bluuebunny/crossref_metadata_2025 huggingface dataset:
Benzimidazole Derivatives as Energetic Materials: A Theoretical Study
Authors: Sarlauskas Jonas , Tamuliene Jelena , Bekesiene Svajone , Kravcov Alexander
Published: July 2021

The explosive properties and stability of benzimidazole compounds are studied to determine the influence of substituents and their position. The results obtained reveal the conjugation of substituents as one of the crucial factors for the thermal stability of these compounds. We also found that two -CH3 substituents increase the thermal stability of the parent compound, while nitro groups decrease it. Moreover, the study clearly exhibits that the combination of an -NO2 substituent with -CH3 does not change the stability of the benzimidazole. On the other hand, nitro groups increase the chemical stability and explosive properties of the compounds under investigation, but their sensitivity could not fully satisfy the requirements of their safety and increase their toxicity. The main results of the study indicate that high thermal and chemical stability, low toxicity and sensitivity, and good explosive properties could be achieved by the precise combination of nitro, -CH3, and triazole ring substituents. These findings are very important for the design of new, effective, and non-sensitive explosives.
Speciation of Main Nutrients (N/P/K) in Hydrochars Produced from the Hydrothermal Carbonization of Swine Manure under Different Reaction Temperatures
Authors: Xiong Jiangbo , Chen Shuaiwei , Wang Jiaxin , Wang Yujie , Fang Xiaolin , Huang Huajun
Published: July 2021

Hydrothermal carbonization (HTC) has been proved to be a promising technology for swine manure (SM) treatment. Currently, there is a lack of systematic understanding of the transformation characteristics of nutrient speciation in the HTC of SM. In this study, the speciation of the main nutrients (N/P/K) in SM-derived hydrochar produced at different reaction temperatures (200–280 °C) was investigated. The recovery of P (61.0–67.1%) in hydrochars was significantly higher than that of N (23.0–39.8%) and K (25.5–30.0%), and the increase in reaction temperature promoted the recovery of P and reduced the recovery of N. After the HTC treatment, the percentage of soluble/available P was reduced from 61.6% in raw SM to 4.0–23.9% in hydrochars, while that of moderately labile/slow-release P was improved from 29.2% in raw SM feedstock to 65.5–82.7%. An obvious reduction was also found in the amounts of available N (from 51.3% in raw SM feedstock to 33.0–40.5% in hydrochars). The percentages of slow-release N and residual N in hydrochars produced at 240 °C reached the maximum and minimum values (46.4% and 18.9%), respectively. A total of 49.5–58.3% of K retained in hydrochars was residual (invalid) potassium. From the perspective of the mobility and availability of N, P and K only, it was suggested that the HTC of SM should be carried out at 220–240 °C. Compared with the original SM, it is safer and more effective to use the SM-derived hydrochar as an organic fertilizer.
Numerical Assessment of the Structural Effects of Relative Sliding between Tissues in a Finite Element Model of the Foot
Authors: Bocanegra Marco A. Martínez , López Javier Bayod , Vidal-Lesso Agustín , Tobar Andrés Mena , Vallejo Ricardo Becerro de Bengoa
Published: July 2021

Penetration and shared nodes between muscles, tendons and the plantar aponeurosis mesh elements in finite element models of the foot may cause inappropriate structural behavior of the tissues. Penetration between tissues caused using separate mesh without motion constraints or contacts can change the loading direction because of an inadequate mesh displacement. Shared nodes between mesh elements create bonded areas in the model, causing progressive or complete loss of load transmitted by tissue. This paper compares by the finite element method the structural behavior of the foot model in cases where a shared mesh has been used versus a separated mesh with sliding contacts between some important tissues. A very detailed finite element model of the foot and ankle that simulates the muscles, tendons and plantar aponeurosis with real geometry has been used for the research. The analysis showed that the use of a separate mesh with sliding contacts and a better characterization of the mechanical behavior of the soft tissues increased the mean of the absolute values of stress by 83.3% and displacement by 17.4% compared with a shared mesh. These increases mean an improvement of muscle and tendon behavior in the foot model. Additionally, a better quantitative and qualitative distribution of plantar pressure was also observed.
Hermite–Hadamard–Fejér-Type Inequalities and Weighted Three-Point Quadrature Formulae
Authors: Ribičić Penava Mihaela
Published: July 2021

The goal of this paper is to derive Hermite–Hadamard–Fejér-type inequalities for higher-order convex functions and a general three-point integral formula involving harmonic sequences of polynomials and w-harmonic sequences of functions. In special cases, Hermite–Hadamard–Fejér-type estimates are derived for various classical quadrature formulae such as the Gauss–Legendre three-point quadrature formula and the Gauss–Chebyshev three-point quadrature formula of the first and of the second kind.
A Theoretical Analysis of Profile Conformance Improvement Due to Suspension Injection
Authors: Fedorov Konstantin Mikhailovich , Gilmanov Alexander Yanovich , Shevelev Alexander Pavlovich , Kobyashev Alexander Vyacheslavovich , Anuriev Denis Alekseevich
Published: July 2021

