Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.

This study investigates the impacts of climate change policies on businesses across various sectors, aiming to understand how these regulations affect operational, financial, and strategic aspects of business management. Utilizing a mixed-methods approach, data was collected from 500 businesses through surveys and interviews, encompassing a wide range of industries, sizes, and geographic locations. The findings reveal a complex landscape where 30% of businesses report positive impacts, primarily in the renewable energy and technology sectors, citing increased demand for green products and improvements in energy efficiency. Conversely, 45% of businesses, especially from manufacturing and agriculture, experience negative impacts, including increased operational costs and regulatory compliance challenges. Notwithstanding, a significant majority of businesses are committed to enhancing their sustainability practices, viewing climate change policies as an opportunity for innovation and long-term growth. The study highlights the nuanced effects of climate change policies, emphasizing the need for sector-specific support measures to alleviate financial and operational burdens on negatively impacted businesses. Moreover, it points to a broader shift towards sustainability within the business community, suggesting that climate policies, despite their varied impacts, are driving significant changes in business strategies towards environmental stewardship.

In a recent paper: “On the time dependency of a₀” the authors claim that they have tested “one of the predictions of the Scale Invariant Vacuum (SIV) theory on MOND” by studying the dependence of the Modified Newtonian Dynamics (MOND) accelera- tion at two data sets, low-z (3.2 × 10⁻⁴ ≤ z ≤ 3.2 × 10⁻²) and high-z (0.5 ≤ z ≤ 2.5). They claim “both samples show a dependency of a₀ from z”. Here, the work men- tioned above is revisited. The explicit analytic expression for the z-dependence of the a0 within the SIV theory is given. Furthermore, the first estimates of the Ω_m within SIV theory give Ω_m = 0.28 ± 0.04 using the low-z data only, while a value of Ω_m = 0.055 is obtained using both data sets. This much lower Ωm leaves no room for non-baryonic matter! Unlike in the mentioned paper above, the slope in the z- dependence of A₀ = log10(a₀) is estimated to be consistent with zero Z-slope for the two data sets. Finally, the statistics of the data are consistent with the SIV predic- tions; in particular, the possibility of change in the sign of the slopes for the two data sets is explainable within the SIV paradigm; however, the uncertainty in the data is too big for the clear demonstration of a z-dependence yet.

Hydrogen sulfide is present in active or extinct volcanic areas (mofettas). The habitable premises in these areas are affected by the presence of hydrogen sulfide, which, even in low concentrations, gives off a bad to unbearable smell. If the living spaces considered are closed enclosures, then a system can be designed to reduce the concentration of hydrogen sulfide. This paper presents a membrane way to reduce the hydrogen sulfide concentration to acceptable limits using a cellulosic derivative-propylene hollow fiber based composite membrane module. The cellulosic derivatives considered were carboxymethyl–cellulose (NaCMC), cellulose acetate (CA), methyl 2–hydroxyethyl–cellulose (MHEC), and 2–hydroxyethyl–cellulose (HEC). In the permeation module, hydrogen sulfide is captured with a solution of cadmium that forms cadmium sulfide, usable as a luminescent substance. The composite membranes were characterized by SEM, EDAX, FTIR, FTIR 2D maps, thermal analysis (TG and DSC) and from the perspective of hydrogen sulfide air removal performance. To determine the process performances, the variables were: the nature of the cellulosic derivative–polypropylene hollow fiber composite membrane, the concentration of hydrogen sulfide in the polluted air, the flow rate of polluted air, and the pH of the cadmium nitrate solution. Pertraction efficiency was maximum for the sodium carboxymethyl–cellulose (NaCMC)-polypropylene hollow fiber membrane, a hydrogen sulfide concentration in the polluted air of 20 ppm, polluted air flow rate of 50 L/min, and a pH of 2 and 4.

The Notch signaling pathway plays a major role in embryological development and in the ongoing life processes of many animals. Its role is to provide cell-to-cell communication in which a Sender cell, bearing membrane -embedded ligands, instructs a Receiver cell, bearing membrane- embedded receptors, to adopt one of two available fates. Elucidating the evolution of this pathway is the topic of this paper, which uses an orthologs approach to build a firm base for such a study. Using BLAST searches, orthologs were identified for all of the 49 listed components of the Notch signaling pathway. The time course of the integration of these proteins as animal evolution proceeded was elucidated. Insofar as cell –to-cell communication is only of relevance in multicellular animals, it is not surprising that the Notch system reached a fully-working configuration only with the evolutionary appearance of the Metazoa, the first multicellular animals The roles of the Notch system’s 49 components in contemporary descendants of the ortholog-contributing ancestors were ascertained from a survey of the literature. A single protein, the protein tyrosine kinase (PTK) of the protozoan Ministeria vibrans was identified as a possible pre-Metazoan ancestor of the DLL, JAG, and NOTCH proteins. A scenario for the evolution of the Notch signaling pathway is presented and described as the co-option of its components, clade by clade, in a repurposing of genes already present in the ancestral unicellular organisms.

In Caucasians, basal cell carcinoma, a type of non-melanoma skin cancer, is most often found on the nose. This presents challenges for surgeons due to anatomical, functional, and aesthetic concerns. The study aimed to evaluate the distribution of tumor localization, size, morphological subtypes, surgical outcomes, radicality levels, and their correlation with recurrence rates. The research utilized data from the Hygiene Institute Health Information Centre. A retrospective analysis encompassed 343 cases of nasal skin cancer over a four-year period from January 1, 2019, to December 31, 2022. The research cohort comprised 252 female and 91 male participants, averaging 75,2 years old. Tumors were most found on the left sidewall of the nose (25.4%) and the dorsum (24.8%). The infiltrative morphological subtype was predominant (70.8%). Standard surgical excision with fasciocutaneous plastic was the preferred surgical procedure. Radical excision was achieved in 79.0% of lesions, while 16.9% were incompletely excised. Non-radically excised tumors exhibited a significantly higher recurrence rate (24.1%) compared to those with radical excision (6.3%). In nasal reconstruction, diverse surgical techniques are essential for precise adaptation based on factors like tumor characteristics and patient needs. Despite surgeons' careful adherence to excision guidelines, the potential for non-radical procedures cannot be entirely eliminated.

Thorium is a weak radioactive element, but the control of its concentration in natural aqueous systems is of great interest for health, because it is a toxic heavy metal. The present paper presents the recovery of thorium from diluted synthetic aqueous systems by nanofiltration. The membranes used for nanofiltration of systems containing thorium species are composites containing 4′-Aminobenzo-15-crown-5 ether (ABCE) and sulfonated poly–ether–ether–ketone (sPEEK). The composite membranes (ABCE–sPEEK) were characterized by scanning electron microscopy (SEM), energy dispersive X–ray spectroscopy EDAX, thermal analysis (TG and DSC) and from the perspective of thorium removal performance. To determine the process performances, the variables were: the nature of the composite membrane, the concentration of thorium in the aqueous systems, the rotation speed of the stirrer, the pressure and the pH of the thorium aqueous system. When using pure water, a permeate flux value of 12 L·m⁻2 h⁻1 was obtained for sPEEK membrane, and up to 15 L·m⁻2 h⁻1 for the ABCE–sPEEK composite membrane. The use of mechanical stirring, with a propeller stirrer, leads to an increase in the permeate flux of pure water by about 20 % for each of the studied membrane. Depending on the concentration of thorium and the pH of the feed solution, retentions between 84.9 % and 98.4 % were obtained. An important observation is the retention jump at pH 2 for the ABCE–sPEEK composite membrane. In the paper, a thorium ion retention mechanism is proposed for the sPEEK membrane and the ABCE–sPEEK composite membrane.

As an International Union for Conservation of Nature (IUCN) voluntary reviewer of the natural World Heritage sites nominations focusing on criteria (vii) superlative natural phenomena and (viii) geological history I had the opportunity of evaluating 13 nominations from 12 countries from 2009 - 2022 from the Central Highlands of Sri Lanka to the Vatnajokull National Park Iceland. An early appreciation of the natural history and landscapes were developed as a geologist studying, working and visiting various areas in the USA and Canada. Further experience, as an academic in Sri Lanka and Australia, where I also had the opportunity of various assignments and meetings that afforded field trips and study tours to many World Heritage sites in Asia, Africa, South America and Europe. In this paper, I highlight the following sites that were subject to IUCN World Heritage evaluations and their potential for geo-education: Central Highlands Sri Lanka, China Danxia, Ningaloo Australia, Trang An Vietnam, Lut Desert Iran, Barberton South Africa, Trondek Klondike Canada, Vatnajokull Iceland, Classic Karst Slovenia, Sof Omar Ethiopia, Ha Long Bay – Cat Ba Archipelago, Vietnam and Evaporitic Karst Caves of Northern Apennines, Italy. From these experiences it is apparent that this relevant topic, the conservation of nature, should be an important part of the geoscience’s study curriculum along with other social and environmental subjects.

The Einstein’s Boxes paradox was developed by Einstein, de Broglie, Heisenberg, and others to demonstrate the incompleteness of the Copenhagen Formulation of quantum mechanics. I explain the paradox using the Copenhagen Formulation. I then show how a Time-Symmetric Formulation of quantum mechanics resolves the paradox in the way envisioned by Einstein and de Broglie. Finally, I describe an experiment that can distinguish between these two formulations.

Materials based on platinum metals with very good catalytic activity were tested in the reduction of p–nitrophenol (pNP) to p–aminophenol (pAP). The majority of presented catalytic materials are based on the adsorption of p–nitrophenol on the surface of the catalyst simultaneously with molecular hydrogen, coming from sodium borohydride in an aqueous medium, which reduces it. In the present paper, a catalytic material based on osmium dispersed in n–decanol or n–dodecanol is presented, which also works as an emulsion membrane, for the absorption of p–nitrophenol and molecular hydrogen at the n–alcohol aqueous solution interface. The hydrogenation of p–nitrophenol is carried out in a reaction and separation column in which the acid receiving phase emulsion is dispersed in the osmium nanodispersion, in n–alcohols. This emulsion circulates from the base of the column to its upper part in co-current or counter-current with the source phase consisting of p–nitrophenol and sodium borohydride. Experiments show that the circulation of counter-current phases is superior to that in co-current, and the emulsion based on n–decanol is more efficient than the one based on n–dodecanol. The increase in the pH difference between the source and receiving phases leads to the increase in the conversion of p–nitrophenol to p–aminophenol. The efficiency of separation of the reaction product in the receiving phase is lower than the conversion at the same operating time. The apparent catalytic rate constant (kapp) of the new catalytic material based on the emulsion membrane with nanodispersion of osmium nanoparticles (0.1×10−3 for n–dodecanol and 0.9×10−3 for n-decanol) is lower by an order of magnitude compared to those based on adsorption on catalysts from platinum metal group. The advantage of the tested membrane catalytic material is that it extracts p–aminophenol in the acid receiving phase. The paper proposes a mechanism of the studied reduction system.

Surface–subsurface soil-rock modeling is crucial for infrastructure design and groundwater yield optimization, especially in the complex crystalline basement terrains of Penang Island, Malaysia. This study conducted large-scale characterization of soil-rock profiles using ERT, SRT, rock quality designation, and soil penetration test (SPT N-values) data, optimized through regression modeling. The approach effectively identified soil-rock structures and their suitability to prevent structural failures and enhance groundwater productivity. Correlations between borehole lithologic logs and velocity–resistivity models revealed distinct soil compositions across the study area. The results highlighted thick, saturated, and loose silty to sandy bodies in the eastern to northern sections, contrasting with sandy compositions and penetrative fractures in the southern part. The study also found good correlations between rock mass quality and N-values for different soil types. Depths of intra-bedrock weathered/fractured units varied between 12 and >35 m. This has significant implications for determining optimal foundation depths in the study area. Groundwater productivity was associated with intra-bedrock planes of weakness at depths exceeding 40 m. Overall, this study developed empirical relations between geophysical and geotechnical parameters for wet tropical granitic terrains, filling critical gaps in understanding subsurface characteristics.

