• 11-Step Total Synthesis of Pallambins C and D

      Martinez, LP; Umemiya, S; Wengryniuk, SE; Baran, PS (2016-06-22)
      © 2016 American Chemical Society. The structurally intriguing terpenes pallambins C and D have been assembled in only 11 steps from a cheap commodity chemical: furfuryl alcohol. This synthesis, which features a redox-economic approach free of protecting-group manipulations, assembles all four-ring systems via a sequential cyclization strategy. Of these four-ring constructing operations, two are classical (Robinson annulation and Mukaiyama aldol) and two are newly devised. During the course of this work a method for the difunctionalization of enol ethers was developed, and the scope of this transformation was explored.
    • 1D-3D hybrid modeling-from multi-compartment models to full resolution models in space and time

      Grein, S; Stepniewski, M; Reiter, S; Knodel, MM; Queisser, G (2014-07-29)
      Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator-which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics. © 2014 Grein, Stepniewski, Reiter, Knodel and Queisser.
    • A bag-of-words approach for Drosophila gene expression pattern annotation

      Ji, S; Li, YX; Zhou, ZH; Kumar, S; Ye, J; Kumar, Sudhir|0000-0002-9918-8212 (2009-04-21)
      Background: Drosophila gene expression pattern images document the spatiotemporal dynamics of gene expression during embryogenesis. A comparative analysis of these images could provide a fundamentally important way for studying the regulatory networks governing development. To facilitate pattern comparison and searching, groups of images in the Berkeley Drosophila Genome Project (BDGP) high-throughput study were annotated with a variable number of anatomical terms manually using a controlled vocabulary. Considering that the number of available images is rapidly increasing, it is imperative to design computational methods to automate this task. Results: We present a computational method to annotate gene expression pattern images automatically. The proposed method uses the bag-of-words scheme to utilize the existing information on pattern annotation and annotates images using a model that exploits correlations among terms. The proposed method can annotate images individually or in groups (e.g., according to the developmental stage). In addition, the proposed method can integrate information from different two-dimensional views of embryos. Results on embryonic patterns from BDGP data demonstrate that our method significantly outperforms other methods. Conclusion: The proposed bag-of-words scheme is effective in representing a set of annotations assigned to a group of images, and the model employed to annotate images successfully captures the correlations among different controlled vocabulary terms. The integration of existing annotation information from multiple embryonic views improves annotation performance. © 2009 Ji et al; licensee BioMed Central Ltd.
    • A Biomimetic Microfluidic Tumor Microenvironment Platform Mimicking the EPR Effect for Rapid Screening of Drug Delivery Systems

      Tang, Y; Soroush, F; Sheffield, JB; Wang, B; Prabhakarpandian, B; Kiani, MF; Kiani, Mohammad|0000-0003-1533-0179 (2017-12-01)
      © 2017 The Author(s). Real-time monitoring of tumor drug delivery in vivo is a daunting challenge due to the heterogeneity and complexity of the tumor microenvironment. In this study, we developed a biomimetic microfluidic tumor microenvironment (bMTM) comprising co-culture of tumor and endothelial cells in a 3D environment. The platform consists of a vascular compartment featuring a network of vessels cultured with endothelial cells forming a complete lumen under shear flow in communication with 3D solid tumors cultured in a tumor compartment. Endothelial cell permeability to both small dye molecules and large liposomal drug carriers were quantified using fluorescence microscopy. Endothelial cell intercellular junction formation was characterized by immunostaining. Endothelial cell permeability significantly increased in the presence of either tumor cell conditioned media (TCM) or tumor cells. The magnitude of this increase in permeability was significantly higher in the presence of metastatic breast tumor cells as compared to non-metastatic ones. Immunostaining revealed impaired endothelial cell-cell junctions in the presence of either metastatic TCM or metastatic tumor cells. Our findings indicate that the bMTM platform mimics the tumor microenvironment including the EPR effect. This platform has a significant potential in applications such as cell-cell/cell-drug carrier interaction studies and rapid screening of cancer drug therapeutics/carriers.
    • A cluster randomized trial of an organizational linkage intervention for offenders with substance use disorders: study protocol

