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Showing papers by "University at Buffalo published in 2016"


Journal ArticleDOI
TL;DR: These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia.
Abstract: It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

2,359 citations


Journal ArticleDOI
TL;DR: The American Pain Society, with input from the American Society of Anesthesiologists, developed a clinical practice guideline to promote evidence-based, effective, and safer postoperative pain management in children and adults.

1,806 citations


Journal ArticleDOI
27 Sep 2016-JAMA
TL;DR: The period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage are characterized are characterized.
Abstract: Importance Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of treatment time with outcomes would help to guide implementation. Objective To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. Design, Setting, and Patients Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. Exposures Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. Main Outcomes and Measures The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. Results Among all 1287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, −6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, −5.2% [95% CI, −8.3% to −2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, −0.9% to 4.2%]). Conclusions and Relevance In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.

1,544 citations


Journal ArticleDOI
TL;DR: The obtained M-MoS2 exhibits excellent stability in water and superior activity for the hydrogen evolution reaction, with a current density of 10 mA cm−2 at a low potential of −175 mV and a Tafel slope of 41‬mV per decade.
Abstract: Metallic molybdenum disulfide is a metastable phase of the material. Here, the authors synthesize two-dimensional metallic molybdenum disulfide nanosheets, stabilized by adsorbed aqueous monolayers, and evaluate their catalytic hydrogen evolution activity.

691 citations


Journal ArticleDOI
Vardan Khachatryan1, Albert M. Sirunyan1, Armen Tumasyan1, Wolfgang Adam  +2283 moreInstitutions (141)
TL;DR: Combined fits to CMS UE proton–proton data at 7TeV and to UEProton–antiproton data from the CDF experiment at lower s, are used to study the UE models and constrain their parameters, providing thereby improved predictions for proton-proton collisions at 13.
Abstract: New sets of parameters ("tunes") for the underlying-event (UE) modeling of the PYTHIA8, PYTHIA6 and HERWIG++ Monte Carlo event generators are constructed using different parton distribution functions. Combined fits to CMS UE data at sqrt(s) = 7 TeV and to UE data from the CDF experiment at lower sqrt(s), are used to study the UE models and constrain their parameters, providing thereby improved predictions for proton-proton collisions at 13 TeV. In addition, it is investigated whether the values of the parameters obtained from fits to UE observables are consistent with the values determined from fitting observables sensitive to double-parton scattering processes. Finally, comparisons of the UE tunes to "minimum bias" (MB) events, multijet, and Drell-Yan (q q-bar to Z / gamma* to lepton-antilepton + jets) observables at 7 and 8 TeV are presented, as well as predictions of MB and UE observables at 13 TeV.

686 citations


Journal ArticleDOI
TL;DR: This paper study and solve the problem of personalized multi-keyword ranked search over encrypted data (PRSE) while preserving privacy in cloud computing with the help of semantic ontology WordNet, and proposes two PRSE schemes for different search intentions.
Abstract: In cloud computing, searchable encryption scheme over outsourced data is a hot research field. However, most existing works on encrypted search over outsourced cloud data follow the model of “one size fits all” and ignore personalized search intention. Moreover, most of them support only exact keyword search, which greatly affects data usability and user experience. So how to design a searchable encryption scheme that supports personalized search and improves user search experience remains a very challenging task. In this paper, for the first time, we study and solve the problem of personalized multi-keyword ranked search over encrypted data (PRSE) while preserving privacy in cloud computing. With the help of semantic ontology WordNet, we build a user interest model for individual user by analyzing the user’s search history, and adopt a scoring mechanism to express user interest smartly. To address the limitations of the model of “one size fit all” and keyword exact search, we propose two PRSE schemes for different search intentions. Extensive experiments on real-world dataset validate our analysis and show that our proposed solution is very efficient and effective.

665 citations


Journal ArticleDOI
TL;DR: An international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide is developed.
Abstract: Objective: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. Results: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. Conclusion: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.

664 citations


Journal ArticleDOI
TL;DR: The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change.
Abstract: The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

572 citations


Journal ArticleDOI
TL;DR: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis, with fewer treatment-associated symptoms related to immunosuppressive medications and lower distress levels related to symptoms.
Abstract: BackgroundThymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. MethodsWe compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednison...

