Previous high throughput screening studies indicated trans-eQTLs tend to be tissue specific. In this study, I probed if this feature can be used to identify tissue-specific gene regulatory networks. eQTL data (P<5e-8) for 16,259 genes were identified and their summary association statistics were obtained from the eQTLGene database. Next, eQTLs that display both cis and trans regulatory effects were selected and the association between their corresponding genes were examined using Mendelian randomization. A total of 169 genes that exerted trans-regulatory impacts on 692 genes were identified. 90% of the genes (N=749) aggregated into a gene regulatory network significantly enriched in hemo-immune processes. The robustness of finding was confirmed through simulation. The identified network displayed the scale-free topology. This provided the reason to examine the association of the network’s hub genes with the phenome. The outcome of analyses revealed GSDMB and ORMDL3 impact several disorders of immune origin and ALDH2 overexpression contributes to obesity. This study reports trans-eQTLs can be used to identify tissue-specific gene regulatory networks and describes a workflow to achieve this purpose. The network identified in this study showed scale-free topology indicating the hub genes of a GRN could be targeted to prevent disease outcomes.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

The One Health approach often reaches classrooms through Environmental Education (EE), which aims to guide society's response to current crises (environmental, health, economic, values). However, traditional EE teaching has focused on isolated ecological concepts and standardized solutions, ignoring the multidimensional nature of EE and failing to integrate the interdependence between environmental, animal, and human health. Moreover, teacher training often neglects didactic content knowledge, preventing students from acquiring the systemic vision needed to address eco-social problems and create sustainable solutions aligned with the Sustainable Development Goals (SDGs). This limits teachers’ ability to influence students' concerns and behaviours. In this context, this study aims to reflect on the current state of the issue and propose strategies informed by Science Education research to improve EE teaching, enabling the integration of One Health dimensions through effective didactics to achieve Transformative Environmental Education (TEE). For this purpose, we begin by addressing the limitations identified in recent systematic reviews, shifting the paradigm towards a symbiosis of EE and Science Education through scientific practices. We then present practical examples showcasing successful EE initiatives that foster a deeper understanding of socio-environmental issues, encourage innovative solutions, and nurture engaged citizens from early education onwards. These proposals can support classroom practice and ongoing teacher self-development. Pedagogical strategies include tackling issues that require systemic and critical thinking by developing scientific and epistemic practices while raising awareness of environmental justice. Thus, this study advocates for a new vision of EE, integrating the One Health approach, which could be applied to develop new educational programs, including teacher training. This would lead to a new learning evaluation model and help identify key determinants that trigger pro-environmental behaviours.

The dysregulation of cellular metabolism is a hallmark of ageing. To understand the metabolic changes that occur as a consequence of the ageing process and to find biomarkers for age-related diseases, we conducted a metabolomic analysis of brain, heart, kidney, liver, lung and spleen in young (9-10 weeks) and old (96-104 weeks) wild type (mixed genetic background of 129/J and C57BL/6) mice using NMR spectroscopy. We found differences in metabolic fingerprints of all tissues and identified several metabolites to be altered in most tissues, suggesting that they may be universal biomarkers of ageing. In addition, we found distinct tissue-clustered sets of metabolites throughout the organism. The associated metabolic changes may reveal novel therapeutic targets for the treatment of ageing and age-related diseases. Moreover, the identified metabolite biomarkers could provide a sensitive molecular read-out to age determine the age of biologic tissues and to validate the effectiveness and potential off-target effects of senolytic drug candidates on both a systemic and tissue-specific level.

Mesenchymal stem cells (MSCs) hold immense therapeutic potential due to their regenerative and immunomodulatory properties. However, to utilize this potential, it is crucial to optimize their in vitro cultivation conditions. Three-dimensional (3D) culture methods using cell-laden hydrogels aim to mimic the physiological microenvironment in vitro, thus preserving MSC biological functionalities. Cellulosic hydrogels are particularly promising due to their biocompatibility, sustainability, and tunability in terms of chemical, morphological, and mechanical properties. This study investigated the impact of (1) two physical crosslinking scenarios for hydrogels derived from anionic cellulose nanofibers (CNF) used to encapsulate adipose-derived MSCs (adMSCs) and (2) physiological culture conditions on the in vitro proliferation, differentiation, and extracellular vesicle (EV) production of these adMSCs. Our results revealed that additional Ca2+-mediated crosslinking, intended to complement self-assembly and gelation of aqueous to-CNF in the adMSC cultivation medium, adversely affected both the mechanical properties of the hydrogel spheres and the growth of the encapsulated cells. However, cultivation under dynamic and hypoxic conditions significantly improved the proliferation and differentiation of the encapsulated adMSCs. Furthermore, we demonstrated that adMSCs in CNF hydrogel spheres exhibited potential for scalable EV production with potent immunosuppressive capacities in a bioreactor system. These findings underscore the importance of physiological culture conditions and the suitability of cellulosic materials for enhancing the therapeutic potential of MSCs. Overall, our study provides valuable insights for optimizing the in vitro cultivation of MSCs for various applications, including tissue engineering, drug testing, and EV-based therapies.

Uterine tube extracellular matrix is a key component that regulates tubal tissue physiology, and it has a region-specific structural distribution, which are directly associated to their functions. Considering this, application of biological matrices in culture systems is an interesting strategy to develop biomimetic tubal microenvironments and enhance their complexity. However, there are no established protocols to produce tubal biological matrices that consider the organ morphophysiology for such applications. Therefore, this study aimed to establish region-specific protocols to obtain decellularized scaffolds derived from porcine infundibulum, ampulla, and isthmus to provide suitable sources of biomaterials for tissue-engineering approaches. Porcine uterine tubes were decellularized in solutions of 0.1% SDS and 0.5% Triton X-100. Decellularization efficiency was evaluated by DAPI staining and DNA quantification. We analyzed ECM composition and structure by optical and scanning electronic microscopy, FTIR and Raman spectroscopy. DNA and DAPI assays validated the decellularization, presenting significative reduction of cellular content. Structural and spectroscopy analyses revealed that produced scaffolds remained well structured and with ECM composition preserved. YS and HEK293 cells were used to attest cytocompatibility, allowing cell survival and successful interaction with the scaffolds. These results suggest that such matrices are applicable for future biotechnological approaches in the reproductive field.

In most Eukaryotes, ubiquitin either exists as free monoubiquitin or as a molecule that is covalently linked to other proteins. These two forms cycle between each other and due to the concerted antagonistic activity of ubiquitylating and deubiquitylating enzymes, an intracellular ubiquitin equilibrium is maintained that is essential for normal biological function. However, measuring the level and ratio of these forms of ubiquitin has been difficult and time consuming. In this paper, we have adapted a simple immunoblotting technique to monitor ubiquitin content and equilibrium dynamics in different developmental stages and tissues of Drosophila. Our data show that the level of total ubiquitin is distinct in different developmental stages, lowest at the larval-pupal transition and in three days old adult males, and highest in first instar larvae. Interestingly, the ratio of free mono-ubiquitin remains within 30-50% range of the total throughout larval development, but peaks to 70-80% at the larval-pupal and the pupal-adult transitions. It stays within the 70-80% range in adults. In developmentally and physiologically active tissues, the ratio of free ubiquitin is similarly high, most likely reflecting a high demand for ubiquitin availability. We also used this method to demonstrate the disruption of the finely tuned ubiquitin equilibrium by the abolition of proteasome function or the housekeeping deubiquitylase, Usp5. Our data support the notion that the ubiquitin equilibrium is regulated by tissue- and developmental stage-specific mechanisms.

Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly expanding giving a reason for optimism for several healthcare practitioners regarding management of multiple diseases, including socially significant ones. However, mechanisms underlying the biological effects of H2 are still being actively argued. In this review, we focus on mast cells as a potential target for H2 at the level of a specific tissue microenvironment. H2 regulates processing of pro-inflammatory components of the mast cell secretome and their entry into the extracellular matrix; this can significantly affect the state of the integrated-buffer metabolic environment and the structure of the immune landscape of the local tissue microenvironment. The analysis performed highlights several potential mechanisms for developing the biological effects of H2 and offers great opportunities for translating the obtained findings into clinical practice.

Immunohistochemistry is a widely used technique for research and diagnostic purposes that relies on the recognition by antibodies of antigens expressed in tissues. However, tissue processing and particularly formalin fixation affect the conformation of these antigens through the formation of methylene bridges. Although antigen retrieval techniques can partially restore antigen immunoreactivity, it is difficult to identify antibodies that can recognize their target especially in formalin-fixed paraffin-embedded tissues. Most of the antibodies currently used in immunohistochemistry have been obtained by animal immunization; however, in vitro display techniques represent alternative strategies that have not been fully explored yet. This review provides an overview of phage display-based antibody selections using naïve antibody libraries on various supports (fixed cells, dissociated tissues, tissue fragments, and tissue sections) that have led to the identification of antibodies suitable for immunohistochemistry.

Dysregulation of cartilage homeostasis and the changes in the density and the architecture of the subchondral bone were postulated as a potent mechanically pathological activity contributing to osteoarthritis (OA) pathogenesis. Extracorporeal shockwave therapy (ESWT) is a new, none invasive and effective method in the treatment of animal OA model. In the current study, we demonstrated that shockwave induced the expression of protein-disulfide isomerase-associated 3 (Pdia-3) which is a multifunctional protein hypothesized to be a significant mediator for 1α,25-Dihydroxyvitamin D3 (1α,25(OH)₂D₃) signaling pathway using two-dimensional electrophoresis. Histological analysis and quantitative polymerase chain reaction (qPCR) were verified and observed that the expression of Pdia-3 at 2 weeks was significantly higher than that of any other group at 4 weeks, 8 weeks, and 12 weeks post-shockwave treatment in early OA knee of rat. The other factors of the 1α,25(OH)₂D₃ rapid membrane signaling pathway including extracellular signal-regulated protein kinases 1 (ERK1), osteopontin (OPG), alkaline phosphatase (ALP), and matrix metallopeptidase 13 (MMP13) were measured and significantly increased by qPCR at 2 weeks post-shockwave treatment in early OA knee. Our proteomic data revealed significant Pdia-3 expression in microenvironments of joint tissue that could be actively responded to ESWT, which may potentially regulate biological function of chondrocytes and osteoblasts in the treatment of OA knee.

Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM), having an essential role in the regulation of hematopoietic stem cell (HSCs) differentiation and proliferation. Myelodysplastic syndromes (MDS) are a group of myeloid disorders impacting hematopoietic stem and progenitor cells (HSCPs) and characterised by BM failure, ineffective haematopoiesis, cytopenia, a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as cell cycle arrest and pro-tumorigenic roles including induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, immunomodulation function, and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators secreted by MSCs abnormally, including increased expressions of inflammatory factors and decreased expressions of hematopoietic factors, contributing to the development and progression of MDS. Therefore, MSCs can be targeted for the treatment of MDS and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.

Coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2) has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis. We used Acss2 knockout mice (Acss2-/-) to further investigate the roles this enzyme plays in three physiologically distinct organ systems that make extensive use of lipid synthesis and storage including the liver, brain and adipose tissue. We examined the resulting transcriptomic changes resulting from Acss2 deletion and assessed these changes in relation to fatty acid constitution. We find that loss of Acss2 leads to dysregulation of numerous canonical signaling pathways, upstream transcriptional regulatory molecules, cellular processes, and biological functions, which were distinct in the liver, brain and mesenteric adipose tissues. The detected organ-specific transcriptional regulatory patterns reflect the complementary functional roles of these organ systems within the context of systemic physiology. While alterations in transcriptional states were evident, the loss of Acss2 resulted in few changes in fatty acid constitution in all three organ systems. Overall, we demonstrate Acss2 loss institutes organ-specific transcriptional regulatory patterns reflecting the complementary functional roles of these organ systems. Collectively, these findings provide further confirmation that Acss2 regulates key transcription factors and pathways under well-fed, non-stressed conditions, and acts as a transcriptional regulatory enzyme.