This study is focused on a solution for the problem of suspension penetration in a porous formation. Such a solution forms the basis of injection profile diversion technology for oil reservoir sweep improvement. A conventional model of deep-bed suspension flow was used to describe the suspension injection process. The suspension slug was followed by water injection, and the inflow injection profile before and after treatment was investigated. For the first time, the criteria that determine the effectiveness of the inflow profile improvement process are introduced. The effect of the suspension filtration coefficient on the particle penetration depth was studied. A specific filtration coefficient value for the maximum penetration depth was achieved. The obtained analytical solution was generalized on multi-reservoir strata with poor interlayer crosslinking. The efficiency of profile conformance improvement was described by the differences in the root-mean-square deviations of the inflow velocities in interlayers from mean values before and after the treatment. It was shown that the complex criterion of suspension treatment efficiency should include a reduction in total injectivity. An increase in suspension slug volume improves the injectivity profile but decreases the total injectivity of an injector.
Editorial for the Special Issue on Micro-Manufacturing and Applications
Authors: Ivanov Atanas
Published: July 2021

This editorial is for collating the Special Issue on micro-manufacturing and applications, based on stringently selected papers presented to the editorial board of this Special Issue [...]
Low-Cost Laser Micromachining Super Hydrophilic–Super Hydrophobic Microgrooves for Robotic Capillary Micromanipulation of Microfibers
Authors: Chang Bo , Feng Yuhang , Jin Jialong , Zhou Quan
Published: July 2021

Capillary self-alignment technique can achieve highly accurate and fast alignment of micro components. Capillary self-alignment technique relies on the confinement of liquid droplets at receptor sites where hydrophobic–hydrophilic patterns are widely used. This paper reports a low-cost microsecond pulse laser micromachining method for fabrication of super hydrophilic–super hydrophobic grooves as receptor sites for capillary self-alignment of microfibers. We investigated the influence of major manufacturing parameters on groove sizes and wetting properties. The effects of the width (20 µm–100 µm) and depth (8 µm–36 µm) of the groove on the volume of water droplet contained inside the groove were also investigated. We show that by altering scanning speed, using a de-focused laser beam, we can modify the wetting properties of the microgrooves from 10° to 120° in terms of the contact angle. We demonstrated that different types of microfibers including natural and artificial microfibers can self-align to the size matching super hydrophilic–super hydrophobic microgrooves. The results show that super hydrophilic–super hydrophobic microgrooves have great potential in microfiber micromanipulation applications such as natural microfiber categorization, fiber-based microsensor construction, and fiber-enforced material development.
Investigation of the Influence of Temperature and Humidity on the Bandwidth of an Accelerometer
Authors: Huang Haoyu , Fang Weidong , Wang Chen , Bai Jian , Wang Kaiwei , Lu Qianbo
Published: July 2021

Bandwidth is an important parameter for accelerometers, in some cases, even surpassing sensitivity. However, there are few studies focused on the relationship between bandwidth and environmental conditions in practical application of accelerometers. In this paper, we systematically analyze the influence of environment on the bandwidth of accelerometers, obtaining the amplitude–frequency response curves versus damping ratio and properties of materials, wherein temperature and humidity were found as the two dominant factors that influence the bandwidth of accelerometers. Common temperature and humidity variations can result in bandwidth degradation of about 25% according to our theoretical analysis. The finite element method (FEM) is introduced to verify our theoretical analysis, and the accordance of the FEM simulation results and the theoretical results confirmed the validity of our analysis. Furthermore, a modification design is proposed to compensate for the influence of temperature and humidity on the bandwidth of accelerometers. By choosing materials with an appropriate Young’s modulus and coefficient of thermal expansion, the degradation of the bandwidth was substantially diminished by more than one order of magnitude, which can serve as a strong guide for the future realization of accelerometers with a steady and large bandwidth.
Emerging Topochemical Strategies for Designing Two-Dimensional Energy Materials
Authors: Liu Na , Chang Libo , Wu Jiang , Fang Jianhua , Xiao Xu
Published: July 2021