The small business sector in Kazakhstan demonstrates dynamic growth, but its sustainable development in modern conditions requires activation from government agencies, society and entrepreneurs themselves The purpose of the article is to study the development of small entrepreneurship in Kazakhstan and develop a mechanism for sustainable development based on network interaction "business entities - society-state" with the identification of priority areas of development based on a rating approach. The methods of bibliographic analysis of scientific literature, statistical, correlation analysis, survey, comparative analysis, ranking based on data normalization were used. The results revealed the need to formalize indicators of sustainable development of the small business sector in strategic development programs; create conditions, support, explain the importance and prospects of investing in sustainable innovations by small businesses; form a balanced strategy for achieving carbon neutrality based on network interaction "business entities - society-state" with the identification of priority areas of development based on a rating approach to ensure transparency and publicity of decisions made. Conclusions are made about the need to popularize sustainable development among business entities, stimulate investment activity through government participation, legislative regulation of public presentation of non-financial reporting, and assist society in the formation of an ESG culture.

We show how the Poincar\'e--Riemann--Hilbert boundary-value problem enables us to construct effective estimates of the potential in the Schr\"odinger equation. The apparatus of the three-dimensional inverse problem of quantum scattering theory is developed for this. It is shown that the unitary scattering operator can be studied as a solution of the Poincar\'e--Riemann--Hilbert boundary-value problem. This allows us to go on to study the potential in the Schr\"odinger equation

The purpose of this paper was to examine the differences in using agricultural entrepreneurship support and in how it relates to characteristics such as the agrarian structure, socioeconomic de-velopment level and land use across the Polish territory. The analyses were carried out at district (poviat) level which is an intermediate administrative unit. The study found that the decisions on co-financing the measures dedicated to non-agricultural economic activity heavily depend on the agrarian structure. The highest levels of activity were witnessed in districts where the agrar-ian structure is particularly fragmented.

A substantial amount of phosphorus (P) in soil is not readily available for plant uptake. Certain species may enhance P availability from poorly soluble P forms. This research aimed to compare the P solubilization capacity of the soil of two Lupine species, L. albus, and L. angustifolius, with a control crop of oats (Avena strigosa L.). Plants were planted in pots in four soils with varying texture, organic matter content, acidity, and P availability. Phosphorus solubilization capacity was assessed on variations of P availability (PBray1) at four points in time, comparing soils with lupine to oat-containing soils and their baseline values. At harvest, measurements of plant shoot biomass included their shoot dry weight and some nutrient concentrations such as P, nitrogen (N), manganese (Mn), and lupine nitrogen fixation. Compared to soils containing oats, lupine soils significantly increased PBray1 concentrations; increments ranged from 0.9 to 5.4 mg kg-1, depending on species, sampling time, and soil type. Lupine-induced soil acidification did not fully explain this P increase., As a proxy measurement of organic acid exudation, Manganese concentration was high in both lupine species' shoot biomass; however, these legumes had divergent Mn accumulation responses to soil acidity and P availability. Nitrogen fixed quantity varied with Lupine species (105-240 mg pot-1) and soil type (60-240 mg pot-1). Lupinus albus had a higher ability to mobilize non-labile P and provide N through biological N fixation (BNF), positioning it as a suitable crop for diversifying Uruguay's agricultural crop rotation systems.

A superparamagnetic graphene oxide based drug carrier Fe3O4@SiO2/N–rGO was prepared through surface modification, material doping, and composite methods. This carrier has a large number of active sites, suitable for loading anticancer drugs, It can increase the drug load. Currently, the widely used drug in clinical use is epirubicin hydrochloride (EPI). The graphene based complex has a pH sensitive property and exhibits a pH sensitive property at pH=4.3. The release efficiency (RE) is 77.4%, making it suitable for drug release in cancerous acidic liquids. The physicochemical properties of drug carriers were studied using X–ray diffraction, Raman spectroscopy, and Fourier transform infrared spectroscopy. Electrochemical signals confirm that the anticancer drug EPI acts on the graphene plane through hydrogen bond interactions and π – π stacking.

The hydrocarbon generation potential of Chia Gara strata and their genetic link with produced oils from the Zagros basin are still not comprehensively investigated. Forty-seven rock samples from the Tithonian–Berriasian interval were subjected to geochemical analyses to infer organic matter enrichment, hydrocarbon potential, thermal maturity, and timing for hydrocarbon generation/expulsion and their implications regarding upcoming petroleum explorations in the Zagros basin. The results showed that the Chia Gara rock samples have fair to very-good generation potential, as confirmed by higher total organic carbon (TOC=0.68–3.95 wt%) and Rock-Eval (S1+S2=3.37–8.52 mg HC/g rock). The hydrogen index (HI=171–462) and Rock-Eval Tmax over 430 °C support the presence of Types II and mixed Types II/III kerogen. These results confirm the high generation potential of the Chia Gara Formation in the study region. 1D basin models of the KK–109 well show that over 55% of kerogens were converted into oil in the Cretaceous (77–67 Ma). Expulsion started from the Miocene until now (22–0 Ma), consistent with 0.71–0.80 of modeled Easy%Ro and 55–80 %TR. Consequently, this project confirms the potential oil expulsion from the Chia Gara Formation, which can be a resource for upcoming hydrocarbon investigation in the Zagros basin, Iraq.

Understanding how humans perceive animals is important for biodiversity conservation, however, only a few studies about this issue were carried out in South America. We selected two Brazilian cities to assess people’s perceptions of birds: Bauru (São Paulo, Brazil) and Belo Horizonte (Minas Gerais, Brazil). From the bird data we gathered, we developed a questionnaire and applied it between September 2020 and June 2021. The data obtained were analyzed by simple counts, Likert scale, and percentages. Also, open questions were placed on the Free Word Cloud Generator website. Our study confirmed that most respondents are aware of the importance of birds to ecological balance and that respondents had a generally positive attitude towards most of the bird species. However, they disliked exotic species such as the Domestic Dove and the House Sparrow, which are associated with disease, dirt, and disgust. Respondents also underestimated the number of birds that can live in urban areas and the song of birds is still a sense less explored and perceived by people. The concept of environmental perception seeks to cover aspects and understanding these human–biodiversity relationships is essential to successfully guide public policies, urban planning interventions, and environmental education activities.

We report the synthesis and characterization of Mn(III) chloride (MnIIICl3) complexes coordinated with N-oxide ylide ligands, namely trimethyl-N-oxide (Me3NO) and pyridine-N-oxide (PyNO). The compounds are reactive and, while isolable in the solid-state at room temperature, readily decompose into Mn(II). For example, “[MnIIICl3(ONMe3)n]” decomposes into the 2D polymeric network compound complex salt [MnII(µ-Cl)3MnII(µ-ONMe3)]n[MnII(µ-Cl)3]n•(Me3NO•HCl)n (4). The reaction of MnIIICl3 with PyNO forms varied Mn(III) compounds with PyNO coordination and these react with hexamethylbenzene (HMB) to form the chlorinated organic product 1-cloromethyl-2,3,4,5,6-pentamethylbenzene (8). In contrast to N-oxide coordination to Mn(III), the reaction between [MnIIICl3(OPPh3)2] and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) resulted in electron transfer forming d5 manganate of the [TEMPO] cation instead of TEMPO–Mn(III) adducts. The reactivity affected by N-oxide coordination is discussed through comparisons with other L–MnIIICl3 complexes within the context of reduction potential.

The Katerini-Kolindros aquifer system (KKas) is a critical freshwater resource, essential for the local and regional economy. To understand contamination sources, groundwater flow paths, and assess the aquifer's health, an extensive dataset of 751 samples from 113 wells collected between 2010 and 2020 was analyzed using multivariate statistical analysis (MVSA) and hydrogeochemical diagrams. The prevailing water types identified were Ca-HCO₃ and Mg-HCO₃, with mixed water types resulting from various factors affecting groundwater quality. The chemistry of groundwater in the KKas is shown to be affected by ion exchange processes and to a lesser extent by reverse ion exchange processes. No indications of sea-water intrusion have been identified in the water wells monitored. On the other hand, nitrate contamination has been detected in specific water wells spatially associated with urban-type land uses and activities. It is considered that nitrate contamination originates primarily from septic tanks and urban sewage networks or secondarily from fertilization of football pitches, cemeteries or urban waste management practices.

Accurately predicting drug-drug interactions (DDIs) is crucial for preventing adverse drug events in clinical settings. However, existing methodologies often rely on complex models built from diverse data sources, posing challenges in computational drug discovery. To address the need for precise computational methods in predicting unknown DDIs, this study introduces a novel Deep Neural Network (DNN)-based approach. By leveraging a wide range of drug-related information, including substructure, targets, side effects, pathways, and indications, our method calculates multiple drug similarities. These similarities are then synthesized using a nonlinear fusion method to extract high-level features. Subsequently, a tailored neural network is deployed for interaction prediction. Comparative evaluation against three prominent machine learning classifiers—Extreme Gradient Boosting (XGBoost), Adaptive Gradient Boosting (AdaBoost), and Light Gradient-Boosting Machine (LGBM)—using three benchmark datasets demonstrates the superior performance of DNN. It achieves outstanding accuracy, precision, recall, and F1-score metrics, all reaching 94.6% in cross-validation. Additionally, case studies involving numerous drug pairs confirm the reliability of DNN in accurately predicting unknown DDIs. These findings underscore DNN as a potent and reliable method for DDI prediction, with promising implications for drug discovery and healthcare applications.

This study aimed to determine the correlation of colour M-mode velocity propagation in the assessment of left ventricular diastolic function among acute decompensated heart failure patients with preserved ejection fraction (HFpEF). This research is an observational analytical study using a cross–sectional study design conducted from April to June 2022. The subjects of this study were patients diagnosed with acute HFpEF and treated at Dr. Soetomo General Academic Hospital, Surabaya. Patients with heart rhythm disturbances, moderate to severe valvular heart disease, and congenital heart defects were excluded from this study. Patients were measured for diastolic function including mitral valve early mitral inflow velocity (MV E Velocity), mitral peak velocity of early filling (E’) (E' Septal and E' Lateral), left atrial volume index (LAVI), The maximal tricuspid regurgitation velocity (TR V Max), Vp, the ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/E'), the ratio between early and late ventricular filling velocity (E/A) and E/Vp Ratio. N-terminal-pro hormone B-type natriuretic peptide (NT–ProBNP) examination was also performed on study subjects as an additional diagnosis of acute heart failure. There were 33 patients who met the inclusion and exclusion criteria and were included in our study. There were 26 patients (78.8%) with grade I diastolic dysfunction, 4 patients (12.1%) with grade II diastolic dysfunction, and 3 patients (9.1%) with grade III diastolic dysfunction. There is a strong positive correlation between Vp with parameters E' Septal (p = < 0.001; r = 0.636) and E' Lateral (p = < 0.001; r = 0.650). Vp is negatively correlated with the ratio E/E' (p = 0.029; r = –0.37). The PCWP estimate with E/Vp ratio had a strong correlation with the NT–Pro BNP value > 300 pg/ml in acute HFpEF patients (p = < 0.001; r = 0.726) compared to the PCWP estimate with E/E' (p = < 0.001; r = 0.549). There is no correlation between Vp value and degree of diastolic dysfunction in patients with acute HFpEF.

Rational delineation of urban–rural boundaries is a foundational prerequisite for holistic urban and rural development planning and rational resource allocation. However, the results of division of urban–rural boundaries extracted using a single data source are non-comprehensive. To address this problem, the present study proposes a method for using multiple sources such as population data, nighttime light data, land use, and points of interest (POI) data to extract urban–rural boundaries. Considering Guizhou Province for a case study, we here present a two-step method for identifying urban–rural boundaries. First, the random forest model was combined with the dasymetric mapping method to obtain the population spatialization data with a 30-m resolution in the studied province. Second, using the breaking point method, we extracted the urban–rural boundary for Guizhou Province in 2020 based on the spatialized population. This method fully integrated the benefits of various data and judiciously extracted the boundaries of the main urban areas and small- and medium-sized towns of each city in the study province at the same spatial scale. The stratified random sampling method revealed that the average overall accuracy was 88.05%. The method proposed has certain universality and application value and allows identifying the urban–rural boundaries more accurately and practically.

In two previous articles, the extended $(k, t)$--Fibonacci numbers were presented and some of their properties were studied, both in general and particularizing them for the Leonardo numbers. In a second article we study the sum of the extended $(k, t)$--Fibonacci numbers as well as the sums of these odd and even numbers.\\ In this article we study the sum of the squares of these numbers with their properties as well as the generating function, the recurrence relation and the Binet formula.\\ Finally we particularize these results for the generalized $t$--Leonardo numbers.

