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Light-Responsive and Antibacterial Graphenic Materials as a Holistic Approach to Tissue EngineeringWhile the continuous development of advanced bioprinting technologies is under fervent study, enhancing the regenerative potential of hydrogel-based constructs using external stimuli for wound dressing has yet to be tackled. Fibroblasts play a significant role in wound healing and tissue implants at different stages, including extracellular matrix production, collagen synthesis, and wound and tissue remodeling. This study explores the synergistic interplay between photothermal activity and nanomaterial-mediated cell proliferation. The use of different graphene-based materials (GBM) in the development of photoactive bioinks is investigated. In particular, we report the creation of a skin-inspired dressing for wound healing and regenerative medicine. Three distinct GBM, namely, graphene oxide (GO), reduced graphene oxide (rGO), and graphene platelets (GP), were rigorously characterized, and their photothermal capabilities were elucidated. Our investigations revealed that rGO exhibited the highest photothermal efficiency and antibacterial properties when irradiated, even at a concentration as low as 0.05 mg/mL, without compromising human fibroblast viability. Alginate-based bioinks alongside human fibroblasts were employed for the bioprinting with rGO. The scaffold did not affect the survival of fibroblasts for 3 days after bioprinting, as cell viability was not affected. Remarkably, the inclusion of rGO did not compromise the printability of the hydrogel, ensuring the successful fabrication of complex constructs. Furthermore, the presence of rGO in the final scaffold continued to provide the benefits of photothermal antimicrobial therapy without detrimentally affecting fibroblast growth. This outcome underscores the potential of rGO-enhanced hydrogels in tissue engineering and regenerative medicine applications. Our findings hold promise for developing game-changer strategies in 4D bioprinting to create smart and functional tissue constructs with high fibroblast proliferation and promising therapeutic capabilities in drug delivery and bactericidal skin-inspired dressings.
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Encapsulation and delivery of mitoxantrone using zirconium-based metal–organic frameworks (MOFs) and their cytotoxic potential in breast cancer cellsMitoxantrone (MTX) is a drug employed in breast cancer treatment, but its application is largely limited due to side effects. A controlled delivery approach can potentially reduce the side effects. In this study, two zirconium (Zr)-based MOFs, UiO-66 and UiO-66-NH2, were studied for a more controlled delivery of MTX with a 40% and 21% loading capacity, respectively. Characterisation via powder X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectrometry, scanning electron microscopy, and dynamic light scattering confirmed the integrity of structure post-MTX loading. UV–vis spectrophotometry revealed distinctive release profiles, with UiO-66-MTX exhibiting a 25% cumulative release after 96 h in water and 120 h in PBS +10% FBS. UiO-66-NH2-MTX displayed a more sustained release, reaching 62% in water and 47% in PBS +10% FBS after 168 h. The interaction between MTX and the MOFs was also proposed based on computational modelling, suggesting a stronger interaction of UiO-66NH2 and MTX, and an optimised interaction of MTX in the tetrahedral and octahedral pores of the MOFs. The study also reports the release profile of the drug and antiproliferative activity against a panel of breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF7) and a normal breast epithelial cell line (MCF10A). MTX-encapsulated MOFs were thoroughly characterised, and their biological activity was assessed in vitro. MTT cell viability assay indicated a higher IC50 value for MTX-loaded MOFs compared to free MTX in physiological conditions, albeit with a slower release profile. These findings suggest the potential of these MTX-loaded MOFs as an alternative avenue for formulation to mitigate side effects.
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Effectual Endeavors of Silk Protein Sericin against Isoproterenol Induced Cardiac Toxicity and Hypertrophy in Wistar RatsThe silkworm cocoon has been used in the treatment of various ailments in different Asian countries. This research was designed to evaluate the effect of sericin on myocardial necrosis and hypertrophy in isoproterenol-challenged rats. The rats were administered with sericin (500 and 1000 mg/kg, p.o.) for 28 days, followed by administration of isoprenaline (85 mg/kg, s.c.) on the 29th and 30th days. The cardioprotective activity was assessed by various physical, enzymatic, and histopathological parameters along with apoptotic marker expression. The cardioprotective effect showed that pre-treatment of rats with sericin significantly increased the non-enzymatic antioxidants marker in serum and heart tissue (glutathione, vitamin E, and vitamin C). The results were the same in enzymatic antioxidant marker, mitochondrial enzymes, and protein. The grading of heart, heart/body weight ratio, gross morphology, cardiac markers, oxidative stress markers in serum and heart tissue, glucose, serum lipid profiling and Lysosomal hydrolases, heart apoptotic markers such as MHC expression by western blot, apoptosis by flow cytometry, total myocardial collagen content, fibrosis estimation, myocyte size were significantly decreased when compared with isoproterenol (ISG) group however histopathological studies showed normal architecture of heart in both control and treated rats. The pharmacological study reflects that sericin on both doses i.e., 500 mg/kg and 1000 mg/kg have potent cardioprotective action against the experimental model which was confirmed by various physical, biochemical, and histopathological parameters evaluated further research is required to examine the molecular mechanism of cardioprotective effect of sericin.
