Biological Usage Research Articles

Amidation strategy for final-step α-hydroxytropolone diversification

α-Hydroxytropolones (αHTs) are excellent metalloenzyme-inhibiting fragments that have been the basis for the development of potent inhibitors of various therapeutically important enzymes. The following manuscript describes a final-step amidation approach for αHT diversification. The method takes advantage of a scalable, chromatography-free synthesis of a carboxylic acid-appended αHT, and the present manuscript describes the conversion of this compound to eight amide-containing αHTs, three of which should be useful as chemical probes. This general strategy is expected to find widespread usage in both chemical biology and medicinal chemistry studies on αHTs.

Wild-type Kras expands and exhausts hematopoietic stem cells.

Oncogenic Kras expression specifically in hematopoietic stem cells (HSCs) induces a rapidly fatal myeloproliferative neoplasm in mice, suggesting that Kras signaling plays a dominant role in normal hematopoiesis. However, such a conclusion is based on expression of an oncogenic version of Kras. Hence, we sought to determine the effect of simply increasing the amount of endogenous wild-type Kras on HSC fate. To this end, we utilized a codon-optimized version of the murine Kras gene (Krasex3op) that we developed, in which silent mutations in exon 3 render the encoded mRNA more efficiently translated, leading to increased protein expression without disruption to the normal gene architecture. We found that Kras protein levels were significantly increased in bone marrow (BM) HSCs in Krasex3op/ex3op mice, demonstrating that the translation of Kras in HSCs is normally constrained by rare codons. Krasex3op/ex3op mice displayed expansion of BM HSCs, progenitor cells, and B lymphocytes, but no evidence of myeloproliferative disease or leukemia in mice followed for 12 months. BM HSCs from Krasex3op/ex3op mice demonstrated increased multilineage repopulating capacity in primary competitive transplantation assays, but secondary competitive transplants revealed exhaustion of long-term HSCs. Following total body irradiation, Krasex3op/ex3op mice displayed accelerated hematologic recovery and increased survival. Mechanistically, HSCs from Krasex3op/ex3op mice demonstrated increased proliferation at baseline, with a corresponding increase in Erk1/2 phosphorylation and cyclin-dependent kinase 4 and 6 (Cdk4/6) activation. Furthermore, both the enhanced colony-forming capacity and in vivo repopulating capacity of HSCs from Krasex3op/ex3op mice were dependent on Cdk4/6 activation. Finally, BM transplantation studies revealed that augmented Kras expression produced expansion of HSCs, progenitor cells, and B cells in a hematopoietic cell-autonomous manner, independent from effects on the BM microenvironment. This study provides fundamental demonstration of codon usage in a mammal having a biological consequence, which may speak to the importance of codon usage in mammalian biology.

Unraveling the Enzymatic Activity of Oxygenated Carbon Nanotubes and Their Application in the Treatment of Bacterial Infections.

Carbon nanotubes (CNTs) and their derivatives have emerged as a series of efficient biocatalysts to mimic the function of natural enzymes in recent years. However, the unsatisfiable enzymatic efficiency usually limits their practical usage ranging from materials science to biotechnology. Here, for the first time, we present the synthesis of several oxygenated-group-enriched carbon nanotubes (o-CNTs) via a facile but green approach, as well as their usage as high-performance peroxidase mimics for biocatalytic reaction. Exhaustive characterizations of the enzymatic activity of o-CNTs have been provided by exploring the accurate effect of various oxygenated groups on their surface including carbonyl, carboxyl, and hydroxyl groups. Because of the "competitive inhibition" effect among all of these oxygenated groups, the catalytic efficiency of o-CNTs is significantly enhanced by weakening the presence of noncatalytic sites. Furthermore, the admirable enzymatic activity of these o-CNTs has been successfully applied in the treatment of bacterial infections, and the results of both in vitro and in vivo nanozyme-mediated bacterial clearance clearly demonstrate the feasibility of o-CNTs as robust peroxidase mimics to effectively decrease the bacterial viability under physiological conditions. We believe that the present study will not only facilitate the construction of novel efficient nanozymes by rationally adjusting the degree of the "competitive inhibition" effect, but also broaden the biological usage of o-CNT-based nanomaterials via their satisfactory enzymatic activity.

