REVIEW | doi:10.20944/preprints202201.0400.v1
Subject: Biology, Agricultural Sciences & Agronomy Keywords: Aflatoxin contamination; Cereals; Intrinsic factors; Extrinsic factors; Climate change; Mitigation strategies
Online: 26 January 2022 (13:12:06 CET)
Aflatoxins (AFs) contamination of cereals is considered one of the greatest food safety concerns worldwide. Occurrence of AFs in maize, wheat, rice and sorghum is highly prevalent with each commodity accounting for more than 10% of world’s AF exposure. Their occurrence as food contaminants is also associated with huge economic losses. AFs are highly stable compounds that cannot be eliminated by regular processing of grains. Hence, prevention of AFs in food and feed is now considered more important than the subsequent interventions to mitigate the deleterious health effects of AFs in human and animals. However, the development of an effective preventive strategy hinges on a clear understanding of the underlying factors influencing AFs production. Therefore, the present review aims to highlight the most significant factors influencing AFs contamination of cereals at pre-and post-harvest stages. This is crucial for effective monitoring of critical control points and optimisation of preventive strategies in food and feed supply chains. Several intrinsic and extrinsic factors have been reported of which nutritional composition, environmental factors (temperature, water activity and relative humidity) and climate change have been identified as primary factors, while pH of the substrate, carbon dioxide (CO2) levels in the gaseous environment, and agronomic and socioeconomic status are the main secondary factors promoting AFs biosynthesis in cereals. Additionally, an overview of global occurrence of AFs in cereals, with their health impacts and various preventive measures have also been highlighted.
ARTICLE | doi:10.20944/preprints202110.0309.v1
Subject: Physical Sciences, General & Theoretical Physics Keywords: intrinsic perception; Hausdorff dimension; fractal
Online: 21 October 2021 (13:54:24 CEST)
In this speculative analysis, interdimensionality is introduced as the (co)existence of universes embedded into larger ones. These interdimensional universes may be isolated or intertwined, suggesting a variety of interdimensional intrinsic phenomena that can only be understood in terms of the outer, extrinsic reality.
REVIEW | doi:10.20944/preprints201810.0616.v1
Subject: Life Sciences, Molecular Biology Keywords: peptidylprolyl isomerase; chaperone; immunophilin; extremophile; intrinsic disorder
Online: 26 October 2018 (05:20:51 CEST)
The dual-family peptidylprolyl cis-trans isomerases (immunophilins) represent naturally occurring chimera of classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker, and are found exclusively in monocellular organisms. The modular builds of these molecules represent two distinct types: CYN-(linker)-FKBP and FKBP-3TPR-CYN. Abbreviated respectively as CFBP and FCBP, the two classes also exhibit distinct organism preference, the CFBP being found in prokaryotes, and FCBP, in eukaryotes. This review summarizes the mystery of these unique class of prolyl isomerases, focusing on their host organisms, potential physiological role, and likely routes of evolution.
ARTICLE | doi:10.20944/preprints201805.0254.v1
Online: 18 May 2018 (05:21:32 CEST)
The patterns of food consumption in general and those of meat, in particular, are constantly changing. These changes are due not only to socio-economic and cultural trends that affect the whole society but also to the specific lifestyles of consumer groups. Due to the importance of consumer lifestyle, the objectives of this study were i) to identify the profiles of lamb meat consumers according to their orientation toward convenience, as defined by their eating and cooking habits; ii) to characterize these profiles according to their socio-economic characteristics and their preferences regarding the intrinsic and extrinsic quality signals of lamb meat; and iii) to analyze the willingness to pay for lamb confit. In this study, four types of consumers have been differentiated according to their lifestyles related to lamb consumption. These groups, due to their characteristics, could be called "Gourmet", "Disinterested", "Conservative" and "Basic". The Gourmet group has characteristics that make it especially interesting to market a product such as lamb confit; however, this group is unaware of this product. Therefore, a possible strategy to expand the commercialization of light lamb and the confit product would be guided marketing to this niche market.