Background: A Morel–Lavallée lesion (MLL) is a traumatic, internal closed degloving injury that results from shearing of subcutaneous tissue away from underlying fascia, usually associated with high-velocity trauma. Case presentation: A 52-year-old man was transported to hospital for further follow-up of a superficial femoral artery injury. Examination on admission showed bruising seen around the left thigh. Contrast-enhanced computed tomography of the left thigh revealed hematoma with extravasation from a branch of the left superficial femoral artery, but no apparent aneurysms or femoral fractures. The patient was treated with compression bandages and discharged on hospital day 6. He left hospital able to walk unaided. He subsequently complained of left thigh pain with swelling and visited the hospital several times. He was treated at another outpatient clinic and was diagnosed with MLL. Single-use disposable portable negative pressure wound therapy (NPWT) was applied for about 2 months, achieving a stable wound site. Conclusion: We encountered a case of MLL successfully treated with single-use portable NPWT. This report presents the case of a patient with isolated MLL without fracture in the left thigh, in which the diagnosis was missed on initial admission. Finally, the patient received minor interventions including drainage along with tissue debridement and portable NPWT. We reviewed the relevant literature and summarize the pathogenesis, clinical manifestations, and treatment strategies for MLL. Emergency physicians require an increased understanding of MLL to avoid misdiagnosis and missed diagnosis.

Antibiotic beads were used to treat surgical infections. In this study, polylactide–polyglycolide (PLGA) was mixed with vancomycin, osteogenic enhancer lithium chloride (LiCl), and hot com-pressing to form PLGA-vancomycin-LiCl delivery beads to treat bone infection. An elution method was employed to characterize the in vitro release characteristics of the vancomycin and the Li over a 42-day period. The released profiles lasted for more than 42 days for vancomycin and 28 days for Li. The concentration of vancomycin in each sample was well above the breakpoint sensitivity. Lithium co-treatment enhanced the bactericidal effect of vancomycin. Released Li and vancomycin increased mRNA or protein expressions of osteogenic markers of mesenchymal stem cells (MSCs). In vivo, the PLGA delivery systems were implanted into the rabbit distal femoral cavities and the cavity fluid content was aspirated and analyzed at each time point. The released Li and vancomycin lasted more than 6 weeks, and vancomycin concentrations were much above the breakpoint sensitivity. Four rabbits in each group were killed at 8 weeks for histologic observation. More mature bone tissue was shown in the Li treatment group. This study provides a PLGA drug delivery system to meet the requirements of patients with bone infections.

The opportunistic pathogen Pseudomonas aeruginosa is responsible for numerous chronic infections and has a case fatality rate of 50%. All P. aeruginosa strains express β–lactamase, an enzyme capable of inactivating β–lactam antibiotics, including penicillins. However, β–lactams are still considered desirable therapeutics by physicians due to their low toxicity. The short-term goal of this study was to create an optimal model for ampC expression in P. aeruginosa and determine the selecting antibiotic to be used during mutagenesis. In the long term, this study aims to renew effectiveness of β–lactams by identifying potential allosteric binding sites on β–lactamase for the development of novel β–lactamase inhibitors. To create a system for ampC expression, the chromosomal P. aeruginosa ampC gene encoding for β–lactamase was cloned into Escherichia coli, then conjugated into P. aeruginosa ∆ampC. β– lactamase assays on recombinant E. coli and P. aeruginosa detected much higher production of β–lactamase in pMMB67HE, which was confirmed with antibiotic susceptibility testing (AST) to numerous β-lactams. From AST, carbenicillin was chosen as the antibiotic to select functional β–lactamase production during mutagenesis. Future work includes conducting mutagenesis on ampC to identify allosteric binding sites on the β–lactamase enzyme that may enable the discovery of new β–lactamase inhibitors. This work allows for the development of novel β–lactamase inhibitors that could renew the utility of β–lactams and drastically reduce morbidity and mortality from chronic Pseudomonas infections.

Cardiovascular diseases are a broadly understood concept focusing on vascular and heart dys-function. Lack of physical exercise, type 2 diabetes, obesity, hypertension, dyslipidemia, throm-boembolism, kidney, and lung diseases all contribute to the development of heart and blood vessel dysfunction. Although effective and important, traditional treatment with diuretics, statins, beta–blockers, calcium inhibitors, ACE inhibitors, and anti–platelet drugs remain a second–line treatment after dietary intervention and lifestyle changes. Scientists worldwide are still looking for an herbal product that would be quite effective and free from side effects, either taken together or before the standard pharmacological intervention. Such herbal–originated medication therapy may include Morus alba L. (white mulberry), Elaeagnus rhamnoides (L.) A. Nelson (sea–buckthorn), Allium sativum L. (garlic), Convallaria majalis L. (lily of the valley), Leonurus cardiaca L. (mother-wort), and Crataegus spp. (hawthorn). Valuable herbal raw materials include leaves, fruits, seeds, and even thorns. This short review focuses on six herbs that can constitute an interesting and po-tential therapeutic option in the management of cardiovascular disorders.

Oxidative stress (OS) plays a crucial role in placental pathogenesis and pregnancy-related complications. This review explores OS's impact on placental development and function, focusing on novel biomarkers for early detection of at-risk pregnancies and emerging therapeutic strategies. We analyzed recent research on OS in placental pathophysiology, examining its sources, mechanisms, and effects. While trophoblast invasion under low-oxygen conditions and hypoxia-induced OS regulate physiological placental development, excessive OS can lead to complications like miscarriage, preeclampsia, and intrauterine growth restriction. Promising OS biomarkers, including malondialdehyde, 8-isoprostane, and the sFlt-1/PlGF ratio, show potential for early detection of pregnancy complications. Therapeutic strategies targeting OS, such as mitochondria-targeted antioxidants, Nrf2 activators, and gasotransmitter therapies, demonstrate encouraging preclinical results. However, clinical translation remains challenging. Future research should focus on validating these biomarkers in large-scale studies and developing personalized therapies to modulate placental OS. Emerging approaches like extracellular vesicle-based therapies and nanomedicine warrant further investigation for both diagnostic and therapeutic applications in pregnancy-related complications. Integrating OS biomarkers with other molecular and cellular markers offers improved potential for early identification of at-risk pregnancies.

New conjugated 2,6-diphenylaniline-azulene co-oligomers of linear and branched structure were synthesized by the interaction of borylazulenes with diphenylaniline bromides under Suzu-ki-Miyaura cross-coupling conditions. The obtained diphenylaniline-azulene co-oligomers inten-sively absorb and emit visible light (410-700 nm region), in particular, exhibits strong emission in the green as well as orange range with maxima of 510 / 590 nm. It is shown that such properties appear as a result of the positive resonance exposure to ani-line fragments significantly rearranging the electronic structure of azulene, in particular, the lev-els and energy gaps of frontal HOMO - LUMO orbitals.

The demand for improved service in mobile networks is always increasing. That means signal transmission with higher capacity is required. To achieve that goal a combined optical and wireless link using double polarization multiplexing has been developed. A high quality signal transmission is achieved by applying high polarization extinction ratio. The new concept is validated by experiments varying the bit rate and fiber length. A signal with 12 Gbit/s bit rate was transmitted over a 25 km long combined link with about 1.10-8 bit error rate. That result is much better than the already published data which were measured on links transmitting information with 2.5 Gbit/s bit rate. The polarization multiplexing technique is very practical for capacity enhancement in a specific section of an existing optical fiber by inserting a new link into it without deploying a new fiber.

Recent studies releaved that the high production of reactive oxidative species due to exposure of fine or ultrafine particles are implicated in many chronical respiratory disorders. However, the poor standard of clinical data in sub-Saharan countries makes very difficult the assessment of knowledge of air pollution health impact in urban cities. Objective: the aim of this study was to evaluate distribution of respiratory disorders associated to exposure of air fine and ultrafine particles through changes of some oxidative stress biomarkers among motorbike drivers from two cities of Cameroon Methods: A cross-sectional survey using a standardized questionnaire was conducted in 2019 on 191 motorcycle drivers (MD) working in Douala and Dschang. Then, the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) were measured by colorimetric methods. The data of participants after clustered in Excel Microsoft were analysed and statistically compared using Spss 2.0 software. Results: The motorbike drivers recruited to both cities were aged from 21 to 40, with mean age of 29.93 (± 0.82). The distribution of respiratory disorders as running nose, cold, dry cough, chest discomfort, and breathlessness, was significantly increased among MD in Douala. According to results of biological assays, SOD and MDA, were significantly more increased among MD recruited in Douala, compared to those of Dschang. The change of these oxidative stress markers was significantly correlated with mobilization of neutrophils and Monocytes showing initiation and evolution of subjacent inflammatory reactions, and seemed to be significantly influenced by place of habitation of MD. Conclusion: Through this study it is confirmed the evidence of initiation and evolution of oxidative stress with long-term exposure to air fine or ultrafine particles among active people in Urban cities. Further studies should be conducted with more analysis to provide evidence cellular damage and dysfunction related to chronically exposure to fine air PM among active people in metropolitan of sub-Saharan Africa context.

Melting, solidification and viscosity properties of a multicomponent Fe-Cu-Nb-Mo-Si-B alloys with low aluminum addition up to 0.42 at.% Al were studied using an oscillating cup viscometer. It is shown that melting and solidification are divided into two stages with a knee point at 1461 K. The temperature dependences of the liquid fraction between the liquidus and solidus temperatures during melting and solidification are calculated. It has been proven that aluminum accelerates the processes of melting and solidification and leads to an increase in liquidus and solidus temperatures. In the liquid state at temperatures above 1700 K in an alloy with a low aluminum content, the activation energy of viscous flow increases. This growth was associated with the liquid – liquid structure transition caused by the formation of large clusters based on the metastable Fe23B6 phase. Aluminum atoms attract iron and boron atoms and contribute to the formation of clusters based on the Fe2AlB2 phase and metastable phases of a higher order.

The retrieval of tree height percentiles with satellite lidar waveforms over the mountainous ar-eas is greatly challenged due to slanted and rugged topographic relief of underlying ground. A novel algorithm is proposed to extract the height percentiles based on the target response waveform (TRW) that is resolved by using a Richardson–Lucy deconvolution algorithm with an adaptive iterative time. The height metrics of the energy percentiles of 25%, 50%, 75% and 95% for the cumulative TRW distribution are determined by their vertical distances relative to the ground elevation in this study. To validate the proposed algorithm, we select the received waveforms of the Global Ecosystem Dynamics Investigation (GEDI) lidar over the Pahvant Mountains of central Utah, USA. The results reveal that the resolved TRWs resemble closely to the actual target response waveforms from the coincident airborne lidar data, with the mean values of the coefficient of correlation, total bias and root mean square error (RMSE) taking val-ue of 0.92, 0.0813 and 0.0016. In addition, the accuracies of the derived height percentiles from the proposed algorithm have been greatly improved compared with the conventional Gaussian de-composition method and the slope-adaptive waveform metrics method. The RMSE values de-crease by the mean values of 1.96 m and 2.72 m, respectively. It demonstrates that the proposed algorithm has good potential in the extraction of forest structure parameter over rugged moun-tainous areas.

Regeneration is a fundamental process much attributed to functions of adult stem cells. In last decades delivery of suspended adult stem cells is widely adopted in regenerative medicine as a leading mean of cell therapy. However, adult stem cells can not complete the task of human body regeneration effectively by themselves as far as they need a receptive microenvironment (the niche) to engraft and perform properly. Understanding of mechanisms underlying mammalian regeneration lead us to an assumption that improved outcomes of cell therapy requires a specific microenvironment generated in damaged area prior to stem cell delivery. To certain extent it may be achieved by delivery of mesenchymal stromal cells (MSC), not in dispersed form, but rather self-organized in cell sheets (CS) – tissue-like structures comprising of viable cells and microenvironment components: extracellular matrix and soluble factors deposited in the matrix. In this communication we highlight a potential role of mesenchymal stromal cells (MSC) as regeneration organizers and speculate that this function emerges in CS. This concept shifts our understanding of therapeutic mechanism underlying a widely known CS-based delivery method for regenerative medicine.

