Nonparametric conditional autoregressive expectile model via neural network with applications to estimating financial risk

The parametric conditional autoregressive expectiles (CARE) models have been developed by [1] to estimate expectiles that can be used to assess value at risk (VaR) and expected shortfall (ES). The challenge lies in parametric CARE modelling is speci cation of a parametric form. To avoid any model misspeci cation, we propose a nonparametric CARE model via neural network. The nonparametric CARE model can be estimated by a classical gradient based nonlinear optimization algorithm. We then apply the nonparametric CARE model to estimating VaR and ES of six stock indices. Empirical results for the new model is competitive with those classical models and parametric CARE models.This work was supported by the National Natural Science Foundation of PR China (71490725, 71071087, 71101134), the National Social Science Foundation of PR China (15BJY008) and the Humanity and Social Science Foundation of Ministry of Education of PR China (No. 14YJA790015)

Quad-mode functional and molecular photoacoustic microscopy

A conventional photoacoustic microscopy (PAM) system typically has to make tradeoffs between its spatial resolution and penetration depth, by choosing a fixed configuration of optical excitation and acoustic detection. The single-scale imaging capability of PAM may limit its applications in biomedical studies. Here, we report a quad-mode photoacoustic microscopy (QM-PAM) system with four complementary spatial resolutions and maximum penetration depths. For this we first developed a ring-shaped focused ultrasound transducer that has two independent elements with respective central frequencies at 20 MHz and 40 MHz, providing complementary acoustically-determined spatial resolutions and penetration depths. To accommodate the dual-element ultrasound transducer, we implemented two optical excitation modes to provide tightly-and weakly-focused light illumination. The dual-element acoustic detection combined with the two optical focusing modes can thus provide four imaging scales in a single imaging device, with consistent contrast mechanisms and co-registered field of views. We have demonstrated the multiscale morphological, functional, and molecular imaging capability of QM-PAM in the mouse head, leg and ear in vivo. We expect the high scale flexibility of QM-PAM will enable broad applications in preclinical studies.Peer reviewe

Granulocyte colony-stimulating factor affects the distribution and clonality of TRGV and TRDV repertoire of T cells and graft-versus-host disease

<p>Abstract</p> <p>Background</p> <p>The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recent data indicated that gamma delta⁺T cells might participate in mediating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation. However, whether G-CSF could influence the T cell receptors (TCR) of gamma delta⁺T cells (<it>TRGV </it>and <it>TRDV </it>repertoire) remains unclear. To further characterize this feature, we compared the distribution and clonality of <it>TRGV </it>and <it>TRDV </it>repertoire of T cells before and after G-CSF mobilization and investigated the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT.</p> <p>Methods</p> <p>The complementarity-determining region 3 (CDR3) sizes of three <it>TRGV </it>and eight <it>TRDV </it>subfamily genes were analyzed in peripheral blood mononuclear cells (PBMCs) from 20 donors before and after G-CSF mobilization, using RT-PCR and genescan technique. To determine the expression levels of <it>TRGV </it>subfamily genes, we performed quantitative analysis of <it>TRGV</it>I~III subfamilies by real-time PCR.</p> <p>Results</p> <p>The expression levels of three <it>TRGV </it>subfamilies were significantly decreased after G-CSF mobilization (<it>P </it>= 0.015, 0.009 and 0.006, respectively). The pattern of <it>TRGV </it>subfamily expression levels was <it>TRGV</it>II ><it>TRGV </it>I ><it>TRGV </it>III before mobilization, and changed to <it>TRGV </it>I ><it>TRGV </it>II ><it>TRGV </it>III after G-CSF mobilization. The expression frequencies of <it>TRGV </it>and <it>TRDV </it>subfamilies changed at different levels after G-CSF mobilization. Most <it>TRGV </it>and <it>TRDV </it>subfamilies revealed polyclonality from pre-G-CSF-mobilized and G-CSF-mobilized samples. Oligoclonality was detected in <it>TRGV </it>and <it>TRDV </it>subfamilies in 3 donors before mobilization and in another 4 donors after G-CSF mobilization, distributed in <it>TRGV</it>II, <it>TRDV</it>1, <it>TRDV</it>3 and <it>TRDV</it>6, respectively. Significant positive association was observed between the invariable clonality of <it>TRDV</it>1 gene repertoire after G-CSF mobilization and low incidence of GVHD in recipients (<it>P </it>= 0.015, <it>OR </it>= 0.047).</p> <p>Conclusions</p> <p>G-CSF mobilization not only influences the distribution and expression levels of <it>TRGV </it>and <it>TRDV </it>repertoire, but also changes the clonality of gamma delta⁺T cells. This alteration of <it>TRGV </it>and <it>TRDV </it>repertoire might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT.</p

