Search results for: small molecule inhibitors

Authors: Samira Melki, Moncef Gueddari

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In Tunisia, solid wastes storage continue to be uncontrolled. It is eliminated by land raising without any protection measurement against water table and soil contamination. Several industries are located in Sfax area, especially those of the Tunisian Chemical Group (TCG) for the enrichment and transformation of phosphate. The activity of the TCG focuses primarily on the production of chemical fertilizers and phosphoric acid, by transforming natural phosphates. This production generates gaseous emissions, liquid discharges and huge amounts of phosphogypsum (PG) stored directly on the soil surface. Groundwater samples were collected from Tunisian Chemical Group (TCG) site, to assess the effects of phosphogypsum leatchate on groundwater quality. The measurements of various physicochemical parameters including heavy metals (Al, Fe, Zn and F) and stable isotopes of the water molecule (¹⁸O, ²H) were determined in groundwater samples and are reported. The moderately high concentrations of SO₄⁼, Ortho-P, NH₄⁺ Al and F⁻ in groundwater particularly near to the phosphogypsum storage site, likely indicate that groundwater quality is being significantly affected by leachate percolation. The effect of distance of the piezometers from the pollution source was also investigated. The isotopic data of water molecule, showed that the waters of the Sfax-Agreb aquifer amount to recent-evaporation induced rainfall.

Keywords: phosphogypsum leatchate, groundwater quality, pollution, stable isotopes, Sfax-Agareb, Tunisia

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Authors: Latife Merve Oktay, Berrin Tugrul

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Hydroxytyrosol (HT) is a phenolic phytochemical molecule derived from the hydrolysis of oleuropein, which originates during the maturation of the olives. It has recently received particular attention because of its antioxidant, anti-proliferative, pro-apoptotic and anti-inflammatory activities. In this study, we investigated the cytotoxic and apoptotic effects of hydroxytyrosol and its effects on phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK 1/2) signaling pathways in human ovarian cancer cell lines OVCAR-3 and MDAH-2774. XTT cell proliferation kit, Cell Death Detection Elisa Plus Kit (Roche) and Human Apoptosis Array (R&D Systems) were used to determine the cytotoxic and apoptotic effects of HT in OVCAR-3 and MDAH-2774 cell lines at 24, 48, 72, and 96 h. Effect of HT on PI3K/Akt and ERK 1/2 signaling pathways were investigated by using specific inhibitors of these pathways. IC50 values of HT were found to be 102.3 µM in MDAH-2774 cells at 72 h and 51.5 µM in OVCAR-3 cells at 96 h. Apoptotic effect of HT in MDAH-2774 cells was the highest at 50 µM at 72 h, and kept decreasing at 100 and 150 µM concentrations and was not seen at 200 µM and higher concentrations. Highest apoptotic effect was seen at 100 µM concentration in OVCAR-3 cells at 96 h, however apoptotic effect was decreased over 100 µM concentrations. According to antibody microarray results, HT increased the levels of pro-apoptotic molecules Bad, Bax, active caspase-3, Htra2/Omi by 2.0-, 1.4-, 1.2-, 4.2-fold, respectively and also increased the levels of pro-apoptotic death receptors TRAIL R1/DR4, TRAIL R2/DR5, FAS/TNFRSF6 by 2.1-, 1.7-, 1.6-fold, respectively, however, it decreased the level of Survivin by 1.6-fold which is one of the inhibitor of apoptosis protein (IAP) family in MDAH-2774 cells. In OVCAR-3 cells, HT decreased the levels of anti-apoptotic proteins Bcl-2, pro-caspase 3 by 3.1-, 8.2-fold, respectively and IAP family proteins CIAP-1, CIAP-2, XIAP, Livin, Survivin by 6.5-, 6.0-, 3.2-, 2.2-, 2.7-fold, respectively and increased the level of cytochrome-c by 1.2-fold. We have shown that HT shows its cytotoxic and apoptotic effect through inhibiting ERK 1/2 signaling pathway in both OVCAR-3 and MDAH-2774 cells. Further studies are needed to investigate molecular mechanisms and modulatory effects of hydroxytyrosol.

Keywords: apoptosis, cytotoxicity, hydroxytyrosol, ovarian cancer

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Authors: Harish Rajak, Preeti Patel

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The application of histone deacetylase inhibitors is a well-known strategy in prevention of cancer which shows acceptable preclinical antitumor activity due to its ability of growth inhibition and apoptosis induction of cancer cell. Molecular docking were performed using Histone Deacetylase protein (PDB ID:1t69) and prepared series of hydroxamic acid based HDACIs. On the basis of docking study, it was predicted that compound 1 has significant binding interaction with HDAC protein and three hydrogen bond interactions takes place, which are essential for antitumor activity. On docking, most of the compounds exhibited better glide score values between -8 to -10 which is close to the glide score value of suberoylanilide hydroxamic acid. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. The 3D-QSAR models provided a good correlation between predicted and actual anticancer activity. Best QSAR model showed Q2 (0.7974), R2 (0.9200) and standard deviation (0.2308). QSAR visualization maps suggest that hydrogen bond acceptor groups at carbonyl group of cap region and hydrophobic groups at ortho, meta, para position of R9 were favorable for HDAC inhibitory activity. We established structure activity correlation using docking, pharmacophore modeling and atom based 3D QSAR model for hydroxamic acid based HDACIs.

