Complex Formation Research Articles

‘Playing the System’: Agency and Everyday Negotiations during LTTE Rule

ABSTRACT This article focuses on the ways in which civilians and members of the Liberation Tigers of Tamil Eelam (LTTE) in Eastern and Northern Sri Lanka negotiated their demands with the rebel leadership and exercised agency. While much of the rebel governance scholarship emphasizes the top-down, rationalistic and instrumental approach of rebel regimes, we argue that the everyday negotiations we investigated were never simply one-directional, top-down or oppositional. Despite LTTE governance being coercive, our empirical evidence based on fieldwork reveals a more complex and relational form of agency. Here, the everyday roles, identities and practices of those involved were intermingled and co-constitutive, sometimes even cooperative and supportive. We contend that the conduct and outcomes of negotiations depended on several factors: the sympathy for the movement among the civilians, the need of the LTTE to garner local support, the position and (family) networks of the persons involved, the risk and sensitivity of the issue, and the timing. In conclusion, we present a depiction of agency that was co-constitutive and relational, often hidden, indirect, or secretive, but clearly beyond a simple oppositional or one-sided relationship.

SARS-CoV-2 S protein disrupts the formation of ISGF3 complex through conserved S2 subunit to antagonize type I interferon response.

This study unveils a new mechanism by which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein attenuates the host's antiviral immune response. The interferon-inhibitory mechanism of the S protein was universal among SARS-CoV-2 variants and other human coronaviruses, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, and HCoV-HKU1, through conserved S2 domains. Our study expands the understanding of SARS-CoV-2 and other human coronaviruses in evading antiviral immune strategies, which is very important for the design and optimization of vaccine antigens, thus providing a theoretical basis for human anti-coronavirus immunity and understanding the interaction between the host and coronavirus.

Nigericin modifies the mechanism of the uncoupling action of bile acids in rat liver mitochondria by converting ΔpH into Δψ.

Cholestasis caused by impaired bile secretion in the liver is associated with the accumulation of primary bile acids (BA): cholic acid (CA) and chenodeoxycholic acid (CDCA) in the cells of this organ. The paper studies the uncoupling effect of the CA and CDCA on the succinate-fueled rat liver mitochondria under conditions of ΔpH to Δψ conversion by nigericin. It has been established that without nigericin, the dependence of the resting-state (state 4) respiration rate on the concentrations of these BA is nonlinear and is described by a parabolic equation. Under these conditions, the specific inhibitor of the ADP/ATP-antiporter - carboxyatractylate and the substrate of the aspartate/glutamate-antiporter - glutamate do not affect the state 4 respiration of mitochondria stimulated by these BA. It is suggested that without nigericin, the protonophore action of BA is due to the formation of a dimeric complex of their anion with the acid. In the presence of nigericin, the dependence of state 4 respiration rate on BA concentration is linear. Under these conditions, carboxyatractylate inhibits BA-stimulated respiration. Unlike the CDCA, the uncoupling action of CA is also suppressed by the substrates of the aspartate/glutamate-antiporter. The obtained results are considered as evidence that in the presence of nigericin, uncoupling action of CDCA is carried out primarily with the participation of ADP/ATP-antiporter. Both ADP/ATP-antiporter and aspartate/glutamate-antiporter are involved in the uncoupling action of CA. It is concluded that nigericin modifies the mechanism of the uncoupling action of BA in liver mitochondria by converting ΔpH to Δψ.

Single-cell RNA sequencing uncovers heterogenous immune cell responses upon exposure to food additive (E171) titanium dioxide