Diabetes mellitus is one of the most common endocrinopathies, estimated to affect about 5.4% of the world's population around 2025. It is thought that nearly a third of diabetic patients have some type of skin condition. Frequently, the cutaneous effects of this heterogeneous syndrome are ac-curately detected late in the progressive form of the disease. The main objective of the present study was to identify the main cellular characteristics of the cutaneous microenvironment in exper- imentally induced diabetes mellitus. Skin fragments were harvested from adult white Wistar rats of both sexes, with the weight of 200 g, 12 weeks after streptozotocin diabetes was induced. In parallel with histopathological diagnosis by using hematoxylin and eosine staining, samples were processed by transmission electron microscopy technique and examined with a Philips CM100 microscope. In the apparently macroscopically unchanged tegument, photon microscopy revealed both progres ive thinning of the epidermis in the early stages of diabetes and a significant process of fibrosis and collagen hyalinization in the dermis. In addition, in the early stages, the electron microscopic study provided ultrastructural details characteristic of a senescent phenotype with reduced cell proliferation. The morphological changes in the skin may be the first signs of disruption of carbohydrate metabolism and in the case of established diabetes may reflect its progression and the efficacy of therapy.

The barley (Hordeum vulgare) genome comprises over 32,000 genes, with differentiated cells expressing only a subset of genes; the remainder being silent. Mechanisms by which tissue-specific genes are regulated are not entirely understood, although DNA methylation is likely to be involved. DNA methylation patterns are not static during plant development, but it is still unclear whether different organs possess distinct methylation profiles. Methylation-sensitive GBS was used to generate DNA methylation profiles for roots, leaf-blades and leaf-sheaths from five barley varieties, using seedlings at the three-leaf stage. Differentially Methylated Markers (DMMs) were characterised by pairwise comparisons of roots, leaf-blades and leaf-sheaths of three different ages. While very many DMMs were found between roots and leaf parts, only a few existed between leaf-blades and leaf-sheaths, with differences decreasing with leaf rank. Organ-specific DMMs appeared to target mainly repeat regions, implying that organ differentiation partially relies on the spreading of DNA methylation from repeats to promoters of adjacent genes. Furthermore, the biological functions of differentially methylated genes in the different organs correlated with functional specialisation. Our results indicate that different organs do possess diagnostic methylation profiles and suggest that DNA methylation is important for both tissue development and differentiation and organ function.

Yerba maté, an herbal tea derived from Ilex paraguariensis, has previously been reported to be protective against obesity-related and other cardiometabolic disorders. Using high-resolution respirometry and reverse-phase high-performance liquid chromatography, the effects of four weeks of yerba maté consumption on mitochondrial efficiency and cellular redox status in skeletal muscle, adipose, and liver, tissues highly relevant to whole body metabolism, were explored in healthy adult mice. Yerba maté treatment increased mitochondrial oxygen consumption in adipose, but not in other tissues examined. Yerba maté increased ATP concentration in skeletal muscle and decreased ATP concentration in adipose. Combined with observed changes in oxygen consumption, these data yielded a significantly higher ATP:O2, a measure of mitochondrial efficiency, in muscle and a significantly lower ATP:O2 in adipose, which were consistent with yerba maté-induced weight loss. Yerba maté treatment also altered the hepatic glutathione (GSH)/glutathione disulfide (GSSG) redox potential to a more reduced redox state, suggesting potential protective effects against oxidative stress and preservation of cellular function. Together, these data indicate beneficial, tissue-specific effects of yerba maté supplementation on mitochondrial bioenergetics and redox states in healthy mice that are protective against obesity.

Small RNAs are essential for the coordination of many cellular processes, including the regulation of gene expression patterns, the prevention of genomic instability, and the suppression of mutagenic transposon activity. These processes determine aging, longevity, and sensitivity of cells and an organism to stress factors (particularly, ionizing radiation). The biogenesis and activity of small RNAs are provided by proteins of the Argonaute family. These proteins participate in the processing of small RNA precursors and the formation of an RNA-induced silencing complex. However, the role of Argonaute proteins in the regulation of lifespan and radioresistance remains poorly explored. We studied the effect of knockdown of Argonaute genes (AGO1, AGO2, AGO3, piwi) in various tissues on the Drosophila melanogaster lifespan and survival after the γ-irradiation at a dose of 700 Gy. In most cases, these parameters were reduced or did not change significantly in flies with tissue-specific RNA interference. Surprisingly, piwi knockdown in both the fat body and the nervous system caused a lifespan increase. But changes in radioresistance depended on the tissue in which the gene was knocked out. In addition, analysis of changes in retrotransposon levels and expression of stress response genes allowed us to determine associated molecular mechanisms.

For Lentinula edodes, its characteristic flavor is the key determinant for consumer pref-erences. However, the tissue-specific volatile flavor variations of the fruiting body have been overlooked. Here, we comprehensively investigated volatile flavor profiles of different tissues including the pileus skin, context, gill and stipe of the fruiting body of two widely cultivated L. edodes strains (T2 and 0912). We show that the eight-carbon and sulfur com-pounds, which represented 43.2-78.0% and 1.4-42.9% to the total volatile emissions for strain 0912 and T2, dominated their volatiles profiles. The sulfur compounds could rep-resent 32.2% and 42.9% to the total volatile emissions for the context of the strain 0912 and T2, respectively, whereas only represented 1.4% for the stipes of the strain 0912 and 9.0% for the skin of strain T2. Proportions of the predominant C8 compounds (1-Octen-3-one, 1-Octen-3-ol and 3-Octanone) and sulfur compounds (Lenthionine, 1,2,4-Trithiolane, Di-methyl disulfide and Dimethyl trisurfide) changed depending on tissues and strains. We further reveal that the overall volatile flavor profiles varied greatly in different tissues and strains. With machine learning algorithm, we show that volatile profiles could 100% pre-dict strains 0912 and T2. The prediction accuracy for different tissues could also reach 100%. Our results highlight the tissue-specific volatile flavor variations of the L. edodes fruiting body.

mTORC1 regulates mammalian cell metabolism and growth, in response to diverse environmental stimuli. Nutrient signals control the localization of mTORC1 onto lysosome-surface scaffolds that are critically implicated in its amino acid-dependent activation. Arginine, Leucine and S-Adenosyl-Methionine (SAM) can serve as major mTORC1-signaling activators, with SAM binding to SAMTOR (SAM + TOR), a fundamental SAM sensor, abolishing protein’s (SAMTOR’s) inhibitory action(s) against mTORC1, thereby releasing its (mTORC1) kinase activity. Given the lack of knowledge regarding the role of SAMTOR in invertebrates, we have, in silico, identified the Drosophila SAMTOR homologue (dSAMTOR) and have, herein, genetically targeted it, through utilization of the GAL4/UAS transgenic tool. Survival profiles and negative geotaxis patterns were examined both in control and dSAMTOR-downregulated adult flies, during aging. One of the two gene-targeted schemes resulted in lethal phenotypes, whereas the other one caused rather moderate pathologies in most tissues. Screening of head-specific kinase activities, via PamGene technology application, unveiled the significant upregulation of several kinases, including the dTORC1 characteristic substrate, dp70S6K, in dSAMTOR-downregulated flies, thus strongly supporting the inhibitory dSAMTOR function(s) upon dTORC1/dp70S6K signaling axis in Drosophila-brain settings. Importantly, genetic targeting of the Drosophila BHMT -bioinformatics- counterpart (dBHMT), an enzyme that catabolizes Betaine to produce Methionine (the SAM precursor), led to severe compromises in fly longevities, with glia-, motor neuron- and muscle-specific dBHMT downregulations exhibiting the strongest effects. Abnormalities in wing-vein architectures were also detected in dBHMT-targeted flies, thereby justifying their notably reduced negative geotaxis capacities, herein, observed, mainly in the brain-(mid)gut axis. In vivo adult-fly exposure to clinically relevant doses of Methionine revealed the mechanistic synergism of decreased dSAMTOR and increased Methionine levels in pathogenic longevity, thus rendering (d)SAMTOR an important component in Methionine-associated disorders, including Homocystinuria(s).

Introduction This study was conducted to validate the findings of a prior study published in JDD in September 2023, which reported that a topical firming and toning body lotion (FTB – SkinMedica®, Allergan Aesthetics, an AbbVie Company, Irvine, CA) upregulated several genes in a UV irradiated 3D full-thickness human skin model, outperforming other products, including TransFORM Body Treatment with TriHex Technology® (ATF – Alastin Skincare®, a Galderma company Fort Worth, Texas, USA ). Given the unique response reported for FTB, we conducted this study to assess the reproducibility of these results and explore gene expression at multiple time points, along with validating protein expression in an ex vivo model. Materials and Methods Experiments were conducted using an ex vivo model with photodamaged skin from facelift patients, under an Institutional Review Board approved study. Skin samples were processed, cultured in transwells with Skin Media, and treated daily with either TransFORM or FTB for 7 days. A control group was left untreated. Gene expression was assessed using RT-PCR on days 1 and 3, immunofluorescence after 3 and 7 days of treatment. Skin samples were fixed, paraffin-embedded, sectioned, and stained with an anti-tropoelastin antibody. Fluorescence detection and imaging were conducted to assess protein expression changes. Results Gene expression data from our study and the initial study showed a few similarities but multiple discrepancies. In particular, as opposed to results previously reported at only the 24-hour time point, additional time points showed complete reversal of many of these results. For example, COL1A1 expression at 24 hours was similar for FTB in both studies but differed for TransFORM which showed higher levels at 24 hours. However, at day 3, COL1A1 expression decreased markedly for FTB and was sustained for TransFORM. Other genes, such as COL3A1, COL5, ELN, VEGFC, ATG7, ATG12, BECN1, POMP, PSMB5, and PSMB6, exhibited varying expression patterns between the studies and across different time points. From a translational perspective, histological analysis showed that TransFORM enhanced elastin fiber presence in the dermal-epidermal junction (DEJ) more effectively than FTB at both day 3 and day 7. FTB-treated samples maintained a gap in the DEJ, while TransFORM-treated samples exhibited increased cellular proliferation and DEJ undulation, indicative of a healthier regenerative response. Conclusion This study highlights the problems of examining data and drawing conclusions using a single point of examination. In addition, when a study reports positive results for only 1 product among a range of 8 competitive products, further questioning is essential to exclude the possibility of the experimental model favoring that particular product. The additional 3-day timepoint and further translational examination of histological changes, paints a completely different picture to that reported in the prior publication TransFORM outperformed FTB in most gene expression and histological parameters when assessed over multiple time points in a physiologically relevant ex vivo model.

Although researchers have proposed various indentation size effect (ISE) models, these models often involve different form and number of parameters that can make our wonder which is the best in existed ISE models. Three types of ISE test data, namely, normal ISE, reverse ISE and transition of normal to reverse ISE, are used to evaluate the sixteen ISE models. The comparatively study indicates that H-J, N-G-Fs, N-G-H, N-G-A and N-G-Qs models can accurately predict the normal ISE. The reason for this is that the friction stress that is not related to dislocation activities or the indentation size effect of plastic zone has been introduced into these models. Therefore, these two factors should be considered in future ISE models. The sixteen ISE models are originally proposed to describe the normal ISE of different materials. However, to our surprise, some of these models are able to capture the reverse ISE and the transition of normal to reverse ISE of different materials. The determination coefficients (DC) of the sixteen ISE models are also determined for different materials. For reverse ISE, the highest DC value for NiCSi, TC4 and PED Ni are given by the EXP, N-G-Fs and N-G-A models, respectively. For the transition of normal to reverse ISE, the N-G-YC, N-G-Fs, and N-G-H models produce the maximum DC for ZrO2, Cu and Y2O3-ZrO2, respectively. Moreover, the mean DC of the N-G-Fs model is the maximum among the sixteen ISE models, followed by the N-G-H model, but they cannot accurately predict the reverse ISE. Therefore, the N-G-Fs and N-G-H models should be further modified to accurately predict the reverse ISE.

