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In 1961, Jacob and Monod proposed the operon model of gene regulation. At the model's core was the modular assembly of regulators, operators, and structural genes. To illustrate the composability of these elements, Jacob and Monod linked phenotypic diversity to the architectures of regulatory circuits. In this review, we examine how the circuit blueprints imagined by Jacob and Monod laid the foundation for the first synthetic gene networks that launched the field of synthetic biology in 2000. We discuss the influences of the operon model and its broader theoretical framework on the first generation of synthetic biological circuits, which were predominantly transcriptional and posttranscriptional circuits. We also describe how recent advances in molecular biology beyond the operon model—namely, programmable DNA- and RNA-binding molecules as well as models of epigenetic and posttranslational regulation—are expanding the synthetic biology toolkit and enabling the design of more complex biological circuits.

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases., National Institutes of Health (U.S.) (Grant DK095045), National Institutes of Health (U.S.) (Grant DK099465), National Institutes of Health (U.S.) (Grant DK103658), National Institutes of Health (U.S.) (Grant DK083511), National Institutes of Health (U.S.) (Grant DK093746)

Opioids are the preferred medications for the treatment of pain in the intensive care unit. While undertreatment leads to unrelieved pain and poor clinical outcomes, excessive use of opioids puts patients at risk of experiencing multiple adverse effects. In this work, we present a sequential decision making framework for opioid dosing based on deep reinforcement learning. It provides real-time clinically interpretable dosing recommendations, personalized according to each patient's evolving pain and physiological condition. We focus on morphine, one of the most commonly prescribed opioids. To train and evaluate the model, we used retrospective data from the publicly available MIMIC-3 database. Our results demonstrate that reinforcement learning may be used to aid decision making in the intensive care setting by providing personalized pain management interventions., 2019 41st Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC)

The growing prevalence of antibiotic resistance calls for new approaches in the development of antimicrobial therapeutics. Likewise, improved diagnostic measures are essential in guiding the application of targeted therapies and preventing the evolution of therapeutic resistance. Discovery platforms are also needed to form new treatment strategies and identify novel antimicrobial agents. By applying engineering principles to molecular biology, synthetic biologists have developed platforms that improve upon, supplement, and will perhaps supplant traditional broad-spectrum antibiotics. Efforts in engineering bacteriophages and synthetic probiotics demonstrate targeted antimicrobial approaches that can be fine-tuned using synthetic biology-derived principles. Further, the development of paper-based, cell-free expression systems holds promise in promoting the clinical translation of molecular biology tools for diagnostic purposes. In this review, we highlight emerging synthetic biology platform technologies that are geared toward the generation of new antimicrobial therapies, diagnostics, and discovery channels., Defense Threat Reduction Agency (DTRA) (Grant HDTRA1-14-1-0006), Defense Threat Reduction Agency (DTRA) (Grant HDTRA1-15-1-0051)

Drug-eluting stents are accepted as mainstream endovascular therapy, yet concerns for their safety may be under-appreciated. While failure from restenosis has dropped to below 5%, the risk of stent thrombosis and associated mortality remain relatively high. Further optimization of drug release is required to minimize thrombosis risk while maintaining therapeutic dose. The complex three-dimensional geometry of deployed stents together with the combination of diffusive and advective drug transport render an intuitive understanding of the situation exceedingly difficult. In situations such as this, computational modeling has proven essential, helping define the limits of efficacy, determine the mode and mechanism of drug release, and identify alternatives to avoid toxicity. A particularly challenging conformation is encountered in coronary arteries with overlapping stents. To study hemodynamics and drug deposition in such vessels we combined high-resolution, multi-scale ex vivo computed tomography with a flow and mass transfer computational model. This approach ensures high geometric fidelity and precise, simultaneous calculation of blood flow velocity, shear stress and drug distribution. Our calculations show that drug uptake by the arterial tissue is dependent both on the patterns of flow disruption near the wall, as well as on the relative positioning of drug-eluting struts. Overlapping stent struts lead to localized peaks of drug concentration that may increase the risk of thrombosis. Such peaks could be avoided by anisotropic stent structure or asymmetric drug release designed to yield homogeneous drug distribution along the coronary artery and, at the least, suggest that these issues need to remain in the forefront of consideration in clinical practice., National Institutes of Health (U.S.) (Grant R01 GM 49039)

Contemporary endovascular stents are the product of an iterative design and development process that leverages evolving concepts in vascular biology and engineering. This article reviews how insights into vascular pathophysiology, materials science, and design mechanics drive stent design and explain modes of stent failure. Current knowledge of pathologic processes is providing a more complete picture of the factors mediating stent failure. Further evolution of endovascular stents includes bioresorbable platforms tailored to treat plaques acutely and to then disappear after lesion pacification. Ongoing refinement of stent technology will continue to require insights from pathology to understand adverse events, refine clinical protocols, and drive innovation. Keywords: Coronary artery disease; Pathology; Bare metal stent; Drug-eluting stent; In-stent restenosis; In-stent thrombosis; Atherosclerosis; Neoatherosclerosis, National Institutes of Health (U.S.) (Grant R01 GM-49039)

Purpose To compare visualization of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) using an ultrahigh-speed swept-source (SS) optical coherence tomography angiography (OCTA) prototype vs a spectral-domain (SD) OCTA device. Design Comparative analysis of diagnostic instruments. Methods Patients were prospectively recruited to be imaged on SD OCT and SS OCT devices on the same day. The SD OCT device employed is the RTVue Avanti (Optovue, Inc, Fremont, California, USA), which operates at ∼840 nm wavelength and 70 000 A-scans/second. The SS OCT device used is an ultrahigh-speed long-wavelength prototype that operates at ∼1050 nm wavelength and 400 000 A-scans/second. Two observers independently measured the CNV area on OCTA en face images from the 2 devices. The nonparametric Wilcoxon signed rank test was used to compare area measurements and P values of, National Institutes of Health (U.S.) (R01-EY011289-28), National Institutes of Health (U.S.) (R44-EY022864-03), National Institutes of Health (U.S.) (R01-CA075289-17), United States. Air Force Office of Scientific Research (FA9550-10-1-0551), United States. Air Force Office of Scientific Research (FA9550-12-1-0499)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer. Keywords: Pancreatic cancer; Chemoresistance; Local delivery; Patient-derived xenograft; Paclitaxel; Poly(lactic-co-glycolic acid), National Institutes of Health (U.S.) (Grant P30-CA14051)