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Discovery of 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one derivatives as possible antileishmanial agentsA series of uniquely functionalized 2,3,-dihydro-1H-pyyrolo[3,4-b]quinolin-1-one derivatives were synthesized in one to two steps by utilizing a post-Ugi modification strategy and were evaluated for antileishmanial efficacy against visceral leishmaniasis (VL). Among the library compounds, compound 5m exhibited potential in vitro antileishmanial activity (CC50 = 65.11 μM, SI = 7.79, anti-amastigote IC50 = 8.36 μM). In vivo antileishmanial evaluation of 5m demonstrated 56.2% inhibition in liver and 61.1% inhibition in spleen parasite burden in infected Balb/c mice (12.5 mg kg-1, i.p.). In vitro pharmacokinetic study ascertained the stability of 5m in both simulated gastric fluid and simulated intestinal fluid. All the active compounds passed the PAINS filter and showed no toxicity in in silico predictions.
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Chemoselective solution- and solid-phase synthesis of disulfide-linked glycopeptidesGlycosylation of peptides and proteins is a widely employed strategy to mimic important post-translational modifications or to modulate the physicochemical properties of peptides to enhance their delivery. Furthermore, glycosylation via a sulfur atom imparts increased chemical and metabolic stability to the resulting glycoconjugates. Herein, we report a simple and chemoselective procedure to prepare disulfide-linked glycopeptides. Acetate-protected glycosylsulfenyl hydrazines are shown to be highly reactive with the thiol group of cysteine residues within peptides, both in solution and as part of conventional solid-phase peptide synthesis protocols. The efficiency of this glycosylation methodology with unprotected carbohydrates is also demonstrated, which avoids the need for deprotection steps and further extends its utility, with disulfide-linked glycopeptides produced in excellent yields. Given the importance of glycosylated peptides in structural glycobiology, pharmacology, and therapeutics, the methodology outlined provides easy access to disulfide-linked glycopeptides as molecules with multiple biological applications.
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CD-44 targeted nanoparticles for combination therapy in an in vitro model of triple-negative breast cancer: Targeting the tumour inside outTriple-negative breast cancer (TNBC) is an aggressive form of breast cancer defined by the lack of three key receptors: estrogen, progesterone, and HER2. This lack of receptors makes TNBC difficult to treat with hormone therapy or drugs, and so it is characterised by a poor prognosis compared to other kinds of breast cancer. This study explores photoactive Poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a potential therapeutic strategy for TNBC. The nanoparticles are functionalised with hyaluronic acid (HA) for targeted delivery to CD-44 receptors overexpressed in TNBC cells, especially under hypoxic conditions. Additionally, we co-loaded the nanoparticles with Doxorubicin (Dox) and Indocyanine Green (ICG) to enable combinatorial chemo-photothermal therapy. After carefully optimising the formulation, we propose an effortless and reproducible preparation of the nanodrugs. We demonstrate that HA-conjugated nanoparticles effectively target TNBC cells and inhibit their proliferation while the treatment efficiency is enhanced during near-infrared light irradiation. We also prove that our treatment is effective in a 3D cell culture model, highlighting the importance of tumour architecture and the metabolic stage of the cells in the tumour microenvironment. This approach is promising for a tumour-targeted theragnostic for TNBC with improved efficacy in hypoxic microenvironments.
