ResearchPad - concept-paper https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Whole Organism Model to Study Molecular Mechanisms of Differentiation and Dedifferentiation <a href="#fn1-biology-09-00079">†</a>]]> https://www.researchpad.co/article/elastic_article_11818 Cancer recurrence has remained a significant challenge, despite advances in therapeutic approaches. In part, this is due to our incomplete understanding of the biology of cancer stem cells and the underlying molecular mechanisms. The phenomenon of differentiation and dedifferentiation (phenotypic switching) is not only unique to stem cells but it is also observed in several other organisms, as well as evolutionary-related microbes. Here, we propose the use of a primitive eukaryotic unicellular organism, Acanthamoeba castellanii, as a model to study the molecular mechanisms of cellular differentiation and dedifferentiation.

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<![CDATA[Direct Ink Writing Glass: A Preliminary Step for Optical Application]]> https://www.researchpad.co/article/N9e9fcbf1-61b3-4cab-8f19-febd92ffa60b

In this paper, we present a preliminary study and conceptual idea concerning 3D printing water-sensitive glass, using a borosilicate glass with high alkali and alkaline oxide contents as an example in direct ink writing. The investigated material was prepared in the form of a glass frit, which was further ground in order to obtain a fine powder of desired particle size distribution. In a following step, inks were prepared by mixing the fine glass powder with Pluoronic F-127 hydrogel. The acquired pastes were rheologically characterized and printed using a Robocasting device. Differential scanning calorimetry (DSC) experiments were performed for base materials and the obtained green bodies. After sintering, scanning electron microscope (SEM) and X-ray diffraction (XRD) analyses were carried out in order to examine microstructure and the eventual presence of crystalline phase inclusions. The results confirmed that the as obtained inks exhibit stable rheological properties despite the propensity of glass to undergo hydrolysis and could be adjusted to desirable values for 3D printing. No additional phase was observed, supporting the suitability of the designed technology for the production of water sensitive glass inks. SEM micrographs of the sintered samples revealed the presence of closed porosity, which may be the main reason of light scattering.

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<![CDATA[A Challenging View: Antibiotics Play a Role in the Regulation of the Energetic Metabolism of the Producing Bacteria]]> https://www.researchpad.co/article/N5c9ee719-6a56-4291-a615-b1f180360dff

Antibiotics are often considered as weapons conferring a competitive advantage to their producers in their ecological niche. However, since these molecules are produced in specific environmental conditions, notably phosphate limitation that triggers a specific metabolic state, they are likely to play important roles in the physiology of the producing bacteria that have been overlooked. Our recent experimental data as well as careful analysis of the scientific literature led us to propose that, in conditions of moderate to severe phosphate limitation—conditions known to generate energetic stress—antibiotics play crucial roles in the regulation of the energetic metabolism of the producing bacteria. A novel classification of antibiotics into types I, II, and III, based on the nature of the targets of these molecules and on their impact on the cellular physiology, is proposed. Type I antibiotics are known to target cellular membranes, inducing energy spilling and cell lysis of a fraction of the population to provide nutrients, and especially phosphate, to the surviving population. Type II antibiotics inhibit respiration through different strategies, to reduce ATP generation in conditions of low phosphate availability. Lastly, Type III antibiotics that are known to inhibit ATP consuming anabolic processes contribute to ATP saving in conditions of phosphate starvation.

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<![CDATA[Critical Parameters for the Development of Novel Therapies for Severe and Resistant Infections—A Case Study on CAL02, a Non-Traditional Broad-Spectrum Anti-Virulence Drug]]> https://www.researchpad.co/article/Ndc1ac412-90c7-47e5-83e4-fe507fbba76c

Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among “non-traditional” approaches, blocking virulence could be a game changer. Objectives: This review offers a perspective on parameters that have determined the development path of CAL02, a novel anti-virulence agent, with a view to steering clear of the obstacles and limitations that impede market sustainability for new anti-infective drugs. Conclusions and implications of key findings: This case study highlights four pillars that may support the development of other non-traditional drugs and, concurrently, provide a new model that could reshape the field. Therapeutic triggers, study designs, and economic parameters are discussed.

