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Background: To demonstrate the safety and performance of the Arrow EZ-IO Intraosseous Vascular Access System, particularly in the pediatric patient population, a retrospective observational study was conducted in 2021 and 2022. Methods: Following study design, IRB approval, and investigator selection, data were collected for all patients needing intraosseous access—adult and pediatric. The primary endpoint was the success rate for achieving intraosseous access; the secondary endpoint was the rate of adverse events. Following initial data collection, additional data were collected and a sub-set analysis was conducted to demonstrate the same in pediatric patients only, which is the focus of this report. Results: Data for 106 pediatric cases were collected. The success rate for achieving intraosseous access and infusion was 96.2%. There were three adverse events in two patients (1.9%); none serious or previously unreported. The mean duration of device use was 60 h (SD = 46). For 46 patients, the device was used for up to 48 h, and for another 45 patients, the device was used for a longer duration. Conclusions: This report is the first characterization of the safety and performance of the Arrow EZ-IO Intraosseous Vascular Access System when used in the pediatric population for longer dwell times (>24 h), with no serious complications reported. Performance and safety objectives were met. The results of this real-world evidence study are in alignment with findings from the clinical literature concluding that, for pediatric patients, the Arrow EZ-IO Intraosseous Vascular Access System is safe and effective for providing vascular access in urgent, emergent, and medically necessary situations, in which intravenous access is difficult or impossible to obtain. In addition, this study supports the use of intraosseous access for dwell times greater than 24 h.

Objective To collect real-world data to demonstrate the safety and performance of Arrowg+ard Blue® /Arrowg+ard Blue Plus® (AGB/AGB+) central venous catheters (CVCs). Methods This observational, retrospective study involved patients who required AGB/AGB+ CVCs at designated general hospitals in USA (22), UK (19) and Germany (2). Data were extracted from electronic medical records. There were no specific inclusion/exclusion criteria. Primary endpoint was successful treatment without an adverse event (AE). Secondary endpoint was rate of AEs. Results In total, 384 cases were included from 43 centres and most patients (74%) were >35 years of age. A success rate of 99%, and an overall AE rate of 0.8% were observed. Moreover, the overall infection rate was lower than typically reported for standard catheters. In addition, power injection of contrast media was successful in all 51 cases. Conclusions This study indicates the AGB/AGB+ CVCs perform as intended with a high success rate and few AEs. Further large-scale, controlled studies are required to confirm our findings.

Abstract. In 2012, traditional Chinese medicine (TCM) practitioners in Australia became nationally-registered allied health professionals in three categories: acupuncturist, Chinese herbal medicine practitioner, and Chinese herbal medicine dispenser. Australia was the first Western country to introduce national registration for Chinese medicine, followed by Portugal and, recently, New Zealand. The practice of TCM in Australia can be traced back to the beginning of Chinese immigration to Australia during the Victorian Gold Rush which began in the 1850s. The process which led to national registration commenced in the early 1970s with the establishment of the first acupuncture courses. Decades of gradual development of courses from unaccredited part-time diplomas to accredited bachelor degrees, and the development, by the profession, of national consensus on educational standards were essential elements in the process which led to registration. Professional associations, such as the Australian Acupuncture and Chinese Medicine Association Ltd. (AACMA), also developed a framework of professional self-regulation, including Codes of Ethics, Codes of Conduct, ongoing professional development requirements and Infection Control Guidelines, and provided leadership in the development of the profession. After decades of tribalism and division within the TCM profession, the National Academic Standards Committee brought almost all stakeholders together to reach a consensus on the Australian Guidelines for Traditional Chinese Medicine Education which were published by AACMA in 2001. Professional associations also collaborated on joint submissions to the government in support of registration, which was introduced first in the state of Victoria in 2000, and subsequently became national in 2012. Despite national registration, some barriers still remain, and professional associations continue to lobby the federal government for inclusion in Medicare, chronic disease management scheme, and Veterans Affairs.

Hypotheses concerning the modern distribution of Orchestia gammarellus (Crustacea, Amphipoda, Talitridae) and its causes in the North Atlantic are discussed. The synanthropic dispersal hypothesis of Henzler and Ingólfsson (2008) considers O. gammarellus as originating on the eastern shore of the North Atlantic and being transported by humans to Iceland and the western Atlantic shore (Newfoundland and the Maritime Provinces of Canada). The Eocene and natural dispersal hypothesis of Myers and Lowry (2020) proposes a geologically earlier origin of O. gammarellus when the west and east shores of the North Atlantic were still connected. Present day amphi-Atlantic distribution was explained by vicariance, with the vicariant event causing separation of O. gammarellus being continental drift drawing apart the west and east shores of the North Atlantic. A post-glacial natural dispersal hypothesis proposed herein, involves transport on ice floes or in driftwood from European shores to Iceland and the Atlantic Provinces of Canada. The small genetic distances amongst populations found by Henzler and Ingólfsson (2008) at the COI gene are inconsistent with the Eocene vicariance hypothesis. On evolutionary grounds, we question Myers and Lowry’s (2020) designation of the Icelandic and Canadian populations as a new species of Orchestia. Existing molecular and morphological data are insufficient to distinguish between human-aided dispersal and natural rafting.