The unique properties of two-dimensional (2D) materials make them increasingly attractive in various fields, especially for energy harvesting, conversion, or storage. Simultaneously, numerous synthetic methods have been rapidly developed. Recently, topochemical strategies were demonstrated, and they show tremendous promising potential for synthesizing 2D materials due to their simplicity, scalability, and high efficiency. Considering the suitability of material structures and their synthesis methods, as well as the relationship between material properties and applications, it is necessary for researchers to comprehensively review and determine the prospects of 2D materials based on topological chemical synthesis methods and their related applications. Therefore, in this review, we systematically summarize and analyze the representative topochemical strategies for synthesizing 2D materials, including salt-templating methods for non-layered 2D materials, molten Lewis acid etching strategy for novel MXenes, and the chalcogen vapors etching and substituting strategy for phase-controlled 2D materials and so on, with the application of these 2D materials in energy-related fields including batteries, supercapacitors, and electrocatalysis. At the end of the paper, the corresponding perspective was also illustrated, and we expect that this could provide a reference for the future research in the field.
Nanomotion Spectroscopy as a New Approach to Characterize Bacterial Virulence
Authors: Villalba Maria I. , Venturelli Leonardo , Willaert Ronnie , Vela Maria E. , Yantorno Osvaldo , Dietler Giovanni , Longo Giovanni , Kasas Sandor
Published: July 2021

Atomic force microscopy (AFM)-based nanomotion detection is a label-free technique that has been used to monitor the response of microorganisms to antibiotics in a time frame of minutes. The method consists of attaching living organisms onto an AFM cantilever and in monitoring its nanometric scale oscillations as a function of different physical-chemical stimuli. Up to now, we only used the cantilever oscillations variance signal to assess the viability of the attached organisms. In this contribution, we demonstrate that a more precise analysis of the motion pattern of the cantilever can unveil relevant medical information about bacterial phenotype. We used B. pertussis as the model organism, it is a slowly growing Gram-negative bacteria which is the agent of whooping cough. It was previously demonstrated that B. pertussis can expresses different phenotypes as a function of the physical-chemical properties of the environment. In this contribution, we highlight that B. pertussis generates a cantilever movement pattern that depends on its phenotype. More precisely, we noticed that nanometric scale oscillations of B. pertussis can be correlated with the virulence state of the bacteria. The results indicate a correlation between metabolic/virulent bacterial states and bacterial nanomotion pattern and paves the way to novel rapid and label-free pathogenic microorganism detection assays.
Inhibitory Effect of Ophthalmic Solutions against SARS-CoV-2: A Preventive Action to Block the Viral Transmission?
Authors: Petrillo Francesco , Chianese Annalisa , De Bernardo Maddalena , Zannella Carla , Galdiero Marilena , Reibaldi Michele , Avitabile Teresio , Boccia Giovanni , Galdiero Massimiliano , Rosa Nicola , Franci Gianluigi
Published: July 2021

In 2020, a global pandemic was declared following the spread of SARS-CoV-2, the pathogen responsible for COVID-19. The risk of infection is high due to the ease of transmission, which can occur orally, through droplets, or via contact with contaminated surfaces and objects. It has also been demonstrated that the ocular surface can constitute a transmission route, especially in hospital settings, where health care workers can become a dangerous source of infection. In order to increase prevention and reduce the spread of the virus on the ocular surface, the antiviral activity of already-marketed eye drops against SARS-CoV-2 was evaluated. Iodim, Ozodrop, Septavis, and Dropsept were tested against SARS-CoV-2 in plaque-assay experiments at different stimulation times. Furthermore, the expression levels of early and late genes were evaluated through molecular assays. Results indicated that three of the four ophthalmic solutions showed a considerable dose-dependent inhibition of viral replication, highlighting their use as potential antiviral drugs against SARS-CoV-2 and preventing other ocular infections.
Organic Amendments Alter Soil Hydrology and Belowground Microbiome of Tomato (Solanum lycopersicum)
Authors: Readyhough Taylor , Neher Deborah A. , Andrews Tucker
Published: July 2021

Manure-derived organic amendments are a cost-effective tool that provide many potential benefits to plant and soil health including fertility, water retention, and disease suppression. A greenhouse experiment was conducted to evaluate how dairy manure compost (DMC), dairy manure compost-derived vermicompost (VC), and dehydrated poultry manure pellets (PP) impact the tripartite relationship among plant growth, soil physiochemical properties, and microbial community composition. Of tomato plants with manure-derived fertilizers amendments, only VC led to vigorous growth through the duration of the experiment, whereas DMC had mixed impacts on plant growth and PP was detrimental. Organic amendments increased soil porosity and soil water holding capacity, but delayed plant maturation and decreased plant biomass. Composition of bacterial communities were affected more by organic amendment than fungal communities in all microhabitats. Composition of communities outside roots (bulk soil, rhizosphere, rhizoplane) contrasted those within roots (endosphere). Distinct microbial communities were detected for each treatment, with an abundance of Massilia, Chryseolinea, Scedosporium, and Acinetobacter distinguishing the control, vermicompost, dairy manure compost, and dehydrated poultry manure pellet treatments, respectively. This study suggests that plant growth is affected by the application of organic amendments not only because of the soil microbial communities introduced, but also due to a synergistic effect on the physical soil environment. Furthermore, there is a strong interaction between root growth and the spatial heterogeneity of soil and root-associated microbial communities.
Cognitive Dysfunction in Multiple Sclerosis: Educational Level as a Protective Factor
Authors: Estrada-López Mar , García-Martín Sheila , Cantón-Mayo Isabel
Published: July 2021

