In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD). Psychological stress and various inflammatory comorbidities contribute to such immune activation. Still, this is not uncommon that patients with depression do not have defined inflammatory comorbidities, and alternative mechanisms of immune activation need to take place. The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. There is a broad range of reciprocal interactions between the GI tract, intestinal microbiota, increased intestinal permeability, activation of immune-inflammatory response, and the CNS that has crucial implications in brain function and mental health. This intercommunication takes place within the microbiota-gut-immune-glia (MGIG) axis, and glial cells are the main orchestrator of this communication. A broad range of factors, including psychological stress, inflammation, dysbiosis and other, may compromise the permeability of this barrier. This leads to excessive bacterial translocation and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. This chapter summarizes the role of increased intestinal permeability in MDD and mechanisms of how the "leaky gut" may contribute to immune-inflammatory response in this disorder.

In our previous study, a novel barrier processing on a porous low-dielectric constant (low-k) film was developed: an ultrathin Mn oxide on a nitrogen-stuffed porous carbon-doped organosilica film (p-SiOCH(N)) as a barrier of the Cu film was fabricated. To form a better barrier Mn₂O_3-xN film, an additional annealing at 450°C was implemented. In this study, the electrical characteristics and reliability of this integrated Cu/Mn₂O_3-xN/p-SiOCH(N)/Si structure is investigated. The proposed Cu/Mn₂O_3-xN/p-SiOCH(N)/Si capacitors exhibited poor dielectric breakdown characteristics in the as-fabricted stage, although, less degradation was found after thermal stress. Moreover, its time-dependence-dielectric-breakdown electric-field acceleration factor slightly increased after thermal stress, leading to a larger dielectric lifetime in a low electric-field as compared to other MIS capacitors. Furthermore, its Cu barrier ability under electrical or thermal stress was improved. As a consequent, the proposed Cu/Mn₂O_3-xN/p-SiCOH(N) scheme is a promising integrity for back-end-of-line interconnects.

Using co-precipitation to synthesize (CeO2)0.95(Y2O3)0.05 (YDC) and solid reaction method to synthesize (CeO2)0.75(ZrO2)0.25 (ZDC), and the characterization for both crystal structure and micro-structure of the two materials was conducted with X-ray diffraction (XRD) and scanning electron microscope (SEM) methods. Prepare the YDC and ZDC based limited current O2 sensor by employing platinum pasting bonding method. Sensing characteristics of the sensor were obtained at different conditions and study on the impact of temperature, O2 concentration as well as water vapor pressure on the sensing characteristics had been conducted. XRD results show that the phase structure of both YDC and ZDC is cubic phase. SEM results show that both YDC and ZDC layers are dense layers, which are then qualified to be the composition materials of the sensor. This limited current O2 sensor shows good sensing performance and conforms to the Knudsen model. Log(IL•T) depends linearly on 1000/T with R2 of 0.9904, IL depends linearly on x(O2) with R2 of 0.9726 and sensing characteristics are not affected by p(H2O).

The neurodegenerative diseases (Alzheimers, Parkinsons, amyotrophic lateral sclerosis, Huntingdons) and the prion disorders, have in common a dysregulation of metalloprotein chemistry involving redox metals (Cu,Fe,Mn). The consequent oxidative stress gives rise to protein plaques and neuronal cell death. An equilibrium exists between the functional requirement of the brain for Cu and Fe and their destructive potential with the production of reactive oxygen species. The importance of the brain barrier is highlighted in regulating the import of these metals. Upregulation of key transporters occurs in foetal and neonatal life when brain metal requirement is high and is down-regulated in adult life when need is minimal. By contrast a neonatal mode of CTR1 upregulation persists in feral N.Ronaldsay sheep. This has led to the premise that metal regulation may return to the default setting in ageing with implications for neurodegenerative disease.

Patterns of age and growth of a sedentary damsel fish Acanthochromis polyacanthus were tested over a latitudinal range of approximately 10 degrees (1,200 km) on the Great Barrier Reef, Australia. Within latitudes these patterns were also compared on reefs across a continental shelf that ranged in width from 52 to 128 km. Although variation in length-max, growth, age-max and the von-Bertalanffy metrics of L, and K were found within and among latitudes, greatest variation in some demographic characteristics were found across the shelf regardless of latitude. Fish were always smaller at inner shelf reefs and grew more slowly when compared to mid and outer shelf reefs. The oldest fish collected was 11 years old and, there were no consistent variation in age-max among distances from shore. On outer reefs, there was a linear relationship with age-max and latitude. This ‘tropical gradient’ of age only explained 34% of the variation, further this was not found when the oldest 10% of fish were considered. Fish only reached an age-max of 6 years on the southern-most reefs. There was a trend for a smaller L with latitude but, it was not significant and L did not vary predictably with water temperature. The sampling of MPAs did not confound the resultant patterns. Instantaneous mortality rates were 0.245-0.685, highest at inner reefs and showed no consistent MPA-related patterns. Our study suggested that the mid and outer shelf waters of the GBR appeared best suited for growth of A. polyacanthus. In conclusion, position on continental shelves and related local environmental conditions needs to be considered in spatial models of growth.

Glioblastoma (GBM) is the most aggressive brain cancer. To model GBM in research, orthotopic brain tumor models, including syngeneic models like GL261 and genetically engineered mouse models like TRP, are used. In longitudinal studies, tumor growth and treatment response are typ-ically tracked with in vivo imaging, including bioluminescence imaging (BLI), which is quick, cost-effective, and easily quantifiable. However, BLI requires luciferase-tagged cells, and recent studies indicate that the luciferase gene can elicit an immune response, leading to tumor rejection and experimental variation. We sought to optimize the engraftment of two luciferase-expressing GBM models, GL261 Red-FLuc and TRP-mCherry-FLuc, showing differences in tumor take, with GL261 Red-FLuc cells requiring immunocompromised mice for 100% engraftment. Immuno-histochemistry and MRI revealed distinct tumor characteristics: GL261 Red-FLuc tumors were well-demarcated with densely packed cells, high mitotic activity, and vascularization. In con-trast, TRP-mCherry-FLuc tumors were large, invasive, and necrotic, with perivascular invasion. Quantifying tumor volume using the HALO® AI analysis platform yielded results comparable to manual measurements, providing a standardized and efficient approach for reliable high-throughput analysis of luciferase-expressing tumors. Our study highlights the importance of considering tumor engraftment when using luciferase-expressing GBM models, providing in-sights for preclinical research design.

Temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal net-works, gliosis, neuroinflammation, loss of integrity of the blood-brain barrier (BBB) in humans and animal models. More than 30% of epilepsies remain intractable and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new thera-peutic strategies. In this work, we induced status epilepticus in rats by injection of the proconvul-sant drug pilocarpine that leads to TLE. Using RT-qPCR, double immunohistochemistry and con-focal imaging, we studied at different time points of epileptogenesis (latent phase, 3, 7, 14 days; chronic phase, 1 and 3 months) the regulation of reactive glia and vascular markers. In the hippo-campus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neu-roinflammatory status. We report for the first time the concomitant induction in endothelial cells, pericytes and basement membrane of the BBB of specific proteins CD31, PDGFR and ColIV, that peaks at the same time points as inflammation. The altered expression of these proteins occurs ear-ly in TLE, during the latent phase, suggesting that they could be associated with early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy.

