bluuebunny/crossref_metadata_2025 huggingface dataset:
Omega-3 Supplementation and Heart Disease: A Population-Based Diet by Gene Analysis of Clinical Trial Outcomes
Authors: Fernandez Maria Luz , Blomquist Sarah A. , Hallmark Brian , Chilton Floyd H.
Published: June 2021

Omega-3 (n-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of n-3 PUFAs on major cardiovascular events including death. While some studies document that n-3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active n-3 and omega 6 (n-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 n-6) and alpha-linolenic (ALA, 18:3, n-3). Here, we discuss the role of a FADS gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of n-3 PUFA supplementation. We also review recent clinical trials with n-3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase (FADS) gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of FADS variants that impact the efficiency of n-3 and n-6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing “one size fits all” n-3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that n-3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from n-3 PUFA supplementation.
Pyruvate Kinase, Inflammation and Periodontal Disease
Authors: Grant Melissa M.
Published: June 2021

Pyruvate kinase (PK) is the final and rate-limiting enzyme in glycolysis. It has four isoforms PKM1, PKM2, PKL and PKR. PK can form homo tetramers, dimers or monomers. The tetrameric form has the most catalytic activity; however, the dimeric form has non-canonical functions that contribute to the inflammatory response, wound healing and cellular crosstalk. This brief review explores these functions and speculates on their role in periodontal disease.
Propolis Extract and Chitosan Improve Health of Nosema ceranae Infected Giant Honey Bees, Apis dorsata Fabricius, 1793
Authors: Naree Sanchai , Ponkit Rujira , Chotiaroonrat Evada , Mayack Christopher L. , Suwannapong Guntima
Published: June 2021

Nosema ceranae is a large contributing factor to the most recent decline in honey bee health worldwide. Developing new alternative treatments against N. ceranae is particularly pressing because there are few treatment options available and therefore the risk of increased antibiotic resistance is quite high. Recently, natural products have demonstrated to be a promising avenue for finding new effective treatments against N. ceranae. We evaluated the effects of propolis extract of stingless bee, Tetrigona apicalis and chito-oligosaccharide (COS) on giant honey bees, Apis dorsata, experimentally infected with N. ceranae to determine if these treatments could improve the health of the infected individuals. Newly emerged Nosema-free bees were individually inoculated with 106N. ceranae spores per bee. We fed infected and control bees the following treatments consisting of 0%, 50%, propolis extracts, 0 ppm and 0.5 ppm COS in honey solution (w/v). Propolis extracts and COS caused a significant increase in trehalose levels in hemolymph, protein contents, survival rates and acini diameters of the hypopharyngeal glands in infected bees. Our results suggest that propolis and COS could improve the health of infected bees. Further research is needed to determine the underlying mechanisms responsible for the improved health of the infected bees.
No Evidence Known Viruses Play a Role in the Pathogenesis of Onchocerciasis-Associated Epilepsy. An Explorative Metagenomic Case-Control Study
Authors: Roach Michael , Cantu Adrian , Vieri Melissa Krizia , Cotten Matthew , Kellam Paul , Phan My , Hoek Lia van der , Mandro Michel , Tepage Floribert , Mambandu Germain , Musinya Gisele , Laudisoit Anne , Colebunders Robert , Edwards Robert , Mokili John L.
Published: June 2021

Despite the increasing epidemiological evidence that the Onchocerca volvulus parasite is strongly associated with epilepsy in children, hence the name onchocerciasis-associated epilepsy (OAE), the pathophysiological mechanism of OAE remains to be elucidated. In June 2014, children with unprovoked convulsive epilepsy and healthy controls were enrolled in a case control study in Titule, Bas-Uélé Province in the Democratic Republic of the Congo (DRC) to identify risk factors for epilepsy. Using a subset of samples collected from individuals enrolled in this study (16 persons with OAE and 9 controls) plasma, buffy coat, and cerebrospinal fluid (CSF) were subjected to random-primed next-generation sequencing. The resulting sequences were analyzed using sensitive computational methods to identify viral DNA and RNA sequences. Anneloviridae, Flaviviridae, Hepadnaviridae (Hepatitis B virus), Herpesviridae, Papillomaviridae, Polyomaviridae (Human polyomavirus), and Virgaviridae were identified in cases and in controls. Not unexpectedly, a variety of bacteriophages were also detected in all cases and controls. However, none of the identified viral sequences were found enriched in OAE cases, which was our criteria for agents that might play a role in the etiology or pathogenesis of OAE.
A Summary of the SARS-CoV-2 Vaccines and Technologies Available or under Development
Authors: Abdulla Zainalabideen A. , Al-Bashir Sharaf M. , Al-Salih Noor S. , Aldamen Ala A. , Abdulazeez Mohammad Z.
Published: June 2021