Experimental and theoretical research on γ-irradiated 7-methoxy-4-methylcoumarin powder through EPR and DFT methods

ABSTRACTIn this paper, the effects of gamma irradiation on 7-Methoxy-4-methylcoumarin (7M4MC) molecule, an essential coumarin derivative, which has an inherent variety of biological activities, therapeutic properties and industrial usage were examined. For this purpose, the sample was irradiated with 60Co-gamma ray source for about 100 kGy total doses. Theoretical calculations were performed using GAUSSIAN03 program for the possible radicals that were modeled from two stable conformations with lowest energies. In order to get well-resolved spectra and to determine the radical identity experimentally, EPR spectra of the irradiated 7M4MC sample were recorded at several spectrometer conditions. By considering the molecular structure and EPR spectra, alkyl-type radical was assumed to be formed by gamma irradiation. To support the estimations, simulations were done using theoretical EPR parameters as an initial value. The experimental spectra were well matched with the sum of simulated spectra obtained from two same type modeled radicals of two different conformations. As a result of experimental estimations and theoretical calculations, radiation-induced radicals were identified as two neutral alkyl radicals, , originated from two stable conformations.

The influence of biopreparations on the reduction of energy consumption and CO2 emissions in shallow and deep soil tillage

The application of innovation in agriculture technologies is very important for increasing the efficiency of agricultural production, ensuring the high productivity of plants, production quality, farm profitability, the positive balance of used energy, and the requirements of environmental protection. Therefore, it is a scientific problem that solid and soil surfaces covered with plant residue have a negative impact on the work, traction resistance, energy consumption, and environmental pollution of tillage machines. The objective of this work was to determine the dependence of the reduction of energy consumption and CO2 gas emissions on different biopreparations. Experimental research was carried out in a control (SC1) and seven different biopreparations using scenarios (SC2–SC8) using bacterial and non-bacterial biopreparations in different consistencies (with essential and mineral oils, extracts of various grasses and sea algae, phosphorus, potassium, humic and gibberellic acids, copper, zinc, manganese, iron, and calcium), estimating discing and plowing as the energy consumption parameters of shallow and deep soil tillage machines, respectively. CO2 emissions were determined by evaluating soil characteristics (such as hardness, total porosity and density). Meteorological conditions such average daily temperatures (2015–20.3 °C; 2016–16.90 °C) and precipitations (2015–6.9 mm; 2016–114.9 mm) during the month strongly influenced different results in 2015 and 2016. Substantial differences between the averages of energy consumption identified in approximately 62% of biological preparation combinations created usage scenarios. Experimental research established that crop field treatments with biological preparations at the beginning of vegetation could reduce the energy consumption of shallow tillage machines by up to approximately 23%, whereas the energy consumption of deep tillage could be reduced by up to approximately 19.2% compared with the control treatment. The experimental research results reveal the reduction of CO2 emissions in shallow tillage to approximately 20.14% (and that in deep tillage to approximately 19.16%) when works were performed by different biological preparation usage scenarios. This experimental research demonstrates the efficient use of the special adaptation of a new biotechnological method for the reduction of the energy consumption and CO2 gas emissions of agricultural machinery.