The prospective use of food additive titanium dioxide (E171 TiO2) in a variety of fields (food, pharmaceutics, and cosmetics) prompts proper cellular cytotoxicity and transcriptomic assessment. Interestingly, smaller-sized E171 TiO2 can translocate in bloodstream and induce a diverse immunological response by activating the immune system, which can be either pro-inflammatory or immune-suppressive. Nevertheless, their cellular or immunologic responses in a heterogeneous population of the immune system following exposure of food additive E171 TiO2 is yet to be elucidated. For this purpose, we have used male Sprague-Dawley rats to deliver E171 TiO2 (5 mg/kg bw per day) via non-invasive intratracheal instillation for 13 weeks. After the 4 weeks recovery period, 3 mL of blood samples from both treated and untreated groups were collected for scRNAseq analysis. Firstly, granulocyte G1 activated innate immune response through the upregulation of genes involved in pro-inflammatory cytokine mediated cytotoxicity. Whereas NK cells resulted in heterogeneity role depending on the subsets where NK1 significantly inhibited cytotoxicity, whereas NK2 and NK3 subsets activated pro-B cell population & inhibited T cell mediated cytotoxicity respectively. While NKT_1 activated innate inflammatory responses which was confirmed by cytotoxic CD8+ T killer cell suppression. Similarly, NKT_2 cells promote inflammatory response by releasing lytic granules and MHC-I complex inhibition to arrest cytotoxic T killer cell responses. Conversely, NKT_3 suppressed inflammatory response by release of anti-inflammatory cytokines suggesting the functional heterogeneity of NKT subset. The formation of MHC-I or MHC-II complexes with T-cell subsets resulted in neither B and T cell dysfunction nor cytotoxic T killer cell inhibition suppressing adaptive immune response. Overall, our research offers an innovative high-dimensional approach to reveal immunological and transcriptomic responses of each cell types at the single cell level in a complex heterogeneous cellular environment by reassuring a precise assessment of immunological response of E171 TiO2.Graphical

Design and Analytical Evaluation of Novel Cardiac Troponin Assays Targeting Multiple Forms of the Cardiac Troponin I-Cardiac Troponin T-Troponin C Complex and Fragmentation Forms.

Current studies suggest that cardiac troponin (cTn) forms in the circulation may vary in different clinical scenarios. Our aim was to design a combination of cTn assays specific to the main cTn forms and to evaluate their analytical performance. We developed immunoassays specific for measuring (1) long-cTnT cTnI-cTnT-TnC (ITC) ternary complex, with cTnT in long form without cleavage at the C-terminal amino acids residue 189-223, designated "long-cTnT ITC complex assay;" (2) both the long-cTnT ITC complex plus short-cTnT ITC complex, designated "hs-total ITC complex assay;" (3) the central part of cTnT of both the long-cTnT ITC complex and free cTnT, designated "hs-cTnT assay." Sex-specific 99th percentile upper reference limits (URLs) were determined. High-sensitivity performance was assessed by examining the imprecision and detectable results above limit of detection (LoD) in the healthy population. Both complex immunoassays exhibited excellent analytical sensitivity, precision, and specificity. The 99th percentile URLs were as follows: long-cTnT ITC complex: male 0.90 ng/L, female 0.87 ng/L; hs-total ITC complex: male 16.15 ng/L, female 10.08 ng/L; hs-cTnT: male 15.57 ng/L, female 14.28 ng/L. The total imprecision at or below the sex-specific 99th percentile URLs was <5% for all assays. The hs-total ITC complex and the hs-cTnT assays showed >50% of measurable concentrations above the LoD. However, <20% were measurable for the long-cTnT ITC complex assay. The cTn assays detected concentrations of major cTn forms in the circulation with high sensitivity, precision, and specificity, supporting their use for monitoring cTn complex and fragmentation forms during myocardial injuries.

A systematic review of racial health disparities among children and youth with physical disabilities.

Children and youth who belong to a racially minoritized group commonly experience multiple and complex forms of discrimination and health disparities. The purpose of this review was to explore racial disparities in health care and health outcomes among children and youth with physical disabilities. Six international databases (Ovid Medline, Healthstar, Embase, PsycINFO, Scopus, and Web of Science) were searched and screened for inclusion. A narrative synthesis was used to identify the common trends. Thirty-seven articles met the inclusion criteria, which involved 218555 children and youth with various types of physical disabilities spanning over 29years. We noted the following trends: (1) racial disparities in accessing or receiving care; (2) racial disparities in health outcomes and mortality rates; and (3) factors affecting racial disparities. Most studies reported at least one finding indicating that racially minoritized youth had differential access to care and/or disparities in health outcomes compared to white youth. Our findings highlight the concerning racial disparities among children and youth with physical disabilities within health care. There is an urgent need for advocacy and interventions at multiple levels to address the perpetual racism and racial disparities that racially minoritized youth with physical disabilities experience.Implications for rehabilitationThere is an urgent need for health care leaders and health care providers to address the systemic health inequalities in rehabilitation for racially minoritized children and youth with physical disabilities.Health care leaders and clinicians should recognize the racial disparities that racially minoritized youth with physical disabilities encounter in accessing or receiving care in addition to health outcomes.Health care leaders and decision-makers should advocate for policy change to optimize equitable and inclusive health care to enhance the well-being of racially minoritized children with disabilities.Health care providers should engage in training to understand how to recognize and address how intersectional forms of a child's identity such as disability, race, and socio-economic status can influence health care experiences and health outcomes.