Abstract: Filipendula ulmaria, commonly known as meadowsweet, is a wild herbaceous flowering plant widely distributed in Europe. A range of salicylic acid derivatives and flavonol glycosides have been previously associated with the antirheumatic and diuretic properties of F. ulmaria. In the present work, an hydroalcoholic extract of F. ulmaria aerial parts was extensively profiled using an efficient NMR-based dereplication strategy. The approach involves fractionation of the crude extract by centrifugal partition chromatography (CPC), ¹³C NMR analysis of the fractions, 2D-cluster mapping of the whole NMR dataset and finally, structure elucidation using a natural metabolite database, validated by 2D NMR data interpretation and liquid chromatography coupled to mass spectrometry. The chemodiversity of the aerial parts was quite broad, with 28 compounds unambiguously identified, belonging to various biosynthetic classes. The F.ulmaria extract and CPC fractions were screened for their potential to improve skin epidermal barrier function and also skin renewal properties using in vitro assays performed on Normal Human Epidermal Keratinocytes. Fractions containing quercetin, kaempferol glycosides, ursolic acid, pomolic acid, naringenin, β-sitosterol, and tellimagrandins I and II were found to be responsible for the up-regulation of genes related to skin barrier function, epidermal renewal and stress responses. This research is significant as it could provide a natural solution for improving hydration and skin renewal properties.

As the name implies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus and a member of the corona virus family, primarily affecting the upper respiratory system and the lungs. Like many other respiratory viruses, SARS-CoV-2 can spread to other organ systems. Apart from causing diarrhea, another most common but debilitating complication caused by the SARS-CoV-2 is neurological symptoms and cognitive difficulties, which occur in up to two thirds of hospitalized covid patients and ranging from shortness of concentration, overall declined cognitive speed to executive or memory function impairment. Neuro-cognitive dysfunction and “brain fog” are frequently present in COVID-19 cases, which can last several months after the infection, leading to disruption of daily life. Cumulative evidence suggests that SARS-CoV-2 affects vasculature in the extra pulmonary systems directly or indirectly, leading to impairment of endothelial function and even multi-organ damage. The post COVID-19 long-lasting neurocognitive impairments have not been studied fully; and the underlying mechanism remains elusive. In this review, we summarize the current understanding of the effects of COVID-19 on vascular dysfunction and how vascular dysfunction leads to cognitive impairment in patients.

: Polymer single screw extrusion is a major industrial processing technique used to obtain plastics products. To assure high outputs, tight dimensional tolerances, and excellent product performance, extruder screws may show different design characteristics. Barrier screws, which contain a second flight in the compression zone, have become quite popular as they promote and stabilize polymer melting. Therefore, it is important to design efficiently extruder screws and decide whether a conventional screw will do the job efficiently, or a barrier-screw should be considered instead. This work uses multi-objective evolutionary algorithms to design conventional and barrier screws (Maillefer screws will be studied) with optimized geometry. Processing of two polymers, Low Density Polyethylene and Polypropylene, is analyzed. A methodology based on the use of Artificial Intelligence (AI) techniques, namely data mining, decision making and evolutionary algorithms, is presented and utilized to obtain results with practical significance, based on relevant performance measures (objectives) used in the optimization. For the various case studies selected, Maillefer screws were generally advantageous for processing LDPE, while for PP the use of both types of screws would be feasible.

Current lines of research into mood disorders indicate that immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain functions, even when these mediators are produced in peripheral tissues. Elevated levels of circulating immune molecules have been consistently associated with depressive symptoms in a number of clinical populations and experimental models, to the extent that major depressive disorder (MDD) is now seen, at least in part, as a disorder of immunity. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy with the hope to improve treatment efficacy, particularly in those cohorts that do not respond well to standard medication. Such new practice requires the availability of biomarkers to tailor these new therapies to those most likely to benefit but also clear mechanisms of action describing the interaction between peripheral immunity and brain function. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease through peripherally induced sickness behaviour as the model for immune-induced MDD. After an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we propose a modified model of periphery-brain interaction that goes beyond the currently established view of interaction between peripheral cytokines and microglia cells as the driver of depression. Instead, we suggest that brain barriers are primary actors in the communication between body and brain and, as a consequence, in the pathophysiology of the disease. This model suggests novel biomarkers, novel targets for therapies as well as a novel mechanism for resistance to standard treatments.

The oral cavity is the gateway for microorganisms into your body where they disseminate not only to the directly connected respiratory and digestive tracts, but also to the many remote organs. Oral microbiota, traveling to the end of the intestine and circulating our body through blood vessels, not only affect a gut microbiome profile, but also many systemic diseases. By gathering information accumulated from the era of focal infection theory to the age of revolution in microbiome research, we propose a pivotal role of “leaky gum”, as an analogy of “leaky gut”, to underscore the importance of the oral cavity in systemic health. The oral cavity has unique structures, the gingival sulcus (GS) and the junctional epithelium (JE) below the GS, which are rarely found anywhere else in our body. The JE is attached to the tooth enamel and cementum by hemidesmosome (HD), which is structurally weaker than desmosome and is thus vulnerable to microbial infiltration. In the GS, microbial biofilms can build up for life, unlike the biofilms on the skin and intestinal mucosa that fall off by natural process. Thus, we emphasize that the GS and the JE are the weakest leaky point for microbes to invade human body, making the leaky gum just as important as, or even more important than, the leaky gut.

Intranasal (i.n.) administration became an alternative strategy to bypass the blood-brain barrier and improve drug bioavailability in the brain. The main goal of this work was to preliminarily study the biodistribution of mixed amphiphilic mucoadhesive nanoparticles made of chitosan-g-poly(methyl methacrylate) and poly(vinyl alcohol)-g-poly(methyl methacrylate) and ionotropically crosslinked with sodium tripolyphosphate in the brain after intravenous (i.v.) and i.n. administration to Hsd:ICR mice. After i.v. administration, the highest nanoparticle accumulation was detected in the liver, among other peripheral organs. After i.n. administration of a 10-times smaller nanoparticle dose, the accumulation of the nanoparticles in off-target organs was much lower than after i.v. injection. In particular, the accumulation of the nanoparticles in the liver was 20 times lower than by i.v. When brains were analyzed separately, intravenously administered nanoparticles accumulated mainly in the “top” brain, reaching a maximum after 1h. Conversely, in i.n. administration, nanoparticles were detected in the “bottom” brain and the head (maximum reached after 2 h) owing to their retention in the nasal mucosa and could serve as a reservoir from which the drug is released and transported to the brain over time. Overall results indicate that i.n. nanoparticles reach similar brain bioavailability, though with a 10-fold smaller dose, and accumulate in off-target organs to a more limited extent and only after redistribution through the systemic circulation. At the same time, both administration routes seem to lead to differential accumulation in brain regions and thus, they could be beneficial in the treatment of different medical conditions.