Keywords: HDACIs, QSAR, e-pharmacophore, docking, suberoylanilide hydroxamic acid

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Authors: Donald Zullick, Cihan Varol

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This research paper begins with a look at current work in business continuity as it relates to the cloud and small to medium business (SMB). While cloud services are an emerging paradigm that is quickly making an impact on business, there has been no substantive research applied to SMB. Seeing this lapse, we have taken a fusion of continuity and cloud research with application to the SMB market. It is an initial reflection with base framework guidelines as a starting point for implementation. In this approach, our research ties together existing work and fill the gap with an SMB outlook.

Keywords: business continuity, cloud services, medium size business, risk assessment, small business

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Authors: Raquel R. Soares-Santos, Daniel P. Machado, Thiago L. Romero, Igor D. G. Duarte

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Tramadol, an analgesic classified as an 'atypical opioid,' exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 μg/paw); AM251 (80 μg/paw) and AM630 (100 μg/paw) as the selective antagonists for type 1 and type 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 μg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol’s effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol’s antinociception effect. Notably, glibenclamide blocked tramadol’s antinociception in a dose-dependent manner. These findings suggest that tramadol’s peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.

Keywords: tramadol, nitric oxide, potassium channels, peripheral analgesia, opioid

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Authors: Ncoza Dlova, Tivani Mashamba-Thompson

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Garcinia livingstonei (Clusiaceae) extracts, morelloflavone- 7″- sulphate and sargaol were shown to be effective against hyper-pigmentation through inhibition of tyrosinase enzyme, in vitro . The aim of this study is to elucidate the structural mechanism through which morelloflavone- 7″- sulphate and sargaol binds human tyrosinase. Implementing a homology model to construct a tyrosinase model using the crystal structure of a functional unit from Octopus hemocyanin (PDB: 1JS8) as a reference template enabled us to create a human tyrosinase model. Molecular dynamics and binding free energy calculations were optimized to enable molecular dynamics simulation of the copper dependent inhibitors. Results show the importance of the hydrogen bond formation morelloflavone- 7″- sulphate and sargaol between compound and active site residues. Both complexes demonstrated the metallic coordination between compound and arginine residue as well as copper ions within the active site. The comprehensive molecular insight gained from this study should be vital in understanding the binding mechanism morelloflavone- 7″- sulphate and sargaol. Moreover, these results will assist in the design of novel of metal ion dependent enzyme inhibitors as potential anti-hyper-pigmentation disorder therapies.

Keywords: hyper-pigmentation disorders, dyschromia African skin, morelloflavone- 7″- sulphate, sagoal

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Authors: Giacomo Barbieri

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In soilless culture, the management of the nutrient solution is the most important aspect for crop growing. Fertigation dose, frequency and nutrient concentration must be planned with the objective of reaching an optimal crop growth by limiting the utilized resources and the associated costs. The definition of efficient fertigation strategies is a complex problem since fertigation requirements vary on the basis of different factors, and crops are sensitive to small variations on fertigation parameters. To the best of author knowledge, a small-scale test bench that is flexible for both nutrient solution preparation and precise irrigation is currently missing, limiting the investigations in standard practices for soilless culture. Starting from the analysis of the state of the art, this paper proposes a small-scale system that is potentially able to concurrently test different fertigation strategies. The system will be designed and implemented throughout a three year project started on August 2018. However, due to the importance of the topic within current challenges as food security and climate change, this work is spread considering that may inspire other universities and organizations.

Keywords: soilless culture, fertigation, test bench, small-scale, automation

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Authors: Erinma Chibuzo Nwandu

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Graduates unemployment has risen astronomically in spite of the emphasis on teaching of small scale business and Entrepreneurship in schools. This study sets out to evaluate the effect of teaching small scale business and Entrepreneurship on graduates’ unemployment in Nigeria. This study adopted the survey research design. Thus the nature of data for this study is primary, sourced by the use of a questionnaire administered to a sample of two thousand and sixty-five (2065) respondents drawn from groups of graduates who are employed, unemployed and self-employed in South East Nigeria. Simple percentages, Chi-square and regression analysis were used to derive useful and meaningful information and test the hypotheses respectively. Findings from the study suggest that Nigeria graduates are ill prepared to embark on small-scale business and entrepreneurship after graduation, and that teaching of small scale business and entrepreneurship in Nigeria tertiary institutions is ineffective on graduate unemployment reduction. Findings also suggest that while a lot of graduates agreed that they have taken a class(s) on small scale or entrepreneurship, they received more theoretical teachings than practical, more so while teachings on small scale business or entrepreneurship motivated graduates to think of self-employment, most of them cannot do a good business plan and hence could not benefit from some kind of Government assisted program for small-scale business and bank loan for the sake of small scale business. Thus, so many graduates are not interested in small scale business or entrepreneurship development as a result of lack of startup capital. The study thus recommends that course content and teaching method of entrepreneurship education needs to be reviewed and re-structured to constitute more practical teachings than theoretical teachings. Also, graduates should be exposed to seminar /workshop for self-employment at least once every semester. There should be practical teaching and practice of developing a business plan that will be viable to attract government or private sponsorship as well for it to be viable to attract financing from financing institutions. Government should provide a fund such as venture capital financing arrangement to empower business startups in Nigeria by graduates’.