Purpose To investigate ultrahigh-speed, swept-source optical coherence tomography (SSOCT) angiography for visualizing vascular changes in eyes with nonexudative age-related macular degeneration (AMD) with geographic atrophy (GA). Design Observational, prospective, cross-sectional study. Participants A total of 63 eyes from 32 normal subjects and 12 eyes from 7 patients with nonexudative AMD with GA. Methods A 1050-nm, 400-kHz A-scan rate SSOCT system was used to perform volumetric optical coherence tomography angiography (OCTA) of the retinal and choriocapillaris (CC) vasculatures in normal subjects and patients with nonexudative AMD with GA. Optical coherence tomography angiography using variable interscan time analysis (VISTA) was performed to assess CC alteration and differentiate varying degrees of CC flow impairment. Main Outcome Measures Qualitative comparison of retinal and CC vasculatures in normal subjects versus those in patients with a clinical diagnosis of nonexudative AMD with GA. Results In all 12 eyes with GA, OCTA showed pronounced CC flow impairment within the region of GA. In 10 of the 12 eyes with GA, OCTA with VISTA showed milder CC flow impairment extending beyond the margin of GA. Of the 5 eyes exhibiting foveal-sparing GA, OCTA showed CC flow within the region of foveal sparing in 4 of the eyes. Conclusions The ability of ultrahigh-speed, swept-source OCTA to noninvasively visualize alterations in the retinal and CC vasculatures makes it a promising tool for assessing nonexudative AMD with GA. Optical coherence tomography angiography using VISTA can distinguish varying degrees of CC alteration and flow impairment and may be useful for elucidating disease pathogenesis, progression, and response to therapy., National Institutes of Health (U.S.) ( R01-EY011289-27), National Institutes of Health (U.S.) ( R44-EY022864-01), National Institutes of Health (U.S.) (R44- EY022864-02), National Institutes of Health (U.S.) (R01-CA075289-16), United States. Air Force Office of Scientific Research (FA9550-10-1-0551), United States. Air Force Office of Scientific Research (FA9550-12-1-0499)

Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.

We present a novel and time-efficient method for intracoronary lumen detection, which produces three-dimensional (3-D) coronary arteries using optical coherence tomographic (OCT) images. OCT images are acquired for multiple patients and longitudinal cross-section (LOCS) images are reconstructed using different acquisition angles. The lumen contours for each LOCS image are extracted and translated to 2-D cross-sectional images. Using two angiographic projections, the centerline of the coronary vessel is reconstructed in 3-D, and the detected 2-D contours are transformed to 3-D and placed perpendicular to the centerline. To validate the proposed method, 613 manual annotations from medical experts were used as gold standard. The 2-D detected contours were compared with the annotated contours, and the 3-D reconstructed models produced using the detected contours were compared to the models produced by the annotated contours. Wall shear stress (WSS), as dominant hemodynamics factor, was calculated using computational fluid dynamics and 844 consecutive 2-mm segments of the 3-D models were extracted and compared with each other. High Pearson's correlation coefficients were obtained for the lumen area ( r = 0.98) and local WSS ( r = 0.97) measurements, while no significant bias with good limits of agreement was shown in the Bland–Altman analysis. The overlapping and nonoverlapping areas ratio between experts’ annotations and presented method was 0.92 and 0.14, respectively. The proposed computer-aided lumen extraction and 3-D vessel reconstruction method is fast, accurate, and likely to assist in a number of research and clinical applications.

Patients with autism spectrum disorder (ASD) often require sedation or general anesthesia. ASD is thought to arise from deficits in GABAergic signaling leading to abnormal neurodevelopment. We sought to investigate differences in how ASD patients respond to the GABAergic drug propofol by comparing the propofol-induced electroencephalogram (EEG) of ASD and neurotypical (NT) patients. This investigation was a prospective observational study. Continuous 4-channel frontal EEG was recorded during routine anesthetic care of patients undergoing endoscopic procedures between July 1, 2014 and May 1, 2016. Study patients were defined as those with previously diagnosed ASD by DSM-V criteria, aged 2–30 years old. NT patients were defined as those lacking neurological or psychiatric abnormalities, aged 2–30 years old. The primary outcome was changes in propofol-induced alpha (8–13 Hz) and slow (0.1–1 Hz) oscillation power by age. A post hoc analysis was performed to characterize incidence of burst suppression during propofol anesthesia. The primary risk factor of interest was a prior diagnosis of ASD. Outcomes were compared between ASD and NT patients using Bayesian methods. Compared to NT patients, slow oscillation power was initially higher in ASD patients (17.05 vs. 14.20 dB at 2.33 years), but progressively declined with age (11.56 vs. 13.95 dB at 22.5 years). Frontal alpha power was initially lower in ASD patients (17.65 vs. 18.86 dB at 5.42 years) and continued to decline with age (6.37 vs. 11.89 dB at 22.5 years). The incidence of burst suppression was significantly higher in ASD vs. NT patients (23.0% vs. 12.2%, p < 0.01) despite reduced total propofol dosing in ASD patients. Ultimately, we found that ASD patients respond differently to propofol compared to NT patients. A similar pattern of decreased alpha power and increased sensitivity to burst suppression develops in older NT adults; one interpretation of our data could be that ASD patients undergo a form of accelerated neuronal aging in adolescence. Our results suggest that investigations of the propofol-induced EEG in ASD patients may enable insights into the underlying differences in neural circuitry of ASD and yield safer practices for managing patients with ASD.

Inertial measurement units (IMUs) have been demonstrated to reliably measure human joint angles—an essential quantity in the study of biomechanics. However, most previous literature proposed IMU-based joint angle measurement systems that required manual alignment or prescribed calibration motions. This paper presents a simple, physically-intuitive method for IMU-based measurement of the knee flexion/extension angle in gait without requiring alignment or discrete calibration, based on computationally-efficient and easy-to-implement Principle Component Analysis (PCA). The method is compared against an optical motion capture knee flexion/extension angle modeled through OpenSim. The method is evaluated using both measured and simulated IMU data in an observational study (n = 15) with an absolute root-mean-square-error (RMSE) of 9.24∘ and a zero-mean RMSE of 3.49∘. Variation in error across subjects was found, made emergent by the larger subject population than previous literature considers. Finally, the paper presents an explanatory model of RMSE on IMU mounting location. The observational data suggest that RMSE of the method is a function of thigh IMU perturbation and axis estimation quality. However, the effect size for these parameters is small in comparison to potential gains from improved IMU orientation estimations. Results also highlight the need to set relevant datums from which to interpret joint angles for both truth references and estimated data., National Science Foundation (U.S.) (GRFP), National Science Foundation (U.S.) (IIS-1453141)