Since the beginning of 2020, the world has been in a race to develop vaccines that can control the COVID-19 pandemic. More than 250 projects have been initiated for this purpose, but only 14 of them have been authorized for use, despite being in phase 3 clinical trials. More than 40 other vaccines are also in phase 1/2 clinical trials and show promising outcomes. Regarding the appropriate choice of vaccines for each country or region, we reviewed the currently used vaccines in light of the different influencing parameters. These factors include the mode of action, dosage protocol, age group of the vaccinee, side effects, storage conditions, mounted immune response, and cost. Technically, there are seven types of vaccines developed against SARS-CoV-2: messenger RNA (mRNA), nonreplicating and replicating vectors, inactivated viruses, protein subunits, viral-like particles, DNA vaccines, and live attenuated vaccines. The mRNA type is being used for the first time in humans. Unfortunately, mutated variants of SARS-CoV-2 have started to appear worldwide, and researchers are investigating the effects of the currently used vaccines on them. There are many concerns regarding the long-term protection afforded by these vaccines and their side effects, and whether they require future modifications to be effective against the mutated variants. The development of new vaccines using more advanced technology is paramount for overcoming the difficulties in controlling the COVID-19 pandemic across the world.
Molecular Identification of Plasmodium falciparum from Captive Non-Human Primates in the Western Amazon Ecuador
Authors: Carrillo Bilbao Gabriel Alberto , Navarro Juan-Carlos , Garigliany Mutien-Marie , Martin-Solano Sarah , Minda Elizabeth , Benítez-Ortiz Washington , Saegerman Claude
Published: June 2021

Background: Malaria is a disease caused by hemoparasites of the Plasmodium genus. Non-human primates (NHP) are hosts of Plasmodium sp. around the world. Several studies have demonstrated that Plasmodium sp. emerged from Africa. However, little information is currently available about Plasmodium falciparum in the neotropical NHP and even less in Ecuador. Indeed, the objective of our study was to identify by molecular phylogenetic analyses the Plasmodium species associated with NHP from the Western Amazon region of Ecuador, and to design a molecular taxonomy protocol to use in the NHP disease ecology. Methods: We extracted DNA from faecal samples (n = 26) from nine species of captive (n = 19) and free-ranging (n = 7) NHP, collected from 2011 to 2019 in the Western Amazon region of Ecuador. Results: Using a pan-Plasmodium PCR, we obtained one positive sample from an adult female Leontocebus lagonotus. A maximum likelihood phylogenetic analysis showed that this sequence unequivocally clustered with Plasmodium falciparum. Conclusions: The identification of Plasmodium sp. in NHP of the Ecuadorian Amazon would be essential to identify their role as potential zoonotic reservoirs, and it is also important to identify their origin in wildlife and their transmission in captive NHP.
Modern Development and Production of a New Live Attenuated Bacterial Vaccine, SCHU S4 ΔclpB, to Prevent Tularemia
Authors: Conlan J. , Sjöstedt Anders , Gelhaus H. , Fleming Perry , McRae Kevan , Cobb Ronald , De Pascalis Roberto , Elkins Karen
Published: June 2021

Inhalation of small numbers of Francisella tularensis subspecies tularensis (Ftt) in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, Ftt was developed into a bona fide biological weapon by the USA, by the former USSR, and their respective allies during the previous century. Although such weapons were never deployed, the 9/11 attack quickly followed by the Amerithrax attack led the U.S. government to seek novel countermeasures against a select group of pathogens, including Ftt. Between 2005–2009, we pursued a novel live vaccine against Ftt by deleting putative virulence genes from a fully virulent strain of the pathogen, SCHU S4. These mutants were screened in a mouse model, in which the vaccine candidates were first administered intradermally (ID) to determine their degree of attenuation. Subsequently, mice that survived a high dose ID inoculation were challenged by aerosol or intranasally (IN) with virulent strains of Ftt. We used the current unlicensed live vaccine strain (LVS), first discovered over 70 years ago, as a comparator in the same model. After screening 60 mutants, we found only one, SCHU S4 ΔclpB, that outperformed LVS in the mouse ID vaccination-respiratory-challenge model. Currently, SCHU S4 ΔclpB has been manufactured under current good manufacturing practice conditions, and tested for safety and efficacy in mice, rats, and macaques. The steps necessary for advancing SCHU S4 ΔclpB to this late stage of development are detailed herein. These include developing a body of data supporting the attenuation of SCHU S4 ΔclpB to a degree sufficient for removal from the U.S. Select Agent list and for human use; optimizing SCHU S4 ΔclpB vaccine production, scale up, and long-term storage; and developing appropriate quality control testing approaches.
An Endophytic Fungi-Based Biostimulant Modulates Volatile and Non-Volatile Secondary Metabolites and Yield of Greenhouse Basil (Ocimum basilicum L.) through Variable Mechanisms Dependent on Salinity Stress Level
Authors: Saia Sergio , Corrado Giandomenico , Vitaglione Paola , Colla Giuseppe , Bonini Paolo , Giordano Maria , Stasio Emilio Di , Raimondi Giampaolo , Sacchi Raffaele , Rouphael Youssef
Published: June 2021