Regeneration is a fundamental perpetual tissue process much attributed to functions of adult stem cell. In last decades delivery of adult stem cells to restore tissue structure is widely adopted in regenerative medicine. However, delivery of stem cells can not complete the task of human body regeneration effectively as far as cells need a basis to form a tissue. Certain improvement can be achieved when cells are organized to cells sheets (CS) – primitive tissue-engineered structures comprising of viable cells and ECM proteins. This led us to an assumption that after damage an intermediate feeder is structure formed as a ground for future tissue resulting in gradients of stimuli required to attract other cells (vascular, neural, epithelial, parenchyma etc.) in an organized manner. This feeder acquires increasing heterogeneity and becomes a guiding feeder that provides basic level of organization to increase complexity of structure up to normal tissue. We also highlight potential role of adult mesenchymal stromal cells (MSC) as the main source of guiding feeder and support it by our recent knowledge of their biological function. Finally, we assume that CS known to be a feasible delivery tool in therapeutics resemble guiding feeder and show our own data indicating properties of MSC-based CS. Furthermore, this concept shifts our understanding of therapeutic mechanism underlying a widely known delivery method for regenerative medicine.

Alzheimer’s disease (AD) is a predominant and incurable chronic debilitating neuro-degenerative disorder occupying more than 60% of all types of dementias. It is inaugurating by a cascade of events initiating from amnesic-type memory impairment and by gradually loss of cognitive and executive capacities, which is an intolerable problem for the patients and their familiars. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated Tau protein aggregate in the brain. These pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis culminating in neurodegeneration and fuelling AD. Thus, at a basic level, abnormality in brain proteins function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is a multifactorial disorder, caused by a combination of age-related changes, genetic, environmental and lifestyle factors that affect the brain over time, its mysterious pathology seems non limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but plethora of substantial and biological processes have been also emerged in its pathogenesis such as — breakdown and/or dysfunction of the blood–brain barrier (BBB); patients’ carriers of the gene variant APOE4; and the immunosenescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) whose have also observed as early markers that may provoke pathogenic pathways that lead or aggravate AD progression and pathology. Notwithstanding, of various pathological pathways, there are numerous substantial AD features that require shedding light on, such as chronic neuroinflammation, decrease glucose utilization and energy metabolism as well as brain insulin resistance (IR). Herein, we come to broadened our understanding & to connect the dots of the multiple comorbidities and their cumulative impact that may have synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement and the role of APOE4 allele and AD-IR pathogenic link - the shared genetics and metabolomics biomarkers between AD and IR disorders. Investment in the future researches brings us closer to know the pathogenesis of AD, and paves the way to build preventive and treatment strategy.

Aims: To investigate the road safety concerns associated with pet dogs in New Zealand. Methods: An online survey was developed and offered to New Zealanders via SurveyMonkey© from 8 January 2019 to 31 March 2019) using New Zealand residents aged ≥18 years. Questions about the demographics of respondents and their number of pet dogs along with those about dog transportation and dog roaming were asked. Results: Of 2744 respondents who completed the online survey, 1494 (65%) owned a dog. Of these, 1511 completed the question about how their dog or dogs travel in vehicles. Of these, 2 % (n = 29) let their dog sit on the driver's knee, and 12 % (n = 179) allowed their dog to sit on the passenger's knee. Only 7 % (n = 105) allowed the dog to roam free throughout the vehicle, while 44% (n = 663) allowed their dogs to roam free in the backseat area only and 19% (n = 280) put their dog in the boot/hatchback area. A minority of respondents (2%, n = 22) indicated they let their dog travel unrestrained on the deck of a ute or truck. Approximately half, 51% (n = 767) of the respondents, indicated that they restrained or crated their dogs in or on the vehicle. Respondents also expressed concerns about roaming dogs being a road safety hazard with the themes of responsible ownership, physical and psychological harm, and the dangers of rescue altruism emerging. Conclusions: Increased awareness about proper pet restraints during transportation and preventing dogs from roaming, especially near and on roads, is crucial to ensure traffic safety for humans and dogs.

The goal of this study is to create regression models estimating the daily Penman–Monteith reference evapotranspiration (PMR) using latitude–temperature data for the state of Sinaloa, Mexico. Daily series of minimum–maximum temperature (1979–2017) were obtained from seven weather stations in Sinaloa. The reference evapotranspiration was calculated by the methods of Penman–Monteith using empirical equations (PMC), Hargreaves (HAC), and PMR. Prior to calculating PMC, the incident solar radiation (SR) was calculated. From the Acaponeta station (2005–2008, 2011–2013 and 2015–2017), all complete observed variables were obtained: mean temperature, incident solar radiation (SRg), average relative humidity and average wind speed at a height of 10 m. The data from the eight weather stations were provided by the National Meteorological Service and the National Water Commission. The daily observed Penman–Monteith reference evapotranspiration (PMO) was calculated. For validation, three simple linear regressions (SLR) were applied: SR vs SRg, PMC vs PMO and PMR vs PMO. hypothesis tests were applied to each SLR: Pearson correlation (Pr) vs critical Pearson correlation (Pcr). All rP were significantly different from zero (> |0.576|): SRg vs SR (Pr = 0.951), PMC vs PMO (Pr = 0.592), and PMR vs PMO (Pr = 0.625). This study provides new models that can motivate and support the design and implementation of intelligent irrigation in the state considered “the breadbasket of Mexico.”

Motor intention is a high-level brain function related to planning for movement. Although studies have shown that motor intentions can be decoded from brain signals before movement execution, it was unclear whether intentions relating to mental imagery of movement could be decoded. Here, we investigated whether differences in spatial and temporal patterns of brain activation were elicited by intentions to perform different types of motor imagery and whether the patterns could be used by a multivariate pattern classifier to detect such differential intentions. The results showed that it is possible to decode intentions before the onset of different types of motor imagery from functional MR signals obtained from fronto-parietal brain regions, such as the premotor cortex and posterior parietal cortex, while controlling for eye movements and for muscular activity of the hands. These results highlight the critical role played by the aforementioned brain regions in covert motor intentions. Moreover, they have substantial implications for rehabilitating patients with motor disabilities.

The PAX8/PPARγ rearrangement, producing the PAX8–PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble docking-based compound screening. Specifically, we investigated which pocket structure should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand binding pocket on the PPARγ side of the PPFP is common to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to PPFP for 97 drug or drug-like compounds with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ, registered in the DrugBank database. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics-Poisson–Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.

The South Asian economy is on the rise but struggling with power shortages and heavy dependence on fossil fuels. For sustained growth, there is a need for access to readily available energy sources, such as electricity. Trading clean electrical energy among neighbouring countries can ensure access to readily available points. South Asia has a diverse range of energy sources, including hydropower, that are available in the region. However, sectorial barriers can impede energy trading. This study has attempted to assess the readiness and barriers to Nepal’s cross-border energy trade with India and Bangladesh using the Analytic Hierarchy Process (AHP). This study also recommends possible measures to strengthen preparedness and address the challenges in energy trade that can be tailored and applied to other cross-country situations.

Molecular cages have promising host-guest properties for drug delivery applications. Specifically, guest⊂cage complexes can be used for on-command release of encapsulated guest molecules in response to specific stimuli. This research explores both dynamic and constrictive binding guest⊂cage systems for drug encapsulation and release in biological environments. In dynamic systems, the guest rapidly passes in and out through the portals of the cage, enabling drug delivery in vitro but facing limitations in vivo due to dilution effects that result in guest release. These challenges are addressed by constrictive binding systems, where the guest is trapped in a "gate-closed" state within the cage. In these systems, the on-command release is triggered by a "gate opening" event, which lowers the guest-out energy barrier. The full guest release is achieved when gate opening reduces the cage-guest affinity, making constrictive binding systems more effective for controlled drug delivery. As a result, this study shows that guest⊂cage complexes have suitable properties for drug delivery in biological contexts.

In this work, an attempt is made to the theoretically substantiate the experimentally known facts of the influence of halogen concentration on the catalytic properties of the neodymium-based Ziegler–Natta system. Based on the structural and thermochemical data obtained using modern methods of quantum chemistry, the process of the 1,3-butadiene cis-1,4-polymerization under the model active centers of the neodymium Ziegler-Natta catalysts with different content of chloride ions was studied. Results are presented that explain the increase in the cis-stereospecificity and activity of the polymerization system with an increase in the content of the chloride ions in the neodymium catalytic system. There were established the reasons for the decrease in the concentration of active centers relative to the introduced Nd(III) with an excess of chloride ions and the occurrence of the anti-syn isomerization as a source of the formation of the trans-1,4-structures in the cis-1,4-polybutadiene.

This study assesses the impact of nurse-originated changes in central venous catheter (CVC) management on the incidence of central line-associated bloodstream infections (CLABSI) and catheter-related bloodstream infections (CRBSI). It is a single-center retrospective cohort study conducted at an urban, tertiary referral, and academic center serving pediatric patients. The study cohort comprised 236 patients and 323 CVCs seen between 2012 and 2022. CLABSI and CRBSI were defined according to the Centers for Disease Control and Prevention definitions. Oncology nurse leaders developed CVC-specific educational modules for CLABSI prevention. All relevant information during the CVC maintenance period was noted in the patient's CVC logbook. 24 (7%) cases of confirmed CLABSI were identified. The incidence of CVC-related infections was 0.32 cases per 1000 catheter days. The incidence decreased by 40% between the first and second three-year study period. Documented exit-site infection was reported in 32 (10%) cases. The correlation between exit-site infection and CLABSI was found in 9 (28%) cases. Our CVC-related infection rates are significantly lower than the incidence reported by the Italian Association of Pediatric Hematology and Oncology, which settles at 3-5 cases per 1000 catheter days. Our data confirm the effectiveness of local CVC management guidelines in preventing CVC-related infectious complications.

How many different writers authored the huge number of texts attributed to Galen of Pergamum (129~216 AD), medical doctor and philosopher, a giant in the history of medicine? To find out which texts were his and which ones were written by others is known as the “Galenic Question”. We propose a “solution” to it through a multidisciplinary approach based: (a) on historical research and (b) on a mathematical analysis of the Greek texts. The historical approach has considered historical independent sources and anachronisms. The mathematical approach has been based on a mathematical theory concerning deep–language variables, rarely consciously controlled by any author, therefore capable of giving indications on similarity of texts, with little or no bias. The multidisciplinary approach has convinced us that at least three authors wrote the texts attributed to Galen. The first two very likely were real historical persons: (a) a certain Galen living between the end of the I century BC and the second half of the I century AD; (b) the historical Galen of Pergamum (II–III centuries AD) and (c) several unknown authors hiding under the name Galen, but surely living after Galen of Pergamum’s death.

Sensory descriptive analysis was used to evaluate the aged Feng-flavored baijiu. The results indicated that there are notable differences in the samples of different ages. The samples with shorter storage times and fresh distilled Baijiu present bran flavor, and fresh green flavor. with the increase of storage time, the fragrance of honey, sweetness, flowers, and aging gradually increases. The samples of Feng-flavored baijiu were dected by Headspace solid-phase microextraction (HS-SPME) combined with comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC–TOFMS) , in total, 496 sustances were identified in all samples, mainly containing 14 types of substances, such as esters, aldehydes etc., of which 42 substances were found in Feng-flavored baijiu for the first time. Chemometrics was used to analyze the key differential compounds. 143 differential compounds closely related to aging were preliminarily screened, and principal component analysis revealed that these samples were separated by year. 65 differential compounds were selected out by partial least squares discriminant analysis(PLS-DA). Furthermore, 43 key differential compounds were selected from the aged Feng-flavored baijiu combined with variable importance in projection and Pearson correlation coefficients. Partial least squares regression (PLSR) was used to research the correlation of sensory properties and key differential compounds, and the results indicated that most compounds were closely related to the aged Baijiu . This study afford theoretical basis and reference for flavor research of Feng-flavored baijiu.

We give a series of numerical examples of competitive evolution in the predation system, showing in some cases how the choice is made to increase the efficiency of the predation mechanism (or other significant parameters) to the detriment of populations (both of prey and predators). We then develop the mathematical theory that enables us to understand the causality involved, and identify a trend towards the emergence of the functional predation mechanism as such (and not of populations of the species involved). The realization of this trend only takes place when the conditions for it are offered by the hazards proposed to successive competitive choices. The logical structure of this trend is similar to that of the « tendency of rate of profit to fall » in certain economic models.