Most people with MS experience cognitive deficits especially in attention, memory, information processing, and executive functions, negatively impacting on their quality of life. Cognitive variables of short-term memory, logical memory, and verbal fluency in 65 patients with multiple sclerosis (MS) were analysed in conjunction with sociodemographic variables such as sex, age, and educational level that might influence disease progression. We found that psychoeducational variables exerted a significant effect on the cognitive status of patients with MS. Thus, when considering sex, age, educational level, and type of MS (SPMS or RRMS), tests for between-subject effects revealed statistically significant differences in all three cognitive variables. In addition, we found that the type of MS and time since onset also generated significant cognitive differences. Our study shows that educational achievement or level is a protective factor against the disease, acting as a source of intellectual enrichment that promotes cognitive reserve in patients with MS. Further longitudinal studies assessing disease progression and prognosis in patients with MS would be useful in order to determine the specific importance of these variables in such patients and in strategies that could enhance their performance in neuropsychological assessment tasks.
Keto-on-the-Clock: A Survey of Dietetic Care Contact Time Taken to Provide Ketogenic Diets for Drug-Resistant Epilepsy in the UK
Authors: Lambert Bridget , Lightfoot Kathryn , Meskell Rachel , Whiteley Victoria J. , Martin-McGill Kirsty J. , Schoeler Natasha E.
Published: July 2021

Medical ketogenic diets (KDs) are effective yet resource-intensive treatment options for drug-resistant epilepsy (DRE). We investigated dietetic care contact time, as no recent data exist. An online survey was circulated to ketogenic dietitians in the UK and Ireland. Data were collected considering feeding route, KD variant and type of ketogenic enteral feed (KEF), and the estimated number of hours spent on patient-related activities during the patient journey. Fifteen dietitians representing nine KD centres responded. Of 335 patients, 267 (80%) were 18 years old or under. Dietitians spent a median of 162 h (IQR 54) of care contact time per patient of which a median of 48% (IQR 6) was direct contact. Most time was required for the classical KD taken orally (median 193 h; IQR 213) as a combined tube and oral intake (median 211 h; IQR 172) or a blended food KEF (median 189 h; IQR 148). Care contact time per month was higher for all KDs during the three-month initial trial compared to the two-year follow-up stage. Patients and caregivers with characteristics such as learning or language difficulties were identified as taking longer. Twelve out of fifteen (80%) respondents managed patients following the KD for more than two years, requiring an estimated median contact care time of 2 h (IQR 2) per patient per month. Ten out of fifteen (67%) reported insufficient official hours for dietetic activities. Our small survey gives insight into estimated dietetic care contact time, with potential application for KD provision and service delivery
Malnutrition in Infants Aged under 6 Months Attending Community Health Centres: A Cross Sectional Survey
Authors: Grijalva-Eternod Carlos S. , Beaumont Emma , Rana Ritu , Abate Nahom , Barthorp Hatty , McGrath Marie , Negesse Ayenew , Abera Mubarek , Abdissa Alemseged , Girma Tsinuel , Allen Elizabeth , Kerac Marko , Berhane Melkamu
Published: July 2021

A poor understanding of malnutrition burden is a common reason for not prioritizing the care of small and nutritionally at-risk infants aged under-six months (infants u6m). We aimed to estimate the anthropometric deficit prevalence in infants u6m attending health centres, using the Composite Index of Anthropometric Failure (CIAF), and to assess the overlap of different individual indicators. We undertook a two-week survey of all infants u6m visiting 18 health centres in two zones of the Oromia region, Ethiopia. We measured weight, length, and MUAC (mid-upper arm circumference) and calculated weight-for-length (WLZ), length-for-age (LAZ), and weight-for-age z-scores (WAZ). Overall, 21.7% (95% CI: 19.2; 24.3) of infants u6m presented CIAF, and of these, 10.7% (95% CI: 8.93; 12.7) had multiple anthropometric deficits. Low MUAC overlapped with 47.5% (95% CI: 38.0; 57.3), 43.8% (95% CI: 34.9; 53.1), and 42.6% (95% CI: 36.3; 49.2) of the stunted, wasted, and CIAF prevalence, respectively. Underweight overlapped with 63.4% (95% CI: 53.6; 72.2), 52.7% (95% CI: 43.4; 61.7), and 59.6% (95% CI: 53.1; 65.9) of the stunted, wasted, and CIAF prevalence, respectively. Anthropometric deficits, single and multiple, are prevalent in infants attending health centres. WAZ overlaps more with other forms of anthropometric deficits than MUAC.
Editorial of Special Issue “Magnesium in Human Health and Disease”
Authors: Castiglioni Sara
Published: July 2021