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<![CDATA[Reconsidering McKenzie’s Six Adventure Education Programming Elements Using an Ecological Dynamics Lens and Its Implications for Health and Wellbeing]]> https://www.researchpad.co/article/N2a4e5df6-192e-4401-9423-541706d6c1d6

Two decades ago, McKenzie’s meta-analysis of literature provided six fundamental elements of adventure education programme design still used to guide research and practice today. While the value of McKenzie’s early work should not be underestimated, adventure education has undergone considerable changes. Adventurous activities are now available in urban and indoor contexts and used to facilitate a growing health and wellbeing agenda. The use of risk as part of adventure education programming has also been critiqued. This paper reflects on contemporary notions of adventure, risk and the emergent narratives emphasising the associated psychological benefits. The Ecological Dynamics framework, along with representative design delivery, are presented as a viable way of building on McKenzie’s work. Both consider how effective outcomes in adventure education programmes are achieved through designs that focus on the unique relationship between the individual and their environment. While McKenzie’s six elements recognise the importance of human relationships, Ecological Dynamics forefronts relational elements, not just between participants but, importantly, the task and the environment. Individual participant needs in relation to their everyday life therefore become the focus of adventure education expanding beyond the traditional long-standing narratives of risk and danger. Through these two important concepts, this paper advocates an approach to the design of adventure representative of a participant’s everyday environment. In this way, adventure education outcomes translate beyond the adventure-specific context and align more holistically with the needs of individual participants while also assuring emphasis on individual health and wellbeing.

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<![CDATA[Sensitivity Comparison of Refractive Index Transducer Optical Fiber Based on Surface Plasmon Resonance Using Ag, Cu, and Bimetallic Ag–Cu Layer]]> https://www.researchpad.co/article/N306bcf71-40c2-472e-a955-7852bece7433

A single-mode optical fiber sensor uses surface plasmon resonance (SPR) with a bimetallic silver–copper (Ag–Cu) coating compared to a single layer of Ag and Cu itself. Bimetallic Ag–Cu sensors are constructed by simple fabrication on a side-polished optical fiber, followed by an electron beam evaporation of Ag and Cu films. For this investigation, the thickness of the single Ag layer was set to 30 nm and the single Cu layer was set to 30 nm; whereas for the bimetallic combined Ag–Cu layer the thickness of Ag was 7 nm and Cu 23 nm. The sensor performance was analyzed and compared experimentally and numerically using the COMSOL Multiphysics. A white light source was used with a broad optical bandwidth to provide a range of wavelengths to the optical fiber. The characteristics of the thin layers of Ag, Cu, and Ag–Cu as alcohol sensors were evaluated. We found that Cu was the most sensitive metallic layer compared to the Ag and the bimetallic Ag–Cu layers. For a 100% alcohol concentration, Cu showed a sensitivity of 425 nm/RIU followed by the bimetallic Ag–Cu layer with 108.33 nm/RIU, whereas the Ag layer was not detected. Interestingly, sensitivity reached saturation beyond the 20 nm thick layer of Ag. This shows that the Cu and the bimetallic Ag–Cu layers are suitable for an alcohol-based optical sensor.

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<![CDATA[Mapping the Human Exposome to Uncover the Causes of Breast Cancer]]> https://www.researchpad.co/article/N117f8ca4-5719-4028-b404-6a33834ec442

Breast cancer is an important cause of morbidity and mortality for women, yet a significant proportion of variation in individual risk is unexplained. It is reasonable to infer that unexplained breast cancer risks are caused by a myriad of exposures and their interactions with genetic factors. Most epidemiological studies investigating environmental contribution to breast cancer risk have focused on a limited set of exposures and outcomes based on a priori knowledge. We hypothesize that by measuring a rich set of molecular information with omics (e.g., metabolomics and adductomics) and comparing these profiles using a case-control design we can pinpoint novel environmental risk factors. Specifically, exposome-wide association study approaches can be used to compare molecular profiles between controls and either breast cancer cases or participants with phenotypic measures associated with breast cancer (e.g., high breast density, chronic inflammation). Current challenges in annotating compound peaks from biological samples can be addressed by creating libraries of environmental chemicals that are breast cancer relevant using publicly available high throughput exposure and toxicity data, and by mass spectra fragmentation. This line of discovery and innovation will extend understanding of how environmental exposures interact with genetics to affect health, and provide evidence to support new breast cancer prevention strategies.

