In clinical trials and other medical studies, it has become increasingly common to observe simultaneously an event time of interest and longitudinal covariates. In the literature, joint modelling ...approaches have been employed to analyse both survival and longitudinal processes and to investigate their association. However, these approaches focus mostly on developing adaptive and flexible longitudinal processes based on a prespecified survival model, most commonly the Cox proportional hazards model. In this paper, we propose a general class of semiparametric hazard regression models, referred to as the extended hazard model, for the survival component. This class includes two popular survival models, the Cox proportional hazards model and the accelerated failure time model, as special cases. The proposed model is flexible for modelling event data, and its nested structure facilitates model selection for the survival component through likelihood ratio tests. A pseudo joint likelihood approach is proposed for estimating the unknown parameters and components via a Monte Carlo EM algorithm. Asymptotic theory for the estimators is developed together with theory for the semiparametric likelihood ratio tests. The performance of the procedure is demonstrated through simulation studies. A case study featuring data from a Taiwanese HIV/AIDS cohort study further illustrates the usefulness of the extended hazard model.
In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of ...damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
Hydrogen and helium ion beams delivering different doses are used in the ion implantation, at room temperature, of China Low Activation Martensitic (CLAM) steel and the induced defects studied by ...Doppler broadening of gamma-rays generated in positron annihilation. Defect profiles are analysed in terms of conventional S and W parameters, measures of relative contributions of low and high-momentum electrons in the annihilation peak, as functions of incident positron energies E up to 30keV. The behaviours of the S–E, W–E and S–W plots under different implantation doses indicate clearly that the induced defect size has obvious variation with depth, taking values that interpolate between surface and bulk values, and depend mainly on helium ion fluences. The S–W plot indicates that two types of defects have formed after ion implantation.
Pearson syndrome is a very rare metabolic disorder that is usually present in infancy with transfusion dependent macrocytic anemia and multiorgan involvement including exocrine pancreas, liver and ...renal tubular defects. The disease is secondary to a mitochondrial DNA deletion that is variable in size and location. Endocrine abnormalities can develop, but are usually not part of the initial presentation. We report two patients who presented with unusual endocrine manifestations, neonatal diabetes and adrenal insufficiency, who were both later diagnosed with Pearson syndrome.
Medical records were reviewed. Confirmatory testing included: mitochondrial DNA deletion testing and sequencing of the breakpoints, muscle biopsy, and bone marrow studies.
Case 1 presented with hyperglycemia requiring insulin at birth. She had several episodes of ketoacidosis triggered by stress and labile blood glucose control. Workup for genetic causes of neonatal diabetes was negative. She had transfusion dependent anemia and died at 24months due to multisystem organ failure. Case 2 presented with adrenal insufficiency and anemia during inturcurrent illness, requiring steroid replacement since 37months of age. He is currently 4years old and has mild anemia. Mitochondrial DNA studies confirmed a 4.9kb deletion in patient 1 and a 5.1kb deletion in patient 2.
The patients reported highlight the importance of considering mitochondrial DNA disorders in patients with early onset endocrine dysfunction, and expand the knowledge about this rare mitochondrial disease.
► Two patients with Pearson syndrome with 4.9 and 5.1kb mtDNA deletions. ► Neonatal diabetes as presenting manifestation of Pearson syndrome. ► Anemia and adrenal insufficiency as presenting features of Pearson syndrome.
Single-molecule spectroscopy and detection are powerful techniques for the study of single fluorescent particles and their interaction with their environment. We present a low-cost system for ...simultaneous real-time acquisition, storage of inter-photon arrival times and the calculation and display of the fluorescence time trace, autocorrelation function and distribution of delays histogram for single-molecule experiments. From a hardware perspective, in addition to a multi-core computer, only a standard low-cost counting board is required as processing is software-based. Software is written in a parallel programming environment with time crucial operations coded in ANSI-C. Crucial to system performance is a simple and efficient real-time autocorrelation algorithm (acf) optimized for the count rates (approximately 10⁴ cps) encountered in single-molecule experiments. The algorithm's time complexity is independent of temporal resolution, which is maintained at all time delays. The system and algorithm's performance was validated by duplicating the signal from the photon detector and sending it to both the ordinary counter board and a commercial correlator simultaneously. The data acquisition system's robustness under typical single-molecule experimental conditions was tested by observing the diffusion of Rhodamine 6G molecules in deionized water.
