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The explosive growth in cloud-computing and overall data center system growth has created an unprecedented demand on system architects and designers to continuously develop more complex system networks to effectively satisfy the insatiable appetite to process, move, and store large amounts of data. Nonlinear system behavior caused by emerging workloads and use-cases, varying end-to-end congestion protocols, and heterogeneity in the various compute and storage capabilities of custom designed accelerators further compounds the design problem. Modern simulation methodologies lack a cohesive and efficient framework to address the interoperability of the intersecting layers at scale. In this paper, we present a simulation framework for evaluating congestion control protocols. Furthermore, we present a set of optimizations that enable analysis for longer simulated times and at network scales up to 128K nodes, which is vital for proper analysis of workloads that require long run times (e.g., AI training) or workloads that are known to have scaling issues (e.g., RDMA). Specifically, we evaluate congestion control performance at various scales, study the implications of topology scaling on congestion, and the performance impact of simultaneous heterogeneous protocols.

The outbreak and transmission of disease-causing pathogens are contributing to the unprecedented rate of biodiversity decline. Recent advances in genomics have coalesced into powerful tools to monitor, detect, and reconstruct the role of pathogens impacting wildlife populations. Wildlife researchers are thus uniquely positioned to merge ecological and evolutionary studies with genomic technologies to exploit unprecedented “Big Data” tools in disease research; however, many researchers lack the training and expertise required to use these computationally intensive methodologies. To address this disparity, the inaugural “Genomics of Disease in Wildlife” workshop assembled early to mid-career professionals with expertise across scientific disciplines (e.g., genomics, wildlife biology, veterinary sciences, and conservation management) for training in the application of genomic tools to wildlife disease research. A horizon scanning-like exercise, an activity to identify forthcoming trends and challenges, performed by the workshop participants identified and discussed 5 themes considered to be the most pressing to the application of genomics in wildlife disease research: 1) “Improving communication,” 2) “Methodological and analytical advancements,” 3) “Translation into practice,” 4) “Integrating landscape ecology and genomics,” and 5) “Emerging new questions.” Wide-ranging solutions from the horizon scan were international in scope, itemized both deficiencies and strengths in wildlife genomic initiatives, promoted the use of genomic technologies to unite wildlife and human disease research, and advocated best practices for optimal use of genomic tools in wildlife disease projects. The results offer a glimpse of the potential revolution in human and wildlife disease research possible through multi-disciplinary collaborations at local, regional, and global scales.

The value of prophylactic neonatal vaccination is challenged by the interference of passively transferred maternal antibodies and immune competence at birth. Taken our previous studies on equine B cell ontogeny, we hypothesized that the equine neonate generates a diverse immunoglobulin repertoire in response to vaccination, independently of circulating maternal antibodies. In this study, equine neonates were vaccinated with 3 doses of keyhole limpet hemocyanin (KLH) or equine influenza vaccine, and humoral immune responses were assessed using antigen-specific serum antibodies and B cell Ig variable region sequencing. An increase (p

Sensitive detection of protein interactions is a critical step toward understanding complex cellular processes. As an alternative to fluorescence-based detection, Renilla reniformis luciferase conjugated to quantum dots results in self-illuminating bioluminescence resonance energy transfer quantum dot (BRET-Qdot) nanoprobes that emit red to near-infrared bioluminescence light. Here, we report the development of an ultrasensitive technology based on BRET-Qdot conjugates modified with streptavidin ([BRET-Qdot]-SA) to detect cell-surface protein interactions. Transfected COS7 cells expressing human cell-surface proteins were interrogated with a human Fc tagged protein of interest. Specific protein interactions were detected using a biotinylated anti-human Fc region specific antibody followed by incubation with [BRET-Qdot]-SA. The luciferase substrate coelenterazine activated bioluminescence light emission was detected with an ultra-fast and -sensitive imager. Protein interactions barely detectable by the fluorescence-based approach were readily quantified using this technology. The results demonstrate the successful application and the flexibility of the BRET-Qdot-based imaging technology to the ultrasensitive investigation of cell-surface proteins and protein-protein interactions.