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<![CDATA[Energy and Delay Aware Data Aggregation in Routing Protocol for Internet of Things]]> https://www.researchpad.co/article/N6787896e-9259-44df-be24-6485a5f47dd1

Energy conservation is one of the most critical problems in Internet of Things (IoT). It can be achieved in several ways, one of which is to select the optimal route for data transfer. IPv6 Routing Protocol for Low Power and Lossy Networks (RPL) is a standardized routing protocol for IoT. The RPL changes its path frequently while transmitting the data from source to the destination, due to high data traffic in dense networks. Hence, it creates data traffic across the nodes in the networks. To solve this issue, we propose Energy and Delay Aware Data aggregation in Routing Protocol (EDADA-RPL) for IoT. It has two processes, namely parent selection and data aggregation. The process of parent selection uses routing metric residual energy (RER) to choose the best possible parent for data transmission. The data aggregation process uses the compressed sensing (CS) theory in the parent node to combine data packets from the child nodes. Finally, the aggregated data transmits from a downward parent to the sink. The sink node collects all the aggregated data and it performs the reconstruction operation to get the original data of the participant node. The simulation is carried out using the Contiki COOJA simulator. EDADA-RPL’s performance is compared to RPL and LA-RPL. The EDADA-RPL offers good performance in terms of network lifetime, delay, and packet delivery ratio.

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<![CDATA[Dialysis Reimbursement: What Impact Do Different Models Have on Clinical Choices?]]> https://www.researchpad.co/article/5ca25bb3d5eed0c4846d2f7c

Allowing patients to live for decades without the function of a vital organ is a medical miracle, but one that is not without cost both in terms of morbidity and quality of life and in economic terms. Renal replacement therapy (RRT) consumes between 2% and 5% of the overall health care expenditure in countries where dialysis is available without restrictions. While transplantation is the preferred treatment in patients without contraindications, old age and comorbidity limit its indications, and low organ availability may result in long waiting times. As a consequence, 30–70% of the patients depend on dialysis, which remains the main determinant of the cost of RRT. Costs of dialysis are differently defined, and its reimbursement follows different rules. There are three main ways of establishing dialysis reimbursement. The first involves dividing dialysis into a series of elements and reimbursing each one separately (dialysis itself, medications, drugs, transportation, hospitalisation, etc.). The second, known as the capitation system, consists of merging these elements in a per capita reimbursement, while the third, usually called the bundle system, entails identifying a core of procedures intrinsically linked to treatment (e.g., dialysis sessions, tests, intradialyitc drugs). Each one has advantages and drawbacks, and impacts differently on the organization and delivery of care: payment per session may favour fragmentation and make a global appraisal difficult; a correct capitation system needs a careful correction for comorbidity, and may exacerbate competition between public and private settings, the latter aiming at selecting the least complex cases; a bundle system, in which the main elements linked to the dialysis sessions are considered together, may be a good compromise but risks penalising complex patients, and requires a rapid adaptation to treatment changes. Retarding dialysis is a clinical and economical goal, but the incentives for predialysis care are not established and its development may be unfavourable for the provider. A closer cooperation between policymakers, economists and nephrologists is needed to ensure a high quality of dialysis care.

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<![CDATA[Does Drying Affect Gel Networks?]]> https://www.researchpad.co/article/5c4a4379d5eed0c4844f3368

The properties of low molecular weight gels are determined by the underlying, self-assembled network. To access information on the network, it is common for techniques to be used that require the gel to be dried, such as transmission electron microscopy or scanning electron microscopy. The implicit assumption is that this drying has no bearing on the data collected. Here, we discuss the validity of this assumption.

