bluuebunny/crossref_metadata_2025 huggingface dataset:
Singular Spectrum Analysis of Tremorograms for Human Neuromotor Reaction Estimation
Authors: Bureneva Olga , Safyannikov Nikolay , Aleksanyan Zoya
Published: May 2022

Singular spectrum analysis (SSA) is a method of time series analysis and is used in various fields, including medicine. A tremorogram is a biological signal that allows evaluation of a person’s neuromotor reactions in order to infer the state of the motor parts of the central nervous system (CNS). A tremorogram has a complex structure, and its analysis requires the use of advanced methods of signal processing and intelligent analysis. The paper’s novelty lies in the application of the SSA method to extract diagnostically significant features from tremorograms with subsequent evaluation of the state of the motor parts of the CNS. The article presents the application of a method of singular spectrum decomposition, comparison of known variants of classification, and grouping of principal components for determining the components of the tremorogram corresponding to the trend, periodic components, and noise. After analyzing the results of the SSA of tremorograms, we proposed a new algorithm of grouping based on the analysis of singular values of the trajectory matrix. An example of applying the SSA method to the analysis of tremorograms is shown. Comparison of known clustering methods and the proposed algorithm showed that there is a reasonable correspondence between the proposed algorithm and the traditional methods of classification and pairing in the set of periodic components.
Organization Patterns of Complex River Networks in Chile: A Fractal Morphology
Authors: Martinez Francisco , Manriquez Hermann , Ojeda Alberto , Olea Gabriel
Published: May 2022

River networks are spatially complex systems difficult to describe by using simple morphological indices. To this concern, fractal theory arises as an interesting tool for quantifying such complexity. In this case of study, we have estimated for the first time the fractal dimension of Chilean networks distributed across the country, analysed at two different scales. These networks insert into variable environments, not only from a climatic and hydrological point of view, but also from a morphological point of view. We investigate to which extent the fractal dimension is able to describe the apparent disorganized character of landscape, by applying two methods. Striking patterns of organization related to Horton ratios and the fractal dimension are reported and discussed. This last parameter depends on the scale of the network, showing interesting groupings by tectonic and climatological factors. Our results suggest that under restricted conditions, the fractal dimension could help to capture the intricate morphology of Chilean networks and its links with the hydrological, climatic, and tectonic conditions present across the country.
Third Order Melnikov Functions of a Cubic Center under Cubic Perturbations
Authors: Liu Yanwei , Zhang Tonghua , Liu Xia
Published: May 2022

In this paper, cubic perturbations of the integral system (1+x)2dH where H=(x2+y2)/2 are considered. Some useful formulae are deduced that can be used to compute the first three Melnikov functions associated with the perturbed system. By employing the properties of the ETC system and the expressions of the Melnikov functions, the existence of exactly six limit cycles is given. Note that there are many cases for the existence of third-order Melnikov functions, and some existence conditions are very complicated—the corresponding Melnikov functions are not presented.
Phytochemical and Potential Properties of Seaweeds and Their Recent Applications: A Review
Authors: El-Beltagi Hossam S. , Mohamed Amal A. , Mohamed Heba I. , Ramadan Khaled M. A. , Barqawi Aminah A. , Mansour Abdallah Tageldein
Published: May 2022

Since ancient times, seaweeds have been employed as source of highly bioactive secondary metabolites that could act as key medicinal components. Furthermore, research into the biological activity of certain seaweed compounds has progressed significantly, with an emphasis on their composition and application for human and animal nutrition. Seaweeds have many uses: they are consumed as fodder, and have been used in medicines, cosmetics, energy, fertilizers, and industrial agar and alginate biosynthesis. The beneficial effects of seaweed are mostly due to the presence of minerals, vitamins, phenols, polysaccharides, and sterols, as well as several other bioactive compounds. These compounds seem to have antioxidant, anti-inflammatory, anti-cancer, antimicrobial, and anti-diabetic activities. Recent advances and limitations for seaweed bioactive as a nutraceutical in terms of bioavailability are explored in order to better comprehend their therapeutic development. To further understand the mechanism of action of seaweed chemicals, more research is needed as is an investigation into their potential usage in pharmaceutical companies and other applications, with the ultimate objective of developing sustainable and healthier products. The objective of this review is to collect information about the role of seaweeds on nutritional, pharmacological, industrial, and biochemical applications, as well as their impact on human health.
Assessment of Eicosapentaenoic Acid (EPA) Production from Filamentous Microalga Tribonema aequale: From Laboratory to Pilot-Scale Study
Authors: Long Jijian , Jia Jing , Gong Yingchun , Han Danxiang , Hu Qiang
Published: May 2022