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Co-Loading of Black Phosphorus Nanoflakes and Doxorubicin in Lysolipid Temperature-Sensitive Liposomes for Combination Therapy in Prostate Cancer.Black phosphorus (BP) is one of the most promising nanomaterials for cancer therapy. This 2D material is biocompatible and has strong photocatalytic activity, making it a powerful photosensitiser for combined NIR photothermal and photodynamic therapies. However, the fast degradation of BP in oxic conditions (including biological environments) still limits its use in cancer therapy. This work proposes a facile strategy to produce stable and highly concentrated BP suspensions using lysolipid temperature-sensitive liposomes (LTSLs). This approach also allows for co-encapsulating BP nanoflakes and doxorubicin, a potent chemotherapeutic drug. Finally, we demonstrate that our BP/doxorubicin formulation shows per se high antiproliferative action against an in vitro prostate cancer model and that the anticancer activity can be enhanced through NIR irradiance.
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Engineering PSMA-targeted nanoparticles co-encapsulating mitoxantrone and indocyanine green for precise combinatory therapy in prostate cancerProstate cancer is the 2nd most common cancer in men worldwide. Chemotherapeutic treatment of prostate cancer with mitoxantrone (MTX) has limited efficacy due to severe side effects in which cardiotoxicity and myelosuppression are the two major causes of its dose-limiting toxicity. This study aimed to obtain a poly (lactic-co-glycolic acid) (PLGA) nanoparticle that can precisely deliver MTX to the prostate cancer cells overexpressing the Prostate-specific membrane antigen (PSMA) receptor-sparing healthy tissues and co-loading Indocyanine green (ICG) as a fluorescent photothermal/photodynamic agent for precise combinatory therapy in prostate cancer. The biocompatible polymer PLGA was covalently modified with the peptide of sequence (WQPDTAHHWATL) to actively target the PSMA receptor. Factors like the peptide-to-polymer ratio or the peptide's orientation during the polymer's chemical modification were investigated to enhance the active targeting of the nanoparticles (NPs). NPs were characterised using dynamic light scattering, scanning electron microscopy, and UV–vis spectroscopy to determine their morphological and colloidal properties and optimal MTX and ICG encapsulation efficiency. Quantitative FACS analysis of LNCaP and PC-3 cells incubated with Nile Red-labelled non-targeted PLGA or PLGA-PSMA targeted NPs was assessed to identify the best formulation that bound selectively to PSMA. The orientation of the peptide conjugated to the polymer, which has the C-terminal end of the peptide sequence accessible for interaction with the cell receptor, maximises the targeting capacity of the system. Photothermal experiments using 808 nm near-infrared laser irradiation were conducted, and cytotoxicity was assessed using the resazurin viability assay. Remarkably, our results confirmed the safety and efficacy of a targeted and activatable therapy using polymeric NPs functionalised with the peptide and co-loaded with MTX and ICG. This pioneer nanosystem opens new perspectives for exploring advanced targeted delivery in prostate cancer. It offers a straightforward methodology for functionalising drug delivery systems with bioactive peptides that can be applied to different types of cancer.
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Formulation, characterisation, and biocompatibility assessment of rifampicin-loaded poly(d,l-lactide-co-glycolide) composites for local treatment of orthopaedic and wound infectionsBackground/Objectives: The escalating challenge of antimicrobial resistance (AMR) necessitates the development of targeted antibiotic delivery platforms, minimising systemic administration. Polymer-based drug delivery emerges as a promising solution, ensuring sustained release and prolonged efficacy of bioactive compounds, ensuring long-term efficacy. Methods: This study focuses on encapsulating rifampicin (RIF), a key antibiotic for orthopaedic and wound-related infections, within Poly(d,l-lactide-co-glycolide) (PLGA), a biodegradable polymer, through solvent casting, to formulate a PLGA-RIF composite membrane. Comprehensive characterisation, employing Fourier-transformed infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), thermal analysis and X-ray Diffraction (XRD), confirmed the integrity of both the starting and produced materials. UV-Vis spectroscopy revealed a controlled drug release profile over 21 days in various media, with the chosen media influencing the drug release, notably the tryptic soya broth (TSB) caused the highest release. The quantitative assessment of the antimicrobial efficacy of the developed PLGA-RIF composite was conducted by measuring the size of the inhibition zones against both Gram-negative and Gram-positive bacteria. Results: The results confirmed the composite’s potential as a robust antibacterial biomaterial, demonstrating a rapid and effective antibacterial response. Cytocompatibility tests incorporated human fibroblast and osteoblast-like cell lines and demonstrated that the RIF:PLGA (1:8) formulation maintained eukaryotic cell viability, indicating the composite’s potential for targeted medical applications in combating bacterial infections with minimal systemic impact. Conclusions: This study presents the significance of investigating drug release within appropriate and relevant physiological media. A key novelty of this work therefore lies in the exploration of drug release dynamics across different media, allowing for a comprehensive understanding of how varying physiological conditions may influence drug release and its effect on biological responses.