Unveiling Active Al3+ Sites for Ethanol Dehydration on γ-Al2O3 with Solid-State Nuclear Magnetic Resonance Spectroscopy.

γ-Al2O3 is a crucial catalyst widely used in industrial alcohol dehydration processes. However, the specific nature of its active sites has remained unclear. In this study, we utilize two-dimensional heteronuclear correlation solid-state nuclear magnetic resonance and density functional theory calculations to uncover the active Al sites on the surface of γ-Al2O3 that facilitate ethanol dehydration. We show the formation of stable pentacoordinated AlV-ethanol complexes upon the adsorption of ethanol on the tetracoordinated AlIV sites. This interaction significantly enhances synergy with adjacent AlV-OH sites, resulting in a marked reduction of the activation energy barrier for ethene production. Furthermore, we reveal an interchange between AlIV and AlV-OH species, allowing hexacoordinated AlVI-OH sites to participate in the dehydration pathway through the migration of ethanol between these coordination sites.

LOC730101 improves ovarian cancer drug sensitivity by inhibiting autophagy-mediated DNA damage repair via BECN1

Drug resistance and recurrence are still the bottlenecks in the clinical treatment of ovarian cancer (OC), seriously affecting patients’ prognosis. Therefore, it is an urgent challenge for OC to be overcome towards precision therapy by studying the mechanism of OC drug resistance, finding new drug resistance targets and developing new effective treatment strategies. In this study, we found that lncRNA LOC730101 played an essential role in attenuating drug resistance in OC. LOC730101 was significantly down-regulated in platinum-resistant ovarian cancer tissues, and ectopic overexpression of LOC730101 substantially increased chemotherapy-induced apoptosis. Mechanistically, LOC730101 specifically binds to BECN1 and inhibits the formation of autophagosome BECN1/VPS34 by reducing phosphorylation of BECN1, thereby inhibiting autophagy and promoting drug sensitivity in ovarian cancer cells following treatment with cisplatin and PARP inhibitors. Moreover, LOC730101 inhibits the expression and activity of RNF168 via p62, which in turn affects H2A ubiquitination-mediated DNA damage repair and promotes drug sensitivity in ovarian cancer cells. Our findings demonstrated that LOC730101 played an important role in regulating the formation of the autophagic complex and that inhibition of autophagy significantly enhances the drug sensitivity of OC. And LOC730101 may be used as a prognostic marker to predict the sensitivity of OC to platinum and PARP inhibitors.

In vitro screening of potential echinochrome delivery systems for the treatment of eye diseases

An important task of topical application of medicines in the treatment of eyes is to achieve a compromise between their effectiveness and safety. The development of new multifunctional local ophthalmic drug delivery systems and in vitro screening of potential medicinal eye products are key areas in solving this problem. In this study, primary in vitro screening of the effect of echinochrome (Ech), the carrageenan complex of echinochrome (CRG/Ech) and its liposomal form (CRG/Ech-Lip) was performed on cultured epithelial cells of the outer shell of the eyeball: conjunctival epithelial cells (Chang Conjunctiva, Clone 1-5c-4) and corneal epithelium human (HCE). The cell viability was assessed by their morphology and metabolic activity using light microscopy and MTT test methods. The direct dependence of the intensity of the cytotoxic effect of Ech on its concentration in the nutrient medium, the form of use, the cellular test system and the incubation time of cells was revealed. Ech in the form of an alcoholic solution in its final concentration of 0.1 mg/ml of the nutrient medium exhibits pronounced cytoxicity against both cellular test systems. The same final concentration of Ech in the nutrient medium, but already as part of the carrageenan complex of echinochrome (CRG/Ech), turned out to be critical only for the viability of corneal epithelial cells, the survival rate of conjunctival cells under these conditions was about 50 %. A high biocompatibility of the liposomal form of the carrageenan complex of echinochrome (CRG/Ech-Lip) with cells of both test systems and a stimulating cytoprotective effect against the cells of the conjunctiva epithelium was revealed.

