Objective We aim to assess the quality of life for women with genitourinary fistulas before and after surgery, utilizing the WHOQOL-BREF questionnaire to contrast the preoperative and postoperative results. Materials and Methods: This quasi-experimental study was conducted at the Department of Urology, SIUT, Karachi, Pakistan, from January to December 2023. We used the WHOQOL-BREF questionnaire to assess the quality of life. Participants completed the questionnaire both before the surgical intervention and three months after successful fistula repair. The collected data were entered and analysed using IBM SPSS v26, with a significance level set at p≤ 0.05. Results The participants had a mean age of 35.50 years, with a standard deviation of 8.87 years. Before undergoing genitourinary fistula repair, the average WHOQOL-BREF score was 12.17 with a standard deviation of 5.77. Following the repair, the mean score showed a significant improvement, rising to 96.67 with a standard deviation of 11.86. This marked improvement was statistically significant, with a p-value of 0.0001. Conclusion This study concludes that genitourinary fistula repair at our tertiary care hospital significantly and positively impacts patients' quality of life. The findings emphasize the critical role of timely and appropriate surgical intervention in improving overall well-being. Continued comprehensive care and support are vital for these patients' holistic recovery and long-term health.

We studied the efficacy of mesenchymal stem cells (MSC), either alone or associated with dapsone (DAP) in the treatment of dermonecrotic wounds caused by Loxosceles laeta spider venom. Twenty-five male adult rabbits were distributed into five groups, of which four groups received an intradermal injection of 20 μg of L. laeta venom and only one received ultrapure water (negative control). After 4 hours, each group that received venom, was treated with MSC, DAP, MSC + DAP and Phosphate-buffered saline – PBS (positive control). Photographic records were made for analysis of the wound area evolution by morphometry. Twelve days after treatment, the skin samples around the lesion were removed for subsequent histological analysis. Concerning the rate of wound contraction, we observed that DAP showed the best percentage of contraction at day 3. In the treatments using MSCs, a negative value of wound contraction was observed for the isolated MSCs, as well as a lower contraction value for the association of the MSC + DAP when compared to PBS group. Histopathological analysis showed diminished tissue lesion and less intense inflammation in MSCs and DAP groups. This could indicated potential use of stem cells in regenerative therapies after loxoscelic accidents.

Background/Objectives Recurrent shoulder instability following Bankart lesion repair often necessitates surgical revision. Identified risk factors include young age, glenoid bone loss, and off-track Hill-Sachs lesions. This systematic review aims to understand failure rates of arthroscopic revision Bankart repair and if these aforementioned factors influence its success. Methods Following PRISMA guidelines, this systematic review, registered on PROSPERO, included twenty-four articles. Two independent reviewers assessed eligibility across three databases, focusing on recurrent instability as the primary endpoint, while also noting functional measures, adverse events, revision operations, and return-to-sport rates when available. Results Key surgical techniques for recurrent instability post-Bankart repair were identified, with revision arthroscopic Bankart being the most common (685/1032). Despite generally endorsed effectiveness, recurrence rates have increased over the past four years. Comparative analysis revealed significantly lower recurrence for open Latarjet compared to revision arthroscopic Bankart (p

Third and fourth-degree anal sphincter injuries are among the most severe traumas women can experience during childbirth, often leading to lifelong continence issues. Despite extensive research, current repair techniques are often inadequate, failing to provide long-term solutions. Women with previous severe injuries face a higher risk of recurrence in subsequent deliveries, making caesarean sections a safer option in many cases. The existing WHO classification system is outdated, as it doesn't account for injuries to muscles like the levator ani, which are crucial for continence. Effective repairs require skilled surgeons and often involve more than just fixing the sphincter. Smaller hospitals may not have the necessary expertise and resources for these complex repairs. Delaying repairs to allow specialists to perform them can be just as effective as immediate repairs. Comprehensive care that includes thorough anatomical knowledge and surgical skill is essential. As maternal age increases and birth rates decline, it's crucial for specialized centers to handle severe perineal injuries to ensure the best outcomes and long-term care for patients.

The outermost layer of the heart, the epicardium, is an essential cell population that contributes, through epithelial-to-mesenchymal transition (EMT), to form different cell types and provide paracrine signals to the developing heart. Despite its quiescent state during adulthood, in response to cardiac injury, adult epicardium reactivates and recapitulates many aspects of embryonic cardiogenesis supporting cardiac tissue remodeling. Thus, the epicardium has been considered as a crucial source of cell progenitors with important contribution to developing and injured heart. Although several studies have provided evidence about cell fate determination in the epicardium, to date it is unclear whether epicardial-derived cells (EPDCs) come from specific, and previously predetermined, epicardial cell subpopulations or if they are derived from a common progenitor. In recent years, different approaches have been used to study cell heterogeneity within the epicardial layer by using different experimental models. However, generated data are still insufficient to understand the complexity of this epithelial layer. In this review, we summarize the previous works supporting the cellular composition, molecular signatures and diversity within the developing and adult epicardium.

Plant-Derived Extracellular Vesicles (PDEVs) contain high levels of antioxidants, especially when deriving from organic. PDEVs from different vegetal sources has shown an increased antioxidant power, compared to PDEVs from single plants, suggesting a synergistic effect of the bioactives constitutively expressed in the PDEVs from single fruits. With this study we wanted to investigate the beneficial effects of a mix of PDEVs on human skin cells. We found detectable levels of Citric Acid, Ascorbic Acid, Glutathione, Catalase and SOD in a mix of PDEVs deriving from 5 different fruits (Grape, Red Orange, Papaya, Pomegranate and Tangerine). We then treated H2O2-conditioned fibroblasts with the mix of PDEVs. The results showed that the PDEVs ‘mix reverted the H2O2-induced redox imbalance, restoring the mitochondrial homeostasis, with a strong reduction of mitochondrial anion superoxide and increase of sirtuin levels. The antioxidant action was consistent with a wound repair on a lesion produced in a Fibroblasts’ monolayer. This result was consistent with an increased level of Vimentin and Matrix Metalloproteinase-9, whose expression is directly related to the efficiency of the reparative processes. These data support a beneficial role of PDEVs in both preventing and treating skin injuries, through their potent antioxidant and reparative activities.

The hemodynamic consequences of the aortic stenosis (AS) on supraortic trunks may have a po-tential role in the diagnosis of concomitant internal carotid artery (ICA) stenosis by dampening blood flow velocity. To investigate the effect of AS on ICA blood flow we evaluated carotid and vertebral blood flow velocity indexes in patients undergoing transcatheter aortic valve implanta-tion (TAVI). Eighty-five patients admitted for endovascular treatment of a severe AS underwent supra-aortic Duplex ultrasound (DUS) examination prior and after TAVI to be enrolled in the study. Patients with other cardiac impairments that could configure a confounding factor were excluded. Pa-tients with symptomatic or severe ICA stenosis defined according to NASCET criteria were ex-cluded. Forty-five patients of a median age of 80 years met the study inclusion criteria. The peak systolic velocity (PSV) of the assessed supraortic arteries increased after TAVI: respectively common ca-rotid artery (CCA) 64 ± 17 cm/s vs 78 ± 23 cm/s, p= 0,01; ICA 68 ± 23 cm/s vs 96 ± 35 cm/s, p= 0,01; vertebral artery (VA) 45 ± 14 cm/s vs 52 ± 15 cm/s, p=0,03. Similarly, the end diastolic velocity (EDV) increased after TAVI: respectively CCA 13 ± 6 cm/s vs 15 ± 7 cm/s, p=ns; ICA 20 ± 9 cm/s vs 24 ± 9 cm/s, p= 0,01; VA 9 ± 4 cm/s vs 11 ± 4 cm/s, p=0,01. Consistently, the mean acceleration time (AC) decreased after TAVI: respectively CCA 0,17 ± 0,05 s vs 0,12 ± 0,05 s, p= 0.01; ICA 0,1 8 ± 0,05 s vs 0,12 ± 0,04 s, p= 0,01; VA 0,16 ± 0,05 s vs 0,11 ± 0,05 s, p=0,02. Severe AS significantly affects supra-aortic arteries blood flow as assessed by duplex, by de-creasing both PSV and EDV and increasing AC. This study suggests that carotid ultrasound cri-teria to assess ICA stenosis severity should be re-evaluated in larger multicenter studies to vali-date their predictive values in patients with concomitant AS.

Blindness or visual impairment following congenital heart repair is a rare complication. It can be transient or permanent depending in underlying etiology and damage to optic pathway. We report first case of transient blindness following congenital heart repair due to unilateral subdural hematoma in occipital region.

The management of wounds is a significant issue that impacts individuals, healthcare systems, and society at large. This study evaluates Rigemed D (RD), a novel compound extracted from Bovine Colostrum with a unique combination of 20 different growth factors and exosomes, known for its exceptional properties in promoting cell proliferation and regeneration. This study aims to determine the effects of different doses of RD on cell survival (using CCK8) and to assess its antioxidant effect using the Comet assay in the presence of hydrogen peroxide (H2O2) on two human cell types, fibroblasts and immortalised keratinocytes (HaCat cell line). The study results revealed that RD, at doses of 1, 1.5, and 2 % v/v, significantly improved cell viability four, six, and 12 times, respectively, compared to the control group (p < 0.00001). Furthermore, the Comet assay showed a two-fold reduction in DNA damage in RD-treated cells at 2% v/v without and with H2O2 (p < 0.001). The effect of RD on cell proliferation and migration was evaluated using a scratch assay on fibroblasts and HaCat cells. The findings demonstrated a four-fold increase in cell proliferation and migration at 1 and 24 hours (p < 0.001). Immunohistochemistry confirmed this claim (p < 0.001). Also, angiogenesis induction of RD was assessed on human vein umbilical endothelial cells (HUVEC), showing that RD significantly enhanced the proliferation of endothelial HUVEC cells (p < 0.0001). In conclusion, RD is a promising vitalising compound with exceptional capabilities in promoting cell proliferation, migration, and regeneration. It also shows a significant antioxidant effect and has the potential to support all phases of wound healing involving cell proliferation, re-epithelialisation, angiogenesis, and tissue maturation. Hence, the present formulation presents a promising foundation for developing a 3D bio-printed membrane, potentially expediting the wound healing process.

Stretch marks are far from being exclusively appearing on pregnant women and appear whenever the body experience a rapid growth. Into the dermis, collagen fibres are altered associated with a loss of orientation and the elastic network is disrupted leading to a fibrotic organisation. This results to epidermal tearing which produce skin lesions. Centella asiatica is a well-known medicinal plants rich in triterpenic actives molecules and traditionally used to treat wounds and help skin repair. The aim of this study was to evaluate Centella asiatica extract as a natural way to solve stretch marks concern and understand its mechanism of action. We have first evaluated the fibroblast’s proliferation based on scratch assay model and their genes expression by RT-qPCR. At the ex vivo level, elastin fibres were quantified by immunofluorescence. Collagen fibre’s orientation and their occupation of the dermis were analysed after Sirius red staining and specific software analysis. We have proven that Centella asiatica has stimulated fibroblasts proliferation, reduced extracellular matrix degradation and fibrosis. On stretch marked skin explant, Centella asiatica increased the occupation of collagen fibres and elastin production. Based on the mechanisms behind the formation of stretch marks, Centella asiatica restores dermis network by optimising fibres organisation for a visible skin remodelling effect.

More than 50% of patients with non-small cell lung cancer (NSCLC) are treated with radiotherapy (RT) during different phases of treatment. However, radiation pneu-monitis (RP) and resistance often lead to RT failure in NSCLC patients. JWA, a tumor suppressor gene, is known to enhance DNA damage in gastric cancer cells while protect normal cells from DNA damage induced by cisplatin. Recently, we have re-ported that JWA agonist compound 4 (JAC4) effectively protects intestinal epithelium from RT triggered damage in mice. However, the potential synergistic and attenuated effects of JAC4 in chest RT of lung cancer are not been illuminated. The aim of this study was to investigate the effects of JAC4 on the radiotoxicities of both NSCLC and normal lung tissue. CCK-8 and colony formation assays showed that JAC4 played a bidirectional role in radiation-treated SPCA-1 and BEAS-2B cells. Western blotting and immunofluorescence assays showed that JAC4 in combination with RT increased DNA damage and apoptosis in SPCA-1 cells, while the opposite effect was observed in BEAS-2B cells. Mechanistically, JAC4 inhibited homologous recombination repair (HR) and non-homologous end joining (NHEJ) in SPCA-1 cells, but not in normal cells. JAC4 increased antioxidant capacity, and reduced oxidative stress and inhibited nu-clear factor Kappa-B (NF-κB, P65) translocation to the nucleus in BEAS-2B cells. Im-portantly, the bidirectional roles of JAC4 on RT were reversed by siJWA in both SPCA-1 and BEAS-2B cells. Finally, the bidirectional effects of JAC4 in combination with RT were further validated in NSCLC xenograft model mice. In conclusion, JAC4 enhanced effect of RT on tumor growth while alleviated RP and lung injury. Our re-sults may provide new strategy for optimizing RT regimen for NSCLC.