We present a low-cost kit based on freeze-dried, cell-free reactions to illustrate synthetic and molecular biology concepts., Hands-on demonstrations greatly enhance the teaching of science, technology, engineering, and mathematics (STEM) concepts and foster engagement and exploration in the sciences. While numerous chemistry and physics classroom demonstrations exist, few biology demonstrations are practical and accessible due to the challenges and concerns of growing living cells in classrooms. We introduce BioBits™ Explorer, a synthetic biology educational kit based on shelf-stable, freeze-dried, cell-free (FD-CF) reactions, which are activated by simply adding water. The FD-CF reactions engage the senses of sight, smell, and touch with outputs that produce fluorescence, fragrances, and hydrogels, respectively. We introduce components that can teach tunable protein expression, enzymatic reactions, biomaterial formation, and biosensors using RNA switches, some of which represent original FD-CF outputs that expand the toolbox of cell-free synthetic biology. The BioBits™ Explorer kit enables hands-on demonstrations of cutting-edge science that are inexpensive and easy to use, circumventing many current barriers for implementing exploratory biology experiments in classrooms.

We present the case of an HIV-negative patient clinically diagnosed with relapsing-remitting MS who achieved significant disease improvement on Combivir (zidovudine/lamivudine). Within months of treatment, the patient reported complete resolution of previously unremitting fatigue and paresthesiae, with simultaneous improvements in lesion burden detected by MRI. All improvements have been sustained for more than three years. This response may be related to the action of zidovudine as a known inhibitor of EBV lytic DNA replication, suggesting future directions for clinical investigation. Keywords: Multiple sclerosis, Epstein-Barr virus

Background Fibronectin in endothelial basement membranes promotes endothelial inflammatory activation and atherosclerosis but also promotes plaque stability and vascular remodeling. The fibronectin receptor α5 subunit is proinflammatory through binding to and activating phosphodiesterase 4D5, which inhibits anti‐inflammatory cyclic adenosine monophosphate and protein kinase A. Replacing the α5 cytoplasmic domain with that of α2 resulted in smaller atherosclerotic plaques. Here, we further assessed plaque phenotype and compensatory vascular remodeling in this model. Methods and Results α5/2 mice in the hyperlipidemic apolipoprotein E null background had smaller plaques in the aortic root, with reduced endothelial NF ‐κB activation and inflammatory gene expression, reduced leukocyte content, and much lower metalloproteinase expression. However, smooth muscle cell content, fibrous cap thickness, and fibrillar collagen were unchanged, indicating no shift toward vulnerability. In vivo knockdown of phosphodiesterase 4D5 also decreased endothelial inflammatory activation and atherosclerotic plaque size. α5/2 mice showed improved recovery from hindlimb ischemia after femoral artery ligation. Conclusions Blocking the fibronectin‐Integrin α5 pathway reduces atherosclerotic plaque size, maintains plaque stability, and improves compensatory remodeling. This pathway is therefore a potential therapeutic target for treatment of atherosclerosis.

Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with resistant hypertension (RH). Determinants of arterial compliance may, however, help to predict the BP response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR. This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at 6-month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg (p

The widely used electroencephalogram-based indices for depth-of-Anesthesia monitoring assume that the same index value defines the same level of unconsciousness for all anesthetics. In contrast, we show that different anesthetics act at different molecular targets and neural circuits to produce distinct brain states that are readily visible in the electroencephalogram. We present a two-part review to educate anesthesiologists on use of the unprocessed electroencephalogram and its spectrogram to track the brain states of patients receiving anesthesia care. Here in part I, we review the biophysics of the electroencephalogram and the neurophysiology of the electroencephalogram signatures of three intravenous anesthetics: propofol, dexmedetomidine, and ketamine, and four inhaled anesthetics: sevoflurane, isoflurane, desflurane, and nitrous oxide. Later in part II, we discuss patient management using these electroencephalogram signatures. Use of these electroencephalogram signatures suggests a neurophysiologically based paradigm for brain state monitoring of patients receiving anesthesia care., National Institutes of Health (U.S.) (Grant DP1-OD003646), National Institutes of Health (U.S.) (Grant TR01-GM104948)

Rationale Factors associated with one-year mortality after recovery from critical illness are not well understood. Clinicians generally lack information regarding post-hospital discharge outcomes of patients from the intensive care unit, which may be important when counseling patients and families. Objective We sought to determine which factors among patients who survived for at least 30 days post-ICU admission are associated with one-year mortality. Methods Single-center, longitudinal retrospective cohort study of all ICU patients admitted to a tertiary-care academic medical center from 2001–2012 who survived 30 days from ICU admission. Cox’s proportional hazards model was used to identify the variables that are associated with one-year mortality. The primary outcome was one-year mortality. Results 32,420 patients met the inclusion criteria and were included in the study. Among patients who survived to 30 days, 28,583 (88.2%) survived for greater than one year, whereas 3,837 (11.8%) did not. Variables associated with decreased one-year survival include: increased age, malignancy, number of hospital admissions within the prior year, duration of mechanical ventilation and vasoactive agent use, sepsis, history of congestive heart failure, end-stage renal disease, cirrhosis, chronic obstructive pulmonary disease, and the need for renal replacement therapy. Numerous effect modifications between these factors were found. Conclusion Among survivors of critical illness, a significant number survive less than one year. More research is needed to help clinicians accurately identify those patients who, despite surviving their acute illness, are likely to suffer one-year mortality, and thereby to improve the quality of the decisions and care that impact this outcome., National Institute of Biomedical Imaging and Bioengineering (U.S.) (grant R01EB017205-01A1), A*STAR (Graduate Scholarship), National Institutes of Health (U.S.) (grant T32 HL007287-39), National Heart, Lung, and Blood Institute, Philips Healthcare Nederland

Deep learning has been proven to yield reliably generalizable solutions to numerous classification and decision tasks. Here, we demonstrate for the first time to our knowledge that deep neural networks (DNNs) can be trained to solve end-to-end inverse problems in computational imaging. We experimentally built and tested a lensless imaging system where a DNN was trained to recover phase objects given their propagated intensity diffraction patterns., United States. Department of Energy (Grant DE-FG02-97ER25308)