Signaling pathways that respond to DNA damage are essential for the maintenance of genome stability and are linked to many diseases, including cancer. Here, a genome-wide siRNA screen was employed to identify additional genes involved in genome stabilization by monitoring phosphorylation of the histone variant H2AX, an early mark of DNA damage. We identified hundreds of genes whose downregulation led to elevated levels of H2AX phosphorylation (gammaH2AX) and revealed links to cellular complexes and to genes with unclassified functions. We demonstrate a widespread role for mRNA-processing factors in preventing DNA damage, which in some cases is caused by aberrant RNA-DNA structures. Furthermore, we connect increased gammaH2AX levels to the neurological disorder Charcot-Marie-Tooth (CMT) syndrome, and we find a role for several CMT proteins in the DNA-damage response. These data indicate that preservation of genome stability is mediated by a larger network of biological processes than previously appreciated.

The measurement of ligand receptor binding parameters for G-protein-coupled receptors is indispensable in the drug discovery process. Traditional ligand receptor binding assays require scale-up of cells and membrane preparations, which is an expensive and time-consuming process. In this report, the authors describe the development of a homogeneous live-cell binding assay for GPCRs using a fluorophore-labeled nonpeptide ligand. The model assay used Cy3B-labeled telenzepine and Chinese hamster ovary cells expressing M1 muscarinic acetylcholine receptors. This homogeneous live-cell fluorescence binding assay format is superior to the traditional binding methods because it measures binding of a ligand to intact receptors on living cells. The assay requires no washing or separation steps, thereby allowing a real-time kinetic readout for the determination of ligand association and dissociation from the intact receptors. The results also suggest that miniaturization is feasible without compromising the data quality.

Common variable immunodeficiency (CVID) is a late-onset humoral deficiency characterized by B lymphocyte dysfunction or loss, decreased immunoglobulin production, and recurrent bacterial infections. CVID is the most frequent human primary immunodeficiency but still presents challenges in the understanding of its etiology and treatment. CVID in equine patients manifests with a natural impairment of B lymphocyte differentiation, and is a unique model to identify genetic and epigenetic mechanisms of disease. Bone marrow transcriptome analyses revealed decreased expression of genes indicative of the pro-B cell differentiation stage, importantly PAX5 (p≤0.023). We hypothesized that aberrant epigenetic regulation caused PAX5 gene silencing, resulting in the late-onset and non-familial manifestation of CVID. A significant increase in PAX5 enhancer region methylation was identified in equine CVID patients by genome-wide reduced-representation bisulfite sequencing and bisulfite PCR sequencing (p=0.000). Thus, we demonstrate that integrating transcriptomics and epigenetics in CVID enlightens potential mechanisms of dysfunctional B lymphopoiesis or function.

A mouse model system for studying the effect of ultraviolet (uv) radiation on reporter gene expression directed by the human immunodeficiency virus type 1 long-terminal repeat (HIV-LTR) has been developed to address the signals required for LTR trans-activation in cells with the reporter gene stably integrated into the genome. In a stable mouse L cell clone, L-15, NF-kappaB DNA binding activity induced by uv-C (254 nm) but not by tumor necrosis factor-alpha (TNF-alpha) or 12-O-tetra-decanoylphorbol-13-acetate (TPA) correlated with the stimulation of HIV-LTR-directed chloramphenicol acetyltransferase (CAT) activity; uv-C was more effective than uv-B (312 nm), while uv-A (365 nm) had little effect on CAT activity. Inducers of oxidative stress, such as H2O2 treatment up to 200 microM or ionizing radiation up to 20 Gy, also had little effect on CAT expression. Pyrrolidine dithiocarbamate (PDTC) inhibited NF-kappaB DNA binding and stimulation of CAT activity by uv-C in a dose-dependent manner. Unexpectedly, PDTC induced NF-kappaB DNA binding that was additive with the response with TNF. In an effort to separate uv irradiation and uv-induced DNA damage from transactivation of the HIV-LTR we devised a heterokaryon system. The fusion of uv-irradiated human fibroblasts with a mouse L cell clone containing the HIV-LTR-directed lacZ gene resulted in the activation of lacZ activity that was detected in heterokaryons at the single-cell level. These data suggest that uv-induced DNA damage in the chromosomal DNA containing the reporter gene cannot explain activation of the HIV-LTR. This finding demonstrates LTR trans-activation in a nonirradiated genome.