Physical activity is well-established as an important protective factor against degenerative conditions and a promoter of tissue growth and renewal. The discovery of FNDC5 as the precursor of irisin in 2012 sparked significant interest in its potential as a diagnostic biomarker and a therapeutic agent for various diseases. Clinical studies have examined the correlation between plasma irisin levels and pathological conditions using a range of assays, but the lack of reliable measurements for endogenous irisin has led to uncertainty about its prognostic/diagnostic potential as an exercise surrogate. Animal and tissue-engineering models have shown the protective effects of irisin treatment in reversing functional impairment and potentially permanent damage, but dosage ambiguities remain unresolved. This review provides a comprehensive examination of the clinical and basic studies of irisin in the context of degenerative conditions and explores its potential as a therapeutic approach in the physiological processes involved in tissue repair/regeneration.

Cardiovascular disease (CVD) is one of the contributing factors to more than one-third of human mortality and the leading cause of death worldwide. Cardiac myocyte death is a fundamental process in cardiac pathologies caused by various heart diseases, including myocardial infarction. Thus, strategies for replacing fibrotic tissue in the infarcted region with functional myocardium have long been a goal of cardiovascular research. This review focuses primarily on induced-pluripotent stem cells (iPSCs), which have emerged as perhaps the most promising source of cardiomyocytes for both therapeutic applications and drug testing. We also briefly summarize other stems- and progenitor-cell populations that have been used for regenerative myocardial therapy and attempt to generate cardiomyocytes directly from cardiac fibroblasts (i.e., transdifferentiation), which, if successful, may enable the pool of endogenous cardiac fibroblasts to be used as an in-situ source of cardiomyocytes for myocardial repair.

Track-structure Monte Carlo simulations are useful tools to evaluate initial DNA damage induced by irradiation. In the previous study, we have developed a Gean4-DNA-based application to estimate the cell surviving fraction of V79 cells after irradiation, bridging the gap between the initial DNA damage and the DNA-rejoining kinetics by means of the two-lesion kinetics (TLK) model. However, since the DNA repair performance depends on cell line, the same model parameters cannot be used for the different cell lines. Thus, we extended the Geant4-DNA application with an updated TLK model for the evaluation of DNA damage repair performance in HSGc-C5 carcinoma cells which are typically used for evaluating proton/carbon radiation treatment effects. For this evaluation, we also performed experimental measurements for cell surviving fractions and DNA-rejoining kinetics of the HSGc-C5s cells. Concerning fast- and slow-DNA rejoining, the TLK model parameters were adequately optimized with the simulated initial DNA damage. Using the optimized TLK model, the Geant4-DNA simulation is now able to predict cell survival and DNA-rejoining kinetics for HSGc-C5s cells.

Pterygium is a common ocular disease caused by abnormal cellular proliferation leading to abnormal fibrovascular growth of the conjunctiva. The main treatment is surgical removal; however, despite the improvement of surgical techniques and development of adjuvant therapies, postoperative recurrence, which can be as high as 89%, remains a challenge. Currently, pterygium excision with conjunctival autograft remains the preferred surgical technique to decrease recurrence, especially when combined with ciclosporin eye drops. Nevertheless, there is no gold standard surgical technique to prevent pterygium recurrence. Therefore, this review aims to assess the safety, effectiveness and, applicability of platelet-rich fibrin membrane for primary pterygium surgery and assess its possible benefits in resource-limited settings.

Non-homologous end-joining (NHEJ) is a major DNA repair pathway in mammalian cells that recognizes, processes and fixes DNA damages throughout the cell cycle, and is specifically important for homeostasis of post-mitotic neurons and developing lymphocytes. Neuronal apoptosis increases in the mice lacking NHEJ factors Ku70 and Ku80. Inactivation of other NHEJ genes, either Xrcc4 or Lig4, leads to massive neuronal apoptosis in the central nervous system (CNS) that correlates with embryonic lethality in mice. Inactivation of either Paxx, Mri or Dna-pkcs NHEJ gene results in normal CNS development due to compensatory effects of Xlf. Combined inactivation of Xlf/Paxx, Xlf/Mri and Xlf/Dna-pkcs, however, results in late embryonic lethality and high levels of apoptosis in CNS. To determine the impact of NHEJ factors on early stages of neurodevelopment, we isolated neural stem and progenitor cells from mouse embryos and investigated proliferation, self-renewal and differentiation capacity of these cells lacking either Xlf, Paxx, Dna-pkcs, Xlf/Paxx or Xlf/Dna-pkcs. We found that XLF, DNA-PKcs and PAXX maintain the neural stem and progenitor cell populations and neurodevelopment in mammals, which is particularly evident in the double knockout models.

Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment.

Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-azacytidine (5azaC) is a potent mutagen for template-switching, dependent on DNA cytosine methylase (Dcm), implicating the trapped Dcm-DNA covalent complex as the initiator for mutagenesis. The leading strand of replication is more mutable than the lagging strand, explained by blocks to the replicative helicase and/or fork regression. We find that template-switch mutagenesis induced by 5-azaC does not require DSB repair via RecABCD. The ability to induce the SOS response is anti-mutagenic by an unknown mechanism. Mutants in recB, but not recA, exhibit high constitutive rates of template-switching and we suggest that RecBCD-mediated DNA degradation prevents template-switching associated with fork regression. A mutation in the DnaB fork helicase also promotes high levels of template-switching. We also find that other DPC-inducers, formaldehyde (a non-specific crosslinker) and ciprofloxacin (a topoisomerase II poison) are also strong mutagens for template-switching. Induction of mutations and genetic rearrangements that occur by template-switching may constitute a previously unrecognized component of the genotoxicity and genetic instability promoted by DPCs.

Several clinically useful anticancer drugs selectively kill cancer cells by inducing DNA damage; the genomic instability and DNA repair defects of cancer cells make them more vulnerable than normal cells to the cytotoxicity of DNA-damaging agents. Because epoxide-containing compounds can induce DNA damage, we have used the MTT assay to evaluate the selective cytotoxicity of three epoxyalkyl galactopyranosides against A549 lung cancer cells and MRC-5 lung normal cells. Compound (2S,3S)-2,3-Epoxydecyl 4,6-O-(S)-benzylidene-β-D-galactopyranoside (EDBGP) showed the highest selective anticancer activity and was selected for mechanistic studies. After observing that EDBGP induced cellular DNA damage (comet assay), we found that cells deficient in nucleotide excision repair were hypersensitive to the cytotoxicity of this compound; this suggests that EDBGP may induce bulky DNA adducts. EDBGP did not inhibit glycolysis (glucose consumption and lactate production). Pre-treatment of lung cancer cells with several antioxidants did not reduce the cytotoxicity of EDBGP, thereby indicating that reactive oxygen species do not participate in the anticancer activity of this compound. Finally, EDBGP was screened against a panel of cancer cells and normal cells from several tissues, including three genetically modified skin fibroblasts with increasing degree of malignancy. Our results suggest that epoxyalkyl galactopyranosides are promising lead compounds for the development of new anticancer agents.

Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins that work in a highly concerted manner to resolve DNA damage efficiently to prevent toxic repair intermediates. During the initiation of BER, the damaged base is removed by one of 11 mammalian DNA glycosylases resulting in abasic sites. Many DNA glycosylases are product inhibited by binding to the abasic site more avidly than the damaged base. Traditionally apurinic/apyrimidinic endonuclease, APE1, was believed to help turnover the glycosylases to undergo multiple rounds of damaged base removal. However, in a series of papers from our laboratory we have demonstrated that UV-damaged DNA binding protein (UV-DDB) stimulates the glycosylase activities of human 8-oxoguanine glycosylase (OGG1), MUTY DNA glycosylase (MUTYH), alkyladenine glycosylase/N-methylpurine DNA glycosylase (AAG/MPG), and single-strand selective monofunctional glycosylase (SMUG1), between three-to-five-fold. Moreover, we have shown UV-DDB can assist chromatin decompaction facilitating access of OGG1 to 8-oxoguanine damage in telomeres. This review summarizes the biochemistry, single-molecule, and cell biology approaches that our group used to directly demonstrate the essential role of UV-DDB in BER.

Salmon aquaculture generates a substantial volume of waste material, offering potential for biomaterial production. This industry produces significant waste, which can be repurposed for various biological applications, particularly in biomaterial production for tissue engineering with pertinent applications in osteo-conduction, osteo-induction, and clinical/surgical bone regeneration and repair. The process involves a standardized pre-treatment stage aimed at minimizing biological waste content. Subsequently, the treatment stage, contingent on the chosen methodology, facilitates the removal of proteins, lipids, molecules, and other compounds, leaving the mineral phase as a valuable substrate. The selection of the optimal method, whether alkaline hydrolysis, calcination, or NaOH hydrolysis, for obtaining this substrate necessitates thorough examination through chemical, physical, and biological assessments, including Raman Spectroscopy and X-Ray Diffraction. This study aims to identify the most efficient laboratory process for biofunctional nano-sized hydroxyapatite mineral production derived from Chilean salmon fish backbone waste.

The risk of malignant transformation of induced pluripotent stem cells (iPSC)-derived cells in response to DNA damage is a potential concern as the tumor suppressor genes TP53 and CDKN2A are transiently inactivated during reprogramming. Here, we evaluated the integrity of cellular senescence pathways and DNA double-strand break (DSB) repair in iPSC-derived human fibroblasts (i-HF) compared to their parental skin fibroblasts (HF). Using a variety of functional assays, we show that the capacity of i-HF to enter senescence and repair DSB is not compromised after damage induced by ionizing radiation (IR) or overexpression of H-RASV12. Still, i-HF lines are transcriptionally different from their parental lines, showing enhanced metabolic activity and higher expression of p53-related effector genes. As a result, i-HF lines generally exhibit increased sensitivity to various stresses, have an elevated senescence-associated secretory phenotype (SASP) and cannot be immortalized unless p53 expression is knocked down. In conclusion, while our results suggest that i-HF are not at a greater risk of transformation, their overall hyperactivation of senescence pathways may impede their function as a cell therapy product.

Earth is a complex material with a mechanical and physical behavior that differs from modern building materials. The conservation of rammed earth (RE) constructions presents specific difficulties that are challenging to overcome. The lack of knowledge about RE due to its abandonment for decades and attempts to adopt materials and repair methodologies designed for new building products has led to inadequate interventions. In the case of historic defensive constructions, the doubts and technical difficulties are even greater due to the nature of the so called military RE (with physical and mechanical characteristics significantly different from those of civil, more common, RE) and, not least, due to the historical and cultural heritage value of these constructions. Some important interventions have been carried out recently and others are underway or in the planning stage, and there is a constant lack of information and technical data on the best ways to intervene. To fill this gap, the state of conservation of the RE defensive structures and the results of interventions carried out throughout history in the southwest of the Iberian Peninsula are being assessed. This article sets out the framework of the subject, identifies the material and construction techniques, and recognizes the main causes of its deterioration and decay. With special focus on the most frequent damages detected in historic military defensive structures built with RE, it analyses and discuss the most common techniques that have been used for the repair and conservation of these particular structures.

Hollow and concrete-filled steel tubes (CFSTs) are widely used as columns in many structural systems and local buckling can occur when they are subjected to axial compression loading. The critical regions for the local buckling of the columns are near the ends of the column where the moments are the highest. To strengthen the critical regions of the CFSTs the CFRP provides a simple and effective method which used previously as an enhancement for both of strength and ductility. So, this study suggests investigating the axial load behaviour of CFST strengthened with CFRP using FE method after a verification study and then a various parametric studies were carried out to cover the effect of the CFRP layers, number, confinement length and position. The FE results proved that, one CFRP sheet with thickness equal to 1.2 mm was strengthened the composite column by 8.5%, two CFRP sheets with total thickness equal to 2.4 mm was strengthened the composite column by 23.5%, three CFRP sheets with total thickness equal to 3.6 mm was strengthened the composite column by 35.1% and four CFRP sheets with total thickness equal to 4.8 mm was strengthened the composite column by 44.5%. Moreover, this study proved that by strengthened the composite columns with CFRP sheets with different lengths, the axial load resistance was improved by 8.5%, 4.6%, 0.1% and 0.0% for length percentages 100%, 75%, 50% and 25% respectively.

Nanotechnology has become an increasingly promising medical field, particularly scar removal. Scar removal is a complex process involving regenerating damaged skin tissue, and nanotechnology presents unique solutions to this issue. One potential application of nanotechnology is using nanofibers as scaffolds to support the growth of new skin tissue. These fibres can also be loaded with drugs or growth factors to promote tissue regeneration and reduce scarring. Another potential application is nanocarriers for drug delivery to specific body areas, which can promote tissue regeneration and reduce scarring.Additionally, nanotechnology has been utilized to create new materials for skin regeneration, such as "nano skin" that mimics the structure of natural skin. Nanoprobes have also been developed for the detection of scar tissue and the monitoring of its progression. These potential nanotechnology applications offer exciting possibilities for the future of scar removal and skin repair. With further research and development, nanotechnology has the potential to revolutionize scar removal and provide more effective solutions for tissue regeneration.

