The rural population percentage decreased from 82.7% to 68.9% in 2011, even though there is an increase in the total rural population, which stands at 833.7 million, and the rural population were now more than three times compared to the population seven decades ago. Another observation is the decrease in cultivators percentage from 71.9% to 45.1 %, while agriculture labour increase from 28.1% to 54.9% during the same period. Despite the increase in irrigated land and net area sown, the average holdings' size under the farmers is continuously decreasing, and it requires a study to look into the reasons. The research probes the role of Minimum Support Price (MSP) in supporting farmers and measuring market price above MSP needed to help marginal and small farmers remain above the poverty level. It explains how different market rates above MSP have a different impact on different categories of agriculture landholding. The study works on developing a common model that relates the impact of MSP on different farmers categories. The model can be generalized to all crops and regions and useful in designing policies that focus on uplifting the income of agricultural farmers.

HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of TAR RNA with acetylpromazine bound to the bulge of TAR RNA, to dock compounds from Enamine database containing 1.6 million individual compounds. Docking identified 173 compounds that were analyzed for the inhibition of HIV-1 infection. Top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50=2.97 μM), T0516-4834 (IC50=0.2 μM) and T5628834 (IC50=3.46 μM), were further tested for HIV-1 transcription inhibition. Only T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas T6780107 compound inhibited equally basal and Tat-induced transcription and T5628834 compound only inhibited basal HIV-1 transcription. The T0516-4834 compound also showed strongest inhibition of HIV-1 gag RNA expression and p24 production in CEM T cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound disrupted Tat-TAR RNA interaction indicating that it might target TAR RNA. Also, of the three tested compounds, T5628834 but not T6780107 or T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. Taken together, our study identified novel compound T0516-4834 that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Understanding surfactant self-assembly in deep eutectic solvents (DES) is important to their potential use in industrial formulations. We have recently reported the formation of a fracto-eutectogel comprising SDS fractal aggregates at a concentration as low as 1.6 wt% in glyceline (a DES comprising glycerol and choline chloride) at room temperature. The building units of the fractals consisted of multilayers of self-assembled SDS lamellae arranged in a dendritic pattern. Here we report that this fractal phase transitions into a fluid phase above a critical gelation temperature, TCG ~ 45 oC, evident from polarized light microscopy (PLM) observations. Small-angle neutron scattering (SANS) reveals that this phase transition is underpinned by the nanoscopic morphological transformation of the SDS lamellae into cylindrical micelles at T > TGC. Fitting SANS profiles confirms that the morphology of the micelles is SDS-concentration (cSDS) dependent at T > TGC: cylindrical at cSDS > 0.6 wt% and spherical at cSDS = 0.6 wt%. At cSDS < 0.6 wt%, only isotropic scattering was observed in the SANS profiles. Such SDS self-assembly behaviors contrast with those we have previously observed in glycerol, which we attribute to the presence of ions (i.e. choline chloride) in glyceline. Our findings have general implications to surfactant self-assembly in DES, solvents that are rich in hydrogen bonding and ions.

The open-bundle structure of cytochrome c’ as an unfolding intermediate was determined by small-angle neutron scattering experiment (SANS). The four-α-helix bundle structure of Cyt c’ at neutral pH was transited to an open-bundle structure (at pD ~13), which is a joint-clubs consisting of four clubs (α-helices) connected by short loops. The compactly folded structure of Cyt c’ (radius of gyration, Rg = 18 Å for the Cyt c’ dimer) at neutral or mildly alkaline pD transitioned to a remarkably larger “open-bundle” structure at pD ~13 (Rg = 25 Å for the Cyt c’ monomer). Cyt c’ adopts an unstructured random coil structure at pD = 1.7 (Rg = 25 Å for the Cyt c’ monomer). Numerical partial scattering function analysis (joint-clubs) and ab initio modelling gave structures similar to the “open-bundle”, which retains the α-helices but loses the bundle structure.

The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds pro-vide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole or-ganisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.

The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is key to increase survival and therapeutic adjustment. Especially in stages II-IV biomarkers are urgently needed for adjuvant therapy purposes after resection and for treatment of metastatic patients. We here investigated if fatty acid (FA) and protein composition of small extracellular vesicles (sEV) deriving from plasma of 0-I, II, and III-IV stage melanoma patients (n=38) could reflect disease stage and thus function as biomarker. The subpopulation of sEV expressing CD81 (CD81sEV) was isolated by an ad hoc immune affinity technique from microvesicle-depleted plasma. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA and a decrease in Saturation Index (C18:0/C18:1), already detectable in early stages, distinguished patients’ from healthy donor CD81sEV. Proteomics (identifier PXD024434) detected an exclusive and significant increase of CD14, PON1, PON3 and APOA5 in stage II and a significant decrease of Rap1b in stage III-IV CD81sEV. The FA and proteomic stage dependent CD81sEV signature strengthens the potential of circulating sEV studies in providing discriminatory information for early diagnosis, prediction of metastatic behavior and follow up of melanoma patients.

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat Shock Protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane-Hsp70 positive tumor cells actively release Hsp70 into lipid microvesicles termed exosomes into the blood. Due to conformational changes of Hsp70 in the lipid environment, most commercially available antibodies fail to detect membrane-bound and exosomal Hsp70. To fill this gap and to assess the role of exosomal Hsp70 in the circulation as a potential tumor biomarker, we established the novel complete Hsp70 (compHsp70) sandwich ELISA using two monoclonal antibodies (mAbs) that are able to recognize both, free and lipid-associated Hsp70 on the cell surface of viable tumor cells and exosomes. The epitopes of the mAbs cmHsp70.1 (aa 451-461) and cmHsp70.2 (aa 614-623) that are conserved among different species reside in the substrate-binding domain of Hsp70, with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/ml, high recovery rates of ‘spiked’ liposomal Hsp70 (>84%), comparable values between human serum and plasma samples, and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy volunteers. Hsp70 concentrations dropped concomitantly with the decrease in viable tumor mass on irradiation of patients with approximately 20 Gy (range 18 – 22.5 Gy) or after completion of radiotherapy (60 - 70 Gy). In summary, the compHsp70 ELISA presented herein provides a highly sensitive and reliable tool for measuring free and exosomal Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a predictive tumor-specific biomarker, risk assessment and for monitoring therapeutic outcome.

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood-brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS=5.75 ± 0.932 L·Kg-1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

Recent studies on seafloor mapping have presented different modelling methods for the automatic classification of seafloor sediments. However, most of these studies have applied these models to seafloor data with appropriate number of ground-truth samples, which raises the question whether these methods are applicable to studies with smaller numbers of ground-truth data. In this study, we aim to address this issue by conducting sediment class-specific predictions using ensemble modelling to map areas with limited or without ground-truth data and combined with hydro-acoustic datasets. The resulting class-specific maps were then assembled into one map, where the most probable class was assigned to the appropriate location. Our approach was able to predict sediment classes without bias to the class with more ground-truth data and produced reliable seafloor sediment distributions maps that can be used for seafloor monitoring. Sediment shifts of a heterogenous seafloor in the Sylt Outer Reef, German North Sea were also assessed to understand the sediment dynamics in the area. The analyses of sediment shifts showed that the western area of the Sylt Outer Reef is highly active, and the results of the analyses assisted in providing recommendations on future seafloor monitoring activities.

Background: Real-world data on the molecular epidemiology of EGFR resistance mutations at or after progression with first- or second-generation EGFR-TKIs in patients with advanced NSCLC are lacking. Methods: This ongoing observational study was carried out by 23 hospital-based physicians in Greece. The decision to perform Cobas® EGFR Mutation Test v2 in tissue and/or plasma at disease progression was made before enrollment. For patients with negative/inconclusive T790M plasma-based results, tissue re-biopsy could be performed. Results: Ninety-six (96) eligible patients were consecutively enrolled (median age: 67.8 years) between July-2017 and September-2019. Of the patients, 98% were tested upon progression using plasma and 2% using tissue/cytology biopsy. The T790M mutation was detected in 16.0% of liquid biopsies. Tissue re-biopsy was performed in 22.8% of patients with a T790M-negative plasma result. In total, the T790M positivity rate was 21.9%, not differing between patients on first- or second-generation EGFR-TKI. Higher (≥2) ECOG performance status and longer (≥10 months) time to disease progression following EGFR-TKI treatment initiation were associated with T790M positivity. Conclusions: Results from plasma/tissue-cytology samples in a real-world setting, yielded a T790M positivity rate lower than previous reports. Fewer than one in four patients with negative plasma-based testing underwent tissue re-biopsy, indicating the challenges in routine care settings.

Vacuum drying can dehydrate materials further than dry heat methods while protecting sensitive materials from thermal degradation. Many industries have shifted to vacuum drying as cost- or time-saving measures. Small-scale vacuum drying, however, has been limited by high costs of specialty scientific tools. To make vacuum drying more accessible, this study provides design and performance information for a small-scale open source vacuum oven, which can be fabricated from off-the-shelf and 3-D printed components. The oven is tested for drying speed and effective-ness on both waste plastic polyethylene terephthalate (PET) and a consortium of bacteria developed for bioprocessing of terephthalate wastes to assist in distributed recycling of PET for both additive manufacturing as well as potential food. Both materials can be damaged when exposed to high temperatures, making vacuum drying a desirable solution. The results showed the open source vacuum oven was effective at drying both plastic and biomaterials, drying at a higher rate than a hot-air dryer for small samples or for low volumes of water. The system can be constructed for less than 20% of commercial vacuum dryer costs for several laboratory-scale applications including dehydration of bio-organisms, drying plastic for distributed recycling and additive manufacturing, and chemical processing.

Small boat fishers are often the lifeblood of remote coastal communities in Iceland, contributing to employment, jobs and economic prosperity. This study conducts exploratory but highly practical research into the efficiency of onboard catch handling practices by Icelandic small boat fishers using fish handling tools called automatic jigging machines. Using applied research methods, this study researches whether standardisation of operations could be applied to make catch handling practices on small boats more time and resource efficient, leading to reduced waste, a consistently higher quality product, and potential increases in economic efficiency and sustainability. Thematic analysis, value stream mapping, flow analysis and Kaizen ideology were adopted to identify gaps and continuous improvement opportunities to standardise processes, leading to exemplary performance. Eight core recommendations are identified, seven of which are classed as straight-forward, ‘do now’ measures according to a Kaizen Priority Matrix. These include human and technological interventions in the areas of safety, organisational arrangements, hygiene, fish handling and bleeding, and cooling. Questionnaire responses reveal four main themes of importance to the sub-sector: changes in recent decades; the importance of small boat fishers; education and improvement; and the particularities of the sub-industry. The latter include the perception of a ‘race against time’ to land the catch, an issue that sometimes contributes to sub-optimal catch handling practices. Although this study has decidedly practical connotations for small boat fishers, its outcomes are also likely to be of interest to academics, particularly those focused on the organisational management of natural resources and general applications of the project management methodology and applied research methods as a means of solving practical problems in everyday life.