It has long been explored to use EPA-rich unicellular microalgae as a fish oil alternative for production of the high-value omega-3 fatty acid eicosapentaenoic acid (EPA, 20:5, n-3). However, none of the efforts have ever reached commercial success. This study reported a filamentous yellow-green microalga Tribonema aequale that possesses the ability to grow rapidly and synthesize significant amounts of EPA. A series of studies were conducted in a glass column photobioreactor under laboratory culture conditions and in pilot-scale open raceway ponds outdoors. The emphasis was placed on the specific nutrient requirements and the key operational parameters in raceway ponds such as culture depth and mixing regimes. When optimized, T. aequale cells contained 2.9% of EPA (w/w) and reached a very high biomass concentration of 9.8 g L−1 in the glass column photobioreactor. The cellular EPA content was increased further to 3.5% and the areal biomass and EPA productivities of 16.2 g m−2 d−1 and 542.5 mg m−2 d−1, respectively, were obtained from the outdoor pilot-scale open raceway ponds, which were the record high figures reported thus far from microalgae-based EPA production. It was also observed that T. aequale was highly resistant to microbial contamination and easy for harvesting and dewatering, which provide two additional competitive advantages of this filamentous microalga over the unicellular counterparts for potential commercial production of EPA and other derived co-products.
Investigation of the Specification Degradation Mechanism of CMOS Power Amplifier under Thermal Shock Test
Authors: Zhou Shaohua , Yang Cheng , Wang Jian
Published: May 2022

To investigate the critical specifications of a power amplifier (PA) under rapidly changing temperature conditions, we fabricated and tested a 0.3–1.1 GHz complementary metal–oxide–semiconductor (CMOS) PA under thermal shock tests. The results show that high- and low-temperature shocks can accelerate the degradation of critical specifications of PAs and that the critical specifications of PAs degrade with the increasing number of shocks. The main reason for the degradation of critical specifications of PAs with increasing thermal shock tests is the mismatch of thermal expansion coefficients of printed circuit boards (PCB) with FR-4 as a substrate. The results of this paper can provide a reference for the development of temperature-robust PAs design guidelines for the implementation of temperature-robust PAs using low-cost silicon technology.
Trajectory Modulation for Impact Reducing of Lower-Limb Exoskeletons
Authors: Zhang Long , Song Guangkui , Zou Chaobin , Huang Rui , Cheng Hong , Hu Dekun
Published: May 2022

Lower-limb exoskeletons have received considerable attention because of their effectiveness in walking assistance and rehabilitation for paraplegic patients. Excessive foot–ground impacts during walking make patients uncomfortable and even lead to injury. In this paper, we propose an optimized knee trajectory modulation (OKTM) for foot–ground impact reduction. The OKTM can reduce the peak of ground reaction force (PGRF) by knee-joint trajectory modulation based on a parameters-optimizing spring-damping system. In addition, a hip trajectory modulation (HTM) is presented to compensate for torso pitch deflections due to the OKTM. Unlike traditional mechanical-device-based methods, the proposed OKTM and HTM require no bulky mechanical structures, and can adaptively adjust parameters to adapt to different impacts. We demonstrated the efficiency of the proposed approach in both simulations and experiments for engineering verifications. Results show that the approach can effectively reduce PGRF.
Resilience and the Gut Microbiome: Insights from Chronically Socially Stressed Wild-Type Mice
Authors: dos Santos Guilherme Malena , Valeri Francesco , Winter Jennifer , Müller Marianne B. , Schwiertz Andreas , Endres Kristina
Published: May 2022

The microbiome is an important player within physiological homeostasis of the body but also in pathophysiological derailments. Chronic social stress is a challenge to the organism, which results in psychological illnesses such as depression in some individuals and can be counterbalanced by others, namely resilient individuals. In this study, we wanted to elucidate the potential contribution of the microbiome to promote resilience. Male mice were subjected to the classical chronic social defeat paradigm. Defeated or undefeated mice were either controls (receiving normal drinking water) or pre-treated with antibiotics or probiotics. Following social defeat, resilient behavior was assessed by means of the social interaction test. Neither depletion nor probiotic-shifted alteration of the microbiome influenced stress-associated behavioral outcomes. Nevertheless, clear changes in microbiota composition due to the defeat stress were observed such as elevated Bacteroides spp. This stress-induced increase in Bacteroides in male mice could be confirmed in a related social stress paradigm (instable social hierarchy) in females. This indicates that while manipulation of the microbiome via the antibiotics- and probiotics-treatment regime used here has no direct impact on modulating individual stress susceptibility in rodents, it clearly affects the microbiome in the second line and in a sex-independent manner regarding Bacteroides.
Host Species Adaptation of Obligate Gut Anaerobes Is Dependent on Their Environmental Survival
Authors: Karasova Daniela , Faldynova Marcela , Matiasovicova Jitka , Sebkova Alena , Crhanova Magdalena , Kubasova Tereza , Seidlerova Zuzana , Prikrylova Hana , Volf Jiri , Zeman Michal , Babak Vladimir , Juricova Helena , Rajova Jana , Vlasatikova Lenka , Rysavka Petr , Rychlik Ivan
Published: May 2022