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Controlling the helical pitch of foldamers through terminal functionality: A solid state studyDeveloping new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho‐azobenzene/2,6‐pyridyldicarboxamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.4 Å–7.3 Å). Additionally, crystallographic analysis of a library ten foldamers has identified general trends in the influence of a range of terminal functionalities, including carboxylbenzyl (Cbz), diphenylcarbamyl (N(Ph)2), ferrocene (Fc) and tert‐butyloxycarbonyl (Boc), in controlling the folding behaviour of these supramolecular scaffolds. These studies could prove useful in the future development of functional foldamers which adopt specific sizes and shapes. A crystallographic study into the influence of varying the terminal functionality on the helical pitch of a series of foldamers is reported. Herein, we show that through systematic modification of the terminal functionality in the foldamer, from carboxylbenzyl (Cbz), diphenylamide (N(Ph)2), ferrocene to tert‐butyloxycarbonyl (Boc) helical pitches between 3.4–7.3 Å can be readily accessed in these supramolecular scaffolds.
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The Arp2/3 complex is critical for colonisation of the mouse skin by melanoblastsThe Arp2/3 complex is essential for the assembly of branched filamentous actin but its role in physiology and development is surprisingly little understood. Melanoblasts deriving from the neural crest migrate along the developing embryo and traverse the dermis to reach the epidermis colonising the skin and eventually homing within the hair follicles. We have previously established that Rac1 and Cdc42 direct melanoblast migration in vivo We hypothesised that the Arp2/3 complex might be the main downstream effector of these small GTPases. Arp3 depletion in the melanocyte lineage results in severe pigmentation defects in dorsal and ventral regions of the mouse skin. Arp3 null melanoblasts demonstrate proliferation and migration defects and fail to elongate as their wild-type counterparts. Conditional deletion of Arp3 in primary melanocytes causes improper proliferation, spreading, migration and adhesion to extracellular matrix. Collectively, our results suggest that the Arp2/3 complex is absolutely indispensable in the melanocyte lineage in mouse development, and indicate a significant role in developmental processes that require tight regulation of actin-mediated motility.
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Exploring Age – Transition Analysis as a tool for detecting the elderly"e growth of gender archaeology has improved the inclusion of female and juvenile narratives in archaeological discourse, enabling us to better understand interactions between groups defined by both social and physiological differences. "ere has been a notable absence of elderly in research, however, that is not simply a question of attitudes but of methodological limitations. "e emergence of biostatistics has offered novel ways to combat common issues such as age mimicry and avoid the problematic nature of culturally loaded descriptive terminology. A test performed on Transition Analysis by Boldsen et al. (2002), generates individual age estimates, which allow for better differentiation between individuals and age groups, such as the ‘45+ older adults’. Further research into biostatistical methods will not only improve objectivity but bring much-needed attention to the elderly, including their narrative into the investigation of family dynamics and adult-juvenile interactions.
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Skeletal analysisTwo early Bronze Age individuals (SF 26319 and SF 17642) and 19 samples of disarticulated remains from RUX6 were analysed and inventoried following procedures and standards set out by the British Association for Biological Anthropology and Osteoarchaeology (BABAO) and the Chartered Institute for Archaeologists (CIfA)
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Isotopic analysis of the human skeletal remainsThis chapter summarises the isotope analysis undertaken on the human remains from RUX6, in order to estimate their diet and physiological changes during life. Carbon (δ13C) and nitrogen (δ15N) stable isotope ratio analysis was carried out using incremental dentine sectioning for collagen for individuals SF 26319 and SF17642 (giving values for childhood and early adolescence) and bulk sampling of bone collagen for these two individuals plus an ulna from a third, disturbed burial from Square G, SF 17437 (providing an average for each of the diet during last 10 years of life). Contemporary faunal bone collage samples were also measured in order to provide an isotopic baseline. In addition, enamel from the teeth of SF 26319 and SF 17642 was sampled for strontium isotope ratios to assess individual migration.