Knowledge-intensive business services (KIBS) are professional services that create new added value by creating, accumulating, and disseminating new knowledge. When it comes to conducting business involving new technology, KIBS play the roles of innovator, user, and producer of new technology that has led to technological innovation. This study aimed to determine the role of KIBS as a tool for innovation in a country’s economic system. Specifically, the degree and role of their impact on the Korean economy were analyzed and compared for the entire KIBS sector, T-KIBS (a new technology-based professional service), P-KIBS (a traditional professional service), and every subsector. For this purpose, the demand-inducement model, supply inducement model, and interlinkage effects method were applied using the 2019 input-output table published in 2022. The analysis showed that the indirect production inducement effect of the entire KIBS industry on other industries was 0.800 KRW, the indirect added value inducement effect was 0.330 KRW, and the supply disruption effect was 1.144 KRW. For T-KIBS, the indirect production inducement effect was 0.687 KRW, the indirect added value inducement effect was 0.272 KRW, and the supply disruption effect was 0.730 KRW. For P-KIBS, the indirect production inducement effect was 1.472 KRW, the indirect added value inducement effect was 0.646 KRW, and the supply disruption effect was 2.657 KRW. Finally, regarding the economic ripple effect of the KIBS subsector, legal and management support services and advertisements corresponding to P-KIBS showed higher figures than the T-KIBS subsectors in all sectors, including production inducement, the added value inducement effect, and the supply disruption effect. These results revealed that in the South Korean economic system, KIBS contribute to production and value addition across all industrial sectors. It is apparent that the absence of supply significantly disrupts other industries. Furthermore, production inducement effects are evenly distributed among all the KIBS subsectors in the secondary and tertiary sectors, while the value-added effects have a greater impact on the tertiary sector. In terms of the supply shortage effects, the secondary sector experiences a more significant impact. This underscores the crucial role of KIBS in sustaining and enhancing overall economic activity in South Korea. This study is significant in that it not only investigated KIBS as an industry group using the advantages provided by industry linkage analysis but also examined and compared detailed subsectors, thereby elaborately evaluating the influence relationship between KIBS and other industries. Therefore, the results presented in this study are expected to be useful for fostering the KIBS industrial sector and establishing economic innovation policies using KIBS.

Physical properties like shape, volume and size affect the dynamics of biological systems. Along these lines, we focus on the topological properties of biological fluids and their biochemical and physiological outcomes. We take as a paradigmatic example the salivary fluid and describe how its topological features may affect the physiopathology of the oral cavity. Topological approaches assess the general properties of saliva, ignoring small-scale physical details such as density, flow rate, stiffness, viscosity. Specifically, the mucin aggregates scattered in the salivary fluid can be tackled in terms of topological holes, i.e., vortical clusters that modify the direction, flow, impulse, local rate-of-change and velocity of saliva. While the current methodological approaches are inclined to remove the effects of impurities assessing systems as homogeneous structures, we argue that the occurrence of mucins breaks up the salivary fluid’s homogeneity, leading to unexpected biophysical modifications. We suggest that every collected salivary sample is not reliable for accurate clinical and experimental investigation, since it displays highly local as well as variable chemical, physical and biological features, not reflecting the current physiological state of the oral cavity. Therefore, the assessment of a single salivary sample is not fully reproducible and cannot provide information about the biophysical, enzymatic and microbiological content of the whole saliva. In sum, the very topological features of the saliva - such as volume, shape, antipodal cells, vortex area, whirling fluid mass, segmentation, discretization, triangulation, node numbering - produce unnoticed biological consequences and network connectivity features with intriguing operational implications.

Tropical sea surface temperature (SST) variability, mainly driven by the El Niño–Southern Oscillation (ENSO), influences the atmospheric circulation and hence the transport of heat and chemical species in both the troposphere and stratosphere. This paper uses Met Office, ERA5 and MERRA2 reanalysis data to examine the impact of SST variability on the dynamics of the polar stratosphere and ozone layer over the period 1980 to 2020. Particular attention is paid to studying the differences in the influence of different types of ENSO (East Pacific (EP) and Central Pacific (CP)) for the El Niño and La Niña phases. It is shown that during the EP El Niño, the zonal wind weakens more strongly and changes direction more often than during the EP El Niño, and the CP El Niño leads to a more rapid decay of the polar vortex (PV), an increase in stratospheric air temperature and an increase in the concentration and total column ozone than during EP El Niño. For the CP La Niña, the PV is more stable, which often leads to a significant decrease in Arctic ozone. During EP La Niña, powerful sudden stratospheric warmings are often observed, which lead to the destruction of PV and an increase in column ozone.

Cellular locomotion is required for survival, fertility, proper embryonic development, regeneration, and wound healing. Cell migration is a major component of metastasis, which accounts for two-thirds of all solid tumor deaths. While many studies have demonstrated increased energy requirements, metabolic rates, and migration of cancer cells compared to normal cells, few have systematically compared normal and cancer cell migration as well as energy requirements side by side. Thus, we investigated how non-malignant and malignant cells migrate utilizing several cell lines from the breast and lung. Initial screening was done in an unbiased high-throughput manner for the ability to migrate/invade on collagen and/or Matrigel. We unexpectedly observed that all the non-malignant lung cells moved significantly faster than cells derived from lung tumors regardless of growth media used. Given the paradigm-shifting nature of our discovery, we pursued possible mechanisms responsible. Neither mass, cell doubling, nor volume, accounted for the individual speed and track length of the normal cells. Non-malignant cells had higher levels of ATP at premigratory-wound induction stages. Meanwhile, cancer cells also increased ATP at premigratory-wound induction – but not to the levels of the normal cells, indicating the possibility for further therapeutic investigation.

The Peripheral giant cell granuloma (PGCG) is an asymptomatic, non-neoplastic and proliferative lesion of unknown etiology. Some possible pre-disposing factors such as hormonal changes dur-ing pregnancy, have been suggested. However, the association between PGCG and pregnancy is controversial. There are few reported clinical cases of pregnancy-associated PGCG in the litera-ture, and they occurred only in the lower jaw. The present report is on a 35-year-old female pa-tient at 36 weeks of gestation who presented with a PGCG in the central and lateral incisors of the upper jaw. The management consisted of surgical excision, along with curettage of the affected bony walls. The diagnosis was based on clinical results and imaging examinations, and it was histopathologically confirmed. The patient underwent postoperative follow-up evaluations at 3, 6 and 12 months, and there were no signs of recurrence.

Plant stem cell cultures have so far been established in only a few plant species using cambial meristematic cells. The presence of stem cells or stem cell-like cells in other organs and tissues of the plant body, as well as the possibility of de novo generation of meristematic cells from differentiated cells, allows to consider the establishment of stem cell cultures in a broader range of species. Therefore, this study aimed to establish a stem cell culture of the medicinal plant Calendula officinalis L. Callus tissues were induced from explants taken from leaves and roots. Appropriate combinations of plant growth regulators and light parameters for in vitro cultivation were selected. Already at this stage, stem and dedifferentiated cells could be identified, and cell suspension cultures were established from specific parts of the formed callus. Cell suspension cultures with a high proportion of stem cells originating from roots (92–93%) or leaves (72–73%) were developed. The amount of stem cells derived from the roots in the cell suspension reached a plateau at a level of 5.60–5.72105.

Cardiac ischemia-reperfusion injury (IRI) occurs when blood flow is restored to the myocardium after a period of ischemia, leading to oxidative stress and subsequent myocardial cell damage, primarily due to the accumulation of reactive oxygen species (ROS). In our previous research, we identified that miR-25 is significantly overexpressed in pressure overload-induced heart failure, and its inhibition improves cardiac function by restoring the expression of SERCA2a, a key protein involved in calcium regulation. In this study, we aimed to investigate the role of miR-25 in the context of ischemia-reperfusion injury. We found that miR-25 was markedly upregulated under hypoxic conditions in both in vitro and in vivo models. Through in silico analysis, we identified Sestrin3 (SESN3), an antioxidant protein known for its protective effects against oxidative stress, as a novel target of miR-25. Based on these findings, we hypothesized that inhibiting miR-25 would restore Sestrin3 expression, thereby reducing ROS-induced myocardial cell damage and improving cardiac function. To test this hypothesis, we employed two model systems: a hypoxia/reoxygenation (H/R) stress model using H9c2 myoblasts and a surgically induced ischemia-reperfusion injury mouse model. Our results demonstrated that the use of miR-25 inhibitors significantly improved cardiac function and reduced myocardial damage in both models through the restoration of SESN3 expression. In conclusion, our findings suggest that targeting miR-25 may serve as a novel therapeutic modality to alleviate oxidative damage in the heart.

Abstract Introduction: In the last thirty years, brain neuromodulation techniques have been used as an alternative to pharmacological treatment of neurological disorders. Parkinson's disease (PD) is a neurodegenerative disorder leading to bradykinesia, rest tremor, postural changes, and non-motor symptoms such as depression, anxiety, sleep disorders, pain, and cognitive decline that compromises executive functions (EFs), responsible for the orderly execution of behaviors and tasks of daily life and intentional and directed actions. To this date, a few studies with transcranial direct current stimulation (tDCS) have shown beneficial effects in PD patients concerning specific motor and non-motor symptoms, targeting the motor cortex and/or prefrontal regions. Objective: The main objective of this study was to evaluate the effects of left prefrontal tDCS across a broad spectrum of motor and non-motor symptoms of PD using established validated scales. Method: Single-blind randomized clinical trial with 18 volunteers with PD, aged between 45 and 80 years (66.1 ± 9.65), who met inclusion and exclusion criteria. Participants were submitted to assessments of motor and non-motor functions employing psychometric scales and tests to evaluate EFs and were randomly divided into two groups: control (sham stimulation) and experimental (active stimulation). All participants were involved in three separate tDCS sessions. The anode was positioned over the left dorsolateral prefrontal cortex and the cathode over the right supraorbital region, with a direct current intensity of 2mA, lasting 20 minutes. At the end of the three sessions, all participants were reassessed. Results: Significant effects of tDCS on non-motor functions were observed for cognition (verbal fluency of actions, clock copy test, appointment by visual confrontation, and verbal memory with immediate free recall) and subjective assessment of sleep quality (overall restlessness and discomfort in the arms and legs at night, leg and arm cramps at night and distressing dreams). There was also an improvement in the rate of errors and successes for congruent and incongruent stimuli of the Stroop Test. The beneficial effects on motor function were decreased rigidity, improved gait, and greater agility in the finger-tapping test. Conclusion: Three tDCS sessions showed positive results for participants with PD, producing significant improvements in various motor and non-motor functions, including sleep quality, cognition, and EFs. Additionally, the present results indicate that tDCS neuromodulation of the left dorsolateral prefrontal cortex region is feasible, safe, and provides significant objective benefits for PD patients.

Few studies have examined the pros and cons of integrated TB and HIV service delivery in public healthcare facilities, and even fewer have proposed conceptual models for improved integration. This study intends to fill that vacuum by outlining the development of a facility-based paradigm for integrating TB, HIV and patients services. The design of the proposed model were in stages that involved the evaluation of existing TB-HIV integration model and synthesis of both quantitative and qualitative data from the study sites which were selected public healthcare facilities at both rural and peri-urban settings in Oliver Reginald (O.R) Tambo District Municipality in Eastern Cape, South Africa. Secondary data on 2009-2013 TB-HIV clinical outcomes were obtained from multiple sources for quantitative analysis. Qualitative data involved focus group discussions among patient and heath care staff, which was thematically analysed. The development of a possibly better model and validation of this model show that the district's health system was reinforced by the model's guiding principles, which placed a strong emphasis on inputs, processes, outcomes, and integration effects.The model is adaptable to different healthcare delivery systems but will require support from healthcare stakeholders and professionals to be successful.

Reduced-order electrothermal models play a key role in the design and control of lithium- ion cell stacks, calling for accurate model parameter calibration. This paper presents a complete electrical and thermal experimental characterization procedure for coupled modeling of cylindrical lithium-ion cells in order to implement them in a prototype Formula SAE hybrid racing car. The main 4goal of the tests is to determine cell capacity variations with temperatures and discharge currents, to predict the open circuit voltage of the cell and its entropic component. A simple approach for the characterization of the battery equivalent electrical circuit and a two-steps thermal characterization method are also shown. The investigations are carried out on four commercial 18650 NMC lithium cells. The model demonstrated to predict the battery voltage at a RMS error lower than 20mV and the temperature to a RMS error equal to 0.5 ◦C. The authors hope that this manuscript can contribute to the development of standardized characterization techniques for such cells, while offering experimental data and validated models that can be used by researchers and BMS designers in different applications.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the ‘dependence’ on the normal cells. This article illustrates the benefits of new, functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in cancer stem cells’ metabolism. This theory highlights the mitochondria in cancer biology and explains how targeted anti-mitochondrial treatments can improve oncological outcomes.