Titanium dioxide (TiO2) and aluminum oxide (Al2O3) coatings have been investigated in a wide range of bio-applications due to their biodegradation and biocompatibility properties, that are key parameters for their use in the food packaging and biomedical devices fields. The present study evaluates and compares the electrochemical behavior of the non-coated, commercial resin-coated, TiO2-coated and Al2O3-coated aluminum in commercial beer electrolyte. For this, TiO2 and Al2O3 thin films were deposited on aluminum (Al) substrates using atomic layer deposition (ALD). The evaluation of the corrosion barrier layer properties was performed by linear sweep voltammetry (LSV) and electrochemical impedance spectroscopy (EIS). In addition, profilometry, grazing incidence X-ray diffractometry (GIXRD), scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FT-IR) analyses were performed to investigate the physical and chemical properties of the pristine and / or corroded samples. TiO2 and Al2O3 films presented an amorphous structure, a morphology that follows Al substrate surface, and a thickness of around 100 nm. Analysis of LSV data showed that ALD coatings promoted a considerable increase in corrosion barrier efficiency being 86.3% for TiO2-coated Al and 80% for Al2O3-coated Al in comparison with 7.1% of commercial resin-coated Al. This is mainly due to the lower electrochemical porosity, 11.4% for TiO2-coated Al and 20.4% for Al2O3-coated Al in comparison with 96% of the resin-coated Al, i.e. an increase of up to twofold in the protection of Al when coated with TiO2 compared to Al2O3 coated. The EIS results allow us to complement the discussions about the reduced corrosion barrier efficiency of the Al2O3 film for beer electrolyte once SEM and FT-IR analyzes did not show drastic changes in both investigated ALD films after the corrosion assays. The above results indicate that ALD TiO2 and Al2O3 films may be a viable alternative to replace the synthetic resin coatings frequently used in aluminum cans of use in the food industry.

In Europe we can see a change in the social structure in the last period. Average life expectancy has increased dramatically over the last 50 years. Because of the improved life situation and advanced level of health care, older people are slower. With advancing age, the likelihood of experiencing a variety of constraints such as visual impairment, reduced hearing or physical ability increases. In such a life stage tenants are often forced to leave their long-term living space because these homes can not serve "new" individual needs and the resulting personal protection goal. This transition from the privacy of their home to the new environment often appears to be a painful change. They will take their familiar and well-known surroundings, because their homes can not be adapted to serve new needs. It must be the policy’s role to create a new inclusive social space and the requirement for architects and designers to create new goals for the design of an adaptable environment. This is a comprehensive approach to the design of the outer and inner space that could serve people even if there is an unexpected situation and changes in movement and physiological limitations of older people. The contribution shows the results of the survey conducted in Germany and Slovakia. In the survey respondents expressed their opinion on what they considered important in creating an adaptive environment. Results are processed graphically with explanation. The results were mainly for designers and developers of the indoor environment. Based on the results of the questionnaire survey, studies of possible modifications in the interior of the flats were then prepared. The contribution yielded these results in three age groups of respondents; i. people aged 35, 50 and over 50.

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. The rise in airways epithelial barrier permeability alters the tissue homeostasis and allows the allergen and other external agents penetration. Different factors contribute to barrier impairment, such as eosinophilic infiltrate and allergens proteases action: the eosinophilic cationic proteins and the allergens' proteolytic activity have a central role in contributing to epithelial damage. In the airways, the allergens proteases degrade the epithelial junctional proteins allowing the allergen penetration and the uptake by dendritic cells. The increase in allergen-immune system interactions induce the release of the alarmins and the activation of type 2 inflammatory pathways causing, or worsening, the main symptoms at skin, bowel and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic proteases-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance and progression. We further will explore clinical and radiological potential biomarkers of airways remodeling in allergic asthma patients.

The Circular Bioeconomy (CBE) combines the concepts of bioeconomy and circular economy. As an alternative concept to the current fossil-based, linear economy, it de-scribes an economy based on the efficient valorization of biomass. It is regional in nature and aims to improve sustainability. An analysis of the transition process, by identifying its success criteria and assessing its impacts through the modelling of technology-specific scenarios is necessary to ensure that CBE concepts are sustainable. However, a compre-hensive consideration of regional influences on both is lacking. Based on extensive literature research and an expert survey, we (i) present a compre-hensive catalog of CBE success criteria and discuss their region-specific character and (ii) develop a methodology based on evaluation matrices that enable to match CBE technolo-gies with regions. The matrices support the evaluation of technological and regional characteristics influencing the successful CBE implementation. The results show that the success criteria "biomass resources", "technological", and "social" are perceived as highly important, and that most of the success criteria are both region- and technology-specific, highlighting the relevance of developing matrices to match them. We describe such matrices indicatively for the two broadest and most im-portant success criteria clusters “social acceptance” and “biomass supply chain”. With this, we substantiate the regional nature of CBE and raise the awareness on the importance of considering regional conditions in CBE transition processes. Furthermore, we provide practical guidance on how regional conditions can be reflected in the selection of technologies, e.g. in regional CBE technology scenarios.

Device-mediated, non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive techniques and devices have been proposed or investigated to enhance drug delivery across the BBB. This paper presents the current state of the art and case studies that address the pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.

Alzheimer’s disease (AD) and vascular dementia (VaD) together contribute to almost 90% of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in Alzheimer’s disease, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. We thus highlight here the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress, inflammation and demyelination and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.

Neurodegenerative diseases encompass a broad spectrum of profoundly disabling disorders that impact millions of individuals globally. While their underlying causes and pathophysiol-ogy display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, constitutes a shared characteristic among them. Con-sequently, targeting the BBB has emerged as an innovative therapeutic strategy for address-ing neurological diseases. Within this review, we not only explore the neuroprotective, neu-rotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will delve into the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological disorders like Alzheimer’s disease, Parkinson’s disease, and stroke as well as immune-mediated conditions such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological con-texts.

A two-layer Fe-Cr-Al-Zr surface alloy was synthesized on a zirconium substrate by magnetron sputtering and subsequent low-energy high-current electron-beam (LEHCEB) processing. Thicknesses of the top Fe69Cr20Al11 (at.%) relatively large-grained (~1 µm) and transition Fe-Zr Cr-Al amorphous layers were about 0.7 and 0.6 µm, respectively. In turn, the amorphous layer consisted of two Fe64–54Zr8–22Cr21–17Al8–7 and Fe40–16Zr42–78Cr12–4Al6–2 (at.%) sublayers, differing in both zirconium and iron concentrations in wide ranges, which were separated by another nanocrystalline interlayer. The Fe-Cr-Al-Zr surface alloy serve as a diffusion barrier, preventing interaction of the zirconium substrate with oxygen from an environment. It was thermally stable up to ≈1173 K.

In this study the formation of thin-film barrier coatings based on a highly-conducting Bi1.60Er0.4O3 (EDB) solid electrolyte on supporting Ce0.8Sm0.2O1.9 (SDC) electrolyte substrates is implemented for the first time using electrophoretic deposition (EPD). Electrokinetic properties of EDB-based suspensions in a non-aqueous dispersion medium of isopropanol modified with small additions of polyethyleneimine (PEI, 0.26 g/L) and acetylacetone (0.15 g/L), as well as in a mixed isopropanol/acetylacetone (70/30 vol.%) medium are studied. The dependences of the thickness of EDB coatings on voltage and deposition time are obtained using deposition on a model Ni-foil electrode. Preliminary synthesis of a conductive polypyrrole (PPy) polymer film is used to create surface conductivity of non-conductive SDC substrates. The efficiency of using a modified dispersion medium based on isopropanol to obtain a continuous EDB coating 12 μm thick, sintered at a temperature of 850 °C for 5 h, is shown. The microstructure and morphology of the surface of the EDB coating are studied. Pt/SDC/EDB/Pt cell is used to characterize the coating conductivity. The EPD method is shown to be promising for the formation of barrier coatings based on doped bismuth oxide. The developed method can be used for creating cathode barrier layers in SOFC technology.