571 citations


Journal ArticleDOI
TL;DR: A unique watermark is directly embedded into the encrypted images by the cloud server before images are sent to the query user, and when image copy is found, the unlawful query user who distributed the image can be traced by the watermark extraction.
Abstract: With the increasing importance of images in people’s daily life, content-based image retrieval (CBIR) has been widely studied. Compared with text documents, images consume much more storage space. Hence, its maintenance is considered to be a typical example for cloud storage outsourcing. For privacy-preserving purposes, sensitive images, such as medical and personal images, need to be encrypted before outsourcing, which makes the CBIR technologies in plaintext domain to be unusable. In this paper, we propose a scheme that supports CBIR over encrypted images without leaking the sensitive information to the cloud server. First, feature vectors are extracted to represent the corresponding images. After that, the pre-filter tables are constructed by locality-sensitive hashing to increase search efficiency. Moreover, the feature vectors are protected by the secure kNN algorithm, and image pixels are encrypted by a standard stream cipher. In addition, considering the case that the authorized query users may illegally copy and distribute the retrieved images to someone unauthorized, we propose a watermark-based protocol to deter such illegal distributions. In our watermark-based protocol, a unique watermark is directly embedded into the encrypted images by the cloud server before images are sent to the query user. Hence, when image copy is found, the unlawful query user who distributed the image can be traced by the watermark extraction. The security analysis and the experiments show the security and efficiency of the proposed scheme.

563 citations


Journal ArticleDOI
TL;DR: In this multicenter, prospective study of bariatric surgery in adolescents, significant improvements in weight, cardiometabolic health, and weight-related quality of life at 3 years after the procedure are found.
Abstract: BackgroundBariatric surgery is increasingly considered for the treatment of adolescents with severe obesity, but few prospective adolescent-specific studies examining the efficacy and safety of weight-loss surgery are available to support clinical decision making. MethodsWe prospectively enrolled 242 adolescents undergoing weight-loss surgery at five U.S. centers. Patients undergoing Roux-en-Y gastric bypass (161 participants) or sleeve gastrectomy (67) were included in the analysis. Changes in body weight, coexisting conditions, cardiometabolic risk factors, and weight-related quality of life and postoperative complications were evaluated through 3 years after the procedure. ResultsThe mean (±SD) baseline age of the participants was 17±1.6 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 53; 75% of the participants were female, and 72% were white. At 3 years after the procedure, the mean weight had decreased by 27% (95% confidence interval [C...

Journal ArticleDOI
TL;DR: In this paper, the authors present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10,000 children for potential fetal alcohol spectrum disorders in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence.
Abstract: The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors’ combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism–funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol.

Journal ArticleDOI
TL;DR: A review of both the tangible and intangible elements of manufacturing systems and a state-of-the-art survey of published work can be found in this article, where the evolution of research in manufacturing starting from past and current trends to future developments is discussed.

Journal ArticleDOI
TL;DR: A new method of keyword transformation based on the uni-gram is developed, which will simultaneously improve the accuracy and creates the ability to handle other spelling mistakes and consider the keyword weight when selecting an adequate matching file set.
Abstract: Keyword-based search over encrypted outsourced data has become an important tool in the current cloud computing scenario. The majority of the existing techniques are focusing on multi-keyword exact match or single keyword fuzzy search. However, those existing techniques find less practical significance in real-world applications compared with the multi-keyword fuzzy search technique over encrypted data. The first attempt to construct such a multi-keyword fuzzy search scheme was reported by Wang et al. , who used locality-sensitive hashing functions and Bloom filtering to meet the goal of multi-keyword fuzzy search. Nevertheless, Wang’s scheme was only effective for a one letter mistake in keyword but was not effective for other common spelling mistakes. Moreover, Wang’s scheme was vulnerable to server out-of-order problems during the ranking process and did not consider the keyword weight. In this paper, based on Wang et al. ’s scheme, we propose an efficient multi-keyword fuzzy ranked search scheme based on Wang et al. ’s scheme that is able to address the aforementioned problems. First, we develop a new method of keyword transformation based on the uni-gram, which will simultaneously improve the accuracy and creates the ability to handle other spelling mistakes. In addition, keywords with the same root can be queried using the stemming algorithm. Furthermore, we consider the keyword weight when selecting an adequate matching file set. Experiments using real-world data show that our scheme is practically efficient and achieve high accuracy.