The gut microbiota of warm-blooded vertebrates consists of bacterial species belonging to two main phyla; Firmicutes and Bacteroidetes. However, does it mean that the same bacterial species are found in humans and chickens? Here we show that the ability to survive in an aerobic environment is central for host species adaptation. Known bacterial species commonly found in humans, pigs, chickens and Antarctic gentoo penguins are those capable of extended survival under aerobic conditions, i.e., either spore-forming, aerotolerant or facultatively anaerobic bacteria. Such bacteria are ubiquitously distributed in the environment, which acts as the source of infection with similar probability in humans, pigs, chickens, penguins and likely any other warm-blooded omnivorous hosts. On the other hand, gut anaerobes with no specific adaptation for survival in an aerobic environment exhibit host adaptation. This is associated with their vertical transmission from mothers to offspring and long-term colonisation after administration of a single dose. This knowledge influences the design of next-generation probiotics. The origin of aerotolerant or spore-forming probiotic strains may not be that important. On the other hand, if Bacteroidetes and other host-adapted species are used as future probiotics, host preference should be considered.
CO2 Hydrogenation Catalyzed by Graphene-Based Materials
Authors: Mihet Maria , Dan Monica , Lazar Mihaela D.
Published: May 2022

In the context of an increased interest in the abatement of CO2 emissions generated by industrial activities, CO2 hydrogenation processes show an important potential to be used for the production of valuable compounds (methane, methanol, formic acid, light olefins, aromatics, syngas and/or synthetic fuels), with important benefits for the decarbonization of the energy sector. However, in order to increase the efficiency of the CO2 hydrogenation processes, the selection of active and selective catalysts is of utmost importance. In this context, the interest in graphene-based materials as catalysts for CO2 hydrogenation has significantly increased in the last years. The aim of the present paper is to review and discuss the results published until now on graphene-based materials (graphene oxide, reduced graphene oxide, or N-dopped graphenes) used as metal-free catalysts or as catalytic support for the thermocatalytic hydrogenation of CO2. The reactions discussed in this paper are CO2 methanation, CO2 hydrogenation to methanol, CO2 transformation into formic acid, CO2 hydrogenation to high hydrocarbons, and syngas production from CO2. The discussions will focus on the effect of the support on the catalytic process, the involvement of the graphene-based support in the reaction mechanism, or the explanation of the graphene intervention in the hydrogenation process. Most of the papers emphasized the graphene’s role in dispersing and stabilizing the metal and/or oxide nanoparticles or in preventing the metal oxidation, but further investigations are needed to elucidate the actual role of graphenes and to propose reaction mechanisms.
The Consciousness of Pain: A Thalamocortical Perspective
Authors: Sgourdou Paraskevi
Published: May 2022

Deep, dreamless sleep is considered the only “normal” state under which consciousness is lost. The main reason for the voluntary, external induction of an unconscious state, via general anesthesia, is to silence the brain circuitry of nociception. In this article, I describe the perception of pain as a neural and behavioral correlate of consciousness. I briefly mention the brain areas and parameters that are connected to the presence of consciousness, mainly by virtue of their absence under deep anesthesia, and parallel those to brain areas responsible for the perception of pain. Activity in certain parts of the cortex and thalamus, and the interaction between them, will be the main focus of discussion as they represent a common ground that connects our general conscious state and our ability to sense the environment around us, including the painful stimuli. A plethora of correlative and causal evidence has been described thus far to explain the brain’s involvement in consciousness and nociception. Despite the great advancement in our current knowledge, the manifestation and true nature of the perception of pain, or any conscious experience, are far from being fully understood.
Moderate Alcohol Use Is Associated with Reduced Cardiovascular Risk in Middle-Aged Men Independent of Health, Behavior, Psychosocial, and Earlier Life Factors
Authors: McEvoy Linda K. , Bergstrom Jaclyn , Tu Xinming , Garduno Alexis C. , Cummins Kevin M. , Franz Carol E. , Lyons Michael J. , Reynolds Chandra A. , Kremen William S. , Panizzon Matthew S. , Laughlin Gail A.
Published: May 2022

We examined whether the often-reported protective association of alcohol with cardiovascular disease (CVD) risk could arise from confounding. Our sample comprised 908 men (56–67 years), free of prevalent CVD. Participants were categorized into 6 groups: never drinkers, former drinkers, and very light (1–4 drinks in past 14 days), light (5–14 drinks), moderate (15–28 drinks), and at-risk (>28 drinks) drinkers. Generalized linear mixed effect models examined the associations of alcohol use with three established CVD risk scores: The Framingham Risk Score (FRS); the atherosclerotic CVD (ASCVD) risk score; and the Metabolic Syndrome (MetS) Severity score, adjusting for group differences in demographics, body size, and health-related behaviors. In separate models we additionally adjusted for several groups of potentially explanatory factors including socioeconomic status, social support, physical and mental health status, childhood factors, and prior history of alcohol misuse. Results showed lower CVD risk among light and moderate alcohol drinkers, relative to very light drinkers, for all CVD risk scores, independent of demographics, body size, and health-related behaviors. Alcohol-CVD risk associations were robust to further adjustment for several groups of potential explanatory factors. Study limitations include the all-male sample with limited racial and ethnic diversity, and the inability to adjust for sugar consumption and for patterns of alcohol consumption. Although this observational study does not address causation, results show that middle-aged men who consume alcohol in moderation have lower CVD risk and better cardiometabolic health than men who consume little or no alcohol, independent of a variety of health, behavioral, psychosocial, and earlier life factors.
Secondary Outcomes of a Front-of-Pack-Labelling Randomised Controlled Experiment in a Representative British Sample: Understanding, Ranking Speed and Perceptions
Authors: Packer Jessica , Russell Simon J. , Ridout Deborah , Conolly Anne , Jessop Curtis , Viner Russell M. , Croker Helen
Published: May 2022