Regeneration is usually regarded as a unique plant or some animal species process. In reality, regeneration is a ubiquitous process in all multicellular organisms. It ranges from response to wounding by healing the wounded tissue to whole body neoforming (remaking of the new body). In a larger context, regeneration is one facet of two reproduction schemes that dominate the evolution of life. Multicellular organisms can propagate their genes asexually or sexually. Here I present the view that the ability to regenerate tissue or whole-body regeneration is also determined by the sexual state of the multicellular organisms (from simple animals like hydra and planaria to plants and complex animals). The above idea is manifested here by showing evidence that many organisms, organs, or tissues show inhibited or diminished regeneration capacity when in reproductive status compared to the same organism organs or tissues in nonreproductive conditions or by exposure to sex hormones.

Physical activity is widely recognized as a biotherapy by WHO in the fight and prevention of bone diseases such as osteoporosis. It reduces the risk of disabling fractures associated with many comorbidities, and whose repair is a major public health and economic issue. Bone tissue is a dynamic supportive tissue that reshapes itself according to the mechanical stresses to which it is exposed. Physical exercise is recognized as a key factor for bone health. However, the effects of exercise on bone quality depend on exercise protocols, duration, intensity and frequency. Today, the effects of different exercise modalities on capillary bone vascularization, bone blood flow and bone angiogenesis remain poorly understood and unclear. As vascularization is an integral part of bone repair process, the analysis of the preventive and/or curative effects of physical exercise is currently very undeveloped. Angiogenesis-osteogenesis coupling may constitute a new way for understanding the role of physical activity, especially in fracturing or in the integration of bone biomaterials. Thus, this review aims to clarify the link between physical activities, vascularization and bone repair.

The idea of replacing the broken linear economy with circular forms to help address the current sustainability crisis is gaining world-wide traction in policy, industry, and academia. This article presents results from an international interview study with 34 repair practitioners and experts in different fields. The article aims to improve understandings of the potential of repair so as to contribute to a more just, sustainable, and circular economy. Through a five-step qualitative method the results reveal and explore three tensions inherent in repair: first, repair activities constitute different forms of subjectivity; second, repair entails different and sometimes contested temporalities; and finally, even though repair is deeply political in practice, the politics of repair are not always explicit, and some repair activities are actively depoliticized. The opportunities and obstacles embodied in these tensions are generative in repair practices and debates, but poorly reflected in contemporary circular economy discourse. We conclude that a richer, more inclusive and politicized understanding of repair can support environmental justice in the implementation of CE and provide greater opportunities for just and transformational sustainability strategies and policies.

CRISPR/Cas genome editing is a widely used research technology. Its simplest variant is gene knockout resulting from reparation errors after introduction of dsDNA breaks by Cas nuclease. We compared the outcomes of the break repair by two commonly used nucleases (SpCas9 and LbCas12a) in zebrafish embryos to reveal if application of one nuclease is advantageous in comparison to the other. To address this question, we injected ribonucleoprotein complexes of nucleases and corresponding guide RNAs in zebrafish zygotes and three days later sequenced the target gene regions. We found that LbCas12a breaks resulted in longer deletions and more rare inserts, in comparison to those generated by SpCas9, while the editing efficiencies of both nucleases were the same. On the other hand, overlapping protospacers were shown to lead to similarities in repair outcome, although they were cut by two different nucleases. Thus, our results indicate that the repair outcome depends both on the nuclease mode of action and on protospacer sequence.

Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP, TRPC may form homo or heterotetrameric ion channel, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase of the expression of different TRPC isoforms has been observed in different animal model of heart infarcts, and in vitro experimental model of ischemia and reperfusion. TRPC-mediated increase of the intracellular Ca²⁺ concentration seems required for the activation of signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we will highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion, and to heart infarction.

Removal of the proliferation component of gene expression by PCNA adjustment has been addressed in numerous survival prediction studies for breast cancer and all cancers in the TCGA. These studies indicate that widespread co-regulation of proliferation upwardly biases survival prediction when gene selection is performed on a genome-wide basis. In addition, removal of the correlative effects of proliferation does not reduce the random bias associated with survival prediction using random gene selection. Since most cancers become addicted to DNA repair as a result of forced cellular replication, increased oxidation, and repair deficiencies from oncogenic loss or genetic polymorphisms, we pursued an investigation to remove the proliferation component of expression in DNA repair genes to determine survival prediction. This translational hypothesis-driven focus on DNA repair genes is directly amenable to finding new sets of DNA repair genes that could potentially be studied for inhibition therapy. Overall survival (OS) prediction was evaluated in 18 cancers by using normalized RNA-Seq data for 126 DNA repair genes with expression available in TCGA. Transformations for normality and adjustments for age at diagnosis, stage, and PCNA metagene expression were performed for all DNA repair genes. We also analyzed genomic event rates (GER) for somatic mutations, deletions, and amplification in driver genes and DNA repair genes. After performing empirical p-value testing with use of randomly selected gene sets, it was observed that OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. Interestingly, PARP1 was not a significant predictor of survival for any of the 11 cancers. Results from cluster analysis of GERs indicates that the most opportunistic cancers for inhibition therapy may be AML, colorectal, and renal papillary, because of potentially less confounding due to lower GERs for mutations, deletions, and amplifications in DNA repair genes. However, the most opportunistic cancer for inhibition therapy is likely to be AML, since it showed the lowest GERs for mutations, deletions, and amplifications in DNA repair genes. In conclusion, our hypothesis-driven focus to target DNA repair gene expression adjusted for the PCNA metagene as a means of predicting OS in various cancers resulted in statistically significant sets of genes.

We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (detected with the comet assay). Cells deficient in the DNA repair pathway nucleotide excision repair (NER) were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. The combinations of AzGalp with either oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also displayed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

Real-time strategy (RTS) game has proposed many challenges for AI research for its large state spaces, enormous branch factors, limited decision time and dynamic adversarial environment. To tackle above problems, the method called Adversarial Hierarchical Task Network planning (AHTN) has been proposed and achieves favorable performance. However, the HTN description it used cannot express complex relationships among tasks and impacts of environment on tasks. Moreover, the AHTN cannot handle task failures during plan execution. In this paper, we propose a modified AHTN planning algorithm named AHTNR. The algorithm introduces three elements essential task, phase and exit condition to extend the HTN description. To deal with possible task failures, the AHTNR first uses the extended HTN description to identify failed tasks. And then a novel task repair strategy is proposed based on historical information to maintain the validity of previous plan. Finally, empirical results are presented for the μRTS game, comparing AHTNR to the state-of-the-art search algorithms for RTS games.

Background: Thoracic endovascular aortic repair (TEVAR) has become the standard treatment for blunt thoracic aortic injury (BTAI). Some small observational studies revealed aortic morphological changes after TEVAR in patients with BTAI. However, these studies were limited by the rarity of the condition and small sample sizes. To address this gap, the current study aims to conduct a systematic review and meta-analysis of existing literature to provide evidence on the degree of immediate and long-term aortic diameter change following TEVAR for BTAI. Methods: This systematic review and meta-analysis of studies published up to March 2023, was conducted in accordance with the PRISMA statement. Studies eligible for inclusion were studies evaluating aortic diameter change post-TEVAR in BTAI patients. Results: 14 articles, including 353 patients, were included after review. Treatment and measurement protocols varied among individual studies resulting in high heterogeneity of the results. Our meta-analysis demonstrated an immediate post-intervention dilation 2.41 mm and 2.63 mm of the proximal and distal aortic necks’, respectively, as well as continuous dilation of the respective regions at a rate of 0.35 mm/year and 0.49 mm/year. Conclusion: TEVAR in BTAI leads to immediate post-intervention and continuous aortic dilation and morphological changes with possible future important clinical consequences.

Advancements in the repair and protection of water and wastewater infrastructure are now focused on using an innovative material called polyurea. Distinguished by its rapid curing time and versatile applications, polyurea is applied using a spray gun with high-pressure pumps. The introduction of new building materials is part of ongoing efforts to meet stringent environmental, health, and performance standards, and polyurea offers significant improvements by eliminating solvents and volatile organic compounds (VOCs). This paper presents a technological protocol starting with inspection and cleaning, followed by drying, and ending with the application of three layers: a moisture-blocking base layer, a rigid polyurethane middle layer for structural reinforcement, and a final sealing and anti-corrosion layer. This innovative method ensures a homogeneous, seamless structure, enhances construction durability, and accelerates the repair process, allowing immediate resumption of operation. Designed specifically for aggressive wastewater environments, this system is characterized by excellent corrosion resistance, making it ideal for water and wastewater infrastructure elements such as reinforced concrete manholes, sewage pumping stations, and tanks. Customizable polyurea properties allow personalization based on environmental aggressiveness, structure size, and abrasion resistance, representing a significant advancement in infrastructure maintenance technology. The paper showcases this modern repair and renovation method, highlighting its applications, benefits, and potential to revolutionize water and wastewater infrastructure maintenance in challenging conditions. The effectiveness of this solution is also compared with traditional methods, demonstrating the superiority of the three-layer system in terms of waterproofing, sulfuric acid resistance, monolithic structure, and application time.

Background: Determining the status of DNA mismatch repair (MMR) proteins is crucial for guiding treatment decisions and predicting prognosis in patients with colorectal cancer. This study evaluates a streamlined panel utilizing two antibodies for MMR protein assessment, aiming to enhance cost-effectiveness, reduce workload, and expedite result delivery. Methods: We re-classified patients with adenocarcinoma requiring MMR determination by evaluating only PMS2 and MSH6 proteins. The diagnostic performance of the proposed two-antibody panel was compared to the traditional four-antibody panel against a polymerase chain reaction (PCR) assay used as the reference standard. Results: A total of 404 cases were analyzed, with the predominant histological type being adenocarcinoma not otherwise specified. The most common histological grade was 2, and 60.9% of cases were in clinical stage II. Comparative analysis showed no statistically significant differences between the two-antibody and four-antibody panels. Sensitivity was 95.35% for the four-antibody panel versus 90.7% for the two-antibody panel; specificity was 98.74% versus 98.11%, respectively. Additionally, the positive predictive value was 95.35% for the four-antibody panel compared to 92.86% for the two-antibody panel, and negative predictive values were 98.74% versus 97.50%. The area under the curve was 0.970 for the four-antibody panel and 0.944 for the two-antibody panel (p=0.419). Conclusion: The analysis shows that determining MMR status using only two antibodies is as effective as employing a traditional four-antibody panel, providing a viable, cost-effective alternative for clinical practice.

Objectives: This study aims to explore the use of murine models in peripheral nerve transection research, evaluating and synthesizing key methods for analyzing nerve regeneration to guide future research and clinical interventions. Methodology: A systematic review was conducted in February 2024, adhering to Cochrane and PRISMA 2020 guidelines, using Medline, Scielo, and Lilacs databases. The focus was on experimental studies of nerve regeneration in animal models post-transection. Only experimental clinical trials reporting nerve regeneration outcomes were included; studies lacking a comparator group or functional evaluation methods were excluded. Results: Out of 273 studies initially identified from MEDLINE, 19 were selected for detailed analysis. The average study included 32.5 subjects, with about 10.16 subjects per intervention subgroup. The predominant model was the sciatic nerve injury with a 10mm gap. The most common intervention involved unprocessed adipose-derived stem cells, utilized in 14 articles. Conclusions: The review underscores the significant potential of current methodologies in peripheral nerve regeneration, particularly highlighting the use of murine models and thorough evaluation techniques. These studies significantly contribute to our understanding of nerve regeneration processes and inform directions for future research.

Traumatic nerve injuries are common lesions that affect several hundred thousand humans, as well as dogs and cats. The assessment of nerve regeneration trough animal models may provide information for translational research and future therapeutic options that can be applied mutually in veterinary and human medicine, in a one health perspective. This review offers a hands-on vision about the non-invasive and conservative approaches on peripheral nerve injury, focusing the role of neurorehabilitation in nerve repair and regeneration. The peripheral nerve injury may lead to hypersensitivity, allodynia and hyperalgesia, with the possibility of joint contractures, decreasing functionality and impairing the quality of life. The question remains regarding how to improve nerve repair with surgical possibilities, but also considering electrical stimulation modalities by modulating sensory feedback, upregulation BDNF, GFNF, TrKB and adenosine monophosphate, maintaining muscle mass and modulating fatigue. This could be improved by the positive synergetic effect of exercises and physical activity with locomotor training, and other physical modalities, such as low-level laser therapy and ultrasounds. In addition, the use of cell-based therapies is an innovative treatment tool in this field. These strategies may help avoiding situations of permanent monoplegic limbs that could lead to amputation.