ARTICLE | doi:10.20944/preprints201804.0243.v1
Subject: Materials Science, Polymers & Plastics Keywords: acrylamide; microwave assistance; intrinsic viscosity; flocculant; phenol removal
Online: 18 April 2018 (15:48:27 CEST)
A composite flocculant P(AM–DMDAAC) was synthesized by the copolymerization of acrylamide (AM) and dimethyl diallyl ammonium chloride (DMDAAC). Using microwave (MV) assistance with ammonium persulfate as initiator, the synthesis provided short reaction time and better solubility product. Nuclear magnetic resonance spectroscopy (1H NMR and 13C NMR), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and differential thermal analysis-thermo gravimetric analyzer (DTA-TGA) were used to determine the structure and morphology of P(AM–DMDAAC). Parameters affecting the intrinsic viscosity ([η]) of P(AM–DMDAAC), such as microwave time, mass ratio of DMDAAC to AM, initiator ammonium persulfatedosage, sodium benzoate dosage, bath time, reaction temperature and pH value were examined. Results showed that the optimum synthesis conditions were microwave time 1.5 min, m(DMDAAC): m(AM) is 4:16, 0.5 wt‰ initiator, 0.4 wt‰ EDTA, 0.3 wt‰ sodium benzoate, 2 wt‰ urea, 4 h bath time, 4.0h reaction time and pH 2. To study the removal of phenol by P(AM–DMDAAC), the influence of flocculant dose, pH value and the stirring speed were investigated, with optimization providing 99.8 % removal.
ARTICLE | doi:10.20944/preprints202012.0600.v1
Subject: Engineering, Automotive Engineering Keywords: Natural language processing; Extrinsic evaluation; Intrinsic evaluation; Word analogy; Word embedding
Online: 23 December 2020 (17:26:11 CET)
Distributional word vector representation orword embedding has become an essential ingredient in many natural language processing (NLP) tasks such as machine translation, document classification, information retrieval andquestion answering. Investigation of embedding model helps to reduce the feature space and improves textual semantic as well as syntactic relations.This paper presents three embedding techniques (such as Word2Vec, GloVe, and FastText) with different hyperparameters implemented on a Bengali corpusconsists of180 million words. The performance of the embedding techniques is evaluated with extrinsic and intrinsic ways. Extrinsic performance evaluated by text classification, which achieved a maximum of 96.48% accuracy. Intrinsic performance evaluatedby word similarity (e.g., semantic, syntactic and relatedness) and analogy tasks. The maximum Pearson (ˆr) correlation accuracy of 60.66% (Ssˆr) achieved for semantic similarities and 71.64% (Syˆr) for syntactic similarities whereas the relatedness obtained 79.80% (Rsˆr). The semantic word analogy tasks achieved 44.00% of accuracy while syntactic word analogy tasks obtained 36.00%
ARTICLE | doi:10.20944/preprints202107.0554.v1
Subject: Biology, Other Keywords: SARS-CoV-2; ORF10; Co-mutations; Intrinsic Protein Disorder; Ubiquitin Ligase Complex
Online: 26 July 2021 (09:07:38 CEST)
The devastating impact of the ongoing coronavirus disease 2019 (COVID-19) on public health, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has made fighting of the COVID-19 pandemic is a top priority in medical research and pharmaceutical development. Surveillance of SARS-CoV-2 mutations is essential for the comprehension of SARS-CoV-2 variant diversity and their impact on virulence and pathogenicity. The SARS-CoV-2 open reading frame 10 (ORF10) protein interacts with multiple human proteins CUL2, ELOB, ELOC, MAP7D1, PPT1, RBX1, THTPA, TIMM8B, and ZYG11B expressed in the lung tissues. Mutations and co-mutations in the emerging SARS-CoV-2 ORF10 variants are expected to impact the severity of the virus and its associated consequences. In this article, We highlight 128 single mutations and 35 co-mutations in the unique SARS-CoV-2 ORF10 variants in this article. The possible predicted effects of these mutations and co-mutations on the secondary structure of ORF10 variants and host protein interactomes are presented. The findings highlight the possible effects of mutations and co-mutations on the emerging 140 ORF10 unique variants from secondary structure and intrinsic protein disorder perspectives.
