Early Entry Research Articles

Procesos de formación en investigación en la Universidad: ¿Qué le queda a los estudiantes?

La formación investigativa es un componente central en la educación del joven universitario en la sociedad actual y la actitud hacia esa formación puede ser un indicador sobre la calidad de los procesos de formación y de la posibilidad de ingreso temprano del estudiante en los sistemas universitarios de investigación y la formación de científicos. En el presente estudio, de tipo transversal-correlacional, se evalúa la actitud del joven a partir de tres elementos: autopercepción, incidencia de los profesores e incidencia de las universidades sobre la formación en investigación en el nivel de grado. Se aplicó un instrumento estructurado a estudiantes de ocho universidades del área metropolitana de Bucaramanga, Colombia, por muestreo aleatorio simple. Se destaca el alto valor que los estudiantes le otorgan al aprendizaje de la investigación en la Universidad, pero la baja proyección y actitud de la mayoría hacia los temas científicos. Adicionalmente se encontró que los profesores tienen un alto nivel de impacto en la actitud del estudiante hacia la investigación mientras que los factores sociales e institucionales no representan una lata incidencia. Finalmente el estudio demuestra una tendencia decreciente de la actitud hacia la investigación a mayor nivel en la Universidad.

Identification of a flavonoid isolated from plum (Prunus domestica) as a potent inhibitor of Hepatitis C virus entry

Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases that often requires liver transplantation. The standard therapies are limited by severe side effects, resistance development, high expense and in a substantial proportion of cases, fail to clear the infection which bespeak the need for development of well-tolerated antivirals. Since most of the drug development strategies target the replication stage of viral lifecycle, the identification of entry inhibitors might be crucial especially in case of liver-transplant recipients. In the present study we have evaluated fruits which are known for their hepatoprotective effects in order to screen for entry inhibitors. We report the identification of a flavonoid, rutin, isolated from Prunus domestica as a new HCV entry inhibitor. Characterization and confirmation of the chemical structure was done by LC-ESI-MS, NMR and IR spectral analyses. Rutin significantly inhibited HCV-LP binding to hepatoma cells and inhibited cell-culture derived HCV (HCVcc) entry into hepatoma cells. Importantly, rutin was found to be non-toxic to hepatoma cells. Furthermore, rutin inhibits the early entry stage of HCV lifecycle possibly by directly acting on the viral particle. In conclusion, rutin is a promising candidate for development of anti-HCV therapeutics in the management of HCV infection.

Timing options for a startup with early termination and competition risks

This paper analyzes the timing options embedded in a startup firm, and the associated market entry and exit timing decisions under the exogenous risks of early termination and competitor's entry. Our valuation approach leads to the analytical study of a non-standard perpetual American installment option nested with an optimal sequential stopping problem. Explicit formulas are derived for the firm's value functions. Analytically and numerically, we show that early termination risk leads to earlier voluntary entry or exit, and the threat of competition has a non-trivial effect on the firm's entry and abandonment strategies.

Enhancing the understanding of international new ventures: a service-oriented perspective

PurposeThis paper aims to challenge the up to now mainly product-centered view on international new ventures by analyzing the influence of service orientation on new venture internationalization behavior. It especially focuses on the utilization of specific market entry modes as a result of a growing service orientation.Design/methodology/approachNewness and complexity of the topic call for a qualitative-empirical research approach. Therefore, the paper is based on an in-depth multiple-case study of six international new ventures operating in fashion and lifestyle industry.FindingsThis paper shows that service-oriented international new ventures make use of different market entry modes at the same time. Service-related capabilities allow them to especially use cooperative market entry modes to fuel lacking market knowledge and thus to overcome resource constraints in value creation processes.Originality/valueThe paper contributes to a more holistic understanding of international new ventures, as it provides empirical evidence for the importance of service-related aspects in new venture internationalization. Furthermore, the paper extends international new venture research by not only considering an early international market entry but also other aspects of internationalization such as the type of offerings or the preferred market entry modes.