Metastatic CTC clusters remain relatively unexplored due to the lack of optimized and practical technologies for their detection. Here the authors report Cluster-Wells to isolate CTC clusters in whole blood; they show this allows viable cluster retrieval for further molecular and functional analysis.

Summary: Stiffness has been observed to decrease for many cancer cell types as their metastatic potential increases. Although cell mechanics and metastatic potential are related, the underlying molecular factors associated with these phenotypes remain unknown. Therefore, we have developed a workflow to measure the mechanical properties and gene expression of single cells that is used to generate large linked-datasets. The process combines atomic force microscopy to measure the mechanics of individual cells with multiplexed RT-qPCR gene expression analysis on the same single cells. Surprisingly, the genes that most strongly correlated with mechanical properties were not cytoskeletal, but rather were markers of extracellular matrix remodeling, epithelial-to-mesenchymal transition, cell adhesion, and cancer stemness. In addition, dimensionality reduction analysis showed that cell clustering was improved by combining mechanical and gene expression data types. The single cell genomechanics method demonstrates how single cell studies can identify molecular drivers that could affect the biophysical processes underpinning metastasis.

IntroductionAs antibiotic resistance has become more prevalent, the social and economic impacts are increasingly pressing. Indeed, bacteria have developed the SOS response which facilitates the evolution of resistance under genotoxic stress. The transcriptional repressor, LexA, plays a key role in this response. Mutation of LexA to a non-cleavable form that prevents the induction of the SOS response sensitizes bacteria to antibiotics. Achieving the same inhibition of proteolysis with small molecules also increases antibiotic susceptibility and reduces drug resistance acquisition. The availability of multiple LexA crystal structures, and the unique Ser-119 and Lys-156 catalytic dyad in the protein enables the rational design of inhibitors.MethodsWe pursued a binary approach to inhibit proteolysis; we first investigated β-turn mimetics, and in the second approach we tested covalent warheads targeting the Ser-119 residue. We found that the cleavage site region (CSR) of the LexA protein is a classical Type II β-turn, and that published 1,2,3-triazole compounds mimic the β-turn. Generic covalent molecule libraries and a β-turn mimetic library were docked to the LexA C-terminal domain using molecular modelling methods in FlexX and CovDock respectively. The 133 highest-scoring molecules were screened for their ability to inhibit LexA cleavage under alkaline conditions. The top molecules were then tested using a RecA-mediated cleavage assay.ResultsThe β-turn library screen did not produce any hit compounds that inhibited RecA-mediated cleavage. The covalent screen discovered an electrophilic serine warhead that can inhibit LexA proteolysis, reacting with Ser-119 via a nitrile moiety. DiscussionThis research presents a starting point for hit-to-lead optimisation, which could lead to inhibition of the SOS response and prevent the acquisition of antibiotic resistance.

Despite a substantial overall decrease in mortality, disparities among ethnic minorities in developed countries persist. This study investigated mortality disparities and their associated risk factors for the three largest ethnic groups in the United Kingdom: Asian, Black, and White. Study participants were sampled from the UK Biobank (UKB), a prospective cohort enrolled between 2006 and 2010. Genetics, biological samples, and health information and outcomes data of UKB participants were downloaded and data-fields were prioritized based on participants with death registry records. Kaplan-Meier method was used to evaluate survival differences among ethnic groups; survival random forest feature selection followed by Cox proportional-hazard modeling was used to identify and estimate the effects of shared and ethnic group-specific mortality risk factors. The White ethnic group showed significantly worse survival probability than the Asian and Black groups. In all three ethnic groups, endoscopy and colonoscopy procedures showed significant protective effects on overall mortality. Asian and Black women show lower relative risk of mortality than men, whereas no significant effect of sex was seen for the White group. The strongest ethnic group-specific mortality associations were ischemic heart disease for Asians, COVID-19 for Blacks, and cancers of respiratory/intrathoracic organs for Whites. Mental health-related diagnoses, including substance abuse, anxiety, and depression, were a major risk factor for overall mortality in the Asian group. The effect of mental health on Asian mortality, particularly for digestive cancers, was exacerbated by an observed hesitance to answer mental health questions, possibly related to cultural stigma. C-reactive protein (CRP) serum levels were associated with both overall and cause-specific mortality due to COVID-19 and digestive cancers in the Black group, where elevated CRP has previously been linked to psychosocial stress due to discrimination. Our results point to mortality risk factors that are group-specific and modifiable, supporting targeted interventions towards greater health equity.

