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The sequential changepoint detection problem is studied in the context of global online monitoring of a large number of independent data streams. We are interested in detecting an occurring event as soon as possible, but we do not know when the event will occur, nor do we know which subset of data streams will be affected by the event. A family of scalable schemes is proposed based on the sum of the local cumulative sum, cusum, statistics from each individual data stream, and is shown to asymptotically minimize the detection delays for each and every possible combination of affected data streams, subject to the global false alarm constraint. The usefulness and limitations of our asymptotic optimality results are illustrated by numerical simulations and heuristic arguments. The Appendices contain a probabilistic result on the first epoch to simultaneous record values for multiple independent random walks.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death, reflecting the need for better understanding the oncogenesis, and developing new diagnostic and therapeutic targets for the malignancy. Emerging evidence suggests that small nucleolar RNAs (snoRNAs) have malfunctioning roles in tumorigenesis. Our recent study demonstrated that small nucleolar RNA 42 ( SNORA42 ) was overexpressed in lung tumors. Here, we investigate the role of SNORA42 in tumorigenesis of NSCLC. We simultaneously assess genomic dosages and expression levels of SNORA42 and its host gene, KIAA0907 , in 10 NSCLC cell lines and a human bronchial epithelial cell line. We then determine in vitro functional significance of SNORA42 in lung cancer cell lines through gain- and loss-of-function analyses. We also inoculate cancer cells with SNORA42-siRNA into mice through either tail vein or subcutaneous injection. We finally evaluate expression level of SNORA42 on frozen surgically resected lung tumor tissues of 64 patients with stage I NSCLC by using quantitative reverse transcriptase PCR assay. Genomic amplification and associated high expression of SNORA42 rather than KIAA0907 are frequently observed in lung cancer cells, suggesting that SNORA42 overexpression is activated by its genomic amplification. SNORA42 knockdown in NSCLC cells inhibits in vitro and in vivo tumorigenicity, whereas enforced SNORA42 expression in bronchial epitheliums increases cell growth and colony formation. Such pleiotropy of SNORA42 suppression could be achieved at least partially through increased apoptosis of NSCLC cells in a p53-dependent manner. SNORA42 expression in lung tumor tissue specimens is inversely correlated with survival of NSCLC patients. Therefore, SNORA42 activation could have an oncogenic role in lung tumorigenesis and provide potential diagnostic and therapeutic targets for the malignancy.

This paper presents a modular software design for the construction of computational modeling technology that will help implement precision medicine. In analogy to a common industrial strategy used for preventive maintenance of engineered products, medical digital twins are computational models of disease processes calibrated to individual patients using multiple heterogeneous data streams. They have the potential to help improve diagnosis, prognosis, and personalized treatment for a wide range of medical conditions. Their large-scale development relies on both mechanistic and data-driven techniques and requires the integration and ongoing update of multiple component models developed across many different laboratories. Distributed model building and integration requires an open-source modular software platform for the integration and simulation of models that is scalable and supports a decentralized, community-based model building process. This paper presents such a platform, including a case study in an animal model of a respiratory fungal infection.

In Arabidopsis, CONSTANS (CO) integrates light and circadian clock signals to promote flowering under long days (LD). In the grasses, a duplication generated two paralogs designated as CONSTANS1 (CO1) and CONSTANS2 (CO2). Here we show that in tetraploid wheat plants grown under LD, combined loss-of-function mutations in the A and B-genome homeologs of CO1 and CO2 (co1 co2) result in a small (3 d) but significant (P<0.0001) acceleration of heading time both in PHOTOPERIOD1 (PPD1) sensitive (Ppd-A1b, functional ancestral allele) and insensitive (Ppd-A1a, functional dominant allele) backgrounds. Under short days (SD), co1 co2 mutants headed 13 d earlier than the wild type (P<0.0001) in the presence of Ppd-A1a. However, in the presence of Ppd-A1b, spikes from both genotypes failed to emerge by 180 d. These results indicate that CO1 and CO2 operate mainly as weak heading time repressors in both LD and SD. By contrast, in ppd1 mutants with loss-of-function mutations in both PPD1 homeologs, the wild type Co1 allele accelerated heading time >60 d relative to the co1 mutant allele under LD. We detected significant genetic interactions among CO1, CO2 and PPD1 genes on heading time, which were reflected in complex interactions at the transcriptional and protein levels. Loss-of-function mutations in PPD1 delayed heading more than combined co1 co2 mutations and, more importantly, PPD1 was able to perceive and respond to differences in photoperiod in the absence of functional CO1 and CO2 genes. Similarly, CO1 was able to accelerate heading time in response to LD in the absence of a functional PPD1. Taken together, these results indicate that PPD1 and CO1 are able to respond to photoperiod in the absence of each other, and that interactions between these two photoperiod pathways at the transcriptional and protein levels are important to fine-tune the flowering response in wheat.

BackgroundAntiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown.MethodsWe undertook an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5'-leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets.ResultsClones carrying proviruses with 5'-leader defects can cause persistent NSV up to approximately 103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor (MSD) site and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced noninfectious virions containing viral RNA, but lacking envelope.ConclusionThese findings show that proviruses with 5'-leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5'-leader can help in understanding failure to completely suppress viremia.FundingOffice of the NIH Director and National Institute of Dental and Craniofacial Research, NIH; Howard Hughes Medical Institute; Johns Hopkins University Center for AIDS Research; National Institute for Allergy and Infectious Diseases (NIAID), NIH, to the PAVE, BEAT-HIV, and DARE Martin Delaney collaboratories.

The WASF3 gene promotes invasion and metastasis in breast cancer cells, which have undergone epithelial-to-mesenchyme transition (EMT). Overexpression of WASF3 in cells that do not show EMT increases their invasion potential as a result of increased ZEB1/2 levels, which specifically suppress the anti-invasion chromosome 1 miR-200a/200b/429 cluster. ZEB1/2 upregulation by WASF3 results from downregulation of KISS1, leading to the release of inhibition of nuclear factor (NF)κB by IκBα. We further show that ZEB1 expression is regulated by the NFκB transcription factor. Knockdown of WASF3 in breast cancer cells leads to reduced ZEB1 levels and increased miR-200 and E-cadherin levels, resulting in loss of invasion potential. The central regulation of this interactive pathway by WASF3 accounts for the increased invasion associated with increased WASF3 expression seen in aggressive breast cancer cells. WASF3 , therefore, is a potential target to suppress invasion and metastasis in breast cancer cells.

Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.

Electrons in Earth's outer radiation belt are highly dynamic, with fluxes changing by up to orders of magnitude. The penetration of electrons from the outer belt to the inner belt is one such change observed during geomagnetic storms and was previously observed in electrons up to 1 MeV for some strong storms observed by the Van Allen Probes. We analyze pulse height analysis data from the Relativistic Electric and Proton Telescope (REPT) on the Van Allen Probes to produce electron flux measurements with lower minimum energy and significantly improved resolution compared to the standard REPT data and show that electron penetrations into the inner belt (L ≤ 2) extend to at least 1.3 MeV and penetrations into the slot region (2 < L < 2.8) extend to at least 1.5 MeV during certain geomagnetic storms. We also demonstrate that these penetrations are associated with butterfly pitch angle distributions from 1 to 1.3 MeV. Plain Language Summary Electrons in Earth's outer radiation belt are highly dynamic with the amount and energy of them changing drastically, especially during geomagnetic storms. The penetration of electrons from the outer belt to the inner radiation belt is one such change and was previously observed in electrons with energies ≤1 MeV during some of the strongest storms during the Van Allen Probes mission. Electrons in the radiation belts also have a pitch angle that describes what portion of their motion is along or perpendicular to the direction of the magnetic field. Pitch angle distributions (PAD) are often used to gain information on the dynamics of the electrons, as unstable distributions can be caused by and indicative of wave activity that cannot always be measured directly. PADs with a minimum at 90°, called butterfly PADs, are one such unstable distribution that have previously been observed in penetrating electrons with energies ∼100–900 keV. We use instrument simulation to analyze data from the Van Allen Probes that could not previously be analyzed to show that the maximum energy of these penetrations is higher than previously observed, up to 1.3 MeV, and that these penetrations are associated with butterfly PADs at 1–1.3 MeV. Key Points REPT PHA data can be used to produce high energy resolution flux spectra of >1 MeV electrons Electron penetrations below L = 2 during strong geomagnetic storms extend in energy up to 1.3 MeV Electron penetrations below L = 2 at energies 1–1.3 MeV are associated with butterfly pitch angle distributions

p53 is a major tumor suppressor whose function is pivotal for protection against cancer. In over half of human cancers, p53 is inactivated due to either point mutation or loss of p53 gene. It has been well established that in addition to abrogating the tumor-suppressive function of wild-type p53, mutant p53 gains new functions and actively contributes to various stages of tumor progression. However, little is known about whether microRNA (miRNA) is involved in the gain-of-function of mutant p53. Here we report miR-27a as a novel downstream transcriptional target of mutant p53-273H. Mutant p53 binds to the miR-27a promoter region and suppresses its expression. We also identify epidermal growth factor receptor (EGFR) as a direct target of miR-27a. Via the miR-27a/EGFR axis, mutant p53-273H promotes a sustained EGF-induced extracellular signal–regulated kinase 1/2 activation, thereby facilitating cell proliferation and tumorigenesis. Collectively, this work reveals a direct link between the gain-of-function of mutant p53 and miRNA and uncovers a novel mutant p53-273H/miR-27a/EGFR pathway that has an important role in promoting tumor development.

The hybrid halide perovskites combine the low-cost processing characteristics of organic materials with the performance factors of inorganic compounds. Recently the power conversion efficiencies of perovskite photovoltaic solar cells have reached a respective value of ~20%. The charge transport properties were indirectly approximated in these compounds because of lack of available field-effect transistors (FETs). Here we report the fabrication and room-temperature operation of FETs based on the hybrid perovskites. We obtained balanced electron and hole transport with mobilities of ~1 cm2/Vs. We also found that the yield, as well as the operational and environmental stability of the fabricated transistors is limited.