Background and Objectives: The arthroscopic biceps rerouting (BR) technique was introduced as a novel technique for large-to-massive rotator cuff tears (LMRCT). This method can restore shoulder stability, and its biomechanical effect was verified in a cadaver experiment. Recent reports have shown favourable clinical outcomes. This study aimed to compare the clinical outcomes of partial repair with those of BR technique in LMRCT. Materials and Methods: We included 72 patients who had undergone LMRCT. Arthroscopic partial repair was performed in 31 patients (group I), while repair with the BR technique was performed in 41 patients (group II). Functional and imaging outcomes were evaluated and compared using a visual analogue scale for pain, range of motion (ROM), American Shoulder and Elbow Surgeons (ASES) score, Constant score, and Korean Shoulder Score (KSS) before the surgery and at 3, 6, and 12 months after the surgery and at the last follow-up. Tendon integrity was investigated using magnetic resonance in all the patients at 12 months postoperative. Results: Mean follow-up period was 22.11 ± 10.47 months (range, 12–53 months). Forward flexion (P=0.02) and external rotation at the side (P=0.04) were significantly higher in group II than in group I on postoperative day (POD) 12. For internal rotation, group II showed significant improvement compared to group I on POD 3 (P=0.002) and at six months postoperative (P=0.01). On POD 12, the ASES (P=0.047) and KSS (P=0.048) were better in group II. Significant improvements in pain and clinical scores were observed in both groups at the last follow-up. However, there were no significant differences in pain, clinical scores, or ROM between the two groups at the last follow-up. Retear of the repaired tendon was observed in nine patients in group I (29.03%) and 8 in group II (19.51%, P = 0.35). Conclusions: Partial repair and repair using the BR technique effectively improved clinical and radiologic outcomes. The BR technique revealed early recovery of ROM and better clinical results than partial repair until one year postoperatively. This could be a useful method in LMRCT.

Repairing of small and isolated delamination area in carbon fiber reinforced polymer (CFRP) without significantly altering the composite structure is studied in this research. A small drilled hole was introduced at the center of the delamination section of CFRP, providing the channel for epoxy infill of sharp delamination cracks. The pressureless infill repair was achieved through the capillary action of an acetone-diluted resin solution (without hardener) with CNT reinforcement, e.g., 89 m/m% of acetone, 10 m/m% of resin and 1m/m% of CNT. Such an acetone-rich resin pre-coating (RPC) solution is easy to prepare and apply to the drilled hole area. Curing of CNT-toughened resin infill was induced by filling the small-drilled hole with a resin-hardener mixture toughened by CNT/Aramid pulp. The effectiveness of delamination repair with curing periods of two weeks and three months were compared. Flexural strength measurements indicated that 77% (potentially 100%) of the restoration was achievable.

Endothelial cells are the crucial inner lining of blood vessels, pivotal in vascular homeostasis and integrity. However, these cells are perpetually subjected to a myriad of mechanical, chemical, and biological stresses that can compromise their plasma membranes. A sophisticated repair system involving key molecules, such as calcium, annexins, dysferlin, and MG53, is essential for maintaining endothelial viability. These components orchestrate complex mechanisms, including exocytosis and endocytosis, to repair membrane disruptions. Dysfunctions in this repair machinery, often exacerbated by aging, are linked to endothelial cell death, subsequently contributing to the onset of atherosclerosis and the progression of cardiovascular diseases (CVD) and stroke, major causes of mortality in the United States. Thus, identifying the core machinery for endothelial cell membrane repair is critically important for understanding the pathogenesis of CVD and stroke and developing novel therapeutic strategies for combating CVD and stroke. This review summarizes the recent advances in understanding the mechanisms of endothelial cell membrane repair. The future directions of this research area are also highlighted.

A randomized control trial (clinicaltrial.gov identification NCT04521504) was conducted to test if the combination of a rehabilitative protocol with a kinematic visual biofeedback tool could improve the functional level of patients arthroscopically treated for rotator cuff tear, both in the short- and medium-term assessments. Forty patients (aged between 35 and 65 y.o., employed at the time of the enrollment) were randomly assigned to two groups: Control group (C, n°21 patients) and Biofeedback group (B, n°19 patients). The primary outcome used for the assessment of shoulder functional performances was the Scapula-Weighted Constant-Murley Score. Patients were assessed longitudinally: before surgery, 45 days after surgery, at time of return-to-work, and at a final follow-up between 6 and 12 months. Results showed no biases for the two groups before the administration of the experimental protocol; significantly higher scores for B compared to C were found only at time of return-to-work. Based on results, we could conclude that the biofeedback training allowed patients to return to work in a better functional condition. This trial was funded by the National Institute for Insurance against Accidents at Work (INAIL).

DNA damage repair lies at the core of all cells’ survival strategy, including cancerous. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of multiple kinases. Recent studies on Tousled like Kinases have brought significant clarity on the effectors of these kinases which stands to regulate DSB repair. In addition to their well-established role in the DDR and cell cycle checkpoint mediation after DNA damage or inhibitors of replication, their suspected involvement in the actual DSB repair process has more recently been strengthened by the important finding that TLK1 phosphorylates RAD54 and regulates some of its activities and localization in the cell. Earlier findings of its regulation of RAD9 during checkpoint deactivation as well as defined steps during NHEJ ends processing were earlier hints of its important involvement broadly in DSB repair. All this has opened up new avenues to target cancer cells in combination therapy with genotoxins and TLK inhibitors.

Single-stand selective monofunctional uracil DNA glycosylase 1 (SMUG1) works to remove uracil and certain oxidized bases from DNA during base excision repair (BER). This review provides a historical characterization of SMUG1 and 5-hydroxymethyl-2'-deoxyuridine (5-hmdU) one important substrate of this enzyme. Biochemical and structural analyses provide remarkable insight into the mechanism of this glycosylase revealing SMUG1 has a unique helical wedge which influences damage recognition during repair. Rodent studies suggest that, while SMUG1 shares substrate specificity with another uracil glycosylase UNG2, loss of SMUG1 can have unique cellular phenotypes. This review highlights the multiple roles SMUG1 may play in preserving genome stability, and how the loss of SMUG1 activity may promote cancer. Finally, we discuss recent studies indicating SMUG1 has moonlighting functions beyond BER, playing a critical role in RNA processing including the RNA component of telomerase.

Centromeres are among the fastest evolving genomic regions in a diverse array of organisms. The evolutionary process driving this rapid evolution has not been unambiguously established. Here I integrate diverse information to motivate a model in which centromeres evolve rapidly because of their intrinsic molecular phenotype: they tightly bind centromeric proteins throughout the cell cycle. DNA-bound proteins have been shown to cause stalling and collapse of DNA replication forks in many genomic regions, including centromeres. Collapsed replication forks generate one-sided double strand breaks (DSBs) that are repaired by the Break-Induced Repair (BIR) pathway. Here I show why this repair is expected to generate tandem repeat structure and three key features at centromeres: i) increased nucleotide substitution mutation rates, ii) out-of- register re-initiation of replication that leads to indels spanning one or more repeat units, and iii) elevated rates of large and small transpositions within centromeres and between genomic regions. These phenotypes lead to: i) a rapid rate of nucleotide substitutions within a clade of centromeric sequences, ii) continual turnover of monomers within centromeres that fosters molecular-drift and molecular-drive, and iii) recurrent quantum leaps in centromere sequence due to the formation of mosaic monomers and new sequences transposed into non-homologous centromeres. These features are plausibly the major reason centromeres evolve so rapidly. I also speculate on how the DNA sequence of centromeres might perpetually coevolve with the protein sequence of histone CENH3 –the major epigenetic mark of centromeres.

Abstract Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, still remain elusive the molecular mechanisms concerning the role of oxidative stress. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyper-activation of mitogen-activated protein kinase (MAPK), and PI3K/Akt, that mediate ErbB signaling. Increased levels of 8-oxoG DNA adducts have been detected in the early stages of thyroid cancer. These DNA lesions are efficiently recognized and removed by the base excision repair (BER) pathway initiated by 8-oxoG glycosylase1 (OGG1). This study investigated the relationship between the EGFR and OGG1-BER pathways and their mutual regulation following oxidative stress stimulus by H2O2 in human thyrocytes. We clarified the modulation of ErbB receptors and their downstream pathways (PI3K / Akt and MAPK / ERK) under oxidative stress (from H2O2) at the level of gene and protein expression, according to the mechanism defined in a non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the obtained results of gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/TPC rearrangement (TPC-1). Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and OGG1-BER pathways in normal thyroid cells (while this is dysregulated in the TPC-1 cells. Gene expression data also delineated that MUTYH gene could play a physiological role in cross-talk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall our data about OGG1 protein expression suggest that the alternative splicing mechanisms may lead to different protein isoforms, physiologically regulated in response to ErbB modulation, and that these could be dysregulated in the progression of thyroid malignancies with RET/TPC rearrangement.

A new mathematical model is presented to study the effects of macrophages on the bone fracture healing process. The model consists of a system of nonlinear ordinary differential equations that represents the interactions among classically and alternatively activated macrophages, mesenchymal stem cells, osteoblasts, and pro- and anti-inflammatory cytokines. A qualitative analysis of the model is performed to determine the equilibria and their corresponding stability properties. Numerical simulations are also presented to support the theoretical results and to monitor the evolution of a broken bone for different types of fractures under various medical interventions. The model can be used to guide clinical experiments and to explore possible medical treatments that accelerate the bone fracture healing process either by surgical interventions or drug administrations.

Fiber reinforced polymer (FRP) is one of the important material used for strengthening and retrofitting of reinforced concrete structures. The commonly used fibers are glass, carbon and aramid fibers. Durability of structures can be extended by selecting appropriate method of strengthening. FRP wrapping is one of the easiest methods for repair, retrofit and maintenance of structural element. Deterioration of structures may be due to moisture content, salt water, or contact with alkali solutions. There is significant effect of permeability, rise in temperature, chemical attack, fatigue action, micro pores on members of structures. Using FRP additional strength can be gained by structural elements. This paper investigates durability of aramid fiber subjected to acid attack and temperature rise. Concrete cubes are prepared as specimens with double wrapping of aramid fibers. Diluted hydrochloric acid solution is used for immersion of specimen for curing period of 7, 30 and 70 days. In case of fire resistance test, such specimens are kept in hot air oven at a temperature of 2000C at different time intervals. The effect of aramid fiber wrapping on compressive strength and weight loss of specimen is studied.

Iron-sulfur (Fe-S) clusters are essential cofactors found in many proteins in the mitochondria, cytosol, and nucleus of the cell. These versatile cofactors may undergo reversible oxidation-reduction reactions to enable electron transfers; they may be structural and confer stability to a folded protein; they may be regulatory and transduce an iron signal that alters the function or stability of a recipient protein. Of the nearly 70 proteins described in mammalian cells that bind Fe-S clusters, about half localize exclusively or partially to the nucleus, where they are required for DNA replication and repair, telomere maintenance, transcription, mitosis, and cell cycle control. Most nuclear Fe-S cluster proteins interact with DNA, including DNA polymerases, primase, helicases, and glycosylases. However, the specific roles of the clusters in the enzymatic activities of these proteins and their interplay with DNA remain a matter of debate. Defects in the metallation of nuclear Fe-S proteins cause genome instability and alter the regulation of cell division and proliferation, which are hallmarks of various genetic diseases and cancers. Here, we provide an inventory of the nuclear Fe-S cluster binding proteins and discuss cluster types, binding sites, the process of cluster acquisition, and potential roles of the cluster in the function of the proteins. However, many questions remain unresolved. We highlight critical gaps in our understanding of cluster delivery to nuclear client proteins, the potential for cluster repair, and the mechanistic roles that clusters play in these enzymes. Taken together, this review brings the focus to the nucleus of the human cell as a hotspot for Fe-S cluster proteins and aims to inspire new research in the roles of iron in DNA metabolism and the maintenance of genome integrity.

Given the pivotal role played by the microbiome in skin health it is important to understand how its composition varies with age, gender and body site, and regular use of topical products. Four studies have been carried out to determine the effects of long term (4 week) use of different dexpanthenol containing topical products on the skin microbiome of a varied population with cosmetically dry skin. Skin microbiome composition was assessed before and after product usage. No significant changes in microbiome richness or diversity were found for the individual test products, however meta-analysis of the combined dataset did show changes in microbiome composition as a function of subject sex, age and body site. The work presented here demonstrates how the use of carefully formulated topical products on skin, when used in a way which is representative of real life usage conditions, can respect the microbial diversity present on skin across a widely varied study population.

Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or Microsatellite Instability (MSI) testing, but concordance between methods is variable in ECs. Here, we investigate this variability by using the amplicon sequencing based Newcastle MSI assay (NCL_MSI) to re-analyse 361 ECs from the Ohio OCCPI/OPTEC (n=196) and Manchester PETALS (n=165) trials. NCL_MSI was consistent with Ohio results (94% and 97% concordance with IHC and original MSI assays respectively), and increased concordance in the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL_MSI was significantly associated with MLH1 promoter methylation status (p=0.0028), and had the highest concordance with methylation, 62/69 samples (90%), indicating utility as a screening tool in this tumour type. However, tumours with germline MSH6 defects were only detected efficiently with IHC; 7/8 LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to 4/12 classified as MSI-H by both (p=0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss (p=0.009 Ohio, p=6.2x10-5 Manchester), and in both ECs and CRCs with germline defects although this only reached significance in CRCs (p=0.002). These results provide further evidence that ECs with MSH6 loss in particular, and LS tumours in general, have an attenuated MSI signal, and supports current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.