Major surgeries can result in high rates of adverse postoperative events. Reliable prediction of which patient might be at risk for such events may help guide peri- and postoperative care. We show how archiving and mining of intraoperative hemodynamic data in orthotopic liver transplantation (OLT) can aid in the prediction of postoperative 180-day mortality and acute renal failure (ARF), improving upon predictions that rely on preoperative information only. From 101 patient records, we extracted 15 preoperative features from clinical records and 41 features from intraoperative hemodynamic signals. We used logistic regression with leave-one-out cross-validation to predict outcomes, and incorporated methods to limit potential model instabilities from feature multicollinearity. Using only preoperative features, mortality prediction achieved an area under the receiver operating characteristic curve (AUC) of 0.53 (95% CI: 0.44–0.78). By using intraoperative features, performance improved significantly to 0.82 (95% CI: 0.56–0.91, P = 0.001). Similarly, including intraoperative features (AUC = 0.82; 95% CI: 0.66–0.94) in ARF prediction improved performance over preoperative features (AUC = 0.72; 95% CI: 0.50–0.85), though not significantly (P = 0.32). We conclude that inclusion of intraoperative hemodynamic features significantly improves prediction of postoperative events in OLT. Features strongly associated with occurrence of both outcomes included greater intraoperative central venous pressure and greater transfusion volumes.

Background Recently there has been a large outbreak of Zika virus infections in Colombia, South America. The epidemic began in September 2015 and continued to April 2017, for the total number of Zika cases reported of 107,870. For those confirmed Zika cases, there were nearly 20,000 (18.5%) suspected to be pregnant women, resulting in 157 confirmed cases of microcephaly in newborns reported by their health government agency. There is a clear under-estimation of the total number of cases and in addition no prior publications have been published to demonstrate the clinical aspects of the Zika infection in Colombia. We characterized one Zika presentation to be able to compare and contrast with other cases of Zika infection already reported in the literature. Case presentation In this case report, we demonstrate congenital microcephaly at week 19 of gestation in a 34-year-old mother who showed symptoms compatible with Zika virus infection from Sincelejo, State of Sucre, in the Colombian Caribbean. Zika virus RNA was detected in the placenta using real-time reverse transcriptase polymerase chain reaction (RT-PCR). At week 25, the fetus weigh estimate was 770 g, had a cephalic perimeter of 20.2 cm (5th percentile), ventriculomegaly on the right side and dilatation of the fourth ventricle. At week 32, the microcephaly was confirmed with a cephalic perimeter of 22 cm, dilatation of the posterior atrium to 13 mm, an abnormally small cerebellum (29 mm), and an augmented cisterna magna. At birth (39 weeks by cesarean section), the head circumference was 27.5 cm, and computerized axial tomography (Siemens Corp, 32-slides) confirmed microcephaly with calcifications. Conclusion We report a first case of maternal Zika virus infection associated with fetal microcephaly in Colombia and confirmed similar presentation to those observed previous in Brazil, 2015–2016.

Designer microbial consortia are an emerging frontier in synthetic biology that enable versatile microbiome engineering. However, the utilization of such consortia is hindered by our limited capacity in rapidly creating ecosystems with desired dynamics. Here we present the development of synthetic communities through social interaction engineering that combines modular pathway reconfiguration with model creation. Specifically, we created six two-strain consortia, each possessing a unique mode of interaction, including commensalism, amensalism, neutralism, cooperation, competition and predation. These consortia follow distinct population dynamics with characteristics determined by the underlying interaction modes. We showed that models derived from two-strain consortia can be used to design three- and four-strain ecosystems with predictable behaviors and further extended to provide insights into community dynamics in space. This work sheds light on the organization of interacting microbial species and provides a systematic framework—social interaction programming—to guide the development of synthetic ecosystems for diverse purposes., National Science Foundation (U.S.) (Grant 1553649), National Science Foundation (U.S.) (Grant 1227034), United States. Office of Naval Research (Award (N00014-16-12525), American Cancer Society (Grant 12SDG12090025), Defense Threat Reduction Agency (DTRA) (Grant HDTRA1-14-1-0006)

1AbstractDistribution-based operational taxonomic unit-calling (dbOTU) improves on other approaches by incorporating information about the input sequences’ distribution across samples. Previous implementations of dbOTU presented challenges for users. Here we introduce and evaluate a new implementation of dbOTU that is faster and more user-friendly. We show that this new implementation has theoretical and practical improvements over previous implementations of dbOTU, making the algorithm more accessible to microbial ecology and biomedical researchers.

Background: Calcific atherosclerosis is a major challenge to intraluminal drug delivery in peripheral artery disease (PAD). Objectives: We evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque. Methods: Diagnostic angiography and 3-D rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using an orbital atherectomy system (OAS) under simulated blood flow and fluoroscopy. Explanted arterial segments underwent either histomorphometric assessment of effect or tracking of [superscript 14]C-labeled or fluorescent–labeled paclitaxel. Radiolabeled drug quantified bulk delivery and fluorescent label established penetration of drug over finer spatial domain in serial microscopic sections. Results: were interpreted using a mathematical model of binding-diffusion mediated arterial drug distribution. Results Lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate-constant of [superscript 14]C-labeled, declining 5.5-fold per calcified quadrant (p = 0.05, n = 7). Compared to controls, OAS-treated femoropopliteal segments exhibited 180 μm thinner intima (p < 0.001), 45% less plaque calcification, and 2 log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls, due to a 70% increase in diffusivity (p < 0.001). Conclusions These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries.Peripheral artery disease Keywords: Drug coated balloons, Drug eluting stents, Atherectomy, Orbital atherectomy, calcified plaque, Paclitaxel, National Institute of Mental Health (U.S.) (Grant R01 GM-49039)

We present HiGlass, an open source visualization tool built on web technologies that provides a rich interface for rapid, multiplex, and multiscale navigation of 2D genomic maps alongside 1D genomic tracks, allowing users to combine various data types, synchronize multiple visualization modalities, and share fully customizable views with others. We demonstrate its utility in exploring different experimental conditions, comparing the results of analyses, and creating interactive snapshots to share with collaborators and the broader public. HiGlass is accessible online at http://higlass.io and is also available as a containerized application that can be run on any platform., National Institutes of Health (U.S.) (U01 CA200059), National Institutes of Health (U.S.) (R00 HG007583), National Institutes of Health (U.S.) (U54 HG007963)

Radiotherapy is a crucial component of cancer care, employed in the treatment of over 50% of cancer patients. Patients undergoing image-guided radiotherapy or brachytherapy routinely have inert radiotherapy (RT) biomaterials implanted into their tumors. The single function of these RT biomaterials is to ensure geometric accuracy during treatment. Recent studies have proposed that the inert biomaterials could be upgraded to ‘smart’ RT biomaterials, designed to do more than one function. Such smart biomaterials include next generation fiducial markers, brachytherapy spacers, and balloon applicators, designed to respond to stimulus and perform additional desirable functions like controlled delivery of therapy-enhancing payloads directly into the tumor sub-volume, while minimizing normal tissue toxicities. More broadly, smart RT biomaterials may include functionalized nanoparticles that can be activated to boost radiotherapy efficacy. This work reviews the rationale for smart radiotherapy biomaterials, the state-of-the-art in this emerging cross-disciplinary research area, challenges/opportunities for further research and development, and a purview of potential clinical applications. Applications covered include using smart RT biomaterials for boosting cancer therapy with minimal side effects, combining radiotherapy with immunotherapy or chemotherapy, reducing treatment time or healthcare costs, and other incipient applications.