      Friedmann, Peter D; Ducharme, Lori J; Welsh, Wayne; Frisman, Linda; Knight, Kevin; Kinlock, Timothy; Mitchell, Shannon Gwin; Hall, Elizabeth; Urbine, Terry; Gordon, Michael; Abdel-Salam, Sami; O’Connell, Dan; Albizu-Garcia, Carmen; Knudsen, Hannah; Duval, Jamieson; Fenster, Juliane; Pankow, Jennifer (2013-12)
      BACKGROUND: Substance use disorders are highly prevalent in community correctional populations, yet these settings frequently are ill-equipped to identify and refer offenders to community-based treatment services. In particular, community corrections staff are often opposed to the use of medication in addiction treatment because of inadequate knowledge, resources, and organizational structures to facilitate client linkages to evidence-based services. METHODS/DESIGN: Each of the NIDA-funded Research Centers recruited 2 criminal justice agencies to participate in the study. Eligibility rules required study sites that were focused on community corrections (i.e., probation or parole), had few or no formal relationships with treatment providers for referring clients to medication-assisted treatment, and had no state or local policies prohibiting such relationships. Sites under the oversight of the same parent agency were eligible only if they were in geographically distinct catchment areas, and could be assigned to different study arms without cross-contamination at any level. The 18 clusters consisted of community corrections officers and their offender caseloads nested within agencies, each of which was partnered with at least one community-based substance abuse treatment program. Randomization was blocked by Research Center, within which one cluster was randomly assigned to a training-only condition (comparison) and the other to training followed by a strategic organizational linkage process (intervention). Line staff received a scientifically-grounded, systematically-delivered training session that addresses gaps in existing knowledge, perceptions, and information about medication-assisted treatment (MAT) and local availability of MAT services. Key decision-makers subsequently were asked to collaborate in a strategic planning process to enhance formal and informal linkages between criminal justice agencies and local MAT providers. It was hypothesized that the two implementation intervention components together would be more likely than staff training alone to improve the process of referring opioid- and alcohol-dependent adults under community supervision to appropriate addiction pharmacotherapy. Outcomes were measured at the client (referrals), line staff (attitudes), and organizational (linkage) levels. DISCUSSION: Through closer collaboration among criminal justice agencies and treatment providers, improved linkages to effective substance abuse treatment should yield significant clinical, public health and public safety benefits.
    • A cluster randomized trial of an organizational process improvement intervention for improving the assessment and case planning of offenders: a Study Protocol

      Shafer, Michael S; Prendergast, Michael; Melnick, Gerald; Stein, Lynda A; Welsh, Wayne N (2014-12)
      BACKGROUND: The Organizational Process Improvement Intervention (OPII), conducted by the NIDA-funded Criminal Justice Drug Abuse Treatment Studies consortium of nine research centers, examined an organizational intervention to improve the processes used in correctional settings to assess substance abusing offenders, develop case plans, transfer this information to community-based treatment agencies, and monitor the services provided by these community based treatment agencies. METHODS/DESIGN: A multi-site cluster randomized design was used to evaluate an inter-agency organizational process improvement intervention among dyads of correctional agencies and community based treatment agencies. Linked correctional and community based agencies were clustered among nine (9) research centers and randomly assigned to an early or delayed intervention condition. Participants included administrators, managers, and line staff from the participating agencies; some participants served on interagency change teams while other participants performed agency tasks related to offender services. A manualized organizational intervention that includes the use of external organizational coaches was applied to create and support interagency change teams that proceeded through a four-step process over a planned intervention period of 12 months. The primary outcome of the process improvement intervention was to improve processes associated with the assessment, case planning, service referral and service provision processes within the linked organizations. DISCUSSION: Providing substance abuse offenders with coordinated treatment and access to community-based services is critical to reducing offender recidivism. Results from this study protocol will provide new and critical information on strategies and processes that improve the assessment and case planning for such offenders as they transition between correctional and community based systems and settings. Further, this study extends current knowledge of and methods for, the study of evidence-based practice adoption and implementation.
    • A cluster randomized trial of utilizing a local change team approach to improve the delivery of HIV services in correctional settings: study protocol