Radiotherapy remains a cornerstone in cancer treatment, leveraging ionizing radiation to eradicate malignant cells. Its efficacy, however, is frequently challenged by the heterogeneous sensitivity of tumors and surrounding tissues to radiation. Therefore, understanding the molecular mechanisms underlying radiosensitivity is crucial for improving treatment outcomes. Among the myriad of molecular players involved, the tumor suppressor protein p53 stands out as a central regulator with significant implications for radiosensitivity. Known as the “guardian of the genome,” p53 plays a pivotal role in maintaining genomic stability and orchestrating cellular responses such as cell cycle arrest, DNA repair, apoptosis, and senescence in response to various stress signals, including radiation-induced DNA damage. Activation of p53 triggers the transcription of target genes involved in DNA repair pathways, such as p21, MDM2, and GADD45, facilitating the repair of radiation-induced DNA damage or the elimination of irreparably damaged cells. This, in turn, influences the overall radiosensitivity of tissues. Mutations in the TP53 gene, which encodes p53, are among the most frequent genetic alterations in human cancers. Loss or dysfunction of p53 can compromise the cellular response to radiation, leading to increased resistance to therapy and poorer clinical outcomes. Conversely, intact p53 function is associated with enhanced radiosensitivity due to its ability to promote cell cycle arrest and apoptosis in response to radiation-induced DNA damage. In conclusion, elucidating the molecular mechanisms by which p53 influences radiosensitivity is essential for advancing our understanding of radiation response in cancer cells and developing more effective therapeutic approaches in cancer treatment. This review provides a comprehensive overview of the multifaceted role of p53 in modulating cellular responses to radiation, emphasizing its influence on radiosensitivity.

Background: Ovarian mesonephric-like adenocarcinoma (MLA) is a newly described histological type known for its aggressive behavior. This study aims to determine the frequency of ovarian MLA, review existing literature, and elucidate its clinicopathological characteristics, including potential therapeutic targets. Methods: We retrospectively reviewed the pathological diagnoses of 516 primary ovarian cancer surgical cases at our institution from 2010 to 2023. MLAs exhibiting typical morphological and immunohistochemical features were included. The frequency and clinicopathological characteristics of these cases were summarized. Additionally, we conducted a literature search using PubMed to collect and summarize previously reported cases of ovarian MLA. Results: Among the 516 primary ovarian cancer cases, we identified 3 cases (0.6%) of MLA. The patients were 52-76 years old, and the initial FIGO stages were IC1 (2 cases) and IIIB (1 case). All cases exhibited HRP, pMMR, PD-L1 negativity (CPS&lt;1), and HER2-low expression. Two cases experienced metastatic recurrence. A literature review identified 97 cases of MLA. MLA frequently exhibited KRAS mutations (90%, 38/42), with a recurrence rate of 39% (26/67). Conclusion: MLA accounted for 0.6% of malignant ovarian tumors at our institution, all of which were advanced or recurrent cases. These cases showed HRP, pMMR, and PD-L1 negativity, indicating a lack of current therapeutic targets. Literature also reports a high incidence of advanced and recurrent cases, highlighting the need for accurate diagnosis and the development of new treatments. The frequent KRAS mutations suggest a potential therapeutic target for recurrent or metastatic MLA.

Abstract: Background: Gender dimorphism and marital status on colorectal cancer mortality have 9 been previously documented, but the relationship between these factors and DNA mismatch repair 10 protein (MMRP) expression status is unknown. Methods: Colectomy specimens were reviewed ret- 11 rospectively for patients between 2018 to 2023 with demographics including race/ethnicity, gender, 12 marital status, faith, body mass index, pathologic staging, and MMRP expression status. Statistical 13 analyses were performed by using baseline characteristics tables and various programs in R-pack- 14 age. Results: A total 1018 colectomies were reviewed, and the tumor stages were significantly higher 15 in right colon (stage 3 and 4) than those in left colon and rectosigmoid colon (p<0.01). Marital status 16 was significantly associated with patients’ gender, age, tumor size and tumor stages (all p<0.01). 17 MMRP status were available in 775 cases, and 139 (17.9%) were MMRP deficient, and 636 (82%) 18 MMRP proficient. MMRP deficiency was significantly associated with older female patients, larger 19 tumor in size, higher tumor stages, higher histologic grade and more common in right colon (all 20 p<0.01). In addition, MMRP deficiency was statistically associated with higher percentage of di- 21 vorced and widowed patients (p<0.01). Multivariate linear regression analysis revealed persistent 22 association of MMRP deficiency with tumor size, tumor grade, tumor stage and nodal metastasis, 23 but the associations with gender and marital status no longer existed. Conclusion: The differences 24 in prevalence of CRC by gender and marital status and tumor MMRP status illustrate the im- 25 portance of these factors on tumor stages and nodal metastasis but these associations were more 26 complex with other confounding factors.

The evolutionary cancer cell biology ECCB explains the deep homology existent between the life cycle of cancer and protists. Due to their origin and sensitivity to oxygen, all non-gametogenic germ lines and germ stem cells (GSCs), including human adult stem cells (ASCs) and cancer stem cells (CSCs), suffer severe DNADSB damage when exposed to stress oxygen content above 6.0% O2 (Urgermline hyperoxia) as occurring in tissue and bloodstream. As a result, GSCs/ASCs/ CSCs lose their stemness potential and convert from a functional asymmetric cyclic phenotype (ACD phenotype) to a dysfunctional symmetric phenotype capable of defective symmetric proliferation (DSCD) that is, however, unable to repair genomic degradation. Genome reconstruction occurs through evolutionary mechanisms evolved by the common ancestor of amoebozoans, metazoans, and fungi. They complete the cycle by removing the damage, reconstructing the functional genome, and reinstating the ASC phenotype. The stemness life cycle acts not only during carcinogenesis, tumorigenesis, and recurrence but also in the life cycle of protists.

Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2's implications. While both share structural similarities, LSD2 possesses unique features. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes.

Histone deacetylases inhibitors (HDACi) have shown promising therapeutic outcomes in haematological malignancies such as leu-kaemia, multiple myeloma and lymphoma, with dis-appointing results in solid tumours when used as monotherapy. As a result, combination therapies either with radiation or other deoxyribonucleic acid (DNA) damaging agents have been suggested as ideal strategy to improve their efficacy in solid tumours. Numerous in vitro and in vivo studies have demonstrated that HDACi can sensitise malignant cells to both electromagnetic and particle types of radiation by inhibiting DNA damage repair. Although the radiosensitising ability of HDACi has been reported as early as 1990s, the mechanisms of radiosensitisation are yet to be fully understood. This review brings forth the various protocols used to sequence the administration of radiation and HDACi treatments in the different studies. The possible contribution of these various protocols on the ambiguity that surrounds the mechanisms of radiosensitisation is also highlighted.

Background: Since cytokine receptor like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. Methods: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno associated virus (AAV) or AAV containing CRLF1 was determined by morpholog-ical, histological and microCT analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were deter-mined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes us-ing real time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Results: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondro-genic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and Cardiotrophin like Cytokine (CLC) stimulated catabolic events via STAT3 activation. Conclusion: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Bone morphogenetic protein (BMP) and platelet-derived growth factor (PDGF) are known to regulate and stimulate osteogenesis, both proteins playing an important role in bone homeostasis, constituting good candidates for osteoporosis´ treatment. Herein we aim to evaluate the effects of recombinant human BMP-7 (rhBMP7) and PDGF-BB (rhPDGF-BB) in oophorectomy-induced osteoporosis in rats. To this end, 40 Sprague-Dawley rats were submitted to oophorectomy surgery and treatments were started at the 100th day after the surgery, when all animals showed signs of osteoporosis. These peptide growth factors were applied intravenously once or twice a week and animals were followed for a total of five weeks. Two weeks after the end of the treatments, the animals were euthanized, the tissues were collected and Alkaline Phosphatase, X-ray, micro-CT and histology were assessed. The results indicate that the most promising treatments are: 20 µg/kg PDGF-BB + 30 µg/kg BMP-7 2x/week and 30 µg/kg BMP-7 2x/week, presenting an increase of 15% (p&lt;0.05) and 13% (p&lt;0.05) in bone volume fraction and 21% (p&lt;0.05) and 23% (p&lt;0.05) in trabecular number, respectively. In conclusion, rhPDGF-BB and rhBMP-7 are capable of inducing an increase in bone volume and density in this osteoporotic animal model, constituting interesting candidates for osteoporosis treatment.

Soil washing is a rapid and efficient method for heavy metals removal. In this study, in order to prove the feasibility of leaching remediation technology for remediation of lead-contaminated soil around a smelter, intermittent oscillating washing tests and extensive continuous tests were conducted to remediate Pb contaminated soils. Plant growth tests with wheat (Bainong Aikang 58) were also conducted to investigate the effects of leaching on plant growth and the Pb content of stems and leaves. The results revealed that in soils, Pb mainly exists in the forms of PbCO3, Pb5(PO4)3Cl2, PbSO4, and in small amounts of PbS. The intermittent oscillating washing tests showed that a lower liquidsolid(L/S) ratio and a higher leaching temperature and time were related to increased Pb removal efficiency. The Pb removal efficiency rates in the oscillating washing tests and the extensive continuous tests were 72.50% and 69.94%, respectively. In addition, the chemical and physical characteristics of the soil were basically unchanged after the leaching regimes. The results of the plant growth tests showed that the leaching regimes did not have a negative effect on the survival rate and growth of the wheat, and the heavy metal contents of the stem and leaf were effectively reduced. This study provides a reference for the large-scale remediation of contaminated soils.

Concrete cracks have a detrimental effect on the strength properties and durability of the structures. So, repairing of concrete cracks to recover their strength parameters is more important task in civil engineering. To repair concrete cracks, MICP has been widely analysed in recent times; but, zero research is conducted to deeply investigate the repair effects of MICP on concrete cracks with rough surface by using the theoretic model. In current research, MICP with a novel mathematical model was attained by taking the precipitation of calcium carbonate (CaCO3), ureolysis, suspended biomass, geochemistry, transport of solute and biofilm growth. Furthermore, crack repair experiments were performed to check the workability of the new mathematical method. The outcomes revealed that the designed suspended biomass concentrations in cracks diminished step by step. The comparison in between the experimental results and calculated results verified the precision of migration behaviour of the suspended biomass. At the inlet, the solute concentrations and biofilm volume fractions was higher, causing in rise of yield amounts for calcium carbonate. The consumed solutes concentrations were higher for cracks of less rough surface, ultimately causing in smaller sonic time; and the values of sonic time for upper portions of cracks was smaller, showing good repair impacts. The recommended mathematical model provides a better tool that controls repair time and microbial metabolism process to report a new adjustive, bioremediation and biomineralization to concrete, which could provide a firm base for remediation of material in civil engineering field.

Background: There is poor evidence about sensitivity to chemotherapy according to microsatellite instability (MSI)/mismatch repair (MMR) status in endometrial cancer (EC). Methodology: The RAME study is a retrospective analysis aiming to assess response to chemotherapy in MSI-high (h) /deficient (d) MMR and MSI- low (l)/proficient (p)MMR EC patients. Primary endpoints were recurrence-free survival (RFS) for patients with localized disease and progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent disease. Results: 312 patients treated between 2010-2022 in 4 high volume Multicenter Italian Trial in Ovarian cancer and gynecological malignancies (MITO) centers were selected. 239 patients had endometrioid EC (76.6%), 151 had FIGO stage I at diagnosis (48.9%) and 71 were MSI-h/dMMR (22.8%). Median age was 65 (range 31–91) years. Among patients with localized disease, median RFS was 100.0 months (95%CI 59.4–140.7) for MSI-l/pMMR and 120.9 months (60.0-181.8) for MSI-h/dMMR (p=0.39). Seventy-seven patients received first-line chemotherapy for advanced/recurrent disease. Patients with MSI-h/dMMR ECs had a significantly worse OS (p=0.039). In patients receiving platinum-based chemotherapy, no statistically significant difference in PFS (p=0.21) and OS (p=0.057) were detected, although PFS and OS were numerically longer in the MSI-l/pMMR population. Conclusion: Patients with metastatic MSI-h/dMMR EC receiving first-line chemotherapy had a significantly worse OS.