Keywords: entrepreneurship, small scale business, startup capital, unemployment

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Authors: Mami Nishida

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This paper presented a study on the development and control of a small biped soft robot using shape memory alloys (SMAs). Author proposed a flexible flat plate (FFP) actuators consisting of a thin　polyethylene plate and SMAs. This actuator has a nail like an insect. This robot moves from the front to back and from left to right using two nails. The walking robot has two degrees of freedom and is controlled by switching the ON-OFF current signals to the SMA based FFPs. The resulting small biped soft robot weighs a mere 4.7 g (with a height of 67 mm). The small robot realizes biped walking by transferring the elastic potential energy (generated by deflections of the SMA based FFPs) to kinematic energy. Experimental results demonstrated the viability and utility of the small biped soft robot with the proposed SMA-based FFPs and the control strategy to achieve walking behavior.

Keywords: biped soft robot with nails, flexible flat plate (FFP) actuators, ON-OFF control strategy, shape memory alloys (SMA)

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Authors: Yi F. Wu, Ai Q. Li, Hao Wang

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Taking a novel type of bridge bearings with the diameter being 100mm as an example, the theoretical analysis, the experimental research as well as the numerical simulation of the bearing were conducted. Since the normal compression-shear machines cannot be applied to the small-size bearing, an improved device to test the properties of the bearing was proposed and fabricated. Besides, the simulation of the bearing was conducted on the basis of the explicit finite element software ANSYS/LS-DYNA, and some parameters of the bearing are modified in the finite element model to effectively reduce the computation cost. Results show that all the research methods are capable of revealing the fundamental properties of the small-size bearings, and a combined use of these methods can better catch both the integral properties and the inner detailed mechanical behaviors of the bearing.

Keywords: ANSYS/LS-DYNA, compression shear, contact analysis, explicit algorithm, small-size

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Authors: Kuhelee Chandel, Julia Åhlén, Stefan Seipel

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This study evaluates the accuracy of Microsoft HoloLens (Version 1) for small-scale industrial activities, comparing its measurements to ground truth data from a Kuka Robotics arm. Two experiments were conducted to assess its position-tracking capabilities, revealing that the HoloLens device is effective for measuring the position of dynamic objects with small dimensions. However, its precision is affected by the velocity of the trajectory and its position within the device's field of view. While the HoloLens device may be suitable for small-scale tasks, its limitations for more complex and demanding applications requiring high precision and accuracy must be considered. The findings can guide the use of HoloLens devices in industrial applications and contribute to the development of more effective and reliable position-tracking systems.

Keywords: augmented reality (AR), Microsoft HoloLens, object tracking, industrial processes, manufacturing processes

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Authors: Simiso Fisokuhle Nyandeni

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Climate change has turned out to be a pandemic that has drawn the attention of many countries’ households around the globe, especially those whose livelihood and economic status depend on agricultural productivity. Hence, the agricultural sector is regarded as the sector that is most dependent on climate conditions for its productivity/harvest, yet in recent years this sector has been experiencing drought. However, adaptation seems to be a tool that every farmer looks upon as a solution to their challenges as their productivity keeps on being vulnerable to climate effects. Thus, exposure/access to the market seems to be a major challenge that faces especially small-scale farmers. We, therefore, examine the small-scale farmers’ constraints or challenges towards getting access to the market for them to get proper sales of their farming products. As a result, the adaptation capacity of every farm household varies on the financial status.

Keywords: climate change, small-scale farming, agriculture sector, adaptation

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Authors: Mike Wei, Nebu Koshy, Koen van Besien, Giorgio Inghirami, Steven M. Horwitz

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T-cell prolymphocytic leukemia (T-PLL) is a rare hematologic disease characterized by a T-cell phenotype, rapid progression, and poor prognosis with median survival of less than a year. Alemtuzumab-based chemotherapy has increased the rate of complete remissions but these are often short-lived, and allogeneic transplant is considered the only curative therapy. In recent studies, JAK3 activating mutations have been identified in T-cell cancers, with T-PLL having the highest rate of JAK3 mutations (30 – 42%). As such, T-PLL is a model disease for evaluating the utility of JAK3 inhibitors. We present a case of a 64-year-old man with relapsed-refractory T-PLL. He was initially treated with alemtuzumab and obtained complete response and was consolidated with matched unrelated donor stem cell transplant. His disease stayed in remission for approximately 1.5 years before relapse, which was then treated with a clinical trial of romidepsin-lenalidomide (partial responses then progression at 6 months) and later alemtuzumab. Due to complications of myelosuppression and CMV reactivation, his treatment was interrupted leading to disease progression. The doubling time of lymphocyte count was approximately 20 days and over a span of 60 days the lymphocyte count rose from 8 x 109/L to 68 x 109/L. Exon sequencing showed a JAK3 mutation. The patient consented to and was treated with FDA-approved tofacitinib (initially 5 mg BID, increased to 10 mg BID after 15 days of treatment). An initial decrease in lymphocyte count was followed by progression. In vitro treatment of the patient’s cells showed modest effects of tofacitinib and ruxolitinib as single agents, in the range of doxorubicin, but synergy between the agents. After 40 days of treatment with tofacitinib and with a lymphocyte count of 150 x 109/L, ruxolitinib (5mg BID) was added. Over the 60 days since dual inhibition was started, the lymphocyte count has stabilized. The patient has remained completely asymptomatic during treatment with tofacitinib and ruxolitinib. Neutrophil count has remained normal. Platelet count and hemoglobin have however declined from ~50 x109/L to ~30 x109/L and from 11 g/dL to 8.1 g/dL respectively, since the introduction of ruxolitinib. The stabilization in lymphocyte count confirms the clinical activity of JAK inhibitors in T-PLL as suggested by the presence of JAK3 mutations and by in-vitro assays. It also suggests clinical synergy between ruxolitinib and tofacitinib in this setting. Prospective studies of JAK inhibitors in PLL patients with formal dose-finding studies are needed.