Attention-control processes transfer relevant information to visual working memory (WM) and prevent irrelevant information from consuming WM resources. Although event-related potentials (ERPs) have revealed attention-control processes associated with enhancement of relevant stimuli (targets) and suppression of irrelevant stimuli (distractors), only the suppressive processes have been found to predict WM capacity. We hypothesised a link between target-enhancement processes and WM capacity would be revealed in a task that requires more control than the conventional visual search paradigms used to study target selection. Here, participants searched for a pop-out target on Go trials and withheld responses on an equal number of randomly intermixed No-Go trials, depending on the colour of the stimulus array. Magnitudes of ERP indices associated with target enhancement (the singleton detection positivity, SDP, and N2pc) were positively correlated with individual differences in WM capacity. These relationships vanished when participants searched for the pop-out target on every trial, regardless of stimulus-array colour. Inhibitory processes associated with suppressing distractors (PD) and withholding responses (no-go P3) on No-Go trials did not predict WM capacity. These findings indicate that target-enhancement mechanisms control access to WM in search tasks that require dynamic control and disconfirm the view that the gateway to WM is entirely inhibitory by nature.

Summary: We describe a consensus approach for network construction based on fully conserved gene-gene interactions from randomly downsampled data subsets for an unbiased differential analysis of gene co-expression networks. The pipeline allows users to identify network nodes lost, conserved, and acquired in cancer as well as interpret the functional significance of these network changes. For proof of concept, the protocol is used to leverage RNA-seq data of tumor samples from TCGA and healthy tissue samples from the GTEx database.For complete details on the use and execution of this protocol, please refer to Arshad and McDonald (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Machine learning has been utilized to predict cancer drug response from multi-omics data generated from sensitivities of cancer cell lines to different therapeutic compounds. Here, we build machine learning models using gene expression data from patients’ primary tumor tissues to predict whether a patient will respond positively or negatively to two chemotherapeutics: 5-Fluorouracil and Gemcitabine. Results We focused on 5-Fluorouracil and Gemcitabine because based on our exclusion criteria, they provide the largest numbers of patients within TCGA. Normalized gene expression data were clustered and used as the input features for the study. We used matching clinical trial data to ascertain the response of these patients via multiple classification methods. Multiple clustering and classification methods were compared for prediction accuracy of drug response. Clara and random forest were found to be the best clustering and classification methods, respectively. The results show our models predict with up to 86% accuracy; despite the study’s limitation of sample size. We also found the genes most informative for predicting drug response were enriched in well-known cancer signaling pathways and highlighted their potential significance in chemotherapy prognosis. Conclusions Primary tumor gene expression is a good predictor of cancer drug response. Investment in larger datasets containing both patient gene expression and drug response is needed to support future work of machine learning models. Ultimately, such predictive models may aid oncologists with making critical treatment decisions.

Summary: Recent findings indicate that changes underlying cancer onset and progression are not only attributable to changes in DNA structure and expression of individual genes but to changes in interactions among these genes as well. We examined co-expression changes in gene-network structure occurring during the onset and progression of nine different cancer types. Network complexity is generally reduced in the transition from normal precursor tissues to corresponding primary tumors. Cross-tissue cancer network similarity generally increases in early-stage cancers followed by a subsequent loss in cross-tissue cancer similarity as tumors reacquire cancer-specific network complexity. Gene-gene connections remaining stable through cancer development are enriched for “housekeeping” gene functions, whereas newly acquired interactions are associated with established cancer-promoting functions. Surprisingly, >90% of changes in gene-gene network interactions in cancers are not associated with changes in the expression of network genes relative to normal precursor tissues.

Y-family DNA polymerases (pols) consist of six phylogenetically separate subfamilies; two UmuC (polV) branches, DinB (pol IV, Dpo4, polκ), Rad30A/POLH (polη), and Rad30B/POLI (polι) and Rev1. Of these subfamilies, DinB orthologs are found in all three domains of life; eubacteria, archaea, and eukarya. UmuC orthologs are identified only in bacteria, whilst Rev1 and Rad30A/B orthologs are only detected in eukaryotes. Within eukaryotes, a wide array of evolutionary diversity exists. Humans possess all four Y-family pols (pols η, ι, κ, and Rev1), Schizosaccharomyces pombe has three Y-family pols (pols η, κ, and Rev1), and Saccharomyces cerevisiae only has polη and Rev1. Here, we report the cloning, expression, and biochemical characterization of the four Y-family pols from the lower eukaryotic thermophilic fungi, Thermomyces lanuginosus. Apart from the expected increased thermostability of the T. lanuginosus Y-family pols, their major biochemical properties are very similar to properties of their human counterparts. In particular, both Rad30B homologs (T. lanuginosus and human polɩ) exhibit remarkably low fidelity during DNA synthesis that is template sequence dependent. It was previously hypothesized that higher organisms had acquired this property during eukaryotic evolution, but these observations imply that polι originated earlier than previously known, suggesting a critical cellular function in both lower and higher eukaryotes.