Corporalidades y subjetividades sexuales: el caso de las mujeres excombatientes de las guerrillas colombianas

El ingreso temprano de mujeres a grupos armados al margen de la ley implica la vivencia de experiencias que transmutan roles de género tradicionales, el cuidado del cuerpo, la construcción de la sexualidad y de las subjetividades. Dentro de la estructura bélica, y posteriormente, en el proceso de reintegración, las mujeres se enfrentan a múltiples decisiones en las distintas etapas de su sexualidad. Con el fin del conflicto armado con las FARC-EP, ellas se encuentran en un nuevo momento de sus vidas, pasando del contexto caracterizado por el miedo, la violencia y las ausencias estatales, a asumir otras posiciones sociales como futuras agentes de cambio. El objetivo de este artículo es reflexionar sobre las dimensiones corporales de las mujeres en las guerrillas colombianas, para contrastar el impacto de la violencia y el conflicto en la constitución de las subjetividades desde una dimensión sexual y de género. Para ello, se utiliza la metodología cualitativa de análisis documental y, además, se tienen en cuenta observaciones a partir de investigaciones anteriores realizadas con la Corporación Descontamina.

Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel.

Wee1 kinase is a crucial negative regulator of Cdk1/cyclin B1 activity and is required for normal entry into and exit from mitosis. Wee1 activity can be chemically inhibited by the small molecule MK-1775, which is currently being tested in phase I/II clinical trials in combination with other anti-cancer drugs. MK-1775 promotes cancer cells to bypass the cell-cycle checkpoints and prematurely enter mitosis. In our study, we show premature mitotic cells that arise from MK-1775 treatment exhibited centromere fragmentation, a morphological feature of mitotic catastrophe that is characterized by centromeres and kinetochore proteins that co-cluster away from the condensed chromosomes. In addition to stimulating early mitotic entry, MK-1775 treatment also delayed mitotic exit. Specifically, cells treated with MK-1775 following release from G1/S or prometaphase arrested in mitosis. MK-1775 induced arrest occurred at metaphase and thus, cells required 12 times longer to transition into anaphase compared to controls. Consistent with an arrest in mitosis, MK-1775 treated prometaphase cells maintained high cyclin B1 and low phospho-tyrosine 15 Cdk1. Importantly, MK-1775 induced mitotic arrest resulted in cell death regardless the of cell-cycle phase prior to treatment suggesting that Wee1 inhibitors are also anti-mitotic agents. We found that paclitaxel enhances MK-1775 mediated cell killing. HeLa and different breast cancer cell lines (T-47D, MCF7, MDA-MB-468 and MDA-MB-231) treated with different concentrations of MK-1775 and low dose paclitaxel exhibited reduced cell survival compared to mono-treatments. Our data highlight a new potential strategy for enhancing MK-1775 mediated cell killing in breast cancer cells.

Enhanced saccharification of lignocellulosic agricultural biomass and increased bioethanol titre using acclimated Clostridium thermocellum DSM1313

Consolidated bioprocess assures an efficient lignocellulosic conversion to fermentable sugars and subsequently to bioethanol. Such a single-step hydrolysis and anaerobic fermentation was achieved with acclimated Clostridium thermocellum DSM 1313 on different mildly pre-treated agricultural lignocellulosic residues without any additional enzymes/and strains. Acclimation was achieved by serially sub-culturing in increasing concentration of individual substrates, such as rice husk, sugarcane bagasse, and banana pseudostem in the standard media, with cellobiose as an adjunct. The acclimated cellulolytic thermophile exhibited an early log phase entry with enhanced growth compared to the direct inoculation experiments with unacclimated culture. Around 672 mg/g of reducing sugar was produced from sugarcane bagasse media and 636 mg/g from rice husk media and 513 mg/g from banana pseudostem media with the acclimated organism. Bioethanol production also doubled in experiments with serially acclimated cultures, with a maximum of 1.21 and 1.0 g/L ethanol titre from sugarcane bagasse and rice husk, respectively. The serial acclimation experiments have increased the saccharification potentials of the organism towards the respective lignocellulosic substrates and also enhanced the bioethanol production.

Imaging HIV-1 Genomic DNA from Entry through Productive Infection.