Keywords: tofacitinib, ruxolitinib, T-cell prolymphocytic leukemia, JAK3

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Authors: John Hang Leung, Shyh-Yau Wang, Hei-Tung Yip, Fion, Ho Tsung-chin, Agnes LF Chan

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Objectives: Platinum-resistant ovarian cancer has a short overall survival of 9–12 months and limited treatment options. The combination of immunotherapy and targeted therapy appears to be a promising treatment option for patients with ovarian cancer, particularly to patients with platinum-resistant recurrent ovarian cancer (PRrOC). However, there are no direct head-to-head clinical trials comparing their efficacy and toxicity. We, therefore, used a network to directly and indirectly compare seven newer immunotherapies or targeted therapies combined with chemotherapy in platinum-resistant relapsed ovarian cancer, including antibody-drug conjugates, PD-1 (Programmed death-1) and PD-L1 (Programmed death-ligand 1), PARP (Poly ADP-ribose polymerase) inhibitors, TKIs (Tyrosine kinase inhibitors), and antiangiogenic agents. Methods: We searched PubMed (Public/Publisher MEDLINE), EMBASE (Excerpta Medica Database), and the Cochrane Library electronic databases for phase II and III trials involving PRrOC patients treated with immunotherapy or targeted therapy plus chemotherapy. The quality of included trials was assessed using the GRADE method. The primary outcomes compared were progression-free survival, the secondary outcomes were overall survival and safety. Results: Seven randomized controlled trials involving a total of 2058 PRrOC patients were included in this analysis. Bevacizumab plus chemotherapy showed statistically significant differences in PFS (Progression-free survival) but not OS (Overall survival) for all interested targets and immunotherapy regimens; however, according to the heatmap analysis, bevacizumab plus chemotherapy had a statistically significant risk of ≥grade 3 SAEs (Severe adverse effects), particularly hematological severe adverse events (neutropenia, anemia, leukopenia, and thrombocytopenia). Conclusions: Bevacizumab plus chemotherapy resulted in better PFS as compared with all interested regimens for the treatment of PRrOC. However, statistical differences in SAEs as bevacizumab plus chemotherapy is associated with a greater risk for hematological SAE.

Keywords: platinum-resistant recurrent ovarian cancer, network meta-analysis, immune checkpoint inhibitors, target therapy, antiangiogenic agents

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Authors: Constantinos Adamides, Petros Petrikkos

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In the era of growing hybrid threats, small states find themselves in need to re-evaluate existing foreign and defense policies. The pressure to establishing or maintain a status of a reliable partner in the community in which they belong to, vis-à-vis their multilateral relations with other organisations and entities, small states may need to shift their policies in the field to accommodate security needs that are not only pertinent to their security, but also to that of the organisations (bloc) in which they interact. Unlike potential shortcomings in a small state’s mainstream security and defence framework where the threat would be limited to the state itself, in more contemporary times with dominating hybrid threats, the small states’ security shortcomings may also become a security problem for the bloc in which these states belong to. An indicative example is small states like Cyprus and Malta, which belong and 'interact' in the European Union. As a result, the nature of hybrid threats can be utilised to hurt bigger states in a bloc by exploiting the small states’ vulnerabilities and security gaps. Inevitably, both the defensive and foreign policy collaborations of small states with bigger states have been and are constantly re-evaluated to tackle and prevent such problems. In essence, the goal of this ‘re-evaluation’ aims to achieve a twofold goal: The first is the small states’ quest to appear as a reliable partner within the bloc, while the second is to avoid being the weakest security link in the bloc’s defence against hybrid threats. Indeed, the hybrid arena is a security area where they can excel in the bloc, despite the potential and expected conventional military deficiencies. This new environment prompts us to think security from the perspective of small states differently and in relation to their role as members or big organisations. The paper focuses on the case of Cyprus following its accession to the European Union and examines how a country that has had a very focused security orientation –not least due to its ongoing security problems– altered its foreign and defence policies within the European Union to ensure compliance with the rest of the bloc, while at the same time maximizing its role as a security player. Specifically, it examines the methods through which the country shifted its policies as well as the challenges and opportunities that emerged from these security shifts.