Front-of-pack labels (FOPLs) provide simplified nutritional information that aims to inform consumer choice and encourage reformulation. We conducted an online randomised controlled experiment on a representative British sample to test the effectiveness of FOPLs across a range of outcomes. The primary outcomes have been published; here, we present the secondary outcomes: the ability to rank the healthiest product and the time to complete the rankings by comparing the FOPL groups and a no-label control, as well as a descriptive analysis of the perceptions. Participants from the NatCen panel were randomised to one of five experimental groups (Multiple Traffic Lights; Nutri-Score; Warning Label; Positive Choice tick; no-label control). Six food/drink categories were selected (pizza, drinks, cakes, crisps, yoghurts, breakfast cereals), and three products were created with varying healthiness. The participants (analytic sample = 4530) were asked to rank the products in order of healthiness twice (baseline: no label; follow-up: experimental group label). Compared to the control, the probability of correctly ranking the healthiest product at follow-up was significantly greater for the N-S, MTL and WL across all products. The time to correctly complete the ranking was fastest for the N-S, PC and no-label control. The descriptive analysis showed that the FOPLs were perceived favourably, and especially N-S and MTL. The findings were supportive of the primary analyses, with those results suggesting that N-S performed the best, and then MTL.
Statistical Methods for the Analysis of Food Composition Databases: A Review
Authors: Balakrishna Yusentha , Manda Samuel , Mwambi Henry , van Graan Averalda
Published: May 2022

Evidence-based knowledge of the relationship between foods and nutrients is needed to inform dietary-based guidelines and policy. Proper and tailored statistical methods to analyse food composition databases (FCDBs) could assist in this regard. This review aims to collate the existing literature that used any statistical method to analyse FCDBs, to identify key trends and research gaps. The search strategy yielded 4238 references from electronic databases of which 24 fulfilled our inclusion criteria. Information on the objectives, statistical methods, and results was extracted. Statistical methods were mostly applied to group similar food items (37.5%). Other aims and objectives included determining associations between the nutrient content and known food characteristics (25.0%), determining nutrient co-occurrence (20.8%), evaluating nutrient changes over time (16.7%), and addressing the accuracy and completeness of databases (16.7%). Standard statistical tests (33.3%) were the most utilised followed by clustering (29.1%), other methods (16.7%), regression methods (12.5%), and dimension reduction techniques (8.3%). Nutrient data has unique characteristics such as correlated components, natural groupings, and a compositional nature. Statistical methods used for analysis need to account for this data structure. Our summary of the literature provides a reference for researchers looking to expand into this area.
Arterial Hypertension and the Hidden Disease of the Eye: Diagnostic Tools and Therapeutic Strategies
Authors: Del Pinto Rita , Mulè Giuseppe , Vadalà Maria , Carollo Caterina , Cottone Santina , Agabiti Rosei Claudia , De Ciuceis Carolina , Rizzoni Damiano , Ferri Claudio , Muiesan Maria Lorenza
Published: May 2022

Hypertension is a major cardiovascular risk factor that is responsible for a heavy burden of morbidity and mortality worldwide. A critical aspect of cardiovascular risk estimation in hypertensive patients depends on the assessment of hypertension-mediated organ damage (HMOD), namely the generalized structural and functional changes in major organs induced by persistently elevated blood pressure values. The vasculature of the eye shares several common structural, functional, and embryological features with that of the heart, brain, and kidney. Since retinal microcirculation offers the unique advantage of being directly accessible to non-invasive and relatively simple investigation tools, there has been considerable interest in the development and modernization of techniques that allow the assessment of the retinal vessels’ structural and functional features in health and disease. With the advent of artificial intelligence and the application of sophisticated physics technologies to human sciences, consistent steps forward have been made in the study of the ocular fundus as a privileged site for diagnostic and prognostic assessment of diverse disease conditions. In this narrative review, we will recapitulate the main ocular imaging techniques that are currently relevant from a clinical and/or research standpoint, with reference to their pathophysiological basis and their possible diagnostic and prognostic relevance. A possible non pharmacological approach to prevent the onset and progression of retinopathy in the presence of hypertension and related cardiovascular risk factors and diseases will also be discussed.
Why Can Organoids Improve Current Organ-on-Chip Platforms?
Authors: Sokolowska Patrycja , Zuchowska Agnieszka , Brzozka Zbigniew
Published: May 2022