      Belenko, Steven; Visher, Christy; Copenhaver, Michael; Hiller, Matthew; Melnick, Gerald; O’Connell, Daniel; Pearson, Frank; Fletcher, Bennett (2013-12)
      BACKGROUND: Persons held in correctional facilities are at high risk for HIV infection and their prevalence of HIV is substantially higher than in the general population. Thus, the need for proper surveillance and care of this high risk population is a paramount public health issue. This study aims to evaluate an organization-level intervention strategy for improving HIV services for persons in prison or jail. METHODS/DESIGN: HIV Services and Treatment Implementation in Corrections (HIV-STIC) is using a cluster randomized trial design to test an organization-level intervention designed to implement improvements in preventing, detecting, and treating HIV for persons under correctional supervision. Matched pairs of prison or jail facilities were randomized using a SAS algorithm. Facility staff members in both Experimental and Control conditions involved in HIV service delivery are recruited to receive training on HIV infection, the HIV services continuum, and relevant web-based resources. Staff members in both conditions are tasked to implement improvements in HIV prevention, testing, or treatment in their facility. In the Control condition facilities, staff participants use existing techniques for implementing improvement in a selected area of HIV services. In contrast, the Experimental condition staff participants work as a Local Change Team (LCT) with external coaching and use a structured process improvement approach to improve a selected part of the HIV services continuum. The intervention period is 10 months during which data are obtained using survey instruments administered to staff members and aggregate services delivery data. The study is being implemented in 13 pairs of correctional facilities across nine states in the US. Experimental sites are hypothesized to show improvements in both staff attitudes toward HIV services and the number and quality of HIV services provided for inmates. DISCUSSION: The current study examines a range of process and outcome data relevant to the implementation of a Change Team approach across diverse correctional settings in the United States. This initial study represents an important step toward a national best practices approach to implementing change in U.S. correctional settings and could serve as an exemplar for designing similar implementation studies.
    • A Co-Design-Based Reliable Low-Latency and Energy-Efficient Transmission Protocol for UWSNs

      Wei, X; Guo, H; Wang, X; Wang, X; Wang, C; Guizani, M; Du, X; Du, Xiaojiang|0000-0003-4235-9671 (2020-11-08)
      Recently, underwater wireless sensor networks (UWSNs) have been considered as a powerful technique for many applications. However, acoustic communications in UWSNs bring in huge QoS issues for time-critical applications. Additionally, excessive control packets and multiple copies during the data transmission process exacerbate this challenge. Faced with these problems, we propose a reliable low-latency and energy-efficient transmission protocol for dense 3D underwater wireless sensor networks to improve the QoS of UWSNs. The proposed protocol exploits fewer control packets and reduces data-packet copies effectively through the co-design of routing and media access control (MAC) protocols. The co-design method is divided into two steps. First, the number of handshakes in the MAC process will be greatly reduced via our forwarding-set routing strategy under the guarantee of reliability. Second, with the help of information from the MAC process, network-update messages can be used to replace control packages through mobility prediction when choosing a route. Simulation results show that the proposed protocol has a considerably higher reliability, and lower latency and energy consumption in comparison with existing transmission protocols for a dense underwater wireless sensor network.
    • A comparison of diarrheal severity scores in the MAL-ED multisite community-based cohort study