Impedimetric Biosensors for the Quantification of Serum Biomarkers for Early Detection of Lung Cancer

Lung cancer is the most common type of cancer diagnosed worldwide and is also among the most fatal. Early detection, before symptoms become evident, is fundamental for patients’ survival. Therefore, several lung cancer biomarkers have been proposed to enable a prompt diagnosis, including neuron-specific enolase (NSE) and carcinoembryonic antigen (CEA). NSE and CEA are two serum proteins whose elevated levels have been associated with lung cancer. Hence, in this study, impedimetric biosensors (immunosensors) able to quantify NSE and CEA were developed as proof-of-concept devices for lung cancer diagnosis. The sensing platform exploited for the immunosensors comprises a novel combination of a magnetic platform, screen-printed gold electrode (SPGE), and magnetic nanobeads (MB). The MB were functionalized with antibodies to capture the analyte from the sample and to move it over the sensing area. The immunosensors were then developed by immobilizing another set of antibodies for either CEA or NSE on the SPGE through formation of self-assembled monolayer (SAM). The second set of antibodies enabled a sandwich assay to be formed on the surface of the sensor, while MB manipulation was applied during the sensor performance to depict a microfluidic system and increase antigen–antibody complex formation prior to CEA or NSE detection and quantification. The optimized immunosensors were successfully tested to measure various concentrations of CEA and NSE (0–100 ng/mL) in both phosphate buffer and 100% human serum samples. Clinically relevant detection limits of 0.26 ng/mL and 0.18 ng/mL in buffer and 0.76 ng/mL and 0.52 ng/mL in 100% serum for CEA and NSE, respectively, were achieved via electrochemical impedance spectroscopy with the use of potassium ferri/ferrocyanide as a redox probe. Hence, the two immunosensors demonstrated great potential as tools to be implemented for the early detection of lung cancer.

Investigation of Host–Guest Interactions in 2-Ureido-4-ferrocenylpyrimidine Derivatives

In the present study, synthesis, conformational behavior, host–guest complex formation, and electrochemical properties of novel 6-substituted-2-ureido-4-ferrocenylpyrimidines were explored. A comprehensive NMR spectroscopic investigation was carried out to confirm the structure and conformational equilibrium of the ureidopyrimidines through studying the temperature- and concentration dependence of NMR spectra. Low-temperature NMR measurements were used to clarify structural changes inflicted by a 2,6-diaminopyridine guest. Association constant (Kassoc) values of host–guest complexes were calculated based on low-temperature titrations. It was shown that the introduction of a pyridin-2-yl substituent in the pyrimidine ring in host 10 induced a considerable change not only in the conformational equilibrium of the host itself but also in that of the host–guest complex. Geometries and relative stabilities of the conformers of host 10 as well as its host–guest complexes were determined by quantum chemical calculations. Electrochemical behavior of ureidopyrimidine hosts and host–guest complexes was investigated by cyclic voltammetry (CV) and linear sweep voltammetry (LSV) measurements. Two ureidopyrimidine derivatives were immobilized on the surface of spectral graphite electrodes, and their electrochemical response on the addition of 2,6-diaminopyridine was compared. These results also supported the importance of the pyridin-2-yl substituent in the efficient sensing of the guest.

The Polyfunctionality and Origins of makee in Chinese Pidgin English

Abstract Words expressing ‘make’ are semantically and functionally versatile in many languages. Focusing on the word makee, derived from English make, in Chinese Pidgin English, a contact language originated in 18th-century Canton, China, this paper examines its origins and functions. Primarily a lexical verb, makee is polyfunctional in that it also occurs in the complex form [makee X] which indicates causation, imperative, and verbalization. Functioning as a main verb and a causative verb, makee largely mirrors the corresponding words in the source languages of the pidgin, namely English and Cantonese. However, makee as an imperative marker and a verbalizer are innovative features. In imperative sentences, makee in combination with another verb indicate commands. As a verbalizer, makee gives a verbal interpretation to the whole construction. These two new features of makee are not attributable to existing models in the source languages.

Strong Acid‐Free Homogeneous Catalytic Systems for the Ester Products Synthesis by Alkenes Alkoxycarbonylation: Recent Advances

AbstractAlkoxycarbonylation represents a method for the ester products synthesis from available reagents – unsaturated compounds, alcohols, and CO. The beginning of research on this reaction was laid in W. Reppe’ works in 1953. In early works, halides and carbonyls of Co, Ni, Rh, and Ir were used as catalysts, and alkoxycarbonylation was often complicated by the unsaturated compounds hydroformylation or alcohol carbonylation. In recent decades, in the presence of the most active and selective Pd‐phosphine systems with strong protonic acids, the products are typically only isomeric esters, which corresponds to the creating waste‐free production principles. At present, a large‐capacity synthesis process for methyl methacrylate, dubbed Alpha, is in operation, with the initial stage being ethylene methoxycarbonylation. In light of these developments, there is a growing interest among chemists and technologists in alkenes alkoxycarbonylation. The use of strong protonic acids as co‐catalysts is essential for the formation of active catalytic complexes. However, these acids are highly corrosive and can cause the alkenes isomerisation. This review is devoted to the analysis of acid‐free homogeneous Pd‐, Ru‐, Co‐, and Ni‐catalysts employed in alkenes alkoxycarbonylation over the past 15 years. As a result, polymers, monomers and other valuable linear and branched esters were obtained.

Quantitative analysis of septin Cdc10 & Cdc3-associated proteome during stress response in the fungal pathogen Cryptococcus neoformans.

Cryptococcus neoformans is a pathogenic basidiomycetous yeast that primarily infects immunocompromised individuals. Fatal outcome of cryptococcosis depends on the ability of C. neoformans to sense and adapt to 37°C. A complex of conserved filament forming GTPases, called septins, composed of Cdc3, Cdc10, Cdc11, and Cdc12, assembles at the mother-bud neck in C. neoformans. Septins Cdc3 and Cdc12 are essential for proliferation of C. neoformans at 37°C and for virulence in the Galleria mellonella model of infection, presumably due to their requirement for septin complex formation, and the involvement in cytokinesis. However, how exactly Cdc3, and Cdc12 contribute to C. neoformans growth at 37°C remains unknown. Based on studies investigating roles of septins in Saccharomyces cerevisiae, septin complex at the mother-bud neck of C. neoformans is predicted to interact with proteins involved in cell cycle control, morphogenesis, and cytokinesis, but the septin-associated proteome in C. neoformans has not been investigated. Here, we utilized tandem mass spectrometry to define C. neoformans proteins that associate with either Cdc3 or Cdc10 at ∼25°C or after the shift to 37°C. Our findings unveil a diverse array of septin-associated proteins, highlighting potential roles of septins in cell division, and stress response. Two proteins, identified as associated with both Cdc3 and Cdc10, the actin-binding protein profilin, which was detected at both temperatures, and ATP-binding multi-drug transporter Afr1, which was detected exclusively at 37°C, were further confirmed by co-immunoprecipitation. We also confirmed that association of Cdc3 with Afr1 was enhanced at 37°C. Upon shift to 37°C, septins Cdc3 and Cdc10 exhibited altered localization and Cdc3 partially co-localized with Afr1. In addition, we also investigated changes to levels of individual C. neoformans proteins upon shift from ∼25 to 37°C in exponentially grown culture and when cells entered stationary phase at ∼25°C. Our study reveals changes to C. neoformans proteome associated with heat and nutrient deprivation stresses and provides a landscape of septin-associated C. neoformans proteome, which will facilitate elucidating the biology of septins and mechanisms of stress response in this fungal pathogen.

α-Synuclein Deletion Impairs Platelet Function: A Role for SNARE Complex Assembly

Granule secretion is an essential platelet function that contributes not only to haemostasis but also to wound healing, inflammation, and atherosclerosis. Granule secretion from platelets is facilitated, at least in part, by Soluble N-ethylmaleimide-Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) complex-mediated granule fusion. Although α-synuclein is a protein known to modulate the assembly of the SNARE complex in other cells, its role in platelet function remains poorly understood. In this study, we provide evidence that α-synuclein is critical for haemostasis using α-synuclein-deficient (−/−) mice. The genetic deletion of α-synuclein resulted in impaired platelet aggregation, secretion, and adhesion in vitro. In vivo haemostasis models showed that α-synuclein−/− mice had prolonged bleeding times and activated partial thromboplastin times (aPTTs). Mechanistically, platelet activation induced α-synuclein serine (ser) 129 phosphorylation and re-localisation to the platelet membrane, accompanied by an increased association with VAMP 8, syntaxin 4, and syntaxin 11. This phosphorylation was calcium (Ca2+)- and RhoA/ROCK-dependent and was inhibited by prostacyclin (PGI2). Our data suggest that α-synuclein regulates platelet secretion by facilitating SNARE complex formation.

Fibroblast growth factor receptor four inhibitor FGF401 improves the efficacy of trastuzumab in FGFR4-overexpressing breast cancer cells.

Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival. However, some HER2+ patients (~15%) still develop drug resistance after receiving trastuzumab treatment, leading to treatment failure. Using CCLE and METABRIC database analyses, we found that fibroblast growth factor receptor 4 (FGFR4) mRNA was highly detected in tumors from HER2+ breast cancer patients (p < .001) and was associated with poorer survival in breast cancer patients. Through retrospective immunohistochemical staining analysis, we detected higher expression of FGFR4 protein in breast cancer tissues collected from patients who were resistant to trastuzumab therapy compared with breast cancer patients who responded to treatment. An FGFR4 inhibitor (FGF401) effectively inhibits tumor growth in trastuzumab-insensitive patient-derived xenograft (PDX) tumor-bearing mice. For molecular mechanism studies, we demonstrated that HER2/FGFR4 protein complexes were detected on the cell membrane of the tumor tissues in these trastuzumab-insensitive PDX tumor tissues. After trastuzumab treatment in these drug-resistant breast cancer cells, FGFR4 translocates and enters the nucleus. However, trastuzumab-induced nuclear translocation of FGFR4/HER2-intracellular domain protein complex in trastuzumab-resistant cancer cells is blocked by FGF401 treatment. We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.

Multielectron Redox Chemistry of Ytterbium Complexes Reaching the +1 and Zero Formal Oxidation States.

Lanthanide redox reactivity remains limited to one-electron transfer reactions due to their inability to access a broad range of oxidation states. Here, we show that multielectron reductive chemistry is achieved for ytterbium by using the tripodal tris(siloxide)arene redox-active ligand, which can store two electrons in the arene anchor. Reduction of the Yb(III) complex of the tris(siloxide)arene tripodal ligand affords the Yb(II) analogue by metal-centered reduction. Two subsequent reduction events occur mainly at the ligand with retention of the ligand framework and formation of analogous complexes of Yb in the formal +1 and zero oxidation states. Four complexes of Yb in four different oxidation states were isolated, crystallographically and spectroscopically characterized, and their electronic structure was confirmed by DFT studies. Reactivity studies show that the "Yb(I)" complex can transfer two electrons to organic azides, with retention of its molecular structure, to form highly reactive imido intermediates, providing a rare example of a two-electron transfer at a single lanthanide center that does not involve accessing the +4 oxidation state.

Stages of formation of the plain part of the Bystrytsia-Pidbuzka valley

Based on a thorough morphological and morphometric analysis of the Bystrytsia-Pidbuzka terraces, the structure of their loose accumulations, and the correlation of the Bystrytsia-Pidbuzka terraces with the terraces of the Stryvihor and Dniester, the key features of the structure and stages of development of the river valley within the Precarpathian region have been reconstructed. It has been established that the history of the development of the plain section of the Bystrytsia-Pidbuzka valley comprised five main stages. At the first stage, which occurred during the Kryzhanivka climatolith (MIS 63‒46), the Starosilska denudation surface was formed. However, its formation is not associated with fluvial morpholithogenetic processes, because the Carpathian rivers of that time, like the Bystrytsia-Pidbuzka, did not penetrate the territory of the Precarpathian region. They discharged their waters to the north, into the pre-San, through a system of longitudinal valleys developed in the Carpathians. The second stage is associated with the exit of the Bystrytsia-Pidbuzka from the Carpathians to the Precarpathian region and the deployment of fluvial morpholithogenetic processes that formed the X Torganivtsi terrace. This event occurred during the Shyrokino time (MIS 38‒28). At the third stage, the IX Dubrovytsia terrace was dismembered and an erosional ledge to the VIII Susidivtsi terrace was formed, which led to the formation of the first morphological contours of the Bystrytsia-Pidbuzka valley in the Precarpathian region. The depth of the river valley at that time was 10‒15 meters. This process unfolded at the end of the Azovian Glacial (MIS 27‒22) through the beginning of the Martonian Interglacial period (MIS 21‒17). During the fourth stage, the VI Galician terrace was formed, with alluvial deposits characterized by a well-defined differentiation into “warm” and “cold” horizons. The accumulation of “warm” alluvium occurred in the Lubny climatolith (MIS 15‒13), and “cold” alluvium – in the Tiligulian climatolith (MIS 12). In Tiligulian times, the river valley served as one of the trunk lines for discharging meltwater to the south. The fifth stage is the most pronounced in the upper part of the river valley, developed above the village of Kotovane. Here, a complex of four floodplain terraces can be traced in the wide, flat bottom of the river valley: I terrace above the flood-plain, II Tustan terrace, III Kolodiivka terrace, and IV Yezupil terrace. The formation of this terrace complex began in the Kaydak period (MIS 7), during which the IV Yezupil terrace was formed, and continues to this day, with the first terrace above the flood-plain still being formed. Key words: Bystrytsia-Pidbuzka; Precarpathian area; Pleistocene; terraces; alluvium; glacial deposits; climatolithic; formationstages.

DCBLD1 Modulates Angiogenesis by Regulation of the VEGFR-2 Endocytosis in Endothelial Cells.

Unwanted angiogenesis is involved in the progression of various malignant tumors and cardiovascular diseases, and the factors that regulate angiogenesis are potential therapeutic targets. We tested the hypothesis that DCBLD1 (discoidin, CUB, and LCCL domain-containing protein 1) is a coreceptor of VEGFR-2 (vascular endothelial growth factor receptor-2) and modulates angiogenesis in endothelial cells. A carotid artery ligation model and retinal angiogenesis assay were used to study angiogenesis using globe knockout or endothelial cell-specific conditional Dcbld1 knockout mice in vivo. Immunoblotting, immunofluorescence staining, plasma membrane subfraction isolation, Coimmunoprecipitation, and mass spectrum assay were performed to clarify the molecular mechanisms. Loss of Dcbld1 impaired VEGF (vascular endothelial growth factor) response and inhibited VEGF-induced endothelial cell proliferation and migration. Dcbld1 deletion interfered with adult and developmental angiogenesis. Mechanistically, DCBLD1 bound to VEGFR-2 and regulated the formation of VEGFR-2 complex with negative regulators: protein tyrosine phosphatases, E3 ubiquitin ligases (Nedd4 and c-Cbl), and also Dcbld1 knockdown promoted lysosome-mediated VEGFR-2 degradation in endothelial cells. These findings demonstrated the essential role of endothelial DCBLD1 in regulating VEGF signaling and provided evidence that DCBLD1 promotes VEGF-induced angiogenesis by limiting the dephosphorylation, ubiquitination, and lysosome degradation after VEGFR-2 endocytosis. We proposed that endothelial DCBLD1 is a potential therapeutic target for ischemic cardiovascular diseases by the modulation of angiogenesis through regulation of the VEGFR-2 endocytosis.

Numerical modeling of single-point incremental sheet metal forming of 3003-O aluminum alloy

Incremental sheet metal forming processes have demonstrated promising results in shaping symmetric, asymmetric, and highly complex forms. Their flexibility and reliability have garnered attention across various application areas. In this research, numerical modeling was conducted to investigate incremental sheet metal forming processes, particularly single-point incremental forming (SPIF). An aluminum sheet was used in the forming process. The results were compared with experimental data, showing reasonable agreement. The forming force in the out-of-plane direction was significantly higher than the forming force components in the x- and y-axes. Additionally, it was found that the stress distribution exhibited an asymmetric evolution.