Keywords: Cyprus, defence, foreign policy, hybrid threats, ontological security, small states

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Authors: Nilay Balkan

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Introductory statement: The purpose of this study is to understand how small business owners develop social media marketing competency, the challenges they encounter in doing so, and establish the social media training needs of such businesses. These challenges impact the extent to which small business owners build effective social media knowledge and, in turn, impact their ability to implement effective social media marketing into their business practices. This means small businesses are not fully able to benefit from social media, such as benefits to customer relationship management or increasing brand image, which would support the overall business operations for these businesses. This research is part one of a two-phased study. The first phase aims to establish the challenges small business owners face in building social media marketing competency and their specific training needs. Phase two will then focus in more depth on the barriers and challenges emerging from phase one. Summary of Methodology: Interviews with ten small business owners were conducted from various sectors, including fitness, tourism, food, and drinks. These businesses were located in the central belt of Scotland, which is an area with the highest population and business density in Scotland. These interviews were in-depth and semi-structured, with the purpose of being investigative and understanding the phenomena from the lived experience of the small business owners. A purposive sampling was used, where small business owners fulfilling certain criteria were approached to take part in the interviews. Key findings: The study found four ways in which small business owners develop their social media competency (informal methods, formal methods, learning through a network, and experimenting) and the various challenges they face with these methods. Further, the study established four barriers impacting the development of social media marketing competency among the interviewed small business owners. In doing so, preliminary support needs have also emerged. Concluding statement: The contribution of this study is to understand the challenges small business owners face when learning how to use social media for business purposes and identifying their training needs. This understanding can help the development of specific and tailored support. In addition, specific and tailored training can support small businesses in building competency. This supports small businesses to progress to the next stage of their development, which could be to further their digital transformation or grow their business. The insights from this study can be used to support business competitiveness and support small businesses to become more resilient. Moreover, small businesses and entrepreneurs share some similar characteristics, such as limited resources and conflicting priorities, and the findings of this study may be able to support entrepreneurs in their social media marketing strategies as well.

Keywords: small business, marketing theory and applications, social media marketing, strategic management, digital competency, digitalisation, marketing research and strategy, entrepreneurship

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Authors: Sharat Chandra, Zilong Wang, Ru-Rong Ji, Andrey Bortsov

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Chronic pain (CP) therapeutic approaches have limited efficacy. As a result, doctors are prescribing opioids for chronic pain, leading to opioid overuse, abuse, and addiction epidemic. Therefore, the development of effective and safe CP drugs remains an unmet medical need. Voltage-gated sodium (Nav) channels act as cardiovascular and neurological disorder’s molecular targets. Nav channels selective inhibitors are hard to design because there are nine closely-related isoforms (Nav1.1-1.9) that share the protein sequence segments. We are targeting the Nav1.7 found in the peripheral nervous system and engaged in the perception of pain. The objective of this project was to screen a 1.5 million compound library for identification of inhibitors for Nav1.7 with analgesic effect. In this study, we designed a protocol for identification of isoform-selective inhibitors of Nav1.7, by utilizing the prior information on isoform-selective antagonists. First, a similarity search was performed; then the identified hits were docked into a binding site on the fourth voltage-sensor domain (VSD4) of Nav1.7. We used the FTrees tool for similarity searching and library generation; the generated library was docked in the VSD4 domain binding site using FlexX and compounds were shortlisted using a FlexX score and SeeSAR hyde scoring. Finally, the top 25 compounds were tested with molecular dynamics simulation (MDS). We reduced our list to 9 compounds based on the MDS root mean square deviation plot and obtained them from a vendor for in vitro and in vivo validation. Whole-cell patch-clamp recordings in HEK-293 cells and dorsal root ganglion neurons were conducted. We used patch pipettes to record transient Na⁺ currents. One of the compounds reduced the peak sodium currents in Nav1.7-HEK-293 stable cell line in a dose-dependent manner, with IC50 values at 0.74 µM. In summary, our computer-aided analgesic discovery approach allowed us to develop pre-clinical analgesic candidate with significant reduction of time and cost.

Keywords: chronic pain, voltage-gated sodium channel, isoform-selective antagonist, similarity search, virtual screening, analgesics development

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Authors: Vaclav Musil, Robert Cep, Sarka Malotova, Jiri Hajnys, Frantisek Spalek

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The new designs of satellite gears comprising a number of small gears pose high requirements on the precise production of small module gears. The objective of the experimental activity stated in this article was to compare the conventional rolling gear cutting technology with the modern wire electrical discharge machining (WEDM) technology for the production of small module gear m=0.6 mm (thickness of 2.5 mm and material 30CrMoV9). The WEDM technology lies in copying the profile of gearing from the rendered trajectory which is then transferred to the track of a wire electrode. During the experiment, we focused on the comparison of these production methods. Main measured parameters which significantly influence the lifetime and noise was chosen. The first parameter was to compare the precision of gearing profile in respect to the mathematic model. The second monitored parameter was the roughness and surface topology of the gear tooth side. The experiment demonstrated high accuracy of WEDM technology, but a low quality of machined surface.

