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101.
Replicability, the ability to replicate scientific findings, is a prerequisite for scientific discovery and clinical utility. Troublingly, we are in the midst of a replicability crisis. A key to replicability is that multiple measurements of the same item (e.g., experimental sample or clinical participant) under fixed experimental constraints are relatively similar to one another. Thus, statistics that quantify the relative contributions of accidental deviations—such as measurement error—as compared to systematic deviations—such as individual differences—are critical. We demonstrate that existing replicability statistics, such as intra-class correlation coefficient and fingerprinting, fail to adequately differentiate between accidental and systematic deviations in very simple settings. We therefore propose a novel statistic, discriminability, which quantifies the degree to which an individual’s samples are relatively similar to one another, without restricting the data to be univariate, Gaussian, or even Euclidean. Using this statistic, we introduce the possibility of optimizing experimental design via increasing discriminability and prove that optimizing discriminability improves performance bounds in subsequent inference tasks. In extensive simulated and real datasets (focusing on brain imaging and demonstrating on genomics), only optimizing data discriminability improves performance on all subsequent inference tasks for each dataset. We therefore suggest that designing experiments and analyses to optimize discriminability may be a crucial step in solving the replicability crisis, and more generally, mitigating accidental measurement error.  相似文献   
102.
Recent technological developments allow us to measure the status of dozens of proteins in individual cells. This opens the way to understand the heterogeneity of complex multi‐signaling networks across cells and cell types, with important implications to understand and treat diseases such as cancer. These technologies are, however, limited to proteins for which antibodies are available and are fairly costly, making predictions of new markers and of existing markers under new conditions a valuable alternative. To assess our capacity to make such predictions and boost further methodological development, we organized the Single Cell Signaling in Breast Cancer DREAM challenge. We used a mass cytometry dataset, covering 36 markers in over 4,000 conditions totaling 80 million single cells across 67 breast cancer cell lines. Through four increasingly difficult subchallenges, the participants predicted missing markers, new conditions, and the time‐course response of single cells to stimuli in the presence and absence of kinase inhibitors. The challenge results show that despite the stochastic nature of signal transduction in single cells, the signaling events are tightly controlled and machine learning methods can accurately predict new experimental data.  相似文献   
103.
Although aquatic plants are discussed as a unified biological group, they are phylogenetically well dispersed across the angiosperms. In this study, we annotated the aquatic taxa on the tree of vascular plants, and extracted the topology of these aquatic lineages to construct the tree of aquatic angiosperms. We also reconstructed the ancestral areas of aquatic families. We found that aquatic angiosperms could be divided into two different categories: the four aquatic orders and the aquatic taxa in terrestrial orders. Aquatic lineages evolved early in the radiation of angiosperms, both in the orders Nymphaeales and Ceratophyllales and among basal monocots (Acorales and Alismatales). These aquatic orders do not have any extant terrestrial relatives. They originated from aquatic habitats during the Early Cretaceous. Asia would have been one of the centers for early diversification of aquatic angiosperms. The aquatic families within terrestrial orders may originate from other areas besides Asia, such as America or Australia. The lineages leading to extant angiosperms diversified early in underexploited freshwater habitats. The four extant aquatic orders were relicts of an early radiation of angiosperm in aquatic environments. Their extinct ancestors might be aquatic early angiosperms.  相似文献   