Preclinical studies are the first stage of introducing a new potential drug to the pharmaceutical market. Many of the compounds with promising results approved in the preclinical stage show poor prognosis during the first stage of clinical studies, which is connected with inadequate in vitro and in vivo models used in this stage. Both basic in vitro models, and in vivo animal models do not represent the human conditions. Therefore, scientists work on creating an appropriate model that will highly reproduce the characteristics of the human body. The solution could be an organoids model: a laboratory-produced human miniature organ, grown in a specially designed Organ-on-Chip microfluidic tools. This review focuses on characterizing the 3D cell culture types, focusing mainly on organoids, the Organ-on-Chip approach, and presenting the latest reports about the application of their combination in biological research, including toxicological studies.
Oral Manifestations of Syphilis: Report of Four Cases
Authors: Mulder van Staden Suné , de Villiers Carl , Alwan Julandi , Moloi Mpho , Mahlangu Sibongile
Published: May 2022

Syphilis is an infectious disease caused by Treponema pallidum. Syphilis can present with an array of oral manifestations at different stages of disease progression. This article reports on four cases of syphilis with oral manifestations diagnosed by oral health professionals. Case 1: 18-year-old female presented with multiple ulcerations and patches involving the hard palate, uvula, retromolar area, and papillary nodules on the tongue. Case 2: 25-year-old male presented with a solitary, exophytic lesion on the anterior tongue. Case 3: 17-year-old female presented with multiple pigmented macules on the palms of hands and soles of feet, as well as multiple exophytic, sessile, soft tissue masses throughout the oral cavity. Case 4: 14-year-old female presented with a solitary, exophytic, verrucous lesion in the incisive papilla area, as well as multiple, coalescing patches involving the soft palate, uvula, and tonsillar areas. All patients were managed by biopsy and serological investigations. Treatment of syphilis was performed at infectious disease clinics with 2.4 million units (MUs) benzathine benzylpenicillin intramuscular (IM) weekly. Oral health professionals need to have knowledge of the oral manifestations of syphilis to ensure that patients are accurately identified and appropriately treated.
Fragmentation of Healthcare Services as a Possible Determinant of the Low Completion for the Tuberculosis Cascade of Prevention among Asylum Seekers: Results from a Prospective Study with Historical Comparison
Authors: Marchese Valentina , Zanotti Paola , Cimaglia Claudia , Rossi Benedetta , Formenti Beatrice , Magro Paola , Gulletta Maurizio , Stancanelli Giovanna , El-Hamad Issa , Girardi Enrico , Cirillo Daniela Maria , Castelli Francesco , Matteelli Alberto
Published: May 2022

Background: Effective screening for tuberculosis infection (TBI) among asylum seekers (AS) is crucial for tuberculosis (TB) elimination in low incidence countries. Methods: We assessed the proportion of completion of the screening for TBI among asylum seekers with a centralized delivery method compared to the decentralized model previously adopted in the study area (historical control). In the historical model (January 2017 to May 2018) screening of AS was performed at the arrival offering TBI testing (TST followed by IGRA among those positive), radiological investigation, treatment initiation and hospital referral, if needed, at three sites: migrant health clinic, pneumology clinic and infectious diseases department for active disease (decentralized model). In the study model (June 2018, centralized) all steps of screening were performed at a single site, at a minimum of 6 months after arrival. Multivariable Poisson regression analysis, with robust variance, was used to assess variables associated with the completion of screening for infection. Multivariable logistic regression was used to identify factors associated with the diagnosis of TB infection. Results: The intervention approach was offered to 144 AS with an overall 98.6% proportion of completion (98.7% for those with a positive TST). In the historical screening model, 1192 AS were candidates for screening, which was completed by 74.5% of those who started it (44.7% for those resulted TST positive). Major losses (55%) were detected in the TST/CXR-IGRA sequential step, followed by the execution of TST test (25%). The ratio of screening completion was significantly higher in the intervention period (aIRR 1.78, 95% CI 1.68–1.88) and for AS coming from high incidence TB countries (aIRR 1.14, 95% CI 1.04–1.25). Screening after 6 months from arrival and age were associated with TB infection (2.09, 95% CI 1.36–3.2 and 1.14, 95% CI 1.01–1.29). Conclusions: Screening for TBI can be improved by a centralized approach. Higher prevalence of TBI 6 months after arrival could reflect recent (either during travel or in Italy) acquisition of the infection.
Sequencing-Based Genotyping of Pakistani Burkholderia mallei Strains: A Useful Way for Investigating Glanders Outbreaks
Authors: Brangsch Hanka , Saqib Muhammad , Sial Awais ur Rehman , Melzer Falk , Linde Jörg , Elschner Mandy Carolina
Published: May 2022