In order to track the fate of HIV-1 particles from early entry events through productive infection, we developed a method to visualize HIV-1 DNA reverse transcription complexes by the incorporation and fluorescent labeling of the thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) into nascent viral DNA during cellular entry. Monocyte-derived macrophages were chosen as natural targets of HIV-1, as they do not divide and therefore do not incorporate EdU into chromosomal DNA, which would obscure the detection of intranuclear HIV-1 genomes. Using this approach, we observed distinct EdU puncta in the cytoplasm of infected cells within 12 h postinfection and subsequent accumulation of puncta in the nucleus, which remained stable through 5 days. The depletion of the restriction factor SAMHD1 resulted in a markedly increased number of EdU puncta, allowing efficient quantification of HIV-1 reverse transcription events. Analysis of HIV-1 isolates bearing defined mutations in the capsid protein revealed differences in their cytoplasmic and nuclear accumulation, and data from quantitative PCR analysis closely recapitulated the EdU results. RNA fluorescence in situ hybridization identified actively transcribing, EdU-labeled HIV-1 genomes in productively infected cells, and immunofluorescence analysis confirmed that CDK9, phosphorylated at serine 175, was recruited to RNA-positive HIV-1 DNA, providing a means to directly observe transcriptionally active HIV-1 genomes in productively infected cells. Overall, this system allows stable labeling and monitoring of HIV genomic DNA within infected cells during cytoplasmic transit, nuclear import, and mRNA synthesis.IMPORTANCE The fates of HIV-1 reverse transcription products within infected cells are not well understood. Although previous imaging approaches identified HIV-1 intermediates during early stages of infection, few have connected these events with the later stages that ultimately lead to proviral transcription and the production of progeny virus. Here we developed a technique to label HIV-1 genomes using modified nucleosides, allowing subsequent imaging of cytoplasmic and nuclear HIV-1 DNA in infected monocyte-derived macrophages. We used this technique to track the efficiency of nuclear entry as well as the fates of HIV-1 genomes in productively and nonproductively infected macrophages. We visualized transcriptionally active HIV-1 DNA, revealing that transcription occurs in a subset of HIV-1 genomes in productively infected cells. Collectively, this approach provides new insights into the nature of transcribing HIV-1 genomes and allows us to track the entire course of infection in macrophages, a key target of HIV-1 in infected individuals.

Significant association between perceived HIV related stigma and late presentation for HIV/AIDS care in low and middle-income countries: A systematic review and meta-analysis.

BackgroundLate presentation for human immunodeficiency virus (HIV) care is a major impediment for the success of antiretroviral therapy (ART) outcomes. The role that stigma plays as a potential barrier to timely diagnosis and treatment of HIV among people living with HIV/AIDS (acquired immunodeficiency syndrome) is ambivalent. This review aimed to assess the best available evidence regarding the association between perceived HIV related stigma and time to present for HIV/AIDS care.MethodsQuantitative studies conducted in English language between 2002 and 2016 that evaluated the association between HIV related stigma and late presentation for HIV care were sought across four major databases. This review considered studies that included the following outcome: ‘late HIV testing’, ‘late HIV diagnosis’ and ‘late presentation for HIV care after testing’. Data were extracted using a standardized Joanna Briggs Institute (JBI) data extraction tool. Meta- analysis was undertaken using Revman-5 software. I2 and chi-square test were used to assess heterogeneity. Summary statistics were expressed as pooled odds ratio with 95% confidence intervals and corresponding p-value.ResultsTen studies from low- and middle- income countries met the search criteria, including six (6) and four (4) case control studies and cross-sectional studies respectively. The total sample size in the included studies was 3,788 participants. Half (5) of the studies reported a significant association between stigma and late presentation for HIV care. The meta-analytical association showed that people who perceived high HIV related stigma had two times more probability of late presentation for HIV care than who perceived low stigma (pooled odds ratio = 2.4; 95%CI: 1.6–3.6, I2 = 79%).ConclusionsHigh perceptions of HIV related stigma influenced timely presentation for HIV care. In order to avoid late HIV care presentation due the fear of stigma among patients, health professionals should play a key role in informing and counselling patients on the benefits of early HIV testing or early entry to HIV care. Additionally, linking the systems and positive case tracing after HIV testing should be strengthened.