ARTICLE | doi:10.20944/preprints202208.0531.v1
Subject: Life Sciences, Virology Keywords: Rabies; intrinsic disorder; intrinsically disordered protein; intrinsically disordered protein region; protein-protein interaction
Online: 31 August 2022 (03:47:31 CEST)
Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host’s immune response once it has entered the cells of the brain, making death likely. This study aims to make use of disorder-based proteomics and bioinformatics to determine the impact that intrinsically disordered protein regions (IDPRs) in the proteome of the rabies virus have on the infectivity and lethality of the disease. This study uses the proteome of Rabies Lyssavirus (RABV) strain Pasteur Vaccins (PV), one of the best understood strains due to its use in the first rabies vaccine, as a model. The study suggests that the high levels of intrinsic disorder in the phosphoprotein (P-protein) and nucleoprotein (N-protein) allow them to participate in creation of the Negri bodies and help this virus suppress the antiviral immune response in the host cells. Additionally, the study suggests that there is a link between disorder in the matrix (M) protein and the modulation of viral transcription. The disordered regions in the M protein have a possible role in initiating viral budding within the cell. Furthermore, we checked the prevalence of functional disorder in a set of 37 host proteins directly involved in the interaction with the RABV proteins. The hope is that these new insights will aid in the development of treatments for rabies that are effective after infection.
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: EGFR-mutated non-small cell lung cancer; EGFR-TKI; intrinsic resistance; resistance mechanisms
Online: 22 April 2019 (11:08:42 CEST)
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.
ARTICLE | doi:10.20944/preprints202107.0012.v1
Subject: Engineering, Automotive Engineering Keywords: Air Handling Unit; Battery Room; HVACS; Network Control Panel; and Intrinsic Safe Barrier Module
Online: 1 July 2021 (11:11:23 CEST)
Lead-acid batteries utilised in electrical substations release hydrogen and oxygen when these are charged. These gases could be dangerous and cause a risk of fire if they are not properly ventilated. Therefore, this research seeks to design and implement a network control panel for heating, ventilation, and air-conditioning systems (HVACS). This is done using a specific range of controllers, which have more than thirty loops of proportional, integral and derivative (PID) control to achieve a cost-effective design. It performs the required function of extracting hydrogen, oxygen, and maintaining the desired temperature of the battery storage room within the recommended limits (i.e. 25°C ±1°C tolerance) without compromising quality as set out in the user requirement specification in Appendix-A. The system control panel allows the user to access control parameters such as changing temperature set-points, fan-speed, sensor database amongst others. The hardware is configured to detect extreme hydrogen and oxygen gas content in the battery room and ensure that the HVACS extract the gas content to the outside environment. The results of the system show that the network control panel effectively operates as per the recommended system requirements. Therefore, the effective operation of the HVACS ensures sufficient gas ventilation, thus mitigating the risk of fire in a typical battery storage room. Furthermore, the effective operation of HVACS enhances battery lifespan because of regulated operating temperature, which is conducive to minimise the effect of sulfation in lead acid Batteries (LABs).
ARTICLE | doi:10.20944/preprints202011.0036.v1
Subject: Social Sciences, Microeconomics And Decision Sciences Keywords: Cultural Heritage; Adaptive Reuse; Urban Regeneration; Community-Based Approach; Decision-Making Process, Intrinsic Value
Online: 2 November 2020 (11:36:31 CET)
The international debate on the adaptive re-use of cultural heritage sites following the Sustainable Development Goals becomes more central than ever in the implementation of circular economy models for urban policies. The new values that characterise the cultural assets, considered as the result of a collaborative process, can enhance both the manufactured capital and the human capital, and to carry out the system of relationships that bind them. At the same time, the values of historical-artistic assets and produced by community-based regeneration processes are particularly relevant when they characterise abandoned commons and cult buildings, to which communities attribute an identity and symbolic value. Starting from the definition of the concept of Complex Social Value, we propose a methodological process that combines approaches and techniques typical of deliberative evaluations and collaborative decision-making processes. The aim is to identify the complex value chains generated by adaptive re-use, in which intrinsic values can play a driving role in the regeneration strategies of discarded cultural heritage. The experimentation, tested with the project “San Sebastiano del Monte dei Morti Living Lab” (SSMOLL), activates a creative and cultural Living Lab in the former church of “Morticelli”, in the historic centre of Salerno, in southern Italy. The re-use project is part of a more comprehensive process of social innovation and culture-led urban regeneration triggered in Salerno starting from SSMOLL.