: Carcinoma-associated fibroblasts (CAFs) are highly accumulated in the tumor surrounding stroma of primary epithelial ovarian cancer (OC). CAFs exert important functions for the vascularization, growth and progression of ovarian tumor cells. However, no attention has been shown to their origin so far. It has been mainly assumed that CAFs in primary OC arise from the activation of resident fibroblasts. Here, we compare CAFs with ovarian location to CAFs found in peritoneal implants from patients with advanced OC. Our findings show that CAFs from primary tumors and peritoneal metastases share the expression of mesothelial-related markers. Therefore, as in peritoneal carcinomatosis, CAFs in primary ovarian carcinomas could be originated via a mesothelia-to-mesenchymal transition (MMT) process. The detection of mesothelial-derived CAFs in tumors confined to the ovary and associated biomarkers could be the key to early detection of peritoneal spread in affected patients.

PARP inhibitors are used in tumor therapy exploiting their inhibitory role in DNA repair. Radiation therapy leads to DNA damage in the affected region comprising both tumor tissue and adjacent normal tissue. In addition, radiotherapy has long-standing effects on DNA integrity. The mechanisms for this are not well understood. We studied normal tissue damage of the lung after application of ionizing radiation (IR) in two well established rat models comprising both external (eIR) and internal (iIR) ionizing radiation. We found a nearly complete (~350-fold) loss of PARP-1 in the irradiated tissue in both models but no change in PARylated protein. This may be explained by the strong decrease in both ARH3 and PARG, both deparylating enzymes. We demonstrate, that of all these proteins are expressed in type II pneumocytes, but also in type I pneumocytes and the bronchiolar epithelium. The data suggest a severe disturbance of PARylation in these cells which may affect their major functions such as maintenance of the integrity of the alveolar wall. It is likely that the application of PARP inhibitors could have cumulative effects in radiation-damaged normal tissue.

In ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural differences in complex proteomes. PLF applied to published young and aged intervertebral disc (IVD) MS datasets (posterior, lateral and anterior regions of the annulus fibrosus), identified 268 proteins with age-related structural differences. For several ECM assemblies (collagens I, II and V and aggrecan), these differences were markedly conserved between degeneration-prone (posterior and lateral) and resistant (anterior) regions. Significant differences in peptide yields, observed within collagen I, II and V α-chains (COL1A2, COL2A1, COL5A1), were located within their triple helical regions and/or cleaved C-terminal propeptides, indicating potential accumulation of damage and impaired maintenance in ageing. Several proteins (COL5A1, COL2A1 and aggrecan) also exhibited tissue region (lateral)-specific differences in structure between aged and young, suggesting that some ageing mechanisms may act locally within tissues. This study not only provides evidence of age-related changes in ECM protein structures which are tissue-region specific, but also highlights the ability of PLF to identify potential protein biomarkers of localised tissue remodelling.

Methylmercury (MeHg) intoxication is a global health concern. Although MeHg neurotoxicity is well-recognized, less is known about MeHg's effects on metabolism. In this study, we evaluated MeHg intoxication (20mg/L in drinking water for 20 days) effects on liver and epididymal white fat (EWF) in young ApoE knockout (ko) and wild-type mice. The former is well-known to show spontaneous dyslipidemia. Hg levels in hair, liver, and EWF were measured to assess the degree of MeHg exposure. We also evaluated body weight gain, plasma triglycerides, total cholesterol levels, and liver injury by assessing steatosis score, AST, ALT, SOD, and TBAR levels. To evaluate EWF, we analyzed mean wet weight and adipocyte diameter, plasma leptin levels and metabolomics. Hg levels were markedly higher among intoxicated mice. ApoE ko mice showed higher Hg in the hair but lower levels in the liver and EWF than wild-type controls. Among wild-type mice, MeHg compromised weight gain and increased liver TBAR levels compared to non-challenged controls. Among non-intoxicated mice, ApoE deficiency significantly increased triglyceride, total cholesterol, and liver transaminases with reduced EWF wet weight, hepatic SOD, and plasma leptin levels. MeHg accumulation together with ApoE deficiency elevated total cholesterol, triglycerides, hepatic transaminases, and TBARS. We found distinct EWF metabolite activity in different scenarios of ApoE deficiency and MeHg intoxication, highlighting increased cardiovascular risk especially when both challenges occur. Further studies are required to elucidate the underlying mechanisms involved in these effects and the target nutritional interventions in most need to ameliorate them.

Nanoencapsulation has emerged as a recent improvement in the delivery of drugs, offering and improving stability and bioavailability, and allowing for the controlled and targeted delivery of substances to specific cells or tissues. However, traditional nanoparticle delivery faces challenges such as short circulation time and immune recognition. To address these issues, cell membrane-coated nanoparticles have been proposed as a promising alternative. The production of cell membrane-coated nanoparticles involves three key stages: cell lysis and membrane fragmentation, membrane isolation, and nanoparticle coating. Typically, cell membranes are fragmented using hypotonic lysis in combination with homogenization or sonication. Subsequent membrane fragments are isolated through multiple centrifugation steps. The coating of nanoparticles can be achieved through extrusion, sonication, or a combination of both methods. This analysis shows the absence of a universally applicable method for nanoparticle coating, as the three stages exhibit notable differences in their procedures. Here we review ongoing developments and approaches to cell membrane-coated nanoparticles that position this technology as a promising alternative for effective targeted drug delivery and many other therapeutic applications.

Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here we studied the effect of 12 weeks drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males with slightly higher adipocyte area values in both males and females under clozapine medication. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine medication. IR-ß expression changed sex-specifically in the clozapine medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-medicated females. Taken together, clozapine and haloperidol have a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined and probably in their effect on liver metabolism.

Foliage-feeding fall armyworm (Spodoptera frugiperda) and root-feeding western corn rootworm (Diabrotica virgifera virgifera) are maize (Zea mays L.) pests that cause significant yield losses. Jasmonic acid (JA) play pivotal defense role against insects. 12-oxo-phytodienoic acid (12-OPDA) is converted into JA by peroxisome-localized OPDA reductases (OPR). However, little is known about the physiological functions of cytoplasmic OPRs. Here, we show that disruption of ZmOPR2 reduced wound-induced JA production and defense against FAW while accumulating more JA catabolites. Overexpression of ZmOPR2 in Arabidopsis enhanced JA production and defense against beet armyworm (Spodoptera exigua). In addition, lox10opr2 double mutants were more susceptible than either single mutant, suggesting that ZmOPR2 and ZmLOX10 uniquely and additively contributed to defense. In contrast to the defensive role of ZmOPR2 and ZmLOX10 in leaves, single mutants did not display any alteration in root herbivory defense against WCR. Feeding on lox10opr2 double mutants resulted in increased WCR mortality associated with greater herbivory-induced production of insecticidal death acids and ketols. Thus, ZmOPR2 and ZmLOX10 cooperatively inhibit synthesis of these metabolites during herbivory by WCR. We conclude that ZmOPR2 and ZmLOX10 regulate JA-mediated resistance in leaves against FAW while suppressing insecticidal oxylipin synthesis in roots during WCR infestation.

Compared to the general population, patients with inflammatory bowel disease (IBD) are less likely to be vaccinated, putting them at an increased risk of vaccine-preventable illnesses. This risk is further compounded by the immunosuppressive therapies commonly used in IBD management. Therefore, developing new treatments for IBD that maintain immune function is crucial, as successful management can lead to better vaccination outcomes and overall health for these patients. Here, we investigate the potential of recombinant banana lectin (rBanLec) as a supporting therapeutic measure to improve IBD control and possibly increase vaccination rates among IBD patients. By examining the therapeutic efficacy of rBanLec in a murine model of experimental colitis, we aim to lay the foundation for its application in improving vaccination outcomes. After inducing experimental colitis in C57BL/6 and BALB/c mice with 2,4,6-trinitrobenzene sulfonic acid, we treated animals orally with varying doses of rBanLec 0.1-10 µg/ml (0.01 – 1 µg/dose) during the course of the disease. We assessed the severity of colitis and rBanLec’s modulation of the immune response compared to control groups. rBanLec administration resulted in a dose-dependent reduction in colitis severity (less pronounced weight loss, less shortening of the colon) and an improved recovery profile, highlighting its therapeutic potential. Notably, rBanLec-treated mice exhibited significant modulation of the immune response, favoring anti-inflammatory pathways (primarily reduction in a local [TNFα]/[IL-10]) crucial for effective vaccination. Our findings suggest that rBanLec could mitigate the adverse effects of immunosuppressive therapy on vaccine responsiveness in IBD patients. By improving the underlying immune response, rBanLec may increase the efficacy of vaccinations, offering a dual benefit of disease management and prevention of vaccine-preventable illnesses. Further studies are required to translate these findings into clinical practice.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Tissue-like phantoms are widely used as a model for mimicking the optical properties of live tissue. This paper presents the results of a diffusion reflection method as well as fluorescence lifetime imaging microscopy measurements of fluorescein-conjugated gold nanorods in solution as well as inserted in solid tissue-imitating phantoms. A lack of consistency between the fluorescence lifetime results of the solutions and the phantoms raises a question about the ability of tissue-like phantoms to maintain the optical properties of inserted contrast agents.

Human Papillomavirus (HPV) related cancers account for a large percentage of cancers. The tumor microenvironment (TME) is a complex structure and contributes significantly to tumor development, progression, and invasion. The TME is particularly pronounced in HPV-related cancers and HPV is known to influence the TME. In cancer research, there is an urgent need for new models to deepen our understanding of the pathophysiology of the disease and to facilitate the development of innovative therapies. In this context, 3D cell culture has emerged as a promising method in cancer research, that offers significant potential compared to conventional approaches. 3D modelling can produce results that are more consistent with clinical outcomes without the ethical concerns and problems of animal models. In this review, our aim is to discuss the tumor microenvironment in HPV-related cancers and demonstrate the importance of advancing 3D cell culture models for this purpose.

Prostate cancer is the most occurred malignant disease in the male population in over one-half of the countries and still constitutes the fifth leading cause of death in 2020, worldwide. Metastatic prostate cancer is a lethal malignancy that mostly is terminated within several years through the patient's death. Researchers should focus on the phenomenon which is rigorously appertaining to metastatic cascade and operating as an initiator of metastases to provide the knowledge needed to solve the problem of diagnostics and treatment of advanced prostate cancer patients. The epithelial-mesenchymal transition is one such phenomenon. The current review is based mainly on three papers published in 2021, which describe the most important tissue-specific factors managing epithelial-mesenchymal transition and are discussed with scientific papers published in acknowledged journals. The effect of the current review is the specification of profiles of precise tissue factors predicting the progression of the prostate neoplasm to its metastatic stage in a new edition.

Disease, trauma, and aging account for a significant number of clinical disorders. Regenerative medicine is emerging as a very promising therapeutic option. The design and development of new cell-customized biomaterials able to mimic ECM functionalities represent one of the major strategy to control the cell fate and stimulate tissue regeneration. Recently, hydrogels have received a considerable interest for their use in the modulation and control of cell fate during regeneration processes. Several synthetic bioresponsive hydrogels are being developed in order to facilitate cell-matrix and cell-cell interactions. In this review new strategies and future perspectives of such synthetic cell microenvironment will be highlighted.