Higher-risk myelodysplastic syndrome (HR-MDS) has a poor prognosis in the absence of efficient therapy. The evaluation of new therapies in animal models of HR-MDS is hampered by the absence of accurate in vivo biomarkers of the disease. In this study we compared [18F]Fluoro-desoxyglucose Positron Emission Tomography (FDG-PET) and [18F]Fluoro-thymidine (FLT)-PET imaging for disease follow-up in a triple transgenic MMTVtTA/TetoBCL-2/MRP8NRASD12 mouse model of HR-MDS. Normal control FVB/N mice (G1,n=9) and HR-MDS mice (G2,n=12) underwent both FDG- and FLT-PET procedures at 2-day intervals, on a dedicated small animal device. Blood cell counting, BCL-2 and Mac-1hi/Gr-1lo expression measurements in blood were performed before each PET procedure. Visually, PET images of G2 mice demonstrated homogeneous FDG uptake in the whole skeleton similar to that observed in G1 mice, and abnormal FLT hot spots in bone marrow not observed in G1 mice. The intensity of FLT hot spots in bone marrow was higher in 3-months old G2 mice than in 2-months old G2 mice, concordant with a higher percentage of cells expressing Mac-1hi/Gr-1lo and lower platelets counts. We conclude that FLT-PET/CT imaging is a more valuable surrogate non-invasive quantitative marker of HR-MDS bone marrow involvement than FDG-PET/CT in our mouse model of HR-MDS.

In an insightful article published in Nature human behavior on November 2020, the effectiveness of 46 “non-pharmaceutical interventions” (NPI) regarding Covid-19 pandemic have been compared¹. One of these 46 categories, the one which is ranked as the most effective measure, is named “small gatherings cancelation”. In the discussion section of that article, the authors introduce a list of what they probably assume to be representative examples of this category, namely, “closures of shops”, “closure of restaurants,” “mandatory home–working”, “gathering of 50 people or less” and so on. The name that the authors have given to this category could give rise to confusions and misunderstandings. We used corpus analysis to show that “small gathering” is commonly used to denote a planned or spontaneous “event”, and consequently does not convey what the authors intend this term to cover as its most representative instances i.e., Simultaneous presence of people (crowd) in shops or offices. Furthermore, taking a top-down approach, we focused on the information which was provided in reference material like CDC and WHO documents. The analysis showed that “small gatherings” is encoded in those sources to denote “events” and “small gatherings cancelation” is used to denote cancelling preplanned events. In conclusion, neither unspecialized language nor official/institutional discourse uses “small gathering” the way that the authors of the aforementioned article use it i.e., to refer to simultaneous presence of people (crowd) in shops or offices. Therefore, when language users come across this phrase, if they do not read the entire article, the only semantic frame that is evoked in their mind would be that of a festive or social “event” rather than of crowded shops or offices; this misunderstanding is cognitively justified and consequently changing this terminology is recommended.

Recently, there has been renewed interest in the performance, functionality, and sustainability of traditional small-scale storage interventions (check dams, farm bunds and tanks) used across India for the improvement of local water security. The Central Groundwater Board of India is en-couraging the construction of such interventions for the alleviation of water scarcity. It is of critical importance to understand the hydrological effect of these interventions at basin scales to maximise their effectiveness. The quantification of small-scale interventions in hydrological modelling is often neglected, especially in large-scale modelling exercises. A bespoke version of the GWAVA model was developed to assess the impact of interventions on the water balance of the Cauvery Basin and two smaller sub-catchments. Model results demonstrate that farm bunds appear to have a negligible effect on the estimated average annual simulated streamflow at the outlets of the two sub-catchments and the basin whereas tanks and check dams have a more significant effect. In-terventions generally were found to increase evaporation losses across the catchment. The model adaption used in this study provides a step-change in the conceptualisation and quantification of the consequences of small-scale storage interventions in large- or basin-scale hydrological models.

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

In the last years, more and more studies highlight the advantages of complementing traditional master classes with additional activities that improve students´ learning experience. This combination of teaching techniques is specially advised in the field of structural engineering, where intuition of the structural response it is of vital importance to understand the studied concepts. This paper deals with the introduction of a new (and more encouraging) educational tool to introduce intuitively students in the dynamic response of structures excited with an educational shaking table. Most of the educational structural health monitoring systems use sensors to determine the dynamic response of the structure. The proposed tool is based on a radically different approach, as it is based on low-cost image-recognition techniques. In fact, it only requires the use an amateur camera, a black background and a computer. In this study, the effects of both the camera location and the image quality are also evaluated. Finally, to validate the applicability of the proposed methodology, the dynamic response of small-scale buildings with different typologies is analyzed. In addition, a series of surveys were conducted in order to evaluate the activity based on student´s satisfaction and the actual acquisition and strengthening of knowledge.

Plant pathogenic fungi are the largest group of disease-causing agents on crop plants and represent a persistent and significant threat to agriculture worldwide. Conventional approaches based on the use of pesticides raise social concern for the impact on the environment and human health and alternative control methods are urgently needed. The rapid improvement and extensive implementation of RNAi technology for various model and non-model organisms has provided the initial framework to adapt this post-transcriptional gene silencing technology for the management of fungal pathogens. In this review, we describe exogenous RNAi involved in plant pathogenic fungi and discuss small RNA production, formulation, and RNAi delivery methods. We explore some challenges with possible solutions. Furthermore, exogenous RNAi holds great potential for RNAi-mediated plant pathogenic fungal disease control.

Non-coding RNAs (ncRNAs) comprise a diverse class of non-protein coding transcripts that regulate critical cellular processes associated with cancer. Advances in RNA-sequencing (RNA-Seq) have led to the characterization of non-coding RNA expression across different types of human cancers. Through comprehensive RNA-Seq profiling, a growing number of studies demonstrate that ncRNAs, including long non-coding RNA (lncRNAs) and microRNAs (miRNA), play central roles in progenitor B-cell Acute Lymphoblastic Leukemia (B-ALL) pathogenesis. Furthermore, due to their central roles in cellular homeostasis and their potential as biomarkers, the study of ncRNAs continues to provide new insight into the molecular mechanisms of B-ALL. This article reviews the ncRNA signatures reported for all B-ALL subtypes, focusing on technological developments in transcriptome profiling and recently discovered examples of ncRNAs with biologic and therapeutic relevance in B-ALL.

Background: The phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer(ES-SCLC). Intergrated the clinical benefits of pembrolizumab and its high cost into account, this study aim to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the the US payer perspective. Methods: A Markov model was developed to compared the costs and quality-adjusted life-years (QALYs) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy, treatment utilization and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examined the robustness of our model. Results: Adding pembrolizumab to standard first-line EP, resulted in better effectiveness than the use of EP alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio(ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerts no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide rang of willingness to pay were modest. Conclusion: From the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compare with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary measure to improve its cost-effectiveness.

A sufficient amount of tissue sample is required to perform next-generation sequencing (NGS) with a high success rate, but the majority of patients with advanced non-small-cell lung cancer (NSCLC) are diagnosed with small biopsy specimens. Biopsy samples were collected from 184 patients with bronchoscopically diagnosed NSCLC. The tissue surface area, tumor cell count, and tumor content rate of each biopsy sample were evaluated. The impact of the cut-off criteria for the tissue surface area (≥ 1 mm2) and tumor content rate (≥ 30%) on the success rate of Oncomine Dx Target Test (ODxTT) was evaluated. The mean tissue surface area of the transbronchial biopsies was 1.23 ± 0.85 mm2 when small endobronchial ultrasonography with a guide sheath (EBUS-GS) was used, 2.16 ± 1.49 mm2 with large EBUS-GS, and 1.81 ± 0.75 mm2 with endobronchial biopsy (EBB). The proportion of samples with a tissue surface area of ≥ 1 mm2 was 48.8% for small EBUS-GS, 79.2% for large EBUS-GS, and 78.6% for EBB. Sixty-nine patients underwent ODxTT. The success rate of DNA sequencing was 84.1% and that of RNA sequencing was 92.7% over all patients. The success rate of DNA (RNA) sequencing was 57.1% (71.4%) for small EBUS-GS (n = 14), 93.4% (96.9%) for large EBUS-GS (n = 32), 62.5% (100%) for EBB (n = 8), and 100% (100%) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 15). Regardless of the device used, a tissue surface area of ≥ 1 mm2 is adequate for samples to be tested with NGS.

Medical and translational scientific research requires the use of animal models as an initial approach to the study of new therapies and treatments, but when the objective is an exploration of translational potentialities, classical models fail to adequately mimic problems in humans. Among the larger animal models that have been explored more intensely in recent decades, small ruminants, namely sheep and goats, have emerged as excellent options. The main advantages associated to the use of these animals in research works are related to their anatomy and dimensions very similar to those of humans in most physiological systems, in addition to their low maintenance and feeding costs, tendency to be docile, long life expectancies and few ethical complications raised in society. The most obvious disadvantages are the significant differences in some systems such as the gastrointestinal, and the reduced amount of data that limits the comparison between works and the validation of the characterization essays. Despite everything, recently these species have been increasingly used as animal models for diseases in different systems, and the results obtained open doors for their more frequent and advantageous use in the future. The purpose of this review is to summarize the general principles related to the use of small ruminants as animal models, with focus on regenerative medicine, to group the most relevant works and results published recently and to highlight the potentials for the near future in medical research.

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification, resulting in angiogenin (ANG) dependent tsRNA formation. More specifically, m5U54 hypomodification is followed by ANG overexpression and tRNA cleavage near the anticodon, resulting in accumulation of 5’tRNA-derived stress-induced RNAs (5’tiRNAs), in particular 5’tiRNA-GlyGCC and 5’tiRNA-GluCTC. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tsRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tsRNA formation in mammalian cells. These results establish a link between tRNA demethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.

In the past few decades, the tourism sector has emerged as a significant economic activity in island nations, particularly in tropical regions. However, most of the tropical islands face similar constraints. National and international tourists visit the SIDS including A & N Islands and contribute to the GDP to significant share. The Covid-19 outbreaks in SIDs including A & N islands shows that number of people infected were less as compared to metros or big cities. However, tourism activities completely stopped due to lockdown resulting in decreasing tourist’s arrival, declined GDP and per capita income of SIDs to greater extent. The information gathered from various sources, mass media and net analysed and interpreted in this chapter. Due to Covid-19 tourist’s arrival declined which has serious consequences on the livelihood of islander. Our analysis revealed A&N Islands deficit in energy available at from different sources by 18.26%. However, they are surplus in protein. The burden of high expenditure coupled with poor infrastructure makes them more vulnerable in the circumstance of pandemic outbreaks. This outbreak has created the question of survival due to loss of jobs, halted economic activates, psychological, health unrest and livelihood threats among the depending people of these Island nations. Therefore, government interventions and subsidized package is very much essential to revive the tourism industry.

Effective biomarkers are essential to the early diagnosis of non-small cell lung cancer (NSCLC). Herein, a retrospective study of 49 newly diagnosed and recurrent NSCLC patients, 31 patients with benign pulmonary disease and 24 healthy volunteers was conducted, to evaluate the diagnostic value of circulating rare cells for NSCLC. The expression of circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in peripheral blood were measured by subtraction enrichment-immunostaining-fluorescence in situ hybridization (SE-iFISH). The level of CTCs (P＜0.001) and CTECs (P＜0.001) was significantly higher in NSCLC group than that in benign pulmonary disease group. The proportion of small CTCs (P＜0.001) and CTECs (P＜0.0001) significantly increased from benign lung disease individuals to NSCLC patients. The AUC of ROC curves of total CTCs and CTECs were 0.815 (95%CI: 0.722~0.907), 0.739 (95%CI: 0.618~0.860), respectively. The cut-off values for discriminating NSCLC with benign lung disease patients were total CTCs 11.5 units/6ml and total CTECs 10.5 units/6ml, with sensitivity and specificity being 67.3% and 83.9%, 77.6% and 77.4%, respectively. When CTCs and CTECs were combined, predictive value significantly increased to 82.6% as measured by the area under the curve. Small CTCs and triploid CTCs had high positive predictive value (PPV) and positive likelihood ratio (LR+) of the diagnosis of NSCLC in early stage. CTCs and CTECs can not only be used as new biomarkers for the diagnosis of NSCLC, but can also improve diagnostic performance of the early stage NSCLC. Moreover, the combined examination of CTCs and CTECs is be superior to the single.

