• 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.
    • 2021 International Conference on Virtual Rehabilitation Proceedings

      International Society for Virtual Rehabilitation (ISVR) (2021-07-16)
    • 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 Better Way to Spend $500,000: How the Juvenile Justice System Fails Girls

      Beyer, Marty; Blair, Gillian; Katz, Sarah; Simkins, Sandra (2003)
    • 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 Buddhist Contribution to Artificial Intelligence?

      Duckworth, Douglas S. (2020)
      Significant questions confront Buddhist traditions in the wake of emergent technologies: can the human body be configured in a certain way, such that it reveals a new world or environment to inhabit beyond optimized self-preservation or survival? Can we manipulate our bodies with technologies—inhibited (or enhanced) by a chemical, a trauma, a contemplative technique, or an implant—such that we are reoriented to a transformed and liberating understanding of the nature of the world and our being in it? As new technologies enhance certain domains of cognitive performance by modelling and extending the structure and capacities of cognition, Buddhism, with a theory of mind and mental development in the absence of an independent essence, owner, or agent like a self, can potentially be a valuable resource. Buddhism provides a useful theoretical foundation to articulate not only the potentials for engineering intelligence, but also by identifying problems in this project.
    • A Cannabinoid 2-Selective Agonist Inhibits Allogeneic Skin Graft Rejection In Vivo

      Center for Substance Abuse Research (Temple University) (2022-02-03)
      Previous work from our laboratory showed that a CB2 selective agonist, O-1966, blocked the proliferative response of C57BL/6 mouse spleen cells exposed to spleen cells of C3HeB/FeJ mice in vitro in the mixed lymphocyte reaction (MLR). The MLR is widely accepted as an in vitro correlate of in vivo grant rejection. Mechanisms of the immunosuppression induced by the cannabinoid were explored, and it was shown that O-1966 in this in vitro assay induced CD25+Foxp3+ Treg cells and IL-10, as well as down-regulated mRNA for CD40 and the nuclear form of the transcription factors NF-κB and NFAT in T-cells. The current studies tested the efficacy of O-1966 in prolonging skin grafts in vivo. Full thickness flank skin patches (1-cm2) from C3HeB/FeJ mice were grafted by suturing onto the back of C57BL/6 mice. O-1966 or vehicle was injected intraperitoneally into treated or control groups of animals beginning 1 h pre-op, and then every other day until 14 days post-op. Graft survival was scored based on necrosis and rejection. Treatment with 5 mg/kg of O-1966 prolonged mean graft survival time from 9 to 11 days. Spleens harvested from O-1966 treated mice were significantly smaller than those of vehicle control animals based on weight. Flow cytometry analysis of CD4+ spleen cells showed that O-1966 treated animals had almost a 3-fold increase in CD25+Foxp3+ Treg cells compared to controls. When dissociated spleen cells were placed in culture ex vivo and stimulated with C3HeB/FeJ cells in an MLR, the cells from the O-1966 treated mice were significantly suppressed in their proliferative response to the allogeneic cells. These results support CB2 selective agonists as a new class of compounds to prolong graft survival in transplant patients.
    • A Case Against Collaboration

      Rebouché, Rachel (2017)
      In family law, as in other legal disciplines, the use of alternative dispute resolution has dramatically increased. In a process called collaborative divorce, separating spouses hire attorneys who agree to work together—almost entirely outside of the court system—to reach a settlement ending the marriage. A team of experts, including mental health professionals, financial neutrals, and parenting coordinators, helps the parties resolve conflicts and settle property, support, and custody disputes. For divorcing couples, the collaborative process promises emotional healing and avoidance of contentious litigation. Advocates for collaborative divorce describe the transformational effects of the process in an evangelical tone. But collaborative divorce has costs. Collaboration can include considerations of marital fault that feminists helped eliminate from divorce laws. By focusing on conflict resolution, even for the purpose of building post-divorce relationships, collaborative negotiations introduce judgments of “good” and “bad” marital conduct, potentially reinforcing stereotyped gender roles, such as the blameless wife and the guilty husband. These heteronormative paradigms are out of date: gender roles have evolved, the population of married people has changed, and marriage rights have extended to couples of the same sex. Collaborative processes also have distributive consequences. Collaboration privileges wealthy parties who may understate their bargaining power. At the same time, collaboration may not reach vulnerable spouses who could benefit from therapeutic interventions. Collaborative divorce can be blind to situational power and structural inequality. The purpose of these critiques is not to undermine therapeutic approaches or to argue that law should ignore spousal misconduct. Rather, this Article suggests that advocates for collaborative divorce—including some feminist scholars who have theorized the shortcomings of no-fault divorce laws—might understand better how parties negotiate, and what they may sacrifice, within a collaborative framework.
    • A case of peroneal neuropathy-induced footdrop. Correlated and compensatory lower-extremity function