The global incidence of cutaneous squamous cell carcinoma (cSCC), a prevalent and aggressive skin cancer, has risen significantly, posing a substantial public health challenge. This study investigates the tumor microenvironment (TME) of cSCC by focusing on the spatial distribution patterns of immune and vascular markers (CD31, CD20, CD4, and CD8) using fractal dimension (FD) analysis. Our analysis encompassed 141 cases, including 100 invasive cSCC and 41 specimens with pre-invasive lesions exclusively, and the rest being peripheral pre-invasive lesions from the invasive cSCC class. The FD values for each marker were computed and compared between pre-invasive and invasive lesion classes. The results revealed significant differences in FD values between the two classes for CD20 and CD31 markers, suggesting distinct alterations in B cell distribution and angiogenic activity during cSCC progression. However, CD4 and CD8 markers did not exhibit significant changes individually. Still, the CD4/CD8 ratio showed a significant difference, indicating a potential shift in the immune landscape as lesions progress from pre-invasive to invasive stages. These findings underscore the complexity and heterogeneity of the TME in cSCC and highlight the potential of FD analysis as a quantitative tool for characterizing tumor progression. Further research is needed to elucidate the implications of these differences in the clinical management of cSCC.

The breast holds significant importance in women's lactation process. The breast has diverse tissues such as glandular, Cooper’s ligament, lactiferous ducts, adipose, muscles, and skin with various mechanical properties. Most soft tissues exhibit nonlinear, viscoelastic, and anisotropic mechanical behaviour. Stiffness is one of the commonly used mechanical properties for measuring mechanical behaviour in soft tissues. However, this is typically used in simplifying cases where analysis is limited to within the linear elastic region. Young’s modulus is the prevailing measure for quantifying stiffness in tissues. This systematic review examines commonly used techniques for mechanically characterising breast soft tissues to close the gap in the literature. Additionally, this systematic review summarises the mechanical behaviour of the breast tissues available in the literature and highlights the uncovered areas to understand the mechanical behaviour of breast tissues fully. These include a) more mechanical behaviour studies, allowing more accurate modelling for other applications, b) Viscoelastic analysis studies, and c) mechanical analysis on other breast tissues, such as the lactiferous duct, also known as the milk duct. The data obtained in the review can be used as inputs in computational models to analyse the behaviour of the breast tissues.

Spider silks, renowned for their exceptional mechanical and biocompatible properties, offer significant potential as scaffolds in tissue engineering. This paper explores the feasibility of using spidroins, the primary proteins in spider silk, to develop scaffolds that closely mimic the extracellular matrix (ECM) essential for tissue regeneration. Spidroins (spider silk proteins) are particularly valuable due to their unique strength, elasticity, and biocompatibility, which support cellular growth and differentiation. The paper examines current methods for producing recombinant spider silk, including using unicellular hosts like E. coli and multicellular systems like transgenic plants and silkworms. It also examines current scaffolds that utilize spidroins and their shortcomings, such as immunogenicity and protein production, which must be urgently addressed for more practical and effective widespread biomedical applications. In addition, it stresses the need for further research to solve these challenges and fully realize the potential of spider silk in biomedical applications.

The aim of the study was the comparison of conventional sintering versus additive manufacturing techniques for β-TCP bioceramics, focusing on mechanical properties and biocompatibility. A "critical" bone defect requires surgical intervention beyond simple stabilization. Autologous bone grafting is the gold standard treatment for such defects but it has its limitations. Alloplastic bone grafting using synthetic materials is becoming increasingly popular. The use of bone graft substitutes has increased significantly and current research was focused on optimizing these substitutes, whereas this study compares two existing manufacturing techniques and the thereby produced β-TCP implants. The 3D-printed β-TCP hybrid structure implant was fabricated using two components, a column structure and a freeze-foam, which were sintered together. The conventionally manufactured ceramics were made by pouring. Both scaffolds were characterized according to porosity, mechanical properties and biocompatibility. The hybrid structure had a total porosity of 74.4 ± 0.5%. Microporous β-TCP implants had a porosity of 43.5 ± 2.4%, while macroporous β-TCP implants had a porosity of 61.81%. Mechanical testing revealed that the hybrid structure had a compressive strength of 10.4 ± 6 MPa, significantly lower than the microporous β-TCP implant’s with 32.9 ± 8.7 MPa. Biocompatibility evaluations showed a steady increase in cell proliferation over time for all β-TCP implants, with minimal cytotoxicity. This study provides valuable insight into the potential of additive manufacturing for β-TCP bioceramics in the treatment of bone defects.

The color of carcass fat is an important factor in meat quality. To investigate the characteristics and changes in lipid metabolism of SAT in Mongolian cattle at 34 M of age compared with the control group, we evaluated the color, relative expression of genes associated with browning, and profiles of lipid metabolites by using qPCR and non-targeted lipidomics techniques. Overall, the yellowness value and relative expression of mitochondrial biogenesis–specific markers, thermogenic, UCP2, and beige adipocyte marker genes in the SAT of 34 M cattle were higher than those control (p &lt; 0.05). Using multivariate analysis, 172 significantly different lipids (SDLs) were identified. Triacylglycerols (TGs) and phosphatidylcholines (PCs) had high relative contents with abundant unsaturated fatty acids. The upregulation of TGs observed in the SAT of 34 M cattle mainly consisted of medium- and long-chain fatty acids. Pathway analysis demonstrated that 172 SDLs were primarily involved in glycerophospholipid, glycerolipid, ether lipid, and sphingolipid metabolism. In summary, yellow fat of naturally grazed cattle was impacted by many factors such as lipid metabolism, browning genes expression and age. These findings provide new insight into the characteristics and metabolic pathways of adipose tissue in natural grazing Mongolian cattle.

Similarly to our healthy organs, tumor tissue also generates an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells, alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix, all promoting the epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment, so the successful inhibition of tumorous matrix remodeling could further enhance the success of tumor treatment. Numerous publications describe efforts to inhibit tumor matrix components, but the true breakthrough has yet to be achieved. If, on the other hand, we assume that tumorous blood vessels and inflammatory cells are residents of the tumorous stroma, then two steps forward have occurred.

This study aimed to identify miRNA editing sites during adipose tissue development in Ningxiang pigs and analyze their characteristics and functions. Based on the small RNA-seq data from subcutaneous adipose tissue samples of Ningxiang pigs at four stages (30, 90, 150 and 210 days), we constructed a developmental atlas of the miRNA editome in adipose tissue of Ningxiang pigs. The characteristics and functions of this editome were further explored through bioinformatics analysis. The findings revealed that a total of 505 miRNA editing sites were identified with C-to-U editing types being the most prevalent, followed by U-to-C, A-to-G and G-to-U. Importantly, these four types of miRNA editing exhibited a base preference. The number of editing sites showed obvious differences among age groups, with the highest occurrence of miRNA editing events observed at 90 days of age and the lowest at 150 days of age. In the miRNA seed region, a total of 9 miRNA editing sites were identified with significant differences in editing levels (P &lt; 0.05), and located in ssc-miR-23a, ssc-miR-27a, ssc-miR-30b-5p, ssc-miR-15a, ssc-miR-497, ssc-miR-15b, and ssc-miR-425-5p, respectively. Target gene prediction and enrichment analysis revealed that the editing of miR-497 may potentially regulate fat deposition by inhibiting adipose synthesis via influencing target binding. These results provide new insights into the regulatory mechanism of pig fat deposition.

Poa crymophila is a perennial, cold-tolerant, native grass species, widely distributed to the Qing-hai-Tibet Plateau. However, the molecular mechanism behind the cold stress tolerance and role of key regulatory genes and pathways of P. crymophila are poorly understood yet. Therefore, the present study investigated the physiological and transcriptome responses of P. crymophila’s roots, stems, and leaves under cold stress to explore the molecular mechanism of cold tolerance. Results of the present study suggested that cold stress significantly changed the physiologic characteristics of roots, stems, and leaves of P. crymophila. In addition, the transcriptome results showed that 4434, 8793, and 14942 differentially expressed genes (DEGs) were identified in roots, stems, and leaves, respectively; however, 464 DEGs were commonly identified in these three tissues. The Gene On-tology (GO) results showed that a large numbers of DEGs were significantly enriched in the pho-tosynthetic related categories in leaves. In addition, the “response to stimulus” category was sig-nificantly enriched in roots and stems. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that DEGs involved in “phenylpropanoid biosynthesis” were significantly enriched in roots, “photosynthesis” and “circadian rhythm-plant” pathways significantly enriched in stems and leaves, starch and sucrose metabolism, and galactose metabolism were pathways significantly enriched in three tissues. Weighted gene coexpression network analysis (WGCNA) identified Hub genes involved in P. crymophila cold response. This study provides new insights into the molecular mechanisms underlying the cold tolerance of P. crymophila belowground and aboveground tissues. In addition, specific genes involved in Ca2+ signaling, ROS scavenging system, hormones, circadian clock, photosynthesis, and transcription factors (TFs) were identified in P. crymophila. The identi-fication of key genes may provide valuable resources for further functional genomic and breeding studies.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

During the last few years, the world witnessed one of the worst calamities to humankind- the COVID-19 pandemic. We also witnessed the development of vaccines at an unprecedented pace against the SARS-CoV-2- the causative agent. India was among the hard-hit countries by COVID-19, developed its indigenous vaccine and implemented vaccines developed in other countries as well. Initially, the antibody level and the neutralizing antibody titer against the pathogen were considered as the correlates of immune protection from the disease. However, the long-term protection from the pathogen was provided by the immune memory cells viz. T and B memory cells and their ability to efficiently make recall responses. In this regard, globally the research studies focused mainly on the mRNA-based vaccines. The studies on immune memory response, particularly- the B cell memory response bestowed by the vaccines given to Indians is relatively obscure. We studied the level of RBD specific memory B cells in the peripheral circulation of the study participants and the ability of B cells to secrete antigen-specific antibodies among Indians vaccinated with Covaxin (BBV152), Covishield (AZD1222), Corbevax (BECOV2D) and Sputnik Light (Gam-COVID-Vac) as well as unvaccinated individuals. Our study revealed that Corbevax and Sputnik Light conferred better antibody-secreting cell (ASC) responses.

Corneal diseases are the third leading cause of blindness worldwide. There are numerous causes of corneal blindness, and the common treatment for this condition often involves corneal tissue transplantation, such as Descemet's Membrane Endothelial Keratoplasty (DMEK). DMEK has been established as the preferred surgical technique for the treatment of corneal endothelial disorders. The success of DMEK depends largely on the quality of the donor endothelial cells and the trans-plantation procedure. However, the scarcity of suitable donor tissue and the sensitivity of endo-thelial cells pose a major challenge. In recent years, tissue engineering has attracted attention as potential solutions to these problems. This review offers an outline of the current landscape of DMEK in the context of bioengineering, exploring various methodologies, advancements, and fu-ture prospects.

This study presents an innovative method for producing thermosensitive bio-ink from chitosan hydrogels saturated with carbon dioxide and agarose. It focuses on a detailed characterization of their physicochemical properties and potential applications in biomedicine and tissue engineering. The ORO test approved rapid regeneration of the three-dimensional structure of chitosan-agarose composites in the unidirectional bench press simulation test. The diffusion of dyes through chitosan-agarose hydrogel membranes strongly depended on the share of both polymers in the composite and the molecular weight of the dyes. Glucose, as a nutrient marker, also diffused through all membranes regardless of composition. Biocompatibility assessment using MTT tests on 46BR.1N fibroblasts and HaCaT keratinocytes confirmed the safety of the bioink. The regenerative potential of the bioink was confirmed by efficient cell migration, especially HaCaT. Long-term viability studies showed that chitosan-agarose scaffolds, unlike the agarose ones, support cell proliferation and survival, especially 14 days after bioink extrusion. Experiments in a skin wound model in mice confirmed the biocompatibility of tested dressing and the beneficial action of chitosan on healing. Studies on vessel formation in chicken embryos highlight the potential of the chitosan-agarose composition for enhancing proangiogenic effects. This composition meets all entry criteria and possesses excellent biological properties.

