Prevalence of Trachoma After Three Rounds of Antibiotic Mass Drug Administration in 13 Woredas of Gambella Region, Ethiopia.

Background: Following baseline surveys in 2013 and 2014, trachoma elimination interventions, including three rounds of azithromycin mass drug administration (MDA), were implemented in 13 woredas (administrative districts) of Gambella Regional State, Ethiopia. We conducted impact surveys to determine if elimination thresholds have been met or if additional interventions are required.

Methods: Cross-sectional population-based surveys were conducted in 13 woredas of Gambella Regional State, combined into five evaluation units (EUs), 6─12 months after their last MDA round.

ECG Arrhythmia Classification on an Ultra-Low-Power Microcontroller.

Wearable biomedical systems allow doctors to continuously monitor their patients over longer periods, which is especially useful to detect rarely occurring events such as cardiac arrhythmias. Recent monitoring systems often embed signal processing capabilities to directly identify events and reduce the amount of data. This work is the first to document a complete beat-to-beat arrhythmia classification system implemented on a custom ultra-low-power microcontroller.

Humanity's Attitudes about Democracy and Political Leaders: Patterns and Trends.

For decades, researchers have examined people's beliefs across countries and over time using national samples of citizens. Yet, in an era when economies, societies, and policymaking have become increasingly interconnected, nation-states may no longer be the only or most relevant units of analysis for studying public opinion. To examine what people think about politics on a global scale, we develop tools for measuring public opinion that allow us to transcend national and regional boundaries.

Learning Without Feedback: Fixed Random Learning Signals Allow for Feedforward Training of Deep Neural Networks.

While the backpropagation of error algorithm enables deep neural network training, it implies (i) bidirectional synaptic weight transport and (ii) update locking until the forward and backward passes are completed. Not only do these constraints preclude biological plausibility, but they also hinder the development of low-cost adaptive smart sensors at the edge, as they severely constrain memory accesses and entail buffering overhead. In this work, we show that the one-hot-encoded labels provided in supervised classification problems, denoted as targets, can be viewed as a proxy for the error sign.

MorphIC: A 65-nm 738k-Synapse/mm Quad-Core Binary-Weight Digital Neuromorphic Processor With Stochastic Spike-Driven Online Learning.

Recent trends in the field of neural network accelerators investigate weight quantization as a means to increase the resource- and power-efficiency of hardware devices. As full on-chip weight storage is necessary to avoid the high energy cost of off-chip memory accesses, memory reduction requirements for weight storage pushed toward the use of binary weights, which were demonstrated to have a limited accuracy reduction on many applications when quantization-aware training techniques are used. In parallel, spiking neural network (SNN) architectures are explored to further reduce power when processing sparse event-based data streams, while on-chip spike-based online learning appears as a key feature for applications constrained in power and resources during the training phase.

A 0.086-mm 12.7-pJ/SOP 64k-Synapse 256-Neuron Online-Learning Digital Spiking Neuromorphic Processor in 28-nm CMOS.

Shifting computing architectures from von Neumann to event-based spiking neural networks (SNNs) uncovers new opportunities for low-power processing of sensory data in applications such as vision or sensorimotor control. Exploring roads toward cognitive SNNs requires the design of compact, low-power and versatile experimentation platforms with the key requirement of online learning in order to adapt and learn new features in uncontrolled environments. However, embedding online learning in SNNs is currently hindered by high incurred complexity and area overheads.

A mixed-utility theory of vote choice regret.

The paper builds upon an original pre- and post-election survey that we conducted before and after the 2015 Canadian election. Directly after Election Day, we asked Canadians for which party they voted, and whether they regret their choice. We find that 39% of them are not perfectly happy with their decision, and 4% even say that they made a bad decision.

A phase I dose-ranging study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of AVN944, an IMPDH inhibitor, in healthy male volunteers.

A phase I study of AVN944, an inosine monophosphate dehydrogenase (IMPDH) inhibitor, was carried out to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics. Healthy male volunteers (N = 25) participated in this double-blind, randomized, placebo-controlled trial. Sixteen received oral doses ranging from 25 to 250 mg on 3 separate occasions at intervals of 3 or 6 days after overnight fasting.