Mutual growth-promoting effect between Bifidobacterium bifidum WBBI03 and Listeria monocytogenes CMCC 54001

In this study, Bifidobacterium bifidum WBBI03 and Listeria monocytogenes CMCC 54001 were selected to detect the changes in their growth pattern after mutual interaction between them. The proteomic changes after the interaction between the 2 bacteria were detected by the isobaric tags for relative and absolute quantitation method. The proteins related to the biosynthesis and cell reproduction were selected, and their changes at the transcriptional level were monitored by fluorescent quantitative PCR. Also, 3 other types of probiotic organisms and opportunistic pathogens were used to verify the results mentioned above. The results showed that growing the 2 organisms together could promote the growth of each other, resulting in earlier entry into the logarithmic phase. The results also showed that the expression of these proteins mostly tended to be upregulated at the translational and transcriptional level. The increase in the expression of these proteins might help promote the growth and reproduction of B. bifidum WBBI03 and L. monocytogenes CMCC 54001. One aspect of the biological significance of their presence in the normal intestine may be that the opportunistic pathogens promote the growth of the probiotics.

Lost in Transition: UN Mediation in Libya, Syria, and Yemen

The violence in the Middle East obfuscates the fact that there exists also a story of peace efforts across the region — a story of small successes, big frustrations, setbacks, and failures. Through these efforts, UN mediators have sought to achieve the often irreconcilable goals of ending violence while facilitating a political transition and reconciling the parties.Building on the findings of papers previously published by IPI on UN mediation in Libya, Syria, and Yemen, this report draws crosscutting lessons for ongoing and future UN mediation in similarly complex and violent political transitions. These lessons are organized around five key challenges that mediators confront:-Mandate: Much of the success or failure of a mediation depends on the mandate. While mediators do not necessarily need a clear mandate from the beginning, their success depends on unequivocal support from the Security Council at certain key stages of their mediation. This lack of clarity and the perception that the end result — political transition — was a precondition for negotiation frustrated the processes in Libya and Syria.-Impartiality and inclusivity: It is neither possible nor always necessary for mediators to be completely impartial, but they must make proposals agreeable to the parties — a particular challenge during political transitions. Regarding inclusivity, every mediator is forced to make choices about who to include, and though any deficiencies generally involve leaving key actors out, sometimes a less inclusive process could have worked better.-Entry and consent: Finding a favorable entry point — a moment when the conflict is “ripe” for resolution — is a challenge for mediators. While in Syria the UN is often faulted for being late to the conflict, the UN’s early entry in Libya did not improve the chances of mediation. The case of Yemen, however, demonstrates how early, low-profile engagement can help develop more favorable entry points.-Strategy: Mediators face a dilemma in how to use cease-fires as conflict management tools; they can help build confidence among the parties, but they can also prolong the conflict by creating a tolerable stalemate. Cease-fires were only a minor part of the strategy of the mediators in all three countries. Greater emphasis on this mediation tool should be considered in future processes.-Leverage: The greatest challenge UN mediators faced in leveraging power is that they represented a multilateral organization made up of many member states with competing agendas. But mediators who are UN insiders can also work the system in their favor. There are also other forms of leverage available to them, such as personal prestige and informational power.

Gender Gap in Academic Achievement in Brunei Tertiary Education: Qualitative Perspective

This study explores the potential factors causing a gender gap in academic achievement in the higher learning institutions of Brunei using in-depth interviews. Given that the gender gap is a worldwide phenomenon and problem in many educational settings, this study investigates the reasons for its persistence and how it can be resolved in the Brunei context. The findings of the study indicate that: 1) there are gender similarities in practices of good academic performance at school; 2) teaching methods and school facilities and environment may affect students’ academic performance; 3) problems or challenges faced in academic performance or achievement at school; and 4) early entry to workplace. A mixed-methods research is recommended to gain additional insights into the problem and its solutions.

Implications on Domestic Non-Profit Organizations of Japanese Home Care Service

China’s aging problem is continuing to ferment, so that the state is advocating the non-profit organizations to actively provide home care services. However, China’s non-profit organizations lack of the prophets in home care service, so they need to learn a lot from foreign advanced experience. Japan, which is a neighbor of our country, has been rich in old service experience because of its early entry into the aging country of Asia. Therefore, the main content of this paper is the implications of Japanese home care service to our nonprofit organization. After analyzing the present situation of non-profit organization’s participation in home-based old-age service and the experience of non-profit organization in Japan, this paper analyzes the obstruction and deficiency of non-profit organization’s participation in home care service. On the basis of the previous analysis, the author further explores the implications of Japan’s experience of old service to China’s non-profit organization’s participation in home care, with a view to China’s non-profit organizations in the future to provide home care services to provide reference.