We present a rare case of prostatic endobronchial metastases that was successfully treated with total androgen blockade (TAB). This case demonstrates prolonged remission on continuous TAB and continued remission employing intermittent therapy.

New tools have been created to allow a superconducting design flow for schematic design, verification, and optimization. These tools integrate with the Cadence design environment. In single flux quantum superconducting electronics, individual component values, such as wire inductances, Josephson junction critical currents, and bias currents, must be optimized to allow for maximum deviance from the designer value, which is also known as the device margin. One tool is used to create a description of the proper circuit behavior. Included with this tool is the ability to automatically create the description from a Cadence netlist. The other tool is an automated device margin circuit schematic verification and optimization tool, which widens device margins while maintaining proper circuit behavior derived from the first tool. Additionally, this optimization tool can automatically correct the circuit schematic using the proper circuit behavior description. In this paper, the functionality of the language used to create the description of the proper circuit behavior is presented. Several circuits are then verified and optimized based on their correct behavior.

Given the achievements in automatically translating text from one language to another, one would expect to see similar advancements in translating between signed and spoken languages. However, progress in this effort has lagged in comparison. Typically, machine translation consists of processing text from one language to produce text in another. Because signed languages have no generally-accepted written form, translating spoken to signed language requires the additional step of displaying the language visually as animation through the use of a three-dimensional (3D) virtual human commonly known as an avatar. Researchers have been grappling with this problem for over twenty years, and it is still an open question. With the goal of developing a deeper understanding of the challenges posed by this question, this article gives a summary overview of the unique aspects of signed languages, briefly surveys the technology underlying avatars and performs an in-depth analysis of the features in a textual representation for avatar display. It concludes with a comparison of these features and makes observations about future research directions.

A platform for studying spinal cord organogenesis in vivo where embryonic stem cell (ESC)-derived neural progenitor cells (NPC) self-organize into spinal cord-like tissue after transplantation in subarachnoid space of the spinal cord has been described. We advance the applicability of this platform by imaging in vivo the formed graft through T2w magnetic resonance imaging (MRI). Furthermore, we used diffusion tensor imaging (DTI) to verify the stereotypical organization of the graft showing that it mimics the host spinal cord. Within the graft white matter (WM) we identified astrocytes that form glial limitans, myelinating oligodendrocytes, and myelinated axons with paranodes. Within the graft grey matter (GM) we identified cholinergic, glutamatergic, serotonergic and dopaminergic neurons. Furthermore, we demonstrate the presence of ESC-derived complex vasculature that includes the presence of blood brain barrier. In addition to the formation of mature spinal cord tissue, we describe factors that drive this process. Specifically, we identify Flk1+ cells as necessary for spinal cord formation, and synaptic connectivity with the host spinal cord and formation of host-graft chimeric vasculature as contributing factors. This model can be used to study spinal cord organogenesis, and as an in vivo drug discovery platform for screening potential therapeutic compounds and their toxicity. Keywords: Embryonic stem cells, Neural progenitor cells, Spinal cord organogenesis, Flk1

Abstract High-throughput technologies have identified significant changes in patterns of mRNA expression over cancer development but the functional significance of these changes often rests upon the assumption that observed changes in levels of mRNA accurately reflect changes in levels of their encoded proteins. We systematically compared the expression of 4436 genes on the RNA and protein levels between discrete tumor samples collected from the ovary and from the omentum of the same OC patient. The overall correlation between global changes in levels of mRNA and their encoding proteins is low (r = 0.38). The majority of differences are on the protein level with no corresponding change on the mRNA level. Indirect and direct evidence indicates that a significant fraction of the differences may be mediated by microRNAs.