ARTICLE | doi:10.20944/preprints201611.0052.v1
Subject: Physical Sciences, Acoustics Keywords: empirical mode decomposition; intrinsic mode function; permutation entropy; multi-scale permutation entropy; feature extraction
Online: 9 November 2016 (10:24:35 CET)
In order to solve the problem of feature extraction of underwater acoustic signals in complex ocean environment, a new method for feature extraction from ship radiated noise is presented based on empirical mode decomposition theory and permutation entropy. It analyzes the separability for permutation entropies of the intrinsic mode functions of three types of ship radiated noise signals, and discusses the permutation entropy of the intrinsic mode function with the highest energy. In this study, ship radiated noise signals measured from three types of ships are decomposed into a set of intrinsic mode functions with empirical mode decomposition method. Then, the permutation entropies of all intrinsic mode functions are calculated with appropriate parameters. The permutation entropies are obviously different in the intrinsic mode functions with the highest energy, thus, the permutation entropy of the intrinsic mode function with the highest energy is regarded as a new characteristic parameter to extract the feature of ship radiated noise. After that, the characteristic parameters, namely, the energy difference between high and low frequency, permutation entropy, and multi-scale permutation entropy, are compared with the permutation entropy of the intrinsic mode function with the highest energy. It is discovered that the four characteristic parameters are at the same level for similar ships, however, there are differences in the parameters for different types of ships. The results demonstrate that the permutation entropy of the intrinsic mode function with the highest energy is better in separability as the characteristic parameter than the other three parameters by comparing their fluctuation ranges and the average values of the four characteristic parameters. Hence, the feature of ship radiated noise can be extracted efficiently with the method.
REVIEW | doi:10.20944/preprints202101.0337.v1
Subject: Life Sciences, Biochemistry Keywords: Diffuse intrinsic pontine glioma; molecular biology; patient derived xenografts; genetically engineered mouse model; humanized mouse model
Online: 18 January 2021 (12:50:14 CET)
Diffuse intrinsic pontine gliomas (DIPGs) account for ~15% of pediatric brain tumors, which invariably present with poor survival regardless of treatment mode. Several seminal studies have revealed that 80% of DIPGs harbor H3K27M mutation coded by HIST1H3B, HIST1H3C and H3F3A genes. The H3K27M mutation has broad effects on gene expression and is considered a tumor driver. Determination of the effects of H3K27M on posttranslational histone modifications and gene regulations in DIPG is critical for identifying effective therapeutic targets. Advanced animal models play critical roles in translating these cutting-edge findings into clinical trial development. Here, we review current molecular research progress associated with DIPG. We also summarize DIPG animal models, highlighting novel genomic engineered mouse models (GEMMs) and innovative humanized DIPG mouse models. These models will pave the way towards personalized precision medicine for the treatment of DIPGs.