Small Island States (SIDS) are among the nations most exposed to climate change (CC) and are characterised by a high degree of vulnerability. Their special nature means there is a need for more studies focused on the limits to CC adaptation on such fragile nations, particularly in respect of their problems and constraints. This paper addressed a perceived need for research into the limitations of adaptation on SIDS, focusing on the many restrictions which are unique to them. The main research question raised by this study was that how and to what extent the challenges by human activities (e.g., agriculture and tourism) posed to coastlines of SIDS could be addressed. This paper identified and described the adaptation limits they have, by using a review of the literature and an analysis of case studies from a sample of five SIDS in the Caribbean and Pacific regions (Barbados, Trinidad and Tobago, Cook Islands, Fiji, Solomon Islands, and Tonga). The findings of this research showed that an adaptable SIDS is characterised by awareness of various values, appreciation and understanding of a diversity of impacts and vulnerabilities, and acceptance of certain losses through change. The implications of this paper are two-fold. It explains why island nations continue to suffer from the impacts of CC, and suggest some of the means via which adequate policies may support SIDS in their efforts to cope with the threats associated with a changing climate. This study concluded that, despite the technological and ecological limits (hard limits) affecting natural systems, adaptation to CC is not only limited by such complex forces, but also by societal factors (soft limits) that could potentially be overcome by more adequate adaptation strategies.

To contribute to small and medium enterprises (SMEs) sustainable transition into the circular economy, the study proposes the activation of organizational learning (OL) processes – denoted here as multi-level knowledge creation, transfer, and retention processes – as a key phase in introducing circular business models (CBMs) at SME and supply chain (SC) level. The research employs a mixed-method approach, using the focus group methodology to identify contextual elements impacting on CBM-related OL processes, and a survey-based evaluation to single out the most frequently used OL processes inside Italian construction SMEs. As main result, a CBM-oriented OL multi-level model offers a fine-grained understanding of contextual elements acting mutually as barriers and drivers for OL processes, as possible OL dynamics among them. The multi-level culture construct – composed of external stakeholders’, SC stakeholders’, and organizational culture – identify the key element to activate CBM-oriented OL processes. Main implications are related to the identification of cultural, structural, regulatory, and process contextual elements across the external, SC, and organizational levels, and their interrelation with applicable intraorganizational and interorganizational learning processes. The proposed model would contribute to an improved implementation of transitioning into the circular economy utilizing sustainable business models in the construction SMEs.

Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

Heterogeneous distribution of delivery or treatment modalities within the tumor mass is a crucial limiting factor for a vast range of theranostic applications. Understanding the interactions between a nanomaterial and the tumor microenvironment will help to overcome challenges associated with tumor heterogeneity as well as the clinical translation of nanotheranostic materials. This study aims to evaluate the influence of protein surface adsorption on gold nanoparticle (GNP) biodistribution using high resolution Computed Tomography (CT) preclinical imaging in C57BL/6 mice harboring Lewis Lung Carcinoma (LLC) tumors. LLC provides a valuable model for study due to its highly heterogenous nature which makes drug delivery to the tumor challenging. By controlling the adsorption of proteins on the GNP surface, we hypothesize that we can influence the intratumoral distribution pattern and particle retention. We performed an in vitro study to evaluate the uptake of GNPs by LLC cells and an in vivo study to assess and quantify the GNP biodistribution by injecting concentrated GNPs citrate stabilized or passivated with Bovine Serum Albumin (BSA) intratumorally into LLC solid tumors. Quantitative CT and Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) results both confirm the presence of particles in the tumor 9 days post-injection (n=8 mice/group). Significant difference is highlighted between citrate-GNP and BSA-GNP groups (**p < 0.005, Tukey’s multiple comparisons test), confirming the protein corona of GNPs modifies intratumoral distribution and retention of the particles. In conclusion, our investigations show that the surface passivation of GNPs influences the mechanism of cellular uptake and intratumoral distribution in vivo highlighting the spatial heterogeneity of the solid tumor.

Shrinking farm size and fragile farm resources pose a significant challenge to the sustainability of small-scale farms. Efficient resource utilization in small-scale farms is crucial to achieving farm sustainability through endogenous mechanisms. However, the precise mechanisms to integrate physical resources to achieve farm sustainability are not very clear yet. By capturing the interaction among farm resources as a network phenomenon, we identify the discrete resource interactions (RIs) in different types of small-scale farms of Indian Sundarbans, which are associated with higher farm sustainability. Thirty-two linkages, 11 reciprocal linkages, 22 triads, and three ‘core elements’ that occurred and cooccurred on highly sustainable farms are found to be critical in achieving farm sustainability. Using the properties of resource interaction networks as explanators of farm sustainability, we anticipate that sustainability in small-scale farms can be achieved by strategically creating new RIs on the farm. However, there may be limitations to such achievement depending on the nature of RI and type of farm. The analytical approach helps to understand the structural basis of sustainability in small-scale farms, and this approach can be used to achieve farm sustainability through the strategic integration of existing farm resources in the smallholder systems.

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from serosal surface of abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within 3 years. The dismal survival makes DSRCT an orphan disease with urgent need of new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors have been evaluated in small studies. Recent works using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

Human cytomegalovirus (HCMV) is a leading cause of severe diseases in immunocompromised individuals, including AIDS and transplanted patients, and in congenitally infected newborns. The utility of available drugs is limited by poor bioavailability, toxicity, and emergence of resistant strains. Therefore, it is crucial to identify new targets of therapeutic intervention. Among the latter, viral protein-protein interactions are becoming increasingly attractive. Since dimerization of HCMV DNA polymerase processivity factor ppUL44 plays an essential role in the viral life cycle being required for oriLyt-dependent DNA replication, we performed an in silico screening and selected 18 small molecules (SMs) potentially interfering with ppUL44 homodimerization. Antiviral assays using recombinant HCMV TB40-UL83-YFP in the presence of the selected SMs led to the identification of four active compounds. The most active one, B3, also efficiently inhibited AD169 in plaque reduction assays and impaired replication of an AD169-GFP reporter virus and its ganciclovir-resistant counterpart to a similar extent. As assessed by Western blotting experiments, treatment of infected cells with B3 specifically reduced viral gene expression starting from 48 h post infection, consistent with activity on viral DNA synthesis. Therefore, inhibition of ppUL44 dimerization could represent a new class of HCMV inhibitors, complementary to those targeting the DNA polymerase catalytic subunit or the viral terminase complex.

This paper presents an optimal design for the inner current control loop of the continuous current conduction mode (CCM) power factor correction (PFC) stage, which it can be used as the front stage of the two stages alternating current-direct current (AC-DC) telecom power supply. Conventional single-phase CCM-PFC boost converter usually implemented with using of the proportional-integral (PI) controllers in both of the voltage and current control loops, to regulate the output DC voltage to the specified value, moreover to maintains the input current follows the input voltage which offers converter with high power factor (P.F) and low current total harmonic distortion (THD). However, due to the slow dynamic response of the PI controller at the zero-crossing point of the input supply current, input current can’t fully follow the input voltage which leads to high THD. Digitally controlled PFC converter with an optimal design of the inner current control loop using doubly control loops IP controller to reduce the THD and to offer input current with unity P.F was performed in this paper. Furthermore, for the economic design of the digitally control PFC converter, two isolated AC and DC voltage sensors are proposed and designed for the interfacing with the microcontroller unit (MCU). PSIM software was used to test the converter performance with using the proposed designed current controllers and isolated voltage sensors. High power density digitally controlled telecom PFC stage with P.F of about 99.93%, full load efficiency of about 98.70% and THD less 5.50% is achieved in this work.

Although researchers have investigated widely the impact of IOD phases on human lives, only a few have examined such impacts on fisheries. In this study, we analyzed the influence of negative (positive) of IOD on a chlorophyll a (Chl-a) concentration as an indicator of phytoplankton biomass and small pelagic fish production in the eastern Indian Ocean (EIO) off Java. We also conducted field surveys in the EIO off Palabuhanratu Bay at the peak (October) and the end (December) of the 2019 positive IOD phase. Our findings show that the Chl-a concentration had a strong and robust association with the 2016 (2019) negative (positive) IOD phases. The negative (positive) anomalous Chl-a concentration in the EIO off Java associated with the negative (positive) IOD phase induced strong downwelling (upwelling), leading to the preponderant decrease (increasing) of small pelagic fish production in the EIO off Java.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for translating amino acids for protein synthesis. Their function in pathogen-derived infectious diseases has been well established, which has led to development of small molecule therapeutics. The applicability of ARS inhibitors for other human diseases such as fibrosis has recently been explored in the clinical setting. There are active studies to find small molecule therapeutics for cancers. Studies on central nervous system (CNS) disorders are burgeoning as well. In this regard, we present a concise analysis of the recent development of ARS inhibitors based on small molecules from the discovery research stage to clinical studies as well as a recent patent analysis from the medicinal chemistry point of view.

Sanitation, water supply and their governance remain major challenges in many Pacific Island Countries. National sustainable development strategies (NSDSs) are promoted throughout the Pacific as overarching improved governance instruments to identify priorities, plan solutions and fulfill commitments to sustainable development. Their relevance to local village-level development priorities is uncertain. The Kingdom of Tonga provides opportunities to compare both. Tonga’s Strategic Development Frameworks (TSDFI 2011-2014 and TSDFII 2015-2025) were developed to focus government and its agencies on national outcomes. From 2007 to 2016, 136 villages throughout Tonga’s five Island Divisions (IDs) formulated Community Development Plans (CDPs) involving separately 80% of women, youth and men in each village. Censuses in 2006 and 2016 show linked improvements in water supply and sanitation systems but reveal IDs with continuing challenges. Sanitation and water are prominent in TSDFI but absent from the current TSDFII. In contrast, CDPs show in one ID, 53% of villages ranked sanitation as a priority with marked differences between IDs and between women, youth and men. CDPs’ sanitation priorities in IDs mostly correspond to sanitation and water metrics in the Censuses, but some reflect impacts of natural disasters. Explanations for differences in sanitation priorities between national and local development plans, as well as suggestions for improving NSDS processes in island countries, are advanced.