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a crucial role in monocyte survival and differentiation. Its overexpression is associated with aggressive tumor characterized by an immunosuppressive microenvironment and poor prognosis. CSF-1R ligands, IL-34 and M-CSF, are produced by many cells in the tumor microenvironment (TME), suggesting a key role for the receptor in the crosstalk between tumor, immune and stromal cells in the TME. Recently, CSF-1R expression was reported at the cell membrane of cancer cell from different solid tumors, capturing the interest of various research group interested in investigating the role of this receptor in non-myeloid cells. This review summarizes current data available on the expression and activity of CSF-1R in different tumor types. Notably, CSF-1R+ cancer cells have been shown to produce CSF-1R ligands, indicating that CSF-1R signaling is positively regulated in autocrine manner in cancer cells. Recent research demonstrated that CSF-1R signaling enhances cell transformation by supporting tumor cell proliferation, invasion, stemness and drug resistance. In addition, this review covers recent therapeutic strategies, including monoclonal antibodies and small molecule inhibitors, targeting the CSF-1R and designed to block the pro-oncogenic role of CSF-1R in cancer cell.

This comprehensive review delves into the multifaceted aspects of ERK signaling and the intricate mechanisms underlying distinct cellular fates. ERK1 and ERK2 (ERK) govern proliferation, transformation, epithelial-mesenchymal transition, differentiation, senescence, or cell death, con-tingent upon activation strength, duration, and context. The biochemical mechanisms underlying these outcomes are inadequately understood, shaped by signaling feedback and the spatial localization of ERK activation. Generally, ERK activation aligns with the Goldilocks principle in cell fate determination. Excessive or insufficient ERK activity inhibits growth, whereas moderated activation supports proliferation and survival. Unraveling the intricacies of how the degree of ERK activation dictates cell fate requires deciphering mechanisms encompassing protein stability, transcription factors downstream of ERK, and the chromatin landscape.

A sustainable, scalable source of energy‐dense chemical fuel is urgently needed to ensure the security of our energy supply for future generations. Solar energy is the only renewable energy source of sufficient scale to replace fossil fuels and meet rising environmental demand. Hydrogen is expected to play a key role as an energy carrier in future energy systems of the world. As fossil fuel supplies become scarcer and environmental concerns increase, hydrogen is likely to become an increasingly important chemical energy carrier and eventually may become the principal chemical energy carrier. When most of the world’s energy sources become non-fossil based, hydrogen and electricity are expected to be the two dominant energy carriers for the provision of end-use services. Photocatalytic hydrogen evolution from water by solar energy over semiconductors offers a promising way for clean and renewable production of hydrogen. The TiO2-based materials have received considerable attention in recent years due to their extensive application in photocatalysis for hydrogen evolution. Though TiO2 is the most widely investigated photocatalyst for hydrogen evolution, it still provides low photocatalytic activity due to the wide bandgap that results in photocatalytic activity only under ultraviolet (UV) irradiation. Modification of TiO2 photocatalysts with several transition metals has been extensively studied to extend the absorbance capacity of TiO2 into the visible range. The effect of different photocatalytic deposition and reaction parameters also play major roles in enhancing the photostability of photoanode and increasing the hydrogen gas output, respectively.

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming. iCMs exited cell cycle along the process of reprogramming with decreased percentage of EdU⁺/αMHC-GFP⁺ cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFP^high iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFP^low cells; however, S-phase synchronization didn’t enhance the polycistronic-MGT reprogramming, in which cell-cycle exit had been accelerated. In conclusion, post-infection synchronization of S-phase facilitated the early progression of GMT-reprogramming through a mechanism of enhanced cell-cycle exit.

We investigate emergent conductive phenomena triggered by collinear antiferromagnetic orderings. We show that an up-down-zero spin configuration in a triangle cluster leads to linear and nonlinear spin conductivities even without the relativistic spin–orbit coupling; the linear spin conductivity is characterized by the Drude-type one, while the nonlinear spin conductivity is characterized by the Hall-type one. We demonstrate the emergence of both spin conductivities in the breathing kagome system consisting of a triangle cluster. The nonlinear spin conductivity becomes larger than the linear one when the Fermi level lies near the region where a small partial band gap opens. Our results indicate that collinear antiferromagnets with the triangle geometry give rise to rich spin conductive phenomena.

Additive manufacturing (AM) techniques are widely investigated for the cost-effective use of titanium (Ti) alloys in various aerospace applications. One of the AM techniques developed for such applications is plasma transferred arc solid free-form fabrication (PTA-SFFF). Materials manufactured through AM techniques often exhibit anisotropies in mechanical properties due to the layer-by-layer material build. In this regard, the present study investigates the isothermal directional fatigue of Ti-TiB metal matrix composite (MMC) manufactured by PTA-SFFF. This investigation includes rotating beam fatigue test, electron microscopy, and fatigue calculations. The fatigue experiments were performed at 350 ºC using specimen with the test axis oriented diagonally (45º) and parallel (90º) to the AM builds directions. The fatigue values from the current experiments along with literature data find that Ti MMC manufactured via PTA-SFFF exhibit fatigue anisotropy reporting highest strength in 90º and lowest in perpendicular (0º) AM build directions. Further, the electron microscopy investigations on 0º, 45º, and 90º AM build specimens reveal frequent TiB clusters in all three AM build directions and suggest that the spread of these TiB clusters play a role in fatigue anisotropy. Moreover, the fatigue calculations were performed using both the Paris’ and recently reported modified Paris’ equations. Comparison of R^2 values for these calculations show that modified Paris’ equation predicts the fatigue life of AM Ti-TiB MMC more accurately than the Paris’ equation.

Real and complex analytic functions are largely studied in the field of complex analysis and are seen as very useful tools in solving problems in mathematics, physics and engineering. Real and complex numbers are a subset of semi-structured complex numbers (a new number set created to algebraically solve division by zero). Nevertheless, the properties of analytic functions made up of semi-structured complex variables (called semi-structured complex analytic functions) is yet to be explored. This limits the range of possible problems that can be resolved using analytic functions). In this regard, the aim of this paper was to expound upon the properties of semi-structured complex analytic functions and show their application in solving engineering problems. The results of this paper included (1) developing a full set of Cauchy–Riemann Equations for the semi-structured complex -space; (2) define sufficient and necessary conditions for a semi-structured complex function to be analytic; (3) determine the relationship between semi-structured complex analytic functions, Laplace’s Equations and Poisson’s Equations; and (5) provide an example of the use of these functions.

Background: Cardiac development is a complex developmental process. The early cardiac straight tube is composed of an external myocardial layer and an internal endocardial lining. Soon after rightward looping, the embryonic heart becomes externally covered by a new epithelial lining, the embryonic epicardium. A subset of these embryonic epicardial cells migrate and colonize the embryonic myocardium, contributing to distinct cell types. In recent years, our understanding of the molecular mechanisms that govern proepicardium and embryonic epicardium formation has greatly increased. We have recently witnessed a novel layer of complexity governing gene regulation with the discovery of non-coding RNAs. Our laboratory recently identified three distinct lncRNAs, adjacent to the Wt1, Bmp4 and Fgf8 chicken gene loci, with enhanced expression in the proepicardium that are distinctly regulated by Bmp, Fgf and thymosin 4, providing support of their plausible implication in epicardial formation. Methods: Expression of lncRNAs was analyzed in different chicken and mouse tissues as well as their subcellular distribution in chicken proepicardial, epicardial, ventricle explants and in different murine cardiac cell types. lncRNA transcriptional regulation was analyzed by using siRNAs and expression vectors of different transcription factors in chicken and mouse. Antisense oligonucleotides were used to inhibit Gm14014 expression. Cardiac injury was induced ex vivo in mouse ventricle explants by cryoinjury. Furthermore, RT-qPCR, immunocytochemistry, RNA pulldown, Western blot, viability and cell migration assays were conducted to investigate the biological function of Wt1_76127 and Gm14014. Results: We demonstrated that Wt1_76127 in chicken and its evolutionarily conserved homologue Gm14014 in mice are widely distributed in different embryonic and adult tissues and distinctly regulated by cardiac enriched transcription factors, particularly Mef2c and Nkx2.5. Gm14014 is distinctly regulated in mouse ventricular cryoinjury ex vivo models, displaying a negative correlation with epicardial and epithelial to mesenchymal transition markers. Furthermore, silencing assays demonstrated that mouse Gm14014, but not chicken Wt1_76127, is essential for epicardial, but not endocardial or myocardial cell migration. Such process is governed by partnering with Myl9, promoting cytoskeletal remodeling. Conclusion: Our data evidence that Gm14014 plays a pivotal role in epicardial cell migration essential for heart regeneration.

Background. Currently, most of the research in breast cancer has been carried out in conventional two-dimensional (2D) cell culture due to its practical benefits, however, the three-dimensional (3D) cell culture is becoming the model of choice in cancer research because it allows cell-cell and cell-extracellular matrix (ECM) interactions, mimicking the native microenvironment of tumors in vivo. Methods. in this work, we evaluated the effect of 3D cell organization on the expression pattern of miRNAs (by Small-RNAseq) and mRNAs (by microarrays) in the breast cancer SKBR3 cell line and analyzed the biological processes and signaling pathways regulated by the differ-entially expressed protein-coding genes (DE-mRNAs) and miRNAs (DE-microRNAs) found in the organoids. Results. We obtained well-defined cell-aggregated organoids with a grape cluster-like morphology with a size up to 9.2×105 μm3. The transcriptomic assays showed that cell growth in organoids significantly affected (all p < 0.01) the gene expression patterns of both, miRNAs and mRNAs, finding 20 upregulated and 19 downregulated DE-microRNAs, as well as 49 upregulated and 123 downregulated DE-mRNAs. In silico analysis showed that a subset of 11 upregulated DE-microRNAs target 70 downregulated DE-mRNAs. These genes are involved in 150 gene on-tology (GO) biological processes such as regulation of cell morphogenesis, regulation of cell shape, regulation of canonical Wnt signaling pathway, morphogenesis of epithelium, regulation of cy-toskeleton organization, as well as in the MAPK and AGE-RAGE signaling KEGG-pathways. In-terestingly, hsa-mir-122-5p (Fold Change (FC)=15.4), hsa-mir-369-3p (FC=11.4), and hsa-mir-10b-5p (FC=20.1) regulated up to the 81 % of the 70 downregulated DE-mRNAs. Conclu-sion, the organotypic 3D cell-organization architecture of breast cancer SKBR3 cells impacts the expression pattern of miRNAs-mRNAs network mainly through overexpression of hsa-mir-122-5p, hsa-mir-369-3p, and hsa-mir-10b-5p. All these findings suggest that the interaction between cell-cell and cell-ECM as well as the change in the culture architecture impacts gene ex-pression, and therefore, support the pertinence of migrating breast cancer research from conven-tional cultures to 3D models.

LCK, a member of the Scr kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibition of Lck has been mainly to treat hematologic malignancies with a high rate of success. They may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown inter-esting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs host disease. Drug repurposing and bioinformatics can aid in solving several unsolved is-sues on the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

Transfer factor is the name given to material derived from activated lymphocytes that is probably composed of a complex of a peptide and a short segment of RNA and which has the reported ability to transfer specific T cell immunity to uncommitted lymphocytes. Many independent groups around the world reported isolating transfer factors between 1955 and 1990 and demonstrating their ability to transfer passive immunity from one animal or individual to another, often within 24 hours of inoculation. Such activity is potentially revolutionary both in making T cell vaccines readily manufacturable and also because the existence of transfer factors would undermine the basic assumptions of the clonal selection theory, which currently dominates immunological theory. Unfortunately, lack of the microanalytical and synthetic techniques required to properly identify transfer factors, combined with safety factors associated with it derivation from blood sources susceptible to HIV and prion infections, put an end to transfer factor research after 1990. This paper reviews the evidence supporting transfer factor activity and suggests that this potentially revolutionary concept be resurrected and subjected to renewed scrutiny in light of CRISPR-Cas mechanisms and because of its potential to make possible T cell vaccination and provide a novel basis for understanding immunological function.

Cell viability refers to the proportion of living, healthy cells within a given population. This information is crucial in any cell-based research, especially in toxicology. Over the past century, numerous methods for assessing cell viability have been developed. These methods can be categorized into five main types: non-invasive cell structure damage, invasive cell structure damage, cell growth, cellular metabolism, and cell membrane potential. Each method operates on different principles and has its own advantages and disadvantages, making it essential for researchers to choose the method that best fits their experimental design. Despite the variety of cell viability methods available, most rely on indirect measurements of cell viability, which may compromise their accuracy. In this sense, there is insufficient information regarding their accuracy, highlighting the need for researchers to investigate the accuracy of both existing and future methods.