ARTICLE | doi:10.20944/preprints201808.0036.v1
Subject: Life Sciences, Microbiology Keywords: ESKAPE-bacteria; persistence; resistance; Intrinsic/Acquired/ Multidrug (MDR) and Pan – Resistance; genetic background; experimental evolution; collateral sensitivity; agrocin
Online: 2 August 2018 (06:29:07 CEST)
The challenge posed by multi-drug resistance (MDR) of pathogenic organisms, spectacularly manifested in the 6 “ESKAPE” bacterium (two Gram-positive, four Gram-negative) species, should invoke new comprehensive strategies, and needs cooperation of scientists with medical, veterinary and natural science background. This review is aimed at informing newcomers, coming from the field of biology and genetics, about problems related to rapidly emerging, new multi-drug resistant, pathogenic, bacteria. Unlike persistence, the antibiotic resistance is inherited. A functioning “resistance gene” makes a susceptible organism resistant to a given antibiotic, encoding for polypeptides capable of acting either as decomposing enzymes, or acting as trans-membrane pumps, or membrane structure components capable of modifying the permeability implementing a «by pass» mechanism enabling the antibiotic molecule to reach its cellular target(s). A functioning “sensitivity gene” encode for a polypeptide, capable (directly or indirectly) of transferring toxic molecules into target cells, or of metabolizing non-transferable to transferable, or non-toxic molecules to toxic derivatives. A gene of a normal function could act as a “sensitivity” gene in the presence of antibiotics of chemical structures similar to the natural substrate of the gene product, (enzyme or binding/ trans-membrane protein). The Agrocin 84 story is a good example. Multi-drug resistance is a phenotypic consequence of the sequential accumulation of mutations, and/or up-take of plasmids or genomic islands carrying resistance genes from the environment via horizontal gene transfer, mediated by conjugative plasmid or bacteriophage carrying mobile genetic elements. Both multi-drug resistance and collateral sensitivity are evolutionary products. Some revealed evolutionary process and their Lamarckian and Darwinian interpretations are discussed. Toolkits of comparative full-genome sequencing, genomics, experimental evolution and population genetics may provide perspectives for overcoming the invincibility of multi-drug panresistance. The status of some recently emerging pathogenic bacterium species with zoonic features and of veterinary background is also discussed.
Subject: Keywords: Pangolin; Intrinsic; Disorder; Protein; Nucleocapsid; Virulence; Shell; Covid; Coronavirus; Vaccine; Immune; Antibody; Shell; Nucleoprotein; Matrix; Attenuate; Severe Acute Respiratory
Online: 4 May 2021 (16:24:51 CEST)
SARS-CoV-2 was empirically and computationally found to be of a specific but peculiar evolution. Shell disorder models found that the outer shell (M protein) of SARS-CoV-2 to be among the hardest in its CoV family. The hard outer shell (low M percentage of disorder (PID)) is likely to be related to the SARS-CoV-2 resistance to the antimicrobial enzymes in saliva and mucus, and be responsible for the high-level of viral shedding which has been observed clinically. Experimental studies have also shown that SARS-CoV-2 is more resilient in the environment than many other CoVs, including SARS-CoV-1. Another aspect of the shell disorder models predicts that SARS-CoV-1 is more virulent than SARS-CoV-2 because of higher inner shell disorder (N PID) that helps SARS-CoV-1 replicate faster in vital organs despite being of lesser viral loads in the saliva and mucus, unlike SARS-CoV-2. This has been reaffirmed experimentally, where higher levels (50 folds) of infectious particles were detected in the SARS-CoV-1 samples in comparison with those of SARS-CoV-2. The hard outer shell of SARS-CoV-2 has been found to be associated with burrowing animals, particularly pangolins, which are often in contact with buried feces. For these reasons, the M protein is highly conserved among close relatives of SARS-CoV-2. The phylogenetic tree using M, unlike the genome-wide one, shows that pangolin-CoVs are more closely related to SARS-CoV-2 than bat-RaTG13. Previous phylogenetic studies may have been confused by recombinations that are usually poorly handled. According to the shell disorder models based on the N PID, an attenuated COVID-19 strain is likely to have entered humans via pangolins in 2017 or before, which provides the virus enough time to adapt to humans. This could explain why the SARS-CoV-2 S protein is highly adapted to the human ACE-2. The specific but peculiar evolution has a wide range of clinical, immunological, and epidemiological implications.