Exportin-1, the ubiquitous nuclear protein transporter, is widely confirmed as an active chemotherapeutic target in non-small cell lung cancer condition while Juglans mandshurica is a well-studied anticancer plant in some lung cancer cell lines. We intend to find novel exportin-1 inhibitor from Juglans mandshurica with better potential tolerability and pharmaco-dynamo-kinetic properties than the current selective inhibitors of nuclear export in non-small cell lung cancer treatment. Osiris property explorer DataWarrior, Glide standard precision docking, quantum mechanics polarized ligand docking, MMGBSA binding free energy calculations, Jaguar density functional theory analysis, and the online web-based SwissADME were employed respectively in this study to filter the retrieved compounds based on tolerability, toxicity, and Lipinsky’s rule of five violation potential, determine their druggability, establish relative stability of the lead compound in water solvation model, and evaluates druglikeness, lead-likeness, as well as synthetic accessibility of the lead compound. This study reveals eriodictyol as having higher binding free energy (-40 kcal/mol) than that of standard (-39.56 kcal/mol) in exportin-1 active site, better synthetic accessibility score (3.15 versus 3.29), high GI absorption, non-blood brain barrier permeant, lacks Brenk and PAINS alert, obeying Lipinski’s, Ghose’s, Veber’s, Egan’s, and Muegge’s rule of druglikeness and lead-likeness as well as non-cytotoxic to HepG2 cells. We therefore found eriodictyol as a lead-like, non-toxic exportin-1 inhibitor with good predictive stability and pharmacokinetic potential and thus provided data for further validation of eriodictyol as a candidate exportin-1 inhibitor in both preclinical and clinical studies involving lung cancer therapy.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four-dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits a greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

Indian cities are increasingly becoming susceptible to PM10 induced health effects which have become a matter of concern for the policymakers of the country. Air pollution is engulfing the comparatively smaller cities as the rapid pace of urbanization, and economic development seems not to lose steam ever. A review of air pollution of 28 cities of India, which includes tier-I, II, and III cities of India, found to have grossly violated both WHO and NAAQS standards in respect of acceptable daily average PM10 concentrations by a wide margin. Predicting the city level PM10 concentrations in advance and accordingly initiate prior actions is an acceptable solution to save the city dwellers from PM10 induced health hazards. Predictive ability of three models, linear MLR, nonlinear MLP (ANN), and nonlinear CART, for one day ahead PM10 concentration forecasting of tier-II Guwahati city, were tested with 2016-2018 daily average observed climate data, PM10, and gaseous pollutants. The results show that the non-linear algorithm MLP with feedforward backpropagation network topologies of ANN class, giving the best prediction value when compared with linear MLR and nonlinear CART model. ANN (MLP) approach, therefore, may be useful to effectively derive a predictive understanding of one day ahead PM10 concentration level and thus provide a tool to the policymakers for improving decision-making associated with air pollution and public health.

UN 2030 Sustainable Development Goal 6 presents difficulties for small island developing states such as the Kingdom of Tonga, which relies on rainwater and groundwater lenses for freshwater supply. Planning and managing water resources to supply demands in dispersed small islands under variable climate and frequent extreme events is challenging. Tensions between water planning using top-down versus bottom-up processes have long been recognized. Tonga’s overarching national planning instrument is the Tonga Strategic Development Framework, 2015-2025 (TSDFII). This identifies desired national outcomes and is used to direct and resource Ministries and address international and regional commitments. Water supply was a low priority in the three-month consultations that led to TSDFII. Community Development Plans (CDPs), developed by rural villages throughout Tonga’s five Island Groups over nine years, involved participation from 80% of each village population who ranked local priorities. Analysis of priorities in 117 available village CDPs reveals improvements to village water supply was the highest overall priority in all five Island Groups and ranked within the top three priorities by 76% of all villages, with women, youth and men returning figures of 83%, 66% and 80% respectively. The mismatch between top-down and bottom-up priorities appears to result from an urban/rural divide.

The development of targeted therapeutics for cancer continues to receive intense research attention as laboratories and pharmaceutical companies seek to develop drugs and technologies that improve treatment efficacy and mitigate harmful side effects. In the aftermath of World War I, it was discovered that mustard gas destroys rapidly dividing cells and could be used to treat cancer. Since then, chemotherapy has remained a predominant treatment for cancer; however, the destruction of dividing cells throughout the body yields devastating side effects including off-target damage of the digestive tract, bone marrow, skin, and reproductive tract. Furthermore, the high mutation rate of cancerous cells often renders chemotherapy ineffective long-term. Therapies with improved specificity, localization, and efficacy are redefining cancer treatment. Herein, we define and summarize the principal advancements in targeted cancer treatment and briefly comment on the march towards personalized medicine in the treatment of human cancer.

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Hyperhomocysteinemia (HHcy) is typically defined as levels >15 micro mols/L. Elevated plasma levels of Hcy can be caused by the deficiency of either vitamin B12 or folate. The active role of homocysteine is quite ambivalent: many studies detected its potential impact on neurological events; others try to identify it as one of the possible risk factors of cardiovascular events, but with a complementary and secondary role. HHcy has been reported in many neurologic disorders, including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Nowadays, homocysteine could be considered as a possible link between a common vascular risk factor and potential alterations in degenerative neuronal disorders. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum stress; all these aspects have been considered to play an essential role in the pathogenesis of several diseases, including atherosclerosis, major stroke, and vascular dementia. Specific models of astrocytes impairment in HHcy-mice, which mimic small vessel disease, have been developed with a three-step investigation (at 6, 10, 14 weeks of B6, B9, and B12 detrimental diet in wild type HHcy mouse). These studies found out that after ten weeks on a diet (at the most after 14 weeks), end-feet disruption occurs. This phenomenon is concomitant to reduced vascular labeling for aquaporin -4-water channels, lower protein/mRNA levels for Kir4.1, and BK potassium channels, associated with a higher expression of MMP-9. The most exciting finding is that microglial activation in this mice model was evident since the precocious time of observation (6-week time) and precedes astrocytic changes. Our research aims to review the possible role of HHcy in neurodegenerative disease and small-vessel disease and to understand its pathogenic impact.

To address the severe distresses of asphalt pavement, a new type of pavement maintenance treatment, porous ultra-thin overlay (PUTO) with small particle size was proposed. The PUTO has a thickness of 1.5~2.5 cm and a large void ratio of 18~25%. As a newly asphalt mixture, the structure characteristics differ from traditional pavement. Therefore, it is necessary to investigated the fabrication schemes in laboratory and on-site, respectively. In this study, the optimal fabrication schemes, including compaction temperature and number of blows of PUTO were determined based on Cantabro test and volumetric parameters. Then, the corresponding relationship between laboratory and on-site compaction work was then established based on the energy equivalent principle. On this basis, the numbers of on-site rolling passes and the combination method were calculated. The results show that increased compaction temperature and number of blows reduce the height and enhance the compactness of the Marshall sample. With the same temperature and number of blows, the scattering resistance of coarse gradation (PAC-1) is better than that of fine gradation (PAC-2), and the increased asphalt viscosity significantly improves the scattering resistance of the asphalt mixture. To ensure the scattering resistance and volumetric characteristic, the initial compaction temperature of the PAC-1 and PAC-2 should not be lower than 150 °C and 165 °C, respectively. Then, the laboratory compaction work and on-site compaction work were calculated and converted based on the principle of energy equivalence. Consequently, the on-site compaction combination of rolling machines for four asphalt mixtures was determined. According to the volumetric parameters, the paving test section proved that the construction temperature and the on-site rolling combination determined by laboratory tests are reasonable, and ultra-thin overlay has good structural stability, drainage and skid resistance.

Drug design is used for different applications of bioinformatics tools analyze DNA, genome, and sequence target region of a small organic molecule in order to understand the molecules of disease. Bioinformatics tools are identified a newly wide research field and minimize future risks through web servers and data mining. Clinical sample test performed with the bioinformatics tools as the biomedical detective. A particular structure and configuration of protein obliging in Drug design concluded Bioinformatics. This review bioinformatics tools and webserver will discuss functions of small organic molecules according to clinical pharmacology.

Small-scale fishers are considered as one of the most vulnerable communities in Bangladesh but very few studies focused on the livelihood sustainability and vulnerabilities of this professional group. A fieldwork in lower Padma and upper Meghna hilsa sanctuaries identifies different livelihood characters and associated vulnerabilities of the fishers. A conceptual framework known as Sustainable Livelihood Approaches (SLA) has been introduced to analyses the qualitative and quantitative data. The insights of the livelihood strategies provide on small-scale fishers and fisheries management have been explained and explored. Fishers are found solely dependent on fishing, economically insolvent and neglected. In addition, some socio-economic abstractions such as low income, credit insolvency, lack of substitute earning flexibility make them more vulnerable. A number of effective suggestions are elicited from fishers’ perceptions, the implementation of which is crucial to ensure livelihood sustainability of the small-scale fishers.

Potato is among one of the most important food crops, yet maintaining plant productivity in this drought-sensitive crop has become a challenge. Competition for scarce water resources and the continued effects of global warming exacerbate current constraints on crop production. While plants’ response to drought in above-ground tissues has been well documented, the regulatory cascades in developing tubers have been largely unexplored. Using the commercial Canadian cultivar ‘Vigor’, plants were subjected to a drought treatment under high-tunnels causing a 4 ℃ increase in canopy temperature when compared to the well-watered control. Tubers were sampled for RNAseq and metabolite analysis. Approximately 2600 genes and 3898 transcripts were differentially expressed by at least four-fold in drought-stressed potato tubers, with 75 % and 69 % being down-regulated respectively. A further 229 small RNAs were implicated in gene regulation during drought. The comparison of protein homologues between Solanum tuberosum L. and Arabidopsis thaliana L. indicates that downregulated genes are associated with phenylpropanoid, carotenoid, and patatin biosynthesis. This suggests that there may be nutritive implications to drought stress occurring during the potato tuber bulking phase in sensitive cultivars.

COVID-19 is now a major global health crisis, can lead to severe food crisis unless proper measures are not taken. Though a number of scientific studies have addressed the possible impacts of COVID-19 in Bangladesh on variety of issues, problems and food crises associated with aquatic resources and communities are missing. Therefore, this study aimed at bridging the gap in the existing situation and challenges of COVID-19 by linking its impact on aquatic food sector and small-scale fisheries with dependent population. The study was conducted based on secondary data analysis and primary fieldwork. Secondary data focused on COVID-19 overview and number of confirmed, recovered and death cases in Bangladesh; at the same time its connection with small-scale fisheries, aquatic food production, demand and supply was analyzed. Community perceptions were elicited to present how the changes felt and how they affected aquatic food system and small-scale fisheries and found devastating impact. Sudden illness, reduced income, complication to start production and input collection, labor crisis, transportation abstraction, complexity in food supply, weak value chain, low consumer demand, rising commodity prices, creditor’s pressure were identified as the primary affecting drivers. Dependent people felt the measures taken by the Government should be based on protecting the health and food security, although it could be detrimental to economic growth in the short term. The study provides insight into policies adopted by the policy makers to mitigate the effects of the pandemic on aquatic food sector and small-scale fisheries.