Oilseed plants of the Brassicaceae plant family are cultivated for food, feed and industrial purposes on large-scale in Europe. This review gives an overview of current market-oriented applications of new genomic techniques (NGTs) in relevant Brassicaceae oilseed crops based on a literature survey. In this respect, changes in oil quality, yield, growth and resistance to biotic and abiotic stress are goals in oilseed rape (B. napus) and camelina (C. sativa). Environmental risk assessment scenarios are developed for specific NGT applications in Brassicaceae oilseed crops with either a changed oil composition or with fitness related traits. In case of a changed oil composition an increase or decrease of polyunsaturated fatty acids (PUFA) demonstrates risks for health and survival of pollinators. In case of fitness related traits other risks were identified, i. e. an increased risk of spread and persistence of NGT plants. Furthermore, there are indications for potential disturbance of interactions with the environment, involving signalling pathways and reaction to stress conditions. It is shown that for a comprehensive risk assessment the technological potential of NGTs, the plants’ biology and the scale of releases have to be considered in combination. Therefore, the release of NGT plants into the environment for agricultural purposes will require risk assessment and monitoring of single traits as well as of combinatorial and long-term cumulative effects. In addition, risk management should develop concepts and measures to control and potentially restrict the scale of releases. This is especially relevant for NGT Brassicaceae in Europe which is a centre of diversity of this plant family.

Air pollution, climate change and global warming show direct linkage. Introduction - Background: Research in the field has proposed and demonstrated their link to increased allergenicity in plants, leading to increased allergic diseases. Allergen patterns are changing in response to climate change. Across Europe, up to 12% of the population suffers from allergic diseases (bronchial asthma and allergic rhinitis) caused by the pollen grains. The medical costs of these types of allergies are enormous and are increasing with the spread of common ragweed - Ambrosia artemisiifolia* in Europe. In practice, more and more patients are turning to allergists. Methods: Based on these data, the research aims to identify safety measures and specific legislation to control and eradicate common ragweed in the countries most affected by the spread of this plant in Europe, increase in population exposure in countries affected by the presence of common ragweed and the socio-economic impact of allergic rhinitis and bronchial asthma at European level.[1][2] Our database search did not reveal any other research that has addressed this topic to date. Results: This research identifies specific legislation to the countries most affected by the spread of this plant pollen grains at European level, changes in allergen patterns and monitoring/safety eradication measures decided by local authorities, and data on the spread of common ragweed over the last two decades, costs per treatment, increased allergic rhinitis and bronchial asthma morbidity in the most affected areas. Conclusions: At European level, there are no universally valid models for eradicating this weed. Various methods can be used to limit the spread of common ragweed and its pollen production (e.g. mowing once or twice a year of overgrown land, ploughing, chemical control, public information, etc.). Local and regional cooperation should be considered essential to promote phytosanitary &amp; safety measures and exchange of information on methods to identify and manage the spread of common ragweed. Unified legislation at European level would help all affected countries; reduce morbidity from respiratory allergic diseases and the costs of treating these diseases.

Urinary tract diseases are common in cats, and often require surgical reconstruction. Here, to explore the possibility of urinary tract reconstruction in cats using in-vivo tissue architecture (iBTA), biosheets fabricated using iBTA technology were implanted into the feline bladder and the regeneration process was histologically evaluated. The biosheets were prepared by embedding molds into the dorsal subcutaneous pouches of six cats for 2 months. A section of the bladder wall was removed, and the biosheets were sutured to the excision site. After 1 and 3 months of implantation, the biosheets were harvested and evaluated histologically. Implantable biosheets were formed with a success rate of 67%. There were no major complications following implantation, including tissue rejection, severe inflammation, or infection. Urinary incontinence was also not observed. Histological evaluation revealed the bladder lumen was almost entirely covered by urothelium after 1 month, with myofibroblast infiltration into the biosheets. After 3 months, the urothelium became multilayered, and mature myocytes and nerve fibers were observed at the implantation site. In conclusion, this study showed that tissue reconstruction using iBTA can be applied to cats, and that biosheets have the potential to be useful in both the structural and functional regeneration of the feline urinary tract.

The quest for youthful, healthy skin and full, vibrant hair has long been a driving force in the dermocosmetics field. However, traditional approaches often struggle to address the underlying causes of aging, damage, and hair loss. Regenerative cosmetics, powered by skin tissue engineering, offer a transformative alternative. This review explores the emerging field of using engineered skin tissues for cosmetic purposes, focusing specifically on their potential for anti-aging, repair, and hair restoration applications. We discuss how these technologies aim to rejuvenate aging skin by promoting collagen production, reducing wrinkles, and improving overall skin function. Additionally, the use of engineered skin for wound healing and scar reduction is examined, highlighting their potential to improve the appearance and functionality of damaged skin. Finally, we advance the exciting prospects of utilizing skin tissue engineering techniques to regenerate hair follicles, potentially offering solutions for hair loss and promoting denser hair growth.

Poikilodermatous plaque-like hemangioma (PPH) is a recently described clinical and pathological entity, with only 18 cases reported in the literature. Although uncommon, this benign condition presents consistent clinical and histological findings. We present a new case of PPH in an 81-year-old male and review the existing literature. The persistence over time and the need to distinguish PPH from more significant lesions underscore the importance of its clinical and pathological recognition.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical mem-braneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vascula-ture are shown to have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Overproduction of lipids by the tumor is suspected to be due to a combination of two processes: i) dysfunctional oxidative phosphorylation in mitochondria that causes metabolic backup and ac-cumulation of acetyl-CoA, as well as ii) the overproduction of pyruvate due to the tumor cell reli-ance on overactive glycolysis. Tumor cells use lipids for structural components but cannot use them for energy if their oxidative phosphorylation is dysfunctional, which seems to be the case in the tumor cells we examined. This lipid-rich environment, however, offers tumor cells certain advantages: protection from the immune system, non-lipophilic drugs, and oxidative stress. Our research highlights the significant presence of lipid overproduction in both IDH1-wild type glio-blastoma and IDH1-mutant astrocytoma tumors, leading to diverse lipid accumulations in var-ious cellular compartments and structures. This lipid excess stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune re-sponses, non-lipophilic drugs, and free radicals.

Based on its large surface area and covering the whole human body, the skin body’s largest organ and its main function is protection. Injuries and wound healing involving the skin offer valuable lessons shared with and of relevance to other organ systems and the diseases that impact them. Arguably the most complex human body process, wound healing is a multifaceted process that involves multiple cells and the extracellular matrix (ECM), with each component playing a specific role in the different stages of the healing process. Importantly, studies indicate that cells with stem cell-like properties are present within many of the human tissues and play key roles in case of tissue and cellular injury. Cell-to-cell and cell-to-ECM interactions are salient in wound healing subsequent to an injury. Microenvironment related factors and the variations therein including hypoxia or the abundance of oxygen, the presence/absence of growth factors and cytokines add to the complexity of the wound healing process and impact cell function and result in compromised or enhanced wound healing. This expert review critically examines the advances in biochemical and analytical tools that are enable the analysis of numerous cells and molecules within the wound microenvironment, revealing great cellular heterogeneity as well as novel molecular targets of importance to enhance wound healing. In a broader angle, we emphasize the ways in which wound healing is significant in the search for perfect skin after injury and in many common complex human diseases including cancer. In all, wound healing is a centrepiece of integrative biology research and applications in medicine as well as dermatology as discussed in this review.

Endometriosis occurs when endometrial-like tissue grows outside the uterine cavity, leading to pelvic pain, infertility, and increased risk of ovarian cancer. The present study describes the optimization and characterization of cellular spheroids as building blocks for Kenzan scaffold-free method biofabrication and proof-of-concept models of endometriosis and the endometriotic microenvironment. The spheroid building blocks must be a specific diameter (~500 m), compact, round, and smooth to withstand Kenzan biofabrication. Under optimized spheroid conditions for biofabrication, the endometriotic epithelial-like cell line, 12Z, expressed high levels of estrogen-related genes and secreted high amounts of endometriotic inflammatory factors that were independent of TNF stimulation. Heterotypic spheroids, composed of 12Z and T-HESC, an immortalized endometrial stromal cell line, self-assembled into a biologically relevant pattern, consisting of epithelial cells on the outside of the spheroids and stromal cells in the core. 12Z spheroids were biofabricated into large three-dimensional constructs alone, with HEYA8 spheroids, or as heterotypic spheroids with T-HESC. These three-dimensional biofabricated constructs containing multiple monotypic or heterotypic spheroids represent the first scaffold-free biofabricated in vitro models of endometriosis and the endometriotic microenvironment. These efficient and innovative models will allow us to study the complex interactions of multiple cell types within a biologically relevant microenvironment.

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression in CD4+T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brain, suggesting a weakened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.

The investigation by the integrated approach newly introduced for this study indicates that insulin resistance (IR) would develop first preferentially in the muscle tissue with a relatively low cell turnover and then progress in sequence to the subcutaneous adipose tissue, to the visceral adipose tissue, and to the liver with higher cell turnovers. Moreover, metabolic disruptions due to IR vary widely from tissue to tissue, contrary to the conventional notion that IR merely impairs glucose uptake in the whole body. This warrants that IR be divided better into four distinct tissue specific IRs: muscle insulin resistance (MIR), subcutaneous adipose insulin resistance (s-AIR), visceral adipose insulin resistance (v-AIR), and hepatic insulin resistance (HIR). Tissue-specific IRs developing in the order of MIR, s-AIR, v-AIR, and HIR – producing tissue specific metabolic disruptions – would amount to nothing but the whole body insulin resistance (WBIR) evolving in four distinctively insulin resistant stages. The four stage metabolic evolution from rapid weight gain to visceral obesity to rapid weight loss to full blown diabetes not only complies well with the natural development history of diabetes but also resolves most of the controversies regarding obesity or diabetes, including visceral obesity, obesity paradox, and dawn phenomenon that have long remained metabolic puzzles. In addition, the four-stage WBIR evolution model refutes the entrenched notion of the lipid-induced insulin resistance (LIIR) but supports instead the glycation-induced insulin resistance (GIIR) proposed in this study. A speculation is that the glycation reaction activated ever more with WBIR evolving may serve as the common thread connecting each other a cluster of disorders or diseases that are often collectively referred to as the metabolic syndrome, such as obesity, diabetes, cardio/cerebral vasculopathy, nephropathy, neuropathy, and retinopathy.

Accurate diagnosis for the 400 million people with rare diseases is critical for healthcare decisions, prognosis, understanding disease mechanisms, and identification of treatments. Despite advances in genome sequencing, barriers such as high interpretation costs, diagnostic expertise, throughput associated delays, and uncertain variant classifications persist, with demand exceeding capacity. Many variant classification methods focus narrowly on specific consequences, leading to the use of complex integrative pipelines that often overlook transcript variability and lack prediction transparency. To overcome these limitations, we introduce DITTO. This transparent, transcript-aware machine-learning method demonstrates superior overall performance in accuracy, recall, and precision when compared to existing tools. DITTO is publicly available at https://github.com/uab-cgds-worthey/DITTO

Tissue engineering, also called “regenerative medicine”, refers to attempt to create functional human tissue from cells in laboratory. This is a field that uses living cells, biocompatible materials, suitable biochemical and physical factors and their combinations, to create tissue-like structures.. To date, no tissue engineered skeletal muscle implants have been developed for clinical use, but it may represent a valid alternative to treat volumetric muscle loss in the near future. Herein, we reviewed the literature and showed different techniques to produce synthetic tissues with the same architectural, structural and functional properties of native tissues.