ARTICLE | doi:10.20944/preprints202104.0427.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Intrinsic capacity; integrated care; multi-domain intervention; physical exercise; nutrition; psy-chological wellbeing; frailty; complex intervention; intervention development study
Online: 15 April 2021 (18:22:44 CEST)
The World Health Organization has developed the Integrated Care of Older People (ICOPE) strategy, a program based on the measurement of intrinsic capacity (IC) as “the composite of all physical and mental attributes on which an individual can draw”. Multicomponent interventions appear to be the more effective approach to enhance IC and to prevent frailty and dependence, being adapted physical activity is the preventive intervention that has shown more evidence in the treatment of frailty and risk of falls. The present study aims to describe the development of a multi-domain group-based intervention addressed to frail older people living in the community aimed to improve and/or maintain intrinsic capacity by means of promoting physical activity, healthy nutrition, and psychological wellbeing in frail older people. We used the GUIDED checklist to describe the development process of AMICOPE (Aptitude Multi-domain group-based intervention to improve and/or maintain IC in frail Older PEople). The intervention was built upon the ICOPE framework and it is described with Template for Intervention Description and Replication (TIDieR) guidelines and it includes dietary advice, cognitive stimulation strategies, medication review, goal setting, and activities to strengthen social support and manage depressive symptoms, as well as strength, balance and flexibility exercise using the Vivifrail program. The study represents the first stage of the UK Medical Research Council framework for developing and evaluating a complex intervention. The next step should be carrying out a feasibility study for the AMICOPE intervention, and in a later stage, assessing the effectiveness in a randomized controlled trial.
REVIEW | doi:10.20944/preprints202208.0065.v1
Subject: Biology, Other Keywords: EPR spectroscopy; double electron electron resonance; FRET; ensemble model; intrinsic disorder; structural biology; site-directed spin labelling; molecular force fields
Online: 2 August 2022 (11:21:32 CEST)
Labelling techniques such as electron paramagnetic resonance spectroscopy and single-molecule fluorescence resonance energy transfer, allow access to distances in the range of tens of angstroms, corresponding to the size of proteins and small to medium-sized protein complexes. Such measurements do not require long-range ordering and are therefore applicable to systems with partial disorder. Data from spin-label-based measurements can be processed into distance distributions that provide information about the extent of such disorder. Using such information in modelling presents several challenges, including a small number of restraints, the influence of the label itself on the measured distance and distribution width, and balancing the fitting quality of the long-range restraints with the fitting quality of other restraint subsets. Starting with general considerations about integrative and hybrid structural modelling, this review provides an overview of recent approaches to these problems and identifies where further progress is needed.
ARTICLE | doi:10.20944/preprints201808.0298.v1
Subject: Biology, Physiology Keywords: Heterodimeric G protein coupled receptor; saturation transfer difference nuclear magnetic resonance spectroscopy; differential scanning calorimetry; circular dichroism; intrinsic fluorescence spectroscopy
Online: 17 August 2018 (11:15:39 CEST)
Taste signaling is a complex process that is linked to obesity and its associated metabolic syndromes. The sweet taste is mediated through a heterodimeric G protein coupled receptor (GPRC) in a species-specific manner and at multi-tissue specific levels. The sweet receptor recognizes a large number of ligands with structural and functional diversities to modulate different amplitudes of downstream signaling pathway(s). The human sweet-taste receptor has been extremely difficult to study by biophysical methods due to inadequate methods for producing large homogeneous quantities of the taste-receptor protein and a lack of reliable in vitro assays to precisely measure productive ligand binding modes leading to activity upon their interactions with the receptor protein. We report a multimodal high throughput assays to monitor ligand binding, receptor stability and conformational changes to model the molecular interactions between ligand-receptor. We applied saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR) complemented by differential scanning calorimetry (DSC), circular dichroism (CD) spectroscopy, and intrinsic fluorescence spectroscopy (IF) to characterize binding interactions. Our method using complementary NMR and biophysical analysis is advantageous to study the mechanism of ligand binding and signaling processes in other GPCRs.
ARTICLE | doi:10.20944/preprints202204.0183.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: resistant TNBC; intra-tumoral heterogeneity; breast cancer relapse; breast cancer epigenome; me-tastasis prevention; intrinsic resistance of cancer; tumor adaptability; targeting resistant cancer
Online: 20 April 2022 (04:16:31 CEST)
We previously described a model of deep intrinsic resistance of breast cancer wherein we used a function-based approach to selection of cancer cells that can survive a variety of challenges in prolonged but reversible quiescence. Our experimental results suggested that resistant cancer cells possess a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in our breast cancer model. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than was the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of our experimental strategy for evaluating anticancer agents such as JIB-04 that may halt cancer evolution and prevent development of cancer resistance to currently used therapies.