      Vlahovic, Tracey; Ribiero, Carla E.; Lamm, Bradley M.; Denmark, James A.; Walters, Robert G.; Talbert, Todd; Penugonda, Sharada; Furmato, James A.; Brower, David J.; McMahon, John; Bhimji, Safta; Hillstrom, Howard J.; Vlahovic|0000-0002-5310-4706 (2000-09-01)
      This article reports on the case of a man with peroneal neuropathy-induced footdrop who was seen at the authors' institution 3 years after open reduction and internal fixation of a proximal fibular fracture and a distal, spiral, oblique tibial fracture of the right leg. A comprehensive gait analysis was conducted. A significant footdrop in gait resulted in a "reverse check mark" center-of-pressure pattern, an increased transverse-plane rotation of the foot, and excessive knee and hip flexion in the sagittal plane. These objective findings documented significant dysfunction within the involved lower extremity; in addition, aberrant biomechanics were observed in structures other than the site of initial injury within both limbs.
    • A Clearer Picture: Journalistic identity practices in words and images on Twitter

      Lough, Kyser; Molyneux, Logan; Holton, Avery E.; 0000-0001-7382-3065 (2017-10-27)
      As journalists continue integrating social media into their professional work, they wrestle with ways to best represent themselves, their organizations, and their profession. Several recent studies have examined this trend in terms of branding, raising important questions about the changing ways in which journalists present themselves and how these changes may indicate shifts in their personal and professional identities. This study combines a visual content analysis of the images journalists use in their Twitter profiles with analyses of their profile text and tweets to examine how journalists present themselves online with an eye toward individual and organizational branding. Findings indicate journalists choose a branding approach and apply it consistently across their profiles, with most profiles consisting of a professional headshot while notably lacking organizational identifiers such as logos. Journalists also tend to lean toward professional rather than personal images in their profile and header photographs, indicating a possible predilection for professional identity over personal on social media.
    • 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 Collective Response to Mass Violence: Reparations and Healing in Cambodia

      Van Schaack, Beth; Ramji-Nogales, Jaya (2005)
      This piece (authored by Jaya Ramji-Nogales) examines an area long neglected in current discussions of Khmer Rouge accountability-reparations for victims. It discusses the Khmer Rouge tribunal law's silence on this matter and presents several arguments, drawing on international human rights law, for the tribunal's awarding of reparations notwithstanding this textual blindspot. The chapter then reviews the various goals reparations can achieve-restitution, rehabilitation, and reconciliation; the types of reparations that can be awarded; and the mechanisms, individual versus collective, that can be used to distribute reparations. Turning to the Cambodian context, it emphasizes the need for a comprehensive study to understand the opinions of Cambodians with respect to reparations. The piece concludes by suggesting several alternative approaches to reparations that are sensitive to Cambodian attitudes and the unique Cambodian cultural context.
    • 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 complex dynamic systems perspective on identity and its development: The dynamic systems model of role identity

      Kaplan, Avi; Garner, Joanna K.; 0000-0002-2898-0085 (2017)
      Current prominent models of identity face challenges in bridging across divergent perspectives and apparent dichotomies such as personal or social-collective, conscious or unconscious, and epigenetic or discursive-relational, and affording pursuit of research questions that allows integrative answers. This article presents a coherent theoretical perspective on the integrative nature of identity and its developmental mechanisms. Adopting the contextual social role as a primary unit of analysis, the Dynamic Systems Model of Role Identity (DSMRI) conceptualizes role identity as a Complex Dynamic System (CDS) anchored in action that comprises the actor’s ontological and epistemological beliefs, purpose and goals, self-perceptions and self-definitions, and perceived action possibilities in the role. These system components are conceptualized as interdependent, and identity development is viewed as emergent, continuous, nonlinear, contextualized, and given to influences from within and without the system. The role identity itself constitutes an element within a multilevel hierarchy, which at the unit of analysis of the individual reflects a CDS of the multiple roles that constitute the person’s psychosocial identity. Identity development involves the formation and restructuring of relations within and among role identities through intra- and interpersonal processes that are mediated by sociocognitive and cultural means, and framed by the context as well as by implicit dispositions. The DSMRI provides a framework to conceptualize and investigate the nature of the identity system, its development, and the relationship between identity development and psychological functioning at different units of-analysis, across different developmental stages and contexts, and using quantitative and qualitative methodologies.