This study evaluated the anti-inflammatory effects, protection of gut barrier integrity, and stimulation of phagocytosis in peripheral cells of a nutritional supplement based on a synergistic combination of yeast-based ingredients with a unique 1,3/1,6-glucan complex and a consortium of postbiotic Saccharomyces cerevisiae rich in selenium and zinc. The anti-inflammatory effect in Caco-2 cells in the presence and absence of a pro-inflammatory challenge (tumour necrosis factor alpha [TNF-α]/interferon gamma [IFN-ɣ]) showed statistically significant reductions of IFN-ɣ induced protein-10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) levels vs. controls (p < 0.001). Disruption of the gut integrity in the presence or absence of Escherichia coli (ETEC H10407) showed transepithelial electrical resistance (TEER) values higher in the ABB C1® group after 6 hours of testing. Spontaneous build-up of the gut epithelium monolayer over 22 days was also greater in the ABB C1® condition vs. a negative control. ABB C1® showed a significantly higher capacity to stimulate phagocytosis as compared with controls of algae β-1,3-glucan and yeast β-1,3/1,6 glucan (p < 0.001). This study supports the mechanism of action by which ABB C1® may improve the immune response and be useful to prevent infection and allergy in clinical practice.

Cancer is the second biggest cause of death in children. With the development of chemotherapy, there is a substantial increase in overall survival rate over recent 30 years. However, the overall mortality rate in children with cancer still remains 25%, and many survivors experience a decline in overall quality of life and long-term adverse effects caused by treatments. Although cancer cells share common characteristics, pediatric cancers are different from adult cancers in their prevalence, mutation load, and drug response. Therefore, there is an urgent unmet need to develop therapeutic approaches specifically designed for children with cancer. Nanotechnology can potentially overcome the deficiencies of conventional methods of administering chemotherapy and ultimately improve clinical outcomes. The nanoparticle-based drug delivery systems can decrease the toxicity of therapy, provide a sustained or controlled drug release, improve pharmacokinetic properties of loading contents, and achieve a targeted drug delivery with achievable modifications. Further, therapeutic approaches based on combining nanoformulated drugs with novel immunotherapeutic agents are emerging. In this review, we discuss the recently developed nanotechnology-based strategies for treating blood and solid pediatric cancers.

The objective of this study was to assess the ability of producing laminated edible films manufactured using the following proteins; gelatin (G), whey protein isolate (WPI), and polysaccharide; sodium alginate (SA), and to evaluate their physical properties. Additionally, films’ preparation employing these ingredients was optimized through the addition of corn oil (O), Overall, 8-types of laminated films (G-SA, G-WPI, SA-WPI, SA-G-WPI, GO-SAO, GO-WPIO, SAO-WPIO, SAO-GO-WPIO were developed in this study. The properties of the prepared films were characterized through the measurement of; tensile strength (TS), elongation at break point (EB), puncture resistance (PR), tear strength (TT), water vapour permeability (WVP) and oxygen permeability (OP). The microstructure of cross-sections of laminated films was investigated by scanning electron microscopy (SEM). Mechanical properties of films were dramatically enhanced through the addition of film layers. GO-SAO laminate showed the best barrier properties to water vapour (22.6 ± 4.04 g mm/kPa d m2) and oxygen (18.2 ± 8.70 cm3 mm/kPa d m2). SAO-GO-WPIO laminate film was the strongest of all laminated films tested, having the highest TS of 55.77 MPa, PR of 41.36 N and TT of 27.32 N. SA-G-WPI film possessed the highest elasticity with an EB value of 17.4%.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

A frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed over past decades. Accordingly, much evidence has been reported which indicates that microvascular endothelial dysfunction, due to cerebrovascular risk factors (e.g., atherosclerosis, obesity, diabetes, smoking, hypertension, aging), precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis. By incorporating appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the blood-brain barrier (BBB). Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment. This in vivo targeting advantage may be particularly important for repurposing an FDA-approved drug, especially one which has shown the added ability to restore some cognitive functions in certain animal models of Alzheimer's disease (e.g., the anticancer drug bexarotene); this (candidate repurposing) drug up to now, by itself (i.e, without nanocarrier), displayed poor CNS penetration in human subjects.

The central nervous system (CNS) is the final frontier in drug delivery because of the blood-brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in behavioral functions and abnormal KYNA levels have been observed in neuropsychiatric conditions. The current challenge lies in delivering KYNA to the CNS owing to its polar side chain. Recently, C-3 side chain modified KYNA analogs have been shown to cross the BBB; however, it is unclear whether they retain the biological functions of the parent molecule. This study examined the impact of KYNA analogs, specifically SZR-72, SZR-104, and the newly developed SZRG-21, on behavior. The analogs were administered intracerebroventricularly (i.c.v.), and their effects on the motor domain were compared with those of KYNA. Specifically, open field (OF) and rotarod (RR) tests were employed to assess motor activity and skills. SZR-104 increased horizontal exploratory activity in the OF test at a dose of 0.04 μmol/4 μL, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 μmol/4 μL. In the RR test, however, neither KYNA nor its analogs showed any significant differences in motor skills at either dose. Side chain modification affects affective motor performance and exploratory behavior, as the results show for the first time. In this study, we showed that KYNA analogs alter emotional components such as motor-associated curiosity and emotions. Consequently, drug design necessitates the development of precise strategies to traverse the BBB while paying close attention to modifications in their effects on behavior.

Intestinal mucositis (IM) is a common adverse effect of chemotherapy, limiting its clinical application. Edible Chinese medicine, specifically Codonopsis pilosula-derived CP-A, with anti-inflammatory and gastrointestinal protective effects. The present work was to investigate CP-A's role in ameliorating IM and its mechanism using in vitro and rat models. Western blot, immunohistochemical (IHC) and real-time PCR (RT-PCR) analyses were used to assess protein expression related to the extracellular-regulated protein kinases (ERK)/myosin light chain kinase (MLCK)/myosin light chain 2 (MLC2) signaling pathway and tight junction proteins. Enzyme-linked immunosorbent assay (ELISA) was conducted to measure inflammatory factors, and 16S rRNA Amplicon Sequencing was employed for cecum content analysis. The results indicated that CP-A could restore body weight, food intake and histopathological changes in IM rats. Besides, abnormal MLCK activation induced by 5-fluorouracil (5-FU) was attenuated by CP-A via the ERK/MLCK/MLC2 pathway. CP-A treatment improved tight junction protein levels and reduced inflammatory factor expression. On the other hand, intestinal flora experiment demonstrated that CP-A intervention could increase the abundance of lactobacillus. In conclusion, CP-A mitigates 5-FU-induced IM by inhibiting the ERK/MLCK/MLC2 pathway, reducing the expression of inflammatory factors, improving the intestinal mucosal barrier and regulating intestinal flora. This study sheds light on CP-A's therapeutic potential in IM treatment, providing insights for future research.