Abstract Background Gene-fusion or chimeric transcripts have been implicated in the onset and progression of a variety of cancers. Massively parallel RNA sequencing (RNA-Seq) of the cellular transcriptome is a promising approach for the identification of chimeric transcripts of potential functional significance. We report here the development and use of an integrated computational pipeline for the de novo assembly and characterization of chimeric transcripts in 55 primary breast cancer and normal tissue samples. Methods An integrated computational pipeline was employed to screen the transcriptome of breast cancer and control tissues for high-quality RNA-sequencing reads. Reads were de novo assembled into contigs followed by reference genome mapping. Chimeric transcripts were detected, filtered and characterized using our R-SAP algorithm. The relative abundance of reads was used to estimate levels of gene expression. Results De novo assembly allowed for the accurate detection of 1959 chimeric transcripts to nucleotide level resolution and facilitated detailed molecular characterization and quantitative analysis. A number of the chimeric transcripts are of potential functional significance including 79 novel fusion-protein transcripts and many chimeric transcripts with alterations in their un-translated leader regions. A number of chimeric transcripts in the cancer samples mapped to genomic regions devoid of any known genes. Several ‘pro-neoplastic’ fusions comprised of genes previously implicated in cancer are expressed at low levels in normal tissues but at high levels in cancer tissues. Conclusions Collectively, our results underscore the utility of deep sequencing technologies and improved bioinformatics workflows to uncover novel and potentially significant chimeric transcripts in cancer and normal somatic tissues.

In Escherichia coli, damage to the chromosomal DNA induces the SOS response, setting in motion a series of different DNA repair and damage tolerance pathways. DNA polymerase IV (pol IV) is one of three specialised DNA polymerases called into action during the SOS response to help cells tolerate certain types of DNA damage. The canonical view in the field is that pol IV primarily acts at replisomes that have stalled on the damaged DNA template. However, the results of several studies indicate that pol IV also acts on other substrates, including single-stranded DNA gaps left behind replisomes that re-initiate replication downstream of a lesion, stalled transcription complexes and recombination intermediates. In this study, we use single-molecule time-lapse microscopy to directly visualize fluorescently labelled pol IV in live cells. We treat cells with the DNA-damaging antibiotic ciprofloxacin, Methylmethane sulfonate (MMS) or ultraviolet light and measure changes in pol IV concentrations and cellular locations through time. We observe that only 5-10% of foci induced by DNA damage form close to replisomes, suggesting that pol IV predominantly carries out non-replisomal functions. The minority of foci that do form close to replisomes exhibit a broad distribution of colocalisation distances, consistent with a significant proportion of pol IV molecules carrying out postreplicative TLS in gaps behind the replisome. Interestingly, the proportion of pol IV foci that form close to replisomes drops dramatically in the period 90-180 min after treatment, despite pol IV concentrations remaining relatively constant. In an SOS-constitutive mutant that expresses high levels of pol IV, few foci are observed in the absence of damage, indicating that within cells access of pol IV to DNA is dependent on the presence of damage, as opposed to concentration-driven competition for binding sites.

Dynamic tubular extensions from chloroplasts called stromules have recently been shown to connect with nuclei and function during innate immunity. We demonstrate that stromules extend along microtubules (MTs) and MT organization directly affects stromule dynamics since stabilization of MTs chemically or genetically increases stromule numbers and length. Although actin filaments (AFs) are not required for stromule extension, they provide anchor points for stromules. Interestingly, there is a strong correlation between the direction of stromules from chloroplasts and the direction of chloroplast movement. Stromule-directed chloroplast movement was observed in steady-state conditions without immune induction, suggesting it is a general function of stromules in epidermal cells. Our results show that MTs and AFs may facilitate perinuclear clustering of chloroplasts during an innate immune response. We propose a model in which stromules extend along MTs and connect to AF anchor points surrounding nuclei, facilitating stromule-directed movement of chloroplasts to nuclei during innate immunity.

We have previously evaluated the feasibility of a serial code accelerator core with 3-D DRAM stacked on the core operating at high frequencies. While operating at such high frequencies (>24 GHz), there are concerns with removing heat from the 3-D stack. We propose the use of thin diamond sheets, which have high thermal conductivity, as a heat spreader by bonding it close to the processor core substrate and memory stacks. We show, through thermal modeling using COMSOL finite-element analysis tools, the feasibility of diamond as an effective heat spreader in a processor-memory 3-D stack.

Precision medicine is a rapidly growing area of modern medical science and open source machine-learning codes promise to be a critical component for the successful development of standardized and automated analysis of patient data. One important goal of precision cancer medicine is the accurate prediction of optimal drug therapies from the genomic profiles of individual patient tumors. We introduce here an open source software platform that employs a highly versatile support vector machine (SVM) algorithm combined with a standard recursive feature elimination (RFE) approach to predict personalized drug responses from gene expression profiles. Drug specific models were built using gene expression and drug response data from the National Cancer Institute panel of 60 human cancer cell lines (NCI-60). The models are highly accurate in predicting the drug responsiveness of a variety of cancer cell lines including those comprising the recent NCI-DREAM Challenge. We demonstrate that predictive accuracy is optimized when the learning dataset utilizes all probe-set expression values from a diversity of cancer cell types without pre-filtering for genes generally considered to be "drivers" of cancer onset/progression. Application of our models to publically available ovarian cancer (OC) patient gene expression datasets generated predictions consistent with observed responses previously reported in the literature. By making our algorithm "open source", we hope to facilitate its testing in a variety of cancer types and contexts leading to community-driven improvements and refinements in subsequent applications.

Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis. Indeed, TE insertion mutations have been implicated in the etiology of a number of different cancer types. Nevertheless, the full extent of somatic TE activity, along with its relationship to tumorigenesis, have yet to be fully explored. Recent developments in bioinformatics software make it possible to analyze TE expression levels and TE insertional activity directly from transcriptome (RNA-seq) and whole genome (DNA-seq) next-generation sequence data. We applied these new sequence analysis techniques to matched normal and primary tumor patient samples from the Cancer Genome Atlas (TCGA) in order to analyze the patterns of TE expression and insertion for three cancer types: breast invasive carcinoma, head and neck squamous cell carcinoma, and lung adenocarcinoma. Our analysis focused on the three most abundant families of active human TEs: Alu, SVA and L1. We found evidence for high levels of somatic TE activity for these three families in normal and cancer samples across diverse tissue types. Abundant transcripts for all three TE families were detected in both normal and cancer tissues along with an average of ~80 unique TE insertions per individual patient/tissue. We observed an increase in L1 transcript expression and L1 insertional activity in primary tumor samples for all three cancer types. Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis. We used genome feature analysis to investigate two specific cases of putative cancer-causing TE mutations in further detail. An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma. Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.

This study examines how entrepreneurial marketing dimensions (proactiveness, opportunity focused, leveraging, innovativeness, risk taking, value creation, and customer intensity) are related to qualitative and quantitative outcome measures for the SME and the entrepreneur (including company success, customer success, financial success, satisfaction with return goals, satisfaction with growth goals, excellence, and the entrepreneurʼs standard of living). Using factor analysis, three success outcome variables (financial, customer, and strong company success) emerged together. A separate factor analysis identified satisfactory growth and return goals. Stepwise regression revealed entrepreneurial marketing impacts outcome variables, particularly value creation. Implications for entrepreneurs and areas for research are included.

Abstract We monitored 142 radiocollared adult (≥1.0 yr old) white‐tailed deer (Odocoileus virginianus) in 3 study areas of Massachusetts, USA, to estimate annual survival and mortality due to legal hunting. We then applied these rates to deer harvest information to estimate deer population trends over time, and compared these to trends derived solely from harvest data estimates. Estimated adult female survival rates were similar (0.82–0.86), and uniformly high, across 3 management zones in Massachusetts that differed in landscape composition, human density, and harvest regulations. Legal hunting accounted for 16–29% of all adult female mortality. Estimated adult male survival rates varied from 0.55 to 0.79, and legal hunting accounted for 40–75% of all mortality. Use of composite hunting mortality rates produced realistic estimates for adult deer populations in 2 zones, but not for the third, where estimation was hindered by regulatory restrictions on antlerless deer harvest. In addition, the population estimates we calculated were generally higher than those derived from population reconstruction, likely due to relatively low harvest pressure. Legal harvest may not be the dominant form of deer mortality in developed landscapes; thus, estimates of populations or trends that rely solely on harvest data will likely be underestimates. © 2011 The Wildlife Society.

We present a rigorous electrical and optical analysis of a strained and graded base SiGe Heterojunction Bipolar Transistor (HBT) electrooptic (EO) modulator. In this paper, we propose a 2-D model for a graded base SiGe HBT structure that is capable of operating at a data bit rate of 80 Gbit/s or higher. In this structure, apart from a polysilicon/monosilicon emitter (Width = 0.12 μm) and a strained SiGe graded base (Depth = 40 nm) , a selectively implanted collector (SIC) (Depth = 0.6 μm) is introduced. Furthermore, the terminal characteristics of this new device modeled using MEDICI are closely compared with the SiGe HBT in the IBM production line, suggesting the possibility of fast deployment of the EO modulator using established commercial processing. At a subcollector depth of 0.4 μm and at a base-emitter swing of 0 to 1.1 V, this model predicts a rise time of 5.1 ps and a fall time of 3.6 ps. Optical simulations predict a π phase shift length (Lπ) of 240.8 μm with an extinction ratio of 7.5 dB at a wavelength of 1.55 μm. Additionally, the tradeoff between the switching speed, Lπ and propagation loss with a thinner subcollector is analyzed and reported.

We present a rigorous electrical and optical analysis of a highly scaled, graded-base, SiGe heterojunction bipolar transistor (HBT) electrooptic (EO) modulator. In this study, we propose a 2-D electrical model and a 3-D optical model for a graded-base SiGe HBT structure that is capable of operating at a data bit rate of 250 Gbit/s or higher. In this structure, apart from a polysilicon/low doped emitter ( width = 90 nm) and a strained SiGe graded base ( depth = 8.5 nm), a selectively implanted collector (SIC) (depth = 26 nm) is introduced. Furthermore, at a base-emitter swing of 0 to 1.0 V, this model predicts a rise time of 3.48 ps and a fall time of 0.55 ps. Optical simulations predict a π phase shift length (Lπ) of 204 μm, with an extinction ratio of 13.2 dB at a wavelength of 1.55 μm.