Salinity in water and soil is one of the major environmental factors limiting the productivity of agronomic and horticultural crops. In basil (Ocimum basilicum L., Lamiaceae) and other Ocimum species, information on the plant response to mild salinity levels, often induced by the irrigation or fertigation systems, is scarce. In the present work, we tested the effectiveness of a microbial-based biostimulant containing two strains of arbuscular mycorrhiza fungi (AMF) and Trichoderma koningii in sustaining greenhouse basil yield traits, subjected to two mild salinity stresses (25 mM [low] and 50 mM [high] modulated by augmenting the fertigation osmotic potential with NaCl) compared to a non-stressed control. The impact of salinity stress was further appraised in terms of plant physiology, morphological ontogenesis and composition in polyphenols and volatile organic compounds (VOC). As expected, increasing the salinity of the solution strongly depressed the plant yield, nutrient uptake and concentration, reduced photosynthetic activity and leaf water potential, increased the Na and Cl and induced the accumulation of polyphenols. In addition, it decreased the concentration of Eucalyptol and β-Linalool, two of its main essential oil constituents. Irrespective of the salinity stress level, the multispecies inoculum strongly benefited plant growth, leaf number and area, and the accumulation of Ca, Mg, B, p-coumaric and chicoric acids, while it reduced nitrate and Cl concentrations in the shoots and affected the concentration of some minor VOC constituents. The benefits derived from the inoculum in term of yield and quality harnessed different mechanisms depending on the degree of stress. under low-stress conditions, the inoculum directly stimulated the photosynthetic activity after an increase of the Fe and Mn availability for the plants and induced the accumulation of caffeic and rosmarinic acids. under high stress conditions, the inoculum mostly acted directly on the sequestration of Na and the increase of P availability for the plant, moreover it stimulated the accumulation of polyphenols, especially of ferulic and chicoric acids and quercetin-rutinoside in the shoots. Notably, the inoculum did not affect the VOC composition, thus suggesting that its activity did not interact with the essential oil biosynthesis. These results clearly indicate that beneficial inocula constitute a valuable tool for sustaining yield and improving or sustaining quality under suboptimal water quality conditions imposing low salinity stress on horticultural crops.
[18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue
Authors: Di Iorio Valentina , Boschi Stefano , Sarnelli Anna , Cuni Cristina , Bianchini David , Monti Manuela , Gorgoni Giancarlo , Paganelli Giovanni , Matteucci Federica , Masini Carla
Published: June 2021

Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [68Ga]Ga-PSMA-11 has been the forerunner but a [18F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental 18F-labelled radiopharmaceutical [18F]F-PSMA-1007 with [18F]F- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [18F]F- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [18F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentation which allowed the submission and approval of the Investigational Medicinal Product Dossier (IMPD) to the Competent Authority, addressing the quality problems due to different external suppliers. The result indicates that no significant differences have been found between the [18F]F- from the two suppliers in terms of radionuclidic and radiochemical purity and [18F]F- impacted neither the radiochemical yield of the labelling reaction nor the quality control parameters of the IMP [18F]F-PSMA-1007. These results prove how a correct quality assurance system can overcome some Regulatory Authorities issue that may represent an obstacle to the clinical use of F-18-labelled radiopharmaceuticals without an on-site cyclotron.
CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody
Authors: Collado Camps Estel , van Lith Sanne A. M. , Frielink Cathelijne , Lankhof Jordi , Dijkgraaf Ingrid , Gotthardt Martin , Brock Roland
Published: June 2021

Nanobodies are well-established targeting ligands for molecular imaging and therapy. Their short circulation time enables early imaging and reduces systemic radiation exposure. However, shorter circulation time leads to lower tracer accumulation in the target tissue. Cell-penetrating peptides (CPPs) improve cellular uptake of various cargoes, including nanobodies. CPPs could enhance tissue retention without compromising rapid clearance. However, systematic investigations on how the functionalities of nanobody and CPP combine with each other at the level of 2D and 3D cell cultures and in vivo are lacking. Here, we demonstrate that conjugates of the epidermal growth factor receptor (EGFR)-binding nanobody 7D12 with different CPPs (nonaarginine, penetratin, Tat and hLF) differ with respect to cell binding and induction of endocytosis. For nonaarginine and penetratin we compared the competition of EGF binding and performance of L- and D-peptide stereoisomers, and tested the D-peptide conjugates in tumor cell spheroids and in vivo. The D-peptide conjugates showed better penetration into spheroids than the unconjugated 7D12. Both in vivo and in vitro, the behavior of the agent reflects the combination of both functionalities. Although CPPs cause promising increases in in vitro uptake and 3D penetration, the dominant effect of the CPP in the control of biodistribution warrants further investigation.
Kynurenines as a Novel Target for the Treatment of Malignancies
Authors: Mor Adrian , Tankiewicz-Kwedlo Anna , Pawlak Dariusz
Published: June 2021

Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need for research on solutions aimed at overcoming this problem. An accumulation of tryptophan metabolites belonging to the kynurenine pathway can enhance neoplastic progression because it causes the suppression of immune system response against cancer cells. They are also involved in the development of the mechanisms responsible for the resistance to antitumor therapy. Kynurenine belongs to the most potent immunosuppressive metabolites of this pathway and has a significant impact on the development of malignancies. This fact prompted researchers to assess whether targeting the enzymes responsible for its synthesis could be an effective therapeutic strategy for various cancers. To date, numerous studies, both preclinical and clinical, have been conducted on this topic, especially regarding the inhibition of indoleamine 2,3-dioxygenase activity and their results can be considered noteworthy. This review gathers and systematizes the knowledge about the role of the kynurenine pathway in neoplastic progression and the findings regarding the usefulness of modulating its activity in anticancer therapy.
Detection of Microplastic in Human Placenta and Meconium in a Clinical Setting
Authors: Braun Thorsten , Ehrlich Loreen , Henrich Wolfgang , Koeppel Sebastian , Lomako Ievgeniia , Schwabl Philipp , Liebmann Bettina
Published: June 2021

Environmental pollution with microplastics (MPs) is a major and worldwide concern. Involuntary exposure to MPs by ingestion or inhalation is unavoidable. The effects on human health are still under debate, while in animals, cellular MP translocation and subsequent deleterious effects were shown. First reports indicate a potential intrauterine exposure with MPs, yet readouts are prone to contamination. Method: To establish a thorough protocol for the detection of MPs in human placenta and fetal meconium in a real-life clinical setting, a pilot study was set up to screen for MPs > 50 µm in placental tissue and meconium sampled during two cesarean sections for breech deliveries. After chemical digestion of non-plastic material, Fourier-transform infrared (FTIR) microspectroscopy was used to analyze the presence of 10 common types of microplastic in placenta and stool samples. Results: Human placenta and meconium samples were screened positive for polyethylene, polypropylene, polystyrene, and polyurethane, of which only the latter one was also detected as airborne fallout in the operating room—thus representing potential contamination. Conclusion: We found MPs > 50 µm in placenta and meconium acquired from cesarean delivery. Critical evaluation of potential contamination sources is pivotal and may guide future clinical studies to improve the correct detection of MPs in organ tissue. Studies investigating nano-sized plastics in human tissue are warranted.
3D Printing—A “Touch-Button” Approach to Manufacture Microneedles for Transdermal Drug Delivery
Authors: Sirbubalo Merima , Tucak Amina , Muhamedagic Kenan , Hindija Lamija , Rahić Ognjenka , Hadžiabdić Jasmina , Cekic Ahmet , Begic-Hajdarevic Derzija , Cohodar Husic Maida , Dervišević Almir , Vranić Edina
Published: June 2021

Microneedles (MNs) represent the concept of attractive, minimally invasive puncture devices of micron-sized dimensions that penetrate the skin painlessly and thus facilitate the transdermal administration of a wide range of active substances. MNs have been manufactured by a variety of production technologies, from a range of materials, but most of these manufacturing methods are time-consuming and expensive for screening new designs and making any modifications. Additive manufacturing (AM) has become one of the most revolutionary tools in the pharmaceutical field, with its unique ability to manufacture personalized dosage forms and patient-specific medical devices such as MNs. This review aims to summarize various 3D printing technologies that can produce MNs from digital models in a single step, including a survey on their benefits and drawbacks. In addition, this paper highlights current research in the field of 3D printed MN-assisted transdermal drug delivery systems and analyzes parameters affecting the mechanical properties of 3D printed MNs. The current regulatory framework associated with 3D printed MNs as well as different methods for the analysis and evaluation of 3D printed MN properties are outlined.
Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice
Authors: Alhazzani Khalid , Ahmad Sheikh F. , Al-Harbi Naif O. , Attia Sabry M. , Bakheet Saleh A. , Sarawi Wedad , Alqarni Saleh A. , Algahtani Mohammad , Nadeem Ahmed
Published: June 2021

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy.
An Effective and Safe Enkephalin Analog for Antinociception
Authors: Viswanadham K. K. DurgaRao , Böttger Roland , Hohenwarter Lukas , Nguyen Anne , Rouhollahi Elham , Smith Alexander , Tsai Yi-Hsuan , Chang Yuan-Yu , Ortiz Christopher Llynard , Yang Lee-Wei , Jimenez Liliana , Li Siyuan , Hur Chan , Li Shyh-Dar
Published: June 2021

Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.
Poly(l-Lactic Acid)-co-poly(Butylene Adipate) New Block Copolymers for the Preparation of Drug-Loaded Long Acting Injectable Microparticles
Authors: Karava Vasiliki , Siamidi Aggeliki , Vlachou Marilena , Christodoulou Evi , Bikiaris Nikolaos D. , Zamboulis Alexandra , Kostoglou Margaritis , Gounari Eleni , Barmpalexis Panagiotis
Published: June 2021

The present study evaluates the use of newly synthesized poly(l-lactic acid)-co-poly(butylene adipate) (PLA/PBAd) block copolymers as microcarriers for the preparation of aripiprazole (ARI)-loaded long acting injectable (LAI) formulations. The effect of various PLA to PBAd ratios (95/5, 90/10, 75/25 and 50/50 w/w) on the enzymatic hydrolysis of the copolymers showed increasing erosion rates by increasing the PBAd content, while cytotoxicity studies revealed non-toxicity for all prepared biomaterials. SEM images showed the formation of well-shaped, spherical MPs with a smooth exterior surface and no particle’s agglomeration, while DSC and pXRD data revealed that the presence of PBAd in the copolymers favors the amorphization of ARI. FTIR spectroscopy showed the formation of new ester bonds between the PLA and PBAd parts, while analysis of the MP formulations showed no molecular drug–polyester matrix interactions. In vitro dissolution studies suggested a highly tunable biphasic extended release, for up to 30 days, indicating the potential of the synthesized copolymers to act as promising LAI formulations, which will maintain a continuous therapeutic level for an extended time period. Lastly, several empirical and mechanistic models were also tested, with respect to their ability to fit the experimental release data.
Maturation and Protection Effect of Retinal Tissue-Derived Bioink for 3D Cell Printing Technology
Authors: Kim Jongmin , Kong Jeong Sik , Kim Hyeonji , Han Wonil , Won Jae Yon , Cho Dong-Woo
Published: June 2021

Retinal degeneration is a leading cause of incurable vision loss and blindness. The increasing incidence of retinal degeneration has triggered research into the development of in vitro retinal models for drug development and retinal alternatives for transplantation. However, the complex retinal structure and the retinal microenvironment pose serious challenges. Although 3D cell printing technology has been widely used in tissue engineering, including in vitro model development and regeneration medicine, currently available bioinks are insufficient to recapitulate the complex extracellular matrix environment of the retina. Therefore, in this study, we developed a retinal decellularized extracellular matrix (RdECM) from the porcine retina and evaluated its characteristics. The RdECM conserved the ECM components from the native retina without cellular components. Then, we mixed the RdECM with collagen to form a bioink and confirmed its suitability for 3D cell printing. We further studied the effect of the RdECM bioink on the differentiation of Muller cells. The retinal protective effect of the RdECM bioink was confirmed through a retinal degeneration animal model. Thus, we believe that the RdECM bioink is a promising candidate for retinal tissue engineering.
Diabetes and Frail Older Patients: Glycemic Control and Prescription Profile in Real Life
Authors: Mangé Anne-Sophie , Pagès Arnaud , Sourdet Sandrine , Cestac Philippe , McCambridge Cécile
Published: June 2021

(1) Background: The latest recommendations for diabetes management adapt the objectives of glycemic control to the frailty profile in older patients. The purpose of this study was to evaluate the proportion of older patients with diabetes whose treatment deviates from the recommendations. (2) Methods: This cross-sectional observational study was conducted in older adults with known diabetes who underwent an outpatient frailty assessment in 2016. Glycated hemoglobin (HbA1c) target is between 6% and 7% for nonfrail patients and between 7% and 8% for frail patients. Frailty was evaluated using the Fried criteria. Prescriptions of glucose-lowering drugs were analyzed based on explicit and implicit criteria. (3) Results: Of 110 people with diabetes with an average age of 81.7 years, 67.3% were frail. They had a mean HbA1c of 7.11%. Of these patients, 60.9% had at least one drug therapy problem in their diabetes management and 40.9% were potentially overtreated. The HbA1c distribution in relation to the targets varied depending on frailty status (p < 0.002), with overly strict control in frail patients (p < 0.001). (4) Conclusions: Glycemic control does not seem to be routinely adjusted to the health of frail patients. Several factors can lead to overtreatment of these patients.
Breeding Buckwheat for Nutritional Quality in the Czech Republic
Authors: Janovská Dagmar , Jágr Michal , Svoboda Pavel , Dvořáček Václav , Meglič Vladimir , Hlásná Čepková Petra
Published: June 2021