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognized, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P and its NK1 receptor have been widely studied as a potential therapeutic target. There is evidence that NK1 receptor antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1 receptor has been shown to reduce blood-brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1 receptor has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonist may have some benefit in reducing infection-driven inflammation. However, the NK1 receptor may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. As such, the purpose of this review is to provide a summary of the involvement of substance P in acute inflammation, particularly in the context of traumatic brain injury and stroke.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of blood-brain barrier (BBB) seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Motivated for improving the efficiency and reliability of wind turbine energy conversion, this paper presents an advanced control design that enhances the power regulation efficiency and re-liability. The constrained behaviour of the wind turbine is taken into account, by using the barrier Lyapunov function in the analysis of the Lyapunov direct method. This, consequently, guarantees that the generated power remains within the desired bounds to satisfy the grid power demand. Moreover, a Nussbaum-type function is utilized in the control scheme, to cope with the unpre-dictable wind speed. This eliminates the need for accurate wind speed measurement or estimation. Furthermore, via properly designed adaptive laws, a robust actuator fault-tolerant capability is integrated into the scheme, handling the model uncertainty. Numerical simulations are performed on a high-fidelity wind turbine benchmark model, under different fault scenarios, to verify the effectiveness of the developed design. Also, a Monte-Carlo analysis is exploited for the evaluation of the reliability and robustness characteristics against the model-reality mismatch, measurement errors and disturbance effects.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized mainly by the gradual decay in neuronal function as a consequence of diverse degenerating events primarily including mitochondria dysfunction and cascades of neuro-immune reactions. Besides the acquired harmful reactive oxygen species (ROS), neurotoxins, and amyloid-beta (Aβ) and TAU pathologies in neurons, accumulating evidence with time underlined the roles of cytokines and growth factors in the AD pathogenesis. It may help us in evaluating the propensities and specific mechanism(s) of cytokines and factors impacting neuron upon apoptotic decline. Proinflammatory cytokines often induce inflammation in AD and AD-like pathogenesis in response to the apoptotic scenarios where some growth factors are involved in cytokinetic reactions to activate microglia and causing inflammation in AD. In this report, we comprehensively reviewed role of cytokines and chemokines in immune response to AD and neuropsychiatry. We provided insights into the neuroinflammation and the role of diverse factors including the pro-/anti-inflammatory cytokines, APP, TAU phosphorylation, glycation end products, complement system, and the role of glial cells. Also, we discussed the pathogenic and protective role of macrophage migration inhibitory factors, choroid plexus-, neurotrophic- and hematopoietic -related growth factors in AD. We further shed light on the availability and accessibility of the cytokines across the blood-brain barrier in AD pathophysiology. Taken together, the emerging role of these factors in AD pathology emphasized the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics.

Neuroscience has overwhelmingly and understandably focused on the synaptic modality of signal transmission. There is evidence, however, that from an evolutionary perspective, non-synaptic transmission (NST) preceded synaptic signaling. Moreover, in modern nervous systems, NST coexists and extensively interacts with synaptic transmission modifying neuronal dynamics. In fact, NST remains widespread in complex animals, especially within the interoceptive system where the dearth of insulating barriers such as myelin sheaths and the blood-brain barrier enhances the communication between neural and non-neural tissues mediated by NST. We suggest that this physiological arrangement makes a fundamental contribution to interoception¾the process of sensing visceral states¾which is an essential underpinning of the capacity to feel and the foundation of affective processing.

In this study, Plasma-Activated Water (PAW) was synthesized using a coaxial Dielectric Barrier Discharge (DBD) reactor, benefiting from the elevated capacity of air-flow-assisted DBD discharges to enhance nitrogen-based species concentration. By manipulating operational parameters, including gas flow rate, activation time, and DI water volume, we achieved significant concentrations of Reactive Oxygen and Nitrogen Species (RONS). As a result, the PAW obtained displayed pronounced physicochemical attributes: a pH of 2.06, an ORP of 275mV, conductivity of 3mS/cm, and TDS of 1200 mg/L. A pivotal aspect of this research was the evaluation of the reactor's efficiency, as indicated by metrics like the specific input energy and ozone efficiency yield. The antimicrobial potential of the PAW was also assessed against pathogenic microbes, with remarkable reductions in viability for both Staphylococcus aureus and Escherichia coli (99.99%) and a more moderate decrease for Candida albicans (37%). These findings underscore the capability of the coaxial DBD reactor in crafting high-quality PAW with significant antimicrobial properties, necessitating further studies to validate its broad-spectrum and safe application.

Central Nervous System (CNS) cancers pose a formidable challenge in the medical world, characterized by aggressive behaviors and limited therapeutic options. The emergence of nanomedicine has offered new hope in CNS cancer treatment. The COVID-19 pandemic has further accelerated the need for innovative therapeutic strategies, emphasizing the significance of nanomedicine in this era. This mini review explores the current status of nanomedicine in CNS cancer therapy, with a particular focus on the post-COVID-19 landscape. We discuss the unique challenges presented by CNS cancers, the potential of nanomedicine in overcoming these challenges, and the recent developments in the field. Additionally, we highlight the lessons learned from the pandemic and how they can be applied to improve CNS cancer therapeutics. We also shed light on the evolving regulatory landscape and the prospects of personalized nanomedicine in CNS cancer treatment. The integration of nanomedicine in CNS cancer therapy is becoming increasingly promising, and its role in the post-COVID-19 era is poised to shape the future of neuro-oncology.

Given the accelerating scientific, clinical and consumer interest in highly-prevalent functional gastrointestinal disorders, appropriate therapeutic strategies are needed to address the many aspects of digestive dysfunction. Accumulating evidence for the crucifer-derived bioactive molecule, sulforaphane in upstream cellular defence mechanisms highlights its potential as a therapeutic candidate in targeting functional gastrointestinal conditions together with systemic disorders. This article catalogues the evolution of and rationale for a hypothesis that utilises multifunctional sulforaphane as the initial step in restoring the ecology of the gut ecosystem; it does this primarily by targeting the functions of intestinal epithelial cells. A growing body of work has identified the colonocyte as the driver of dysbiosis, so that targeting gut epithelial function could provide an alternative to targeting the microbes themselves for remediation of microbial dysbiosis. The hypothesis discussed herein has evolved over several years and is supported by case studies showing the application of sulforaphane in gastrointestinal disorders, related food intolerance and several systemic conditions. To our knowledge, this is the first time the effects of sulforaphane have been reported in a clinical environment where several of its key properties within the gut ecosystem appear to be related to its nutrigenomic effects on gene expression.

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates cAMP response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of NMDA receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood-brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.

To contribute to small and medium enterprises (SMEs) sustainable transition into the circular economy, the study proposes the activation of organizational learning (OL) processes – denoted here as multi-level knowledge creation, transfer, and retention processes – as a key phase in introducing circular business models (CBMs) at SME and supply chain (SC) level. The research employs a mixed-method approach, using the focus group methodology to identify contextual elements impacting on CBM-related OL processes, and a survey-based evaluation to single out the most frequently used OL processes inside Italian construction SMEs. As main result, a CBM-oriented OL multi-level model offers a fine-grained understanding of contextual elements acting mutually as barriers and drivers for OL processes, as possible OL dynamics among them. The multi-level culture construct – composed of external stakeholders’, SC stakeholders’, and organizational culture – identify the key element to activate CBM-oriented OL processes. Main implications are related to the identification of cultural, structural, regulatory, and process contextual elements across the external, SC, and organizational levels, and their interrelation with applicable intraorganizational and interorganizational learning processes. The proposed model would contribute to an improved implementation of transitioning into the circular economy utilizing sustainable business models in the construction SMEs.