The Ramazzottius varieornatus tardigrade is an extremotolerant terrestrial invertebrate belonging to the phylum of Tardigrada. At a length of 0.1-1.0 mm, tardigrades are small animals with an exceptional tolerance to extreme conditions such as high pressure, chemicals and irradia-tion. These properties have been attributed to the recently-discovered Dsup protein. Dsup is a nucleosome-binding protein that prevents DNA damage against X-ray and oxidative stress without impairing cell life, also in Dsup-transfected animal and plant cells. However, the precise “protective” role of this protein is still under study. We performed experiments on human cells and shows that, as compared to control cells, Dsup+ cells are more resistant to UV-C exposure and H2O2. Real-time PCR identified different expression patterns of endogenous genes involved in apoptosis, cell survival and DNA damage repair in Dsup+ cells in response to H2O2 and UV-C. While H2O2 treatment in Dsup+ cells only marginally involved the activation of pathways responsible for DNA repair reinforcing the idea of a direct protective effect of the protein on DNA, in UV-C exposed cells, Dsup efficiently upregulates DNA damage repair genes. In conclusion, our data may help to delineate the different mechanisms by which the Dsup protein operates in response to different insults.

Packaging of the eukaryotic DNA genome with histone and other proteins forms a chromatin structure that regulates the outcome of all DNA mediated processes. The cellular pathways that ensure genomic stability detect and repair DNA damage through mechanisms which are critically dependent upon chromatin structures established by histones and, particularly, transient histone post-translational modifications . Though subject to a range of modifications, histone methylation is especially crucial for DNA damage repair as the methylated histones often form platforms for subsequent repair protein binding at damaged sites. In this review, we highlight and discuss how histone methylation impacts the maintenance of genome integrity through effects related to DNA repair and repair pathway choice.

Abstract5′,8-Cyclo-2′-deoxyadenosine (cdA), in the 5′R and 5′Sdiastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA. So far, it was unknown whether the diastereomeric cdA lesions could induce specific PARP1 binding. Here we provide the first evidence of PARP1 to selectively recognize the diastereomeric lesions 5′S-cdA and 5′R-cdA in vitro as compared to deoxyadenosine in model DNA substrates (23-mers) by using circular dichroism,fluorescence spectroscopy, immunoblotting analysis and gel mobility shift assay. Several features of the recognition of the damaged and undamaged oligonucleotides by PARP1were characterized. Remarkably, PARP1 efficiently binds to both cdA lesions in the double stranded (ds)-oligonucleotides. In particular, PARP1 proved to bind 5′S-cdAwith a higher affinity constant for the 5'S lesion in a model of ds DNA than 5′R-cdA, showing different recognition patterns, also compared with undamaged dA. This new finding highlights the ability of PARP1 to recognize and differentiate the distorted DNA backbone in a biomimetic system caused by different diastereomeric forms of a cdA lesion.

Fanconi syndrome is a disorder of renal proximal tubule transport characterized by metabolic acidosis, amino aciduria, glucosuria, and phosphaturia. There are acquired and hereditary forms of this disorder. Fanconi syndrome in Basenjis was first described in 1976 and is now recognized as an inherited disease in these dogs. Linkage analysis within a large family of Basenjis that included both affected and unaffected individuals was performed to localize the causative variant within the genome. Significant linkage was identified between chromosome 3 (CFA3) makers and the disease phenotype. Fine mapping restricted the region to a 2.7 Mb section of CFA3. A whole genome sequence of a Basenji affected with Fanconi syndrome was generated, and the sequence data were examined for the presence of potentially deleterious homozygous variants within the mapped region. A homozygous 317 bp deletion was identified in the last exon of FAN1 of the proband. 78 Basenjis of known disease status were genotyped for the deletion variant. Among these dogs, there was almost complete concordance between genotype and phenotype. The only exception was one dog that was homozygous for the deletion variant but did not exhibit signs of Fanconi syndrome. These data indicate that the disorder is very likely the result of FAN1 deficiency. The mechanism by which this deficiency causes the disease signs remains to be elucidated. FAN1 has endonuclease and exonuclease activity that catalyzes incisions in regions of double-stranded DNA containing interstrand crosslinks. FAN1 inactivation may cause Fanconi syndrome in Basenjis by sensitization of kidney proximal tubule cells to toxin-mediated DNA crosslinking resulting in accumulation of genomic and mitochondrial DNA damage in the kidney. Differential exposure to environmental toxins that promote DNA crosslink formation may explain the wide age-at-onset variability for the disorder in Basenjis.

Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024. This rise correlates with aging populations, the obesity epidemic, and changing reproductive patterns, including delayed childbearing. Despite the early diagnosis in 67% of cases, approximately 30% of cases present with regional or distant spread, leading to nearly 20% mortality rates. Unlike many cancers, EC mortality rates are escalating, outpacing therapeutic advancements until recently. One of the reasons for this was the lack of effective therapeutic options for advanced disease until recently. The introduction of immunotherapy has marked a turning point in EC treatment, particularly benefiting patients with defects in mismatch repair proteins (dMMRs). However, dMMR status alone does not ensure a favorable response, underscoring the need for precise patient selection. This review explores the pivotal role of mismatch repair proteins in EC, emphasizing their heterogeneity, the challenges in their assessment, and their potential as predictive biomarkers.

The study objective is to evaluate the reliability of the Göttingen Mini-pig (G-MP) as a large animal model for preclinical studies addressing articular cartilage treatment procedures. Second this work compared the G-MP to the domestic pig (DP) in terms of surgical anatomy, postoperative management, and follow-up period possibilities and challenges. Six G-MP and four DP underwent a two-stage surgical procedure including cartilage harvesting using a superolateral approach followed by cartilage implantation using a medial parapatellar tendon approach. The superolateral approach exposed 11% (SD ± 5) of the entire trochlea in G-MP and 20% in the DP model. The medial parapatellar tendon approach in G-MP exposed 63% (SD ± 4) of the trochlear surface and exposed 34% (SD ± 13) of the medial femoral condyle, allowing 4 trochlear lesions of 6mm of diameter and one to the medial condyle in 4 out of 6 G-MP and in all DPs. Cartilage thickness was under 1mm in G-MP compared to more than 2mm in DP. Weight-progression was + 4 kg/week in DP and + 0.2 kg/week for G-MP. The G-MP is a feasible model for cartilage research, with adequate access to the joint via the dual approach. Thus enabling 4-5 lesions of 6mm, however a thinner cartilage in the G-MP needs to be considered.

In the United States, the Federal Aviation Administration has officially classified flight crew (FC) consisting of commercial pilots, cabin crew or flight attendants as “radiation workers” since 1994 due to the potential for cosmic ionizing radiation (CIR) exposure at cruising altitudes originating from solar activity and galactic sources. Several epidemiological studies have documented elevated incidence and mortality for several cancers in FC, but it has not yet been possible to establish whether this is attributable to CIR. CIR and its constituents are known to cause a myriad of DNA lesions, which can lead to carcinogenesis unless DNA repair mechanisms remove them. But critical knowledge gaps exist with regard to CIR dosimetry, the role of other genotoxic exposures among FC, and possible biological mechanisms underlying higher cancer rates observed in FC exist. This review summarizes our understanding of the role of DNA damage and repair responses relevant to CIR exposure in FC. We aim to stimulate new research directions and provide information that will be useful for guiding regulatory, public health, and medical decision-making to protect and mitigate risks for those who travel by air.

It was of great practical significance to repair the toxicity of salt stress environment to soybean seedlings and maintain the balance between agricultural production and ecological environment in the Yellow River valley of China. ‘Xudou 20’ was used as the experimental material, a large-scale planting variety in the old Yellow River basin. Endophytes 131 and 137 isolated from soybean root nodule were taken as the research objects, and the soybean plants were cultivated by pot culture in intelligent artificial incubator. Salt stress group, bacteria suspension group and control group were set up to study the effects of inoculation treatments on the activities of superoxide dismutase (SOD) and catalase (CAT) of soybean seedlings under different NaCl stress. The results showed that when inoculated with endophyte 131 bacterial suspension and cultured for 14 days, the SOD activity was the highest (14.89 U•g−1•FW) at the salt concentration 50 mmol•L-1. When inoculated with 131 bacterial suspension (2:1) and cultured for 28 days, the SOD activity reached the highest (0.94 ug-1FW) at the salt concentration of 50 mmol•L-1, and the CAT activity amounted to the highest (1910 U•g−1•min−1). The 16S rDNA sequencing and phylogenetic analysis showed that the most similar strain of strain 137 was Bacillus cereus, and the most similar strain of strain 131 was Enterobacter ludwigii. Therefore, the activities of SOD and CAT in soybean seedlings inoculated with endophytes 131 and 137 increased at different degrees under salt stress, which could effectively alleviate the damage of salt stress environment to plants, and thus improve the stress resistance of plants.

Recent successes in the field of evolutionary cancer cell biology (ECCB) have brought to a head two of the most important controversies regarding cancer origin. The first concerns the question of whether carcinogenesis is initiated only by genetic alterations, mutations, and driver genes, as the mutational theory teaches. The ECCB, claims that a large number of polyploidy-related cancers (PGCC cancers) are not due to mutations, but rather to inadequate ancient repair mechanisms used by DNA-damaged stem cells for their repair. Somatic mutations are merely secondary. The second controversy, described in the previous article, concerns the non-mutational theory itself: Are non-mutational polyploid cancers an atavism - as previously thought - or rather the effect of an ancient gene regulatory network aGRN that controls genome reprogramming in precancerous DNA-damaged cells as well in the transformed cells. Finally, the unicellular gene module of cancer, of which the aGRN is a part, has evolved along with the multicellular genome during the last 1000 My of evolution. and non-mutated cancer cell systems are under the control of the aGRN. The atavistic theory relies on phylostratigraphic evidence to determine the age of cancer genes. It states that most cancer-like genes arose during the transition period from unicellularity to multicellularity, but also during the early metazoan era. In our opinion, the atavistic theory is flawed and suffers from many misunderstandings. It provides little insight into the origin and coevolution of the cancer cell system and its control by the ancient gene regulatory network aGRN.

On the analyzed section of 2.4 km of the national road No. 50 of the Młodzieszyn bypass, it was carried out by a consortium of OAT and SAT companies in the period April-September 2019, under constant traffic in the field of repairing the concrete pavement by replacing slabs, levelling them and sealing expansion joints, roughening and roadside reinforcements.

Angiogenesis is new blood vessel formation from existing vessels and is a critical first step in tissue repair following chronic disturbances in healing and degenerative tissues. Chronic pathoanatomic tissues are characterized by a high number of inflammatory cells, overexpression of inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), the presence of mast cells, T cells, reactive oxygen species, and matrix metalloproteinases, and a decreased angiogenic capacity. Multiple studies have demonstrated that autologous orthobiological cellular preparations (e.g., platelet-rich plasma [PRP]) im-prove tissue repair and regenerate tissues. There are many PRP devices on the market. Unfortunately, they differ greatly in platelet numbers, cellular composition, and bioformulation. PRP is a platelet concentrate consisting of a high concentration of platelets with or without certain leukocytes, platelet-derived growth factors (PGFs), cytokines, molecules, and signaling cells. Several PRP products have immunomodulatory capacities that can influence resident cells in a diseased microenvironment, inducing tissue repair or re-generation. Generally, PRP is a blood-derived product, regardless of its platelet number and bioformulation, and the literature indicates both positive and negative patient treatment outcomes. Strangely, the literature does not designate specific PRP preparation qualifications that can potentially contribute to tissue re-pair. Moreover, the literature scarcely addresses the impact of platelets and leukocytes in PRP on (neo)angiogenesis other than a general one-size-fits-all statement that “PRP has angiogenic capabilities.” Here, we review the cellular composition of all PRP constituents, including leukocytes, and describe the importance of platelet dosing and bioformulation strategies in orthobiological applications to initiate angiogenic pathways that re-establish microvasculature networks, facilitating the supply of oxygen and nutrients to impaired tissues.

Bone marrow derived adult human mesenchymal stem cells (hMSCs) possess therapeutic qualities that enable them to enhance wound repair. However, the mechanisms by which this occurs remains poorly understood. Basic mechanisms may include the directed migration of delivered cells to target sites and/or the production and release of soluble factors that act at a distance. Allogeneic and even xenogeneic cells may effectively participate in wound repair. Labeled hMSCs were delivered to full-thickness skin wounds that were created in immunologically competent mice. The delivery occurred on day 3 post-wounding using two different carriers; one which released cells and one which retained cells. The fates of the delivered cells were tracked for up to 25 days. During this period, released cells migrated as a tight cohort deep into the wound to reach the subdermal vascular plexus. Simultaneously, enhanced formation of granulation tissue was evident. This migration of hMSCs was not essential in that enhanced granulation tissue formation and wound contraction occurred when cells were retained in the carrier matrix. This provided further evidence for the release of therapeutic factors by hMSCs to sites of injury.

Chromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs). Methods: KMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis. Results: Chaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation; and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death. Conclusion: KMT inhibitors can function as sensitizers to DNA damage-based therapies and be used in novel synthetic lethality strategies for sarcoma treatment.