Nicotine exposure may affect NSCLC is associated with lung cancer in humans. Whether nicotine exhibits carcinogenesis promoted activities in tumor growth still unknown. Nicotine is known to have dichotomous effects on cancer biology, acting like a pro- or anti-carcinogenesis agent. There are different functions between adenocarcinoma and squamous NSCLC cancer cells. Excess generation of nicotine may inhibit mitochondrial metabolism, protein modification, and DNA cleavage. Materials and Methods: We used the H520 NSCLC line obtained from human lung epithelial cells to detected nicotine growth and toxicity using MTT assay and western blotting. The concentration of nicotine stimulated cell growth to correspond to low concentration, while high concentration was cytotoxic. Results: According to MTT assay results, at 1.0 μM nicotine has significantly enhanced the H520 cell viability (%). Nicotine induced lung cancer carcinogenesis through mechanisms of α7nAchR, EGFR, HDAC2/4/5, Cyclin D/Cyclin E, Bcl-2, p-Akt, and inflammatory proteins of NF-KappaB and COX2 increases at 1.0 μM. Apoptosis proteins were decreases at 1.0 μM nicotine by p21, p27, c-jun, and p38α using western blotting. Nicotine stimulates tumor growth is mediated through α7nicotinic-acetylcholine receptors (α7nAChR), possibly involving inflammation. On the other hand, at high nicotine concentrations (> 1.0 μM) with consistent cytotoxic effects and appeared to be due to direct cell kill. Nicotine can prevent apoptosis induced by NSCLC. Conclusion: Therefore, the effects on chemotherapeutics by NSCLC malignant cell lines, nicotine in concentrations as low as 1.0 μM decreased. These mechanisms are responsible for the genotoxic effects caused by nicotine. This leads to downstream effects on decreased apoptosis, increased cell proliferation and transformation. The malignant NSCLC cells respond to the treatment with nicotine in lung cancer, the nicotine-mediated induction of growth may provide one of its links to α7nAchR or EGFR.

As early as February 2020, many countries have started imposing measures to curb the spread of Covid-19. Despite the right intention, it is a challenging moment for the people, especially the rural population living in the coastal areas. The document presents the preliminary findings on the impacts of Covid-19 on the small scale fisheries in Tun Mustapha Park, Sabah, Malaysia.

Immune checkpoint inhibitors (ICIs) – anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. Many immune-related adverse events have been linked to these agents. However, tuberculosis (TB) reactivation during their use is increasingly reported. Herein, we present a 58-year-old lady with advanced non-small cell lung cancer (NSCLC) ALK-negative, EGFR wild, and PD-L1 Immune histochemistry (IHC) strongly positive in 95% of tumor cells. The patient presented with high-grade fever and a history of productive cough for a 1-week duration. A few days later, she was diagnosed with pulmonary tuberculosis following the 6th cycle of Pembrolizumab, an anti-PD-1 monoclonal antibody. AFB smear and TB PCR from BAL were positive (rifampin resistance not detected), and she was accordingly started on Anti-TB medications. Immunotherapy was held. Of note, the patient had a history of sick contact with a patient with active TB infection ten years ago, but there was no documentation of latent TB or previous TB infection. Her HIV status is negative. Her sputum AFB smear continued to be positive after four weeks of anti-TB medications. Later, the patient was discharged after her sputum was cleared from AFB (negative x 2 sets). We assumed that our patient developed reactivation of pulmonary tuberculosis secondary to an immune checkpoint inhibitor (Pembrolizumab). She was not re-challenged with Pembrolizumab following TB diagnosis. To our knowledge, this is the first reported case from the Arab and the Middle East; it reinforces the previous observations of the association between ICIs administration and the development of MTB. Nevertheless, further studies in the clinical setting are necessary to establish the exact mechanism involved in this association. Oncologists' awareness & prompt recognition of this potential hazardous consequence are essential. Since there is no clear evidence whether LTBT prior PD-1/PD targeted immunotherapy is required, targeted LTBT before starting ICIs immunotherapy with TB chemoprophylaxis; yet to be explored, particularly in the regions where the MTB prevalence is high.

The signal transduction pathways of estrogen receptors (ER) mainly includes gene pathway and non-gene pathway. Studies have shown that the gene pathway of ER is related with the expression of nuclear proteins, and this is the key issue for our current research. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in adenocarcinoma of lung (LUAD), and the co-expression of CENPF and ERβ was found in the nucleus of LUAD cells. Meanwhile, CENPF and ERβ2/5 were related with T stage and poor prognosis (P<0.05). Knockdown of CENPF gene significantly inhibited the biological effects of LUAD cells, the tumor growth of mice and the expression of ERβ2/5 (P<0.05). Further, group experiments showed that knockdown CENPF inhibits biological effects of LUAD cells mediated by ERβ pathway. All the results indicated that both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown of CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERβ2/5 subtype and CENPF remained more effective in improving the therapeutic effect of LUAD.

The paper presents a new vision on the energy consumption management in the case of the Small and Medium Enterprises (SMEs), integrated into an advanced decision support platform, with technical and economic benefits on increasing the energy efficiency, which contains modules for database management, profiling, forecasting, and production scheduling. Inside each module, Artificial Intelligence and Data Mining techniques were proposed to remove the uncertainties regarding the dynamic of technological flows. Thus, the data management module includes the Data Mining techniques, that extract the technical details on the energy consumption needed in the development of production scheduling strategies, the profiling module uses an original approach based on clustering techniques to determine the typical energy consumption profiles required in the optimal planning of the activities, the forecasting module contains a new approach based on an expert system to forecast the total energy consumption of the SMEs, and production scheduling module integrates a heuristic optimization method to obtain the optimal solutions in flattening the energy consumption profile. The testing was done for a small enterprise from Romania, belonging to the domain of trade and repair of vehicles. The obtained results highlighted the advantages of the proposed decision support platform on the decrease in the intensity of energy consumption per unit of product, reduction of the purchase costs, and modification of the impact whom the energy bills have on the operational costs.

Importance: The COVID-19 pandemic is currently accelerating. Patients with locally advanced non-small cell lung cancer (LA-NSCLC) may require treatment in locations where resources are limited and the prevalence of infection is high. Patients with LA-NSCLC frequently present with comorbidities that increase the risk for severe morbidity and mortality from COVID-19. These risks may be further increased by treatments for LA-NSCLC. Observation: We present expert thoracic oncology multidisciplinary (radiation oncology, medical oncology, surgical oncology) consensus of alternative strategies for the treatment of LA-NSCLC during a pandemic. The overarching goals of these approaches are to reduce the number of visits to a healthcare facility, reduce the risk of SARS-CoV-2 exposure, and attenuate the immunocompromising effects of lung cancer therapies. Patients with resectable disease can be treated with definitive non-operative management if surgical resources are limited or the risks of perioperative care are high. Non-operative options include chemotherapy, chemoimmunotherapy, and radiation therapy with sequential schedules. The order of treatments may be based on patient factors and clinical resources. Whenever radiation therapy is delivered without concurrent chemotherapy, hypofractionated schedules are appropriate. For patients who are confirmed to have COVID-19, usually cancer therapies may be withheld until symptoms have resolved with negative viral test results. Conclusions and Relevance: The risk of severe treatment-related morbidity and mortality is significantly elevated for patients undergoing treatment for LA-NSCLC during the COVID-19 pandemic. Adapting alternative treatment strategies as quickly as possible may save lives and should be implemented through communication with the multidisciplinary cancer team.

Water quality retrieval for small urban waterbodies by remote sensing get used to be difficult due to coarse spatial resolution of the remote sensing imagery. The recently launched Sentinel-2 produces imagery with a spatial resolution of 10 m. It provides an opportunity to solve the problem of retrieving water quality for small waterbodies. Additionally, many water management issues also require fine resolution of imagery, e.g. illegal discharge to an urban waterbody. Since illegal discharges are an important issue for urban water management, chemical oxygen demand (COD), total phosphorous (TP), and total nitrogen (TN) were chosen as the target parameters for water quality retrieval in this study. COD, TP and TN, however, are non-optically active parameters. There were limited studies in the past to retrieve these parameters in comparison with optically active parameters, e.g. Chlorophyll-A etc. This study compared three machine learning models, namely Random Forest (RF), Support Vector Regression (SVR), and Neural Networks (NN), to investigate the opportunity to retrieve the above non-optically active parameters. Results showed that R² of TP, TN, and COD by NN, RF and SVR were 0.94, 0.88, and 0.86, respectively. The performances of water quality retrieval for these non-optically active parameters were significantly improved by the optimized machine learning models. These models hence solved the problem to use remote sensing data to retrieve these non-optically active water quality parameters and provided a new monitoring strategy for small waterbodies. Water quality mapping obtained by Sentinel-2 imagery provided a full spatial coverage of the water quality characterization for the entire water surface. Compared with water samples collecting and testing, it greatly reduced labor cost, reagents cost, and waste treatment cost. It also may help identify illegal discharges to urban waterbodies. The method developed in this research provides a new practical and efficient water quality monitoring strategy in managing water with consideration of environmental sustainability.

Land degradation is a critical issue globally putting our future generations at risk. The decrease in farm productivity over the years is evidence of land degradation severity in Nepal. Among the many strategies in place, agroforestry, which is an integrated tree-based farming, is widely recommended to address this productivity issue. This paper thoroughly examines what influences the choice of agroforestry adoption by farmers and what discourages the adoption. For this, a total of 288 households were surveyed using a structured questionnaire. Two agroforestry practices were compared with conventional agriculture with the help of the Multinomial Logistic Regression (MNL) model. The likelihood of adoption was found to be influenced by gender; the male-headed households were more likely to adopt the tree-based farming practice. Having a source of off-farm income was positively associated with the adoption decision of farmers. Area of farmland was found being the major constraint to agroforestry adoption for smallholder farmers. Some other variables that affected positively included livestock herd size, provision of extension service, home-to- forest distance, farmers’ group membership and awareness of farmers about environmental benefits of agroforestry. Irrigation was another adoption constraint that the study area farmers were faced with. The households with means of transport and with larger family (household) size were found to be reluctant towards agroforestry adoption. A collective farming practice could be a strategy to engage the smallholder farmers in agroforestry.

The operation feasibility of small hydropower plants in mountainous sites is subjected to the run-of-river flow which is also depending on a high variability in precipitation and snow cover. Moreover, the management of this kind of systems has to be performed with some particular operation conditions of the plant (e.g. turbine minimum and maximum discharge) but also some environmental flow requirements. In this context, a technological climate service is conceived in tight connection with end users, perfectly answering the needs of the management of small hydropower systems in a pilot area, and providing forecast of river streamflow together with other operation data. This paper presents an overview of the service but also a set of lessons learnt related to features, requirements and considerations to bear in mind from the point of view of climate services developers. In addition, the outcomes give insight into how this kind of services could change the traditional management (normally based on the past experience), providing a probability range of future river flow based on future weather scenarios according to the range of future weather possibilities. This highlights the utility of the co-generation process to implement climate services for water and energy fields but also that seasonal climate forecast could improve the business as usual of this kind of facilities.

Over the last three decades, special economic zones (SEZs) have given new impetus to the ever-growing export-oriented industrialization in developing countries. Where various economies have benefited from SEZs, many zones have ended up becoming enclaves with trifling advantage. The SEZs in Pakistan have experienced the same fate and failed to contribute to exports, employment and creating linkages with the domestic economy. Recently under China Pakistan Economic Corridor (CPEC), SEZs are proposed to be set up in Pakistan; with a hope to fuel the stuttering economy. However, it is pertinent to first understand the local context and device policies considering stakeholders' perspectives. This study aims to identify the factors for the successful implementation of SEZs derived from the regional context of Pakistan. In-depth interviews are conducted from most relevant stakeholders, who have been involved in the development of SEZs. The results pointed towards the removal of political influence over zones and government taking the lead role in deciding the types of industry to be invited in these zones. Each zone should have a clear vision of development based on its regional advantage. The zone promotions should be based on competitiveness rather than fiscal incentives. Joint ventures and PPP to be encouraged inside the zones for sustainable operations.