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSA/MAA) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies, may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD (n=558). Our PH cohort (n=121) showed a significantly higher prevalence of overall weak positive MSA/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group (p

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates that reach 60%, mainly due to an excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules reported to be dysregulated in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting the reverse interplay between miRNA-levels and their target-genes’ expression. Incorporating gene expression data from our group’s experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia and early-invasion OSCC, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is underexpressed in dysplasia and early-invasion. Malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p and miR-34a-5p. The identification of stage-specific miRNA molecules may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Nanotechnology is a multidisciplinary science covering matters involving nanoscale level that is being developed for a great variety of applications. Nanomedicine is one of these attractive and challenging uses focused on the employment of nanomaterials in medical applications such as drug delivery. However, the uses of these nanometric systems requires specific parameters to establish the possible advantages and disadvantages in specific applications. This review presents the fundamental factors of nanoparticles and it´s microenvironment that must be considered to make an appropriate design for medical applications: (i) Interactions between nanoparticles and their biological environment, (ii) the interaction mechanisms, (iii) and the physicochemical properties of nanoparticles. On the other hand, the repercussions of the control, alteration and modification of these parameters in the final applications. Additionally, we here briefly report the implications of nanoparticles in nanomedicine and provide perspectives for some particular applications which still are challenged

Bartonella species, intracellular parasitic zoonotic pathogens, has drawn increasing attention for their diverse host range and associated human diseases. This study investigates Bartonella infection in small mammals in Yunnan Province, China, focusing on tissue tropism. 333 small mammals were sampled from 13 species, 3 orders, 4 families, and 4 genera in Heqing and Gongshan Counties. Conventional PCR and real-time quantitative PCR (qPCR) were utilized for detection and quantification, followed by bioinformatic analysis of obtained DNA sequences. Results show a 31.5% detection rate, varying across species. Notably, Apodemus chevrieri, Eothenomys eleusis, Niviventer fulvescens, Rattus tanezumi, Episoriculus leucops, Anourosorex squamipes, and Ochotona Thibetana exhibited infection rates of 44.4%, 27.7%, 100.0%, 6.3%, 60.0%, 23.5%, and 22.2%, respectively. Genetic analysis identified 30, 10, and 5 strains based on ssrA, rpoB, and gltA genes, with nucleotide identities ranging from 92.1% to 100.0%. Bartonella strains were assigned to B. grahamii, B. rochalimae, B. sendai, B. koshimizu, B. phoceensis, B. taylorii, and a new species identified in the Episoriculus leucops (GS136). Tissue distribution analysis revealed varied copy numbers across different tissues, with the highest load in spleen. These findings underscore Bartonella's diverse species and host range in Yunnan Province, highlighting its broad tissue tropism in small mammals.

Solid tumours are characterized by an altered microenvironment (TME) from the physi-cochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hy-poxia results from uncontrolled proliferation, aberrant vascularization and altered can-cer cell metabolism. Tumour cellular apparatus adapt to hypoxia by altering its metab-olism and behaviour, increasing its migratory and metastatic abilities by acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance by selecting for more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are pH and hypoxia sensors and alterations in Ca2+ homeostasis in cancer progression and vascularization have been extensively reported. The present review will focus on Ca2+ permeable ion channels, with a major focus on TRP, SOC and PIEZO channels, that are modulated by tumour hypoxia and acidosis as well as the role of the resulted altered Ca2+ signals on cancer progression hallmarks. A deeper compre-hension of the Ca2+ signaling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutics targets.

The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

The main purpose of the study was to study the effects of a specific rowing ergometer training program on the athletic performance of young adolescents (n=56; 11.73 ± 1.4 years old) com-pared to a workout based on general strength training. Eight-week training program was im-plemented, with four sessions per week and two-hours per session. Sample was divided in two groups: a control group (CG) that performed circuit training with exercises aimed at building general strength and an experimental group (EG) who focused on specifically training on a rowing ergometer (rowing machine). The data obtained in a rowing meter test over the compe-tition distance were analyzed to obtain the average power attained (W) at the beginning of the training, at the middle (4 weeks), at the end of the training (8 weeks) and one year after the ex-perimentation. The results show that, although both forms of training improve the average W obtained in both categories, the EG subjects (+29.94W) obtained better averages in all phases of the study compared to the CG (+5.88W). Furthermore, this increase was greater in male rowers (+ 34.06W) than in female rowers (+24.54W). These results reveal that a specific rower rowing ergometer training program has a significant effect than a general strength program and these effects can even be observed a year after the intervention.

Despite saltmarshes being considered as nature-based solutions (NbS) towards climate change mitigation, India’s saltmarsh ecosystems are least studied. This study quantifies the seasonal variation in carbon stocks mono-specific saltmarsh species (Porteresia coarctata) and its potential to play an important role in India’s climate change mitigation plans. Seasonal (pre-and post-monsoon) sampling of P. coarctata surface water, biomass and 30 cm sediment core was collected across four locations on the east coast of India to quantify sediment dry bulk density (DBD), organic matter (OM%), organic carbon (Corg%), Corg stocks of sediment and biomass, total carbon (C%) and nitrogen (N%) and stable isotopes of δ13C and δ15N. In general, the sediment DBD, OM and Corg of P. coarctata meadows was higher in post-monsoon and was influenced by salinity and pH changes. Isotope (δ¹³C) modelling of various sediment C sources suggested, particulate organic matter (POM) contribution was highest (0.04-0.79%) followed by P. coarctata (0.01–052%) and other macrophytes across our study locations. The seasonal variation of δ¹³C showed increased contribution of marine derived particulate and dissolved organic matter into P. coarctata meadows in post-monsoon season. Heavier δ¹⁵N values were observed in post-monsoon season suggesting anthropogenic input, that was utilized by P. coarctata to increase its above and below-ground biomass and shoot density. The combined ecosystem (30 cm sediment + biomass) Corg stocks of P. coarctata was 1.7-fold higher in post-monsoon (4021.20± 917 Mg C) compared to pre-monsoon (2297.36 ±647 Mg C) season among the four locations with a sediment Corg contribution >70%. Based on the International Panel for Climate Change Tier II assessment the P. coarctata meadows (443 ha) can help in avoiding the pre and post-monsoon emissions of 8431.34 and 14757.84 Mg CO₂ respectively. The combined price of the total CO₂ equivalent stored in P. coarctata meadows in pre- and post-monsoon is US$ 14.50 and US$ 25.38 million respectively. Further studies quantifying the NbS potential of P. coarctata mono-specific and mixed meadows of India’s coast is needed along with integration of saltmarsh ecosystems into India’s National Action Plan on Climate Change.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

The present review compared the efficacy of soft tissue substitutes (STS) and autogenous free gingival graft (FGG) or connective tissue graft (CTG) in mucogingival procedures to increase keratinized tissue (KT) width around teeth and implants. Two independent examiners performed the electronic search on Medline and Cochrane Library based on the following PICO’s format: (P) adult patients; (I) soft tissue substitutes and FGG/CTG; (C) STS vs CTG; STS vs FGG; STS vs CTR; (O) KT width gain; (S) Systematic Reviews, Randomized Controlled Trials. Results showed that around teeth, all biomaterials showed superior performance compared to CAF alone for treating gingival recessions. However, when compared to CTG, ADM yields the most similar outcomes to the gold standard (CTG), even though in multiple recessions CTG still continue to be considered the most favorable approach. Use of STSs (acellular matrix or tissue engineered) in combination with an apically positioned flap resulted in a significantly less gain of KTW compared to what achieved with FGG and APF. Around dental implants, free gingival grafts were deemed more effective than soft tissue substitutes in enhancing keratinized mucosa width.

The clinical application of collagen-based biomaterials is expanding rapidly, especially in tissue engineering and cosmetics. While oral supplements and injectable skin boosters are popular for enhancing skin health, clinical evidence supporting their effectiveness remains limited. Injectable products show potential in revitalizing skin, but safety concerns persist due to challenges in sterilization and the risk of biological contamination. Traditional methods of sterilization (heat and irradiation) can denature collagen. This study addresses these issues by introducing a novel technique: double filtration and low-temperature steam sterilization of a collagen gel. In vitro tests document sterility and confirm that the collagen structure remained intact without modification. An in vivo study found no adverse effects in rats or significant lesions at the implantation site over 13 weeks. These results suggest that this novel method to process collagen gels is a safe and effective skin booster. Advanced processing methods are likely to mitigate safety risks associated with injectable collagen products, though further research is needed to validate their biological effectiveness and clinical benefits.

Recycling information can be complex and often confusing which may subsequently reduce the participations in any waste recycling schemes. As a result, this research explored the roles as well as the importance of a holistic approach in designing recycling information using 15 expert-based in-depth interviews. The rationale was to offer a better understanding of what constitutes waste, recycling, and how recycling information should be designed and presented to make recycling more attractive/convenient. Based on the research participants’ perceptions with supports from the existing studies, this research sub-categorised recycling information into three different themes, termed the “WWW” of recycling information components. As a result, these components (or attributes) were extensively described (using findings of semi-structured interviews) to elicit pragmatic guidance for practitioners, policy-makers, and other stakeholders in designing structured communication or information strategies that may simplify and subsequently increase waste-recycling practices. The policy implications of holistic information in enhancing recycling are further discussed.

The hospital indoor environment plays a significant role in shaping the microbial exposures that humans encounter. Resistance to antibiotics is one of the mechanisms employed by bacteria to develop resilience against stress in indoor environments. The extensive usage of antibiotics has been a key factor in driving changes in the ecological function of antibiotic resistance genes (ARGs) and their acquisition by pathogenic bacteria. By integrating the 16S rRNA Illumina sequencing and high throughput-qPCR approaches with water and air dust samples across seven departments at Peking University Shenzhen Hospital, China, this study yielded intriguing findings regarding the department-specific variation, transmission, and correlation of bacteria, ARGs and MGEs within the hospital indoor environment. One notable observation was that the seasonal variation played a vital role in shaping the bacterial composition in the overall hospital indoor environment across seven studied departments. Nevertheless, a similar significant seasonal impact was only observed in the blood test room and emergency departments, rather than in the other five departments. Another intriguing finding was the correlation between ARGs and MGEs abundance. This correlation was evident in the overall hospital indoor environment, which was conversely not found in the emergency, pneumology and gynecology departments. Additionally, while there was no significant relationship that occurred between bacterial communities and ARGs/MGEs within the hospital, the gynecology department demonstrated a close link between bacterial communities and the presence of ARGs/MGEs. Notably, the gynecology department also stood out as an important source of bacteria and ARGs/MGEs for other departments. This study underscores the need for careful surveillance and monitoring of antibiotic resistance, particularly in Legionella spp. in man-made water systems. The findings also show the importance of monitoring and understanding the genetic elements such as Tp614 involved in gene transfer and recombination, as well as their impact on antimicrobial treatment efficacy.

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.

Scaffold guided breast tissue regeneration (SGBTR) can both transform reconstructive and cosmetic breast surgery. Implant-based surgery is the most common method. However, there are inherent limitations as there is replacement of tissue rather than regeneration. Regenerating autologous soft tissue has the potential to provide a more like-for-like reconstruction with minimal morbidity. Our SGBTR approach regenerates soft tissue by implanting additively manufactured bioresorbable scaffolds filled with autologous fat graft. A pre-clinical large animal study was conducted implanting 100 ml breast scaffolds (n=55) made from medical-grade polycaprolactone in 11 minipigs for 12 months. Various treatment groups were investigated where immediate or delayed autologous fat graft, as well as platelet rich plasma were added to scaffolds. Computed Tomography and Magnetic Resonance Imaging was performed on explanted scaffolds to determine volume and distribution of regenerated tissue. Histological analysis was performed to confirm tissue type. At 12 months we were able to regenerate and sustain a mean soft tissue volume of 60.9 4.5 ml (95% CI) across all treatment groups. There was no evidence of capsule formation. There were no immediate or long-term post-operative complications. In conclusion, we were able to regenerate clinically relevant soft tissue volumes utilizing SGBTR in a pre-clinical large animal model.