Spatial regulation is often encountered as a component of multi-tiered regulatory systems in eukaryotes, where processes are readily segregated by organelle boundaries. Well-characterized examples of spatial regulation are less common in bacteria. Low-fidelity DNA polymerase V (UmuD'2C) is produced in Escherichia coli as part of the bacterial SOS response to DNA damage. Due to the mutagenic potential of this enzyme, pol V activity is controlled by means of an elaborate regulatory system at transcriptional and posttranslational levels. Using single-molecule fluorescence microscopy to visualize UmuC inside living cells in space and time, we now show that pol V is also subject to a novel form of spatial regulation. After an initial delay (~ 45 min) post UV irradiation, UmuC is synthesized, but is not immediately activated. Instead, it is sequestered at the inner cell membrane. The release of UmuC into the cytosol requires the RecA* nucleoprotein filament-mediated cleavage of UmuD→UmuD'. Classic SOS damage response mutants either block [umuD(K97A)] or constitutively stimulate [recA(E38K)] UmuC release from the membrane. Foci of mutagenically active pol V Mut (UmuD'2C-RecA-ATP) formed in the cytosol after UV irradiation do not co-localize with pol III replisomes, suggesting a capacity to promote translesion DNA synthesis at lesions skipped over by DNA polymerase III. In effect, at least three molecular mechanisms limit the amount of time that pol V has to access DNA: (1) transcriptional and posttranslational regulation that initially keep the intracellular levels of pol V to a minimum; (2) spatial regulation via transient sequestration of UmuC at the membrane, which further delays pol V activation; and (3) the hydrolytic activity of a recently discovered pol V Mut ATPase function that limits active polymerase time on the chromosomal template.

Myelination of axons is important for central nervous system function, but oligodendrocytes, which constitute CNS myelin, are vulnerable to excitotoxic injury and death. Although mature oligodendrocytes express functional α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) and kainate-type glutamate receptors, the relative roles of these subtypes in excitotoxicity are not well understood. Using recently developed selective antagonists for subtypes of ionotropic non-NMDA receptors, we addressed this issue. By examining the pharmacological, biochemical, and morphologic features of kainite-induced excitotoxic death, we also determined whether it occurs by apoptosis, necrosis, or both. We conclude that when mature oligodendrocytes die after exposure to kainate: (1) AMPA receptors are the most important mediators, (2) kainate receptors play a smaller role, and (3) death occurs predominantly by necrosis, not apoptosis.

INTRODUCTION:Recently, multicellular spheroids were isolated from a well-established epithelial ovarian cancer cell line, OVCAR-3, and were propagated in vitro. These spheroid-derived cells displayed numerous hallmarks of cancer stem cells, which are chemo- and radioresistant cells thought to be a significant cause of cancer recurrence and resultant mortality. Gene set enrichment analysis of expression data from the OVCAR-3 cells and the spheroid-derived putative cancer stem cells identified several metabolic pathways enriched in differentially expressed genes. Before this, there had been little previous knowledge or investigation of systems-scale metabolic differences between cancer cells and cancer stem cells, and no knowledge of such differences in ovarian cancer stem cells. METHODS:To determine if there were substantial metabolic changes corresponding with these transcriptional differences, we used two-dimensional gas chromatography coupled to mass spectrometry to measure the metabolite profiles of the two cell lines. RESULTS:These two cell lines exhibited significant metabolic differences in both intracellular and extracellular metabolite measurements. Principal components analysis, an unsupervised dimensional reduction technique, showed complete separation between the two cell types based on their metabolite profiles. Pathway analysis of intracellular metabolomics data revealed close overlap with metabolic pathways identified from gene expression data, with four out of six pathways found enriched in gene-level analysis also enriched in metabolite-level analysis. Some of those pathways contained multiple metabolites that were individually statistically significantly different between the two cell lines, with one of the most broadly and consistently different pathways, arginine and proline metabolism, suggesting an interesting hypothesis about cancerous and stem-like metabolic phenotypes in this pair of cell lines. CONCLUSIONS:Overall, we demonstrate for the first time that metabolism in an ovarian cancer stem cell line is distinct from that of more differentiated isogenic cancer cells, supporting the potential importance of metabolism in the differences between cancer cells and cancer stem cells.

BACKGROUND: Clinicians often rely on review material rather than analysis of primary research to guide therapy. Systematic reviews use methods to insure thoroughness and to minimize bias, but many clinicians are not familiar with systematic reviews and continue to rely on narrative reviews.