Buckwheat is a nutritionally valuable crop, an alternative to common cereals also usable in gluten-free diets. The selection of buckwheat genotypes suitable for further breeding requires the characterization and evaluation of genetic resources. The main objective of this work was to evaluate selected phenotypic and morphological traits using international buckwheat descriptors, including total phenolic content and antioxidant activity, on a unique set of 136 common buckwheat accessions grown in 2019–2020 under Czech Republic conditions. In addition, UHPLC-ESI- MS/MS was used to analyze a wide spectrum of 20 phenolic compounds in buckwheat seeds, including four flavanols, three phenolic acids, seven flavonols, four flavones, and two flavanones. Significant differences among years and genotypes were observed for morphological traits (plant height and 1000-seed weight) and antioxidant activity, as well as levels of observed chemical compounds. Antioxidant activity, crude protein content, plant height and rutin content were characterized by higher mean values in 2020 than in 2019 and vice versa for total polyphenol content and 1000-seed weight. Crude protein content was the most stable across years, while total polyphenol content and rutin content varied greatly from year to year. The most abundant phenolic compounds were rutin, hyperoside, epicatechin, catechin, vitexin, isovitexin, orientin and isoorientin. Protein content was negatively correlated with plant height, catechin and epicatechin content. On the other hand, AA and TPC were positively correlated with rutin, hyperoside and chlorogenic acid. Five accessions showed high stability of the evaluated traits under changing conditions within both years of observation. These materials can be used in breeding programmes aimed at improving buckwheat genotypes with emphasis on quality traits.
Importance of Landraces in Cereal Breeding for Stress Tolerance
Authors: Marone Daniela , Russo Maria A. , Mores Antonia , Ficco Donatella B. M. , Laidò Giovanni , Mastrangelo Anna M. , Borrelli Grazia M.
Published: June 2021

The renewed focus on cereal landraces is a response to some negative consequences of modern agriculture and conventional breeding which led to a reduction of genetic diversity. Cereal landraces are still cultivated on marginal lands due to their adaptability to unfavourable conditions, constituting an important source of genetic diversity usable in modern plant breeding to improve the adaptation to abiotic or biotic stresses, yield performance and quality traits in limiting environments. Traditional agricultural production systems have played an important role in the evolution and conservation of wide variability in gene pools within species. Today, on-farm and ex situ conservation in gene bank collections, together with data sharing among researchers and breeders, will greatly benefit cereal improvement. Many efforts are usually made to collect, organize and phenotypically and genotypically analyse cereal landrace collections, which also utilize genomic approaches. Their use in breeding programs based on genomic selection, and the discovery of beneficial untapped QTL/genes/alleles which could be introgressed into modern varieties by MAS, pyramiding or biotechnological tools, increase the potential for their better deployment and exploitation in breeding for a more sustainable agricultural production, particularly enhancing adaptation and productivity in stress-prone environments to cope with current climate changes.
Collagenase and Tyrosinase Inhibitory Effect of Isolated Constituents from the Moss Polytrichum formosum
Authors: Marques Raíssa Volpatto , Guillaumin Agnès , Abdelwahab Ahmed B. , Salwinski Aleksander , Gotfredsen Charlotte H. , Bourgaud Frédéric , Enemark-Rasmussen Kasper , Miguel Sissi , Simonsen Henrik Toft
Published: June 2021

Mosses from the genus Polytrichum have been shown to contain rare benzonaphthoxanthenones compounds, and many of these have been reported to have important biological activities. In this study, extracts from Polytrichum formosum were analyzed in vitro for their inhibitory properties on collagenase and tyrosinase activity, two important cosmetic target enzymes involved respectively in skin aging and pigmentation. The 70% ethanol extract showed a dose-dependent inhibitory effect against collagenase (IC50 = 4.65 mg/mL). The methanol extract showed a mild inhibitory effect of 44% against tyrosinase at 5.33 mg/mL. Both extracts were investigated to find the constituents having a specific affinity to the enzyme targets collagenase and tyrosinase. The known compounds ohioensin A (1), ohioensin C (3), and communin B (4), together with nor-ohioensin D (2), a new benzonaphthoxanthenone, were isolated from P. formosum. Their structures were determined by mass spectrometry and NMR spectroscopy. Compounds 1 (IC50 = 71.99 µM) and 2 (IC50 = 167.33 µM) showed inhibitory activity against collagenase. Compound 1 also exhibited inhibition of 30% against tyrosinase activity at 200 µM. The binding mode of the active compounds was theoretically generated by an in-silico approach against the 3D structures of collagenase and tyrosinase. These current results present the potential application from the moss P. formosum as a new natural source of collagenase and tyrosinase inhibitors.
Validation of Reference Genes for Studying Different Abiotic Stresses in Oat (Avena sativa L.) by RT-qPCR
Authors: Tajti Judit , Pál Magda , Janda Tibor
Published: June 2021

