and the size-exclusion chromatography experiment also suggested that the enzyme exists as an octamer in solution. The structural analysis of CaPTB identifies the substrate binding mode of the enzyme and comparisons with other acyltransferase structures lead us to speculate that the enzyme undergoes a conformational change upon binding of its substrate.
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