We present a summary of our protocol for employment of small-molecule circadian rhythm modulators. The abilities of compounds to affect oscillations have received significant attention. We outline assessments of circadian changes using indirubin-3’-oxime (IO), 5-iodo-indirubin-3’-oxime (5I-IO), and 5-sulfonic acid-indirubin-3’-oxime (5SA-IO), analyzing effects on Bmal1 and Per2 oscillations and oncogenic features.

Previously, we demonstrated that IR triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9, and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

“White matter disease” identifies series of different conditions and pathological mechanisms: autoimmune, infectious, toxic-metabolic and vascular. Each of these leads to a global impairment of the neural myelination process through the secondary destruction of previously myelinated structures. To date, the imaging spectrum represents an irreplaceable tool to detect these lesions, describe their distribution patterns and stage them over time. This study aims presents a pictorial review of white matter disease, from pathology to imaging spectrum, reporting current main staging systems with greater emphasis to relationship between cerebrovascular disease and white matter hyper-intensity appearance, and the newest advances in this field.

The development of nucleic acid sequencing technology and the unprecedented availability of metadata has evidenced that 45% of human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically needed. Aberrant regulation of TEs, and of human retroviral endogenous sequences (HERVs) in particular, associates with several neurologic and autoimmune diseases, including the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) frequently comorbid with fibromyalgia (FM). However, no study has yet addressed whether abnormal expression of these sequences correlates with FM. The work presented here shows, for the first time, that in fact HERVs of the H, K and W types are overexpressed in the cells of the immune system of FM patients with or without comorbid ME/CFS. The patients with increased HERV expression (N=14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. In support of our proposal that TE activation is a contributor to FM, we find that the tRNA pools are decreased in comparison to matched healthy participants (N=14). The findings reported here could explain the flu-like symptoms FM patients present with in the absence of concomitant infections. Future work towards identifying specific genomic loci differentially affected in FM and ME/CFS is granted.

After globalization, South Korea’s retail landscape has been saturated with large-scale, corporate type retails. However, recently new commercial districts composed of small retail units are returning and bringing about a change. This study sought to take note of this phenomenon and identify its features and meanings from the perspective of urban ecology. A density-distribution analysis was conducted to investigate how they were forms, and an analysis of traces on the Internet and an analysis on the types of businesses were done to identify sociocultural characteristics. Results showed that they had similar type of locations and growth patterns, that they harmoniously congregated in a form of smaller-individual stores, and that their use of similar names for their stores had an impact of branding their entire districts. It was also noted that a shared culture through social networking services served as a growth boost for their unfavorable location. The spontaneous formation of such commercial districts can be an outcome of an urban ecological process geared toward blank niches burgeoning in the current retail structure of Korea. The causes and conditions found in the cases reveal meaningful policy implications for cities facing the same urban crisis diversity.

Electrical properties of the thin films of poly(arylene ether ketone) copolymers (co-PAEKs) with the fraction of phthalide-containing units of 3, 5 and 50 mol% in the main chain were investigated by using radiation induced conductivity (RIC) measurements. Transient current signals and current-voltage (I-V) characteristics were obtained under exposing 20÷25 thick films of the co-PAEKs to monoenergetic electron pulses of the energy ranged from 3 to 50 keV in the electric field ranged from 5 to 40 V/μm. The Rose-Fowler-Vaisberg semi-empirical model based on a multiple trapping formalism was used for an analysis of the RIC data and the parameters of the highly dispersive charge carrier transport were evaluated. The analysis revealed that charge carriers moved in isolation from each other and the applied electric fields were below the threshold field triggering the switching effect (a reversible high-to-low resistivity transition) in the co-PAEK films. It was also found that the co-PAEK films due to the super-linear I-V characteristics are highly resistant to electrostatic discharges arising from the effects of ionizing radiation. This property is important for the development of protective coatings for electronic devices.

Mediterranean catchments are characterized by significant spatial and temporal hydrological variability caused by the interaction of natural as well human-induced abiotic and biotic factors. This study investigates the (non-)linearity rainfall-runoff relationship at multiple temporal scales in representative small Mediterranean catchments (i.e., < 10 km2) to achieve a better understanding of the hydrological response. Rainfall-runoff relationship was evaluated in 44 catchments at annual and event –203 events in 12 of these 44 catchments– scales. A linear rainfall-runoff relation was observed at annual scale with higher scatter in pervious than impervious catchments. Larger scattering was observed at event scale, although pervious lithology and agricultural land use promoted significant rainfall-runoff linear relations in winter and spring. These relationships were particularly analysed during five hydrological years in Es Fangar catchment (3.35 km2; Mallorca, Spain) as a temporal downscaling to assess intra-annual variability in which antecedent wetness conditions played a significant role in runoff generation.

In general, remote sensing has proven to be a powerful tool in the overall understanding of natural and anthropogenic phenomena. Satellites have become useful tools for tasks such as characterization, monitoring, and the continuous prospecting of natural resources. This research aims to analyze spatial dynamic and destructive on coral reefs area and correlation between live coral reduction and population on small islands. Landsat MSS, TM, ETM, and OLI-TIRS are used to spatial analyze of coral reef dynamics from 1972 to 2016. The image processing includes gap-filling, atmospheric correction, geometric correction, image composite (true color), water column correction, unsupervised classification, reclassification, accuracy assessment. The statistical analysis identifies the relationship between dynamic population data with a reduction of live coral, namely Principal Component Analysis (PCA) and Multiple Regression Analysis. The effect of the population shows a positive correlation with the reduction in the area of live coral, although it is significant. The fact is the practice of coral destruction on an island; it is usually not only caused or carried out by residents who live on the island but also carried out by other residents of different islands.

The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. The use of small molecules, called pharmacological chaperones (PCs), that can restore the folding, trafficking and biological activity of mutated enzymes has been extensively explored in LSDs as a therapeutic alternative. PCs have the advantage of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules, mainly based in molecules mimicking the enzyme substrates, have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of the identified PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

We propose a new estimator for creating expansion factors for survey plots in the USDA Forest Inventory and Analysis program. This is a regularized version of the raking estimator widely used in sample surveys. The regularized raking method differs from other predictive modeling methods for integrating survey and ancillary data in that it produces a single set of expansion factors that can have general purpose use to produce small area estimates and wall-to-wall maps of any plot characteristic. This method also differs from other more widely used survey techniques, such of GREG estimation, in that it is guaranteed to produce positive expansion factors. We extend the previous method here to include cross-validation, and provide a comparison to expansion factors between the regularized raking and ridge GREG survey calibration.

Membranes based on sulfonated synditoactic polystyrene were thoroughly characterized by contrast variation SANS over a wide Q-range in dry and hydrated states. The film samples were prepared by solid-state sulfonation that allowed a uniform sulfonation of only the amorphous phase while preserving the crystallinity of the membrane. The samples were loaded with different guest molecules in either the amorphous (fullerenes) or the crystalline (toluene) regions, in order to vary the neutron contrast or to reproduce the conditions enabling an increased resistance of the membranes to chemical decomposition. The use of uni-axially deformed film samples and contrast variation with different H2O/D2O mixtures allowed for the identification and characterization of different structural levels with sizes between nm and μm, which form and evolve in the membrane morphology in dry and hydrated states and produce scattering features on different detection sectors and at different detection distances after the sample, depending on their size and orientation.

This study demonstrates a global, non-parametric, non-iterative optimization of time-mean value of a kind of index vibrated by time-varying forcing. It is based on the fact that the (steady) forced vibration of non-autonomous ordinary differential equation systems is well approximated by an analytical solution when the amplitude of forcing is sufficiently small and its base state without forcing is linearly stable and steady. It is applied to optimize a time-averaged heat-transfer rate on a two-dimensional thermal convection field in a square cavity with horizontal temperature difference, and the globally optimal way of vibrational forcing, i.e. the globally optimal, spatial distribution of vibrational heat and vorticity sources, is first obtained. The maximized vibrational thermal convection corresponds well to the state of internal gravity wave resonance. In contrast, the minimized thermal convection is weak, keeping the boundary layers on both sidewalls thick.

Sustainable Development Goal (SDG) 6.2 sets an ambitious target of leaving no one without adequate sanitation by 2030. The key concern is the lack of local human and financial capital to fund the collection of reliable information to monitor progress towards the goal. As a result, national and local records may be telling a different story of the proportion of safely managed sanitation that counts towards achieving the SDGs. This paper unveils such inconsistency in sanitation data generated by urban authorities and proposes a simple approach for collecting reliable and verifiable information on access to safely managed sanitation. The paper is based on a study conducted in Babati Town Council in Tanzania. Using a smartphone-based survey tool, city health officers were trained to map 17,383 housing units in the town. A housing unit may comprise of two or more households. The findings show that 5% practice open defecation, while 82% of the housing units have some forms of sanitation. Despite the extensive coverage, only 31% of the faecal sludge generated is safely contained, while 64% is not. This study demonstrates the possibility of using simple survey tools to collect reliable data for monitoring progress towards safely managed sanitation in the towns of global south.

Beta adrenoblockers is a large class of drugs mainly used to manage abnormal heart rhythms. Over the last couples of decades, the anticancer effects of these compounds has been extensively studied. There is much evidence about their activity in non-small cell lung, pancreatic, breast, colorectal, prostate and ovarian cancer. However, the mechanism of beta blockers anticancer activity is still not known, and more detailed studies are needed. The aim of our study was to evaluate the anticancer activity of beta adrenoblockers in non-small cell lung cancer cell lines A549 and H1299. In order to find the relationship with their selectivity to beta adrenoreceptors, in our study we used selective (atenolol, betaxolol, esmolol, metoprolol) and non-selective (pindolol, propranolol and timolol) beta blockers. The effect on cell viability was evaluated by MTT assay and the activity on cell ability to form colonies was tested by clonogenic assay. The type of cell death was evaluated by cell double staining with Hoechst 33342 and Propidium iodide. The most active adrenoblockers against both tested cancer cell lines were propranolol and betaxolol. They completely inhibited lung cancer cell colony formation at 90% of EC50 (half maximal effective concentration) value. Most tested compounds induced cell death through apoptosis and necrosis. In A549 cell lines apoptosis was mainly induced while in H1299 cell line compounds induced both apoptosis and necrosis. There was no correlation established between beta adrenoblocker anticancer activity and their selectivity to beta adrenoreceptors.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies mainly originated from hormones secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout MEN-1 gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signaling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally, act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the roles and the potential therapeutic implications of gene mutations and NOTCH signaling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential roles across all NEN subtypes is required.

Management of multiple primary cancers, a not so infrequent event in oncology practice, is a critical issue due to the lack of literature . In this study, we reported the case of a patient with metachronous double metastatic non small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. She achieved a progression free survival and an overall survival (OS) of 28 months for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapies treatments displayed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. it is interesting to note that two neoplasms shared a commune mutation of B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a putative justification of the long survival of the patient considered in this report.