Burkholderia (B.) mallei is a host-adapted equine pathogen that causes glanders, a re-emerging zoonotic disease, which is endemic in Pakistan and other developing countries and seriously impacts the global equine movement. Due to globalization, the geographical restriction of diseases vanishes and the lack of awareness of and experience with eradicated diseases in industrialized countries also promotes the re-introduction of infections in these regions. Owing to the high equine population, the Pakistani province Punjab is a potential hotspot where several glanders outbreaks have been seen over last two decades. For determining the genomic diversity of B. mallei in this and other equine-populated prefectures, the genomes of 19 B. mallei strains isolated between 1999 and 2020 in different locations were sequenced and their genotypes were determined. Particularly, for genetically highly homogenous pathogens like B. mallei genotyping techniques require a high discriminatory power for enabling differentiation on the strain level. Thus, core-genome single nucleotide polymorphism (cgSNP) analysis was applied for distinguishing the highly similar strains. Furthermore, a whole-genome sequence-based core genome multi locus sequence typing (cgMLST) scheme, specific to B. mallei, was developed and additionally applied to the data. It was found that B. mallei genotypes in Pakistan persisted over time and space and genotype clusters preferred connection with a time point rather than the place of isolation, probably due to frequent equine movement, which promotes the spread of glanders. The cgMLST approach proved to work in accord with SNP typing and may help to investigate future glanders outbreaks.
Role of Vaginal Mucosa, Host Immunity and Microbiota in Vulvovaginal Candidiasis
Authors: Balakrishnan Subatrra Nair , Yamang Haizat , Lorenz Michael C. , Chew Shu Yih , Than Leslie Thian Lung
Published: May 2022

Vulvovaginal candidiasis (VVC) is a prevalent gynaecological disease characterised by vaginal wall inflammation that is caused by Candida species. VVC impacts almost three-quarters of all women throughout their reproductive years. As the vaginal mucosa is the first point of contact with microbes, vaginal epithelial cells are the first line of defence against opportunistic Candida infection by providing a physical barrier and mounting immunological responses. The mechanisms of defence against this infection are displayed through the rapid shedding of epithelial cells, the presence of pattern recognition receptors, and the release of inflammatory cytokines. The bacterial microbiota within the mucosal layer presents another form of defence mechanism within the vagina through acidic pH regulation, the release of antifungal peptides and physiological control against dysbiosis. The significant role of the microbiota in maintaining vaginal health promotes its application as one of the potential treatment modalities against VVC with the hope of alleviating the burden of VVC, especially the recurrent disease. This review discusses and summarises current progress in understanding the role of vaginal mucosa and host immunity upon infection, together with the function of vaginal microbiota in VVC.
Determination of the Dissolution/Permeation and Apparent Solubility for Microencapsulated Emamectin Benzoate Using In Vitro and Ex Vivo Salmo salar Intestine Membranes
Authors: Molina Victoria , Plessing Carlos von , Romero Alex , Benavides Sergio , Troncoso José Miguel , Pérez-Correa José Ricardo , Franco Wendy
Published: May 2022

In this work, two microencapsulation techniques were used to protect and improve the absorption of emamectin benzoate (EB), which is an antiparasitic drug used to control Caligus rogercresseyi. EB has a low aqueous solubility, which affects its absorption in the intestine of Salmo salar. Microparticles were produced by spray drying and ionic gelation, using Soluplus® (EB–SOL) and sodium alginate (EB–ALG) as polymers, respectively. Studies were conducted on dissolution/permeation, apparent permeability (Papp), apparent solubility (Sapp), and absorption using synthetic and biological membranes. Based on these results, the amount of EB in the microparticles needed to achieve a therapeutic dose was estimated. The EB–ALG microparticles outperformed both EB–SOL and free EB, for all parameters analyzed. The results show values of 0.45 mg/mL (80.2%) for dissolution/permeation, a Papp of 6.2 mg/mL in RS–L, an absorption of 7.3% in RS, and a Sapp of 53.1% in EM medium. The EB–ALG microparticles decrease the therapeutic dose necessary to control the parasite, with values of 3.0−2 mg/mL and 1.1−2 mg/mL for EB in EM and RS, respectively. The Korsmeyer–Peppas kinetic model was the best model to fit the EB–ALG and EB–SOL dissolution/permeation experiments. In addition, some of our experimental results using synthetic membranes are similar to those obtained with biological membranes, which suggests that, for some parameters, it is possible to replace biological membranes with synthetic membranes. The encapsulation of EB by ionic gelation shows it is a promising formulation to increase the absorption of the poorly soluble drug. In contrast, the spray-dried microparticles produced using Soluplus® result in even less dissolution/permeation than free EB, so the technique cannot be used to improve the solubility of EB.
Technologies for Solubility, Dissolution and Permeation Enhancement of Natural Compounds
Authors: Alshamrani Meshal , Khan Muhammad Khalid , Khan Barkat Ali , Salawi Ahmad , Almoshari Yosif
Published: May 2022

The current review is based on the advancements in the field of natural therapeutic agents which could be utilized for a variety of biomedical applications and against various diseases and ailments. In addition, several obstacles have to be circumvented to achieve the desired therapeutic effectiveness, among which limited dissolution and/or solubility and permeability are included. To counteract these issues, several advancements in the field of natural therapeutic substances needed to be addressed. Therefore, in this review, the possible techniques for the dissolution/solubility and permeability improvements have been addressed which could enhance the dissolution and permeability up to several times. In addition, the conventional and modern isolation and purification techniques have been emphasized to achieve the isolation and purification of single or multiple therapeutic constituents with convenience and smarter approaches. Moreover, a brief overview of advanced natural compounds with multiple therapeutic effectiveness have also been anticipated. In brief, enough advancements have been carried out to achieve safe, effective and economic use of natural medicinal agents with improved stability, handling and storage.
Development of Photoremovable Linkers as a Novel Strategy to Improve the Pharmacokinetics of Drug Conjugates and Their Potential Application in Antibody–Drug Conjugates for Cancer Therapy
Authors: Johan Audrey Nathania , Li Yi
Published: May 2022