Journal ArticleDOI
TL;DR: A flexible and wearable pressure sensor based on the giant piezocapacitive effect of a three-dimensional microporous dielectric elastomer, which is capable of highly sensitive and stable pressure sensing over a large tactile pressure range and marks the realization of a true tactile pressure sensor.
Abstract: We report a flexible and wearable pressure sensor based on the giant piezocapacitive effect of a three-dimensional (3-D) microporous dielectric elastomer, which is capable of highly sensitive and stable pressure sensing over a large tactile pressure range. Due to the presence of micropores within the elastomeric dielectric layer, our piezocapacitive pressure sensor is highly deformable by even very small amounts of pressure, leading to a dramatic increase in its sensitivity. Moreover, the gradual closure of micropores under compression increases the effective dielectric constant, thereby further enhancing the sensitivity of the sensor. The 3-D microporous dielectric layer with serially stacked springs of elastomer bridges can cover a much wider pressure range than those of previously reported micro-/nanostructured sensing materials. We also investigate the applicability of our sensor to wearable pressure-sensing devices as an electronic pressure-sensing skin in robotic fingers as well as a bandage-type pr...

Journal ArticleDOI
TL;DR: In 2006, the OPPERA project (Orofacial pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD) as discussed by the authors.
Abstract: In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a "symptom iceberg" when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA's separate case-control study. The puzzle was resolved in OPPERA's nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD's onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.

Journal ArticleDOI
06 May 2016-Science
TL;DR: Structural changes associated with the earliest steps in the trans-to-cis isomerization of the chromophore in photoactive yellow protein are identified.
Abstract: A variety of organisms have evolved mechanisms to detect and respond to light, in which the response is mediated by protein structural changes after photon absorption. The initial step is often the photoisomerization of a conjugated chromophore. Isomerization occurs on ultrafast time scales and is substantially influenced by the chromophore environment. Here we identify structural changes associated with the earliest steps in the trans-to-cis isomerization of the chromophore in photoactive yellow protein. Femtosecond hard x-ray pulses emitted by the Linac Coherent Light Source were used to conduct time-resolved serial femtosecond crystallography on photoactive yellow protein microcrystals over a time range from 100 femtoseconds to 3 picoseconds to determine the structural dynamics of the photoisomerization reaction.

Journal ArticleDOI
TL;DR: It is shown PIEZO1 is activated by bilayer tension in bleb membranes, gating at lower pressures indicative of removal of the cortical cytoskeleton and the mechanoprotection it provides.
Abstract: Mechanosensitive ion channels are force-transducing enzymes that couple mechanical stimuli to ion flux. Understanding the gating mechanism of mechanosensitive channels is challenging because the stimulus seen by the channel reflects forces shared between the membrane, cytoskeleton and extracellular matrix. Here we examine whether the mechanosensitive channel PIEZO1 is activated by force-transmission through the bilayer. To achieve this, we generate HEK293 cell membrane blebs largely free of cytoskeleton. Using the bacterial channel MscL, we calibrate the bilayer tension demonstrating that activation of MscL in blebs is identical to that in reconstituted bilayers. Utilizing a novel PIEZO1–GFP fusion, we then show PIEZO1 is activated by bilayer tension in bleb membranes, gating at lower pressures indicative of removal of the cortical cytoskeleton and the mechanoprotection it provides. Thus, PIEZO1 channels must sense force directly transmitted through the bilayer.

Journal ArticleDOI
TL;DR: This survey focuses on providing a comprehensive overview of truth discovery methods, and summarizing them from different aspects, and offers some guidelines on how to apply these approaches in application domains.
Abstract: Thanks to information explosion, data for the objects of interest can be collected from increasingly more sources. However, for the same object, there usually exist conflicts among the collected multi-source information. To tackle this challenge, truth discovery, which integrates multi-source noisy information by estimating the reliability of each source, has emerged as a hot topic. Several truth discovery methods have been proposed for various scenarios, and they have been successfully applied in diverse application domains. In this survey, we focus on providing a comprehensive overview of truth discovery methods, and summarizing them from different aspects. We also discuss some future directions of truth discovery research. We hope that this survey will promote a better understanding of the current progress on truth discovery, and offer some guidelines on how to apply these approaches in application domains.

Journal ArticleDOI
TL;DR: Research integrating experimental data and modelling to improve representation of plant physiological thresholds infers largely temperature-driven loss of conifer trees by 2100 across the southwestern USA and much of the Northern Hemisphere.
Abstract: Research integrating experimental data and modelling to improve representation of plant physiological thresholds infers largely temperature-driven loss of conifer trees by 2100 across the southwestern USA and much of the Northern Hemisphere.

Journal ArticleDOI
TL;DR: An overview of the recent research on how the complex interactions of environmental, psychological, and biological factors contribute to the development and maintenance of the functional gastrointestinal disorders from a biopsychosocial perspective is provided.