The fundamental role of magnesium in human health is extensively discussed in the review by Fiorentini and colleagues [...]
Development of a Scale to Measure Infant Eating Behaviour Worldwide
Authors: Wright Charlotte M. , Gurney Jessica Megan , Mutoro Antonina N. , Shum Claudia , Khan Amara , Milligan Beatrice , Indriani Widya , Georgiou Loukia , Chambers Stephanie , Bryant-Waugh Rachel , Garcia Ada L.
Published: July 2021

In order to create a short, internationally valid scale to assess eating behaviour (EB) in young children at risk of undernutrition, we refined 15 phrases describing avidity or food refusal (avoidance). In study one, 149 parents matched phrases in English, Urdu, Cantonese, Indonesian or Greek to videos showing avidity and avoidance; 82–100% showed perfect agreement for the avidity phrases and 73–91% for the avoidant phrases. In study two, 575 parents in the UK, Cyprus and Indonesia (healthy) and in Kenya, Pakistan and Guatemala (healthy and undernourished) rated their 6–24 months old children using the same phrases. Internal consistency (Cronbach’s α) was high for avidity (0.88) and moderate for avoidance (0.72). The best-performing 11 items were entered into a principal components analysis and the two scales loaded separately onto 2 factors with Eigen values > 1. The avidity score was positively associated with weight (r = 0.15 p = 0.001) and body mass index (BMI) Z scores (r = 0.16 p = 0.001). Both high and low avoidance were associated with lower weight and BMI Z scores. These scales are internationally valid, relate to nutritional status and can be used to inform causes and treatments of undernutrition worldwide.
Social Inequalities in Breakfast Consumption among Adolescents in Spain: The DESKcohort Project
Authors: Esquius Laura , Aguilar-Martínez Alicia , Bosque-Prous Marina , González-Casals Helena , Bach-Faig Anna , Colillas-Malet Ester , Salvador Gemma , Espelt Albert
Published: July 2021

Breakfast has a critical role in energy balance and dietary regulation. Consequently, it is considered an important component of a healthy diet, especially in adolescence, when there are great opportunities to consolidate habits and establish future patterns of healthiness in adulthood. Socioeconomic position (SEP) causes inequalities that are reflected in health behaviors, physical activity, mental health, and diet. Therefore, we conducted a cross-sectional study using data from the 2019–2020 DESKcohort project (Spain) to explore the relationships between breakfast and sociodemographic characteristics, health-related behaviors, and school performance of 7319 adolescents. Our findings showed that the prevalence of skipping breakfast every day was 19.4% in girls and 13.7% in boys and was related to students’ SEP. The risk of skipping breakfast was 30% higher in girls from the most disadvantaged SEP, in comparison to those in the most advanced SEP (prevalence ratio (PR) = 1.30; 95% confidence interval (CI) = 1.11–1.54). Also, boys from the most disadvantaged SEP showed 28% higher risk of skipping breakfast than those in the most advanced SEP (PR = 1.28; 95% CI = 1.04–1.59). In conclusion, future public policies should be adapted considering a SEP and gender perspective to avoid increasing nutritional and health inequalities.
Does Each Menstrual Cycle Elicit a Distinct Effect on Olfactory and Gustatory Perception?
Authors: Stanić Žana , Pribisalić Ajka , Bošković Maria , Bućan Cvitanić Jasna , Boban Kristina , Bašković Gabriela , Bartulić Antonija , Demo Suzana , Polašek Ozren , Kolčić Ivana
Published: July 2021