New in vivo imaging reagents with increased sensitivity and penetration depth are needed to advance our understanding of metastases and accelerate the development of therapeutics. The folate receptor (FR) is a promising imaging target that is up-regulated in many human carcinomas, including cancers of the ovary, breast, pancreas, endometrium, lungs, kidneys, colon, brain, and myeloid cells. Zymera has developed a self-illuminating Bioluminescence Resonance Energy Transfer Quantum Dot (BRET-Qdot) nanoprobe conjugated with folate (BQ-Folate) for in vivo imaging of cancers overexpressing FR. BQ-Folate is a novel nanoprobe formed by co-conjugating Renilla reniformis luciferase enzyme and folate to near-infrared (NIR) emitting quantum dots. The luciferase substrate, coelenterazine, activates the BQ-Folate nanoprobe generating luminescence emission in the near-infrared (NIR) region (655 nm) for increased sensitivity and penetration depth. Because BQ-Folate requires no external light source for light emission, it has significant advantages for challenging in vivo preclinical optical imaging applications, such as the detection of early stage metastases. Zymera and OncoMed Pharmaceuticals have demonstrated that in vivo imaging with the BQ-Folate nanoprobe detected the primary tumor and early stage metastases in an orthotopic NOD/SCID mouse model of human pancreatic cancer.

Autofluorescence arising from normal tissues can compromise the sensitivity and specificity of in vivo fluorescence imaging by lowering the target-to-background signal ratio. Since bioluminescence resonance energy transfer quantum dot (BRET-QDot) nano-particles can self-illuminate in near-infrared in the presence of the substrate, coelenterazine, without irradiating excitation lights, imaging using BRET-QDots does not produce any autofluorescence. In this study, we applied this BRET-QDot nano-particle to the in vivo lymphatic imaging in mice in order to compare with BRET, fluorescence or bioluminescence lymphatic imaging. BRET-QDot655, in which QDot655 is contained as a core, was injected at different sites (e.g. chin, ear, forepaws and hind paws) in mice followed by the intravenous coelenterazine injection, and then bioluminescence and fluorescence imaging were serially performed. In all mice, each lymphatic basin was clearly visualized in the BRET imaging with minimal background signals. The BRET signal in the lymph nodes lasted at least 30 min after coelenterazine injections. Furthermore, the BRET signal demonstrated better quantification than the fluorescence signal emitting from QDot655, the core of this BRET particle. These advantages of BRET-QDot allowed us to perform real-time, quantitative lymphatic imaging without image processing. BRET-Qdots have the potential to be a robust nano-material platform for developing optical molecular imaging probes.

Sound speed variations within the human body degrade contrast and resolution in ultrasound images. Many algorithms have been proposed to compensate for these variations, but few have been tested on human subjects. We describe a programmable, adaptive imager that allows the realtime implementation of a wide class of algorithms, those which modify the imager's beamforming based upon individual transducer signals. A GE LOGIQ 700 imager is connected to a commercial multiprocessor system. The imager's channel data are captured in the multiprocessor system, which calculates arrival time errors for each beamforming channel. These errors are used to correct the imager's beamforming time delays at the acoustic frame rate. We describe an algorithm which iteratively estimates time-delay errors by correlating the signal from each element in a multirow transducer with the beamsum signal. The system successfully corrects for two-dimensional model aberrations during realtime scanning of tissue-mimicking phantoms and human subjects.

B-flow is a new technique that extends the resolution, frame rate, and dynamic range of B-mode to simultaneously image blood flow and tissue. B-flow relies on coded excitation to boost weak signals from blood scatterers and on tissue equalization to simultaneously display flowing blood and tissue without threshold decision and overlay. Various classes of codes such as Barker and Golay may be used. Clinical B-flow cineloops demonstrate 3/spl times/ resolution and frame rate improvement over color flow, which, together with over 60 dB of display dynamic range, are able to image hemodynamics and vessel walls with unprecedented clarity.