REVIEW | doi:10.20944/preprints202011.0290.v1
Subject: Keywords: plant diversity; plant productivity; humped pattern; intrinsic rate of species richness; complementary effect; resource availability; disturbance; species pool effect; competition exclusion; process integration
Online: 10 November 2020 (08:28:28 CET)
The plant productivity-richness relationship (PPR) is one of the most debated and important issues in ecology. There have been distinct stages in the research of this issue, including the discovery of the different PPR shapes, respective tests of influencing processes, and integrative research with vegetation investigation, manipulation experiments, and theoretical analysis. The debate largely focuses on what the dominant shapes and underlying mechanisms are. Recent integrative research works following analyses of respective processes affecting PPR have found that the humped, asymptotic, positive, negative, and irregular shapes of PPR are linked to each other. One shape of PPR may change into another. The balance between positive and negative processes determines the different shapes of PPR. Plant diversity has a globally positive effect on plant productivity.
Subject: Keywords: pangolin; intrinsic; disorder; protein; nucleocapsid; Nipah; virulence; viral protein; protein structure; protein function; shell; covid; coronavirus; ebola; vaccine; immune; antibody; shell; nucleoprotein; matrix; attenuate
Online: 28 June 2020 (09:16:27 CEST)
A model to predict the relative levels of respiratory and fecal-oral transmission potentials of coronaviruses (CoVs) by measuring the percentage of protein intrinsic disorder (PID) of the M (Membrane) and N (nucleoprotein) proteins in their outer and inner shells, respectively, was built before the MERS-CoV outbreak. Application of this model to the 2003 SARS-CoV indicated that this virus with MPID = 8.6% and NPID = 50.2% falls into group B, which consists of CoVs with intermediate levels of both fecal-oral and respiratory transmission potentials. Further validation of the model came with MERS-CoV (MPID = 9%, NPID = 44%) and SARS-CoV-2 (MPID = 5.5%, NPID = 48%) falling into the groups C and B, respectively. Group C contains CoVs with higher fecal-oral but lower respiratory transmission potentials. Unlike SARS-CoV, SARS-CoV-2 with MPID = 5.5% has one of the hardest outer shells among CoVs. This shell hardness is believed to be responsible for high viral loads in the mucus and saliva making it more contagious than SARS-CoV. The hard shell is able to resist the anti-microbial enzymes in body fluids. Further searches have found that high rigidity of outer shell is characteristic for the CoVs of burrowing animals, such as rabbits (MPID = 5.6%) and pangolins (MPID = 5-6%), which are in contact with the buried feces. A closer inspection of pangolin-CoVs from 2017-19 reveals that these animals provided a unique window of opportunity for the entry of an attenuated SARS-CoV-2 precursor into the human population in 2017 or earlier, with the subsequent slow and silent spread as a mild cold that followed by its mutations into the current more virulent form. Evidence of this lies in the similarity of shell disorder and genetic proximity of the pangolin-CoVs to SARS-CoV-2 (~90%). A 2017 pangolin-CoV strain shows evidence of higher levels of attenuation and higher fecal-oral transmission associated with lower human infectivity via having lower NPID (44.8%). Our shell disorder analysis also revealed that lower inner shell disorder is associated with the lesser virulence in a variety of viruses.