Activating mutations in the Epidermal Growth Factor Receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20-30% of patients do not respond or respond for a very short time (< 3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

Background: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six plasma metabolites (two plasma phosphatidylcholines [PCs]: PC aa C36:5 and PC aa 36:6 and four sphingomyelins [SMs]: SM C26:0, SM [OH] C22:1, SM [OH] C22:2, SM [OH] C24:1) with magnetic resonance imaging (MRI) features of cerebral SVD and neurodegeneration in older adults. Methods: This study included 238 older adults in the Atherosclerosis Risk in Communities study at the fifth exam. Multiple linear regression was used to assess the association of each metabolite (log-transformed) in separate models with MRI measures except lacunar infarcts, for which binary logistic regression was used. Results: Higher concentrations of plasma PC aa C36:5 had adverse associations with MRI features of cerebral SVD (odds ratio of 1.69 [95% confidence interval: 1.01, 2.83] with lacunar infarct, and beta of 0.16 log [cm³] [0.02, 0.30] with log [White Matter Hyperintensities (WMH) volume]) while higher concentrations of 3 plasma SM (OH)s were associated with higher total brain volume (beta of 12.0 cm³ [5.5, 18.6], 11.8 cm³ [5.0, 18.6], and 7.3 cm³ [1.2, 13.5] for SM [OH] C22:1, SM [OH] C22:2, and SM [OH] C24:1, respectively). Conclusions: This study identified associations between certain plasma metabolites and brain MRI measures of SVD and neurodegeneration in older adults, particularly higher SM (OH) concentrations with higher total brain volume.

Ebola Virus Disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and caused by members of the Filoviridae family. The recent large outbreak of EVD in West Africa (2013-2016), highlighted the worldwide danger of this disease and its impact on global public health and economy. The development of highly needed anti-Filoviridae antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, and therefore screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to in vitro study of Filoviridae entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus like particles, tremendously boosted both our knowledge on viral life cycle and the identification of promising anti-Filoviridae compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD.

Here we evaluate the chemistry of mineral soil solutions collected by suction lysimeters in a small mountain catchment that was affected by acidification-related spruce die-back. The aim was to obtain new insights into spatial patterns of nutrient partitioning during acidification recovery. This was achieved by comparing nutrient concentrations in soil solutions, collected along a V-shaped valley, with those in runoff. Five nests of suction lysimeters were installed in the 33-ha UDL catchment at different topographic positions (hilltops, slopes and valley). Following a 1-year equilibration, monthly samples of soil solutions were collected over a 2-year period. In the vicinity of each lysimeter nest, soil pits were excavated for a study of soil chemistry. Soil solutions were analyzed for SO42-, NO3-, DOC, NH4+, Na+, K+, Ca2+, Mg2+, and total dissolved Al concentrations, DOC and pH. For a P release estimation, ammonium oxalate extraction of soil samples was performed. Comparison of soil water data from this study with other European studies indicated that major environmentally relevant chemical species at UDL had concentrations similar to median concentrations across numerous previously acidified sites. CEC (≤ 58 meq kg-1) and BS (≤ 13 %), however, were significantly lower at UDL than at other European sites, documenting incomplete recovery from acidification. Spatial trends and seasonality in soil water chemistry support belowground inputs from mineral-stabilized legacy pollutants and soil nutrients. Seasonal variability of soil water sulfate and nitrate was significant. High nitrate in soil solutions during summer originated during the preceding dormant season, and high sulfate concentrations observed during the winter originating from recycled organic S during the summer. Higher concentrations of SO42-, NO3-, and base cations in runoff than in soil solutions may be explained by lateral surficial runoff leaching pollutants and nutrients from very shallow soil horizons. Nearly 30 years after peak acidification, solutions in mineral subsoil at UDL exhibited similar concentrations of SO42-, Ca2+ and Mg2+ as median values at the Pan-European International Co-operative Program (ICP) Forest sites, yet NO3- concentrations were an order of magnitude higher than the ICP sites. Calcium applied on soil surface by liming 32 to 11 years ago affected runoff more than soil solutions, suggesting contribution of both shallow soil water and groundwater to runoff.

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for Herg channel blockage and Ames carcinogenicity, there was considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

Since the 1970s, land subsidence has been developing rapidly in the Beijing Plain, the systematic study of its evolution mechanism is of great significance to the sustainable development of the regional economy. First, based on ENVISAT ASAT and RADARSAT2 data, the land subsidence data in Beijing Plain were obtained using permanent interferometer technology. Second, based on the GIS platform and using fishing net tools, vector data of ground settlement with different resolutions were obtained. Through a series of tests, a scale of 960 metres was selected as the research unit, and the subsidence rate of the grid was obtained from 2004 to 2015. Finally, based on the Mann-Kendall mutation test method, a trend analysis of land subsidence changes in various grids was carried out. The results showed that single-year mutation mainly distributed in the middle and lower parts of the Yongding River alluvial fan and the Chaobai River alluvial fan, mainly occurring in 2015, 2005 and 2013, respectively. The upper and middle alluvial fan of the Chaobai River, the vicinity of the emergency water source and the edge velocity of the groundwater funnel have undergone several sudden changes. Combined with hydrogeology, basic geological conditions and the impact of the South-to-North Water transfer project, we analysed the causes of the mutations in the grid. The research results can provide a basis for the study and prevention of land subsidence in this area and help to further explore the trend characteristics of land subsidence in this area.

To examine the role of RNA silencing in defense against viroid, a Dicer-like 2 and 4 (DCL2&4)—double knockdown transgenic tomato line 72E was created. The expression of endogenous DCL2 and DCL4 in line 72E decreased to about a half of the empty cassette line EC. When challenged with potato spindle tuber viroid (PSTVd), 72E allowed significantly higher level of PSTVd accumulation early in infection and showed lethal systemic necrosis. The size distribution of PSTVd-derived small RNA was significantly changed: the numbers of 21 and 22 nucleotides (nt) species in line 72E was approximately 66.7% and 5% of those in line EC, respectively. Conversely, the numbers of 24-nt species increased by 1100%. Furthermore, expression of miR398a-3p and miR398 increased 770–868% in the PSTVd-infected 72E, compared to the PSTVd-infected EC. In parallel, superoxide dismutase (SOD1) in PSTVd-infected 72E showed higher expression levels. In concert with miR398a-3p, SOD1 controls detoxification of reactive oxygen species (ROS) generated in cells. Since high levels of ROS production and its scavenging activity were observed in PSTVd-infected 72E, the lack of full-activity of DCLs was thought to have made the plant incapable to control excessive ROS production and thus resulted in to develop lethal systemic necrosis.

Computation of Common Middle Point seismic sections and their subsequent time migration and diffraction imaging provides very important knowledge about the internal structure of 3D heterogeneous geological media and are key elements for successive geological interpretation. Full-scale numerical simulation, that computes all single shot seismograms, provides a full understanding of how the features of the image reflect the properties of the subsurface prototype. Unfortunately, this kind of simulations of 3D seismic surveys for realistic geological media needs huge computer resources, especially for simulation of seismic waves’ propagation through multiscale media like cavernous fractured reservoirs. In order to significantly reduce the query of computer resources we propose to model these 3D seismic cubes directly rather than the shot-by-shot simulation with subsequent CMP stacking. To do that we modify the well known "exploding reflectors principle" for 3D heterogeneous multiscale media by use of the finite-difference technique on the base of grids locally refined in time and space. To be able to simulate realistic models and acquisition we develop scalable parallel software, which needs reasonable computational costs. Numerical results for simulation of Common Middle Points sections and their time migration are presented and discussed.

Social customer relationship management (SCRM) is a new philosophy influencing the relationship between customer and organization, where the customer gets opportunity to control relationship through social media. The paper aims on (a) identification of current level of SCRM and also on (b) influence of basic organizational characteristics on SCRM level. The data were gathered through the questionnaire distributed in 362 organization headquartered in the Czech Republic. The questionnaire comprised 54 questions focusing on the significance of marketing and CRM practices, establishing a relationship with the customer, online communities, the use of social media in marketing, and acquiring and managing information. The majority of questions were scalable and used typical five-level Likert scale. Results showed that larger firms more often set up their own online communities and manage them strategically, moreover they are able to manage information better. Contrariwise, small sized organizations use social networks as a way to establish communication with the customer more than large sized entities. Use of social media for marketing purposes is significantly higher in organizations oriented on consumer markets than on business markets.

During recent years UAVs have been increasingly used in agriculture and forestry research and application. Nevertheless, most of this work has been devoted to improving accuracy and explanatory power, often at the cost of usability and affordability. We tested a low-cost UAV and a simple workflow to apply four different greenness indices to the monitoring of pine (Pinus sylvestris and P. nigra) after-fire regeneration in a Mediterranean forest. We selected two sites and masured all pines within a pre-selected plot. Winter flights were carried out at each of the sites, at two flight altitudes (50 and 100 m). Automatically normalizing images entered an SfM based photogrammetric software for restitution and the obtained point cloud and orthomosaic processed to get a canopy height model and four different greenness indices. Sum of pine DBH was regressed on summary statistics of greenness indices and canopy height model. ExGI and GCC indices outperformed VARI and GRVI in estimating pine DBH, while canopy height model slightly improved the models. Flight altitude did not severely affect model performance. Our results show that low cost UAVs may improve forest monitoring after disturbance, even in those habitats and situations were resource limitation is an issue.

The advent of RNA-sequencing (RNA-Seq) technologies has markedly improved our knowledge and expanded the compendium of small non-coding RNAs, most of which derive from the processing of longer RNA precursors. In this review article, we will discuss about the biogenesis and function of small non-coding RNAs derived from eukaryotic ribosomal RNA (rRNA), called rRNA fragments (rRFs), and their potential role(s) as regulator of gene expression. This relatively new class of ncRNAs remained poorly investigated and underappreciated until recently, due mainly to the a priori exclusion of rRNA sequences—because of their overabundance—from RNA-Seq datasets. The situation surrounding rRFs resembles that of microRNAs (miRNAs), which used to be readily discarded from further analyses, for more than five decades, because we could not believe that RNA of such a short length could bear biological significance. As if we had not yet learned our lesson not to restrain our investigative, scientific mind from challenging widely accepted beliefs or dogmas, and from looking for the hidden treasures in the most unexpected places.

This study investigated the roles of transactions cost in MSMEs access to finance. This was done by investigating the impact of transactions cost on access to credit from both MSMEs and financial institutions (commercial banks and microfinance banks). From the MSMEs’ side, borrowing experience, decision lag, firm size and borrowers’ distance to the loan office were investigated. On the financial institution’s side, the costs of information gathering, loan administration, monitoring and loan enforcement were investigated. We used the questionnaire survey method, in-depth interviews and case studies, as well as the annual financial statements of the banks. We identified interest rate and collateral value as constraints to access to finance for MSMEs. We also found financial institutions’ attitude to MSMEs access to credit was not friendly. Financial institutions need to do more to bring down transaction cost of lending. This hopefully can be achieved by investing more in agent banking which would lower operating costs, as well as spreading risk, and ultimately increase credit intermediation to small businesses.

The increasing use of energy resources recovered from the subsurface environments and the resulting carbon imbalance in the environment has motivated the need to develop thermodynamically downhill pathways to convert and store CO₂ as water insoluble calcium or magnesium carbonates. While previous studies extensively explored aqueous routes to produce calcium and magnesium carbonates from CO₂, there has been a limited scientific understanding of the phase evolution and textural changes during the direct gas-solid conversion routes to produce calcium carbonate from calcium hydroxide, which is one of the abundant constituents of alkaline industrial residues. With increasing interest in developing integrated pathways for capturing, converting and storing CO₂ from dilute flue gases, understanding the compositions of the product phases as they evolve is essential for evaluating the efficacy of a given processing route. Therefore, in this study, we investigate the phase evolution and the corresponding textural changes as calcium hydroxide is converted to calcium carbonate under the continuous flow of CO₂ at an ambient pressure of 1 atm and on heating continuously from 30 °C to 500 °C using in-operando wide angle X-ray scattering (WAXS), small angle X-ray scattering (SAXS), and ultra-small angle X-ray scattering (USAXS) measurements.