Exposure of wild-type DT40 lymphoma B cells or Bruton's tyrosine kinase (BTK)-deficient DT40 cells reconstituted with the human btk gene to a 1-gauss 60-Hz electromagnetic field (EMF) has been reported to rapidly increase inositol 1,4,5-trisphosphate (Ins 1,4, 5-P3) production (1,2). Here we have used BTK-deficient DT40 B cells reconstituted with the human btk gene to evaluate the reproducibility of these findings. An experimental design with blinded exposures and anti-IgM treatment to induce Ins 1,4,5-P3 production as a positive control, showed no significant effect of a 1-gauss 60-Hz EMF on Ins 1,4,5-P3 production. Because recent work has shown that the activation of BTK was required for EMF-responsiveness (2), we also evaluated the reproducibility of this finding in wild-type DT40 cells. BTK was activated in a dose- and time-dependent manner by treatment with the tyrosine phosphatase inhibitor pervanadate. However, the ability to detect BTK activation, as measured by increased autophosphorylation by immune complex kinase assay, was dependent on the kinase buffer. Using cells from the original investigators, no evidence was obtained to support the hypothesis that exposure to a 1-gauss 60-Hz EMF had a causal effect on protein-tyrosine kinase activities affecting Ins 1,4,5-P3 production.

A system and method of ultrasound imaging includes a beamformer including a plurality of channels, a two-dimensional transducer array including a plurality of elements, and a plurality of signal pathways linking the plurality of elements to the plurality of channels. The system and method also include a plurality of switches positioned along the plurality of signal pathways. The plurality of switches being configured to actively connect a subset of the plurality of elements to the plurality of channels in order to form a receive aperture. The plurality of switches are further configured to control an aspect ratio of the receive aperture by changing which of the plurality of elements are actively connected to the plurality of channels.

Pre-existing metastases at the time of diagnosis are often the cause of death in patients suffering from a number of malignancies, including pancreatic cancer and melanoma. Successful development of effective anti-metastatic cancer therapies requires preclinical metastasis models that mimic the clinical condition of human cancer, sensitive methods of metastasis detection in mice bearing orthotopic tumors, and real-time evaluation of anti-metastatic activity of novel treatments. We have developed orthotopic tumor models in NOD/SCID mice utilizing pancreatic and melanoma tumor cells that are derived directly from human cancer patient specimens. These tumors retain much of the original human cancer heterogeneity, phenotype, and the ability to form metastases in the lungs, liver, intestines, and brain _ recapitulating the metastatic invasiveness seen in the clinic. Since the ability of optical imaging methods to detect tumors and metastases in deep tissues is limited by tumor size and light penetration depth, we employed Zymera's Bioluminescence Resonance Energy Transfer-Quantum Dot (BRET-Qdot®) nanoprobes conjugated with streptavidin ([BRET-Qdot]-SA) to improve sensitivity for detection of both early stage primary tumors and small metastases. The cell surface proteins, MCAM in melanoma and EpCAM in pancreatic tumors, were targeted with human specific biotinylated anti-MCAM or -EpCAM antibodies, (respectively) delivered intravenously or intraperitoneally into NOD/SCID mice and detected with the [BRET-Qdot®]-SA nanoprobe. Light emission from the tumor-bound [BRET-Qdot®]-SA was activated by the catalytic conversion of the luciferase substrate coelenterazine. The novel and highly sensitive BRET-Qdot® technology emits 655 nm bioluminescence light for in vivo imaging of deep tissues. This technology allowed the growth of primary tumors and metastases to be measured overtime in the same mice. Moreover, in efficacy studies we have treated the mice with antibodies developed against the human and the murine DLL4 to target both tumor cells and vasculature that cooperate for the formation and growth of primary tumor and metastases. Treatment with anti-DLL4 inhibits metastases in the lungs, liver, intestine and brain. Finally, we have developed a more clinically relevant melanoma metastasis model consisting of the surgical excision of the primary tumor. This model, characterized by an enrichment of aggressive growth of metastases in the lungs, has been also utilized to evaluate the inhibitory activity of anti-DLL4 antibodies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2698. doi:10.1158/1538-7445.AM2011-2698

A medical imaging system is provided that includes a plurality of circuit boards configured to be tested using boundary scan test vectors. A controller of the medical imaging system is configured to test the plurality of circuit boards. The controller is further configured to access test profiles to perform boundary scan tests on the plurality of circuit boards based on the test profiles.

