High-Throughput miRNA and mRNA Sequencing of Paired Colorectal Normal,Tumor and Metastasis Tissues and Bioinformatic Modeling of miRNA-1 Therapeutic Applications

MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are, so far, hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina sequencing. We validated six miRNAs in a large tissue screen containing 16 additional tumor entities and identified miRNA-1, miRNA-129, miRNA-497 and miRNA-215 as constantly de-regulated within the majority of cancers. Of these, we investigated miRNA-1 as representative in a systems-biology simulation of cellular cancer models implemented in PyBioS and assessed the effects of depletion as well as overexpression in terms of miRNA-1 as a potential treatment option. In this system, miRNA-1 treatment reverted the disease phenotype with different effectiveness among the patients. Scoring the gene expression changes obtained through mRNA-Seq from the same patients we show that the combination of deep sequencing and systems biological modeling can help to identify patient-specific responses to miRNA treatments. We present this data as guideline for future pre-clinical assessments of new and personalized therapeutic options.     

Predictors of Raised Viral Load during Antiretroviral Therapy in Patients with and without Prior Antiretroviral Use: A Cross-Sectional Study

Objectives

In Lagos, Nigeria, Médecins Sans Frontières (MSF) and the Ministry of Health (MoH) commenced free antiretroviral treatment (ART) in a hospital-based clinic. We performed a cross-sectional study to compare factors associated with raised viral load between patients with (“experienced”) and without (“naïve”) prior antiretroviral (ARV) exposure at commencement of ART at the clinic. We also examined factors influencing ARV adherence in experienced patients prior to clinic entry.

Methods

We included adult patients receiving ART from MSF who answered a questionnaire about previous antiretroviral use. Multivariate logistic regression was used to estimate odds ratios (OR) for raised viral load (≥1000 copies/mL).

Results

1246 (96%) patients answered: 1075 (86%) reported no, and 171 (14%) some, prior ARV exposure. ARV-naïve patients were more immunosuppressed at baseline: 65% vs 37% (p<0.001) had CD4<200; 17% vs 9% (p = 0.013) were WHO stage 4. Proportionately more experienced than naïve patients had raised viral loads (20% vs 9%, p<0.001) on ART in the MSF/MoH clinic. Raised viral load was associated with prior ARV experience (adjusted OR = 3.74, 95%CI 2.09–6.70, p<0.001) and complete interruption of current ART (adjusted OR = 3.71, 95%CI 2.06–6.68, p<0.001). Higher CD4 at time of VL and a higher self-rated score of recent adherence were associated with lower OR of a raised viral load. Among experienced patients who missed pills before joining MSF/MoH, most common reasons were because ARVS were not affordable (58%) or available (33%), with raised viral load associated with being unsure how to take them (OR = 3.16, 95%CI 1.10–9.12, p = 0.033).

Conclusions

Patients previously exposed to ARVs had increased OR of raised viral load. The cost and availability of ARVs were common reasons for missing ARVs before joining the MSF/MoH clinic, and inadequate patient knowledge was associated with raised viral load.     

Abundance,Condition and Size of a Foundation Species Vary with Altered Soil Conditions,Remnant Type and Potential Competitors

Ecosystems - Native biodiversity often depends on remnant vegetation for survival in agricultural landscapes. However, the size and shape of remnant patches can affect their conservation values...     

Bergmann's rule in alien birds

Native bird species show latitudinal gradients in body size across species (Bergmann's rule), but whether or not such gradients are recapitulated in the alien distributions of bird species are unknown. Here, we test for the existence of Bergmann's rule in alien bird species worldwide, and investigate the causes of the observed patterns. Published databases were used to obtain the worldwide distributions of established alien bird populations, the locations of alien bird introductions, and bird body masses. Randomisation tests and linear models were used to assess latitudinal patterns in the body masses of introduced and established alien bird populations. Established alien bird species exhibit Bergmann's rule, but this is largely explained by where alien bird species have been introduced: latitudinal variation in the body masses of established alien bird species simply reflects latitudinal variation in the body masses of introduced species. There is some evidence that body mass is implicated in whether or not established species’ alien ranges spread towards or contract away from the Equator following establishment. However, most alien bird ranges are encompassed by the latitudinal band(s) to which the species was introduced. Bergmann's rule in alien birds is therefore a consequence of where humans have introduced different species, rather than of natural processes operating after population introduction.     