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Interdisciplinary study of human remains from the Early Iron Age cemetery at Zagorje ob Savi (Slovenia)This paper presents the results of interdisciplinary investigations of human remains, discovered in 2011 at the Early Iron Age cemetery at Zagorje ob Savi (Cesta Borisa l(jdrica) in Slovenia. The present study is a part of a larger isotopic and osteological investigation of Bronze/Iron Age (14th-4th centuries BC) skeletal assemblages from Croatia and Slovenia. The osteological analysis of the six individuals uncovered on this site indicates that they represent the remains of two adult males, two adult females and two infants of unknown sex. The results of carbon and nitrogen stable isotope analysis on the bone and dentine collagen extracted from these six individuals is strongly indicative of a terrestrial based diet, including animal-based protein (meat and/or dairy) and a mix of C3 and C4 plants.
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Preliminary survey results: how do professionals in the UK view and approach working with disarticulated human remainsDisarticulated human remains (DHR) are commonly found on archaeological sites within the UK, yet they are often overlooked as a valuable archaeological resource. A review of the literature shows that this is due to numerous factors, the main one being budgetary constraints, an issue which is reflective of broader issues within commercial archaeology. Competitive tendering has led to archaeological work often being selected based on the cheapest contract (Belford 2022). Additionally, negative historic attitudes towards DHR (Hamerow 2006), and a lack of clear guidance on how they should be assessed, have led to them being overlooked. The best guidance available discusses the issues that may be encountered when working with DHR but does not give recommendations for how methods should be utilised (McKinley and Smith 2017). This paper presents the results of a preliminary survey of professionals working with human remains in the UK, and their approaches towards DHR.
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Understanding the anomaly: reinterpreting Porolissum Roman town with emerging GPR and ER dataThe Roman Porolissum (Romania) was first surveyed with magnetics in 2010. Local geology is propitious for magnetic prospection. In 2021 the Polish-Romanian team carried out a complementary ER and GPR survey. Emerging geophysical data allowed reinterpretation of the previous survey results. Complementary survey data and geological setting analysis yet enhanced the archaeological interpretation.
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Interaction of Acinetobacter sp. RIT 592 induces the production of broad-spectrum antibiotics in Exiguobacterium sp. RIT 594Antimicrobial resistance (AMR) is one of the most alarming global public health challenges of the 21st century. Over 3 million antimicrobial-resistant infections occur in the United States annually, with nearly 50,000 cases being fatal. Innovations in drug discovery methods and platforms are crucial to identify novel antibiotics to combat AMR. We present the isolation and characterization of potentially novel antibiotic lead compounds produced by the cross-feeding of two rhizosphere bacteria, Acinetobacter sp. RIT 592 and Exiguobacterium sp. RIT 594. We used solid-phase extraction (SPE) followed by liquid chromatography (LC) to enrich antibiotic extracts and subsequently mass spectrometry (MS) analysis of collected fractions for compound structure identification and characterization. The MS data were processed through the Global Natural Product Social Molecular Networking (GNPS) database. The supernatant from RIT 592 induced RIT 594 to produce a cocktail of antimicrobial compounds active against Gram-positive and negative bacteria. The GNPS analysis indicated compounds with known antimicrobial activity in the bioactive samples, including oligopeptides and their derivatives. This work emphasizes the utility of microbial community-based platforms to discover novel clinically relevant secondary metabolites. Future work includes further structural characterization and antibiotic activity evaluation of the individual compounds against pathogenic multidrug-resistant (MDR) bacteria.
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Between Life and Death: Continuing Bonds at Late Neolithic Tell Sabi Abyad, SyriaIn this paper, we pay tribute to the career-long interest of Prof Peter Akkermans in the mortuary practices of prehistoric southwest Asia. It highlights the significant discovery of burial grounds at Tell Sabi Abyad and the diverse range of mortuary behaviours observed at this key Late Neolithic site. While traditional approaches to the treatment of the dead often focus on social status, this paper proposes a fresh perspective by examining the agency of the bereaved and the impact of their emotional needs on mortuary rituals. Drawing on an extensive dataset of over 300 burials, the paper centres on a subset of burials from Tell Sabi Abyad I and III, dating back to the 7th and early 6th millennium BCE. In contrast to the typical interments, these burials reveal extended interaction with the deceased, involving bodily manipulation and close spatial proximity to the living. In this paper, we delve into new interpretations of this evidence, shedding light on the emotional relationships between the living and the dead. We explore possible motivations behind maintaining a tangible connection with the deceased and examine whether such practices offer insights into experiences of grief and bereavement – dimensions often overlooked in archaeological analysis. By incorporating emotion, sensory experiences, and mourning into the interpretation of mortuary evidence, in this paper, we aim to enrich our understanding of mortuary practices’ significance in southwest Asia’s prehistoric context.