A method of medical ultrasound imaging is provided. The method includes transmitting ultrasound waves into a volume at a first rate, receiving ultrasound echoes for each of the ultrasound waves, each echo is indicative of a density interface within the volume, each set of received echoes that corresponds to a single transmitted wave defines a steering frame, detecting motion of the array transducer, and combining a plurality of steering frames into a compound image based on the detected array transducer motion.

The present invention relates to a method and apparatus providing tissue harmonic imaging using an ultrasound machine. Coded pulses and the phase inverted version of the said coded pulses with time bandwidth greater than 1 are transmitted into the tissue. Backscattered echoes are received and filtered before or after coherent summation. Decoding/compressing of the received echoes of the coded pulses is implemented naturally through the propagation of the specially designed ultrawide band (>80%) waveforms inside tissue and pulse inversion. Costly decoding/compression filter are not necessary.

A method and an apparatus for spatially compounding ultrasound frames by using multiple angle views. Successive image frames of pixel data are processed using a Sum of Absolute Difference registration algorithm. The multiple angle views are achieved by operator manipulation of a probe ( 2 ).

The present invention provides speech and audio user-computer interface mechanisms for accessing and editing information in electronic records. A mechanism is provided by which the user can direct inputs to any of a variety of fields without following a predetermined order of input. This allows the user to be proactive in making entries rather than simply reacting to requirements set by computer-generated prompts. Audio is provided as feedback to the user, not as a fixed path prompt for the user. This feedback can be in the form of non-verbal auditory signals or synthesized speech. The invention uses audio to inform the user of whether or not the system understood the spoken words or phrases as valid inputs to the electronic record, what the system recognized as the input, and to identify the contents of various fields in the electronic record. The precise wording for the speech inputs can be changed from one implementation of the invention to another, depending on what terminology is most meaningful to users, works best with the speech recognition engine being used, etc. Likewise, the audio outputs from the system, both nonverbal sounds and synthesized speech, used in implementing this invention can vary from one application to another.

A number of studies have reported that human leukemia cells respond to exposure to power-line frequency electromagnetic fields (EMFs), providing evidence for an EMF-induced signaling pathway involving activation of protein tyrosine kinases (PTKs), phospholipase-Cy and protein kinase C (PKC). Because activation of PKC is also important in the signaling pathways that regulate the transcription factors NF-kappaB and AP-1, we evaluated the effect of exposure to a 60 Hz EMF on NF-kappaB or AP-1-dependent reporter gene expression in cells of the human promonocytic U937 leukemia cell line. Reporter genes were electroporated into U937 cells and activation of the NF-kappaB or AP-1 signaling pathway was evaluated by measuring chloramphenicol acetyltransferase (CAT) protein by CAT ELISA. In contrast to the effects of well-understood chemical or biological agents, the exposure to magnetic-field intensities of 0.08, 0.1, 1.0 or 1.3 mT had no effect on the NF-kappaB or AP-1 signaling pathways.

An apparatus for generating the required beamforming delays for an ultrasound imaging system with minimal hardware and software. The apparatus performs an algorithm which allows the required computations to be separated into three groups. The first group includes transducer array geometry computations which are beam independent. The second group includes a small number of beam-dependent computations which are channel independent. The final group includes the channel- and beam-dependent calculations which combine the results of the first two groups to generate the required beamforming delays. This last computation is distributed to logic (62) and simple real-time state machines (64) per channel. This approach reduces the required computations and takes advantage of simple parallel processing to reduce the required hardware and computational time relative to conventional beamformer designs. Beam-dependent parameters are broadcast to all channels simultaneously, where they are combined with channel parameters to provide the required delay controls.