There is a huge interest in developing novel hollow fiber (HF) membranes able to modulate neural differentiation to produce in vitro blood-brain barrier (BBB) models for biomedical and pharmaceutical research, due to the low cell-inductive properties of the polymer HFs used in current BBB models. In this work, poly(ε-caprolactone) (PCL) and composite PCL/graphene (PCL/G) HF membranes were prepared by phase inversion and were characterized in terms of mechanical, electrical, morphological, chemical, and mass transport properties. The presence of graphene in PCL/G membranes enlarged the pore size and the water flux and presented significantly higher electrical conductivity than PCL HFs. Biocompatibility assay showed that PCL/G HFs significantly increased C6 cells adhesion and differentiation towards astrocytes, may be attributed to their higher electrical conductivity in comparison to PCL HFs. On the other hand, PCL/G membranes produced a cytotoxic effect on the endothelial cell line HUVEC presumably related with a higher production of intracellular reactive oxygen species induced by the nanomaterial in this particular cell line. These results prove the potential of PCL HF membranes to grow endothelial cells and PCL/G HF membranes to differentiate astrocytes, the two characteristic cell types that could develop in vitro BBB models in future 3D co-culture systems.

This paper presents a novel adaptive fault-tolerant neural-based control design for wind turbines with unknown dynamic and unknown wind speed. By utilizing the barrier Lyapunov function in the analysis of the Lyapunov direct method, the constrained behavior of the system is provided in which the rotor speed, its variation and generated power remain in the desired bounds. In addition, input saturation is also considered in terms of smooth pitch actuator bounding. Furthermore, by utilizing a Nussbaum-type function in designing the control algorithm, the unpredictable wind speed variation is captured without requiring accurate wind speed measurement, observation or estimation. Moreover, with the proposed adaptive analytic algorithms, together with the use of radial basis function neural networks, a robust adaptive and fault-tolerant control scheme is developed without the need for precise information about the wind turbine model nor the pitch actuator faults. Additionally, the computational cost of the resultant control law is reduced by utilizing a dynamic surface control technique. The effectiveness of the developed design is verified using theoretical analysis tools and illustrated by numerical simulations on a high-fidelity wind turbine benchmark model with different fault scenarios. Comparison of the achieved results to the ones that can be obtained via an available industrial controller shows the advantages of the proposed scheme.

Placental growth factor (PlGF or PGF) is a member of the VEGF family, which is known to play a critical role in pathological angiogenesis, inflammation, and endothelial cell barrier function. However, the molecular mechanisms by which PlGF mediates its effects in non-proliferative diabetic retinopathy (DR) remain elusive. In this study, we performed transcriptome-wide profiling of differential gene expression for human retinal endothelial cells (HRECs) treated with PlGF antibody. The effect of antibody treatment on the samples was validated using trans-endothelial electric resistance (TEER), and western blot. A total of 3760 genes (1750 upregulated and 2010 downregulated) were found to be differentially expressed between the control and PlGF antibody treatment group. These differentially expressed genes (DEGs) were used for gene ontology and enrichment analysis to identify gene function, signal pathway, and interaction networks. The gene ontology results revealed that catalytic activity (GO:0003824) of molecular function, cell (GO:0005623) of the cellular component, and cellular process (GO:0009987) were among the most enriched biological processes. Pathways such as TGF-β, VEGF-VEGFR2, p53, apoptosis, pentose phosphate pathway, and ubiquitin-proteasome pathway, were among the most enriched, and TGF-β1 was identified as a primary upstream regulator. These data provide new insights into the underlying molecular mechanisms of PlGF in mediating biological functions, in relation to DR.

Over past decades, a frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed. Numerous published studies indicate that preservation of healthy cerebrovascular endothelium can be an important therapeutic target. By incorporating appropriate drug(s) into biomimetic (lipid cubic-phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type 1 (i.e., SR-BI), and crosses the blood-brain barrier. This targeting allows for various Alzheimer’s-related cell types to be simultaneously searched out for localized drug treatment in vivo.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and as such provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may results in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in the epigenetic regulation primarily via modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extra nuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases and we will discuss the potential of their inhibitors for lung injury prevention.

Understanding the dynamic interaction between piles and surrounding soil under vehicular impacts is essential for effectively designing and optimizing soil-embedded vehicle barrier systems. The complex behavior of pile-soil systems under impact loading, attributed to the soil’s nonlinear behavior and large deformation experienced by both components, presents significant simulation challenges. Popular computation techniques, such as the Updated Lagrangian Finite Element Method (UL-FEM), encounter difficulties in scenarios marked by large soil deformation, e.g., impacts involving rigid piles. While mesh-free particle and discrete element methods offer another option, their computational demands for field-scale pile-soil impact simulations are considerable. We introduce the erosion method to bridge this gap by integrating UL-FEM with an erosion algorithm designed for simulating large soil deformations during vehicular impacts. Validation against established physical impact tests confirmed the method’s effectiveness for flexible and rigid pile failure mechanisms. Additionally, this method was used to investigate the effects of soil mesh density, soil domain sizes, and boundary conditions on the dynamic impact response of pile-soil systems. Our findings provide guidelines for optimal soil domain size, mesh density, and boundary conditions. This investigation sets the stage for improved, computationally efficient techniques for the pile-soil impact problem, leading to better pile designs for vehicular impacts.

Abstract: The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may considered as the 1st barrier of a tripartite blood-brain barrier (BBB) consisting of 1) ecGCx; 2) BECs; (3) extravascular compartment of pericytes, extracellular matrix, and perivascular astrocytes, Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally-derived leukocytes into the perivascular spaces (PVS) to result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the 5th review of a series quintet that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are progressively being regarded as a marker of cerebrovascular and neurodegenerative pathology.

Time-domain spectroscopy (TDS) in the Terahertz (THz) frequency range is gaining in importance in nondestructive testing of dielectric materials. One application is the layer thickness measurement of a coating layer. To determine the thickness from the measurement data, the refractive index of the coating layer must be known in the surveyed frequency range. For perpendicular incidence of the radiation, methods exist to extract the refractive index from the measurement data itself without prior knowledge. This paper extends these methods for non-perpendicular incidence, where the polarization of the radiation becomes important. Furthermore, modifications considering effects of surface roughness of the coating are introduced. The new methods are verified using measurement data of a sample of Inconel steel coated with yttria-stabilized zirconia (YSZ) and with COMSOL simulations of the measurement setup. To validate the thickness measurements, scanning electron microscopy (SEM) images of the layer structure are used. The results show good agreement with an average error of 1% for the simulation data and under 4% for the experimental data compared to reference measurements.