The Distribution of Surplus in the US Pharmaceutical Industry: Evidence from Paragraph (iv) Patent Litigation Decisions

Using an event study approach, and unique data on Paragraph (iv) pharmaceutical patent litigation decisions, we estimate that brand rms value deterrence at $4.6 billion on average while generic entrants value the right to enter, on average, at $236.8 million. These estimates account for probabilistic district court decisions and an appellate process. In 2002, the Schering-Plough vs. FTC decision led to a surge in pay-for-delay settlements. We estimate that surpluses at stake in decided cases are 73% lower after this decision, reducing the direct (per-case) consumer surplus gains anticipated by the 1984 Hatch-Waxman Act's procedures for early generic entry.

Conventional markets vs. online markets: brand effects and entry decisions

Why did conventional retailers with established brands hesitate to enter online markets for a substantial period of time? I model the entry decision of a conventional firm as a dilemma: a firm's early entry to the online market would increase that market's popularity and, as a result, shift the demand for the product from the conventional market to the online market. On the other hand, a firm's failure to enter the online market early will allow the competing online firm to increase its brand value due to the increase in demand for its online product. The results show that given the take-off probability - the probability that the popularity of the online market will increase - a conventional firm will delay its entry into the online market whenever brand effects are not substantial, to protect its profits in the monopolistic conventional market.

Uric Acid in the Follow-Up Determines 30% Decline in Estimated GFR Over 2 Years: a Propensity Score Analysis

Background/Aims: Higher level of serum uric acid (SUA) predicts early entry to dialysis in chronic kidney disease (CKD) patients. However, a short-term effect of SUA remains to be elucidated using a novel surrogate endpoint. Methods: Japanese CKD stage 3 to 4 patients were retrospectively examined (n= 701). The follow-up level of SUA was estimated as time-averaged uric acid (TA-UA). A propensity score for 6.0, 6.5 or 7.0 mg/dL of TA-UA was respectively calculated using baseline 23 covariates. The time-to-event analysis was performed for 30% decline in estimated GFR over 2 years. Results: Incidence rates over 2 years were 90 of 440 in men and 36 of 261 in women (p = 0.03). Despite the negative result of baseline SUA, stratified Cox regression on the quintiles of the estimated propensity score showed that higher TA-UA of the three thresholds were all significant (crude HR 2.10 to 2.44) even after adjusting for the confounders. Kaplan-Meier analysis after propensity score matching likewise showed worse survival in the patients with the higher TA-UA (HR 3.11 to 4.26). Conclusion: Higher SUA increases likelihood of reaching a surrogate endpoint over 2 years. Early intervention for SUA less than 6.0 mg/dL is recommended for slowing CKD progression.

Value added medicines: what value repurposed medicines might bring to society?