      Lee, GO; Richard, SA; Kang, G; Houpt, ER; Seidman, JC; Pendergast, LL; Bhutta, ZA; Ahmed, T; Mduma, ER; Lima, AA; Bessong, P; Jennifer, MS; Hossain, MI; Chandyo, RK; Nyathi, E; Lima, IF; Pascal, J; Soofi, S; Ladaporn, B; Guerrant, RL; Caulfield, LE; Black, RE; Kosek, MN (2016-01-01)
      Copyright © 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Objectives: There is a lack of consensus on how to measure diarrheal severity. Within the context of a multisite, prospective cohort study, we evaluated the performance of a modified Vesikari score (MAL-ED), 2 previously published scores (Clark and CODA [a diarrheal severity score (Community DiarrheA) published by Lee et al]), and a modified definition of moderate-to-severe diarrhea (MSD) based on dysentery and health care worker diagnosed dehydration. Methods: Scores were built using maternally reported symptoms or fieldworker-reported clinical signs obtained during the first 7 days of a diarrheal episode. The association between these and the risk of hospitalization were tested using receiver operating characteristic analysis. Severity scores were also related to illness etiology, and the likelihood of the episode subsequently becoming prolonged or persistent. Results: Of 10,159 episodes from 1681 children, 143 (4.0%) resulted in hospitalization. The area under the curve of each score as a predictor of hospitalization was 0.84 (95% confidence interval: 0.81, 0.87) (Clark), 0.85 (0.82, 0.88) (MAL-ED), and 0.87 (0.84, 0.89) (CODA). Severity was also associated with etiology and episode duration. Although families were more likely to seek care for severe diarrhea, approximately half of severe cases never reached the health system. Conclusions: Community-based diarrheal severity scores are predictive of relevant child health outcomes. Because they require no assumptions about health care access or utilization, they are useful in refining estimates of the burden of diarrheal disease, in estimating the effect of disease control interventions, and in triaging children for referral in low- and middle-income countries in which the rates of morbidity and mortality after diarrhea remain high.
    • A complete non-perturbative renormalization prescription for quasi-PDFs

      Alexandrou, C; Cichy, K; Constantinou, M; Hadjiyiannakou, K; Jansen, K; Panagopoulos, H; Steffens, F (2017-10-01)
      © 2017 In this work we present, for the first time, the non-perturbative renormalization for the unpolarized, helicity and transversity quasi-PDFs, in an RI′ scheme. The proposed prescription addresses simultaneously all aspects of renormalization: logarithmic divergences, finite renormalization as well as the linear divergence which is present in the matrix elements of fermion operators with Wilson lines. Furthermore, for the case of the unpolarized quasi-PDF, we describe how to eliminate the unwanted mixing with the twist-3 scalar operator. We utilize perturbation theory for the one-loop conversion factor that brings the renormalization functions to the MS‾-scheme at a scale of 2 GeV. We also explain how to improve the estimates on the renormalization functions by eliminating lattice artifacts. The latter can be computed in one-loop perturbation theory and to all orders in the lattice spacing. We apply the methodology for the renormalization to an ensemble of twisted mass fermions with Nf=2+1+1 dynamical quarks, and a pion mass of around 375 MeV.
    • A computational approach to map nucleosome positions and alternative chromatin states with base pair resolution

      Zhou, X; Blocker, AW; Airoldi, EM; O’Shea, EK; Airoldi, Edoardo|0000-0002-3512-0542 (2016-09-13)
      © Zhou et al. Understanding chromatin function requires knowing the precise location of nucleosomes. MNase-seq methods have been widely applied to characterize nucleosome organization in vivo, but generally lack the accuracy to determine the precise nucleosome positions. Here we develop a computational approach leveraging digestion variability to determine nucleosome positions at a base-pair resolution from MNase-seq data. We generate a variability template as a simple error model for how MNase digestion affects the mapping of individual nucleosomes. Applied to both yeast and human cells, this analysis reveals that alternatively positioned nucleosomes are prevalent and create significant heterogeneity in a cell population. We show that the periodic occurrences of dinucleotide sequences relative to nucleosome dyads can be directly determined from genome-wide nucleosome positions from MNase-seq. Alternatively positioned nucleosomes near transcription start sites likely represent different states of promoter nucleosomes during transcription initiation. Our method can be applied to map nucleosome positions in diverse organisms at base-pair resolution.
    • A conserved cell growth cycle can account for the environmental stress responses of divergent eukaryotes