We consider the problem of estimating the power spectral density of the neural covariates underlying the spiking of a neuronal population. We assume the spiking of the neuronal ensemble to be described by Bernoulli statistics. Furthermore, we consider the conditional intensity function to be the logistic map of a second-order stationary process with sparse frequency content. Using the binary spiking data recorded from the population, we calculate the maximum a posteriori estimate of the power spectral density of the process while enforcing sparsity-promoting priors on the estimate. Using both simulated and clinically recorded data, we show that our method outperforms the existing methods for extracting a frequency domain representation from the spiking data of a neuronal population.

Current techniques for cell culture routinely use animal-derived components. Fetal bovine serum (FBS) is the most widely applied supplement, but it often displays significant batch-to-batch variations and is generally not suitable for clinical applications in humans. A robust and xeno-free alternative to FBS is of high interest for cellular therapies, from early in vitro testing to clinical trials in human subjects. In the current work, a highly consistent human plasma derived supplement (SCC) has been tested, as a potential substitute of FBS in primary human vascular cells culture. Our results show that SCC is able to support proliferation, preserve cellular morphology and potentiate functionality analogously to FBS. We conclude that SCC is a viable substitute of FBS for culture and expansion of cells in advanced therapies using human vascular cells and fibroblasts.

Modern intensive care units (ICUs) collect large volumes of data in monitoring critically ill patients. Clinicians in the ICUs face the challenge of interpreting large volumes of high-dimensional data to diagnose and treat patients. In this work, we explore the use of Hierarchical Dirichlet Processes (HDP) as a Bayesian nonparametric framework to infer patients' states of health by combining multiple sources of data. In particular, we employ HDP to combine clinical time series and text from the nursing progress notes in a probabilistic topic modeling framework for patient risk stratification. Given a patient cohort, we use HDP to infer latent 'topics' shared across multimodal patient data from the entire cohort. Each topic is modeled as a multinomial distribution over a vocabulary of codewords, defined over heterogeneous data sources. We evaluate the clinical utility of the learned topic structure using the first 24-hour ICU data from over 17,000 adult patients in the MIMIC-II database to estimate patients' risks of in-hospital mortality. Our results demonstrate that our approach provides a viable framework for combining different data modalities to model patient's states of health, and can potentially be used to generate alerts to identify patients at high risk of hospital mortality., National Institutes of Health (U.S.) (Grant R01-EB017205), National Institutes of Health (U.S.) (Grant R01-EB001659), National Institutes of Health (U.S.) (Grant R01GM104987)

Objective To demonstrate the incremental benefit of using free text data in addition to vital sign and demographic data to identify patients with suspected infection in the emergency department. Methods This was a retrospective, observational cohort study performed at a tertiary academic teaching hospital. All consecutive ED patient visits between 12/17/08 and 2/17/13 were included. No patients were excluded. The primary outcome measure was infection diagnosed in the emergency department defined as a patient having an infection related ED ICD-9-CM discharge diagnosis. Patients were randomly allocated to train (64%), validate (20%), and test (16%) data sets. After preprocessing the free text using bigram and negation detection, we built four models to predict infection, incrementally adding vital signs, chief complaint, and free text nursing assessment. We used two different methods to represent free text: a bag of words model and a topic model. We then used a support vector machine to build the prediction model. We calculated the area under the receiver operating characteristic curve to compare the discriminatory power of each model. Results A total of 230,936 patient visits were included in the study. Approximately 14% of patients had the primary outcome of diagnosed infection. The area under the ROC curve (AUC) for the vitals model, which used only vital signs and demographic data, was 0.67 for the training data set, 0.67 for the validation data set, and 0.67 (95% CI 0.65–0.69) for the test data set. The AUC for the chief complaint model which also included demographic and vital sign data was 0.84 for the training data set, 0.83 for the validation data set, and 0.83 (95% CI 0.81–0.84) for the test data set. The best performing methods made use of all of the free text. In particular, the AUC for the bag-of-words model was 0.89 for training data set, 0.86 for the validation data set, and 0.86 (95% CI 0.85–0.87) for the test data set. The AUC for the topic model was 0.86 for the training data set, 0.86 for the validation data set, and 0.85 (95% CI 0.84–0.86) for the test data set. Conclusion Compared to previous work that only used structured data such as vital signs and demographic information, utilizing free text drastically improves the discriminatory ability (increase in AUC from 0.67 to 0.86) of identifying infection.

Among critically-ill patients, hypotension represents a failure in compensatory mechanisms and may lead to organ hypoperfusion and failure. In this work, we adopt a datadriven approach for phenotype discovery and visualization of patient similarity and cohort structure in the intensive care unit (ICU). We used Hierarchical Dirichlet Process (HDP) as a non-parametric topic modeling technique to automatically learn a d-dimensional feature representation of patients that captures the latent 'topic' structure of diseases, symptoms, medications, and findings documented in hospital discharge summaries. We then used the t-Distributed Stochastic Neighbor Embedding (t-SNE) algorithm to convert the d-dimensional latent structure learned from HDP into a matrix of pairwise similarities for visualizing patient similarity and cohort structure. Using discharge summaries of a large patient cohort from the MIMIC II database, we evaluated the clinical utility of the discovered topic structure in phenotyping critically-ill patients who experienced hypotensive episodes. Our results indicate that the approach is able to reveal clinically interpretable clustering structure within our cohort and may potentially provide valuable insights to better understand the association between disease phenotypes and outcomes., National Institutes of Health (U.S.) (Grant R01-EB017205), National Institutes of Health (U.S.) (Grant R01-EB001659), National Institutes of Health (U.S.) (Grant R01GM104987)