Helicases are proteins that use the energy of ATP to unwind nucleic acids and to remodel protein-nucleic acid complexes. They are involved in almost every aspect of the DNA and RNA metabolisms and participate in numerous repair mechanisms that maintain cellular integrity. Helicases are classified into 6 superfamilies (SF1-6). The archaeal Lhr-type proteins are SF2 helicases that are mostly uncharacterized. They have been proposed to be a DNA helicase that acts in DNA recombination and repair processes in Sulfolobales and Methanothermobacter. In parallel, a protein annotated as an Lhr2 protein was also found in the network of proteins involved in RNA metabolism in Thermococcales. To this respect, we performed in-depth phylogenomic analyses to report the classification and taxonomic distribution of Lhr-type proteins in Archaea, and to better understand their relationship with bacterial Lhr. Furthermore, with the goal of envisioning the role(s) of aLhr2 in archaeal cells, we deciphered the enzymatic activities of aLhr2 from Thermococcus barophilus (Tbar). We showed that Tbar-aLhr2 is a DNA/RNA helicase acting on DNA:RNA and RNA:RNA duplexes and proposed that aLhr2 helicases are involved in processes dependent of DNA and RNA transactions.

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, Mri) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.

In intermediary metabolism, enzymes are mainly for the specific provision of one small molecule from another, B from A, for its further use. But there are also decades of work relating to another evolved purpose, which is to prevent untoward effects of odd compounds of various origins, and of ordinary intermediates, whose improper concentrations may be avoided by hydrolases and other activities of metabolic correction.

The treatment of large-area bone defects remains a challenge; however, various strategies have been developed to improve the performances of scaffolds in bone tissue engineering. In this study, poly(lactide-co-glycolide)/hydroxyapatite (PLGA/HA) scaffold was coated with Asp-Gly-Glu-Ala (DGEA)-incorporated collagen for the repair of rat skull defect. Our results indicated that the mechanical strength and hydrophilicity of PLGA/HA scaffold were clearly improved and conducive to cell adhesion and proliferation. The collagen-coated scaffold with DGEA significantly promoted the repair of skull defect. These findings indicated that a combination of collagen coating and DGEA improved scaffold properties for bone regeneration, thereby providing a new potential strategy for scaffold design.

Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underly chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei followed by incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA-repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome and Bloom syndrome. In addition, germline variations of TP53 have been associated with chromothripsis in Sonic-Hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA-repair genes resulting in chromosome instability and chromothripsis-like rearrangements.

Objective: To explore the application effect of a bimodal collaborative nursing model in patients undergoing gastric cancer surgery with concurrent inguinal hernia repair. Methods: Sixty patients with gastric cancer and concurrent inguinal hernia who were admitted to our hospital between August 2019 and August 2021 were selected as the study subjects. Based on the different nursing approaches, all patients were divided into a control group and an observation group, with 30 patients in each group. The control group received conventional nursing care, while the observation group received the bimodal collaborative nursing model in addition to conventional care. The postoperative recovery, psychological status, and quality of life of the two groups of patients were compared. Results: The postoperative recovery of the observation group was superior to that of the control group, and the difference was statistically significant (P < 0.05). The anxiety and depression scores of the observation group were lower than those of the control group, with statistically significant differences (P < 0.05). The quality of life score of the observation group was higher than that of the control group, with statistically significant differences (P < 0.05). Conclusion: The application of a bimodal collaborative nursing model in gastric cancer surgery with concurrent inguinal hernia repair is effective. It not only promotes postoperative physical recovery and improves the psychological well-being of patients but also enhances their quality of life. It is worthy of clinical promotion and application.

In this study, Clostridium butyricum TO-A culture supernatant (CBCS) or butyric acid was added to a culture medium of human cervical carcinoma HeLa S3 cells, and changes in DNA repair-related gene promoter activi-ties were investigated. HeLa S3 cells were transfected with a luciferase (Luc) expression vector containing ap-proximately 500-bp of the 5′-upstream region of several human DNA repair-related genes and cultured with a medium containing CBCS (10%) or butyric acid (2.5 mM). Cells were harvested after 19 to 42 h of incubation. Luc assay revealed that the human ATM, PARG, PARP1, and RB1 gene promoter activities were significantly increased. Western blot analysis showed that amounts of the proteins encoded by those genes markedly in-creased. Furthermore, 8, 24, and 48 h after the addition of the CBCS (10%), total RNA was extracted and subjected to RNAseq analysis. The result showed that the expression of several DNA replication/repair-related genes, including NFKB, and the MCM gene groups, decreased markedly after 8 h. However, the expression of the histone genes increased after 24 h. Elucidation of the mechanism by which CBCS and butyrate affect DNA-repair associated protein-encoding gene expression may contribute to the prevention of carcinogenesis, of which the risk rises in accordance with aging.

Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regu- lated, individually. A recently developed search engine ranked combinations of DNA repair gene-X (X, a particular gene/protein) at 2nd order level after drug administration. These rankings reveal which Wnt-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and determine the mechanism of functioning between the Wnt and X. In this re- search work, we cover combinations of RAD with X-ray repair cross complementing (XRCC) family, 5’-3’ exoribonuclease 2 (XRN2), NFKB repressing factor (NKRF), B cell CLL/lymphoma (BCL) family, exosome component (EXOSC) family, FA comple- mentation group (FANC) family and XRCC with EXOSC.

Vascular rings are a rare congenital anomaly of the aortic arch in which a ring-shaped structure forms surrounding the trachea and/or esophagus, potentially causing compression. We describe the case of a 14-month-old female patient with failure to thrive secondary to dysphagia, and a vascular ring formed by a right aortic arch, an aberrant left subclavian artery, and a left liga-mentum arteriosum. Surgical repair involved ligamentum arteriosum division, Kommerell’s di-verticulum obliteration, and left subclavian artery re-implantation into the left carotid artery. Endoscopy and EndoFLIPTM evaluated intraoperative improvement in esophageal narrowing and impedance, respectively. Postoperative period was uneventful and follow-up visits demonstrated dysphagia resolution and a patent re-implanted left subclavian artery.

Chronic Myeloid Leukemia, resulting due to chromosomal aberration t(9;22) through formation of oncogenic BCR-ABL fusion oncogene. Modern BCR-ABL inhibitors, called TKIs, have revolutionized CML treatment. CML has three stages: chronic, accelerated, and blast crisis. TKIs work well in CP-CML, where patients survive as long as the normal population, but they don't work in AP- and BC-CML. Even with advances in treatment, BC-CML has an average overall survival of less than a year, giving oncologists little time to clinically intervene. Oncologists can delay or prevent CML advancement by detecting patients at risk of disease progression early and making timely treatment decisions, especially with third and fourth generation TKIs. However, no universal molecular biomarkers exist to diagnose CML patient groups at risk of disease progression. A recent study found that all BC-CML patients have mutant FANCD2. Our study was designed to detect mutant FANCD2 in AP-CML (early progression phase) to investigate its potential as a novel biomarker of early CML progression from chronic phase to accelerated phase due to the urgent need for such a biomarker. Our study comprised of 123 CP-CML (control group) and 60 AP-CML patients (as experimental group) from Hayatabad Medical Complex, Peshawar, Pakistan, from Jan 2020 to July 2023. DNA was extracted from the patients and FANCD2 gene was sequenced using Illumina next generation sequencer (NGS) Illumina MiSeq sequencer. NGS analysis revealed a unique splice site mutation in FANCD2 gene (c. 2022-5C>T). This mutation was detected in all CP-CML patients but in none of CP-CML. The mutation was confirmed by Sanger sequencing. FANCD2 is member of Fanconi anemia (FA-) pathway gene involved in DNA repair and genomic instability. Therefore, our studies show that FANCD2 (c. 2022-5C>T) mutation as a very specific molecular biomarker for early CML progression. We recommend to clinical validate this biomarker is prospective clinical trials.

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. However, functional recovery after surgical repair is often disappointing. The basis for the poor recovery is the progressive deterioration with time and distance, of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. This is despite the retained capacity of chronically denervated and atrophic muscle to accept reinnervation. Progressive decline in regeneration associated genes in both axotomized neurons and denervated SCs accounts for the decline in regenerative success in association with silencing of neural activity in sensory neurons due to their disconnection from their sense organs and, in motoneurons due to loss of their synaptic contacts in the spinal cord. Whilst exogenous neurotrophic factors promote nerve regeneration, the profuse axonal outgrowth and difficulties in delivery are avoided by promoting their endogenous expression with brief (1 hour) low frequency (20Hz) electrical stimulation (ES) proximal to the injury site. ES accelerates axon outgrowth and in turn, target reinnervation in both animals and human subjects. Applying ES to intact nerve days prior to nerve injury, conditional ES (CES) increases axonal outgrowth and regeneration rate with the potential for application in nerve transfer surgeries and end-to-side neurorrhaphies. However, the additional surgery for applying CES electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes.

This review article deals with the design of bioactive calcium phosphate coatings deposited on metallic substrates to produce bone implants. The bioceramic coating properties are used to create a strong bonding between the bone implants and the surrounding bone tissue. They provide a fast response after implantation and increase the lifespan of the implant in the body environment. The first part of the article describes the different compounds belonging to the calcium phosphate family and their main properties for applications in biomaterials science. The calcium to phosphorus atomic ratio (Ca/P)at. and the solubility (Ks) of these compounds define their behavior in a physiological environment. Hydroxyapatite is the gold standard among calcium phosphate materials, but other chemical compositions/stoichiometries have also been studied for their interesting properties. The second part reviews the most usual deposition processes to produce bioactive calcium phosphate coatings for bone implant applications. Plasma spraying is the main industrial process, but magnetron sputtering, pulsed laser deposition, electrospray deposition, electrophoretic deposition, and electrodeposition are also widely studied in academic and industrial research. The last part describes the main physicochemical properties of calcium phosphate coatings and their impact on the bioactivity of bone implants in a physiological environment.

The capability of radially polymerized bio-dendrimers and hyperbranched polymers for medical applications is well established. Among them, perhaps the most important are those that involve interactions with the regenerative mechanisms of cells. Dendritic polymers due to their distinctive architecture may play a multitude of roles such as protein biomimicry (collagen, elastin, hydroxy apatite production), gene and drug delivery (cell differentiation, antimicrobial protection), surface chemistry and charge modulation (adhesion to cells and tissues), polymer cross-linking (eye, skin and internal organ wound healing). The review highlights all the different categories of hard and soft tissues that may be remediated with their contribution. The reader will be also exposed to the incorporation methods to established biomaterials such as scaffolds, the functionalization strategies, and the synthetic paths for the assembly from biocompatible building blocks and natural metabolites.

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta that progressively grows till the rupture. Treatment is typically recommended when the diameter is more than 5 cm. The EVAR (Endovascular aneurysm repair) is a mininvasive procedure that involves the placement of an expandable stent graft within the aorta to treat aortic disease without operating directly on the aorta. For years, stent grafts' essential design was based on metallic stent frames to support the fabric. More recently, a polymer-based technology has been proposed as an alternative method to seal AAA. This review underlines the two platforms that are based on a polymer technology: 1)the polymer-filled endobags, so-called Endovascular Aneurysm Sealing (EVAS) with Nellix stent graft; and 2)the O-ring EVAR polymer-based proximal neck sealing device, so-called Ovation stent graft. Polymer characteristics for this particular aim, clinical applications, and durability results are summarized and commented critically. The platform that embraced the concept of inflating endobags filled with polymer to exclude the aneurysmal sac was not successful because of the lack of an adequate proximal fixation. The platform that used polymer to create a circumferential sealing of the aneurysmal neck has proven safe and effective.

Self-assembling peptide P11-4 is amphiphilic and pH-triggered with demonstrated effectivity repairing early carious lesions in enamel. However, P11-4 effects on dentin biomineralization and repair remain unexplored. Thus, cytocompatibility and effectiveness of P11-4 inducing mineralization and migration of odontoblast-like cells (MDPC-23) were investigated. MDPC-23 were seeded in contact with P11-4(0.5µg/ml and 1µg/ml), Dentin Matrix Protein 1 (DMP1 0.5µg/ml and 1 µg/ml) or Calcium hydroxide (Ca(OH)2 100µg/ml) solutions. Cytotoxicity was verified using MTT (n=6/group). Mineralization was tested using Alizarin Red (n=4/group). Cell migration was assessed by light microscopy (n=2/group). MTT and Alizarin Red data were compared using Krus-kal-Wallis and Mann-Whitney (α=0.05). P11-4 (0.5µg/ml and 1µg/ml) and DMP1 (0.5µg/ml and 1µg/ml) presented the highest cytocompatibility; Ca(OH)2 presented the lowest. DMP1 1µg/ml exhibited the highest mineralization ability, with no difference to P11-4 1µg/ml. Ca(OH)2 presented lower values than DMP1 1µg/ml (p<0.05), but similar to P11-4 1µg/ml. P11-4 and DMP1 at 0.5 µg/ml showed induced less mineralization than P11-4 and DMP1 at 1µg/ml (p<0.05), with no difference to Ca(OH)2. All materials stimulated cell migration, however, lower concentrations of DMP1 and P11-4 provided better results. P11-4 is cytocompatible, induces mineralization and MDPC-23 migration like DMP1. P11-4 could be an alternative for dentin mineralization and tooth repair.