Recent Developments of Coumarin Hybrids as Anti-fungal Agents

Fungi place a huge burden on global healthcare systems attributed to the fact that fungal infections are responsible for the high morbidity and mortality rates in patients who received stem cell transplantation, antineoplastic chemotherapy, organ transplants or suffered Human Immunodeficiency Virus (HIV) infection. Unfortunately, almost none of the representative anti-fungal agents currently used in clinical therapy are ideal in terms of efficacy, anti-fungal spectrum or safety. Moreover, the rapid development of resistance to existing anti-fungal drugs has further aggravated the mortality and spread of fungi, creating an urgent need for novel anti-fungal agents. The broad spectrum of biological activities and successful usage in clinic made coumarins a promising anti-fungal candidate. Furthermore, hybridization of other pharmacophores with coumarin motif may enhance the anti-fungal efficacy, broaden the anti-fungal spectrum and improve the safety profiles. Thus, numerous coumarin hybrids have been assessed for their anti-fungal activities, and some of them showed promising potency and may have a novel mechanism of action. This review aims to outline the recent development of coumarin hybrids as potential anti-fungal agents and summarize their Structure-Activity Relationship (SAR) to provide an insight for rational designs of more active agents.

The modern therapy of systemic vasculitides: perspectives and challenges.

Systemic vasculitis is a heterogeneous group of inflammatory diseases, which are classified according to the diameter of the affected vessels. The treatment of systemic vasculitis is no longer empirical, because of increasing number of randomized clinical trials in this field. In recent years, there was a trend to limit the cumulative dose of glucocorticosteroids and immunosuppressive drugs, partially through biological drugs usage. However, biologic therapy is not always superior to combination of glucocorticosteroids and cytotoxic drugs. The efficacy of different biologic drugs varies in patients with different forms of systemic vasculitis, which creates the ground for personalized therapy of these diseases. Another serious problem is the absence of strict criteria to immunosuppressive therapy intensification, especially in vasculitis, affecting large vessels, due to the lack of reliable laboratory markers of disease activity. The article reviews modern approaches to the treatment of some types of systemic vasculitis, including ANCA-associated vasculitides, giant cell arteritis, Takayasu`s arteritis and cryoglobulinemic vasculitis.

Worldwide Protein Data Bank biocuration supporting open access to high-quality 3D structural biology data.

The Protein Data Bank (PDB) is the single global repository for experimentally determined 3D structures of biological macromolecules and their complexes with ligands. The worldwide PDB (wwPDB) is the international collaboration that manages the PDB archive according to the FAIR principles: Findability, Accessibility, Interoperability and Reusability. The wwPDB recently developed OneDep, a unified tool for deposition, validation and biocuration of structures of biological macromolecules. All data deposited to the PDB undergo critical review by wwPDB Biocurators. This article outlines the importance of biocuration for structural biology data deposited to the PDB and describes wwPDB biocuration processes and the role of expert Biocurators in sustaining a high-quality archive. Structural data submitted to the PDB are examined for self-consistency, standardized using controlled vocabularies, cross-referenced with other biological data resources and validated for scientific/technical accuracy. We illustrate how biocuration is integral to PDB data archiving, as it facilitates accurate, consistent and comprehensive representation of biological structure data, allowing efficient and effective usage by research scientists, educators, students and the curious public worldwide. Database URL: https://www.wwpdb.org/

Changing treatment paradigms for the management of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and progressive inf lammatory condition of the gastrointestinal tract causing bowel damage, hospitalizations, surgeries, and disability. Although there has been much progress in the management of IBD with established and evolving therapies, most current approaches have failed to change the natural course. Therefore, the treatment approach and follow-up of patients with IBD have undergone a significant change. Usage of immunosuppressants and/or biologics early during the course of the disease, known as top-down or accelerated step-up approach, was shown to be superior to conventional management in patients who had been recently diagnosed with IBD. This approach can be applied to selected groups based on prognostic factors to control disease activity and prevent progressive disease. Therapeutic targets have been shifted from clinical remission mainly based on symptoms to objective parameters such as endoscopic healing due to the discrepancies observed between symptoms, objectively evaluated inf lammatory activity, and intestinal damage. The concept of treat-to-target in IBD has been supported by population-based cohort studies, post hoc analysis of clinical trials, and meta-analysis, but more evidence is needed to support this concept to be applied to the clinical practice. In addition, individualized approach with tight monitoring of non-invasive biomarker such as C-reactive protein and fecal calprotectin and drug concentration has shown to improve clinical and endoscopic outcomes. An appropriate de-escalation strategy is considered based on patient demographics, disease features, current disease status, and patients’ preferences.