Keywords: precision of gearing, small module gears, surface topology, WEDM technology

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Authors: Felicia Segeth, Florian G. Klein, Lea Berger, Andreas Kolk, Per S. Holm

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The entry of oncolytic viruses (OVs) into clinical application opens groundbreaking changes in current and future treatment regimens. However, despite their potent anti-cancer activity in vitro, clinical studies revealed limitations of OVs as monotherapy. The same applies to CDK 4/6 inhibitors (CDK4/6i) targeting cell cycle as well as bromodomain and extra-terminal domain inhibitors (BETi) targeting gene expression. In this study, the anti-tumoral effect of XVir-N-31, an YB-1 dependent oncolytic adenovirus, was evaluated in combination with Ribociclib, a CDK4/6i, and JQ1, a BETi. The head and neck squamous cell carcinoma (HNSCC) cell lines Fadu, SAS, and Cal-33 were used. DNA replication and gene expression of XVir-N-31 was measured by RT-qPCR, protein expression by western blotting, and cell lysis by SRB assays. Treatment with CDK4/6i and BETi increased viral gene expression, viral DNA replication, and viral particle formation. The data show that the combination of oncolytic adenovirus XVir-N-31 with CDK4/6i & BETi acts highly synergistic in cancer cell lysis. Furthermore, additional molecular analyses on this subject demonstrate that the positive transcription elongation factor P-TEFb plays a decisive role in this regard, indicating an influence of the combinational therapy on gene transcription control. The combination of CDK4/6i & BETi and XVir-N-31 is an attractive strategy to achieve substantial cancer cell killing and is highly suitable for clinical testing.

Keywords: adenovirus, BET, CDK4/6, HNSCC, P-TEFb, YB-1

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Authors: Kang-In Lee, Woo-Jin Lee, Keun-Deuk Lee, Ju-Seung Chae

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In this study, small scale gap test (SSGT) was performed to measure shock sensitivity of nano-scaled 1,3,5-trinitro-1,3,5-triazacyclohexane (RDX) samples. The shock sensitivity of energetic materials is usually evaluated by the method of large-scale gap test (LSGT) that has a higher reliability than other methods. But LSGT has the disadvantage that it takes a high cost and time by using a large amount of explosive. In this experiment, nano-scaled RDX samples were prepared by spray crystallization in two different drying methods. In addition, 30μm RDX sample produced by precipitation crystallization and 5μm RDX sample produced by fluid energy mill process were tested to compare shock sensitivity. The study of shock sensitivity measured by small-scale gap test shows that small sized RDX particles have greater insensitivity. As a result, we infer SSGT method has higher reliability compared to the literature as measurement of shock sensitivity of energetic materials.

Keywords: nano-scaled RDX, SSGT(small scale gap test), shock sensitivity, RDX

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Authors: E. Kharaishvili

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The paper analyses the role of small farms in socio-economic development of agriculture in Georgia and evaluates modern concepts regarding the development of the farms of this size. The scale of farms in Georgia is studied and the major problems are revealed. Opportunities and directions of diversification are discussed from the point of increasing the share of Georgian grapes and wine both on domestic and international markets. It’s shown that the size of vineyard areas is directly reflected on the grape and wine production potential. Accordingly, vineyard area and grape production dynamics is discussed. Comparative analysis of small farms in Georgia and Italy is made and the major differences are identified. Diversification is evaluated based on cost-benefit analysis on the one hand and on the other hand, from the point of promoting economic activities, protecting nature and rural area development. The paper provides proofs for the outcomes of diversification. The key hindering factors for the development of small farms are identified and corresponding conclusions are made, based on which recommendations for diversification of the farms of this size are developed.

Keywords: small farms, scale of farms, diversification, Georgia

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Authors: Neha Parekh, Divya Ladha, Poonam Wadhwani, Nisha Shah

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Nano scaled materials have attracted tremendous interest as corrosion inhibitor due to their high surface area on the metal surfaces. It is well known that the zinc oxide nanoparticles have higher reactivity towards aqueous acidic solution. This work presents a new method to incorporate zinc oxide nanoparticles with white sesame seeds extract (nano-green inhibitor) for corrosion protection of zinc in acidic medium. The morphology of the zinc oxide nanoparticles was investigated by TEM and DLS. The corrosion inhibition efficiency of the green inhibitor and nano-green inhibitor was determined by Gravimetric and electrochemical impedance spectroscopy (EIS) methods. Gravimetric measurements suggested that nano-green inhibitor is more effective than green inhibitor. Furthermore, with the increasing temperature, inhibition efficiency increases for both the inhibitors. In addition, it was established the Temkin adsorption isotherm fits well with the experimental data for both the inhibitors. The effect of temperature and Temkin adsorption isotherm revealed Chemisorption mechanism occurring in the system. The activation energy (Ea) and other thermodynamic parameters for inhibition process were calculated. The data of EIS showed that the charge transfer controls the corrosion process. The surface morphology of zinc metal (specimen) in absence and presence of green inhibitor and nano-green inhibitor were performed using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) techniques. The outcomes indicated a formation of a protective layer over zinc metal (specimen).