Oat (Avena sativa L.) is a widely cultivated cereal with high nutritional value and it is grown mainly in temperate regions. The number of studies dealing with gene expression changes in oat continues to increase, and to obtain reliable RT-qPCR results it is essential to establish and use reference genes with the least possible influence caused by experimental conditions. However, no detailed study has been conducted on reference genes in different tissues of oat under diverse abiotic stress conditions. In our work, nine candidate reference genes (ACT, TUB, CYP, GAPD, UBC, EF1, TBP, ADPR, PGD) were chosen and analysed by four statistical methods (GeNorm, Normfinder, BestKeeper, RefFinder). Samples were taken from two tissues (leaves and roots) of 13-day-old oat plants exposed to five abiotic stresses (drought, salt, heavy metal, low and high temperatures). ADPR was the top-rated reference gene for all samples, while different genes proved to be the most stable depending on tissue type and treatment combinations. TUB and EF1 were most affected by the treatments in general. Validation of reference genes was carried out by PAL expression analysis, which further confirmed their reliability. These results can contribute to reliable gene expression studies for future research in cultivated oat.
Spatiotemporal Variation in Pollination Deficits in an Insect-Pollinated Dioecious Crop
Authors: Castro Helena , Siopa Catarina , Casais Vinícius , Castro Mariana , Loureiro João , Gaspar Hugo , Dias Maria Celeste , Castro Sílvia
Published: June 2021

Inadequate quantity and quality of pollen reaching the stigmas decreases the sexual reproductive output of plants, compromising yield. Still, the current extent of pollen limitation affecting yield (i.e., pollination deficits) is poorly quantified. This study is aimed at quantifying pollination deficits in kiwifruit orchards, a dioecious plant with a fruit caliber and market value largely dependent on pollination services. For that, we set up a pollination experiment and quantified services and yield provided by current pollination vectors, and under optimal pollination, over two years in a total of twenty-three orchards covering the kiwifruit production range in Portugal. We characterized nine fruit traits and used: (1) fruit weight to calculate pollination deficits and relate them with pollinator diversity and abundance, and environmental variables; and (2) production values, fruit caliber, and market values to calculate economic impact of pollination deficits. Results showed that pollination deficits were variable in time and space and were significantly and negatively correlated with pollinator abundance, while the opposite pattern was obtained for production, supporting the notion that a higher pollinator’s abundance is related to lower pollination deficits and higher yields. Understanding the factors affecting pollination deficits is crucial to depict the need for nature-based solutions promoting pollinators and to resort to management practices assisting pollination.
Comparative Assessment of the Phytochemical Composition and Biological Activity of Extracts of Flowering Plants of Centaurea cyanus L., Centaurea jacea L. and Centaurea scabiosa L.
Authors: Sharonova Natalia , Nikitin Evgeny , Terenzhev Dmitriy , Lyubina Anna , Amerhanova Syumbelya , Bushmeleva Kseniya , Rakhmaeva Adelya , Fitsev Igor , Sinyashin Kirill
Published: June 2021

The data on the phytochemical composition and biological activity for flowering plant extracts of the genus Centaurea (Knapweed)—cornflower (Centaurea cyanus L.), brown knapweed (Centaurea jacea L.), and greater knapweed (Centaurea scabiosa L.), which are typical representatives of the flora in the middle belt of the Russian Federation, were obtained. For the first time, biologically active substances such as pyranone, coumaran (2,3-dihydrobenzofuran), and 5-hydroxymethylfurfural were identified in ethanol and methanol extracts of Centaurea scabiosa L. by gas chromatography–mass spectrometry. Catechol and α-amyrin were the major components of the ethanol extract from Centaurea cyanus L., and flavone was the major component of Centaurea jacea L. flower extract. The greatest antimicrobial activity against phytopathogens was detected in Centaurea scabiosa L. when extracting freshly harvested flower biomass with methyl tert-butyl ether at room temperature: the minimum inhibitory concentrations were 60–120 µg/mL, the minimum fungicidal concentration was 120 µg/mL, and the minimum bactericidal concentration was 250 µg/mL. The low antioxidant activity of the studied plant extracts was established using the maximum values of Centaurea jacea L. Ethanol extract of Centaurea cyanus L. flowers had low antimicrobial and antioxidant activity. The extracts showed no phytotoxicity to garden cress germination but inhibited the growth of juvenile plants, especially roots. The greatest phytotoxic effect was revealed with methyl tert-butyl ether, where the depression of growth indicators was 35% or more.
A Few Points of the Engineering Logic Discussed in ITER EDA on Evaluation of Halo- and AVDE-Induced Loads in Tokamaks
Authors: Sadakov Sergey
Published: June 2021