Subject: Keywords: intrinsic; disorder; protein; nucleocapsid; Nipah; virulence; viral protein; protein structure; protein function, shell; covid; coronavirus; ebola; vaccine; immune; antibody; shell; nucleocapsid; nucleoprotein; matrix; attenuate;
Online: 7 May 2020 (10:04:51 CEST)
A model that predicts levels of coronavirus (CoV) respiratory/fecal-oral transmission potentials based on the outer shell hardness has been built using neural network (artificial intelligence, AI) analysis of the percentage of disorder (PID) in the nucleocapsid, N, and membrane, M, proteins of the inner and outer viral shells, respectively. Based mainly on the PID of N, SARS-CoV-2 is categorized as having intermediate levels of both respiratory and fecal oral transmission potential. Related to this, other studies have found strong positive correlations between virulence and inner shell disorder among numerous viruses, including Nipah, Ebola, and Dengue viruses. There is some evidence that this is also true for SARS-CoV-2 and SARS-CoV, which have N PIDs of 48% and 50%, and are characterized by case-fatality rates of 7.1% and 10.9%, respectively. The link between levels of respiratory transmission and virulence lies in viral load of body fluids and organ respectively. A virus can be infectious via respiratory modes only if the viral loads in saliva and mucus exceed certain minima. Likewise, a person may die, if the viral load is too high especially in viral organs. Inner shell proteins of viruses play important roles in the replication of viruses, and structural disorder enhances these roles by providing greater efficiency in protein-protein/DNA/RNA/lipid binding. This paper outlines a novel strategy in attenuating viruses involving comparison of disorder patterns of inner shells of related viruses to identify residues and regions that could be ideal for mutation. The M protein of SARS-CoV-2 has one of the lowest M PID values (6%) in its family, and therefore this virus has one of the hardest outer shells, which makes it resistant to antimicrobial enzymes in body fluid. While this is likely responsible for its contagiousness, the risks of creating an attenuated virus with a more disordered M are discussed.
COMMUNICATION | doi:10.20944/preprints202007.0709.v1
Subject: Biology, Other Keywords: intrinsic multi-drug resistance; acquired multi-drug resistance; circulating tumor cells; single cells; cell clusters; cell monolayer; multi-cellular spheroids; cytometry of reaction rate constant; ovarian cancer
Online: 30 July 2020 (09:01:50 CEST)
Does cell clustering influence intrinsic and acquired multi-drug resistance (MDR) differently? To address this question, we studied cultured monolayers (representing individual cells) and cultured spheroids (representing clusters) formed by drug-naïve (intrinsic MDR) and drug-exposed (acquired MDR) lines of ovarian cancer A2780 cells by cytometry of reaction rate constant (CRRC). MDR efflux was characterized by accurate and robust “cell number vs. MDR efflux rate constant (kMDR)” histograms. Both drug-naïve and drug-exposed monolayer cells presented unimodal histograms; the histogram of drug-exposed cells was shifted towards higher kMDR value suggesting greater MDR activity. Spheroids of drug-naïve cells presented a bimodal histogram indicating the presence of two subpopulations with different MDR activity. In contrast, spheroids of drug-exposed cells presented a unimodal histogram qualitatively similar to that of the monolayers of drug-exposed cells but with a moderate shift towards greater MDR activity. The observed greater effect of cell clustering on intrinsic than on acquired MDR can help guide the development of new therapeutic strategies targeting clusters of circulating tumor cells.
ARTICLE | doi:10.20944/preprints201910.0227.v1
Subject: Earth Sciences, Oceanography Keywords: lagrangian drifter; rafos floats; empirical model decomposition (emd); deterministic-stochastic emd; intrinsic mode function (imf); eddy radial scale; eddy velocity scale; eddy rossby number; eddy-current kinetic energy ratio
Online: 19 October 2019 (16:41:37 CEST)
Deterministic-stochastic empirical mode decomposition (EMD) is used to obtain low-frequency (non-diffusive, i.e., background velocity) and high-frequency (diffusive, i.e., eddies) components from a Lagrangian drifter‘s trajectory. Eddy characteristics are determined from the time series of eddy trajectories from individual Lagrangian drifter such as the eddy radial scale, eddy velocity scale, eddy Rossby number, and eddy-background kinetic energy ratio. A long-term dataset of the SOund Fixing And Ranging float time series obtained near the California coast by the Naval Postgraduate School from 1992 to 2004 at depth between 150 and 600 m (http://www.oc.nps.edu/npsRAFOS/) is used as an example to demonstrate the capability of the deterministic-stochastic EMD.