The malaria liver stage is an attractive target for antimalarial development, and preclinical malaria models are essential for testing such candidates. Given ethical concerns and costs associated with non‐human primate models, humanized mouse models containing chimeric human livers offer a valuable alternative as small animal models of liver stage human malaria. The best available human liver chimeric mice rely on cellular transplantation into mice with genetically engineered liver injury, but these systems involve a long and variable humanization process, are expensive, and require the use of breeding-challenged mouse strains which are not widely accessible. We previously incorporated primary human hepatocytes into engineered polyethylene glycol (PEG)-based nanoporous human ectopic artificial livers (HEALs), implanted them in mice without liver injury, and rapidly generated human liver chimeric mice in a reproducible and scalable fashion. By re-designing the PEG scaffold to be macroporous, we demonstrate the facile fabrication of implantable porous HEALs that support liver stage human malaria (P. falciparum) infection in vitro, and also after implantation in mice with normal liver function, 60% of the time. This proof-of-concept study demonstrates the feasibility of applying a tissue engineering strategy towards the development of scalable preclinical models of liver stage malaria infection for future applications., Bill & Melinda Gates Foundation (Global Health Grant initiative (Global Health Grant: OPP1023607)), National Cancer Institute (U.S.) (Grant P30-CA14051), National Institute of Environmental Health Sciences (Core Center Grant P30-ES002109), Singapore. Agency for Science, Technology and Research (National Science Scholarship).

Nanotechnology-based approaches hold substantial potential for improving the care of patients with diabetes. Nanoparticles are being developed as imaging contrast agents to assist in the early diagnosis of type 1 diabetes. Glucose nanosensors are being incorporated in implantable devices that enable more accurate and patient-friendly real-time tracking of blood glucose levels, and are also providing the basis for glucose-responsive nanoparticles that better mimic the body's physiological needs for insulin. Finally, nanotechnology is being used in non-invasive approaches to insulin delivery and to engineer more effective vaccine, cell and gene therapies for type 1 diabetes. Here, we analyse the current state of these approaches and discuss key issues for their translation to clinical practice., Leona M. and Harry B. Helmsley Charitable Trust (Grant 09PG-T1D027), Juvenile Diabetes Research Foundation International (17-2007-1063), Juvenile Diabetes Research Foundation International (3-2013-178), Juvenile Diabetes Research Foundation International (3-2011-310), United States. National Institutes of Health (EB000244), United States. National Institutes of Health (EB000351), United States. National Institutes of Health (DE013023), United States. National Institutes of Health (CA151884)

This paper presents the design and characterization of a three-axis thermomechanical actuator-based endoscopic scanner for obtaining ex vivo two-photon images. The scanner consisted of two sub-systems: 1) an optical system (prism, gradient index lens, and optical fiber) that was used to deliver and collect light during imaging and 2) a small-scale silicon electromechanical scanner that could raster scan the focal point of the optics through a specimen. The scanner can be housed within a 7 mm Ø endoscope port and can scan at the speed of 3 kHz x 100 Hz × 30 Hz along three axes throughout a 125 × 125 × 100 μm[superscript 3] volume. The high-speed thermomechanical actuation was achieved through the use of geometric contouring, pulsing technique, and mechanical frequency multiplication (MFM), where MFM is a new method for increasing the device cycling speed by pairing actuators of unequal forward and returning stroke speeds. Sample cross-sectional images of 15-μm fluorescent beads are presented to demonstrate the resolution and optical cross-sectioning capability of the two-photon imaging system., National Institutes of Health (U.S.) (Grant 1-R21-CA118400-01), Chinese University of Hong Kong (Direct Grant 2050495), National Institutes of Health (U.S.) (Grant 9P41EB015871-26A1), National Institutes of Health (U.S.) (Grant 5R01EY017656-02), National Institutes of Health (U.S.) (Grant 5R01 NS051320), National Institutes of Health (U.S.) (Grant 4R44EB012415-02), National Science Foundation (U.S.) (Grant CBET-0939511), Singapore-MIT Alliance for Research and Technology, MIT Skoltech Initiative, Hamamatsu Corporation, David H. Koch Institute for Integrative Cancer Research at MIT (Bridge Project Initiative)

Objectives The aim of this study was to test whether silencing of the transcription factor interferon regulatory factor 5 (IRF5) in cardiac macrophages improves infarct healing and attenuates post–myocardial infarction (MI) remodeling. Background In healing wounds, the M1 toward M2 macrophage phenotype transition supports resolution of inflammation and tissue repair. Persistence of inflammatory M1 macrophages may derail healing and compromise organ functions. The transcription factor IRF5 up-regulates genes associated with M1 macrophages. Methods Here we used nanoparticle-delivered small interfering ribonucleic acid (siRNA) to silence IRF5 in macrophages residing in MIs and in surgically-induced skin wounds in mice. Results Infarct macrophages expressed high levels of IRF5 during the early inflammatory wound-healing stages (day 4 after coronary ligation), whereas expression of the transcription factor decreased during the resolution of inflammation (day 8). Following in vitro screening, we identified an siRNA sequence that, when delivered by nanoparticles to wound macrophages, efficiently suppressed expression of IRF5 in vivo. Reduction of IRF5 expression, a factor that regulates macrophage polarization, reduced expression of inflammatory M1 macrophage markers, supported resolution of inflammation, accelerated cutaneous and infarct healing, and attenuated development of post-MI heart failure after coronary ligation as measured by protease targeted fluorescence molecular tomography–computed tomography imaging and cardiac magnetic resonance imaging (p < 0.05). Conclusions This work identified a new therapeutic avenue to augment resolution of inflammation in healing infarcts by macrophage phenotype manipulation. This therapeutic concept may be used to attenuate post-MI remodeling and heart failure., National Heart, Lung, and Blood Institute (Contract HHSN268201000044C), National Heart, Lung, and Blood Institute (Grant R01-HL096576), National Heart, Lung, and Blood Institute (Grant R01-HL095629), National Heart, Lung, and Blood Institute (Grant R01-HL114477)