Constitutively active receptor tyrosine kinases as oncogenes in preclinical models for cancer therapeutics.

Receptor tyrosine kinases (RTK) remain an area of therapeutic interest because of their role in epithelial tumors, and experimental models specific to these targets are highly desirable. Chimeric receptors were prepared by in-frame fusion of the CD8 extracellular sequence with the cytoplasmic sequences of RTKs. A CD8HER2 fusion protein was shown to form disulfide-mediated homodimers and to transform fibroblasts and epithelial cells.

Gene expression profiling in the discovery, optimization and development of novel drugs: one universal screening platform.

With recent advances in robotics and high-content screening and analysis methods, transcriptional profiling can now be utilized as a comprehensive forward chemical genomics platform for drug discovery, lead selection and lead optimization. It can be used to define the state of a cell on the basis of gene networks, and to search for drugs that can shift cellular states in a manner predicted at the genome level to be therapeutically beneficial. The treatment of cells with compounds produces transcriptional 'fingerprints' that reveal mechanism-of-action, and enable discrimination between individual compounds based on drug behaviors important to all phases of drug discovery and development.

Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.

The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization.

Induction of ornithine decarboxylase activity is a necessary step for mitogen-activated protein kinase kinase-induced skin tumorigenesis.

A transgenic mouse line overexpressing a constitutively active mutant of MEK1, a downstream effector of Ras, driven by the keratin 14 (K14) promoter, has been used to test the hypothesis that ornithine decarboxylase (ODC) induction during tumor promotion following a single initiating event [i.e., the activation of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway], is a necessary step in skin carcinogenesis.

Apoptotic and cytostatic farnesyltransferase inhibitors have distinct pharmacology and efficacy profiles in tumor models.

BMS-214662 and BMS-225975 are tetrahydrobenzodiazepine-based farnesyltransferase inhibitors (FTIs) that have nearly identical structures and very similar pharmacological profiles associated with farnesyltransferase (FT) inhibition. Despite their similar activity against FT in vitro and in cells, these compounds differ dramatically in their apoptotic potency and tumor-regressing activity in vivo. BMS-214662 is the most potent apoptotic FTI known and exhibits curative responses in mice bearing a variety of staged human tumor xenografts such as HCT-116 human colon tumor.

Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis.

In this study, we generated transgenic mice that overexpressed either a constitutively active human c-src mutant (src(530)) or a wild-type human c-src (src(wt)) in epidermal basal cells driven by human keratin 14 (HK14) or bovine keratin 5 (BK5) promoters, respectively. HK14.src(530) transgenic mice developed severe epidermal hyperplasia and hyperkeratosis, and did not survive beyond 3 weeks of age.

Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells.

Brain cells produce cytokines and chemokines during the inflammatory process after stroke both in animal models and in patients. Monocyte chemoattractant protein 1 (MCP-1), one of the proinflammatory chemokines, can attract monocytes to the tissue where MCP-1 is overexpressed. However, the role of MCP-1 elevation in stroke has not been explored in detail.

Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities.

High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared.

Cyclooxygenase-2 overexpression in the skin of transgenic mice results in suppression of tumor development.

Significant evidence has accumulated suggesting that the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin biosynthetic pathway, plays an important role in tumor development. To better understand the role of COX-2 in tumorigenesis, we generated transgenic mice that overexpress COX-2 under control of the human keratin 14 promoter, which allows for expression in the epidermis and some other epithelia. Transgenic mice, referred to as K14.

Constitutive expression of erbB2 in epidermis of transgenic mice results in epidermal hyperproliferation and spontaneous skin tumor development.

The erbB family of receptor tyrosine kinases, which consists of the epidermal growth factor receptor (EGFr/erbB1), erbB2 (neu), erbB3 and erbB4, has been shown to be important for both normal development as well as neoplasia. The expression of rat erbB2 was targeted to the basal layer of mouse epidermis with the bovine keratin 5 promoter. Overexpression of wild type rat erbB2 in the basal layer of epidermis led to alopecia, follicular hyperplasia and sebaceous gland enlargement as well as hyperplasia of the interfollicular epidermis.