Ablation of PRC1 by small interfering RNA demonstrates that cytokinetic abscission requires a central spindle bundle in mammalian cells, whereas completion of furrowing does not

The temporal and spatial regulation of cytokinesis requires an interaction between the anaphase mitotic spindle and the cell cortex. However, the relative roles of the spindle asters or the central spindle bundle are not clear in mammalian cells. The central spindle normally serves as a platform to localize key regulators of cell cleavage, including passenger proteins. Using time-lapse and immunofluorescence analysis, we have addressed the consequences of eliminating the central spindle by ablation of PRC1, a microtubule bundling protein that is critical to the formation of the central spindle. Without a central spindle, the asters guide the equatorial cortical accumulation of anillin and actin, and of the passenger proteins, which organize into a subcortical ring in anaphase. Furrowing goes to completion, but abscission to create two daughter cells fails. We conclude the central spindle bundle is required for abscission but not for furrowing in mammalian cells.     

Role of Abca7 in Mouse Behaviours Relevant to Neurodegenerative Diseases

ATP-binding cassette transporters of the subfamily A (ABCA) are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer’s disease. However, Abca7’s role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety) and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs) and Alzheimer’s disease (i.e. cognitive domains). Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains.     

FoxP3+ Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies

Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.     

Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival

Cell-death and -survival decisions are critically controlled by intracellular Ca^2 + homeostasis and dynamics at the level of the endoplasmic reticulum (ER). Inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) play a pivotal role in these processes by mediating Ca^2 + flux from the ER into the cytosol and mitochondria. Hence, it is clear that many pro-survival and pro-death signaling pathways and proteins affect Ca^2 + signaling by directly targeting IP₃R channels, which can happen in an IP₃R-isoform-dependent manner. In this review, we will focus on how the different IP₃R isoforms (IP₃R1, IP₃R2 and IP₃R3) control cell death and survival. First, we will present an overview of the isoform-specific regulation of IP₃Rs by cellular factors like IP₃, Ca^2 +, Ca^2 +-binding proteins, adenosine triphosphate (ATP), thiol modification, phosphorylation and interacting proteins, and of IP₃R-isoform specific expression patterns. Second, we will discuss the role of the ER as a Ca^2 + store in cell death and survival and how IP₃Rs and pro-survival/pro-death proteins can modulate the basal ER Ca^2 + leak. Third, we will review the regulation of the Ca^2 +-flux properties of the IP₃R isoforms by the ER-resident and by the cytoplasmic proteins involved in cell death and survival as well as by redox regulation. Hence, we aim to highlight the specific roles of the various IP₃R isoforms in cell-death and -survival signaling. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.     

记河北省后城组新发现之小型兽脚类足迹(英文)

几十年前人们就已经开始研究中国东北侏罗纪—白垩纪界线附近地层中的小型兽脚类恐龙足迹,虽然这些遗迹化石比辽宁省义县组带羽毛的恐龙及其他实体化石逊色了许多。本文记述了河北省承德南双庙后城组(土城子组)最下部河流相沉积中发现的一组兽脚类恐龙足迹。南双庙足迹具有三趾,趾粗大,其形态与美国下侏罗统经典的"brontozoid"足迹(Gral- lator,Anchisauripus和Eubrontes)相符。虽然许多产自辽宁土城子组中基本同时的brontozoid足迹被鉴定为小型的跷脚龙足迹属(Grallator),但南双庙足迹更大一些(全长可达28.8 cm),可能应该归入安琪龙足迹属(Anchisauripus)。南双庙足迹很可能是一群小型兽脚类行走而产生。在辽宁义县组的兽脚类恐龙中,最可能留下这类足迹的是小型的窃蛋龙类——尾羽龙(Caudipteryx)。不过这个解释还很勉强,因为这些足迹缺乏鉴定性特征,而且河北的后城组与辽宁的义县组之间还有一定的时间及地理间隔。