      Slavov, N; Airoldi, EM; Van Oudenaarden, A; Botstein, D; Airoldi, Edoardo|0000-0002-3512-0542 (2012-05-15)
      The respiratory metabolic cycle in budding yeast (Saccharomyces cerevisiae) consists of two phases that are most simply defined phenomenologically: low oxygen consumption (LOC) and high oxygen consumption (HOC). Each phase is associated with the periodic expression of thousands of genes, producing oscillating patterns of gene expression found in synchronized cultures and in single cells of slowly growing unsynchronized cultures. Systematic variation in the durations of the HOC and LOC phases can account quantitatively for well-studied transcriptional responses to growth rate differences. Here we show that a similar mechanism - transitions from the HOC phase to the LOC phase - can account for much of the common environmental stress response (ESR) and for the cross-protection by a preliminary heat stress (or slow growth rate) to subsequent lethal heat stress. Similar to the budding yeast metabolic cycle, we suggest that a metabolic cycle, coupled in a similar way to the ESR, in the distantly related fission yeast, Schizosaccharomyces pombe, and in humans can explain gene expression and respiratory patterns observed in these eukaryotes. Although metabolic cycling is associated with the G0/G1 phase of the cell division cycle of slowly growing budding yeast, transcriptional cycling was detected in the G2 phase of the division cycle in fission yeast, consistent with the idea that respiratory metabolic cycling occurs during the phases of the cell division cycle associated with mass accumulation in these divergent eukaryotes. © 2012 Slavov et al.
    • A couple-based HIV prevention intervention for Latino men who have sex with men: Study protocol for a randomized controlled trial

      Martinez, O; Isabel Fernandez, M; Wu, E; Carballo-Diéguez, A; Prado, G; Davey, A; Levine, E; Mattera, B; Lopez, N; Valentin, O; Murray, A; Sutton, M (2018-04-05)
      © 2018 The Author(s). Background: Latino men who have sex with men (MSM) experienced a 13% increase in HIV diagnoses from 2010 to 2014, more than any other racial/ethnic subgroup of MSM in the United States. If current HIV diagnoses rates persist, about one in four Latino MSM in the United States will be diagnosed with HIV during their lifetime. Although some efficacious HIV prevention interventions for Latino MSM exist, none have focused on couples. This paper describes the protocol of a randomized controlled trial (RCT) to test the preliminary efficacy of a couple-based HIV prevention intervention that is culturally tailored for Latino men and their same-sex partners. Methods: The RCT will determine the preliminary efficacy of Connecting Latinos en Pareja (CLP) to increase the proportion of anal sex acts that are HIV protected (i.e., anal sex acts in which condoms, pre-exposure prophylaxis (PrEP), treatment as prevention (TasP), or a combination thereof, are used to reduce risk of HIV transmission). CLP builds upon previous couple-based interventions with white and black MSM by incorporating biomedical prevention techniques, such as PrEP and TasP, implementing a framework responsive to the couple's serostatus, and addressing the socio-cultural factors that influence HIV risk among Latino MSM. We also include input from community stakeholders, members of the target population, and a community advisory board as part of intervention development. Assessments will be conducted at baseline, and 3- and 6-months post-intervention to examine the intervention effects on outcomes (HIV-protected sex acts), and factors potentially mediating or moderating intervention effects. Discussion: This paper describes an innovative RCT that incorporates multiple HIV prevention techniques for Latino MSM in couples, regardless of serostatus. The ongoing involvement of community stakeholders, members of the target population, and a community advisory board is emphasized, and plans for widespread dissemination and application of findings into practice are discussed.
    • A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