The obesity pandemic has brought forth a scientific interest in food intake and sensory perception interactions. Olfactory perception and gustatory perception are very complex and under the influence of many factors, including the menstrual cycle. This study aims to clarify conflicting findings on the influence of the menstrual cycle on olfactory and gustatory perception. Women were assessed during four consecutive phases of one complete cycle (mid-follicular, ovulatory, mid-luteal, and late luteal phases (N = 21)), in contrast to women measured across the same phases belonging to two menstrual cycles (N = 29). Additional control groups were men (N = 17), postmenopausal women (N = 14), oral contraceptive users (N = 10), and women with an anovulatory cycle (N = 8). Olfactory threshold, odor discrimination, and identification were tested using the “Sniffin Sticks“ test kit. Suprathreshold intensity and hedonic ratings for sweet, salty, sour, and bitter solutions were assessed. One-way ANOVA and ANOVA for repeated measurements was applied in the analysis, along with linear and trigonometric data fitting and linear mixed models. Linear increases in olfactory discrimination, identification, and overall olfactory performance were observed only in women followed across a complete menstrual cycle. Compared to other groups, these women displayed a cyclic pattern characterized by a predilection for sweet solution; reduced distaste for salty and sour solutions; and increased intensity perception of salty, sour, and bitter solutions towards the end of the cycle. These results suggest that a distinct hormonal milieu of a complete menstrual cycle may be affecting both olfactory and gustatory perception.
Gut Microbiota, Probiotic Interventions, and Cognitive Function in the Elderly: A Review of Current Knowledge
Authors: Białecka-Dębek Agata , Granda Dominika , Szmidt Maria Karolina , Zielińska Dorota
Published: July 2021

Changes in the composition and proportions of the gut microbiota may be associated with numerous diseases, including cognitive impairment. Over the recent years, the growing interest in this relation is observed, but there are still many unknowns, especially in the elderly. To the best of our knowledge, this is the first work that synthesizes and critically evaluates existing evidence on the possible association between human gut microbiota and cognitive function in the elderly. For this purpose, comprehensive literature searches were conducted using the electronic databases PubMed, Google Scholar, and ScienceDirect. The gut microbiota of cognitively healthy and impaired elderly people may differ in the diversity and abundance of individual taxes, but specific taxes cannot be identified. However, some tendencies to changing the Firmicutes/Bacteroidetes ratio can be identified. Currently, clinical trials involving probiotics, prebiotics, and synbiotics supplementation have shown that there are premises for the claim that these factors can improve cognitive functions, however there is no single intervention beneficial to the elderly population. More reliable evidence from large-scale, long-period RCT is needed. Despite proposing several potential mechanisms of the gut microbiota’s influence on the cognitive function impairment, prospective research on this topic is extremely difficult to conduct due to numerous confounding factors that may affect the gut microbiota. Heterogeneity of research outcomes impairs insight into these relations.
Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists
Authors: Pankiewicz Piotr , Szybiński Marcin , Kisielewska Katarzyna , Gołębiowski Filip , Krzemiński Patryk , Rutkowska-Włodarczyk Izabela , Moszczyński-Pętkowski Rafał , Gurba-Bryśkiewicz Lidia , Delis Monika , Mulewski Krzysztof , Smuga Damian , Dominowski Jakub , Janusz Artur , Górka Michał , Abramski Krzysztof , Napiórkowska Agnieszka , Nowotny Marcin , Dubiel Krzysztof , Kalita Katarzyna , Wieczorek Maciej , Pieczykolan Jerzy , Matłoka Mikołaj
Published: July 2021

TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF’s action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 μM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context.
Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan
Authors: Houzen Hideki , Kano Takahiro , Horiuchi Kazuhiro , Wakita Masahiro , Nagai Azusa , Yabe Ichiro
Published: July 2021

Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2–64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan–Meier analysis, which revealed that the median survival durations were 49 (9–88) and 25 (8–41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS.
Emerging Applications of Nanotechnology in Healthcare Systems: Grand Challenges and Perspectives
Authors: Anjum Sumaira , Ishaque Sara , Fatima Hijab , Farooq Wajiha , Hano Christophe , Abbasi Bilal Haider , Anjum Iram
Published: July 2021

Healthcare, as a basic human right, has often become the focus of the development of innovative technologies. Technological progress has significantly contributed to the provision of high-quality, on-time, acceptable, and affordable healthcare. Advancements in nanoscience have led to the emergence of a new generation of nanostructures. Each of them has a unique set of properties that account for their astonishing applications. Since its inception, nanotechnology has continuously affected healthcare and has exerted a tremendous influence on its transformation, contributing to better outcomes. In the last two decades, the world has seen nanotechnology taking steps towards its omnipresence and the process has been accelerated by extensive research in various healthcare sectors. The inclusion of nanotechnology and its allied nanocarriers/nanosystems in medicine is known as nanomedicine, a field that has brought about numerous benefits in disease prevention, diagnosis, and treatment. Various nanosystems have been found to be better candidates for theranostic purposes, in contrast to conventional ones. This review paper will shed light on medically significant nanosystems, as well as their applications and limitations in areas such as gene therapy, targeted drug delivery, and in the treatment of cancer and various genetic diseases. Although nanotechnology holds immense potential, it is yet to be exploited. More efforts need to be directed to overcome these limitations and make full use of its potential in order to revolutionize the healthcare sector in near future.
Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy
Authors: Lebon Cecile , Neubauer Heike , Berdugo Marianne , Delaunay Kimberley , Markert Elke , Becker Kolja , Baum-Kroker Katja S. , Prestle Jürgen , Fuchs Holger , Bakker Remko A. , Behar-Cohen Francine
Published: July 2021

Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier.
Emulgel Loaded with Flaxseed Extracts as New Therapeutic Approach in Wound Treatment
Authors: Pagano Cinzia , Baiocchi Claudio , Beccari Tommaso , Blasi Francesca , Cossignani Lina , Ceccarini Maria Rachele , Orabona Ciriana , Orecchini Elena , Di Raimo Enrico , Primavilla Sara , Salvini Laura , Michele Alessandro Di , Perioli Luana , Ricci Maurizio
Published: July 2021

Dry (D.E.) and liquid (L.E.) extracts were prepared from flaxseeds and their application in health field was evaluated. The chemical analysis showed that D.E. is rich in the lignan secoisolariciresinol diglucoside and L.E. in unsaturated triglycerides containing linolenic acid. Mainly, D.E. showed reducing (15.73 μmol Fe2+/g) and radical scavenging capacities (5.25 mg TE/g) and ability to down-regulate the expression of the pro-inflammatory cytokines NO (IC50 = 0.136 ± 0.009 mg/mL) and IL-6 (IC50 = 0.308 ± 0.103 mg/mL), suggesting its use in wound treatment. D.E. and L.E. were active against S. pyogenes and D.E. also against S. aureus. The two extracts were combined in a novel O/W emulgel in which the water phase was viscosized using a low molecular weight and highly deacetylated chitosan (1% wt./v). The presence of this polymer in the emulgel decreased the MIC values of the extracts. In fact, MIC shifted from 0.59 mg/mL to 0.052 mg/mL for D.E. and from 0.22 mg/mL to 0.036 mg/mL for L.E., concentrations safe both for keratinocytes and macrophages. Moreover, the emulgel demonstrated to inhibit S. aureus, P. aeruginosa, S. pyogenes, E. coli, and K. pneumoniae growth (inhibition halos 24–36 mm), strains often responsible for diabetic foot ulcer infection.
Lyophilization of Nanocapsules: Instability Sources, Formulation and Process Parameters
Authors: Degobert Ghania , Aydin Dunya
Published: July 2021

Polymeric nanocapsules have gained more and more interest in the medical sciences. Their core-shell structure offers numerous advantages, especially regarding their use as drug delivery systems. This review begins by presenting the different intrinsic sources of the instability of nanocapsules. The physical and chemical potential instabilities of nanocapsules reduce their shelf-life and constitute a barrier to their clinical use and to their commercialization. To overcome these issues, lyophilization is often used as a process of choice in the pharmaceutical industry especially when labile compounds are used. The state of the art of lyophilization nanocapsules is reviewed. The formulation properties and the process parameters are discussed for a complete understanding of their impact on the stability and storage of the final dried product. To assess the quality of the dried product, various characterization methods are also discussed.
Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance
Authors: Altay Benetti Ayça , Bianchera Annalisa , Buttini Francesca , Bertocchi Laura , Bettini Ruggero
Published: July 2021

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the β form and lactose as references. The solid-state properties of crystallized mannitol significantly affected aerosolization behavior, with the δ form affording the worst fine particle fraction with both the hydrophilic (9.3 and 6.5%) and the lipophilic (19.6 and 32%) model drugs, while α and β forms behaved in the same manner (11–13% for SS; 53–58% for BUD) and better than lactose (8 and 13% for SS; 26 and 39% for BUD). Recrystallized mannitol, but also PVA and PVP, proved to be safe excipients toward lung cell lines. We concluded that, also for mannitol, the physicochemical properties stemming from different crystal structures represent a tool for modulating carrier-drug interaction and, in turn, aerosolization performance.
Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
Authors: Joseph Andrea , Nyambura Chris W. , Bondurant Danielle , Corry Kylie , Beebout Denise , Wood Thomas R. , Pfaendtner Jim , Nance Elizabeth
Published: July 2021