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<![CDATA[Controlling Variables in Molecular Gel Science: How Can We Improve the State of the Art?]]> https://www.researchpad.co/article/5c4a433ed5eed0c4844f2244

By design, no references are included in this article. It is intended to be a series of recommendations in which the focus is on lab practices for investigating substances rather than on the substances being investigated. Thus, it discusses some specific areas of concern identified by the author. Other scientists are encouraged to add to or amend the contents. This article should be read as a “living” document, like a blog in which many gel scientists work, over time, to achieve a consensus about reporting everything from acronyms and definitions to procedures and methods. For those entering the field and seeking compendia on the subject, the author suggests “Googling” the words “molecular gels” or “molecular gels books”.

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<![CDATA[Augmentation of 5-Aminolevulinic Acid Treatment of Glioblastoma by Adding Ciprofloxacin, Deferiprone, 5-Fluorouracil and Febuxostat: The CAALA Regimen]]> https://www.researchpad.co/article/5c4273a4d5eed0c484663994

The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its preferential conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently-marketed drugs—the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat—that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial.

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<![CDATA[Biosynthetic Oligoclonal Antivenom (BOA) for Snakebite and Next-Generation Treatments for Snakebite Victims]]> https://www.researchpad.co/article/5c42730dd5eed0c484661d6c

Snakebite envenoming is a neglected tropical disease that each year claims the lives of 80,000–140,000 victims worldwide. The only effective treatment against envenoming involves intravenous administration of antivenoms that comprise antibodies that have been isolated from the plasma of immunized animals, typically horses. The drawbacks of such conventional horse-derived antivenoms include their propensity for causing allergenic adverse reactions due to their heterologous and foreign nature, an inability to effectively neutralize toxins in distal tissue, a low content of toxin-neutralizing antibodies, and a complex manufacturing process that is dependent on husbandry and procurement of snake venoms. In recent years, an opportunity to develop a fundamentally novel type of antivenom has presented itself. By using modern antibody discovery strategies, such as phage display selection, and repurposing small molecule enzyme inhibitors, next-generation antivenoms that obviate the drawbacks of existing plasma-derived antivenoms could be developed. This article describes the conceptualization of a novel therapeutic development strategy for biosynthetic oligoclonal antivenom (BOA) for snakebites based on recombinantly expressed oligoclonal mixtures of human monoclonal antibodies, possibly combined with repurposed small molecule enzyme inhibitors.

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<![CDATA[Modern Prodrug Design for Targeted Oral Drug Delivery]]> https://www.researchpad.co/article/5c2e85bad5eed0c48453fcb0

The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

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<![CDATA[Topography of Photochemical Initiation in Molecular Materials]]> https://www.researchpad.co/article/5c256e0ad5eed0c484478bf1

We propose a fluctuation model of the photochemical initiation of an explosive chain reaction in energetic materials. In accordance with the developed model, density fluctuations of photo-excited molecules serve as reaction nucleation sites due to the stochastic character of interactions between photons and energetic molecules. A further development of the reaction is determined by a competition of two processes. The first process is growth in size of the isolated reaction cell, leading to a micro-explosion and release of the material from the cell towards the sample surface. The second process is the overlap of reaction cells due to an increase in their size, leading to the formation of a continuous reaction zone and culminating in a macro-explosion, i.e., explosion of the entire area, covering a large part of the volume of the sample. Within the proposed analytical model, we derived expressions of the explosion probability and the duration of the induction period as a function of the initiation energy (exposure). An experimental verification of the model was performed by exploring the initiation of pentaerythritol tetranitrate (PETN) with the first harmonic of YAG: Nd laser excitation (1,064 nm, 10 ns), which has confirmed the adequacy of the model. This validation allowed us to make a few quantitative assessments and predictions. For example, there must be a few dozen optically excited molecules produced by the initial fluctuations for the explosive decomposition reaction to occur and the life-time of an isolated cell before the micro-explosion must be of the order of microseconds.