Portal myofibroblasts (PMF) are known to be critical in bile duct injury, but their role in liver fibrogenesis remains underexplored. Thy-1, an adhesion molecule integral to fibroblasts, relevant in fibrogenesis and detectable in serum as soluble Thy-1 (sThy-1), is expressed by PMF but not hepatic stellate cells in vitro. This study aimed to elucidate the correlation between Thy-1 expression in liver histology and sThy-1 levels in serum with the degree of liver fibrosis in patients with primary biliary cholangitis (PBC) and metabolic dysfunction associated steatotic liver disease (MASLD). Liver histology samples were stained for Thy-1 and sThy-1 was measured using an enzyme-linked immunosorbent assay (ELISA). In patients with PBC and MASLD, portal Thy-1 expression significantly correlated with increased fibrosis. The sinusoidal Thy-1 expression also significantly correlated with increased fibrosis in patients with PBC (p

Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed-Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T-cells (CD4 helper, CD8 cytotoxic and regulatory), and tumor-associated macrophages (TAMs) but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through production of various cytokines and/or aberrant expression of immune checkpoint molecules, in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.

Many cellular functions important for tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell adhesion receptors. With recent studies emphasising on the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that a lot of attention is being given to integrins. Several integrins are under trial with many demonstrating appealing activity in patients with different cancers. A deeper knowledge of the functions of integrins within the tumor microenvironment is still required, and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. This review report new data on the differential expression of integrins within solid tumors using two publicly available resources: The Cancer Genomic Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA). In this analysis, I investigated the expression of integrin alpha 2 (ITGα2), ITGα3, ITGβ4 and ITGβ6 in tumor tissues versus adjacent normal tissues. This analysis showed that integrins were differentially expressed in cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), esophageal carcinoma (ESCA) and lung adenocarcinoma (LUAD). This analysis showed that ITGα2 and ITGβ6 expression are upregulated in CESC and ESCA, ITGα3 is upregulated in HNSC and ESCA whilst ITGβ4 is highly expressed in CESC, HNSC, ESCA and LUAD tumor tissues compared to adjacent normal tissues. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This review offers the latest synthesis in terms of current knowledge of integrins functions within the tumor microenvironment and potential targets for different cancers.

In bone tissue engineering, ceramics have been the choice due to their excellent biological properties. But the paradigm changed with the discovery of bioactive glasses (BGs) in 1969 by Larry Hench and co-workers, due to their ability to bond to living tissues through the formation of an interfacial bone-like hydroxyapatite layer when the bioglass was put in contact with biological fluids in vivo. Among a number of tested compositions, the one exhibiting the highest bioactivity index is the well-known trademarked 45S5 Bioglass®. The topic received increasing attention particularly after 1985 when this material entered in the market of biomedical devices, inspiring many other investigations aiming at further exploring the in vitro and in vivo performances of this BG, or developing other related BG compositions. The research efforts gradually revealed a number of shortcomings of 45S5 Bioglass®, mostly derived from its high sodium content, initially intended to decrease the melting temperature and accelerating the degradation of the silicate network over time. But the extensive release of sodium from 45S5 Bioglass® in the biological fluids creates a high pH cytotoxic environment. Other serious drawbacks include a fast degradation rate, and a poor sintering ability, which hinders the reliable fabrication of porous scaffolds. Therefore, sol-gel was regarded as an attractive alternative to prepare alkali-free BG compositions. The process uses inorganic and/or organic precursors, which undergo hydrolysis and condensation at room-temperature, being less costly. When properly conducted, the sol-gel process might result in amorphous structures with all the components intimately mixed at the atomic scale. Moreover, developing new better performing materials for bone tissue engineering is a growing concern, as the ageing of the world’s population leads to lower bone density and osteoporosis. This work describes the sol-gel synthesis of a novel quaternary silicate-based BG with the composition 60 SiO2 – 34 CaO – 4 MgO – 2 P2O5 (mol%) was prepared using acidified distilled water as single solvent. By controlling the kinetics of the hydrolysis and condensation steps, an amorphous glass structure could be obtained. The results of XRD of samples calcined within the temperature range from 600-900 ºC demonstrated that amorphous nature was maintained until 800 ºC, followed by partial crystallization at 900 ºC. The specific surface area, an important factor in osteoconduction, was also evaluated over different temperatures, ranging from 160.6 ± 0.8 m2/g at 600 ºC down to 2.2 ± 0.1 m2/g at 900 ºC, being accompanied consistent changes in average pore size and agreeing pore size distribution. The immersion of the BG particles in simulated body fluid (SBF) led to the formation of an extensive apatite layer on its surface. These overall results indicate the proposed material is very promising for biomedical applications in bone regeneration and tissue engineering.

The global increase in population has placed significant pressure on food security, leading to the emergence of aquaculture as a vital source of aquatic foods. However, rising costs and the limited availability of fishmeal in aquafeeds have spurred the search for alternative protein sources. While plant-based ingredients have been integrated into commercial aquafeeds, they come with challenges, including low protein content, palatability issues, and the presence of antinutritional factors. In this context, fish silage, derived from fish waste and discarded fish, stands out as a promising alternative technology due to its cost-effectiveness and sustainability attributes. The production of fish silage involves the addition of organic/inorganic acids or lactic acid bacteria to homogenized fish waste. This process yields a valuable mixture rich in peptides, free amino acids, and partially hydrolyzed proteins, offering significant nutritional benefits for animal diets. Beyond its nutritional advantages, fish silage contributes to environmental sustainability by reducing the impact of waste disposal and enhancing the value of fish waste. The objective of this review is to promote sustainable practices in the aquaculture industry in response to the increasing demand for high-quality feed nutrients. To achieve this, it includes an analysis of research results related to silage technology, an appraisal of the advantages and disadvantages of using fish silage as a feed additive, and a focus on emerging trends in this field.

Acute lower respiratory tract infection is a major health problem that affects more than 15% of the total population of Saudi Arabia each year. Epidemiological studies conducted over the last three decades have indicated that viruses are responsible for the majority of these infections. The epidemiology of respiratory viruses in Saudi Arabia is believed to be affected mainly by the presence and mobility of large numbers of foreign workers and the gathering of millions of Muslims in Mecca during the Hajj and Umrah seasons. Knowledge concerning the epidemiology, circulation pattern, and evolutionary kinetics of respiratory viruses in Saudi Arabia are scant, with the available literature being inconsistent. After reviewing the available data on epidemiology and evolution of respiratory viruses, this study examines the effect of varying vaccination rates across different age groups during the 2019/2020 influenza season in Saudi Arabia. Utilizing an age-structured SEIR (Susceptible–Exposed–Infectious–Recovered) model, it develops customized vaccination policies by considering age-specific incidence rates. This pioneering research segments the population into five age groups—infants and school-aged children, junior and older youth, young adults and adults, middle-aged, and seniors—across five regional areas in Saudi Arabis: Eastern, Central, Northern, Western, and Southern. A contact matrix, compiled from multiple sources, is used to delineate the dynamics of influenza transmission. The study undertakes a thorough comparison of three distinct vaccination scenarios: no vaccination, national vaccination, and optimized vaccine allocation policy, under various potential pandemic situations. It examines their impact on vaccination campaigns in terms of the total number of infections, mortality, and morbidity rates. The results emphasize the crucial impact of population demographics on disease transmission and vaccine distribution. According to the findings, the optimized vaccination scenario proved to be the most effective strategy in all scenarios.

Aging is the important risk factor for tumorigenesis. Metabolic reprogramming is hallmark of both aging and tumor initiation. However, how the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, termed as MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to depict age-related metabolic plasticity using pan-cancer bulk RNA-seq data. Through MMP3C analysis across 17 age-related cancer types, a high metabolic organized heterogeneity was found across those cancer types. Subsequent analysis revealed a higher degree of glycolysis and impaired oxidative phosphorylation in older patients. Similar phenomenon was also observed at the single cell resolution. Many energy generation pathways, i.e., TCA cycle, oxidative phosphorylation were weakened in activated T cells and macrophages, while it increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter the utilization of glucose, thereby influencing immune function and resulting in the remodeling of the tumor microenvironment. This study provides new insights into the associations between tumor metabolism and TME mediated by aging, linking with novel strategies for cancer therapy.

Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status, playing a crucial role in the clinical therapeutic outcome of conventional treatments and innovative tumor nanomedicines. Scientists, have devoted great effort in conquering the tumor microenvironment (TME) challenges, in respect of effective drug accumulation and activity in tumor site, overcoming the obstacles of abnormal vasculature, dense stroma and extracellular matrix, hypoxia, and pH gradient acidosis. In this conquest, nanomedicines targeting distinct TME features have flourished, in order to increase site specificity and deep penetration, for effective antitumor activity, and further reprogram TME promoting suppression of cancer stem cells and metastasis. Thereby, several successful nanomedicine therapeutics have been under clinical trials, and further applied in clinical practice. Various novel strategies have been employed in preclinical studies and clinical trials, among which nanomedicines based on biomaterial, that have shown great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME targeting. In this review, we have focused on the targeting mechanisms for solid TME by nanomedicines based on the application of natural and synthetic biomaterials. We have described critical formulations that have been considered for the design of stimuli-responsive nanomedicines for TME. The development of such systems, has significantly advanced the application of biomaterials, in combinational therapies and in immunotherapies, for improved effectiveness.

Steroid hormone production by adrenal cortex, gonads and placenta (so called glandular steroidogenesis) is responsible for the endocrine control of the body’s homeostasis and organized by a feedback regulatory mechanism based on the hypothalamus-pituitary-steroidogenic gland axis. On the other hand, recently discovered extraglandular steroidogenesis occurring locally in different tissues is rather linked to paracrine or autocrine signaling and it is independent of the control by the hypothalamus and pituitary. Bone cells, such as bone-forming osteoblast, osteoblast-derived osteocytes and bone-resorbing osteoclasts respond to steroid hormones produced by both glandular and extraglandular steroidogenesis. Recently, new techniques to identify steroid hormones as well as synthetic steroids and steroidogenesis inhibitors have been introduced, which greatly empowered steroid hormone research. Based on recent literature and new advances in the field, here we review the local role of steroid hormones in regulating bone homeostasis and skeletal lesion formation. The novel idea of extraglandular steroidogenesis occurring within the skeletal system raises the possibility of the development of new therapies for the treatment of bone diseases.

Segmental bone defects caused by trauma, infection, tumor resection or osteoporotic fractures present significant surgical treatment challenges. Host bone autograft is considered the gold standard to restore function but comes with the cost of harvest site comorbidity. Allograft bone is a secondary option but has its own limitations in incorporation with host bone as well as cost. Therefore, developing new bone tissue engineering strategies to treat bone defects is critically needed. In the past three decades, the use of stem cells delivered with different scaffolds or growth factors for bone tissue engineering has made tremendous progress. Many varieties of stem cells have been isolated from different tissues for use in bone tissue engineering. This review summarizes the progress in using different postnatal stem cells including bone marrow mesenchymal stem cells, muscle-derived stem cells, adipose-derived stem cells, dental pulp stem cells/periodontal ligament stem cells, periosteum stem cells, umbilical cord-derived stem cells, peripheral blood stem cells and urine-derived stem cells for bone tissue engineering and repair. This review also summarizes the progress using exosomes or extracellular vesicles delivered with various scaffolds for bone repair. The advantages and disadvantages of each type of stem cell are also discussed and explained in detail. It is hopeful in the future that these preclinical results will translate into new therapies for bone defect repair.