MicroRNAs have emerged in recent years as important regulators of cell function in both normal and diseased cells. MiRNAs coordinately regulate large suites of target genes by mRNA degradation and/or translational inhibition. The mRNA target specificities of miRNAs in animals are primarily encoded within a 7 nt "seed region" mapping to positions 2-8 at the molecule's 5' end. We here combine computational analyses with experimental studies to explore the functional significance of sequence variation within the seed region of human miRNAs. The results indicate that a substitution of even a single nucleotide within the seed region changes the spectrum of mRNA targets by >50%. The high functional cost of even single nucleotide changes within seed regions is consistent with their high sequence conservation among miRNA families both within and between species and suggests processes that may underlie the evolution of miRNA regulatory control.

The posterior medial frontal cortex (pMFC) is known to be involved in adaptive goal-directed behavior, but its specific function is not yet clear. Most theories have proposed that the pMFC monitors performance in a reactive manner only, but it is possible that the pMFC also contributes to performance monitoring in a proactive manner. To date, the evidence for proactive pMFC activity is equivocal. Here, we investigated pMFC activity before, during and after the performance of a challenging motor task. Participants navigated a cursor through narrow and wide mazes in randomly intermixed trials. On each trial, participants saw previews of the actual maze display prior to gaining control of the cursor. Event-related potentials (ERPs) to the preview displays were compared to ERPs elicited by no-go signals and errors. Compared to the wider maze, the preview display for the more challenging narrow maze elicited a medial-frontal negativity (MFN) similar to the ERP components elicited by no-go signals and errors. Like these known ERP components, the preview-elicited MFN appeared to be generated from a source in pMFC. This is consistent with the hypothesis that the pMFC participates in adaptive behavior whenever there is a need for increased effort to maintain successful task performance.

Stringent steric exclusion mechanisms limit the misincorporation of ribonucleotides by high-fidelity DNA polymerases into genomic DNA. In contrast, low-fidelity Escherichia coli DNA polymerase V (pol V) has relatively poor sugar discrimination and frequently misincorporates ribonucleotides. Substitution of a steric gate tyrosine residue with alanine (umuC_Y11A) reduces sugar selectivity further and allows pol V to readily misincorporate ribonucleotides as easily as deoxynucleotides, whilst leaving its poor base-substitution fidelity essentially unchanged. However, the mutability of cells expressing the steric gate pol V mutant is very low due to efficient repair mechanisms that are triggered by the misincorporated rNMPs. Comparison of the mutation frequency between strains expressing wild-type and mutant pol V therefore allows us to identify pathways specifically directed at ribonucleotide excision repair (RER). We previously demonstrated that rNMPs incorporated by umuC_Y11A are efficiently removed from DNA in a repair pathway initiated by RNase HII. Using the same approach, we show here that mismatch repair and base excision repair play minimal back-up roles in RER in vivo. In contrast, in the absence of functional RNase HII, umuC_Y11A-dependent mutagenesis increases significantly in ΔuvrA, uvrB5 and ΔuvrC strains, suggesting that rNMPs misincorporated into DNA are actively repaired by nucleotide excision repair (NER) in vivo. Participation of NER in RER was confirmed by reconstituting ribonucleotide-dependent NER in vitro. We show that UvrABC nuclease-catalyzed incisions are readily made on DNA templates containing one, two, or five rNMPs and that the reactions are stimulated by the presence of mispaired bases. Similar to NER of DNA lesions, excision of rNMPs proceeds through dual incisions made at the 8(th) phosphodiester bond 5' and 4(th)-5(th) phosphodiester bonds 3' of the ribonucleotide. Ribonucleotides misinserted into DNA can therefore be added to the broad list of helix-distorting modifications that are substrates for NER.

Neurological recovery in patients with severe spinal cord injury (SCI) is extremely rare. We have identified a patient with chronic cervical traumatic SCI, who suffered a complete loss of motor and sensory function below the injury for six weeks after the injury, but experienced a progressive neurological recovery that continued for 17 years. The extent of the patient’s recovery from the severe trauma-induced paralysis is rare and remarkable. A detailed study of this patient using diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and resting state fMRI (rs-fMRI) revealed structural and functional changes in the central nervous system that may be associated with the neurological recovery. 62% cervical cord white matter atrophy was observed. DTI-derived quantities, more sensitive to axons, demonstrated focal changes, while MTI-derived quantity, more sensitive to myelin, showed a diffuse change. No significant cortical structural changes were observed, while rs-fMRI revealed increased brain functional connectivity between sensorimotor and visual networks. The study provides comprehensive description of the structural and functional changes in the patient using advanced MR imaging technique. This multimodal MR imaging study also shows the potential of rs-fMRI to measure the extent of cortical plasticity.