Although there have been extensive research and progress on the discovery of anticancer drug over the years, the application of these drugs as stand-alone therapy has been limited by their off-target toxicities, poor pharmacokinetic properties, and low therapeutic index. Targeted drug delivery, especially drug conjugate, has been recognized as a technology that can bring forth a new generation of therapeutics with improved efficacy and reduced side effects for cancer treatment. The linker in a drug conjugate is of essential importance because it impacts the circulation time of the conjugate and the release of the drug for full activity at the target site. Recently, the light-triggered linker has attracted a lot of attention due to its spatiotemporal controllability and attractive prospects of improving the overall pharmacokinetics of the conjugate. In this paper, the latest developments of UV- and IR-triggered linkers and their application and potential in drug conjugate development are reviewed. Some of the most-well-researched photoresponsive structural moieties, such as UV-triggered coumarin, ortho-nitrobenzyl group (ONB), thioacetal ortho-nitrobenzaldehyde (TNB), photocaged C40-oxidized abasic site (PC4AP), and IR-triggered cyanine and BODIPY, are included for discussion. These photoremovable linkers show better physical and chemical stabilities and can undergo rapid cleavage upon irradiation. Very importantly, the drug conjugates containing these linkers exhibit reduced off-target toxicity and overall better pharmacokinetic properties. The progress on photoactive antibody–drug conjugates, such as antibody–drug conjugates (ADC) and antibody–photoabsorber conjugate (APC), as precision medicine in clinical cancer treatment is highlighted.
Cardiac 123I-mIBG Imaging in Heart Failure
Authors: Verschure Derk O. , Nakajima Kenichi , Verberne Hein J.
Published: May 2022

Cardiac sympathetic upregulation is one of the neurohormonal compensation mechanisms that play an important role in the pathogenesis of chronic heart failure (CHF). In the past decades, cardiac 123I-mIBG scintigraphy has been established as a feasible technique to evaluate the global and regional cardiac sympathetic innervation. Although cardiac 123I-mIBG imaging has been studied in many cardiac and neurological diseases, it has extensively been studied in ischemic and non-ischemic CHF. Therefore, this review will focus on the role of 123I-mIBG imaging in CHF. This non-invasive, widely available technique has been established to evaluate the prognosis in CHF. Standardization, especially among various combinations of gamma camera and collimator, is important for identifying appropriate thresholds for adequate risk stratification. Interestingly, in contrast to the linear relationship between 123I-mIBG-derived parameters and overall prognosis, there seems to be a “bell-shape” curve for 123I-mIBG-derived parameters in relation to ventricular arrhythmia or appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ischemic CHF. In addition, there is a potential clinical role for cardiac 123I-mIBG imaging in optimizing patient selection for implantation of expensive devices such as ICD and cardiac resynchronization therapy (CRT). Based on cardiac 123I-mIBG data risk models and machine learning, models have been developed for appropriate risk assessment in CHF.
Inflammatory Biomarkers of Traumatic Brain Injury
Authors: Johnson Nathan H. , Hadad Roey , Taylor Ruby Rose , Rodríguez Pilar Javier , Salazar Osman , Llompart-Pou Juan Antonio , Dietrich W. Dalton , Keane Robert W. , Pérez-Bárcena Jon , de Rivero Vaccari Juan Pablo
Published: May 2022

Traumatic brain injury (TBI) has a complex pathology in which the initial injury releases damage associated proteins that exacerbate the neuroinflammatory response during the chronic secondary injury period. One of the major pathological players in the inflammatory response after TBI is the inflammasome. Increased levels of inflammasome proteins during the acute phase after TBI are associated with worse functional outcomes. Previous studies reveal that the level of inflammasome proteins in biological fluids may be used as promising new biomarkers for the determination of TBI functional outcomes. In this study, we provide further evidence that inflammatory cytokines and inflammasome proteins in serum may be used to determine injury severity and predict pathological outcomes. In this study, we analyzed blood serum from TBI patients and respective controls utilizing Simple Plex inflammasome and V-PLEX inflammatory cytokine assays. We performed statistical analyses to determine which proteins were significantly elevated in TBI individuals. The receiver operating characteristics (ROC) were determined to obtain the area under the curve (AUC) to establish the potential fit as a biomarker. Potential biomarkers were then compared to documented patient Glasgow coma scale scores via a correlation matrix and a multivariate linear regression to determine how respective biomarkers are related to the injury severity and pathological outcome. Inflammasome proteins and inflammatory cytokines were elevated after TBI, and the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, tumor necrosis factor (TNF)-α, IL-4 and IL-6 were the most reliable biomarkers. Additionally, levels of these proteins were correlated with known clinical indicators of pathological outcome, such as the Glasgow coma scale (GCS). Our results show that inflammatory cytokines and inflammasome proteins are promising biomarkers for determining pathological outcomes after TBI. Additionally, levels of biomarkers could potentially be utilized to determine a patient’s injury severity and subsequent pathological outcome. These findings show that inflammation-associated proteins in the blood are reliable biomarkers of injury severity that can also be used to assess the functional outcomes of TBI patients.
Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats
Authors: Treshchalin Michael I. , Polozkova Vasilisa A. , Moiseenko Elena I. , Treshalina Helen M. , Shchekotikhin Andrey E. , Pereverzeva Eleonora R.
Published: May 2022