Constitutive expression of insulin-like growth factor-1 in epidermal basal cells of transgenic mice leads to spontaneous tumor promotion.

Transgenic mice overexpressing insulin-like growth factor-1 (IGF-1) in the basal layer of skin epidermis were generated using the bovine keratin 5 promoter (BK5). Neonatal transgenic mice were slightly smaller at birth and exhibited early ear unfolding, wrinkled and thickened skin, and slightly enlarged ears compared with nontransgenic littermates. Morphological evaluation of the skin revealed that persistent overexpression of IGF-1 in the basal layer of the epidermis resulted in epidermal hyperplasia, hyperkeratosis, and an increased labeling index that persisted in adult mice.

Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice.

Transgenic mice expressing human insulin-like growth factor 1 (IGF-1) in basal epithelial cells of prostate have been characterized. Transgene expression led to activation of the IGF-1 receptor and spontaneous tumorigenesis in prostate epithelium. Hyperplasia was evident in these mice by 2-3 months of age.

Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice.

Insulin-like growth factor-1 (IGF-1) and its receptor are believed to play an important role in mitogenesis and neoplastic transformation. The purpose of this study was to further examine the role of IGF-1 during tumor promotion in mouse skin. HK1.

Severe follicular hyperplasia and spontaneous papilloma formation in transgenic mice expressing the neu oncogene under the control of the bovine keratin 5 promoter.

Transgenic mice were developed to explore the role of the erbB2 during epithelial homeostasis and tumorigenesis, through targeted expression of the neu oncogene (neu*). Expression of a neu* cDNA was targeted to the basal layer of skin epidermis as well as other epithelial tissues of transgenic mice via the bovine keratin 5 promoter. Two transgenic founders were obtained that were morphologically distinguishable from non-transgenic littermates by their visibly thickened skin and patchy hair growth by day 3 after birth.

Changes in protein expression during multistage mouse skin carcinogenesis.

To directly compare the expression patterns of different proteins known to be altered during mouse skin carcinogenesis, serial sections of normal and hyperplastic skin and tumors from various stages of 7,12-dimethylbenz[a]anthracene-initiated, 12-O-tetradecanoylphorbol-13-acetate-promoted female SENCAR mice were examined by immunohistochemistry. In untreated, normal mouse skin, keratin 1 (K1) and transforming growth factor-beta1 (TGFbeta1) were strongly expressed in the suprabasal layers, whereas integrin alpha6beta4 was expressed only in basal cells and only moderate staining for transforming growth factor-alpha (TGFalpha) was seen. In hyperplastic skin, TGFalpha expression became stronger, whereas expression of another epidermal growth factor (EGF) receptor ligand, heparin-binding EGF-like growth factor (HB-EGF), was strongly induced in all epidermal layers from no expression in normal skin.

Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice.

Transgenic animals were developed to assess the role of insulin-like growth factor 1 (IGF-1) in skin growth, differentiation and organization, as well as its importance in tumor formation. Expression of a human IGF-1 cDNA was targeted to the interfollicular epidermis of transgenic mice using a human keratin 1 promoter construct (HK1). Transgenic animals (HK1.

Altered expression of insulin-like growth factor I and its receptor during multistage carcinogenesis in mouse skin.

We examined the possible role of insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-Ir) during multistage carcinogenesis in mouse skin. For this purpose, the expression of both IGF-I and IGF-Ir was investigated in mouse skin during tumor promoter treatment and in primary papillomas and squamous cell carcinomas (SCCs) obtained from SENCAR mice treated with standard initiation-promotion regimens. IGF-I transcripts were not detectable or only weakly detectable in normal SENCAR mouse epidermis by northern or reverse transcription (RT)-polymerase chain reaction (PCR) analysis, respectively, whereas IGF-I transcripts (primarily a 7.