Keywords: corrosion, green inhibitor, nanoparticles, zinc

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Authors: Abel Kahuni

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Cooperative game theory (CGT) postulates that groups of players are crucial units of the decision-making and impose cooperative behaviour. Accordingly, cooperative games are regarded as competition between coalitions of players, rather than between individual players. However, the basic supposition in CGT is that the cooperative is formed by all players. One of the emerging questions in CGT is how to develop cooperatives and fairly allocate the payoff. Cooperative Game Theory (CGT) may provide a framework and insights into the ways small holder farmers in rural resettlements may develop competitive advantage through marketing cooperatives. This conceptual paper proposes a non-competition model for small holder farmers of homogenous agri-commodity under CGT conditions. This paper will also provide brief insights into to the theory of cooperative games in-order to generate an understanding of CGT, cooperative marketing gains and its application in small holder farming arrangements. Accordingly, the objective is to provide a basic introduction to this theory in connection with economic competitive theories in the context of small holder farmers. The key value proposition of CGT is the equitable and fair sharing of cooperative gains.

Keywords: game theory, cooperative game theory, cooperatives, competition

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Authors: Victor O. Abegunde, Melusi Sibanda

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There is need for a great deal of attention on small-scale agriculture for livelihood and food security because of the expanding global population. Small-scale agriculture has been identified as a major driving force of agricultural and rural development. However, the high dependence of the sector on natural and climatic resources has made small-scale farmers highly vulnerable to the adverse impact of climatic change thereby necessitating the need for embracing practices or concepts that will help absorb shocks from changes in climatic condition. This study examines the strategic position of small-scale farming in South African agriculture and in ensuring food security in the country, the vulnerability of small-scale agriculture to climate change and the potential of the concept of climate-smart agriculture to tackle the challenge of climate change. The study carried out a systematic review of peer-reviewed literature touching small-scale agriculture, climate change, food security and climate-smart agriculture, employing the realist review method. Findings revealed that increased productivity in the small-scale agricultural sector has a great potential of improving the food security of households in South Africa and reducing dependence on food purchase in a context of high food price inflation. Findings, however, also revealed that climate change affects small-scale subsistence farmers in terms of productivity, food security and family income, categorizing the impact on smallholder livelihoods into three major groups; biological processes, environmental and physical processes and impact on health. Analysis of the literature consistently showed that climate-smart agriculture integrates the benefits of adaptation and resilience to climate change, mitigation, and food security. As a result, farming households adopting climate-smart agriculture will be better off than their counterparts who do not. This study concludes that climate-smart agriculture could be a very good bridge linking small-scale agricultural sector and agricultural productivity and development which could bring about the much needed food security.

Keywords: climate change, climate-smart agriculture, food security, small-scale

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Authors: Fabiola Trejo Perez, Rolando Diaz Loving

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Sexual pleasure consists of the positively valued feelings induced by sexual stimuli, but it is also weighed down by pop-psychological baggage, and subjected to cross-cultural and cross-historical variation. Social and individual interpretations of what can or can’t be considered as pleasurable are intertwined with culture’s predominant values, norms and beliefs. For each culture, sexual norms work as a guide to be followed in order to model socially accepted behaviors. Therefore, cultural messages regarding sexuality are usually directed to restrict men and women from enjoyment, sexual satisfaction and specifically orgasm. Given that sexual pleasure hasn’t been recognized as an accepted topic of open discussion, particularly for women, people have to eventually complement their knowledge using their own experience filling in the blanks from what little has been said. Thus, this research aims to identify which are the particular social messages associated with the easing or inhibition of sexual pleasure. Three hundred Mexican men and women ages 25 to 35 years old answered a self-report survey composed by the Inventory of facilitators and inhibitors of sexual pleasure and the Sexual premises questionnaire via pencil-paper and online. Results show a high endorsement to double standard messages associated with higher levels of sexual pleasure inhibitors like feeling pressured to have sexual activity, guilt and inability to reach orgasm, in contrast with people who endorse more permissive norms and beliefs, feeling connected to their sexual partners and confident with themselves. These results illustrate that the shaping of sexuality, from experience to society, is comprised of an important relationship between culture and sexual pleasure.

Keywords: culture, sexual double standard, sexual norms and beliefs, sexual pleasure

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Authors: Asma Lamin, Anna H. Kaksonen, Ivan Cole, Paul White, Xiao-Bo Chen

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Microbiologically influenced corrosion (MIC) is a process in which microorganisms initiate, facilitate, or accelerate the electrochemical corrosion reactions of metallic components. Several reports documented that MIC accounts for about 20 to 40 % of the total cost of corrosion. Biofilm formation due to the presence of microorganisms on the surface of metal components is known to play a vital role in MIC, which can lead to severe consequences in various environmental and industrial settings. Quorum sensing (QS) system plays a major role in regulating biofilm formation and control the expression of some microbial enzymes. QS is a communication mechanism between microorganisms that involves the regulation of gene expression as a response to the microbial cell density within an environment. This process is employed by both Gram-positive and Gram-negative bacteria to regulate different physiological functions. QS involves production, detection, and responses to signalling chemicals, known as auto-inducers. QS controls specific processes important for the microbial community, such as biofilm formation, virulence factor expression, production of secondary metabolites and stress adaptation mechanisms. The use of QS inhibitors (QSIs) has been proposed as a possible solution to biofilm related challenges in many different applications. Although QSIs have demonstrated some strength in tackling biofouling, QSI-based strategies to control microbially influenced corrosion have not been thoroughly investigated. As such, our research aims to target the QS mechanisms as a strategy for mitigating MIC on metal surfaces in engineered systems.