Pericytes are increasingly recognized as being important in the control of blood-brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse-human species differences have contributed to confusion. Herein we summarize our present knowledge on the identification of pericytes and pericyte subsets in humans, primarily focusing on recent findings in humans and nonhuman primates. Precise identification and definition of pericytes and pericyte subsets in humans may help us to better understand pericyte biology and develop new therapeutic approaches specifically targeting disease-associated pericyte subsets.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four-dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits a greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

In the present work, three different atmospheric plasma sprayed (APS) alumina coatings were fabricated using three fused and crushed alumina powders of different particle size fine, medium and coarse. The influence of the particle size on thermal properties and micro-structural features of the produced coating were investigated by thermal insulation test and detailed image analysis technique, respectively. The analyzed micro-structural features include the total porosity, pore size (fine, medium, and large) and cracks. All types of cracks were considered in calculations as voids and were evaluated according to their sizes as pores. All spray parameters except the particle size were fixed throughout the spraying process. The results revealed that the fine starting powder has produced the densest coating with the lowest total porosity and that the total porosity increases with an increasing particle size. This was expected as powders of smaller particle size will reach a higher in-flight temperature and velocity than powders of bigger particle sizes as long as the same spray parameters are applied. However, a detailed image analysis investigation on the three produced coatings showed that the fraction of fine pores and cracks versus the total porosity is substantially higher in coatings produced by using fine starting powders than those produced using medium and coarse powders. In this work, a connection between the thermal insulation and the porosity fraction, which includes fine pores and cracks, was revealed.

We report a novel dual-band barrier infrared detector (DBIRD) design using type-II superlattices (T2SLs). The DBIRD structure consists of back-to-back barrier diodes: a "blue channel" (BC) diode which has an nBp architecture, an n-type layer of larger bandgap for absorbing blue band infrared/barrier/p-type layer, and a "red channel" (RC) diode which has an pBn architecture, a p-type layer of smaller bandgap for absorbing red band infrared/barrier/n-type layer. Each has a unipolar barrier using a T2SL lattice matched to a GaSb substrate to impede the flow of majority carriers from the absorbing layer. Each channel in the DBIRD can be independently accessed with a low bias voltage, as is preferable for high-speed thermal imaging. Device modeling of DBIRDs and simulation results of the current-voltage characteristics under dark and illuminated conditions are also presented. They predict that dual-band operation of the DBIRD will produce low dark currents and 27-33% quantum efficiencies for the in-band photons in the BC with λc=5.58 μm, and a nearly-constant 33% in the RC with λc=8.05 μm. The spectral quantum efficiency of the BC for 500 K blackbody radiation is approximately 20% over the range of λ=3 − 4.2 μm, while that of the RC has a peak of 42% at 5.7 μm. The DBIRD may provide improved high-speed dual-band imaging in comparison with NBn dual-band detectors.

Glioblastoma multiforme (GBM) is a glioma and the most aggressive type of brain tumor with a dismal average survival time, despite the standard of care. One promising alternative therapy is boron neutron capture therapy (BNCT), which is a noninvasive therapy for treating locally invasive malignant tumors, including glioma. BNCT involves boron-10-released radiation directly into tumor cells with minimal damage to healthy tissues. This therapy lacks clinically approved targeted blood-brain-barrier-permeating delivery vehicles for therapeutic drug/ boron-10. Nanoparticles, particularly gold nanoparticles (GNPs), are selective and effective drug-delivery vehicles because of their desirable properties, facile synthesis, and biocompatibility. This review discusses historical and current GNP therapeutic applications as a drug delivery vehicle for treating glioma. Furthermore, GNPs loaded with therapeutic drugs, imaging agents, and GBM-targeting antibodies/ peptides to treat GBM will be discussed. Additionally, the importance of upper and lower limits on therapeutic efficacy will be described and explored followed by highlighting their advantages, limitations, and possible toxicity. Recent research and selected important findings for GNP-mediated pharmaceutics in GBM will also be considered.

The necessity to reduce the effect of the greenhouse phenomenon imposed the turn of the food packaging technology to the use of biobased raw materials decreasing the carbon dioxide fingerprint. In this direction alginates derived from brown algae species are of the most promising biobased biopolymers, used for development of edible active coatings, capable to protect food from oxidation/bacterial spoilage. In this study sodium alginate, which was plasticized with glycerol and mixed with a biobased thymol/natural halloysite nanohybrid, was used to develop novel edible active coatings. Active nanocomposite coatings developed by mixing of pure halloysite with sodium alginate/glycerol matrix were produced for comparison purposes. X-Ray and Fourier Transform Infrared Spectroscopy indicated higher compatibility of thymol/halloysite nanohybrid with sodium alginate/glycerol matrix compared to the relevant of pure halloysite. This increased compatibility led to higher tensile properties, water/oxygen barrier properties, and total antioxidant activity. All coating samples were applied as edible active coatings for “tsalafouti” spreadable soft cheese, exhibited a reduction of mesophilic microbial population of more than one log10(cfu/g) unit comparing with uncoated cheese. Moreover, the reduction of mesophilic microbial population was increased by increasing halloysite and thymol content which indicates the sodium alginate/glycerol/thymol/halloysite as promising edible active coatings for “tsalafouti”.

A time-sequential working, spatially multiplexed autostereoscopic 3D display design consisting of a fast switchable RGB-color filter array is presented. The wavelength-selective filter barrier emits the light from a display over a larger active area than common autostereoscopic barrier displays. An optical modelling of wavelength-selective barriers has been used for instance to calculate the light ray distribution properties of that arrangement. To find well working display designs, automated searches by simulation and computational evaluation has been proceeded. Wavelength-selective filter barrier arrangements exhibit characteristics different from common barrier displays with similar barrier pitch and ascent. In particular, these constructions show strong angular luminance dependency under barrier inclination specified by correspondent slant angle. In time-sequential implementation it is important to avoid that quick eye or eyelid movement lead to visible color artifacts. In the millisecond regime tunable liquid crystal Fabry-Pérot color filters for the colors red, green and blue are presented. They consist of a sub-micrometer thick nematic layer sandwiched between dielectric mirrors and ITO-electrodes. These cells shall switch narrow-banding light of red, green or blue. An array for a glasses-free 3D display has to be equipped with several thousand switchable filter elements having different color apertures. The newly introduced design is usable as a multi user display as well as a single user system with user adaptive control.

Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research, and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models are essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models as well as in patients with Alzheimer’s disease, These tools have facilitated our understanding of disease mechanisms, and provided longitudinal monitoring of treatment effect in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood-brain barrier impairment and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes, and discuss outstanding challenges in disease animal models and future outlook in on-chip characterization of imaging biomarkers towards clinical translation.

Enzyme replacement therapy (ERT) improves the somatic manifestations in mucopolysaccharidoses (MPS))．However, because intravenously administered enzymes cannot cross the blood brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.

As the world endures the coronavirus disease 2019 (COVID-19) pandemic, conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.

Spent nuclear fuel and high-level radioactive waste can be disposed in deep horizontal drillholes in sedimentary, metamorphic, or igneous rocks. Horizontal drillhole disposal has safety, operational, and economic benefits: The repository is deep in the brine-saturated zone far below aquifers in a reducing environment of formations that can be shown to have been isolated from the surface for millions of years; its depth provides safety against inadvertent intrusion, earth¬quakes, and near-surface perturbations; it can be placed close to the reactors and interim storage facilities, minimizing transportation; disposal costs per ton of waste can be kept substantially lower than for mined repositories by its smaller size, reduced infrastructure needs, and staged imple¬mentation; and, if desired, the waste could be retrieved using “fishing” technology. In the proposed disposal concept, corrosion-resistant canisters containing unmodified fuel assemblies from commercial reactors would be placed end-to-end in up to 50 cm diameter horizontal drill¬holes, a configuration that reduces mechanical stresses and keeps the temperatures below the boiling point of the brine. Other high-level wastes, such as capsules containing 137Cs and 90Sr, can be disposed in small-diameter drillholes. We provide an overview of this novel disposal concept and its technology, discuss some of its safety aspects, and compare it to mined repositories and the deep vertical borehole disposal concept.