Multimodal imaging of the mouse eye using visible light photoacoustic ophthalmoscopy and near-infrared-II optical coherence tomography

Non-invasive imaging plays a crucial role in diagnosing and studying eye diseases. However, existing photoacoustic ophthalmoscopy (PAOM) techniques in mice have limitations due to handling restrictions, suboptimal optical properties, limited availability of light sources and permissible light fluence at the retina. This study introduces an innovative approach that utilizes Rose Bengal, a contrast agent, to enhance PAOM contrast. This enables visualization of deeper structures like the choroidal microvasculature and sclera in the mouse eye using visible light. The integration of near-infrared-II optical coherence tomography (NIR-II OCT) provides additional tissue contrast and insights into potential NIR-II PAOM capabilities. To optimize imaging, we developed a cost-effective 3D printable mouse eye phantom and a fully 3D printable tip/tilt mouse platform. This solution elevates PAOM to a user-friendly technology, which can be used to address pressing research questions concerning several ocular diseases such as myopia, glaucoma and/or age-related macular degeneration in the future.Comment: 14 pages, 4 figure

Using the water quality index (WQI), and the synthetic pollution index (SPI) to evaluate the groundwater quality for drinking purpose in Hailun, China

Due to the impact of human agricultural production, climate and environmental changes. The applicability of groundwater for drinking purposes has attracted widespread attention. In order to quantify the hydrochemical characteristics of groundwater in Hailun and evaluate its suitability for assessing water for drinking purposes, 77 shallow groundwater samples and 57 deep groundwater samples were collected and analyzed. The results show that deep groundwater in aquifers in the study area is weakly alkaline, while that in shallow is acidic. The abundance is in the order HCO3 - > Cl- > SO4 2- for anions, and Ca2+> Na+> Mg2+ for cations. Groundwater chemical type were dominated by HCO3 -Ca, HCO3 -Ca• Mg, and HCO3 -Ca• Na. Correlation analysis (CA) and Durov diagram showed that rock weathering and dissolution, human activities, and the hydraulic connection between shallow and deep water are the main reasons affecting the chemical composition of water in Helen. The analysis of water samples based on the WQI model showed that about 23.37, 23.37, 32.46, 12.98, and 7.79% of the shallow groundwater samples were excellent, good, poor, very poor, and unsuitable for drinking purposes, respectively, and that 61.40, 30.90, 5.26, 1.75, and 1.75% of the deep groundwater samples were excellent, good, poor, very poor, and unsuitable for drinking purposes, respectively. The analysis of groundwater samples based on the SPI model showed that 92.98% of the deep groundwater samples were suitable grade, while that 40.25% of the shallow groundwater samples were suitable grade. The spatial distribution maps of the WQI and SPI show that most of the deep groundwater resources in the study area are clean and suitable for drinking, despite the risks of the shallow groundwater in the north and southwest of the study area

High-speed widefield photoacoustic microscopy of small-animal hemodynamics

Optical-resolution photoacoustic microscopy (OR-PAM) has become a popular tool in small-animal hemodynamic studies. However, previous OR-PAM techniques variously lacked a high imaging speed and/or a large field of view, impeding the study of highly dynamic physiologic and pathophysiologic processes over a large region of interest. Here we report a high-speed OR-PAM system with an ultra-wide field of view, enabled by an innovative water-immersible hexagon-mirror scanner. By driving the hexagon-mirror scanner with a high-precision DC motor, the new OR-PAM has achieved a cross-sectional frame rate of 900 Hz over a 12-mm scanning range, which is 3900 times faster than our previous motor-scanner-based system and 10 times faster than the MEMS-scanner-based system. Using this hexagon-scanner-based OR-PAM system, we have imaged epinephrine-induced vasoconstriction in the whole mouse ear and vascular reperfusion after ischemic stroke in the mouse cortex in vivo, with a high spatial resolution and high volumetric imaging speed. We expect that the hexagon-scanner-based OR-PAM system will become a powerful tool for small animal imaging where the hemodynamic responses over a large field of view are of interest