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The mitochondrial DNA hypervariable segment I (HVS-I) is widely used in studies of human evolutionary genetics, and therefore accurate estimates of mutation rates among nucleotide sites in this region are essential. We have developed a novel maximum-likelihood methodology for estimating site-specific mutation rates from partial phylogenetic information, such as haplogroup association. The resulting estimation problem is a generalized linear model, with a nonstandard link function. We develop inference and bias correction tools for our estimates and a hypothesis-testing approach for site independence. We demonstrate our methodology using 16,609 HVS-I samples from the Genographic Project. Our results suggest that mutation rates among nucleotide sites in HVS-I are highly variable. The 16,400–16,500 region exhibits significantly lower rates compared to other regions, suggesting potential functional constraints. Several loci identified in the literature as possible termination-associated sequences (TAS) do not yield statistically slower rates than the rest of HVS-I, casting doubt on their functional importance. Our tests do not reject the null hypothesis of independent mutation rates among nucleotide sites, supporting the use of site-independence assumption for analyzing HVS-I. Potential extensions of our methodology include its application to estimation of mutation rates in other genetic regions, like Y chromosome short tandem repeats.  相似文献   
107.
Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary lymphoedema and more specifically in those with a phenotype that resembles Milroy disease. This study aims to address this issue and thereby delineate the Milroy disease phenotype. Fifty-two patients with primary lymphoedema were analysed for mutations in the coding regions of VEGFR3. Patients were divided into four groups: Typical Milroy disease with family history (group I), typical Milroy disease with no family history (group II), atypical Milroy disease (group III), and complex primary lymphoedema (group IV). Results demonstrated that with rigorous phenotyping the likelihood of detecting VEGFR3 mutations is optimised. Mutation prevalence is 75% in typical Milroy patients with a family history (group I) and 68% if positive family history is not a diagnostic criterion. A positive family history is not essential in Milroy disease. The likelihood of detecting VEGFR3 mutations in patients who have a phenotype which is not typical of Milroy disease is very small (<5%). For the 22 mutation positive patients, 14 novel VEGFR3 mutations were identified, two of which were in exon 22 and one in exon 17, confirming that these exons should be included in VEGFR3 analysis. No mutations were found outside the kinase domains, showing that analysis of this part of the gene is not useful for Milroy disease patients. VEGFC, which encodes the ligand for VEGFR3, was sequenced in all patients with typical Milroy disease (groups I and II) and no mutations were identified. F. C. Connell and P. Ostergaard contributed equally to this work. An erratum to this article can be found at  相似文献   
108.
Preeclampsia is a common pregnancy complication that is an important cause of preterm birth and fetal growth restriction. Because there is no diagnostic test yet available for preeclampsia, we used a proteomic approach to identify novel serum/plasma biomarkers for this condition. We conducted case control studies comparing nulliparous women who developed preeclampsia at 36-38 weeks of gestation with healthy nulliparous women matched by gestational age at sampling. Serum/plasma was depleted of six abundant proteins and analyzed by two-dimensional gel electrophoresis (n = 12 per group) and difference gel electrophoresis (n = 12 per group). Differences in abundance of protein spots were detected by univariate and multivariate statistical analyses. Proteins were identified by mass spectrometry and expression of selected proteins was validated by immunoblotting. Proteins whose concentrations were selectively associated with preeclampsia included apolipoprotein E (apoE), apoC-II, complement factor C3c, fibrinogen, transthyretin, and complement factor H-related protein 2. An increase in a deglycosylated isoform of apoE3 and concomitantly decreased amounts of one apoE3 glycoisoform were identified in preeclamptic plasma and confirmed by immunoblotting. Altered production of these preeclampsia-related apoE3 isoforms might impair reverse cholesterol transport, contributing to arterial damage. These findings point to a novel mechanistic link between preeclampsia and subsequent cardiovascular disease.  相似文献   
109.
Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits platelet response to collagen and may also inhibit two other major platelet agonists ADP and thrombin although this has been less well explored. We hypothesized that the combined effect of inhibiting these three platelet activating pathways may act to significantly inhibit thrombus formation. We demonstrate a negative relationship between PECAM-1 surface expression and platelet response to cross-linked collagen related peptide (CRP-XL) and ADP, and an inhibitory effect of PECAM-1 clustering on platelet response to CRP-XL, ADP and thrombin. This combined inhibition of multiple signaling pathways results in a marked reduction in thrombus formation.  相似文献   
110.

Background

Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis.

Methods and Findings

We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression.

Conclusions

EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.

Trial Registration

ClinicalTrials.gov NCT00041327  相似文献   
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