Magnetoencephalography (MEG) is an important non-invasive method for studying activity within the human brain. Source localization methods can be used to estimate spatiotemporal activity from MEG measurements with high temporal resolution, but the spatial resolution of these estimates is poor due to the ill-posed nature of the MEG inverse problem. Recent developments in source localization methodology have emphasized temporal as well as spatial constraints to improve source localization accuracy, but these methods can be computationally intense. Solutions emphasizing spatial sparsity hold tremendous promise, since the underlying neurophysiological processes generating MEG signals are often sparse in nature, whether in the form of focal sources, or distributed sources representing large-scale functional networks. Recent developments in the theory of compressed sensing (CS) provide a rigorous framework to estimate signals with sparse structure. In particular, a class of CS algorithms referred to as greedy pursuit algorithms can provide both high recovery accuracy and low computational complexity. Greedy pursuit algorithms are difficult to apply directly to the MEG inverse problem because of the high-dimensional structure of the MEG source space and the high spatial correlation in MEG measurements. In this paper, we develop a novel greedy pursuit algorithm for sparse MEG source localization that overcomes these fundamental problems. This algorithm, which we refer to as the Subspace Pursuit-based Iterative Greedy Hierarchical (SPIGH) inverse solution, exhibits very low computational complexity while achieving very high localization accuracy. We evaluate the performance of the proposed algorithm using comprehensive simulations, as well as the analysis of human MEG data during spontaneous brain activity and somatosensory stimuli. These studies reveal substantial performance gains provided by the SPIGH algorithm in terms of computational complexity, localization accuracy, and robustness., National Institutes of Health (U.S.) (New Innovator Award DP2-OD006454), National Institutes of Health (U.S.) (R01-EB006385-01), National Institutes of Health (U.S.) (P41-RR014075-11)

Atherosclerosis is the leading cause of death in the Western World and has been for decades a field of intense research. Yet, while there is a rich and diverse literature describing in detail the players and mechanisms involved in this complex disease in cell and animal models, we remain today with virtually no reliable markers for early diagnosis and targeted treatments options. This review is centered upon the latter. We summarize the latest studies focused on detecting endothelial dysfunction during the early stages of atherosclerosis, when the disease is asymptomatic and describe strategies recently proposed to image and target advanced plaque.

Objective—The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. Approach and Results—Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (, Novartis (Firm), Boston Scientific Corporation, Behrakis Foundation (Research Fellowship), Hellenic Heart Foundation, Hellenic Atherosclerosis Society, National Institutes of Health (U.S.) (Grant RO1 GM49039)

Cardio-respiratory monitoring is one of the most demanding areas in the rapidly growing, mobile-device, based health care delivery. We developed a 12-lead smartphone-based electrocardiogram (ECG) acquisition and monitoring system (called “cvrPhone”), and an application to assess underlying ischemia, and estimate the respiration rate (RR) and tidal volume (TV) from analysis of electrocardiographic (ECG) signals only. During in-vivo swine studies (n = 6), 12-lead ECG signals were recorded at baseline and following coronary artery occlusion. Ischemic indices calculated from each lead showed statistically significant (p, American Heart Association (15GRNT23070001), United States. National Institutes of Health (1 R01 HL135335–01), American Heart Association (15POST22690003), United States. National Institutes of Health (8UL1TR000170-05)

Background: Though the development and fitting of scleral contact lenses are expanding steadily, there is no simple method to provide scleral metrics for scleral contact lens fitting yet. The aim of this study was to establish formulae for estimation of the axial radius of curvature (ARC) of the anterior sclera using ocular biometric parameters that can be easily obtained with conventional devices. Methods: A semi-automated stitching method and a computational analysis tool for calculating ARC were developed by using the ImageJ and MATLAB software. The ARC of all the ocular surface points were analyzed from the composite horizontal cross-sectional images of the right eyes of 24 volunteers; these measurements were obtained using anterior segment optical coherence tomography for a previous study (AS-OCT; Visante). Ocular biometric parameters were obtained from the same volunteers with slit-scanning topography and partial coherence interferometry. Correlation analysis was performed between the ARC at 8 mm to the axis line (ARC[8]) and other ocular parameters (including age). With ARC obtained on several nasal and temporal points (7.0, 7.5, 8.0, 8.5, and 9.0 mm from the axis line), univariate and multivariate linear regression analyses were performed to develop a model for estimating ARC with the help of ocular biometric parameters. Results: Axial length, spherical equivalent, and angle kappa showed correlations with temporal ARC[8] (tARC[8]; Pearson’s r = 0.653, −0.579, and −0.341; P = 0.001, 0.015, and 0.015, respectively). White-to-white corneal diameter (WTW) and anterior chamber depth (ACD) showed correlation with nasal ARC[8] (nARC[8]; Pearson’s r = −0.492 and −0.461; P = 0.015 and 0.023, respectively). The formulae for estimating scleral curvatures (tARC, nARC, and average ARC) were developed as a function of axial length, ACD, WTW, and distance from the axis line, with good determinant power (72 − 80 %; SPSS ver. 22.0). Angle kappa showed strong correlation with axial length (Pearson’s r = −0.813, P, Korea (South). Ministry of Health & Welfare (Projects A084496 and A120018)

Synthetic biology aims to create functional devices, systems, and organisms with novel and useful functions taking advantage of engineering principles applied to biology. Despite great progress over the last decade, an underlying problem in synthetic biology remains the limited number of high-performance, modular, composable parts. A potential route to solve parts bottleneck problem in synthetic biology utilizes the programmability of nucleic acids inspired by molecular programming approaches that have demonstrated complex biomolecular circuits evaluating logic expressions in test tubes.Using a library of de-novo-designed toehold switches with orthogonality and modular composability, we demonstrate how toehold switches can be incorporated into decision-making RNA networks termed ribocomputing devices to rapidly evaluate complex logic in living cells. We have successfully demonstrated a 4-input AND gate, a 6-input OR gate, and a 12-input expression in disjunctive normal form in E. coli. The compact encoding of ribocomputing system using a library of modular parts is amenable to aggressive scale-up towards complex control of in vivo circuitry towards autonomous behaviors and biomedical applications.

Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug., Israel Cancer Research Fund, Israel Cancer Association, Israel Science Foundation (1852/16), Marie Curie International Outgoing Fellowship (FP7-PEOPLE-2013-IOF, Project 626386)