All tokamaks are designed to withstand a certain number of energetic electromagnetic (EM) transients caused by uncontrolled terminations of plasma pulses, including symmetric and asymmetric plasma vertical displacement events: VDEs and AVDEs. These events generate significant pulsed EM loads in all conductive components and coils. Axially symmetric transient EM loads induced by VDEs without Halo current have been calculated well since the 1980s; however, Halo-related EM load components and lateral loads associated with AVDEs still cause discussions. The author worked on fast plasma and EM transients in tokamaks quite a while ago then deviated to other areas but has been keeping track of the topic since. He is aware of discussions of the modelling of Halo currents and of significant scatter present in current estimates for AVDE-induced lateral loads and contends that some points of engineering logic formulated earlier on this topic may help reduce these uncertainties. This article summarises a few points of the engineering understanding developed in informal discussions within the ITER EDA team with the purpose to preserve these points for all tokamak developments.
3D Printing at Micro-Level: Laser-Induced Forward Transfer and Two-Photon Polymerization
Authors: Mahmood Muhammad Arif , Popescu Andrei C.
Published: June 2021

Laser-induced forward transfer (LIFT) and two-photon polymerization (TPP) have proven their abilities to produce 3D complex microstructures at an extraordinary level of sophistication. Indeed, LIFT and TPP have supported the vision of providing a whole functional laboratory at a scale that can fit in the palm of a hand. This is only possible due to the developments in manufacturing at micro- and nano-scales. In a short time, LIFT and TPP have gained popularity, from being a microfabrication innovation utilized by laser experts to become a valuable instrument in the hands of researchers and technologists performing in various research and development areas, such as electronics, medicine, and micro-fluidics. In comparison with conventional micro-manufacturing methods, LIFT and TPP can produce exceptional 3D components. To gain benefits from LIFT and TPP, in-detail comprehension of the process and the manufactured parts’ mechanical–chemical characteristics is required. This review article discusses the 3D printing perspectives by LIFT and TPP. In the case of the LIFT technique, the principle, classification of derivative methods, the importance of flyer velocity and shock wave formation, printed materials, and their properties, as well as various applications, have been discussed. For TPP, involved mechanisms, the difference between TPP and single-photon polymerization, proximity effect, printing resolution, printed material properties, and different applications have been analyzed. Besides this, future research directions for the 3D printing community are reviewed and summarized.
Recycling of Selective Laser Sintering Waste Nylon Powders into Fused Filament Fabrication Parts Reinforced with Mg Particles
Authors: Uddin Mohammad , Williams Daniel , Blencowe Anton
Published: June 2021

This paper presents recycling of selective laser sintering (SLS) waste nylon into printable filaments and parts reinforced with Mg particles. Waste nylon and waste–Mg powder mixture with 2%, 4%, and 8% Mg to nylon were extruded into the filaments. Moisture absorption, differential scanning calorimetry, and melt flow index experiments were conducted to determine the thermal characteristics, while tensile and flexural tests were conducted to evaluate mechanical properties and failure mechanisms. The results were compared with off-the-self (OTS) nylon. Waste powder was found to be extrudable and printable as FFF filament. Waste filament diameter closely matched standard filament size, while exhibiting reduced moisture absorption. High melting and crystallisation temperature for the waste nylon demonstrated a degradation of the plastic during the SLS process. Young’s modulus and ultimate tensile strength for the waste filament increased by 1.6-fold compared to that for OTS, while Mg-composite filament surpassed the waste and OTS. Waste and Mg composite dog bone results showed an increase in strength and stiffness, but the ductility deteriorated. Both flexural strength and modulus for the waste nylon increased by 13% and 26%, respectively, over OTS, and the addition of Mg enhanced flexural strength by up to 5-fold at 8% Mg over the waste. Printed surface topography demonstrated that the waste and Mg composite filaments can print the parts with desired geometric shapes and acceptable surface texture. The findings showed that recycling waste SLS powder into FFF prints would be a viable and useful alternative to disposal, given its abundance.
Albumin Acts as a Lubricant on the Surface of Hydrogel and Silicone Hydrogel Contact Lenses
Authors: Su Chen-Ying , Yeh Lung-Kun , Fan Tzu-Wei , Lai Chi-Chun , Fang Hsu-Wei
Published: June 2021

Feeling comfortable is the greatest concern for contact lens wearers, and it has been suggested that in vivo comfort could be corresponded to the in vitro friction coefficient of contact lenses. How tear albumin could affect the friction coefficient of silicone hydrogel and hydrogel contact lenses was analyzed by sliding a lens against a quartz glass in normal and extremely high concentration of albumin solution. Albumin deposition testing and surface roughness analysis were also conducted. The results showed that the friction coefficient of tested contact lenses did not correspond to both the albumin deposition amount and surface roughness, but we proposed a model of how albumin might act as a lubricant on the surface of some hydrogel and silicone hydrogel contact lenses. In conclusion, albumin provided lubrication for silicone hydrogel contact lenses regardless of albumin concentrations, while albumin only acted as a lubricant for hydrogel contact under normal concentration.