A latent serotonin-1A receptor-gated spinal afferent pathway inhibiting breathing

Spinal afferents such as nociceptive afferents and group III–IV muscle afferents are known to exert an acute excitatory effect on breathing when activated. Here, we report the surprising existence of latent spinal afferents which exerted tonic inhibitory influence on breathing subliminally in anesthetized rats, an effect which was reversed upon activation of serotonin-1A receptors (5-HT[subscript 1A]Rs) in lumbar spinal cord, lesion of pontine lateral parabrachial nucleus or suppression of the adjacent Kölliker-Fuse nucleus with NMDA receptor blockade. Small-interfering RNA knockdown of 5-HT[subscript 1A]Rs in lumbar spinal cord unequivocally localized the site of 5-HT[subscript 1A]R-mediated gating of these respiratory-inhibiting interoceptive afferents to relay neurons in the spinal superficial dorsal horn at the lumbar level and not cervical spinal or supraspinal levels. Our results reveal a novel somatosensory/viscerosensory mechanism which exerts tonic inhibitory influence on homeostatic regulation of breathing independent from the classical chemoreflex excitatory pathways, and suggest a hitherto unrecognized therapeutic target in spinal dorsal horn for 5-HT[subscript 1A]R-based treatment of a variety of respiratory abnormalities.National Institutes of Health (U.S.) (Grants HL093225 and HL067966

MS-DETR: Multispectral Pedestrian Detection Transformer with Loosely Coupled Fusion and Modality-Balanced Optimization

Multispectral pedestrian detection is an important task for many around-the-clock applications, since the visible and thermal modalities can provide complementary information especially under low light conditions. Most of the available multispectral pedestrian detectors are based on non-end-to-end detectors, while in this paper, we propose MultiSpectral pedestrian DEtection TRansformer (MS-DETR), an end-to-end multispectral pedestrian detector, which extends DETR into the field of multi-modal detection. MS-DETR consists of two modality-specific backbones and Transformer encoders, followed by a multi-modal Transformer decoder, and the visible and thermal features are fused in the multi-modal Transformer decoder. To well resist the misalignment between multi-modal images, we design a loosely coupled fusion strategy by sparsely sampling some keypoints from multi-modal features independently and fusing them with adaptively learned attention weights. Moreover, based on the insight that not only different modalities, but also different pedestrian instances tend to have different confidence scores to final detection, we further propose an instance-aware modality-balanced optimization strategy, which preserves visible and thermal decoder branches and aligns their predicted slots through an instance-wise dynamic loss. Our end-to-end MS-DETR shows superior performance on the challenging KAIST, CVC-14 and LLVIP benchmark datasets. The source code is available at https://github.com/YinghuiXing/MS-DETR

Non-invasive prenatal testing for detection of trisomy 13, 18, 21 and sex chromosome aneuploidies in 8594 cases

Objectives: Cell-free fetal DNA has been widely used in prenatal genetic testing during recent years. We explored the feasibility of non-invasive prenatal testing (NIPT) for analysis of common fetal aneuploidies among pregnancies in northwest China.  Material and methods: A total of 8594 maternal blood samples were collected from October 2014 to December 2017 in the Department of Obstetrics and Gynecology at the First Affiliated Hospital of the Air Force Medical University. Cases with positive screening results by NIPT detection were validated using karyotype analysis.  Results: Of 8594 clinical pregnancies, 88 had positive NIPT results and 78 of 88 (88.6%) positive NIPT results were shown to be false-positive by amniotic fluid puncture and chromosome karyotyping analysis. There were 44 cases (49.44%) with trisomy 21, 18, and 13 syndromes (30 cases of trisomy 21, 9 cases of trisomy 18, and 5 cases of trisomy 13). There were 44 cases (50.56%) with sex chromosome abnormalities, including 11 cases with Turner syndrome (45, X), 17 cases with Triple X syndrome (47, XXX), 2 cases with Klinefelter syndrome (47, XXY), and 14 cases with 47, XYY syndrome (47, XYY).  Conclusions: The accuracy, specificity, high efficiency, and acceptance of NIPT can effectively avoid birth defects and improve the quality of the birth population. We should deepen mining and analysis of the clinical data and explore ways to use NIPT. It is recommended that the NIPT guidelines be extended to low-risk patients to further explore the impact of a significant increase in screening.