Background: In-stent hyperplasia (ISH) may develop in regions of low endothelial shear stress (ESS), but the relationship between the magnitude of low ESS, the extent of ISH, and subsequent clinical events has not been investigated. Methods and Results: We assessed the association of poststent ESS with neointimal ISH and clinical outcomes in patients treated with percutaneous coronary interventions (PCI). Three-dimensional coronary reconstruction was performed in 374 post-PCI patients at baseline and 6 to 10 months follow-up as part of the PREDICTION Study. Each vessel was divided into 1.5-mm-long segments, and we calculated the local ESS within each stented segment at baseline. At follow-up, we assessed ISH and the occurrence of a clinically indicated repeat PCI for in-stent restenosis. In 246 total stents (54 overlapping), 100 (40.7%) were bare-metal stents (BMS), 104 (42.3%) sirolimus-eluting stents, and 42 (17.1%) paclitaxel-eluting stents. In BMS, low ESS post-PCI at baseline was independently associated with ISH (β=1.47 mm 2 per 1-Pa decrease; 95% CI, 0.38-2.56; P < 0.01). ISH was minimal in drug-eluting stents. During follow-up, repeat PCI in BMS was performed in 21 stents (8.5%). There was no significant association between post-PCI ESS and in-stent restenosis requiring PCI. Conclusions: Low ESS after BMS implantation is associated with subsequent ISH. ISH is strongly inhibited by drug-eluting stents. Post-PCI ESS is not associated with in-stent restenosis requiring repeat PCI. ESS is an important determinant of ISH in BMS, but ISH of large magnitude to require PCI for in-stent restenosis is likely attributed to factors other than ESS within the stent., Hellenic Cardiological Society, Schaubert Family, George D. Behrakis Cardiovascular Research Fellowship

High false alarm rates in the ICU decrease quality of care by slowing staff response times while increasing patient delirium through noise pollution. The 2015 PhysioNet/Computing in Cardiology Challenge provides a set of 1250 multi-parameter ICU data segments associated with critical arrhythmia alarms, and challenges the general research community to address the issue of false alarm suppression using all available signals. Each data segment was 5 minutes long (for real time analysis), ending at the time of the alarm. For retrospective analysis, we provided a further 30 seconds of data after the alarm was triggered. A total of 750 data segments were made available for training and 500 were held back for testing. Each alarm was reviewed by expert annotators, at least two of whom agreed that the alarm was either true or false. Challenge participants were invited to submit a complete, working algorithm to distinguish true from false alarms, and received a score based on their program's performance on the hidden test set. This score was based on the percentage of alarms correct, but with a penalty that weights the suppression of true alarms five times more heavily than acceptance of false alarms. We provided three example entries based on well-known, open source signal processing algorithms, to serve as a basis for comparison and as a starting point for participants to develop their own code. A total of 38 teams submitted a total of 215 entries in this year's Challenge. This editorial reviews the background issues for this challenge, the design of the challenge itself, the key achievements, and the follow-up research generated as a result of the Challenge, published in the concurrent special issue of Physiological Measurement. Additionally we make some recommendations for future changes in the field of patient monitoring as a result of the Challenge., National Institutes of Health (U.S.) (Grant R01-GM104987), National Institute of General Medical Sciences (U.S.) (Grant U01-EB-008577), National Institutes of Health (U.S.) (Grant R01-EB-001659)

The current system of biomedical innovation is unable to keep pace with scientific advancements. We propose to address this gap by reengineering innovation processes to accelerate reliable delivery of products that address unmet medical needs. Adaptive biomedical innovation (ABI) provides an integrative, strategic approach for process innovation. Although the term “ABI” is new, it encompasses fragmented “tools” that have been developed across the global pharmaceutical industry, and could accelerate the evolution of the system through more coordinated application. ABI involves bringing stakeholders together to set shared objectives, foster trust, structure decision-making, and manage expectations through rapid-cycle feedback loops that maximize product knowledge and reduce uncertainty in a continuous, adaptive, and sustainable learning healthcare system. Adaptive decision-making, a core element of ABI, provides a framework for structuring decision-making designed to manage two types of uncertainty – the maturity of scientific and clinical knowledge, and the behaviors of other critical stakeholders., Ewing Marion Kauffman Foundation, Alfred P. Sloan Foundation, Massachusetts Technology Collaborative, Robert Wood Johnson Foundation

Single-cell rna-seq can precisely resolve cellular states, but applying this method to low-input samples is challenging. here, we present seq-Well, a portable, low-cost platform for massively parallel single-cell rna-seq. barcoded mrna capture beads and single cells are sealed in an array of subnanoliter wells using a semipermeable membrane, enabling effcient cell lysis and transcript capture. We use seq-Well to profle thousands of primary human macrophages exposed to Mycobacterium tuberculosis., National Institutes of Health (U.S.) (Award DP2 OD020839), National Institutes of Health (U.S.) (Grant U24 AI118762), National Institutes of Health (U.S.) (Grant P50 HG006193), Bill & Melinda Gates Foundation (Grant 03629000189)

Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-κB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-α secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-α in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy., National Institutes of Health (U.S.) ((NIH) R01 grant HL095722), United States. Department of Defense (Grant #W81XWH-13-1-0305)

Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries., Accurate treatment of traumatic brain injuries, a leading cause of neurological disability and death in young people, is hampered by poor accumulation of drugs in the brain. Here, the authors describe a tetrapeptide that can efficiently target brain injuries and deliver therapeutic or diagnostic payload.

Objectives: This study sought to investigate the impact of transcatheter intervention on left ventricular function and aortic hemodynamics in patients with mild coarctation of the aorta (COA). Background: The optimal method and timing of transcatheter intervention for COA remains unclear, especially when the severity of COA is mild (peak-to-peak transcoarctation pressure gradient < 20 mm Hg). Debate rages regarding the risk/benefit ratio of intervention versus long-term effects of persistent minimal gradient in this heterogeneous population with differing blood pressures, ventricular function, and peripheral perfusion. Methods: We developed a unique computational fluid dynamics and lumped parameter modeling framework based on patient-specific hemodynamic input parameters and validated it against patient-specific clinical outcomes (before and after intervention). We used clinically measured hemodynamic metrics and imaging of the aorta and the left ventricle in 34 patients with mild COA to make these correlations. Results: Despite dramatic reduction in the transcoarctation pressure gradient (catheter and Doppler echocardiography pressure gradients reduced by 75% and 47.3%, respectively), there was only modest effect on aortic flow and no significant impact on aortic shear stress (the maximum time-averaged wall shear stress in descending aorta was reduced 5.1%). In no patient did transcatheter intervention improve left ventricular function (e.g., stroke work and normalized stroke work were reduced by only 4.48% and 3.9%, respectively). Conclusions: Transcatheter intervention that successfully relieves mild COA pressure gradients does not translate to decreased myocardial strain. The effects of the intervention were determined to the greatest degree by ventricular–vascular coupling hemodynamics and provide a novel valuable mechanism to evaluate patients with COA that may influence clinical practice. Key Words: aortic hemodynamics, left ventricle function, mild coarctation, peak-to-peak pressure gradient, transcatheter intervention, National Institute of Mental Health (U.S.) (R01 GM 49039), American Heart Association (Postdoctoral Fellowship 16POST26420039)