Cogging torque is a pulsating, parasitic and undesired torque ripple intrinsic of the design of a permanent magnet synchronous generator (PMSG), which should be minimized due to its adverse effects: vibration and noise. In addition, as aerodynamic power is low during start-up at low wind speeds in small wind energy systems, the cogging torque must be as low as possible to achieve a low cut-in speed. A novel mitigation technique using compound pre-slotting, based on a combination of magnetic and non-magnetic materials, is investigated. The finite element technique is used to calculate the cogging torque of a real PMSG design for a small wind turbine, with and without using compound pre-slotting. The results show that cogging torque can be reduced by a factor of 48% with this technique, while avoiding the main drawback of the conventional pre-slotting technique: the reduction of induced voltage due to leakage flux between stator teeth. Furthermore, through a combination of pre-slotting and other cogging torque optimization techniques, 84%, cogging torque can be eliminated for a given design.

[NiFe]-hydrogenases are gas-processing metalloenzymes that catalyze the conversion of dihydrogen (H2) to protons and electrons in a broad range of microorganisms. Within the framework of green chemistry, the molecular proceedings of biological hydrogen turnover inspired the design of novel catalytic compounds for H2 generation. The bidirectional “O2-sensitive” [NiFe]-hydrogenase from Escherichia coli HYD-2 has recently been crystallized; however, a systematic infrared characterization in the presence of natural reactants is not available yet. In this study, we analyze HYD-2 from E. coli by in situ ATR FTIR spectroscopy under quantitative gas control. We provide an experimental assignment of all catalytically relevant redox intermediates alongside the O2- and CO-inhibited cofactor species. Furthermore, the reactivity and mutual competition between H2, O2, and CO was probed in real time, which lays the foundation for a comparison with other enzymes, e.g., “O2-tolerant” [NiFe]-hydrogenases. Surprisingly, only Ni-B was observed in the presence of O2 with no indications for the “unready” Ni-A state. The presented work proves the capabilities of in situ ATR FTIR spectroscopy as an efficient and powerful technique for the analysis of biological macromolecules and enzymatic small molecule catalysis.

Taking four of the United Nations Development Goals as reference, this overview describes the need to see from a systemic perspective, the food certifications programs along the food chain in Mexico as today food certifications are voluntary. Using secondary data, the main objectives were: a) there is a fall short in food safety policies and those federal agencies responsible for food safety, to guarantee safe food along the whole domestic food chain, especially in that for low income players; b) the amount of the Mexican Federal Budget Expenses devoted to safety food issues is really low, considering the health, well- being, and food security consequences; and c) due the structural heterogeneity of the Mexican food market, there is a lack of coordination in food regulations along all agents of the food supply chain, bringing to alternate informal markets that put at risk peoples´ health, increasing poverty and inequalities. According to this exercise, only 0.7- 8.7% of producers, 12.5% of supermarkets as well as 42.8% of restaurants would have some type of certifications. Public policies must attend this issue in order to improve food safety and security for the whole population, reducing inequalities, poverty and ensuring them a healthy live.

The alignment of nanostructures in materials such as lyotropic liquid crystals (LLCs) templated materials has the potential to signicantly improve their performances. However, accurately characterising and quantifying the alignement of such fine structures remains very challenging. In situ small angle X-ray scattering (SAXS) and molecular dynamics were employed for the first time to understand the hexagonal LLC alignment process with magnetic nanoparticles under a magnetic field. The enhanced alignment has been illustrated from the distribution of azimuthal intensity in the samples exposed to magnetic field. Molecular dynamics simulations reveal the relationship between the imposed force of the magenetic nanoparticles under magnetic field and the force transferred to the LLC cylinders which leads to the LLC alignment. The combinational study with experimental measurement and computational simulation will enable the development and control of nanostructures in novel materials for various applications.

This case study assessed marketing arrangements used by small scale farmers in the Lake Basin and Lower Eastern bean corridors of Kenya to determine which markets work for rural producers and what changes are needed to produce and supply sufficient quantities for trade. Using exploratory research, data was collected through focus group discussions with six farmer groups representing a total of 1255 bean farmers and key informant interviews with extension staff. The results indicated that 94% of the farmers produced beans before identifying buyers with only 6% participating in group marketing. Though spot-market transactions with brokers and traders provided ready cash for the farmers, formal buyers were perceived to be more reliable but difficult to find and, operated stringent requirements which were a barrier to entry. A theory of change to integrate smallholders into formal markets to sustainably produce and supply sufficient volumes for trade should entail a transformation agenda at four levels of the value chain: intensification of production through pure stand models with greater use of certified high yielding varieties; stable price guarantees; a market-driven research and extension service and; an enabling political, policy and business environment in the bean value chain. Further research is needed to pilot these changes in a case control study.

The aim of this study is to provide the scientists with a straightforward correlation that can be applied for predicting the Fanning friction factor and consequently the pressure drop during blood flow in small caliber vessels. Due to the small diameter of the conduit, the Reynolds numbers are low and thus the flow is laminar. The study has been conducted using CFD simulations validated with relevant experimental data acquired using an appropriate experimental set-up. The experiments concern pressure drop measurement during the flow of a blood analogue that follows the Casson model, i.e. an aqueous glycerol solution that contains a small amount of xanthan gum and exhibits similar behavior to blood, in a smooth, stainless steel microtube (L=5.6cm and D=400 μm). The interpretation of the resulting numerical data led to the proposal of a simplified model that incorporates the effect of the flow rate, the hematocrit value (35-55%) and the vessel diameter (300-1800 μm) and predicts with better than ±10% the Fanning friction factor and consequently the pressure drop during laminar blood flow in small caliber vessels.

Groundwater is an important resource for many countries and its scarcity is a major concern in small territories, especially in the islands where the constant extraction is creating a high risk of public calamity. This issue has been increasing because of the anthropogenic activities and the climate change and it has called the attention of scientists and stakeholders in order to assess the sustainability of the water management system, and therefore, to establish strategies for a more sustainable water use. San Andres island was taking as case study and a description of the water balance was carried out in order to understand the management system. Then, a water system sustainability assessment was performed with indicators such as water security, water quality, drinking water, sanitation, infrastructure, climate robustness, biodiversity, attractiveness, and governance, according to the City Blueprint Methodology. The result for the 24 evaluated indicators was a score of 3.2, whose interpretation is “an unsustainable water management”. The qualitative assessment was the base to propose water security, water quality, and governance strategies to improve the water management in the island. The assessment and its discussions are relevant for the water management in small islands across the world whose economy is based on the tourism and whose water security is at a high risk.

Purpose: To compare the efficacy and safety of graft-free short tunnel small flap (STSF) technique with that of scleral patch graft (SPG) in Ahmed glaucoma valve (AGV) implantation. Design: Randomized clinical trial. Participants: Eighty-eyes of eighty patients with medically uncontrolled glaucoma including 41 in STSF and 39 eyes in SPG. Methods: Patients were enrolled and assigned randomly to STSF or SPG. Main Outcome Measures: tube exposure, Intraocular pressure (IOP), number of glaucoma medications, best corrected visual acuity (BCVA), surgical complications, and success rate ( defined as intraocular pressure (IOP) >5 mmHg, ≤21 mmHg, and IOP reduction ≥20% from baseline at two consecutive visits after three months, no reoperation for glaucoma). Results: only one case in SPG developed tube exposure at 1-year follow-up. The cumulative probability of success during the first year of follow-up was 70% in the STSF and 65% in SPG (P = 0.36). IOP decreased significantly from 29.6 ± 8.6 mmHg at baseline to 16.4 ± 3.6 mmHg at the final follow-up in STSF (p = 0.001). The corresponding numbers for SPG were 30.9 ± 11.2 and 15.8 ± 4.7, respectively (p = 0.001). The final IOP was comparable between both groups (p = 0.65). Mean ± standard deviation of the number of glaucoma medications was 1.8 ± 0.9 in STSF and 1.6 ± 0.9 in SPG at final follow-up (P = 0.32). Postoperative complications developed in 8 patients (19%) in STSF and 9 patients (23%) in SPG (P = 0.81). Conclusions: STSF and SPG techniques had comparable complication rate at one-year follow-up. Both techniques were comparable in terms of success rate, postoperative IOP, and glaucoma medications.

Currently, companies and SMEs (small and medium enterprises) are looking to be more competitive. In order to achieve this, they are adopting new business models and strategies that allow them to move towards sustainability. Strategies such as CSR (Corporate social responsibility) and supply chain management have become essential for ensuring a company’s permanence and financial consolidation. The literature has stated that the theories of Stakeholders and Sustainability are fundamental pillars for the development and sustained growth of business. The purpose of this article is to examine the effects of CSR and the SC (supply chain) on innovation, image and reputation, and in turn, their influences on profitability in SMEs. This research is based on a sample of 143 companies in the city of Guaymas Sonora, in Mexico. For the analysis and validation of the results, we used the SEM (Structural Equation Modeling) statistical technique based on the variance, through PLS (Partial Least Squares) (using SmartPLS version 3.2.6 Professional). The findings show that SMEs that develop social and sustainable practices increase their level of innovation, and improve their image, their reputation, and their financial profitability. This work contributes mainly to the development of Stakeholders and Sustainability.

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of angiogenic therapies that treat diseases ranging from cardiovascular to cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20uM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases raging from wound healing to cancer.

Filamentous fungi such as Aspergillus spp. are opportunistic pathogens, which cause highly invasive infections, especially in immunocompromised individuals. Control of such fungal pathogens is increasingly problematic due to the small number of effective drugs available for treatment. Moreover, the increased incidence of fungal resistance to antifungal agents makes this problem a global human health issue. The cell wall integrity system of fungi is the target of antimycotic drugs echinocandins, such as caspofungin (CAS). However, echinocandins cannot completely inhibit the growth of filamentous fungal pathogens, which results in survival/escape of fungi during treatment. Chemosensitization was developed as an alternative intervention strategy, where co-application of CAS with the intervention catalyst octyl gallate (OG; chemosensitizer) greatly enhanced CAS efficacy, thus achieved ≥ 99.9% elimination of filamentous fungi in vitro. Based on hypersensitive responses of Aspergillus antioxidant mutants to OG, it is hypothesized that, besides destabilizing cell wall integrity, the redox-active characteristic of OG may further debilitate fungal antioxidant system.

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential pre-referral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA2) inhibitors and metalloprotease (MP) inhibitors.

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

With the inclusion of snakebite envenoming on the World Health Organisation’s list of Neglected Tropical Diseases, an incentive has been established to promote research and development effort in novel snakebite antivenom therapies. Different technological approaches are being pursued by different research groups, including the use of small molecule inhibitors against enzymatic toxins, as well as peptide and oligonucleotide-based aptamers and antibody-based biotherapeutics against both enzymatic and non-enzymatic toxins. In this article, the most recent advances in these fields are presented, and the advantages, disadvantages, and feasibility of using different toxin-neutralizing molecules are reviewed. Particular focus within small molecules is directed towards the inhibitors, varespladib, batimastat, and marimastat, while in the field of antibody-based therapies, novel recombinant polyclonal plantivenom technology is discussed.