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cells transplantation, may hold promise as stroke therapy because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria, potentially transferrable into ischemic cells, may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells, to critically evaluate the potential of mitochondria-based stem cell therapy for stroke.

Structure from Motion with Multi-View Stereo photogrammetry (SfM) is increasingly utilised in geoscience investigations as a cost-effective method of acquiring high resolution (sub-meter) topographic data, but has not been thoroughly tested in gullied savanna systems. The aim of this study was to test the accuracy of topographic models derived from aerial (via an Unmanned Aerial Vehicle, ‘UAV’) and ground-based (via a handheld digital camera, ‘Ground’) SfM in modelling a hillslope gully system in dry-tropical savanna, and to assess the strengths and limitations of the approach at different scales. A UAV survey covered an entire hillslope gully system (0.715 km²), whereas a Ground survey covered a single gully within the broader system (650 m²). SfM topographic models, including Digital Surface Models (DSM) and dense point clouds, were compared against RTK-GPS point data and a pre-existing airborne LiDAR Digital Elevation Model (DEM). Results indicate UAV SfM can deliver topographic models with a resolution and accuracy suitable to define gully systems at a hillslope scale (e.g., 0.1 m resolution with ~ 0.5 – 1.3 m elevation error), while ground-based SfM is more capable of quantifying gully morphology (e.g., 0.01 m resolution with ~ 0.1 m elevation error). Key strengths of SfM for these applications include: the production of high resolution 3D topographic models and ortho-photo mosaics, low survey instrument costs (< $AUD 3,000); and rapid survey time (4 and 2 hours for UAV and Ground survey respectively). Current limitations of SfM include: difficulties in reconstructing vegetated surfaces; uncertainty as to optimal survey and processing designs; and high computational demands. Overall, this study has demonstrated great potential for SfM to be used as a cost-effective tool to aid in the mapping, modelling and management of hillslope gully systems at different scales, in tropical savanna landscapes and elsewhere.

We present a model of infection dynamics that might explain slower approaching the herd immunity during the covid-19 epidemy in Sweden than it was predicted by a variety of other models; see graphs Fig. \ref{GROWTH2}. The new model takes into account the hierarchic structure of social clusters in the human society. We apply the well developed theory of random walk on the energy landscapes represented mathematically with ultrametric spaces. This theory was created for applications to spin glasses and protein dynamics. To move from one social cluster (valley) to another, the virus should cross a social barrier between them. The magnitude of a barrier depends on the number of social hierarchy's levels composing this barrier. As the most appropriate for the recent situation in Sweden, we consider linearly increasing (with respect to hierarchy's levels) barriers. This structure of barriers matches with a rather soft regulations imposed in Sweden in March 2020. In this model, the infection spreads rather easily inside a social cluster (say working collective), but jumps to other clusters are constrained by social barriers. This model's feature matches with the real situation during the covid-19 epidemy, with its cluster spreading structure. Clusters need not be determined solely geographically, they are based on a number of hierarchically ordered social coordinates. The model differs crucially from the standard models of spread of disease, such as the SIR-model. Our model describes such a specialty of spread of covid-19 virus as the presence of ``super-infectors'' who by performing a kind of random walk on a hierarchic landscape of social clusters spreads infection. In future, this model will be completed by adding the SIR-type counterpart. But, the latter is not a specialty of covid-19 spreading.

Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function – and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goals of this review are to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.

In CNS drug discovery, estimation of brain exposure of lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand the unbound brain exposure by deriving the Kp,uu parameter, the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the most commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores and various Machine Learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds and building of a CNS penetrable compounds library as well as optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand these methods' reliability and ability to predict CNS penetration. We review the in silico, in vitro and in vivo data and their correlation with each other and assess published in silico approaches to predict the BBB penetrability of compounds.

Herpes simplex virus type 1 (HSV-1) is a lifelong pathogen characterized by asymptomatic latent infection in the trigeminal ganglia (TG) with periodic outbreaks of cold sores caused by virus reactivation in the TG and subsequent replication in the oral mucosa. While antiviral therapies can provide relief from cold sores, they are unable to eliminate HSV-1. We provide experimental results that highlight non-thermal plasma (NTP) as a new alternative therapy for HSV-1 infection that would resolve cold sores faster and reduce the establishment of latent infection in the TG. Additionally, this study is the first to explore the use of NTP as a therapy that can both treat and prevent human viral infections. We investigated the antiviral effect of NTP using an in vitro model for HSV-1 cold sores, involving the application of NTP from two separate devices to cell-free HSV-1, HSV-1-infected cells, and uninfected cells. We found NTP reduced the infectivity of cell-free HSV-1, reduced viral replication in HSV-1-infected cells, and diminished the susceptibility of uninfected cells to HSV-1 infection. This triad of antiviral mechanisms of action suggest the potential of NTP as a therapeutic agent effective against HSV-1 infection.

While it is well known that 98-99% of the human genome do not encode proteins, but are nevertheless transcriptionally active and give rise to a broad spectrum of noncoding RNAs (ncRNAs) with complex regulatory and structural functions, specific functions have so far been assigned to only a tiny fraction of all known transcripts. On the other hand, the striking observation of an overwhelmingly growing fraction of ncRNAs, in contrast to an only modest increase in the number of protein-coding genes, during evolution from simple organisms to humans, strongly suggests critical but so far essentially unexplored roles of the noncoding genome for human health and disease pathogenesis. Research into the vast realm of the noncoding genome during the past decades thus lead to a profoundly enhanced appreciation of the multi-level complexity of the human genome. Here, we address a few of the many huge remaining knowledge gaps and consider some newly emerging questions and concepts of research. We attempt to provide an up-to-date assessment of recent insights obtained by molecular and cell biological methods, and by the application of systems biology approaches. Specifically, we discuss current data regarding two questions: (1) By which mechanisms could evolutionary recent ncRNAs with critical regulatory functions in a broad spectrum of cell types (neural, immune, cardiovascular) constitute novel thera-peutic targets in human diseases ? (2) Since noncoding genome evolution is causally linked to brain evolution, and given the pro-found interactions between brain and immune system, could human-specific brain-expressed ncRNAs play a direct or indirect (immune-mediated) role in human diseases? Synergistic with the remarkable recent progress regarding delivery, efficacy, and safety of nu-cleic acid-based therapies, the ongoing large-scale exploration of the noncoding genome for human-specific therapeutic targets is encouraging to proceed with the development and clinical evaluation of novel therapeutic pathways suggested by these research fields.

In this paper, we proposed a novel saddle type FinFET (S-FinFET) to effectively solve problems occurring under the capacitor node of dynamic random-access memory (DRAM) cell and showed how its structure was superior to conventional S-FinFETs in terms of short channel effect (SCE), subthreshold slope (SS), and gate-induced drain leakage (GIDL). The proposed FinFET exhibited 4 times lower Ioff than modified S-FinFET called RFinFET with more improved DIBL characteristics while minimizing Ion reduction compared to RFinFET. Our results also confirmed that the proposed device showed improved DIBL and Ioff characteristics as gate channel length decreased.