Proceedings ArticleDOI
24 Oct 2016
TL;DR: The main idea is to first gather a candidate set of heavy hitters using a portion of the privacy budget, and focus the remaining budget on refining the candidate set in a second phase, which is much more efficient budget-wise than obtaining the heavy hitters directly from the whole dataset.
Abstract: In local differential privacy (LDP), each user perturbs her data locally before sending the noisy data to a data collector. The latter then analyzes the data to obtain useful statistics. Unlike the setting of centralized differential privacy, in LDP the data collector never gains access to the exact values of sensitive data, which protects not only the privacy of data contributors but also the collector itself against the risk of potential data leakage. Existing LDP solutions in the literature are mostly limited to the case that each user possesses a tuple of numeric or categorical values, and the data collector computes basic statistics such as counts or mean values. To the best of our knowledge, no existing work tackles more complex data mining tasks such as heavy hitter discovery over set-valued data. In this paper, we present a systematic study of heavy hitter mining under LDP. We first review existing solutions, extend them to the heavy hitter estimation, and explain why their effectiveness is limited. We then propose LDPMiner, a two-phase mechanism for obtaining accurate heavy hitters with LDP. The main idea is to first gather a candidate set of heavy hitters using a portion of the privacy budget, and focus the remaining budget on refining the candidate set in a second phase, which is much more efficient budget-wise than obtaining the heavy hitters directly from the whole dataset. We provide both in-depth theoretical analysis and extensive experiments to compare LDPMiner against adaptations of previous solutions. The results show that LDPMiner significantly improves over existing methods. More importantly, LDPMiner successfully identifies the majority true heavy hitters in practical settings.

Journal ArticleDOI
20 Oct 2016-Nature
TL;DR: The developed computational methods for accurate de novo design of conformationally restricted peptides and the use of these methods to design 18–47 residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N–C backbone-cyclized, provide the basis for development of a new generation of peptide-based drugs.
Abstract: Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for accurate de novo design of conformationally restricted peptides, and the use of these methods to design 18-47 residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N-C backbone-cyclized. Both genetically encodable and non-canonical peptides are exceptionally stable to thermal and chemical denaturation, and 12 experimentally determined X-ray and NMR structures are nearly identical to the computational design models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.

Journal ArticleDOI
01 Sep 2016
TL;DR: The results show that CNO has multiple dose-dependent effects in vivo and is converted to clozapine and N-Des emphasizing the need for a CNO-only DreadD-free control group when designing DREADD-based experiments.
Abstract: Clozapine N-oxide (CNO) is a ligand for a powerful chemogenetic system that can selectively inhibit or activate neurons; the so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system. This system consists of synthetic G-protein-coupled receptors, which are not believed to be activated by any endogenous ligand, but are activated by the otherwise inert CNO. However, it has previously been shown that the administration of CNO in humans and rats leads to detectable levels of the bioactive compounds clozapine and N-desmethylclozapine (N-Des). As a follow-up, experiments were conducted to investigate the effects of CNO in male Long-Evans rats. It was found that 1 mg/kg CNO reduced the acoustic startle reflex but had no effect on prepulse inhibition (PPI; a measure of sensorimotor gating). CNO (2 and 5 mg/kg) had no effect on the disruption to PPI induced by the NMDA antagonist phencyclidine or the muscarinic antagonist scopolamine. In locomotor studies, CNO alone (at 1, 2, and 5 mg/kg) had no effect on spontaneous locomotion, but 5 mg/kg CNO pretreatment significantly attenuated d-amphetamine-induced hyperlocomotion. In line with the behavioral results, fast-scan cyclic voltammetry found that 5 mg/kg CNO significantly attenuated the d-amphetamine-induced increase in evoked dopamine. However, the effects seen after CNO administration cannot be definitively ascribed to CNO because biologically relevant levels of clozapine and N-Des were found in plasma after CNO injection. Our results show that CNO has multiple dose-dependent effects in vivo and is converted to clozapine and N-Des emphasizing the need for a CNO-only DREADD-free control group when designing DREADD-based experiments.