      Fourati, S; Talla, A; Mahmoudian, M; Burkhart, JG; Klén, R; Henao, R; Yu, T; Aydın, Z; Yeung, KY; Ahsen, ME; Almugbel, R; Jahandideh, S; Liang, X; Nordling, TEM; Shiga, M; Stanescu, A; Vogel, R; Abdallah, EB; Aghababazadeh, FA; Amadoz, A; Bhalla, S; Bleakley, K; Bongen, E; Borzacchielo, D; Bucher, P; Carbonell-Caballero, J; Chaudhary, K; Chinesta, F; Chodavarapu, P; Chow, RD; Cokelaer, T; Cubuk, C; Dhanda, SK; Dopazo, J; Faux, T; Feng, Y; Flinta, C; Guziolowski, C; He, D; Hidalgo, MR; Hou, J; Inoue, K; Jaakkola, MK; Ji, J; Kumar, R; Kumar, S; Kursa, MB; Li, Q; Łopuszyński, M; Lu, P; Magnin, M; Mao, W; Miannay, B; Nikolayeva, I; Obradovic, Z; Pak, C; Rahman, MM; Razzaq, M; Ribeiro, T; Roux, O; Saghapour, E; Saini, H; Sarhadi, S; Sato, H; Schwikowski, B; Sharma, A; Sharma, R; Singla, D; Stojkovic, I; Suomi, T; Suprun, M; Tian, C; Tomalin, LE; Xie, L; Yu, X; Pandey, G; Chiu, C; McClain, MT; Woods, CW; Ginsburg, GS; Elo, LL; Tsalik, EL; Mangravite, LM; Sieberts, SK (2018-12-01)
      © 2018, The Author(s). The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses.
    • A cyclic nucleotide-gated channel mutation associated with canine daylight blindness provides insight into a role for the S2 segment Tri-Asp motif in channel biogenesis

      Tanaka, N; Delemotte, L; Klein, ML; Komáromy, AM; Tanaka, JC (2014-02-21)
      Cone cyclic nucleotide-gated channels are tetramers formed by CNGA3 and CNGB3 subunits; CNGA3 subunits function as homotetrameric channels but CNGB3 exhibits channel function only when co-expressed with CNGA3. An aspartatic acid (Asp) to asparagine (Asn) missense mutation at position 262 in the canine CNGB3 (D262N) subunit results in loss of cone function (daylight blindness), suggesting an important role for this aspartic acid residue in channel biogenesis and/or function. Asp 262 is located in a conserved region of the second transmembrane segment containing three Asp residues designated the Tri-Asp motif. This motif is conserved in all CNG channels. Here we examine mutations in canine CNGA3 homomeric channels using a combination of experimental and computational approaches. Mutations of these conserved Asp residues result in the absence of nucleotide-activated currents in heterologous expression. A fluorescent tag on CNGA3 shows mislocalization of mutant channels. Co-expressing CNGB3 Tri-Asp mutants with wild type CNGA3 results in some functional channels, however, their electrophysiological characterization matches the properties of homomeric CNGA3 channels. This failure to record heteromeric currents suggests that Asp/Asn mutations affect heteromeric subunit assembly. A homology model of S1-S6 of the CNGA3 channel was generated and relaxed in a membrane using molecular dynamics simulations. The model predicts that the Tri-Asp motif is involved in non-specific salt bridge pairings with positive residues of S3/S4. We propose that the D262N mutation in dogs with CNGB3-day blindness results in the loss of these inter-helical interactions altering the electrostatic equilibrium within in the S1-S4 bundle. Because residues analogous to Tri-Asp in the voltage-gated Shaker potassium channel family were implicated in monomer folding, we hypothesize that destabilizing these electrostatic interactions impairs the monomer folding state in D262N mutant CNG channels during biogenesis. © 2014 Tanaka et al.
    • A data-driven acute inflammation therapy