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<![CDATA[Brucella spp. at the Wildlife-Livestock Interface: An Evolutionary Trajectory through a Livestock-to-Wildlife “Host Jump”?]]> https://www.researchpad.co/article/5c0fc03cd5eed0c484111a05

Brucella infections in wildlife have gained a lot of interest from the scientific community and different stakeholders. These interests are often different and sometimes conflicting. As a result, different management perspectives and aims have been implemented (One Health, public health, veterinary public health, maintenance of a brucellosis free status in livestock, sustainable wildlife harvesting by hunters, wildlife and environmental health). When addressing Brucella infection in wildlife, the most important features of Brucella infection should be considered and the following questions need to be answered: (1) Is Brucella infection a result of a spillover from livestock or is it a sustainable infection in one or more wildlife host species? (2) Did the epidemiological situation of Brucella infection in wildlife change over time and, if so, what are the main drivers of change and does it impact the wildlife population dynamics? (3) Does Brucella infection in wildlife represent a reservoir of Brucella strains for livestock? (4) Is Brucella infection in wildlife of zoonotic concern? These questions point to the fundamental biological question of how animal (domestic and wildlife)/Brucella spp. partnerships are established. Will we be able to decipher an evolutionary trajectory through a livestock-to-wildlife “host jump”? Whole genome sequencing and new “omics” techniques will help in deciphering the molecular basis of Brucella host preference and open new avenues in brucellosis management aimed at preventing opportunities for Brucella host jumps.

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<![CDATA[Identify-Isolate-Inform: A Modified Tool for Initial Detection and Management of Middle East Respiratory Syndrome Patients in the Emergency Department]]> https://www.researchpad.co/article/5bc4266940307c149bbda1ce

Middle East respiratory syndrome (MERS) is a novel infectious disease caused by a coronavirus (MERS-CoV) first reported in Saudi Arabia in September 2012. MERS later spread to other countries in the Arabian Peninsula, followed by an outbreak in South Korea in 2015. At least 26 countries have reported MERS cases, and these numbers may increase over time. Due to international travel opportunities, all countries are at risk of imported cases of MERS, even if outbreaks do not spread globally. Therefore, it is essential for emergency department (ED) personnel to be able to rapidly assess MERS risk and take immediate actions if indicated. The Identify-Isolate-Inform (3I) tool, originally conceived for initial detection and management of Ebola virus disease patients in the ED and later adjusted for measles, can be adapted for real-time use for any emerging infectious disease. This paper reports a modification of the 3I tool for use in initial detection and management of patients under investigation for MERS. Following an assessment of epidemiologic risk factors, including travel to countries with current MERS transmission and contact with patients with confirmed MERS within 14 days, patients are risk stratified by type of exposure coupled with symptoms of fever and respiratory illness. If criteria are met, patients must be immediately placed into airborne infection isolation (or a private room until this type of isolation is available) and the emergency practitioner must alert the hospital infection prevention and control team and the local public health department. The 3I tool will facilitate rapid categorization and triggering of appropriate time-sensitive actions for patients presenting to the ED at risk for MERS.

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<![CDATA[An Algorithm to Identify Compounded Non-Sterile Products that Can Be Formulated on a Commercial Scale or Imported to Promote Safer Medication Use in Children]]> https://www.researchpad.co/article/5b439267463d7e2aee702250

The lack of commercially-available pediatric drug products and dosage forms is well-known. A group of clinicians and scientists with a common interest in pediatric drug development and medicines-use systems developed a practical framework for identifying a list of active pharmaceutical ingredients (APIs) with the greatest market potential for development to use in pediatric patients. Reliable and reproducible evidence-based drug formulations designed for use in pediatric patients are needed vitally, otherwise safe and consistent clinical practices and outcomes assessments will continue to be difficult to ascertain. Identification of a prioritized list of candidate APIs for oral formulation using the described algorithm provides a broader integrated clinical, scientific, regulatory, and market basis to allow for more reliable dosage forms and safer, effective medicines use in children of all ages. Group members derived a list of candidate API molecules by factoring in a number of pharmacotherapeutic, scientific, manufacturing, and regulatory variables into the selection algorithm that were absent in other rubrics. These additions will assist in identifying and categorizing prime API candidates suitable for oral formulation development. Moreover, the developed algorithm aids in prioritizing useful APIs with finished oral liquid dosage forms available from other countries with direct importation opportunities to North America and beyond.

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