Human BCR/ABL1 induces chronic myeloid leukemia-like disease in zebrafish

Chronic myeloid leukemia (CML) is induced by the BCR/ABL1 oncogene, which encodes a protein tyrosine kinase. We examined the effect of direct overexpression of the human p210BCR/ABL1 oncoprotein in zebrafish. Humanized p210BCR/ABL1 protein was detectable in Tg(hsp70: p210BCR/ABL1) transgenic zebrafish embryos and adult kidney marrow. Transgenic zebrafish developed CML, which could be induced via cells transplanted into recipients. The expression of human BCR/ABL1 promoted myeloid lineages in Tg(hsp70:p210BCR/ABL1) transgenic embryos. A total of 77 of 101 (76.24%) Tg(hsp70:p210BCR/ABL1) adult transgenic zebrafish (age 6 months-1 year) developed CML. CML in zebrafish showed a triphasic phenotype, similar to that in humans, involving a chronic phase predominantly characterized by neutrophils in various degrees of maturation, an accelerated phase with an increase in blasts and immature myeloid elements, and a blast phase with >90% blasts in both the peripheral blood and kidney marrow. Tyrosine kinase inhibitors, as the standard drug treatment for human CML, effectively reduced the expanded myeloid population in Tg(hsp70:p210BCR/ABL1) transgenic embryos. Moreover, we screened a library of 171 compounds and identified ten new drugs against BCR/ABL1 kinase-dependent or -independent pathways that could also reduce lcp1+ myeloid cell numbers in Tg(hsp70:p210BCR/ABL1) transgenic embryos. In summary, we generated the first humanized zebrafish CML model that recapitulates many characteristics of human CML. This novel in vivo model will help to elucidate the mechanisms of CML disease progression and allow high-throughput drug screening of possible treatments for this disease

Guanylate-binding Protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against toxoplasma gondii

Mesenchymal stromal cells (MSCs) have recently been shown to play important roles in mammalian host defenses against intracellular pathogens, but the molecular mechanism still needs to be clarified. We confirmed that human MSCs (hMSCs) pre-stimulated with IFN-γ showed a significant and dose-dependent ability to inhibit the growth of two types of Toxoplasma gondii (type I strain RH/GFP or type II strain PLK/RED). However, in contrast to previous reports, the anti-T. gondii activity of hMSCs was not mediated by indoleamine 2,3-dioxygenase (IDO). Genome-wide RNA-seq analysis revealed that IFN-γ increased the expression of the p65 family of guanylate-binding proteins (hGBPs) in hMSCs, especially hGBP1. To analyze the functional role of hGBPs, stable knockdowns of hGBP1, -2, -5 in hMSCs were established using a lentiviral transfection system. hGBP1 knockdown in hMSCs resulted in a significant loss of the anti-T. gondii host defense property, compared with hMSCs infected with non-targetted control sequences. hGBP2 and -5 knockdowns had no effect. Moreover, the hGBP1 accumulation on the parasitophorous vacuole (PV) membranes of IFN-γ-stimulated hMSCs might protect against T. gondii infection. Taken together, our results suggest that hGBP1 plays a pivotal role in anti-T. gondii protection of hMSCs and may shed new light on clarifying the mechanism of host defense properties of hMSCs

Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acutely decompensated cirrhosis

BACKGROUND AND AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in cirrhosis patients with acute decompensation (AD), focusing on NHVs and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 cirrhosis patients with AD in study cohort. Ten healthy volunteers and 20, 39, and 81 patients with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation in a validation cohort (n = 58) were performed and exploratory treatment instituted. RESULTS: In study cohort, 188 microorganisms were detected in 74.4% (96/129) patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). Patients with AD had an NHV signature, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure (ACLF), and 90-day mortality. The NHV signature in ACLF patients was similar to patients with sepsis and hematological malignancies. The treatable NHV, CMV was detected in 24.1% (14/58) patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, 9 were further validated by DNA RT-PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in exploratory manner with clinical resolutions. CONCLUSIONS: The results of this study suggests that NHVs may have a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated in the routine management of AD patients. IMPACT AND IMPLICATIONS: ●Cirrhosis patients with acute decompensation have a non-hepatotropic virus (NHV) signature, which is similar to that in sepsis and hematological malignancies patients. ●The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. ●The treatable NHV, CMV reactivation may be involved in the clinical outcomes of decompensated cirrhosis. ●Routine screening for NHVs, especially CMV, may be useful for the management of patients with acutely decompensated cirrhosis