ABSTRACTBackground & objectives: Despite the wide interest surrounding drug repurposing, no common terminology has been yet agreed for these products and their full potential value is not always recognised and rewarded, creating a disincentive for further development. The objectives of the present study were to assess from a wide perspective which value drug repurposing might bring to society, but also to identify key obstacles for adoption of these medicines and to discuss policy recommendations.Methods: A preliminary comprehensive search was conducted to assess how the concept of drug repurposing was described in the literature. Following completion of the literature review, a primary research was conducted to get perspective of various stakeholders across EU member states on drug repurposing (healthcare professionals, regulatory authorities and Health Technology Assessment (HTA) bodies/payers, patients, and representatives of the pharmaceutical industry developing medicines in this field). Ad hoc literature review was performed to illustrate, when appropriate, statements of the various stakeholders.Results: Various nomenclatures have been used to describe the concept of drug repurposing in the literature, with more or less broad definitions either based on outcomes, processes, or being a mix of both. In this context, Medicines for Europe (http://www.medicinesforeurope.com/value-added-medicines/) established one single terminology for these medicines, known as value added medicines, defined as ‘medicines based on known molecules that address healthcare needs and deliver relevant improvements for patients, healthcare professionals and/or payers’. Stakeholder interviews highlighted three main potential benefits for value added medicines: (1) to address a number of medicine-related healthcare inefficiencies related to irrational use of medicines, non-availability of appropriate treatment options, shortage of mature products, geographical inequity in medicine access; (2) to improve healthcare system efficiency; and (3) to contribute to sustainability of healthcare systems through economic advantages. Current HTA framework, generic stigma, and pricing rules, such as internal reference pricing or tendering processes in place in some countries, were reported as the current key hurdles preventing the full recognition of value added medicines’ benefits, discouraging manufacturers from bringing such products to the market.Discussion & conclusions: There is currently a gap between increasing regulatory authority interest in capturing value added medicines’ benefits and the resistance of HTA bodies/payers, who tend to ignore this important segment of the pharmaceutical field. This situation calls for policy changes to foster appropriate incentives to enhance value recognition of value added medicines and deliver the expected benefit to society. Policy changes from HTA perspective should include: absence of any legislative barriers preventing companies from pursuing HTA; HTA requirements proportionate to potential reward; HTA decision-making framework taking into account the specific characteristics of value added medicines; eligibility for early HTA dialogues; Policy changes from pricing perspective should encompass: tenders/procurement policies allowing differentiation from generic medicines; eligibility for early entry agreement; non-systematic implementation of external and internal reference pricing policies; recognition of indication-specific pricing.At the same time, the pharmaceutical industry should engage all the stakeholders (patients, healthcare providers, HTA bodies/payers) in early dialogues to identify their expectations and to ensure the developed value added medicines address their needs.

Activities in an S-STEM Program To Catalyze Early Entry into Research

A cohort program to increase retention of under-represented groups in chemistry was developed at the College of Saint Benedict/Saint John’s University. In particular, this program chose to emphasize early career mentoring and early access to research. This goal was chosen because research has been repeatedly shown to increase scientific identity resulting in increased retention of students in the STEM fields. Several elements of this program have been useful in preparing students to access research programs early in their college careers including a summer bridge program, career mentoring, advising, and a second year “research bootcamp” course.

Clinical fellowship for an innovative, integrated BSN-PhD program: An academic and practice partnership.

Opportunities for research-focused doctoral education must be available to nurses early in their careers in order to ensure the further development of nursing science. Early entry into the research doctorate through an integrated BSN-PhD program is one innovative approach. This approach highlights the value of integrating post-licensure clinical training into the doctoral curriculum. To better prepare innovative nurse scientists early in their careers we developed a clinical nurse fellowship within an integrated BSN-PhD program in partnership with an affiliated health system. The aims of this clinical fellowship are to integrate post-licensure clinical experience with academic preparation, cultivate scholarly reflection on the connections between research and practice, educate nurse researchers to work effectively in interdisciplinary teams, and develop nurses' contributions to health care innovation. Major considerations for the development of similar clinical training opportunities include clarifying and articulating the major aims of the fellowship, enlisting the support of executive clinical leadership, and placing fellows on nursing units with experienced and advanced nursing teams and management that supports the fellowship's aims. We emphasize the fully integrated and collaborative activities, decision-making, and commitment required of both academic and health system partners to successfully implement similar clinical training opportunities.

A guide and best practices for R/Bioconductor tool integration in Galaxy

Galaxy provides a web-based platform for interactive, large-scale data analyses, which integrates bioinformatics tools written in a variety of languages. A substantial number of these tools are written in the R programming language, which enables powerful analysis and visualization of complex data. The Bioconductor Project provides access to these open source R tools and currently contains over 1200 R packages. While some R/Bioconductor tools are currently available in Galaxy, scientific research communities would benefit greatly if they were integrated on a larger scale. Tool development in Galaxy is an early entry point for Galaxy developers, biologists, and bioinformaticians, who want to make their work more accessible to a larger community of scientists. Here, we present a guide and best practices for R/Bioconductor tool integration into Galaxy. In addition, we introduce new functionalities to existing software that resolve dependency issues and semi-automate generation of tool integration components. With these improvements, novice and experienced developers can easily integrate R/Bioconductor tools into Galaxy to make their work more accessible to the scientific community.