Journal ArticleDOI
TL;DR: The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology, and highlights recent developments of melatonin receptor ligands, including radioligands, and gives anupdate on the latest phenotyping results ofmelatonin receptor knockout mice.
Abstract: Melatonin receptors are seven transmembrane-spanning proteins belonging to the G protein-coupled receptor super-family. In mammals, two melatonin receptor subtypes exit MT1 and MT2 encoded by the MTNR1A and MTNR1B genes, respectively. The current review provides an update on melatonin receptors by the corresponding sub-committee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor structures will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by its functions in the immune system and the central nervous system. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

Journal ArticleDOI
TL;DR: In this article, a meta-analysis of 260 independent samples assessed the effects of diversity training on four training outcomes over time and across characteristics of training context, design, and participants.
Abstract: This meta-analysis of 260 independent samples assessed the effects of diversity training on 4 training outcomes over time and across characteristics of training context, design, and participants. Models from the training literature and psychological theory on diversity were used to generate theory-driven predictions. The results revealed an overall effect size (Hedges g) of .38 with the largest effect being for reactions to training and cognitive learning; smaller effects were found for behavioral and attitudinal/affective learning. Whereas the effects of diversity training on reactions and attitudinal/affective learning decayed over time, training effects on cognitive learning remained stable and even increased in some cases. While many of the diversity training programs fell short in demonstrating effectiveness on some training characteristics, our analysis does reveal that successful diversity training occurs. The positive effects of diversity training were greater when training was complemented by other diversity initiatives, targeted to both awareness and skills development, and conducted over a significant period of time. The proportion of women in a training group was associated with more favorable reactions to diversity training. Implications for policy and directions for future research on diversity training are discussed. (PsycINFO Database Record

Journal ArticleDOI
TL;DR: This review summarized recent findings on various pharmacological activities and associative signalling pathways of vitexin and isoviteXin to provide a reference for future research and clinical applications.

Journal ArticleDOI
TL;DR: Considering economic, environmental and social impacts, a new sustainable closed-loop location-routing-inventory model under mixed uncertainty is presented in this paper, where the environmental impacts of CO2 emissions, fuel consumption, wasted energy and the social impacts of created job opportunities and economic development are considered.
Abstract: Considering economic, environmental and social impacts, this paper presents a new sustainable closed-loop location-routing-inventory model under mixed uncertainty. The environmental impacts of CO2 emissions, fuel consumption, wasted energy and the social impacts of created job opportunities and economic development are considered in this paper. The uncertain nature of the network is handled using a stochastic-possibilistic programming approach. Furthermore, for large-sized problems, a hybrid meta-heuristic algorithm and lower bounds are developed and discussed. Finally, a real case study is provided to demonstrate the applicability of the model in real-world applications, and several in-depth analyses are conducted to develop managerial implications.

Journal ArticleDOI
TL;DR: It is demonstrated that cloud cover varies strongly in its geographic heterogeneity and that the direct, observation-based nature of cloud-derived metrics can improve predictions of habitats, ecosystem, and species distributions with reduced spatial autocorrelation compared to commonly used interpolated climate data.
Abstract: Cloud cover can influence numerous important ecological processes, including reproduction, growth, survival, and behavior, yet our assessment of its importance at the appropriate spatial scales has remained remarkably limited. If captured over a large extent yet at sufficiently fine spatial grain, cloud cover dynamics may provide key information for delineating a variety of habitat types and predicting species distributions. Here, we develop new near-global, fine-grain (≈1 km) monthly cloud frequencies from 15 y of twice-daily Moderate Resolution Imaging Spectroradiometer (MODIS) satellite images that expose spatiotemporal cloud cover dynamics of previously undocumented global complexity. We demonstrate that cloud cover varies strongly in its geographic heterogeneity and that the direct, observation-based nature of cloud-derived metrics can improve predictions of habitats, ecosystem, and species distributions with reduced spatial autocorrelation compared to commonly used interpolated climate data. These findings support the fundamental role of remote sensing as an effective lens through which to understand and globally monitor the fine-grain spatial variability of key biodiversity and ecosystem properties.

Journal ArticleDOI
TL;DR: This chapter discusses in each cases the chemical and mechanistic background, the kinetics of the reactions and the biological applicability together with the limiting factors, with a focus on those that have shown broad utility in biological systems.
Abstract: In the last decade and a half, numerous bioorthogonal reactions have been developed with a goal to study biological processes in their native environment, i.e., in living cells and animals. Among them, the photo-triggered reactions offer several unique advantages including operational simplicity with the use of light rather than toxic metal catalysts and ligands, and exceptional spatiotemporal control through the application of an appropriate light source with pre-selected wavelength, light intensity and exposure time. While the photoinduced reactions have been studied extensively in materials research, e.g., on macromolecular surface, the adaptation of these reactions for chemical biology applications is still in its infancy. In this chapter, we review the recent efforts in the discovery and optimization the photo-triggered bioorthogonal reactions, with a focus on those that have shown broad utility in biological systems. We discuss in each cases the chemical and mechanistic background, the kinetics of the reactions and the biological applicability together with the limiting factors.