Wide difference in biologics usage and expenditure for the treatment of patients with rheumatoid arthritis in each prefecture in Japan analyzed using "National Database of Health Insurance Claims and Specific Health Checkups of Japan".

To analyze the biologics usage and expenditure for the treatment of patients with rheumatoid arthritis (RA) in each prefecture throughout Japan using the national open database, the Ministry of Health, Labour and Welfare of Japan disclosed; in Oct 2016, the data of the top 30 most-frequently prescribed drugs during a 1-year period from April 2014 to March 2015 in each prefecture in Japan, along with the patients' age and sex. Seldom-used drugs were excluded. We picked up only biologics for the present study. The total expenditure on biologics used in each prefecture was correlated with the population thereof. However, there was a big difference, up to ~ twofold, in the average expenditure used for an RA patient: highest in Toyama and lowest in Wakayama. There was also a big difference, ~ 4.5-fold, in the number of rheumatologists/1000 RA patients, highest in Kyoto and lowest in Aomori. The average expenditure used for an RA patient was correlated with the number of rheumatologists in the western part of Japan. Etanercept seemed to be used most frequently to Japanese RA patients followed closely by infliximab. Abatacept was used more frequently to the elderly than other biologics. There was a big difference in the number of rheumatologists and expenditure on biologics for the treatment of an RA patient among prefectures in fiscal 2014. Factors that brought this unevenness need to be scrutinized for universal implementation of good RA care throughout Japan, where there are uniform health insurance system and free access to rheumatologists.

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Asia-Pacific, the rising region for cancer vaccine clinical trials. Non-small cell lung cancer has largest number of clinical trials in Australia. Global dermatology pipeline to see shift towards increased usage of biologics. FDA approves first 0.1 mg auto-injector for life-threatening allergic reactions in infants and small children. FDA approves first two-drug regimen for certain patients with HIV. New early-breast cancer drug to be made available in Australia, New Zealand and South-East Asia. Multi-omic data analytics collaboration between the University of Oxford and Holmusk. NRGene’s genomic analysis project with Monsanto advances. Samsung BioLogics receives first FDA approval at world’s largest plant. TLC welcomes Mayor of Leiden and delegation to Taipei headquarter. Warren Wang appointed senior vice president and president of Asia Pacific of Boston Scientific. MiRXES reveals globalisation plans for 2018 and 2019. QuintilesIMS is now IQVIA. Quotient Sciences launches as the new global identity for Quotient Clinical. ESMO Asia 2017 Congress. More care is needed for cancer supportive care. ALEX study shows alectinib 600 mg more effective than crizotinib in Asian lung cancer patients. Study analyses mutations in cerebrospinal fluid in lung cancer with brain metastases. Study finds all Myanmar mouth cancer patients chew betel quid.

Biological drug usage and costs escalating in Italy

Biological drug usage and costs escalating in Italy

Propolisin Genel Özellikleri ve Balıklarda Kullanımı

Propolis, bitkilerin tomurcuk ve yaprak kısımlarından toplanan maddelerden bal arıları tarafından üretilen doğal reçineli bir karışımdır. Propolis antikanser, antiinflamator, antibiyotik, antioksidatif, antibakteriyel, antiviral, antifungal, anestetik, immunostimulan ve sitotoksik etkilere sahiptir. Bu derlemede doğal bir ürün olan propolisin fiziksel, kimyasal ve biyolojik özellikleri, bitkisel kaynakları ile balıklarda kullanımı ve uygulama şekiller hakkındaki bilgilerin bir araya getirilmesi amaçlanmıştır.