Keywords: quorum sensing, quorum quenching, biofilm, biocorrosion

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Authors: Hiroyuki Aoki

Abstract:

Polymeric materials are often used in a form of thin film such as food wrap and surface coating. In such the applications, polymer films thinner than 100 nm have been often used. The thickness of such the ultra-thin film is less than the unperturbed size of a polymer chain; therefore, the polymer chain in an ultra-thin film is strongly constrained. However, the details on the constrained dynamics of polymer molecules in ultra-thin films are still unclear. In the current study, the segmental dynamics of single polymer chain was directly investigated by fluorescence microscopy. The individual chains of poly(alkyl methacrylate) labeled by a perylenediimide dye molecule were observed by a highly sensitive fluorescence microscope in a defocus condition. The translational and rotational diffusion of the center segment in a single polymer chain was directly analyzed. The segmental motion in a thin film with a thickness of 10 nm was found to be suppressed compared to that in a bulk state. The detailed analysis of the molecular motion revealed that the diffusion rate of the in-plane rotation was similar to the thin film and the bulk; on the other hand, the out-of-plane motion was restricted in a thin film. This result indicates that the spatial restriction in an ultra-thin film thinner than the unperturbed chain dimension alters the dynamics of individual molecules in a polymer system.

Keywords: polymer materials, single molecule, molecular motion, fluorescence microscopy, super-resolution techniques

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Authors: Yitian Ren, Liyin Shen, Tao Zhou, Xiao Li

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The past urbanization process in China has brought out series of problems, the Chinese government has then positioned small towns in essential roles for implementing the strategy 'The National New-type Urbanization Plan (2014-2020)'. As the connector and transfer station of cities and countryside, small towns are important force to narrow the gap between urban and rural area, and to achieve the mission of new-type urbanization in China. The sustainable development of small towns plays crucial role because cities are not capable enough to absorb the surplus rural population. Nevertheless, there are various types of barriers hindering the sustainable development of small towns, which led to the limited development of small towns and has presented a bottleneck in Chinese urbanization process. Therefore, this paper makes deep understanding of these barriers, thus effective actions can be taken to address them. And this paper chooses the perspective of Southwest China (refers to Sichuan province, Yunnan province, Guizhou province, Chongqing Municipality City and Tibet Autonomous Region), cause the urbanization rate in Southwest China is far behind the average urbanization level of the nation and the number of small towns accounts for a great proportion in mainland China, also the characteristics of small towns in Southwest China are distinct. This paper investigates the barriers of sustainable development of small towns which located in Southwest China by using the content analysis method, combing with the field work and interviews in sample small towns, then identified and concludes 18 barriers into four dimensions, namely, institutional barriers, economic barriers, social barriers and ecological barriers. Based on the research above, questionnaire survey and data analysis are implemented, thus the key barriers hinder the sustainable development of small towns in Southwest China are identified by using fuzzy set theory, those barriers are, lack of independent financial power, lack of construction land index, financial channels limitation, single industrial structure, topography variety and complexity, which mainly belongs to institutional barriers and economic barriers. In conclusion part, policy suggestions are come up with to improve the politic and institutional environment of small town development, also the market mechanism are supposed to be introduced to the development process of small towns, which can effectively overcome the economic barriers, promote the sustainable development of small towns, accelerate the in-situ urbanization by absorbing peasants in nearby villages, and achieve the mission of new-type urbanization in China from the perspective of people-oriented.

Keywords: barrier analysis, sustainable development, small town, Southwest China

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Authors: Evgenia Dimova-Aleksandrova, Elitsa Deianova

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Dynamic changes in modern life and habitation due to demographic, urban, technology, and ecological factors affect the size of modern homes leading to a trend of decreasing their area. The current paper aims to investigate the differences between “micro” homes and “small” homes. In Bulgaria, these two types are not included in legal regulations, and therefore, a precise definition and special requirements are needed and sought in order to include their characteristic features in contemporary individual habitation. The purpose of the current study is to determine limits in built-up volume for the two types, to create a definition of the terms “micro” and “small” home, and to find methods to distinguish them. A comparative analysis will differentiate these types of habitation units, thus determining the boundaries for the built-up area for both concepts. The analysis is based on a case study from European practices and is focused on defining minimal requirements for “micro” and “small” home in the context of contemporary demands for high quality habitation in limited areas.

Keywords: Bulgaria, differentiation, micro home, requirements, small home

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Authors: C. Vrekos, C. Evagelides, N. Samarinas, G. Arampatzis

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As known, the water energy is a renewable and clean source of energy. Energy production from hydropower has been the first, and still is today a renewable source used to generate electricity. The optimal location and sizing of a small hydropower plant is a very important issue in engineering design which encourages investigation. The aim of this paper is to present a formula that can be utilized for locating the position of a small hydropower plant although there is a high dependence on economic, environmental, and social parameters. In this paper, the economic and technical side of the problem is considered. More specifically, there is a critical terrain slope that determines if the plant should be located at the end of the slope or not. Of course, this formula can be used for a first estimate and does not include detailed economic analysis. At the end, a case study is presented for the location of a small hydropower plant in order to demonstrate the validity of the proposed formula.

Keywords: critical terrain slope, economic analysis, hydropower plant locating, renewable energy

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