Accelerating Primal Solution Findings for Mixed Integer Programs Based on Solution Prediction

Mixed Integer Programming (MIP) is one of the most widely used modeling techniques for combinatorial optimization problems. In many applications, a similar MIP model is solved on a regular basis, maintaining remarkable similarities in model structures and solution appearances but differing in formulation coefficients. This offers the opportunity for machine learning methods to explore the correlations between model structures and the resulting solution values. To address this issue, we propose to represent an MIP instance using a tripartite graph, based on which a Graph Convolutional Network (GCN) is constructed to predict solution values for binary variables. The predicted solutions are used to generate a local branching type cut which can be either treated as a global (invalid) inequality in the formulation resulting in a heuristic approach to solve the MIP, or as a root branching rule resulting in an exact approach. Computational evaluations on 8 distinct types of MIP problems show that the proposed framework improves the primal solution finding performance significantly on a state-of-the-art open-source MIP solver

IRES-Mediated Protein Translation Overcomes Suppression by the p14ARF Tumor Suppressor Protein.

Internal ribosome entry sites (IRES elements) have attracted interest in cancer gene therapy because they can be used in the design of gene transfer vectors that provide bicistronic co-expression of two transgene products under the control of a single promoter. Unlike cellular translation of most mRNAs, a process that requires a post-translational 5' modification of the mRNA known as the cap structure, IRES-mediated translation is independent of the cap structure. The cellular conditions that may intervene to modulate IRES-mediated, cap-independent versus cap-dependent translation, however, remain poorly understood, although they could be critical to the choice of gene transfer vectors. Here we have compared the effects of the p14ARF (Alternate Reading Frame) tumor suppressor, a translational suppressor frequently overexpressed in cancer, on cap-dependent translation versus cap-independent translation from the EMCV viral IRES often used in bicistronic gene transfer vectors. We find that ectopic overexpression of p14ARF suppresses endogenous and ectopic cap-dependent protein translation, consistent with other studies. However, p14ARF has little or no effect on transgene translation initiated within an IRES element. This suggests that transgenes placed downstream of an IRES element will retain efficient translation of their gene products in the presence of high levels of ectopic or endogenous p14ARF, a finding that could be particularly relevant to therapeutic gene therapy strategies for cancer

Genetic variants in the calcium signaling pathway genes are associated with cutaneous melanoma-specific survival

Remodeling or deregulation of the calcium signaling pathway is a relevant hallmark of cancer including cutaneous melanoma (CM). In this study, using data from a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center, we assessed the role of 41,377 common single-nucleotide polymorphisms (SNPs) of 167 calcium signaling pathway genes in CM survival. We used another GWAS from Harvard University as the validation dataset. In the single-locus analysis, 1830 SNPs were found to be significantly associated with CM-specific survival (CMSS; P ≤ 0.050 and false-positive report probability ≤ 0.2), of which 9 SNPs were validated in the Harvard study (P ≤ 0.050). Among these, three independent SNPs (i.e. PDE1A rs6750552 T>C, ITPR1 rs6785564 A>G and RYR3 rs2596191 C>A) had a predictive role in CMSS, with a meta-analysis-derived hazards ratio of 1.52 (95% confidence interval = 1.19–1.94, P = 7.21 × 10−4), 0.49 (0.33–0.73, 3.94 × 10−4) and 0.67 (0.53–0.86, 0.0017), respectively. Patients with an increasing number of protective genotypes had remarkably improved CMSS. Additional expression quantitative trait loci analysis showed that these genotypes were also significantly associated with mRNA expression levels of the genes. Taken together, these results may help us to identify prospective biomarkers in the calcium signaling pathway for CM prognosis

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study

Background Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods First, a simple and rapid liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC–MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results The LC–MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies