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Drawing upon the literatures in information privacy, developmental psychology, and family science, this research investigates how parental online privacy concerns can be passed on to adolescents and affect their self-disclosure on social networking sites. We propose that parental privacy concerns decrease adolescents' self-disclosure both directly (i.e., compliance) and indirectly through adolescents' privacy concerns (i.e., internalization) and that such effects are moderated by parent-child privacy dissonance, parental internet evaluative mediation, and adolescents' gender. To test the research model, we collected matched parent-child data from 726 families in China. The results show the indirect effect of parental privacy concerns on adolescents' self-disclosure via their influence on adolescents' privacy concerns. In addition, parent-child privacy dissonance weakens the effect of adolescents' privacy concerns on selfdisclosure. The extent to which parents employ internet evaluative mediation to guide adolescents' online activities reinforces the effect of parental privacy concerns on adolescents' privacy concerns. Statistical analyses further revealed that the mediating effect of adolescents' privacy concerns is weakened by parent-child privacy dissonance but strengthened by internet evaluative mediation. We also found that parental privacy concerns affect sons and daughters through different paths, especially when parents employ high internet evaluative mediation. Under high internet evaluative mediation, parental privacy concerns affect sons' self-disclosure primarily through an indirect path (via sons' privacy concerns), but influence daughters' self-disclosure both directly and indirectly via daughters' privacy concerns. We conclude by discussing theoretical contributions and practical implications. [ABSTRACT FROM AUTHOR]

BamA, an Omp85 superfamily member, is universally conserved and essential for cell viability. Using anti‐Oma87 antibodies, we focus on understanding the effect of Oma87 of Acinetobacter baumannii on pathogenicity. Oma87 was expressed, purified, and used to induce anti‐Oma87 antibodies in BALB/c mice. Acute toxicity of the protein was evaluated in mice. HeLa cells were infected with both live and killed A. baumannii 19606 and a clinical isolate. The effects of anti‐Oma87 sera on A. baumannii adherence, internalization, and proliferation in HeLa cells were studied. The roles of microfilaments and microtubules in A. baumannii invasion were demonstrated by Actin disruption. Reduced bacterial population and biofilm formation were noted. The ability of A. baumannii to provoke autophagy through Oma87 induction leads to incomplete autophagy and potentially facilitates bacterial replication. Actin‐mediated uptake, attachment, and invasion demonstrated A. baumannii survival and multiplication within vacuoles in the host cell. The findings underscore the potential of Oma87 as a therapeutic intervention target in infections caused by A. baumannii. This comprehensive analysis contributes valuable information for understanding the virulence mechanisms of A. baumannii, potentially guiding future strategies to combat infections caused by this pathogen. [ABSTRACT FROM AUTHOR]

Entering a foreign market entails making the important mode decision of how to operate there. But the initial mode choice is not always forever and may be reassessed as business circumstances change. The mode shifting process—that is, how switches from one mode to another unfold—has scarcely been described, so we lack a systematic outline of this process. In this article, we take a first step toward such an outline. Adopting the established distinction between the formation and implementation phases of strategy making and execution, we describe the critical strategic decisions managers need to make about how to carry out a mode switch. Regarding the formation phases, we discuss the identification and consideration of entry mode switches as viable options, and whether companies plan or not for such shifts. Regarding the implementation phases, we differentiate between the integrating and collaborating decisions that define the type of switches made by companies. [ABSTRACT FROM AUTHOR]

Biogenic metallic nanoparticles (NPs) have garnered significant attention in recent years due to their unique properties and various applications in different fields. NPs, including gold, silver, zinc oxide, copper, titanium, and magnesium oxide NPs, have attracted considerable interest. Green synthesis approaches, utilizing natural products, offer advantages such as sustainability and environmental friendliness. The theranostics applications of these NPs hold immense significance in the fields of medicine and diagnostics. The review explores intricate cellular uptake pathways, internalization dynamics, reactive oxygen species generation, and ensuing inflammatory responses, shedding light on the intricate mechanisms governing their behaviour at a molecular level. Intriguingly, biogenic metallic NPs exhibit a wide array of applications in medicine, including but not limited to anti-inflammatory, anticancer, anti-diabetic, anti-plasmodial, antiviral properties and radical scavenging efficacy. Their potential in personalized medicine stands out, with a focus on tailoring treatments to individual patients based on these NPs' unique attributes and targeted delivery capabilities. The article culminates in emphasizing the role of biogenic metallic NPs in shaping the landscape of personalized medicine. Harnessing their unique properties for tailored therapeutics, diagnostics and targeted interventions, these NPs pave the way for a paradigm shift in healthcare, promising enhanced efficacy and reduced adverse effects. [ABSTRACT FROM AUTHOR]

This article invites social scientists to treat video games as social institutions. Starting with a brief presentation of sociological perspectives from Parsons to Giddens on institutions, this article highlights multiple features that characterize video games as such: historicity, internalization, conflict and change, legitimating ideology, State intervention, and interdependence. Through brief examples from games such as Assassin's Creed Origins, Second Life, Far Cry 5, and Metin2, I argue that understanding video games as social institutions would considerably improve both the perspectives of digital sociology and social theory in general, through: understanding the ubiquitous elements of gamification of our material life, understanding gamer identity at the confluence of other social institutions, such as gender and sexuality, highlighting ideology and the neoliberal agenda, emphasizing gamic agency as a form of institutional control, and redefining time-oriented interactions to explain adaptation and resistance with which the play element has crossed multiple cultures and historical periods. [ABSTRACT FROM AUTHOR]

Background: The main objective is to discuss why treatment of non-prostate cancers with [177Lu]Lu-PSMA-radioligand achieved only low tumor dose in most published cases, despite high uptake on PSMA PET. We use a patient with renal cell carcinoma as an illustrative example. Furthermore, we discuss how the problem with early washout and low tumor dose might be overcome by using a radionuclide with shorter half-life, matching the target binding residence time. Case presentation: [68Ga]Ga-PSMA-11 PET/CT of a 56-year old man with metastatic renal cell carcinoma showed high lesion uptake. One dose of 6.9 GBq [177Lu]Lu-PSMA-I&T was administrated. Post-therapy dosimetry was performed with SPECT/CT and whole-body planar imaging after 5, 24 and 48 h. Doses to target lesions were only 0.2–0.5 Gy. No treatment effect was achieved. Conclusion: Rapid tumor washout of [177Lu]Lu-PSMA-I&T and low tumor dose despite high uptake of [68Ga]Ga-PSMA-11 are most likely caused by localization of PSMA-receptors on neovasculature rather than on the tumor cells, and unlike in prostate cancer cells, the PSMA-RL / PSMA-receptor complex is not internalized. To overcome the problem with early washout, the use of a radionuclide with shorter half-life matching the target binding residence time will be needed. [ABSTRACT FROM AUTHOR]

Background. This study aims to assess the psychosocial impact of the scars resulting from total hip arthroplasties (THA) in terms of internalization and adaptation related to the etiology of the joint damage (traumatic versus non-traumatic) and the specific surgical procedure, by using a modern approach. Methods. A prospective study was carried out between October 2020 and September 2022, at the Orthopedics department, Bihor Emergency County Clinical Hospital in Oradea, located in North-west of Romania. Depending on diagnosis, the participants were divided into two relatively homogeneous groups: non-traumatic group with 113 subjects (55.66%) diagnosed with degenerative hip osteoarthritis and traumatic group with 90 (44.33%) patients who underwent total hip arthroplasty (THA) following a trauma. Results. The highest internalization score was noted in uncemented THA cases performed as a consequence of traumatic coxarthrosis. The ANOVA coefficients of intergroup comparisons for the participants with traumatic coxarthrosis indicate that surgical procedures have a significant influence on scar internalization [F (2, 90) = 10.046; p<0.001; Æž2=0.188]. Scheffe's post hoc test indicated that patients with non-traumatic coxarthrosis who underwent uncemented THA procedures presented a higher level of psychosocial internalization compared to those who underwent cemented (Mdf = 3.87; p<0.02) and revision THA (Mdf = 4.60; p<0.004), but without surprising differences compared to revision of the soft tissue (Mdf = 3.31; p<0.08). Conclusions. The relevance of the coxarthrosis etiology for subsequent surgical interventions was emphasized in this study. Coxarthrosis has a strong impact on the psychosocial internalization of postoperative scars, which indicates a change in the perception of social support as well as the perception of the quality of life. [ABSTRACT FROM AUTHOR]

In this discussion of Permeable boundaries: Therapeutic benefits by Richard Geist and Meredith Nocek, the author articulates the way in which Geist's and Nocek's ideas about permeable boundaries and the transformative intimacy that they facilitate express an expansion of Kohut's ideas, an expansion that the era in which his theory evolved would not have tolerated. The author, endorsing the concept of permeable boundaries as a pathway to transformative internalization in treatment, questions the notion that they can only arise organically. She draws from the original article to point out ways that the therapist can and should assume responsibility for facilitating permeable boundaries when they do not arise organically. The author points to the therapist's role in intentionally establishing a regulating "side by side feeling", the therapist's openness to her own vulnerability, her achievement of a level of empathic immersion such that the analyst can actually feel the patient's experience within herself, and the establishment of a therapeutic dialogue which leads to the emergence of ideas that are novel to both patient and therapist, as ways in which the therapist can evoke a permeable boundary for the sake of deep transformation. [ABSTRACT FROM AUTHOR]

Objectives: We developed the 26-item Ethnic–Racial Discrimination Stress Inventory (ERDSI) to assess ethnic–racial discrimination stress in Mexican-origin adults in the United States and Turkish-origin adults in Germany, two groups with similar sociocultural characteristics and immigration experiences. Method: We developed 73 items measuring firsthand, intragroup, and vicarious discrimination, and internalization and expectations of discrimination experiences. If participants reported experiencing a given situation, they were asked to rate its stressfulness. U.S.-based Mexican-origin adults (N = 222) and German-based Turkish-origin adults (N = 105) completed an online survey of these items, measures of related constructs, and sociodemographic measures. Results: Study 1: We eliminated items based on interitem correlations and exploratory factor analyses in the U.S.-based Mexican sample. The exploratory factor analyses yielded four reliable and valid factors (F1: Vicarious Discrimination Stress, seven items; F2: Internalization of Discrimination Stress, seven items; F3: Intragroup Discrimination Stress, seven items; and F4: Firsthand Discrimination Stress, five items). The ERDSI factors predicted well-being measures, even after adjusting for control variables. Study 2: The three ERDSI factors (F1, F2, F4, not F3) that applied to the German-based Turkish sample demonstrated reliability and validity. Confirmatory factor analyses demonstrated metric invariance for F2 and partial scalar invariance for F1, F3, and F4. Conclusions: The ERDSI can be used to assess ethnic–racial discrimination stress in future studies with U.S.-based Mexican-origin adults and German-based Turkish-origin adults. Public Significance Statement: People of Mexican origin in the United States and people of Turkish origin in Germany often report that they experience ethnic–racial discrimination and that this causes stress (i.e., "ethnic–racial discrimination stress"). We developed the Ethnic–Racial Discrimination Stress Inventory to assess discrimination stresses associated with firsthand experiences (i.e., carried out by someone from another ethnic–racial group), intragroup experiences (i.e., carried out by someone of one's own ethnic–racial group), vicarious experiences (i.e., someone from one's own ethnic–racial group experiencing discrimination), and internalization of these experiences (i.e., self-stereotyping) in the two groups. [ABSTRACT FROM AUTHOR]

Introduction: Immunogenicity, the unwanted immune response triggered by therapeutic antibodies, poses significant challenges in biotherapeutic development. This response can lead to the production of anti-drug antibodies, potentially compromising the efficacy and safety of treatments. The internalization of therapeutic antibodies into dendritic cells (DCs) is a critical factor influencing immunogenicity. Using monoclonal antibodies, with differences in non-specific cellular uptake, as tools to explore the impact on the overall risk of immunogenicity, this study explores how internalization influences peptide presentation and subsequently T cell activation. Materials and methods: To investigate the impact of antibody internalization on immunogenicity, untargeted toolantibodies with engineered positive or negative charge patches were utilized. Immature monocyte-derived DCs (moDCs), known for their physiologically relevant high endocytic activity, were employed for internalization assays, while mature moDCs were used for MHC-II associated peptide proteomics (MAPPs) assays. In addition to the lysosomal accumulation and peptide presentation, subsequent CD4+ T cell activation has been assessed. Consequently, a known CD4+ T cell epitope from ovalbumin was inserted into the tool antibodies to evaluate T cell activation on a single, shared epitope. Results: Antibodies with positive charge patches exhibited higher rates of lysosomal accumulation and epitope presentation compared to those with negative charge patches or neutral surface charge. Furthermore, a direct correlation between internalization rate and presentation on MHC-II molecules could be established. To explore the link between internalization, peptide presentation and CD4+ T cell activation, tool antibodies containing the same OVA epitope were used. Previous observations were not altered by the insertion of the OVA epitope and ultimately, an enhanced CD4+ T cell response correlated with increased internalization in DCs and peptide presentation. Discussion: These findings demonstrate that the biophysical properties of therapeutic antibodies, particularly surface charge, play a crucial role in their internalization into DCs. Antibodies internalized faster and processed by DCs, are also more prone to be presented on their surface leading to a higher risk of triggering an immune response. These insights underscore the importance of considering antibody surface charge and other properties that enhance cellular accumulation during the preclinical development of biotherapeutics to mitigate immunogenicity risks. [ABSTRACT FROM AUTHOR]

Human endocannabinoid signaling is primarily mediated by the cannabinoid receptors, CB1 and CB2, which are G protein-coupled receptors (GPCRs). These receptors have been linked to a variety of physiological processes and are being pursued as prospective drug targets due to their potential in treating pain and inflammation. However, because of their homology and shared signaling mechanisms, investigating the individual physiological roles of these receptors and designing subtype-selective ligands has been challenging. Using active-state CB1 and CB2 structures as guides, homologous residues within the orthosteric pocket of each receptor were mutated to alanine to test whether they equally impair CB1 and CB2 activity in response to two high-affinity, nonselective agonists (CP55,940 and AM12033). Interestingly, mutating the Y5.39 position impairs CB1 but not CB2 function. Conversely, mutating residue C6.47 improves CB1 but impairs CB2 signaling. The F7.35A mutation leads to a decrease in CP55,940 potency at CB1 and impairs internalization; however, AM12033 gains potency and promotes CB1 internalization. In CB2, mutation of F7.35A decreases the potency of CP55,940 and neither agonist induces internalization. These observations provide some insight into functional sensitivity of CB1 and CB2 to different agonists when conserved residues are mutated in the orthosteric pocket. [ABSTRACT FROM AUTHOR]

The aim of this paper is to give an account of what it is to internalize a rule. I claim that internalization is the process of redistributing the burden of instruction from the teacher to the student. The process is complete when instruction is no longer needed, and the rule has reshaped perceptual classification of the circumstances in which it applies. Teaching a rule is the initiation of this process. We internalize rules by simulating instruction coming from someone else. Running these simulations enables us to toggle between the perspective of the instructor and our own perspective. By doing this we coordinate our perspectives with that of the teacher. The account given here provides a deeper explanation of why internalizing a rule involves the dispositions and reactive attitudes proponents of Rule Consequentialism often say it does, why moral reflection is variably demanding, how intergenerational moral progress is made possible by our cognitive architectures, and why the adoption of a rule should be understood in terms of teaching that rule. [ABSTRACT FROM AUTHOR]

This article revisits W. R. Bion's theory of thinking by highlighting how thinking and linking are attacked. The author's theoretical reflections and clinical vignettes draw attention to the fact that patients may attack the analyst's thinking-function in two particular states: when they experience the analyst as attacking them precisely when the analyst is able to create a link, but one that is too threatening, painful, unsettling and frustrating or in response to the analyst's failure to create the link the patient had been expecting. How the analyst deals with and reacts to the complexity of the analytic relationship and to these two kinds of attacks is what will be internalized. In turn, it will affect the methods of communication within the psyche and with the environment and the development of a patient's emotional thinking. [ABSTRACT FROM AUTHOR]

While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised β-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

Abstract Malignant mesothelioma, a highly aggressive cancer that primarily affects the serosal membranes, has limited therapeutic options, particularly for cavitary tumors, such as peritoneal and pleural malignant mesothelioma. Intracavitary administration of a radioimmunoconjugate to locally target mesothelioma cancer cells has been proposed as a treatment. CD146, upregulated in mesothelioma but not in healthy tissues, is a promising therapeutic target. This study characterized CD146 expression and binding/internalization kinetics of the CD146-targeting antibody OI-3 coupled with 212Pb (212Pb-TCMC-OI-3) in human mesothelioma cells. Flow cytometry showed that both chimeric (chOI-3) and murine (mOI-3) antibodies rapidly bound and internalized within 1–6 h in MSTO-211H cells. 212Pb-TCMC-chOI-3 exhibited 3.1- to 13.7-fold and 3.1- to 8.5-fold increased internalized 212Pb and 212Bi atoms per cell at 2 and 24 h, respectively, compared to isotype control, underscoring enhanced internalization efficiency. Intraperitoneal administration of 212Pb-TCMC-mOI-3 to mice with intraperitoneal MSTO-211H xenografts improved median survival by a ratio of 1.3 compared to non-binding 212Pb-TCMC-mIgG1. The ability of 212Pb-TCMC-mOI-3 to target and inhibit the growth of intraperitoneal mesothelioma xenografts supports targeted radionuclide therapy’s efficacy for metastatic peritoneal mesothelioma. This study highlights the potential of localized CD146-targeted radioimmunotherapy for malignant mesothelioma, offering a new avenue for improving patient outcomes.

Abstract Background The main objective is to discuss why treatment of non-prostate cancers with [177Lu]Lu-PSMA-radioligand achieved only low tumor dose in most published cases, despite high uptake on PSMA PET. We use a patient with renal cell carcinoma as an illustrative example. Furthermore, we discuss how the problem with early washout and low tumor dose might be overcome by using a radionuclide with shorter half-life, matching the target binding residence time. Case presentation [68Ga]Ga-PSMA-11 PET/CT of a 56-year old man with metastatic renal cell carcinoma showed high lesion uptake. One dose of 6.9 GBq [177Lu]Lu-PSMA-I&T was administrated. Post-therapy dosimetry was performed with SPECT/CT and whole-body planar imaging after 5, 24 and 48 h. Doses to target lesions were only 0.2–0.5 Gy. No treatment effect was achieved. Conclusion Rapid tumor washout of [177Lu]Lu-PSMA-I&T and low tumor dose despite high uptake of [68Ga]Ga-PSMA-11 are most likely caused by localization of PSMA-receptors on neovasculature rather than on the tumor cells, and unlike in prostate cancer cells, the PSMA-RL / PSMA-receptor complex is not internalized. To overcome the problem with early washout, the use of a radionuclide with shorter half-life matching the target binding residence time will be needed.

The developing nations of the Asian continent, especially India, are trying to elevate the educational standards by inaugurating the portals of international institutional linkages. Collaboration with foreign universities provides opportunities for the aspiring students to confer degrees from world premier institutions by stationing in their host nation. At the same time, the consequential impacts of the institutional linkages beyond the contours of countries need special attention to investigate on the dimensions of social, economic and culture. This chapter aims to make an intensive study on the challenges and impacts of institutional linkages between Institutions belonging to developing and developed nations. In this research work the method of neutrosophic relational maps (NRM) is applied to analyze the association between the attributes of Institutional linkages and the consequential impacts of such a system of cross cross-cultural education with special reference to the Indian nation. The associational impacts based on the opinion of the educational experts are well examined using neutrosophic representations. Based on the findings of this research work, some of the suggestive measures of internalizing higher education and future directions are proposed in this chapter. [ABSTRACT FROM AUTHOR]

Abstract Background The bacterial persistence, responsible for therapeutic failures, can arise from the biofilm formation, which possesses a high tolerance to antibiotics. This threat often occurs when a bone and joint infection is diagnosed after a prosthesis implantation. Understanding the biofilm mechanism is pivotal to enhance prosthesis joint infection (PJI) treatment and prevention. However, little is known on the characteristics of Cutibacterium acnes biofilm formation, whereas this species is frequently involved in prosthesis infections. Methods In this study, we compared the biofilm formation of C. acnes PJI-related strains and non-PJI-related strains on plastic support and textured titanium alloy by (i) counting adherent and viable bacteria, (ii) confocal scanning electronic microscopy observations after biofilm matrix labeling and (iii) RT-qPCR experiments. Results We highlighted material- and strain-dependent modifications of C. acnes biofilm. Non-PJI-related strains formed aggregates on both types of support but with different matrix compositions. While the proportion of polysaccharides signal was higher on plastic, the proportions of polysaccharides and proteins signals were more similar on titanium. The changes in biofilm composition for PJI-related strains was less noticeable. For all tested strains, biofilm formation-related genes were more expressed in biofilm formed on plastic that one formed on titanium. Moreover, the impact of C. acnes internalization in osteoblasts prior to biofilm development was also investigated. After internalization, one of the non-PJI-related strains biofilm characteristics were affected: (i) a lower quantity of adhered bacteria (80.3-fold decrease), (ii) an increase of polysaccharides signal in biofilm and (iii) an activation of biofilm gene expressions on textured titanium disk. Conclusion Taken together, these results evidenced the versatility of C. acnes biofilm, depending on the support used, the bone environment and the strain.

Siân Rizzo,1 Mathieu Varache,1 Edward J Sayers,2 Arwyn T Jones,2 Alex Tonks,3 David W Thomas,1 Elaine L Ferguson1 1Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK; 2School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK; 3Department of Haematology, School of Medicine, Cardiff University, Cardiff, UKCorrespondence: Elaine L Ferguson, Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK, Tel +44 2922 510663, Email FergusonEL@cardiff.ac.ukIntroduction: Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different ‘subtypes’ in combination with current chemotherapies. We have previously developed dextrin–colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin’s anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin–colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistin’s cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic.Results: Our results identified a conjugate (containing 8000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently labelled compounds showed both free and dextrin-conjugated colistins were endocytosed and co-localized in lysosomes, and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization.Discussion: Whilst clinical translation of dextrin–colistin conjugates for the treatment of AML is unlikely due to the potential to promote antimicrobial resistance (AMR) and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation. Keywords: polymer therapeutics, biodegradable, internalization, polysaccharide, antibiotic

Introduction: Visceral leishmaniasis (VL) is an important tropical and neglected disease and represents a serious global health problem. The initial interaction between the phagocytes and the parasite is crucial to determine the pathogen's capacity to initiate infection and it shapes the subsequent immune response that will develop. While type-1 T-cells induce IL-6, IL-1β, TNF-α, and IL-12 production by monocytes/macrophages to fight the infection, type-2 T-cells are associated with a regulatory phenotype (IL-10 and TGF-β) and successful infection establishment. Recently, our group demonstrated the role of an important Th1/ Th17 T-cell population, the mucosal-associated invariant T (MAIT) cells, in VL. MAIT cells can respond to L. infantum by producing TNF-α and IFN-γ upon MR1- dependent activation. Objective and methods: Here, we describe the impact of the MR1-blockage on L. infantum internalization on the functional profile of circulating neutrophils and monocytes as well as the impact of the MR1-blockage on the soluble mediator signatures of in vitro whole blood cultures. Results: Overall, our data showed that VL patients presents higher percentage of activated neutrophils than asymptomatic and non-infected controls. In addition, MR1 blockade led to lower TNF-α and TGF-β production by non-activated neutrophils from asymptomatic individuals. Moreover, TNF-α and IL-10 production by monocytes was higher in VL patients. In the analysis of soluble mediators produced in vitro, MR1-blockade induced a decrease of IFN-γ and an increase of IL-10, IL-27 and IL-33 in the cell cultures of AS group, a cytokine pattern associated with type 2 deleterious response. Discussion and conclusion: These data corroborate the hypothesis that MR1- restricted responses are associated to a protective role during Leishmania infection. [ABSTRACT FROM AUTHOR]

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Pancasila is the philosophy of life of the Indonesian people, which has never been swallowed up by the times. Therefore, the values of Pancasila are very important to be internalized by all Indonesian people so that what they do reflects the values of Pancasila. The efforts to internalize the values of Pancasila are through Economics education at the High School (SMA) level. Economic education in high school is reflected in the economic learning activities. This study aims to explain the importance of internalizing Pancasila values in high school economics learning in the digital age. The approach used in this research is a qualitative approach, by conducting a literature study (library research). The results and discussion of this study indicate that in the digital era, it is important to internalize the values of Pancasila in students through economic learning activities, so that they can become a strong fortress and life guide in dealing with any changes that occur in everyday life. The internalization process of Pancasila values is reflected in Economics learning activities, including 1) At the time of teaching, the teacher provides E-Learning guidelines based on Pancasila values in the field of Economics. 2) Teachers instill the values of Pancasila by providing examples of wise management of Economic activities and not destroying nature through visualization with sophisticated technology. 3) Giving group assignments in Economics learning that contains the values of Pancasila. 4) The teacher stimulates students to discuss when solving actual economic issues, both face-to-face and virtual (online) [ABSTRACT FROM AUTHOR]

Background: The bacterial persistence, responsible for therapeutic failures, can arise from the biofilm formation, which possesses a high tolerance to antibiotics. This threat often occurs when a bone and joint infection is diagnosed after a prosthesis implantation. Understanding the biofilm mechanism is pivotal to enhance prosthesis joint infection (PJI) treatment and prevention. However, little is known on the characteristics of Cutibacterium acnes biofilm formation, whereas this species is frequently involved in prosthesis infections. Methods: In this study, we compared the biofilm formation of C. acnes PJI-related strains and non-PJI-related strains on plastic support and textured titanium alloy by (i) counting adherent and viable bacteria, (ii) confocal scanning electronic microscopy observations after biofilm matrix labeling and (iii) RT-qPCR experiments. Results: We highlighted material- and strain-dependent modifications of C. acnes biofilm. Non-PJI-related strains formed aggregates on both types of support but with different matrix compositions. While the proportion of polysaccharides signal was higher on plastic, the proportions of polysaccharides and proteins signals were more similar on titanium. The changes in biofilm composition for PJI-related strains was less noticeable. For all tested strains, biofilm formation-related genes were more expressed in biofilm formed on plastic that one formed on titanium. Moreover, the impact of C. acnes internalization in osteoblasts prior to biofilm development was also investigated. After internalization, one of the non-PJI-related strains biofilm characteristics were affected: (i) a lower quantity of adhered bacteria (80.3-fold decrease), (ii) an increase of polysaccharides signal in biofilm and (iii) an activation of biofilm gene expressions on textured titanium disk. Conclusion: Taken together, these results evidenced the versatility of C. acnes biofilm, depending on the support used, the bone environment and the strain. [ABSTRACT FROM AUTHOR]

This work investigated the influence of surface chirality on cellular internalization, cytotoxicity, and tissue distribution of silver nanoparticles (AgNPs). D-cysteine and L-cysteine are chiral forms of the amino acid cysteine. These enantiomers exhibit distinct spatial arrangements, with D-cysteine having a different configuration from L-cysteine. This structural dissimilarity can lead to variations in how these forms interact with biological systems, potentially impacting their cytotoxic responses. Four distinct types of AgNPs were synthesized, each possessing a unique surface coating: pristine AgNPs (pAgNPs), L-cysteine coated AgNPs (AgNPs@L-Cys), D-cysteine coated AgNPs (AgNPs@D-Cys), and racemic AgNPs coated with both L-Cys and D-Cys (AgNPs@L/D-Cys). We found chiral-dependent cytotoxicity of AgNPs on J774A.1 cells. Specifically, AgNPs@L-Cys exhibited the highest toxicity, and AgNPs@D-Cys exhibited the lowest toxicity. Meanwhile, the cellular uptake of the AgNPs correlated nicely with their cytotoxicity, with AgNPs@L-Cys being internalized to the greatest extent while AgNPs@D-Cys displays the least internalization. Scavenger receptors and clathrin predominantly mediate the cellular internalization of these AgNPs. Strikingly, the dissimilar cellular internalization and cytotoxicity of AgNPs with different chirality were eliminated upon protein corona coverage. Notably, following intravenous injection in mice, these four types of AgNPs showed similar patterns among various organs due to the inevitable protein adsorption in the bloodstream. These findings underscored the pivotal role of surface chirality in governing the biological interactions and toxicity of AgNPs. • Chiral-dependent cytotoxicity of AgNPs on J774A.1 cells was found. • Cellular uptake of the AgNPs correlated with their cytotoxicity. • Protein corona eliminated the chirality of AgNPs. • Four types of AgNPs showed similar tissue distribution pattern. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications The gut hormone glucose‐dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose‐stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR‐targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C‐terminus.The GIPR from humans, mice, rats, pigs, dogs and cats was studied in vitro for cognate ligand affinity, G protein activation (cAMP accumulation), recruitment of beta‐arrestin and internalization. Variants of the mouse, rat and human GIPRs with swapped C‐terminal tails were studied in parallel.The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for Gαs activation, especially, the mouse GIPR shows reduced receptor desensitization, internalization and beta‐arrestin recruitment. Using an enzyme‐stabilized, long‐acting GIP analogue, the species differences were even more pronounced. ‘Tail‐swapped’ human, rat and mouse GIPRs were all fully functional in their Gαs coupling, and the mouse GIPR regained internalization and beta‐arrestin 2 recruitment properties with the human tail. The human GIPR lost the ability to recruit beta‐arrestin 2 when its own C‐terminus was replaced by the rat or mouse tail.Desensitization of the human GIPR is dependent on the C‐terminal tail. The species‐dependent functionality of the C‐terminal tail and the different species‐dependent internalization patterns, especially between human and mouse GIPRs, are important factors influencing the preclinical evaluation of GIPR‐targeting therapeutic compounds. [ABSTRACT FROM AUTHOR]

Micropterus salmoides rhabdovirus (MSRV) is an important pathogen of largemouth bass. Despite extensive research, the functional receptors of MSRV remained unknown. This study identified the host protein, laminin receptor (LamR), as a cellular receptor facilitating MSRV entry into host cells. Our results demonstrated that LamR directly interacts with MSRV G protein, playing a pivotal role in the attachment and internalization processes of MSRV. Knockdown of LamR with siRNA, blocking cells with LamR antibody, or incubating MSRV virions with soluble LamR protein significantly reduced MSRV entry. Notably, we found that LamR mediated MSRV entry via clathrinmediated endocytosis. Additionally, our findings revealed that MSRV G and LamR were internalized into cells and co-localized in the early and late endosomes. These findings highlight the significance of LamR as a cellular receptor facilitating MSRV binding and entry into target cells through interaction with the MSRV G protein. IMPORTANCE Despite the serious epidemic caused by Micropterus salmoides rhabdovirus (MSRV) in largemouth bass, the precise mechanism by which it invades host cells remains unclear. Here, we determined that laminin receptor (LamR) is a novel target of MSRV, that interacts with its G protein and is involved in viral attachment and internalization, transporting with MSRV together in early and late endosomes. This is the first report demonstrating that LamR is a cellular receptor in the MSRV life cycle, thus contributing new insights into host-pathogen interactions. [ABSTRACT FROM AUTHOR]

Copyright of HOW: A Colombian Journal for Teachers of English is the property of Asociacion Colombiana de Profesores de Ingles and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The sodium–potassium pump (NKA) or Na+/K+ ATPase consumes around 30–40% of the total energy expenditure of the animal cell on the generation of the sodium and potassium electrochemical gradients that regulate various electrolyte and nutrient transport processes. The vital role of this protein entails proper spatial and temporal regulation of its activity through modulatory mechanisms involving its expression, localization, enzymatic activity, and protein–protein interactions. The residence of the NKA at the plasma membrane is compulsory for its action as an antiporter. Despite the huge body of literature reporting on its trafficking between the cell membrane and intracellular compartments, the mechanisms controlling the trafficking process are by far the least understood. Among the molecular determinants of the plasma membrane proteins trafficking are intrinsic sequence-based endocytic motifs. In this review, we (i) summarize previous reports linking the regulation of Na+/K+ ATPase trafficking and/or plasma membrane residence to its activity, with particular emphasis on the endocytic signals in the Na+/K+ ATPase alpha-subunit, (ii) map additional potential internalization signals within Na+/K+ ATPase catalytic alpha-subunit, based on canonical and noncanonical endocytic motifs reported in the literature, (iii) pinpoint known and potential phosphorylation sites associated with NKA trafficking, (iv) highlight our recent studies on Na+/K+ ATPase trafficking and PGE2-mediated Na+/K+ ATPase modulation in intestine, liver, and kidney cells. [ABSTRACT FROM AUTHOR]

Aim: Previous reports have suggested successful infection by Epstein–Barr virus (EBV) in various brain cells; however, the entry mechanism is still elusive. In the present study, we investigated the entry pathway of EBV into astrocytes. Materials & methods: For virus entry, receptors are considered as a instrumental moieties for infection. Upon EBV infection, the expression of receptors such as Ephrin, neuropilin and nonmuscle myosin heavy chain-II were assessed in a time-dependent manner. Then, by using inhibitors, we investigated the role of membrane cholesterol, the dynamin protein and, eventually, EBV colocalization in endosomal vesicles. Results: EBV induced changes in the expression of numerous receptors, especially EphA4, EphA10 and NMHC-IIB. Upon binding to its receptor, the virus translocates into the lipid raft region of the plasma membrane, and its depletion results in decreased EBV internalization. The inhibition of dynamin also mitigated EBV entry. Subsequently, EBV colocalized in the endosomal compartment with markers such as EEA1, Rab5, Rab7 and LAMP1. Conclusion: The current work implicitly indicates that EBV follows the endocytic pathway to enter brain cells, although further validation by knocking down these proteins is needed. These findings will further enable us to pinpoint therapeutic targets. Plain Language Summary Epstein–Barr virus (EBV) is linked to neurodegenerative diseases like multiple sclerosis (MS). Immune cells responding to EBV infection have been found in the brain of these patients. The exact way in which the virus enters cells in the brain is unknown. Our study looks at how EBV enters a type of brain cells called astrocytes. Article highlights Epstein–Barr virus enters astrocytes via different receptors, such as EphA4 and NMHC-IIB. EBV internalization decreased upon depletion of the lipid rafts. The dynamin protein plays a crucial role in EBV entry into astrocytes, and its depletion indicates a decrease in EBV entry. The colocalization of EBV with endosomal vesicles was detected via markers such as EEA1, Rab5, Rab7 and LAMP1. [ABSTRACT FROM AUTHOR]

Copyright of Jurnal Manajemen Pendidikan dan Ilmu Sosial (JMPIS) is the property of Dinasti Publisher and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Project management and project portfolio management (PPM) foster competitiveness by facilitating the implementation of organizational strategy. Although organizations often struggle to develop PPM capabilities, the academic community does not have an in-depth understanding of the conditions for successfully developing these capabilities. In response, we conducted a multiple-case study with 50 interviewees to develop a theoretical model of the PPM capability-building process. This model is built on the notion of organizational sensemaking and identifies aspects that comprehensively explain why it usually takes so long to develop PPM capabilities. We conceptualize the PPM capability-building process as one that is strongly influenced by (1) the effects of structural rearrangements, (2) the appropriate use of external resources during that process, (3) the role of executive support and legitimization, (4) episodes of regression, and (5) the need for internalization and habitualization. In addition, we provide starting points for explaining organizational capability building in more general terms. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignancy in women globally. Significant progress has been made in developing structural nanoparticles (NPs) and formulations for targeted smart drug delivery (SDD) of pharmaceuticals, improving the precision of tumor cell targeting in therapy. Magnetic hyperthermia (MHT) treatment using magneto-liposomes (MLs) has emerged as a promising adjuvant cancer therapy. CoFe2O4 magnetic NPs (MNPs) were conjugated with nanoliposomes to form MLs, and the anticancer drug quercetin (Que) was loaded into MLs, forming Que-MLs composites for antitumor approach. The aim was to prepare Que-MLs for DD systems (DDS) under an alternating magnetic field (AMF), termed chemotherapy/hyperthermia (chemo-HT) techniques. The encapsulation efficiency (EE), drug loading capacity (DL), and drug release (DR) of Que and Que-MLs were evaluated. The results confirmed successful Que-loading on the surface of MLs, with an average diameter of 38 nm and efficient encapsulation into MLs (69%). In vitro, experimental results on MCF-7 breast cells using MHT showed high cytotoxic effects of novel Que-MLs on MCF-7 cells. Various analyses, including cytotoxicity, apoptosis, cell migration, western blotting, fluorescence imaging, and cell membrane internalization, were conducted. The Acridine Orange-ethidium bromide double fluorescence test identified 35% early and 55% late apoptosis resulting from Que-MLs under the chemo-HT group. TEM results indicated MCF-7 cell membrane internalization and digestion of Que-MLs, suggesting the presence of early endosome-like vesicles on the cytoplasmic periphery. Que-MLs exhibited multi-modal chemo-HT effects, displaying high toxicity against MCF-7 BC cells and showing promise as a potent cytotoxic agent for BC chemotherapy. [ABSTRACT FROM AUTHOR]

Silent reading frequently entails engaging the “inner voice,” a phenomenon in which individuals sub-vocally articulate words in their minds. This inner voice is understood to stem from the internalization process, wherein external verbal speech transitions into internal dialogue. However, the mechanisms through which foreign language learners internalize written content, particularly in a speed-reading framework, remain under-explored due to the inherent difficulties in observing such a process. To shed light on this, a qualitative study was carried out; it employed journals and the recall technique to examine the initial stages of internalization of written text by foreign language learners within a speed-reading program. This program aims to enhance the pace and comprehension of reading English texts. The study reveals that learners start to internalize the written language through a series of inner speech uses such as subvocalization, literal translation, repetition, fluent reading, and the formation of mental imagery associations with the language. The findings further indicate that, as learners advance in the speed-reading course, their mental translation efforts become more subconscious, facilitating the transition to using inner speech as a cognitive tool through associations with mental images. This shift may play a crucial role in the efficiency and efficacy of acquiring reading skills in a foreign language.

Shailey Gale Twamley,1– 3 Niclas Gimber,4 Héctor Eduardo Sánchez-Ibarra,1,2 Tobias Christaller,1,2 Victoria Isakzai,1,2 Harald Kratz,5 Ronodeep Mitra,6 Lena Kampen,1– 3 Anke Stach,1,2 Heike Heilmann,7 Berit Söhl-Kielczynski,8 Eno Essien Ebong,6,9,10 Jan Schmoranzer,4 Agnieszka Münster-Wandowski,7,&ast; Antje Ludwig1– 3,&ast; 1Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany; 2Department of Cardiology, Angiology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany; 3DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany; 4Advanced Medical Bioimaging Core Facility (AMBIO), Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 5Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 6Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 7Institute of Integrative Neuroanatomy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 8Institute for Integrative Neurophysiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany; 9Department of Bioengineering, Northeastern University, Boston, MA, USA; 10Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA&ast;These authors contributed equally to this workCorrespondence: Shailey Gale Twamley; Antje Ludwig, Tel +49-30-450-528455 ; +49-30-450-513196, Fax +49-30-450-528922 ; +49-30-450941, Email shailey.twamley@charite.de; antje.ludwig@dhzc-charite.dePurpose: To study whether the absence of laminar shear stress (LSS) enables the uptake of very small superparamagnetic iron oxide nanoparticles (VSOP) in endothelial cells by altering the composition, size, and barrier function of the endothelial surface layer (ESL).Methods and Results: A quantitative particle exclusion assay with living human umbilical endothelial cells using spinning disc confocal microscopy revealed that the dimension of the ESL was reduced in cells cultivated in the absence of LSS. By combining gene expression analysis, flow cytometry, high pressure freezing/freeze substitution immuno-transmission electron microscopy, and confocal laser scanning microscopy, we investigated changes in ESL composition. We found that increased expression of the hyaluronan receptor CD44 by absence of shear stress did not affect the uptake rate of VSOPs. We identified collagen as a previously neglected component of ESL that contributes to its barrier function. Experiments with inhibitor halofuginone and small interfering RNA (siRNA) demonstrated that suppression of collagen expression facilitates VSOP uptake in endothelial cells grown under LSS.Conclusion: The absence of laminar shear stress disturbs the barrier function of the ESL, facilitating membrane accessibility and endocytic uptake of VSOP. Collagen, a previously neglected component of ESL, contributes to its barrier function. Keywords: citrate coated nanoparticles, atherosclerosis, blood flow, endothelial barrier, permeability, internalization

Background. Theory of mind is the capacity to explain and predict the behavior of others. Charles Fernyhough’s dialogical model of psychological functions offers a vision of theory of mind that considers the social dimension and the importance of language, especially inner and private speech, for a person’s ability to represent and manipulate multiple perspectives, and its connection to executive function. Objective. There is little direct research on Fernyhough’s model. The present study addressed that gap by studying the relationship between theory of mind, private speech, and executive function (planning) in the preschool years. Design. Data were collected from a total of 86 preschool children from the Mexican state of Tlaxcala; 24 were from the first grade of preschool, 30 from the second, and 32 from the third. Their degree of internalization and their speech types (i.e., social and private) were obtained by coding their utterances during free play and during performance of a Tower of London task. Lastly, their theory of mind was assessed with a change of location and an unexpected contents task. Results. No correlation was found between children’s theory of mind and their degree of internalization. However, inaudible private speech was correlated (negatively) to theory of mind performance in the third grade of preschool. Furthermore, their scores on the Tower of London task were negatively correlated with social speech and positively correlated with inaudible private speech, while the reverse was true for time of execution. Conclusion. The results suggested that the degree of internalization is a measure of the regulative function of language, not the ability to manipulate perspectives, and that it is inadequate for capturing subtle differences between performance and speech types. Role-playing conditions were recommended as better tasks for exploring the capacities for manipulating and understanding different perspectives during the preschool years.

The article reveals the content of one of the components of knowledge management – knowledge generation in an organization. An attempt is being made to identify the mechanism of this generation and to reveal the potential for its effectiveness. It is shown that knowledge for an organization has the status of a special resource: it has its own dynamics of emergence and requires specific management actions. The experience of Japanese companies is used in applying a four-phase spiral model of new knowledge formation in an organization, when knowledge is translated into real technologies and products. Creating new knowledge literally means “reshaping the company and each of its employee in a continuous process of personal and organizational selfrenewal”. The study presents the “ba” platform, which is interpreted as a system in which knowledge is activated as a creative resource and as a context in which interaction between explicit and tacit knowledge develops in a spiral. A SECI model is proposed. It describes such methods of knowledge transformation. By addressing organized processes such as knowledge creation and exchange, the mechanisms that ensure the transfer of knowledge in organizations are analyzed. It is concluded that knowledge transfer is a kind of key to a rare opportunity to understand what the prerequisites for a company competitive advantages are. A mechanism for resolving this paradoxical situation can only be formed by managers representing the creative class.

Adolescents face various experiences of social exclusion in relation to sexuality. In this article we draw attention to how these experiences are internalized. We propose to name the phenomenon internalized social exclusion and provide its definition. Applying reflexive thematic analysis approach, a structure of such internalization is presented and described, distinguishing three themes, each having two subthemes: feeling insecure (avoiding unpleasant situations and forming unhealthy relationships), feeling embarrassed (hiding who they are and expressing sexuality in a detrimental way), and feeling different (distancing from friends and family and creating a fantasy world). Our findings underscore the multi-layered nature of social exclusion, emphasizing the need to address its internalization, which manifests itself in socially excluding feelings. The proposed phenomenon of internalized social exclusion is not limited to the sexuality context but may be applied in various social exclusion contexts in future research.

0D biomaterials (0DBMs) can serve as carriers to enhance and extend the regulatory effects of biological cues they transport on cell fate via bacterial/mammalian cell internalization. However, accurately delivering and amplifying biosignals through 0DBMs remains challenging to cope with ecological niche destabilization induced by factors such as trauma or infection. Herein, the "zero‐dimensional amplification" approach is employed to develop a surface carboxylate carbon dot (CQD‐COOH) conjugated with a neutrophil constitutive peptide (LL‐37), resulting in the formation of a 0D peptide quantum dot (LQD). Hydrogel‐released LQDs, when internalized by bacteria, cause the bacteria to programmatically rupture and die, whereas LQDs internalized by mesenchymal stem cells (MSCs) activate the cellular CXCL12/CXCR4 signaling axis, which directs the stem cells to homing and anchor to the surface of the hydrogel coating. Notably, this strategy of "zero‐dimensional amplification" enables the antimicrobial performance of LL‐37 to be boosted approximately 1.3‐fold, significantly extending the transmission efficiency of biosignals. Meanwhile, 0D lipid nanoparticles (lipo‐NPs) with targeting function incorporated into the hydrogel could deliver the bio‐small molecule MK‐4 to MCSs and induce their endocytosis, further enhancing osseointegration. Thus, the hydrogel coating (HGLL) under this strategy can significantly remodel the ecological niche of the implant–bone interface in infected environment. [ABSTRACT FROM AUTHOR]

Vaspin is a serine protease inhibitor that protects against adipose tissue inflammation and insulin resistance, two key drivers of adipocyte dysfunction and metabolic disorders in obesity. Inhibition of target proteases such as KLK7 has been shown to reduce adipose tissue inflammation in obesity, while vaspin binding to cell surface GRP78 has been linked to reduced obesity‐induced ER stress and insulin resistance in the liver. However, the molecular mechanisms by which vaspin directly affects cellular processes in adipocytes remain unknown. Using fluorescently labeled vaspin, we found that vaspin is rapidly internalized by mouse and human adipocytes, but less efficiently by endothelial, kidney, liver, and neuronal cells. Internalization occurs by active, clathrin‐mediated endocytosis, which is dependent on vaspin binding to the LRP1 receptor, rather than GRP78 as previously thought. This was demonstrated by competition experiments and RNAi‐mediated knock‐down in adipocytes and by rescuing vaspin internalization in LRP1‐deficient Pea13 cells after transfection with a functional LRP1 minireceptor. Vaspin internalization is further increased in mature adipocytes after insulin‐stimulated translocation of LRP1. Although vaspin has nanomolar affinity for LRP1 clusters II‐IV, binding to cell surface heparan sulfates is required for efficient LRP1‐mediated internalization. Native, but not cleaved vaspin, and also vaspin polymers are efficiently endocytosed, and ultimately targeted for lysosomal degradation. Our study provides mechanistic insight into the uptake and degradation of vaspin in adipocytes, thereby broadening our understanding of its functional repertoire. We hypothesize the vaspin‐LRP1 axis to be an important mediator of vaspin effects not only in adipose tissue but also in other LRP1‐expressing cells. [ABSTRACT FROM AUTHOR]