G-quadruplex and calf thymus DNA interaction of quaternized tetra and octa pyridyloxy substituted indium (III) phthalocyanines

The interactions of small molecules with G-quadruplex and double stranded DNA are important due to their potential biological and medical usages. In the present paper, the interactions of indium (III) phthalocyanines (quaternized 2,3,9,10,16,17,23,24-octakis-[(3-pyridyloxy) phthalocyaninato] chloroindium(III): OInPc and quaternized 2(3),9(10),16(17),23(24)-tetrakis-[(3-pyridyloxy) phthalocyaninato] chloroindium(III): TInPc) with hybrid G-quadruplex (Tel 21) and parallel G-quadruplexes (nucleolin, KRAS, c-MYC, vegf) were studied. The interactions of these phthalocyanines with ctDNA were also investigated. These interactions were measured by different spectroscopic techniques such as UV–Vis, fluorescence and circular dichroism. The UV–Vis spectroscopic data treated with Benesi-Hildebrand equation and Benesi-Hildebrand constants (KBH) were calculated. These constants were found higher for octa peripheral pyridyloxy substituted phthalocyanine, OInPc. Besides, UV–Vis analysis showed that the interaction of G-quadruplexes with tetra peripheral pyridyloxy substituted phthalocyanine derivative (TInPc) resulted in removal of central indium (III) atom from the cavity of phthalocyanine macrocycle. The UV–Vis melting studies as well as fluorescence replacement techniques were also employed for clarification of mechanism. The binding mode of molecules with ct DNA was also supported with viscosity measurements. From the results, the stabilization and destabilization of G-quadruplex depending on the concentration of the OInPc and TInPc showed that these two indium (III) phthalocyanines have the potential of both the elucidation role of G-quadruplexes in gene expression and the usage in cancer therapy.

Farmer Satisfaction Analysis on Pseudomonas Fluorescens (PF) Biological Agent Usage of Red Pepper Commodity (A survey conducted at Junrejo Village, Batu)

Consumer satisfaction is the level of feeling perceived after using a product or service that is very important for the company. The purpose of this study is to analyze the attributes considered and to analyze the level of satisfaction of chili farmers that use Pseudomonas fluorescens (PF) biological agents. This study uses Importance Performance Analysis (IPA) and Customer Satisfaction Index (CSI). The results reveal that there are 5 attributes of PF biological agents that the farmers choose, i.e. pest and disease control, eco-friendly, ease of application, instructions manual, and ease of obtaining. The result obtained from the calculation of CSI is 71%, so the chili farmers or the consumer are satisfied with PF biological agents.

Fabrication and characterization of a robust and strong bacterial promoter from a semi-rationally engineered promoter library in Bacillus subtilis

Abstract Robust promoters have substantial usage in synthetic biology. The important biological components of these promoters, however, remain limited in Bacillus subtilis. In this study, an array of variant promoters derived from PsrfA was from a promoter library constructed by randomized mutation. By screening the library, the variant promoter Pv1 displayed the highest transcriptional activity, which was approximately 1.56-fold higher than that of native PsrfA. Moreover, Pv1 was able to trigger GFP expression at constantly increased levels over the culture period. The robustness of Pv1 was confirmed by the over-production of aspartase (aspA). B. subtilis that over-produced aspA exhibited normal cell growth and a constantly increased yield over the cultural period. Finally, aspA expression triggered by the Pv1 variant displayed a higher yield and expression levels of aspA in B. subtilis compared to those of native PsrfA. These results suggest that randomized mutation of sequences adjacent to the −10 region of the bacterial promoter significantly influenced the transcription activity of the promoter. Pv1, which has high activity and robustness, has potential applications in gene expression systems and genetic circuits in B. subtilis.

Melanin, Radiation, and Energy Transduction in Fungi.

Melanin pigments are found in many diverse fungal species, where they serve a variety of functions that promote fitness and cell survival. Melanotic fungi inhabit some of the most extreme habitats on earth such as the damaged nuclear reactor at Chernobyl and the highlands of Antarctica, both of which are high-radiation environments. Melanotic fungi migrate toward radioactive sources, which appear to enhance their growth. This phenomenon, combined with the known capacities of melanin to absorb a broad spectrum of electromagnetic radiation and transduce this radiation into other forms of energy, raises the possibility that melanin also functions in harvesting such energy for biological usage. The ability of melanotic fungi to harness electromagnetic radiation for physiological processes has enormous implications for biological energy flows in the biosphere and for exobiology, since it provides new mechanisms for survival in extraterrestrial conditions. Whereas some features of the way melanin-related energy transduction works can be discerned by linking various observations and circumstantial data, the mechanistic details remain to be discovered.