Glycopeptide antibiotics have side effects that limit their clinical use. In view of this, the development of glycopeptides with improved chemotherapeutic properties remains the main direction in the search for new antibacterial drugs. The objective of this study was to evaluate the toxicological characteristics of new semi-synthetic glycopeptide flavancin. Acute and chronic toxicity of antibiotic was evaluated in Wistar rats. The medium lethal dose (LD50) and the maximum tolerated doses (MTD) were calculated by the method of Litchfield and Wilcoxon. In the chronic toxicity study, the treatment regimen consisted of 15 daily intraperitoneal injections using two dosage levels: 6 and 10 mg/kg/day. Total doses were equivalent to MTD or LD50 of flavancin, respectively. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that no clinical-laboratory signs of toxicity were found after 15 daily injections of flavancin at a total dose close to the MTD or LD50. The pathomorphological study did not reveal any lesions on the organ structure of animals after low-dose administration of flavancin. Thus, flavancin favorably differs in terms of toxicological properties from the glycopeptides currently used in the clinic.
Drug-Drug Interactions of Direct Oral Anticoagulants (DOACs): From Pharmacological to Clinical Practice
Authors: Ferri Nicola , Colombo Elisa , Tenconi Marco , Baldessin Ludovico , Corsini Alberto
Published: May 2022

The direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are becoming the most commonly prescribed drugs for preventing ischemic stroke in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). Rivaroxaban was also recently approved for the treatment of patients with a recent acute coronary syndrome (ACS). Their use demonstrated to have a favorable risk-benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality compared to warfarin, but with increased gastrointestinal bleeding. Nevertheless, their safety profile is compromised in multimorbidity patients requiring contemporary administration of several drugs. Comorbidity and polypharmacy have a high prevalence in elderly patients, who are also more susceptible to bleeding events. The combination of multiple treatments can cause relevant drug–drug interactions (DDIs) by affecting the exposure or the pharmacological activities of DOACs. Although important differences of the pharmacokinetic (PK) properties can be observed between DOACs, all of them are substrate of P-glycoprotein (P-gp) and thus may interact with strong inducers or inhibitors of this drug transporter. On the contrary, rivaroxaban and, to a lower extent, apixaban, are also susceptible to drugs altering the cytochrome P450 isoenzyme (CYP) activities. In the present review, we summarize the potential DDI of DOACs with several classes of drugs that have been reported or have characteristics that may predict clinically significant DDIs when administered together with DOACs. Possible strategies, including dosage reduction, avoiding concomitant administration, or different time of treatment, will be also discussed to reduce the incidence of DDI with DOACs. Considering the available data from specific clinical trials or registries analysis, the use of DOACs is associated with fewer clinically relevant DDIs than warfarin, and their use represents an acceptable clinical choice. Nevertheless, DDIs can be significant in certain patient conditions so a careful evaluation should be made before prescribing a specific DOAC.
A Novel High-Affinity Potassium Transporter IbHKT-like Gene Enhances Low–Potassium Tolerance in Transgenic Roots of Sweet Potato (Ipomoea batatas (L.) Lam.)
Authors: Jiang Wei , Jin Rong , Wang Danfeng , Yang Yufeng , Zhao Peng , Liu Ming , Zhang Aijun , Tang Zhonghou
Published: May 2022

The high-affinity potassium transporters (HKT) mediate K+-Na+ homeostasis in plants. However, the function of enhancing low-potassium tolerance in sweet potato [Ipomoea batatas (L.) Lam.] remains unrevealed. In this study, a novel HKT transporter homolog IbHKT-like gene was cloned from sweet potato, which was significantly induced by potassium deficiency stress. IbHKT-like overexpressing transgenic roots were obtained from a sweet potato cultivar Xuzishu8 using an Agrobacterium rhizogenes-mediated root transgenic system in vivo. Compared with the CK, whose root cells did not overexpress the IbHKT-like gene, overexpression of the IbHKT-like gene protected cell ultrastructure from damage, and transgenic root meristem cells had intact mitochondria, endoplasmic reticulum, and Golgi dictyosomes. The steady-state K+ influx increased by 2.2 times in transgenic root meristem cells. Overexpression of the IbHKT-like gene also improved potassium content in the whole plant, which increased by 63.8% compared with the CK plants. These results could imply that the IbHKT-like gene, as a high-affinity potassium transporter gene, may play an important role in potassium deficiency stress responses.