This work describes practical immunization of European sea bass (Dicentrarchus labrax) juveniles against viral nervous necrosis virus (VNNV), a betanodavirus causing worldwide mortalities in many fish species. Protection was obtained with the so called spinycterin vehicles consisting in irreversibly DNA-damaged DNA-repair-less E.coli displaying at their surface a downsized antigen. In this work we, i) maximized bacterial expression levels by downsizing the C protein to a fragment (frgC91-220) containing most of its antigenicity, ii) developed an scalable autoinduction bacterial media based in soy-bean increasing membrane display and reproducibility, iii) enriched surface expression by screening different anchors from several prokaryotic origins (anchor+frgC91-220), iv) preserved frgC91-220 antigenicity by inactivating bacteria by irreversible DNA-damage by means of Ciprofloxacin, and v) increased safety using a repair-less E.coli strain as spinycterin chassis. These second generation of spinycterins protected fish against VNNV challenge with partial (Nmistic+frgC91-220) or 100 % (YBEL+frgC91-220 ) protection, in contrast to those fish immunized with frgC91-220 spinycterins. The proposed spinycterin platform has high levels of environmental safety and cost effectiveness, thus providing potential for small fish vaccines for sustainable aquaculture.

Background The aim of this literature review was to make future guidelines for clinical tretment and next study about preoperative and postoperative clinical and functional evaluation of symptoms after transanal repair of rectocele and rectal mucosectomy with a single circular stapler(TRREMS procedure),used for treatment of obstructed defecation syndrome (ODS) caused by rectocele and rectal mucosal prolpase (RMP). Since anorectocele is usually associated with mucosa prolapse and/or rectal intussusceptions, it was developed a stapled surgical technique using one circular stapler. Methods An organized search of Medline/PubMed and medical Database of Clinical Trials was performed, from 1996 to 2016 using the key words „rectal prolapse”,”rectocele”, „ODS”,”Defecography”,”STARR”, „TRREMS”.Results The results of clinical studies are good for improving the quality of life of patients who underwent transanal repair of rectocele and rectal mucosectomy with a single circular stapler(TRREMS). The method can be considered as safe. Clearly to be implemented in our practice, for specific indications.

Concrete is a very common construction material. As time prevails, cracks often appear in structures that pose a threat to strength and durability, which ultimately affect the structural integrity of concrete. Extensive work has been carried out in past on utilization of Carbon Fiber Reinforced Polymer (CFRP) as a repair material. But, this research particularly focuses on: multiple fiber layers i.e. single and double, traditional concrete mix ratio with locally available materials and varying flexural reinforcement. Furthermore, this work presents an experimental analysis to strengthen the Reinforced Concrete (RC) beams using SikaWrap- 230 C as a CFRP wrap, and Sikadur-330 as a bonding material. The comparison between single and double layers of CFRP is of major interest in this research. Six reinforced concrete beams were repaired with CFRP and tested under three-point bending test. For these specimens, load deflection behavior along with crack propagation and failure of beams were studied. Experimental results show that beams repaired using CFRP wrapping achieved higher flexural capacity and ductility as compared with reference beam. Moreover, results reveal that introduction of second layer of fiber caused around 4-5.2% increment in flexural strength and resulted in higher ductility of RCC beam.

Background: Mitral regurgitation (MR) is a common valvular disorder linked to high morbidity and mortality. For patients unsuitable for surgery, transcatheter mitral edge-to-edge repair (TEER) with the MitraClip® G4 system offers an alternative. This study aims to evaluate procedural, echocardiographic, functional, and quality of life (QoL) outcomes in patients who underwent TEER with the MitraClip® G4 system, along with possible predictors of New York Heart Associa-tion (NYHA) class I at 30 days and 1 year. Methods: Patients with moderate-to-severe (3+) or se-vere (4+) degenerative MR (DMR) or functional MR (FMR), classified as NYHA class III or IV, who underwent TEER with the MitraClip® G4 system at our center between January 2021 and De-cember 2023 were included. Results: A total of 83 patients [71% FMR, 66% male, median (IQR) age 70 (11) years] underwent TEER, with 100% procedural success. MR ≤2+ was achieved in 100% and 98% of patients at 30 days and 1 year, respectively. NYHA class I or II was achieved in 100% and 96.8% of patients at 30 days and 1 year, respectively. The Kansas City Cardiomyopathy Ques-tionnaire (KCCQ) score improved from 51±20 at baseline to 69±15 at 30 days (p< 0.001) and 70.5±15 at 1 year (p< 0.001). Lower baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) pre-dicted achieving NYHA class I at 30 days (HR: 0.63, 95% CI: 0.41–0.95, p = 0.030), while lower Eu-ropean System for Cardiac Operative Risk Evaluation II (EuroSCORE II) and NT-proBNP pre-dicted it at 1 year [(HR: 0.50, 95% CI: 0.28–0.89, p = 0.019), (HR: 0.67, 95% CI: 0.44–0.99, p = 0.049), respectively]. Conclusions: The MitraClip® G4 system provides significant improvements in MR severity, functional class, and QoL. Lower NT-proBNP and EuroSCORE II were strong predictors of achieving optimal functional status (NYHA class I).

To investigate the repair mechanism of umbilical cord mesenchymal stem cells (UC-MSCs) in hydrogel on pancreatic β-cells in diabetes, MIN-6 damaged by streptozotocin (STZ) in vitro was used in co-culture with UC-MSCs in hydrogel (UC-MSCs + hydrogel). It was found that UC-MSCs + hydrogel had a significant repair effect on injured MIN-6 cells, which was better than the use of UC-MSCs alone (without hydrogel). After repair, the expression of superoxide dismutase (SOD) and catalase (CAT) as well as the total antioxidant capacity (T-AOC) of the repaired MIN-6 cells were increased, effectively reducing the oxidative stress caused by STZ. In addition, UC-MSCs + hydrogel were able to curb the inflammatory response by promoting the expression of anti-inflammatory factor IL-10 and reducing inflammatory factor IL-1β. In addition, the expression of both nuclear antigen Ki67 for cell proliferation and insulin-related genes such as Pdx1 and MafA was increased in the repaired MIN-6 cells by UC-MSCs + hydrogel, suggesting that the repair effect promotes the proliferation of the injured MIN-6 cells. Compared with the use of UC-MSCs alone, UC-MSCs + hydrogel exhibited longer survival time of UC-MSCs, because the porous structure and hydrophilic properties of the hydrogel could affect the growth of cells and slow down their metabolic activities, resulting in a better repair effect on the injured MIN-6 cells.

Late type II endoleak (T2EL) arising from internal iliac artery (IIA) network may occur after endovascular aortic repair (EVAR) of aortoiliac aneurysm and may require embolization if sac enlargement is demonstrated. When direct antegrade access to ipsilateral IIA is not achievable due to previous vessel coverage and/or embolization, access to the nidus can be challenging. We report a case of T2EL originating from IIA network causing iliac sac enlargement in a patient previously treated by EVAR for artoiliac aneurysm with IIA embolization and coverage, in which embolization of the nidus was performed through a percutaneous sheathless access to ip-silateral superior gluteal artery (SGA). A literature review dealing with all cases of percutaneous direct SGA access for retrograde embolization of T2EL arising from IIA after previous EVAR is also reported. The research was conducted on Pubmed database using keywords “superior glu-teal artery access,” “transgluteal embolization” and “retrograde embolization for type II endo-leak”. Related articles and references were screened for suitable articles.

Maker spaces can contribute significantly to the circular economy of cities: they demonstrate not only the economic potential of inner loop circularity, but also provide tangible evidence of spatial and social integration of production into the urban context. This paper presents findings from a typological analysis of 326 maker spaces in seven European cities, with a focus on selected exemplar case studies to reveal design characteristics, principles and opportunities for circular city development. The research shows that circular economy principles of ‘reduce-reuse-recyle’ are aligned with maker spaces such as repair cafés, secondhand shops and fab labs. In the context of cities, circularity is revealed by a spatial tightening of resource cycles that close the loops of product life cycles. Furthermore, urban maker spaces demonstrate social engagement and a relationship to local production which inherently includes maintenance, repair, reuse, and redistribution. This paper defines five maker typologies, presents exemplars of each from different urban contexts and posits hybrid design strategies for the transition to circular maker cities. Through the adoption of these findings into urban planning policy it is possible accelerate circular urban production and close the sustainability gap between small scale local and large scale regional manufacturing.

Introduction Despite efforts to use scaffolds to treat meniscus tears, minimal progress has been made in facilitating meniscus regeneration and return of function. Our research objective was to develop a meniscus repair and regeneration implant by applying a resorbable scaffold in combination with cells and growth factors. We report here the results of using platelet-rich plasma (PRP) as a source of growth factors to induce fibrochondrogenic differentiation of human adipose-derived mesenchymal stem cells (hADSC) in a three-dimensional (3D) Type I collagen-based scaffold in vitro. Methods Scaffold Preparation. Type I collagen scaffolds were prepared following a protocol previously published. Two different densities of scaffolds, high density (HD) and low density (LD), were produced for in vitro study. hADSC and PRP Preparation. hADSCs were cultured to the fifth passage to reach the desired number for experimentation. PRP was collected from human blood and activated. Cell Culture Procedure. Effects of PRP on hADSC proliferation and differentiation into fibrochondrogenic cells were examined in four scaffold groups: LD, HD, LD+PRP and HD+PRP. hADSCs were seeded onto scaffolds (n=5) at a concentration of 2 × 106 cells/scaffold. 1% of PRP was added to the experimental media. Cellular proliferation was assessed at 1, 7, 14, and 21 days. Differentiation was measured using qRT-PCR on Days 14 and 21. qRT-PCR analysis of gene expression was completed with primers for COLLAGEN 1 and AGGRECAN. Data Analysis. ANOVAs were conducted (two-tailed tests) at the .05 significance level. Results Cellular proliferation of hADSCs seeded on each scaffold increased over time. Similar trend was observed for cells seeded on HD scaffolds with and without PRP. hADSC showed significant increase in cellular proliferation on the LD scaffolds at Days 1 and 7. At Day 21, PRP treatment and LD scaffold had a synergistic positive effect on Type I collagen gene expression. PRP did not elevate type I collagen gene in the HD group, the HD scaffold alone had the same level of type I collagen gene expression as LD+PRP. Aggrecan expression was elevated in the presence of PRP in both the HD and LD scaffold groups, indicating enhanced fibrochondrogenic differentiation of hADSCs. Effective cell infiltration was observed across both HD and LD scaffolds with and without PRP treatment. HD scaffolds displayed larger cell clusters and more extensive cell migration over time compared to LD scaffolds. However, LD scaffolds resulted a more uniform cellular distribution than HD scaffolds. Conclusion Our study demonstrates that PRP can play an important role in directing hADSCs towards fibrochondrogenic differentiation in Type I collagen-based scaffolds in vitro. Additionally, our study shows that collagen scaffold density can influence the spatial distribution and cellular behavior of infiltrated cells.

Relative contribution of different repair pathways to the radiation-induced DNA damage responses remains a challenging issue of studying the radiation injury endpoints. Comparative manifestation of homologous recombination (HR) after application of different radiation doses greatly determines an overall effectiveness of recovery in dividing cell after irradiation, since HR is an error-free mechanism intended for repair of DNA double strand breaks (DSB) during S/G2 phases of cell cycle. In this article, we present an experimentally observed evidence of dose-dependent shift in relative contribution of HR in human fibroblasts after X-ray exposure at doses 20-1000 mGy, which is also supported by quantitative modeling of DNA DSB repair. Our findings indicate that the radiation dose increase leads to dose-dependent decrease in relative contribution of HR into the entire repair process.

The functions of annexin A1 (ANXA1) that is expressed on membranes and in cytoplasmic granules have been fully described. Nonetheless, the role of this protein in protecting against DNA damage in the nucleus is still emerging and requires further investigation. Here, we investigated the involvement of ANXA1 in DNA damage response in placental cells. Placenta was collected from ANXA1 knockout mice (AnxA1-/-) and pregnant women with gestational diabetes mellitus (GDM). The placental morphology and ANXA1 expression, which are related to the modulation of cellular response markers in the presence of DNA damage, were analyzed. Total area of AnxA1-/- placenta was smaller because of reduced labyrinth zone, enhanced DNA damage, and impaired base excision repair (BER) enzymes, which resulted in the induction of apoptosis in the labyrinthine and junctional layers. The placentas from pregnant women with GDM showed reduced expression of AnxA1 in the villous compartment, increased DNA damage, apoptosis, and reduction of enzymes involved in the BER pathway. Our translational data provide valuable insights into the possible involvement of ANXA1 in the response of placental cells to oxidative DNA damage and represent advancement in investigations on the mechanisms involved in placental biology.