      Radosavljevic, V; Ristovski, K; Obradovic, Z (2013-11-25)
      Acute inflammation is a severe medical condition defined as an inflammatory response of the body to an infection. Its rapid progression requires quick and accurate decisions from clinicians. Inadequate and delayed decisions makes acute inflammation the 10th leading cause of death overall in United States with the estimated cost of treatment about $17 billion annually. However, despite the need, there are limited number of methods that could assist clinicians to determine optimal therapies for acute inflammation. We developed a data-driven method for suggesting optimal therapy by using machine learning model that is learned on historical patients' behaviors. To reduce both the risk of failure and the expense for clinical trials, our method is evaluated on a virtual patients generated by a mathematical model that emulates inflammatory response. In conducted experiments, acute inflammation was handled with two complimentary pro- and anti-inflammatory medications which adequate timing and doses are crucial for the successful outcome. Our experiments show that the dosage regimen assigned with our data-driven method significantly improves the percentage of healthy patients when compared to results by other methods used in clinical practice and found in literature. Our method saved 88% of patients that would otherwise die within a week, while the best method found in literature saved only 73% of patients. At the same time, our method used lower doses of medications than alternatives. In addition, our method achieved better results than alternatives when only incomplete or noisy measurements were available over time as well as it was less affected by therapy delay. The presented results provide strong evidence that models from the artificial intelligence community have a potential for development of personalized treatment strategies for acute inflammation. © 2013 Radosavljevic et al; licensee BioMed Central Ltd.
    • A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

      Russo, A; Franchina, T; Ricciardi, GRR; Picone, A; Ferraro, G; Mariangela Zanghì; Toscano, G; Giordano, A; Adamo, V; Giordano, Antonio|0000-0002-5959-016X (2015-01-01)
      The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.
    • A first look at ARFome: Dual-coding genes in mammalian genomes

      Chung, WY; Wadhawan, S; Szklarczyk, R; Pond, SK; Nekrutenko, A; Pond, Sergei L. Kosakovsky|0000-0003-4817-4029 (2007-05-01)
      Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology. © 2007 Chung et al.
    • A fog computing solution for context-based privacy leakage detection for android healthcare devices

      Gu, J; Huang, R; Jiang, L; Qiao, G; Du, X; Guizani, M; Du, Xiaojiang|0000-0003-4235-9671 (2019-03-01)
      © 2019 by the authors. Licensee MDPI, Basel, Switzerland. Intelligent medical service system integrates wireless internet of things (WIoT), including medical sensors, wireless communications, and middleware techniques, so as to collect and analyze patients’ data to examine their physical conditions by many personal health devices (PHDs) in real time. However, large amount of malicious codes on the Android system can compromise consumers’ privacy, and further threat the hospital management or even the patients’ health. Furthermore, this sensor-rich system keeps generating large amounts of data and saturates the middleware system. To address these challenges, we propose a fog computing security and privacy protection solution. Specifically, first, we design the security and privacy protection framework based on the fog computing to improve tele-health and tele-medicine infrastructure. Then, we propose a context-based privacy leakage detection method based on the combination of dynamic and static information. Experimental results show that the proposed method can achieve higher detection accuracy and lower energy consumption compared with other state-of-art methods.
    • A generalized birth and death process for modeling the fates of gene duplication

      Zhao, J; Teufel, AI; Liberles, DA; Liu, L; Liberles, David A|0000-0003-3487-8826 (2015-12-08)
      © 2015 Zhao et al. Background: Accurately estimating the timing and mode of gene duplications along the evolutionary history of species can provide invaluable information about underlying mechanisms by which the genomes of organisms evolved and the genes with novel functions arose. Mechanistic models have previously been introduced that allow for probabilistic inference of the evolutionary mechanism for duplicate gene retention based upon the average rate of loss over time of the duplicate. However, there is currently no probabilistic model embedded in a birth-death modeling framework that can take into account the effects of different evolutionary mechanisms of gene retention when analyzing gene family data. Results: In this study, we describe a generalized birth-death process for modeling the fates of gene duplication. Use of mechanistic models in a phylogenetic framework requires an age-dependent birth-death process. Starting with a single population corresponding to the lineage of a phylogenetic tree and with an assumption of a clock that starts ticking for each duplicate at its birth, an age-dependent birth-death process is developed by extending the results from the time-dependent birth-death process. The implementation of such models in a full phylogenetic framework is expected to enable large scale probabilistic analysis of duplicates in comparative genomic studies. Conclusions: We develop an age-dependent birth-death model for understanding the mechanisms of gene retention, which allows a gene loss rate dependent on each duplication event. Simulation results indicate that different mechanisms of gene retentions produce distinct likelihood functions, which can be used with genomic data to quantitatively distinguish those mechanisms.