Neonatal hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Catalase, an antioxidant enzyme, is a promising therapeutic due to its ability to scavenge toxic reactive oxygen species and improve tissue oxygen status. However, upon in vivo administration, catalase is subject to a short half-life, rapid proteolytic degradation, immunogenicity, and an inability to penetrate the brain. Polymeric nanoparticles can improve pharmacokinetic properties of therapeutic cargo, although encapsulation of large proteins has been challenging. In this paper, we investigated hydrophobic ion pairing as a technique for increasing the hydrophobicity of catalase and driving its subsequent loading into a poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticle. We found improved formation of catalase-hydrophobic ion complexes with dextran sulfate (DS) compared to sodium dodecyl sulfate (SDS) or taurocholic acid (TA). Molecular dynamics simulations in a model system demonstrated retention of native protein structure after complexation with DS, but not SDS or TA. Using DS-catalase complexes, we developed catalase-loaded PLGA-PEG nanoparticles and evaluated their efficacy in the Vannucci model of unilateral hypoxic-ischemic brain injury in postnatal day 10 rats. Catalase-loaded nanoparticles retained enzymatic activity for at least 24 h in serum-like conditions, distributed through injured brain tissue, and delivered a significant neuroprotective effect compared to saline and blank nanoparticle controls. These results encourage further investigation of catalase and PLGA-PEG nanoparticle-mediated drug delivery for the treatment of neonatal brain injury.
The Effect of Quality Indicators on Beliefs about Medicines Reuse: An Experimental Study
Authors: Lam Yasmin , McCrindle Rachel , Hui Terence K. L. , Sherratt R. Simon , Donyai Parastou
Published: July 2021

Background: A number of studies have examined beliefs about medicines reuse. Although the practice is prohibited in UK community pharmacy, it does take place elsewhere in the world where it relies on visual checks of returned medicines as an indicator of their quality. One proposal is to integrate sensor technology onto medication packaging as a marker of their quality instead. Our aim was to gauge people’s beliefs about medicines reuse, in an experiment, with or without sensor technology and with or without the promise of visual checks completed by a pharmacist, as experimental conditions, should the practice be sanctioned in the UK in the future. Methods: A between participant study was designed with two independent factors testing the hypothesis that sensors and visual checks would increase pro-medicines-reuse beliefs. A questionnaire was used to measure medicines reuse beliefs and collect qualitative comments. Results: Eighty-one participants took part. Attitudes toward medication offered for reuse, participants’ perceived social pressure to accept the medication, and their intention to take part in medicines reuse all increased with the presence of sensors on packaging and with the promise of pharmacist visual checking, with the former causing a greater increase than the latter, and the combination of both making the greatest increase. People’s qualitative comments explained their concerns about medicines reuse, validating the findings. The use of sensors on medication packaging warrants further investigation if regulators are to consider approving medicines reuse in the UK.
An Ultrastretchable Electrical Switch Fiber with a Magnetic Liquid Metal Core for Remote Magnetic Actuation
Authors: Hong Kyeongmin , Choe Minjae , Kim Seoyeon , Lee Hye-Min , Kim Byung-Joo , Park Sungjune
Published: July 2021

In this work we describe a soft and ultrastretchable fiber with a magnetic liquid metal (MLM) core for electrical switches used in remote magnetic actuation. MLM was prepared by removing the oxide layer on the liquid metal and subsequent mixing with magnetic iron particles. We used SEBS (poly[styrene-b-(ethylene-co-butylene)-b-styrene]) and silicone to prepare stretchable elastic fibers. Once hollow elastic fibers form, MLM was injected into the core of the fiber at ambient pressure. The fibers are soft (Young’s modulus of 1.6~4.4 MPa) and ultrastretchable (elongation at break of 600~5000%) while maintaining electrical conductivity and magnetic property due to the fluidic nature of the core. Magnetic strength of the fibers was characterized by measuring the maximum effective distance between the magnet and the fiber as a function of iron particle concentration in the MLM core and the polymeric shell. The MLM core facilitates the use of the fiber in electrical switches for remote magnetic actuation. This ultrastretchable and elastic fiber with MLM core can be used in soft robotics, and wearable and conformal electronics.
Effect of Process Conditions on the Properties of Resorcinol-Formaldehyde Aerogel Microparticles Produced via Emulsion-Gelation Method
Authors: Kamal Mohamed Seeni Meera , Heinrich Charlotte , Milow Barbara
Published: July 2021

Organic aerogels in the form of powder, microgranules and microsized particles receive considerable attention due to their easy fabrication, low process time and costs compared to their monolithic form. Here, we developed resorcinol-formaldehyde (RF) aerogel microparticles by using an emulsion-gelation method. The main objective of this study is to investigate the influence of curing time, stirring rate, RF sol:oil ratio and initial pH of the sol in order to control the size and properties of the microparticles produced. The emulsion-gelation of RF sol prepared with sodium carbonate catalyst in an oil phase at 60 °C was explored. RF microparticles were washed with ethanol to remove the oil phase followed by supercritical and ambient pressure drying. The properties of the dried RF microparticles were analyzed using FT-IR, N2 adsorption isotherm, gas pycnometry, wide angle X-ray scattering and scanning electron microscope. RF microparticles with high surface area up to 543 m2/g and large pore volume of 1.75 cm3/g with particle sizes ranging from 50–425 µm were obtained.