Ceratovacuna lanigera Zehntner is a major leaf pest of sugarcane. Widely distributed, it affects both the yield and quality of sugarcane in China. This study aimed to assess real yield and sugar ...yield losses, and the effect of C. lanigera damage on emergence of newly planted and ratoon cane under current production levels. Field experiments were carried out from 2014 to 2016 in Yunnan Province China. At maturity, plants were harvested and weighed to determine yield, and the effect on sugarcane quality and sucrose content analyzed. Real yield decreased by average of 46,185 kg hm-2 (range: 37,545-61,845 kg hm-2) in damaged versus undamaged areas, with an average yield loss rate of 35.9% (28.5-45.7%). Juice yield decreased by an average of 3.01% (2.4-4.13%) and sucrose content by 6.38% (5.48-8.16%). Juice brix decreased by an average of 7.66°BX (6.95-9.05°BX) and juice gravity purity by 12.35% (8.43-19.97%). In contrast, the reducing sugar content increased by an average of 1.21% (1.01-1.3%). Emergence rates of newly planted cane decreased by an average of 26.0% (24.7-27.3%). The emergence number of ratoon cane decreased by 66,834 hm2 (57,429-76,238 hm-2) and relative emergence loss rates of ratoon cane decreased by an average of 57.8% (57.6-58.0%). These findings confirm that C. lanigera damage severely affects sugarcane yield and quality in Yunnan Province. The results will help the implementation of effective control measures, thereby supporting sustainable development of the Chinese sugar industry.
The nonuniform sampling (NUS) is a powerful approach to enable fast acquisition but requires sophisticated reconstruction algorithms. Faithful reconstruction from partially sampled exponentials is ...highly expected in general signal processing and many applications. Deep learning (DL) has shown astonishing potential in this field, but many existing problems, such as lack of robustness and explainability, greatly limit its applications. In this work, by combining the merits of the sparse model-based optimization method and data-driven DL, we propose a DL architecture for spectra reconstruction from undersampled data, called MoDern. It follows the iterative reconstruction in solving a sparse model to build the neural network, and we elaborately design a learnable soft-thresholding to adaptively eliminate the spectrum artifacts introduced by undersampling. Extensive results on both synthetic and biological data show that MoDern enables more robust, high-fidelity, and ultrafast reconstruction than the state-of-the-art methods. Remarkably, MoDern has a small number of network parameters and is trained on solely synthetic data while generalizing well to biological data in various scenarios. Furthermore, we extend it to an open-access and easy-to-use cloud computing platform (XCloud-MoDern), contributing a promising strategy for further development of biological applications.
A negative magnetoresistance (MR) was observed at room temperature in a Co/Py transverse “coercivity heterostructures” configuration thin film, and it can be explained by domain wall scattering at ...the boundaries of the Co and Py. We point out that the novel “soft” and “hard” transverse “coercivity heterostructures” not only can be used to study domain wall resistance of variety magnetic materials, but also have potential application in fabricating domain wall devices.
Relapse of Ph chromosome-positive ALL (Ph(+)ALL) results from the persistence of leukemia-propagating cells (LPCs). In Ph(+)ALL, a xenograft assay recently determined that LPCs are enriched in the ...CD34(+)CD38(-)CD58(-) fraction. Therefore, the prognostic significance of LPCs in Ph(+)ALL subjects after allogeneic hematopoietic SCT (allo-HSCT) was investigated. A total of 80 consecutive adults with Ph(+)ALL who underwent allo-HSCT were eligible. A multi-parameter flow cytometry analysis examining CD58-FITC/CD10-PE/ CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia BM blasts was performed at diagnosis. Based on the original blast phenotypes, subjects were stratified into the CD34(+)CD38(-)CD58(-)group (N=15) and other phenotype group (N=65). During minimal residual disease monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in the CD34(+)CD38(-)CD58(-) group than in other phenotype group, especially at 3 months post HSCT. In addition, CD34(+)CD38(-)CD58(-)LPCs are directly correlated with a higher 3-year cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) and OS. Multivariate analyses indicated that presence of CD34(+)CD38(-)CD58(-) LPCs at diagnosis, and BCR-ABL reduction at 3 months post HSCT were independent risk factors for relapse, LFS and OS. Our data suggest that presence of CD34(+)CD38(-)CD58(-) LPCs at diagnosis allows rapid identification of high-risk patients for relapse after allo-HSCT.
Serum paraoxonase (PON1), present on high density lipoprotein, may inhibit low density lipoprotein (LDL) oxidation and protect against atherosclerosis. We generated combined PON1 knockout ...(KO)/apolipoprotein E (apoE) KO and apoE KO control mice to compare atherogenesis and lipoprotein oxidation. Early lesions were examined in 3-month-old mice fed a chow diet, and advanced lesions were examined in 6-month-old mice fed a high fat diet. In both cases, the PON1 KO/apoE KO mice exhibited significantly more atherosclerosis (50–71% increase) than controls. We examined LDL oxidation and clearancein vivo by injecting human LDL into the mice and following its turnover. LDL clearance was faster in the double KO mice as compared with controls. There was a greater rate of accumulation of oxidized phospholipid epitopes and a greater accumulation of LDL-immunoglobulin complexes in the double KO mice than in controls. Furthermore, the amounts of three bioactive oxidized phospholipids were elevated in the endogenous intermediate density lipoprotein/LDL of double KO mice as compared with the controls. Finally, the expression of heme oxygenase-1, peroxisome proliferator-activated receptor γ, and oxidized LDL receptors were elevated in the livers of double KO mice as compared with the controls. These data demonstrate that PON1 deficiency promotes LDL oxidation and atherogenesis in apoE KO mice.
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