Background Glioblastoma (GBM) is a poor prognosis malignant grade 4 glioma. After surgical resection, standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. The DC vaccination increased the amount of intratumoral-activated cytotoxic T lymphocytes and decreased the number of FoxP3-positive regulatory T cells. Based on these da-ta, we have developed a phase II protocol with the DC vaccine concomitant to standard RT-CT in patients undergoing surgery for GBM. Methods This is a single-arm, monocentric, phase II trial evaluating progression-free survival (PFS) and the safety of a DC vaccination integrated with standard therapy in resected GBM patients. The vaccine administration begins at the end of the RT-CT (Induction Phase) and is subsequently al-ternated with TMZ cycles (Maintenance Phase). The primary endpoints are PFS and safety. Among the secondary endpoints, are the in vitro and in vivo Immune response evaluations. Results By December 2022 , nine patients had been enrolled in the first step. Two patients progressed within three months after leukapheresis and none had experienced DC vaccine-related G3-4 tox-icity. Five patients had a positive DTH test against KLH. By June 2023. The median OS from leu-kapheresis was 23.1 months and 24.7 from surgery. Conclusions This combination therapy is well-tolerated, and we have achieved the two endpoints required for the first step. Therefore, the study will proceed to enroll the remaining 19 patients.

Biological parameters extracted from electrical signals from various body parts have been used for many years to analyze the human body and its behavior. In addition, electrical signals from cancer cell lines, normal cells, and viruses, among others, have been widely used for the detection of various diseases. Single-cell parameters such as cell and cytoplasmic conductivity, relaxation frequency, and membrane capacitance are important. There are many techniques available to characterize biomaterials, such as scanning tunneling microscopy (STM), nanotechnology, microstrip cavity resonance measurement, dielectric impedance measurement (DEPIM), etc. This article reviews the single cell isolation and sorting techniques, summarizes the common single cell operations such as impedance flow cytometry, cell electrical impedance, electrical impedance sensing, and summarizes the current single cell analysis techniques and their applications.

A new longitudinal flow heat dissipation theory for cylindrical batteries is proposed in order to increase the energy density and uniform temperature performance of cylindrical lithium-ion battery packs while also shrinking their size by roughly 10%. First, a genetic algorithm is used to identify the single cell's thermal properties. Based on this, modeling and simulation are used to examine the thermal properties of the longitudinal flow-cooled battery pack. It is found that the best coolant flow scheme has one inlet and one outlet from the end face, taking into account the cooling effect of the battery pack and engineering viability. Lastly, Thermal Dummy Cells (TDC) is used to conduct a validation test of the liquid cooling strategy. Additionally, the simulation and test results demonstrated that the liquid cooling solution can keep the battery pack's maximum temperature rise under the static conditions of a continuous, high-current discharge at a rate of 3C to 20 °C and under the dynamic conditions of the New European Driving Cycle (NEDC) to 2 °C. In applications where the space requirements for the battery pack are quite severe, the longitudinal flow cooling method has some advantages.

CD8 T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signal, cytokine stimulation and nutrients availability. This integration is achieved by signaling hubs such as the mechanistic target of Rapamycin (mTOR). mTOR is a conserved protein kinase, controlling cellular growth and metabolism in eukaryotic cells and therefore is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model to comprehend metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here we review the signaling pathways leading to mTOR activation in CD8 T and NK cells, focusing on activation by cytokines. We also discussed how this knowledge can contribute to immunotherapy development for intracellular pathogen and cancer treatment.

Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells’ biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironment, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The patients' reactions to radiation are varied, ranging from a complete response to even cancer progression during treatment. This concept illustrates how different levels of mitochondrial metabolism might contribute to this heterogeneity. Considering this notion can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Microbial symbioses exhibit astounding adaptations, yet all symbionts face the problem of how to reliably associate with host offspring every generation. A common strategy is vertical transmission, in which symbionts are directly transmitted from the female to her offspring. The diversity of symbionts and vertical transmission mechanisms is as expansive as the diversity of eukaryotic host taxa that house them. However, there are several common themes among these mechanisms based on the degree to which symbionts associate with the host germline during transmission. In this review, we detail three distinct vertical transmission strategies, starting with associations that are transmitted from host somatic cells to offspring somatic cells, either due to lacking a germline or avoiding it. A second strategy involves somatically-localized symbionts that migrate into the germline during host development. The third strategy we discuss is one in which the symbiont maintains continuous association with the germline throughout development. Unexpectedly, the vast majority of documented vertically inherited symbionts rely on the second strategy: soma-to-germline migration. Given that not all eukaryotes contain a sequestered germline and instead produce offspring from somatic stem cell lineages, this soma-to-germline migration is discussed in the context of multicellular evolution. Lastly, as recent genomics data have revealed an abundance of horizontal gene transfer events from symbiotic and non-symbiotic bacteria to host genomes, we discuss their impact on eukaryotic host evolution.

Here, we present a staged approach for an innovative repurposing of a portable infant humidicrib into a live cell growth, observation, and imaging system. Furthmore, humidicrib can support different variations of “umbilical” bioreactors, and can be used to conduct electrophysiology experiments and in situ immunohistochemistry. Modifications incorporate a closed loop carbon dioxide (CO₂) concentration control system with umbilical CO₂ and heating support for tailored bioreactors. The repurposing cost is inexpensive and allows for the continued observation and imaging of cells. This prototype unit has been used to continuously observe and image live primary neurons for up to 21 days. This demonstrates the repurposed units’ suitability for use in tissue culture based research, particularly where modifications to microscopes are required or where sensitive manipulation outside of a standard incubator is needed.

This comprehensive overview of the historical milestones in cell culture underscores key breakthroughs that have shaped the field over time. It begins with Wilhelm Roux's seminal experiments in the 1880s, followed by the pioneering efforts of Ross Granville Harrison, who initiated groundbreaking experiments that fundamentally shaped the landscape of cell culture in the early 20th century. Carrel's influential contributions, notably the immortalization of chicken heart cells, mark a significant advancement in cell culture techniques. Holtfreter, Moscona, and Leighton introduced innovations such as 3D cell culture, laying the groundwork for further exploration. The advent of induced pluripotent stem cells by Takahashi and Yamanaka in 2006 was revolutionary, enabling the reprogramming of differentiated cells into a pluripotent state. Since then, recent innovations include spheroids, organoids, and organ-on-a-chip technologies, aiming to mimic the structure and function of tissues and organs in vitro, pushing the boundaries of biological modeling and disease understanding. In this review, we overview the history of cell culture shedding light on the main discoveries, pitfalls and hurdles that were overcome during the transition from 2D to 3D cell culture techniques. Finally, we discussed the future directions for cell culture research that may accelerate the development of more effective and personalized treatments.

Studies performed at single-cell resolution have demonstrated the physiological significance of cell-to-cell variability. Various types of mathematical models and systems analyses of biological networks have further been used to gain a better understanding of the sources and regulatory mechanisms of such variability. In this work, we present a novel sensitivity analysis method, called molecular density function perturbation (MDFP), for the dynamical analysis of cellular heterogeneity. The proposed analysis is based on introducing perturbations to the density or distribution function of the cellular state variables at specific time points, and quantifying how such perturbations affect the state distribution at later time points. We applied the MDFP analysis to a model of signal transduction pathway involved in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in HeLa cells. The MDFP analysis showed that caspase-8 activation regulates the timing of the switch-like increase of cPARP (cleaved poly(ADP-ribose) polymerase), an indicator of apoptosis. Meanwhile, the cell-to-cell variability in the commitment to apoptosis depended on mitochondrial outer membrane permeabilization (MOMP) and events following MOMP, including the release of Smac (second mitochondria-derived activator of caspases) and cytochrome-C from mitochondria, the inhibition of XIAP (X-linked inhibitor of apoptosis) by Smac and the formation of apoptosome.

With worsening environmental degradation and increasing international demand for human health, plant cell based technology will be more important. The aim of this review is to give an overview regarding key points of current progress and development trend of nature medical and edible plants from the framework of whole plant cell engineering including cell cultures, cell fusion and cell splitting derived biotechnology. Here we sum up three main application trends of medical plants cell cultures covering industrial output, technology upgrading and potential resource development. We also provide classification and typification insights to summarize the development of somatic hybridization in cereal, vegetables crops and other medicinal and edible plants as well as application of artificial polyploidy induction in major medicinal herbs. Development medicinal and edible homologous plants based on modern plant cell engineering will bring us a promising future.

Viruses can infect a cell via one or both routes viz. cell-to-cell (c-c) or cell-free (c-f) . Pathogenesis studies of various viruses, including HIV, have shown that c-c transmission yields a significantly higher infection magnitude than the c-f route. Expectedly, potent antibodies inhibited c-f infection more efficiently than with c-cell transmission. To achieve a one-step, synchronous infection cycle that provides amplified infection, we have studied a consistent and efficient c-c HIV infection model since 1992. H9 cells persistently infected with HTLV-IIIB (H3B cells) and uninfected target CD4+ lymphocyte line (HuT78) were mixed in a ratio of 1:4 respectively. We have recently used this model to produce HIV designer antigens that have been shown to elicit monoclonal as well as polyclonal specific antibodies against novel epitopes that are formed post virus-cell engagement, but prior to fusion. The model can be extended for HIV neutralizing antibody assays or drug inhibitors against high multiplicity of infection.

Nanoporous membranes promise energy-efficient water desalination. Hexagonal boron nitride (h-BN), like graphene, exhibits outstanding physical and chemical properties, making it a promising candidate for water treatment. We employed Car–Parrinello molecular dynamics simulations to establish accurate modeling of Na+ and Cl- permeation through hydrogen passivated nanopores in graphene and h-BN membranes. In these complex systems the classical potentials cannot properly account for the physics at play. We demonstrate that ion separation works well for the h-BN by imposing a barrier of 0.13 eV and 0.24 eV for Na+ and Cl- permeation respectively, compared to the graphene where the Cl- ion faces a negative barrier of 0.68 eV and is prone toward blockade and Na+ permeation is associated with a slightly negative barrier of 0.03 eV. From the change in the solvation shell, we get the following trend: Na/h-BN > Na/G > Cl/G > Cl/h-BN. We argue that the trend in the permeation barrier changes to Cl-h-BN > Na-h-BN > Na-G > Cl-G due to a combination of several interactions, including the distortion of the water network induced by the ions, the ion-water interaction, and the ion-nanopore interaction. Overall, the desalination performance of h-BN surpasses that of their graphene counterparts.

The role of initial state (ISI) and final state (FSI) ion–ion interactions in heavy ion double charge exchange (DCE) reactions A(Z,N)→A(Z±2,N∓2) are studied in the context of double single charge exchange (DSCE) reactions given by sequential actions of the isovector nucleon–nucleon (NN) T–matrix. The second order DSCE reaction amplitude is investigated in momentum representation in a formulation, focused on the extraction of nuclear matrix elements under the conditions of strong initial state (ISI) and final state (FSI) interactions. In closure approximation and using the momentum representation, the reaction amplitude is finally separated into ISI/FSI distortion coefficients and reaction kernels and nuclear matrix elements. The ISI/FSI reaction kernels emerge as the result of the repeated scattering on the avoided volume, introduced by the imaginary parts of the ion–ion optical potential and acting as sinks for the quantal probability current. The closure approximation allows derive a set of induced effective two–body isotensor interactions, given by products of spin–scalar, spin–vector central and rank–2 spin–tensor interactions. The intermediate propagator plays a key role in establishing correlation between the DCE transitions in the projectile and target nucleus. The presented approach emphasizes the special features of DSCE reaction dynamics as proceeding like a system of two coupled isospin dipoles whose strengths are determined by the momentum-space form factors of the NN isovector interaction. The properties of the DSCE interaction form factors are investigated and the approach is applied to data.

Periodontitis is a disease that originates from gingival tissue, and if left untreated, can cause inflammation to spread to deeper tissues, altering bone homeostasis, and even leading to tooth loss. When the bacteria in plaque reach sufficient numbers, the immune system responds by activating immune cells that will produce cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These immune signaling molecules will coordinate the inflammatory responses. IL-1 binds to the IL-1 receptor (IL-1R) on the surface of target cells, initiating an inflammatory response by activating intracellular signalling pathways. Inhibition of IL-1R can prevent the interaction of IL-1 with this receptor, thereby halting the activation of the inflammatory pathway. By substituting this connection with active anti-inflammatory substances, it is possible to prevent the contact between IL-1 and IL-1R. The licorice plant, Glycyrrhiza glabra, includes eight types of flavonoids with significant anti-inflammatory potential, namely isoliquiritigenin, glyzaglabrin, prunetin, shinpterocarpin, licochalcone A, glabridin, glisoflavone, and isoangustone A. This study aims to assess the potential of such flavonoids as candidates for periodontitis treatment through molecular docking, using AutoDock Tools v.1.5.6. All tested compounds showed highly stable bonds to IL-1R, with a binding affinity values below -7 kcal/mol. Van der Waals forces, hydrogen bonds, and hydrophobic bonds all contribute to the stability of these interactions. Among the eight tested compounds, glisoflavone, which has a Ki value of 90.89 nM and a ΔG value of -9.61 kcal/mol, has the highest binding stability to IL-1R.

The human scalp is a common site of skin cancer in humans, with non-melanoma skin cancer being exceedingly common. In this review, two dermatologists with extensive experience in cutaneous oncology will discuss unique features of the epidemiology of cancer of the scalp. Clinical observations on these common skin cancers lead to insight into the pathogenesis and potential prevention and treatment of cutaneous scalp neoplasia. Our hypothesis is that the presence of hair protects against the development of skin cancer, but not by serving as a physical shield, but rather by providing a continuous IL-17 biased immunosurveillance. Loss of hair allow release from immunosurveillance, resulting in expansion of neoplastic cells towards skin cancer. Both hair follicles and metabolic changes in stroma allow permissiveness for tumor promotion.

Objective To investigate the functional and biological significance of telomere-related active genes in cholangiocarcinoma (CCA) using single-cell sequencing and cell communication analysis. Methods First, we identified and annotated different cell types in CCA samples using single-cell sequencing data. Pseudotime analysis revealed the transcriptional status and differentiation process of CCA cells. We then explored interactions between CCA cells and their regulatory pathways through cell communication analysis. 47 key genes related to telomere activity were identified, and GO and KEGG pathway enrichment analysis was performed. Additionally, we constructed a prognostic model and verified the model's predictive efficacy. Finally, we identified genes associated with drug sensitivity in CCA patients and identified pathways associated with CCA prognosis through tumor TMB analysis. Results We identified 452 active telomere-associated cells. Then, we assessed telomere associated gene activity, obtaining 47 differentially expressed telomere genes by intersecting with CCA differentially expressed genes. Major up-regulated signaling pathways, including MIF-(CD74+CXCR4) and HLA-A-CD8A, were identified through pseudotime analysis. Three telomere-associated prognostic genes were identified using LASSO analysis, and prognostic-related models were built. In addition, PBRM1 mutation load was found to be highest in the high-risk group, making it a potential diagnostic target. Finally, drug sensitivity analysis revealed higher sensitivity to certain therapeutic drugs in the high-risk group, providing guidance for tailored CCA treatment. Conclusion The MIF-(CD74+CXCR4) and HLA-A-CD8A signaling pathways appear to be major pathways for CCA cell proliferation. Prognostic models based on telomere-associated genes show promise for application, indicating the biological and clinical significance of telomere activity genes in CCA.

CD4+ T cells orchestrate and regulate immunity within jawed vertebrates, yet our understanding of their evolution, development, and cellular physiology has only begun to be unearthed in the past few decades. Discoveries of genetic diseases that ablate this cellular population have provided insight into their critical functions while transcriptomics, proteomics, and highresolution microscopy have recently revealed new insights into CD4+ T cell anatomy and physiology. This article compiles historical, microscopic, and multi omics data which can be used as a reference atlas to dissect cellular physiology within these influential cells and further understand pathologies like HIV infection that inflict human CD4+ T cells.

Novel Cellular Immunotherapy with engineered T cells has improved cancer treatment and established therapeutic promises to prevent tumor formation in clinical studies. Due to certain restrictions and difficulties, CAR and TCR T cells therapies were inadequate at points. CRISPR Cas9 genome-editing tool has a significant potential for these two cell-based therapies. As a specialized gene-editing technique, CRISPR Cas9 is used to repair genetic alternation with minimum damage. It is used as an adjunct to Immunotherapy to stimulate a more robust immune response. CRISPR has long outpaced other target-specific genome editing methods such as ZFNs and TALEN due to its high efficiency, competence in targeting, and stable operating condition. CRISPR can overcome the two major drawbacks of universal CAR T cells: allorejection and graft-vs-host disease. TCR-based T cell treatment can reduce inappropriate binding between endogenous and transgenic TCR, resulting in a reduction of severe toxicity. The CAR and TCR T based cell therapies uphold an excellent future for tumor malignancies This article has elucidated the administration of CRISPR Cas9 in Novel Cellular Immunotherapy, CAR, and TCR T cell therapy. However, this article did not fail to observe this technology's ethical concerns, limitations, and challenges. Furthermore, the article compares CRISPR-mediated allogeneic CAR T cell to TCR-T cell therapy.

The outbreak of the 2019 Novel Coronavirus (2019-nCoV) has rapidly spread from Wuhan, China to multiple countries, causing staggering number of infections and deaths. A systematic profiling of the immune vulnerability landscape of 2019-nCoV is lacking, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development. In this study, we predicted the potential of all the 2019-nCoV viral proteins to induce class I and II MHC presentation and form linear antibody epitopes. We showed that the enrichment for T cell and B cell epitopes is not uniform on the viral genome, with several focused regions that generate abundant epitopes and may be more targetable. We showed that genetic variations in 2019-nCoV, though fewer for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus, which should be considered in the development of therapies. We create an online database to broadly share our research outcome. Overall, we present an immunological resource for 2019-nCoV that could significantly promote both therapeutic development and mechanistic research.

Corneal ulcer (CU) is an ophthalmopathy characterized by depression of the corneal surface with at least one stromal loss. CU is common in canine and feline species and is usually caused, among others, by trauma, infections, toxic contamination and endocrine disorders. They usually result from an increased inflammatory response and are associated with some clinical signs such as blepharospasm, photophobia, epiphora, pain and loss of corneal transparency. Despite advances in conventional and pharmacological therapy, in many cases indolent and recurrent ulcer treatments still lead to loss of visual acuity of the animal. This paper aims to report the effect of topical application of canine adipose tissue-derived mesenchymal stem cell (cATMSCs) as treatment of recurrent CU in a Poodle dog breed that showed clear difficulty in the healing process associated with diabetes. The animal was submitted to two applications of cATMSCs and showed improvement in the blepharospasm, conjunctival hyperemia, mucopurulent ocular secretion, photophobia, corneal opacity, chemosis, pigmentation, neovascularization, and pain parameters. Besides, Fluorescein test, Schirmer test and ocular fundus exam also showed improvement in their values concomitantly with lesion resolution. Due this, we showed that cATMSC therapy contribute to the regeneration of corneal tissue in CU and may contribute to the treatment to others ophthalmopathies.

As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl- 2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silybin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, a 17- to 52-fold improvement in potency as compared with silybin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

A flavonoid Astragalin (kaempferol-3-O-β-D-glucopyranoside, Ast) has several biological activities including anti-oxidant, anti-HIV, and anti-allergic effects. Nonetheless, its insolubility in hydrophilic solvents imposes restrictions on its therapeutic applications. In this study, we investigated the effects of water-soluble astragalin-galactoside (kaempferol-3-O- β-D-isomaltotrioside, Ast-Gal) on dendritic cell (DC) maturation and T helper (Th) cell-mediated immune responses. Ast-Gal significantly increased maturation and activation of DCs through up-regulation of surface markers, such as CD80, CD86, and MHC II in a dose-dependent manner, while Ast had little effects. Also, Ast-Gal-treated DCs markedly secreted immune-stimulating cytokines such as IL-1β, IL-6, and IL-12. Importantly, Ast-Gal strongly increased expression of IL-12, a polarizing cytokine of Th1 cells. In a co-culture system of DCs and CD4+ T cells, Ast-Gal-treated DCs preferentially differentiates naïve CD4+ T cells into Th1 cells. The addition of neutralizing IL-12 mAb to cultures of Ast-Gal-treated DCs and CD4+ T cells significantly increased IFN- γ production, thereby indicating that Ast-Gal-stimulated DCs enhance the Th1 response through IL-12 production by DCs. Injection with Ast-Gal-treated DCs in mice increased IFN-γ-secreting Th1 cell population. Collectively, these findings indicate that hydrophilically modified astragalin can enhance Th1-mediated immune responses via DCs, and point to a possible application of water-soluble astragalin-galactoside as an immune adjuvant.

Tumor microenvironment including cancer-associated fibroblasts (CAF) has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell – tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF into their pathological counterparts. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

Wild-type p53 cancer therapy-induced senescent cells frequently engulf and degrade neighboring ones inside a massive vacuole in their cytoplasm. After clearance of the internalized cell, the vacuole persists, seemingly empty, for several hours. Despite large vacuoles being associated with cell death, this process is known to confer a survival advantage to cancer engulfing cells, leading to therapy resistance and tumor relapse. Previous attempts to resolve the vacuolar structure and visualize their content using dyes were unsatisfying for lack of known targets and ineffective dye penetration and/or retain. Here, we overcame this problem by applying optical diffraction tomography and Raman spectroscopy to MCF7 doxorubicin-induced engulfing cells. We demonstrated a real ability of cell tomography and Raman to phenotype complex microstructures, such as cell-in-cells and vacuoles, and detect chemical species in extremely low concentrations within live cells in a completely label-free fashion. We show that vacuoles had a density indistinguishable to the medium, but were not empty, instead contained diluted cell-derived macromolecules, and we could discern vacuoles from medium and cells using their Raman fingerprint. Our approach is useful for the non-invasive investigation of senescent engulfing (and other peculiar) cells in unperturbed conditions, crucial for a better understanding of complex biological processes.

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.

Metal-supported fuel cells (MSCs) offer potential material cost and robustness advantage over anode supported cells (ASCs). Because of the very good thermal shock stability of such MSCs, these can be heated up very quickly. However the challenge co-firing of metal substrate and electrolyte stays still unsolved. The production of the core component, the tape casted metal substrate, with defined shrinkage resulting from modification of metal powders is presented in the paper. This approach leads to an adjustment of the shrinkage mismatch during sintering, between metal and ceramic components, and adjustment of target specifications like porosity, green density and layer thickness.

Antigen-presenting cells (APCs) are essential for modulating immune responses, and optimizing their differentiation protocols is critical for cell-based immunotherapies. This study compares eight different protocols for differentiating APCs from C57BL/6J mice using GM-CSF and L-929 supernatant. Four groups treated with GM-CSF and four with L-929 supernatant at various concentrations, alongside a control group were evaluated. Flow cytometry was used to analyze the expression of key markers, including MHC II, CD11c, F4/80, and CD11b. Our findings show that GM-CSF resulted in superior differentiation outcomes compared to L-929 supernatant, with higher expression levels of the analyzed markers. This study underscores the importance of considering both cell yield and protein expression quality in selecting differentiation protocols. For researchers developing therapies targeting specific cell populations, these findings demonstrate how different culture conditions influences both the quantity and phenotypic characteristics of differentiated cells. Balancing efficiency and phenotypic fidelity is crucial for optimizing cell-based immunotherapy strategies. Our data provide a valuable reference for future studies and applications involving APC differentiation from bone marrow precursors, ensuring robust foundations for developing advanced immunotherapies. This comprehensive comparison of differentiation protocols offers insights essential for enhancing the effectiveness and cost-efficiency of cell-based therapies.

The main focus of the in vitro toxicity assessment methods is on the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic substances, the cell triggers multiple signals in response. With this in mind, we have developed a promising cell-based toxicity method that observes various cell responses when exposed to toxic substances (either death, division or remaining viable). Based on the collective cell response, we observed and predicted the dynamics of the cell population to determine the toxicity of the toxicant. The method was tested with two different conformations: In the first conformation, we exposed a monoculture model of blood macrophages to UV light, hydrogen peroxide, nutrient deprivation, tetrabromobisphenol A, fatty acids and 5-fluorouracil. In the second, we exposed a coculture liver model consisting of hepatocytes, hepatic stellate cells, Kupffer cells and liver sinusoidal endothelial cells to rifampicin, ibuprofen and 5-fluorouracil. The method showed good accuracy compared to established toxicity assessment methods. In addition, this approach provided more representative information on the toxic effects of the compounds as it considers the different cellular responses induced by toxic agents.