In a previous study glucocorticoids have been shown to depress the rate of fluid-phase endocytosis in a macrophage cell line, P388D1. This effect was observed when either fluorescein-labeled dextran or horseradish peroxidase (HRP) was used to measure endocytosis. In this report the relationship between cholesterol synthesis and endocytosis was examined in light of the ability of glucocorticoids to inhibit cholesterol biosynthesis. Two known inhibitors of cholesterol biosynthesis, ML-236B and 25-hydroxycholesterol (25-OH), were compared with dexamethasone (dex) for the ability to suppress endocytosis in cells grown in media supplemented with either 10% whole or delipidized neonatal bovine serum (NBS). In 10% whole serum all inhibitors reduced the uptake of HRP after 12 h incubation. Dexamethasone (1 microM) suppressed endocytosis by 30% whereas 25-OH (2.5 microM) and ML-236B (11.6 microM) inhibited by 38 and 52%, respectively. Supplementation of the growth medium with mevalonolactone (3.4 mM) prevented the inhibition of endocytosis by ML-236B. In contrast, mevalonolactone supplementation did not prevent either dex or 25-OH from suppressing endocytosis. The same pattern of results was obtained when cultures were grown in delipidized NBS. After 4 h all inhibitors caused a decrease in amount of [14C]acetate incorporated into both nonsaponifiable lipids and digitonin precipitable sterols. Although dex inhibited cholesterol biosynthesis, total cellular cholesterol was unaffected by dex treatment after 24 h incubation. It is suggested that in addition to suppressing mevalonate synthesis, 25-OH, and by analogy dex, may act at some metabolic site(s) distal to the formation of mevalonate.

The coordinated control of cholesterol biosynthesis and esterification by 25-hydroxycholesterol was studied in the macrophage-like cell line P388D1. Since 25-hydroxycholesterol rapidly stimulated incorporation of [3H]oleate into the cholesteryl ester fraction of these cells, we have tested the possibility that the well-known inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) by 25-hydroxycholesterol might be the indirect consequence of an increased cholesterol esterification rather than a direct effect on HMG-CoA reductase. The experimental results show that progesterone, an inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), when added together with 25-hydroxycholesterol, abolished the increased cholesterol esterification without affecting the inhibition of HMG-CoA reductase by 25-hydroxycholesterol. Thus, uncoupling cholesterol esterification had no effect on 25-hydroxycholesterol's ability to inhibit HMG-CoA reductase. Unexpectedly, pretreatment of P388D1 cells with 25-hydroxycholesterol resulted in no elevation of ACAT activity as measured in broken cell preparations. Therefore, the possibility that 25-hydroxycholesterol stimulated cholesteryl ester formation by increasing the amount of cholesterol available for esterification, rather than by acting directly on ACAT activity, was considered. Labeling experiments using [14C]-cholesterol have provided evidence for this assumption.

We have previously shown the presence of 17 beta-estradiol in extracts of commercially prepared Saccharomyces cerevisiae ss well as the production of estradiol by yeast grown in the laboratory. In our current study, yeast grown in a chemically defined medium synthesized estradiol in only small amounts, (less than 500 pg/liter). We have analyzed a variety of media commonly used for growing yeast and found that substantial estradiol production (greater than 5 ng/liter) was obtained when yeast were grown in medium supplemented with Bacto-peptone. The peptone was shown to contain significant amounts of estrone, and the results of the experiments establish a precursor-product relationship where estrone from the medium is metabolized to estradiol by S. cerevisiae. Studies with added [3H]estrone demonstrated rapid conversion into [3H]estradiol and a 3H-labeled nonpolar estrogen derivative. The commercially obtained yeast used previously had been grown in a molasses medium. We demonstrate here that the molasses medium contains substantial amounts of estrone and estradiol. We conclude that the conversion of estrone in a culture medium to estradiol in laboratory grown yeast and estrone and estradiol present in the commercially grown yeast medium account for the majority of estradiol found in yeast.

• Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). Clinical studies have been divided on the efficacy of protirelin (TRH) despite strong experimental findings that are consistent with a role for the peptide in ALS. Recent findings provide evidence of a gender-related specificity in the ability of protirelin to potentiate the mono-synaptic reflex. While castration in male neonatal rats lowered the sensitivity to protirelin, testosterone treatment restored that sensitivity. An examination of the clinical studies reveals a failure either to identify patients' sex or to separate the results on the basis of sex. These findings provide convincing evidence for the potential efficacy of protirelin in ALS if the patient's sex and underlying hormonal status are taken into account.