Assessment of Rheumatoid Arthritis Quality Process Measures and Associated Costs.

The objective was to examine the relationship between health care costs and quality in rheumatoid arthritis (RA). Administrative claims were used to calculate 8 process measures for the treatment of RA. Associated health care costs were calculated for members who achieved or did not achieve each of the measures. Medical, pharmacy, and laboratory claims for RA patients (International Classification of Diseases, Ninth Revision, Clinical Modification 714.x) were extracted from the Optum Clinformatics Datamart database for 2011. Individuals were predominately female and in their mid-fifties. Measure achievement ranged from 55.9% to 80.8%. The mean cost of care for members meeting the measure was $18,644; members who did not meet the measures had a mean cost of $14,973. Primary cost drivers were pharmacy and office expenses, accounting for 42.4% and 26.3% of total costs, respectively. Regression analyses revealed statistically significant associations between biologic usage, which was more prevalent in groups attaining measures, and total expenditure across all measures (Ps < 0.001). Pharmacy costs were similar between both groups. Individuals meeting the measures had a higher proportion of costs accounted for by office visits; those not meeting the measures had a higher proportion of costs from inpatient and outpatient visits. These findings suggest that increased quality may lead to lower inpatient and outpatient hospital costs. Yet, the overall cost of RA care is likely to remain high because of intensive pharmacotherapy regimens.

The Role of Intermetal Competition and Mis-Metalation in Metal Toxicity.

The metals manganese, iron, cobalt, nickel, copper and zinc are essential for almost all bacteria, but their precise metal requirements vary by species, by ecological niche and by growth condition. Bacteria thus must acquire each of these essential elements in sufficient quantity to satisfy their cellular demand, but in excess these same elements are toxic. Metal toxicity has been exploited by humanity for centuries, and by the mammalian immune system for far longer, yet the mechanisms by which these elements cause toxicity to bacteria are not fully understood. There has been a resurgence of interest in metal toxicity in recent decades due to the problematic spread of antibiotic resistance amongst bacterial pathogens, which has led to an increased research effort to understand these toxicity mechanisms at the molecular level. A recurring theme from these studies is the role of intermetal competition in bacterial metal toxicity. In this review, we first survey biological metal usage and introduce some fundamental chemical concepts that are important for understanding bacterial metal usage and toxicity. Then we introduce a simple model by which to understand bacterial metal homeostasis in terms of the distribution of each essential metal ion within cellular 'pools', and dissect how these pools interact with each other and with key proteins of bacterial metal homeostasis. Finally, using a number of key examples from the recent literature, we look at specific metal toxicity mechanisms in model bacteria, demonstrating the role of metal-metal competition in the toxicity mechanisms of diverse essential metals.

Effective production of fermentable sugars from brown macroalgae biomass.

Brown macroalgae are renewable and sustainable biomass resources for the production of biofuels and chemicals, owing to their high levels of carbohydrates and low levels of lignin. To increase the biological usage of brown macroalgae, it is necessary to depolymerize the polysaccharides that generate macroalgal monomeric sugars or sugar derivatives and to convert them into fermentable sugars for the production of biofuels and chemicals. In this review, we discuss the chemical and enzymatic saccharification of the major carbohydrates found in brown macroalgae and the use of the resulting constituents in the production of biofuels and chemicals, as well as high-value health-benefiting functional oligosaccharides and sugars. We also discuss recently reported experimental results, novel enzymes, and technological breakthroughs that are related to polysaccharide depolymerization, fermentable sugar production, and the biological conversion of non-favorable sugars for fermentation using industrial microorganisms. This review provides a comprehensive perspective of the efficient utilization of brown macroalgae as renewable resources for the production of biofuels and chemicals.