In 2018, Iran witnessed approximately 21,000 fatalities resulting from road accidents, ranking it as the fifth leading cause of death across all age groups. These incidents carry substantial economic and social burden for the nation, claiming more than 5% of its GDP. Human behavior emerges as a significant contributing factor to high-risk driving offenses. It has been proposed that by influencing general deterrence, a rigorous defense can be established against such violations. Various theories posit that by reinforcing or diminishing influential factors, general deterrence perception can be molded, presenting a potential avenue for an effective deterrent against traffic infractions. This study examines deterrence perceptions prevailing among the public in Iran regarding the enforcement of traffic laws. Employing Structural Equation Modeling (SEM), we delve into the intricate relationships between variables, allowing for a comprehensive exploration of the factors influencing general deterrence. The study draws on the data derived from a survey comprising 548 questionnaires for modeling purposes. An innovative concept, private sector enforcement, is introduced and incorporated into the questioning and modeling process. The findings reveal that socioeconomic status (p-value&lt;0.01), police enforcement (p-value&lt;0.05), private sector enforcement (p-value&lt;0.05), specific deterrence (p-value&lt;0.01), and the use of technology (p-value&lt;0.01) have direct and indirect impacts on the general deterrence perception of drivers.

The advancements achieved in Tissue Engineering are based on a careful and in-depth study of cell-tissue interaction. The choice of a certain biomaterial in Tissue Engineering is fundamental as it represents an interface for adherent cells in the creation of a microenvironment suitable for cell growth and differentiation. The knowledge of the biochemical and biophysical properties of the extracellular matrix is a useful tool for the optimization of polymeric scaffolds. The aim of this re-view is to analyse the chemical, physical and biological parameters on which it is possible to act in Tissue Engineering for the optimization of polymeric scaffolds. Understanding the scaffold impact on cell fate is of paramount importance for the successful advancement of Tissue Engineering.

Recent research efforts in bone tissue engineering have been primarily directed towards manufacture-viable synthesis of biomaterials that can significantly enhance the biocompatibilities and osteogenic capabilities on the new biomaterials. This paper presents a straightforward, cost-effective, optimized, and well-controlled hydrothermal synthesis of Nb-doped potassium titanate nanofibers in high-purity. Characterization data revealed that the Nb-doping potassium titanate maintained the crystal structure, showing great promise for applications in bone tissue engineering.

Microwave radiation diagnosis technology can detect thermal changes in skin tissue earlier than anatomical changes, but its detection accuracy is limited by non-target radiation interference in the measurement environment, additional measurement errors of system units, and energy scattering and transmission between skin tissues. This paper aims to address the scientific challenges of analyzing the forward and inversion modelling detection mechanism of layered accurate temperature measurement of human skin tissue based on multi-band. The study focuses on the construction of a pencil beam antenna optimization system, the optimization strategy of high-sensitivity correlated radiometer architecture, and the high-precision multi-band forward and inversion modelling detection algorithm. The key technologies include: (1) A new method of integrated modeling and multi-index optimization of antenna with high directivity and small aperture is proposed, and a priori knowledge-guided neural network of pencil beam distribution is constructed to realize the inversion model of antenna structural parameters; (2) The influence mechanism of high sensitivity correlated radiometer architecture error is analyzed, and a periodic phase shift error correction algorithm based on uniform polar circle is designed; (3) Combining deep learning theory and hyperparameter optimization framework, an iterative model is established, and the objective function modified by the penalty factor is defined to realize a new detection method combining forward and inversion. This paper presents a theoretical foundation for the industrialization of microwave radiation diagnostic technology.

CO2 emission activity of xylotrophic fungi response to an increase in temperature in the range of 10-30 °C on the example of pure dikaryotic cultures of Fomes fomentarius s. str., F. inzengae, Fomitopsis betulina, F. pinicola, Phellinus igniarius was analyzed. Emission activity was assessed by the difference in CO2 concentration in 0.5-liter exposure chambers with Petri dishes with mycelium growing on agar at the beginning of exposure and an hour later using a Gasmet DX-4030 FTIR spectrometer (Gasmet Technologies Oy, Finland), error measurements ±50 ppm. Specific (μg CO2/cm2/h) and total (μg CO2/h) emission activity and its relationship with temperature and size (area) of the mycelium were assessed. It has been shown that in the range of 10-30 °C, the specific and total CO2 emission activity of the mycelium is closely and positively related to temperature. Specific emission, which is an indicator of the respiratory activity of the mycelium, does not depend on its size; its only driver is temperature, the relationship with which is linear: an increase in temperature by 10 °C causes an increase in the specific emission activity of the mycelium by 1.7 times. The total CO2 emission activity, which is an indicator of the total amount of CO2 emitted, is directly proportional to the specific emission activity and the size of the mycelium. In the range of 10-30 °C, an increase in temperature causes an almost equal increase in both the specific emission activity of the mycelium (Q10 1.7) and its growth (Q10 1.5) and causes an exponential increase in the total emission of CO2. This must be taken into account when predicting CO2 emissions from woody debris under climate change, as it could potentially contribute to accelerating climate change.

Salivary gland tumors are highly variable in clinical presentation and histology. The World Health Organization (WHO) classifies 22 types of malignant and 11 types of benign tumors of the salivary glands. Diagnosis of salivary gland tumors is based on imaging (ultrasound, magnetic resonance imaging) and fine-needle aspiration biopsy, but the final diagnosis is based on histopathological examination of the removed tumor. In this pilot study, we are testing a new approach to identifying peptide biomarkers in saliva that can be used to diagnose salivary gland tumors. The research material for the peptidomic studies was extracts from washings of neoplastic tissues and healthy tissues (control samples). At the same time, saliva samples from patients and healthy individuals were analysed. The comparison of the peptidome composition of tissue extracts and saliva samples may allow the identification of potential peptide markers of salivary gland tumors in patients' saliva. The peptidome composition extracted from 18 tumor and 18 healthy tissue samples, patient (11 samples) and healthy saliva samples (8 samples) was analysed by LC-MS tandem mass spectrometry. A group of 109 peptides were identified that were present only in the tumor tissue extracts and in the patient saliva samples. Some of the identified peptides were derived from proteins previously suggested as potential biomarkers of salivary gland tumors (ANXA1, BPIFA2, FGB, GAPDH, HSPB1, IGHG1, VIM) or tumors of other tissues or organs (SERPINA1, APOA2, CSTB, GSTP1, S100A8, S100A9, TPI1). Unfortunately, none of the identified peptides were present in all samples analysed. This may be due to the high heterogeneity of this type of cancer. The surprising result was that extracts from tumor tissue did not contain peptides derived from salivary gland-specific proteins (STATH, SMR3B, HTN1, HTN3). These results could suggest that the developing tumor suppresses the production of proteins that are essential components of saliva.

Yaba monkey tumor virus (YMTV) and Tanapox virus (TPV) are members of the Yatapoxvirus genus and can infect humans and other primates. Despite the threat posed by yatapoxviruses, the factors determining their host range are poorly understood. In this study, we analyzed the ability of YMTV and TPV orthologs of vaccinia virus K3 (called 012 in YMTV and TPV), which share 75% amino acid identity with one another, to inhibit PKR from 15 different primate species. We first used a luciferase-based reporter, and found that YMTV and TPV K3 orthologs inhibited PKR in a species-specific manner and showed distinct PKR inhibition profiles. TPV 012 inhibited PKR from 11 primates, including human, substantially better than YMTV 012. In contrast, both K3 orthologs inhibited the other four primate PKRs comparably well. Using YMTV 012 and TPV 012 hybrids, we mapped the region responsible for the differential PKR inhibition to the C- terminus of the K3 orthologs. Next, we generated chimeric vaccinia virus strains to investigate whether TPV K3 and YMTV K3 orthologs could rescue replication of a vaccinia virus strain that lacks PKR inhibitors K3L and E3L. Virus replication in primate-derived cells generally correlated with the patterns observed in the luciferase-based assay. Together, these observations demonstrate that yatapoxvirus K3 orthologs have distinct PKR inhibition profiles and inhibit PKR in a species-specific manner, which may contribute to the differential susceptibility of primate species to yatapoxvirus infections.

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. Current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities – immune checkpoint inhibitors, cancer vaccines, oncolytic viruses, chimeric antigen receptor T cells and NK cells have shown promise. Clinical trials incorporating combination therapies of the above have overcome the microenvironment resistance and yielded survival and prognostic benefit. Rolling these new therapies out in the real-world scenario in a low cost, high throughput manner is the unmet need of the hour. These will bring practice changing implications to the glioma treatment landscape. In this review article, we focus on describing the hallmarks of the glioma microenvironment and its interplay with the different emerging modalities of immunotherapy.

Background: Diffuse glioma is a malignant human brain cancer that is hard to overcome. This represents a high risk of mortality. The current challenge is limited to the control of tumor progression and survival improvement. Immunotherapy consists of stimulating the immune system in order to eliminate the non-self-elements that damage the human body, including cancer cells. However, in human glioma, the current immunotherapeutic targets did not show significant benefit. In this study, we aimed at evaluating the expression and potential role of a new immunosuppressive molecule, TIGIT in glioma patients. Methods: A cohort of 667 patients from the TCGA database along with a cohort of 53 Moroccan patients, were analyzed in order to assess the role of TIGIT in human glioma progression and to estimate whether blocking this immune checkpoint molecule would be of a potential therapeutic benefit. Real time RT-PCR from fresh human biopsies and RNAseq data analysis were performed in this study. Results: Our results showed that high expression of TIGIT had prognostic value with some known clinical glioma risk factors such as sex, age and IDH mutation status. High expression of TIGIT was positively associated with advanced grades of glioma. Interestingly, elevated rates of TIGIT were significantly associated to elevated levels of other inhibitory immune checkpoint molecules (PD-1, VISTA and Tim-3) in human glioma patients, also TIGIT showed strong association with Treg cell-secreted cytokines (TGF-beta and IL-10), indicating the high potential involvement of TIGIT in immunosuppression in human glioma. Moreover, we reported that high TIGIT expressing CD8 T-cells displayed more surface inhibitory molecules and, elevated levels of Treg cells and FoxP3 were linked to higher rates of TIGIT, supporting the likely involvement of TIGIT in the suppression of the intra-tumoral immune cells. Finally, high expression of TIGIT was significantly linked to advanced histological subtypes of glioma and was associated with poor overall survival in human glioma. Conclusion: TIGIT blockade might be of valuable therapeutic benefit in patients with advanced glioma.

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They are invisible to antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation, and “educate” (i.e., reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies, targeting not only tumor cells but also the tumor microenvironment, are being developed. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become protective or immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

Preventing the rebound of black and odorous water bodies is critical for improving the ecological environment of water bodies. This study investigated the effect and mechanism of in-situ improvement of sediment microenvironment by nitrate in tailwater of wastewater treatment plants combined with aerobic denitrifying bacteria under low-DO regulation (TailN+CFM+LDO). On the 60th day of remediation, the dissolved oxygen and oxidation-reduction potential in the overlying water increased to 5.6 mg/L and 300 mV, respectively, the acid volatile sulfide in the sediment decreased by 70.4%, and the organic matter in the sediment was reduced by 62.7%, in which the HFOM was degraded from 105 g/kg to 56 g/kg, and the potential risk of water reverting to black and odorous conditions significantly decreased. Amplicon sequencing analysis revealed that the relative abundance of electroactive bacteria Thiobacillus and Pseudomonas with denitrification capacity was found to be significantly higher in the TailN+CFM+LDO group than in the other remediation groups. Functional prediction of 16S sequencing results indicated that both the quantity and activity of critical microbial enzymes involved in nitrification and denitrification processes could enhance in the TailN+CFM+LDO group. These results improved our understanding of the improvement of the sediment microenvironment and could thus facilitate its application.

The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within the tumor. This microbiome primarily originates from the local microbiome of the tu-mor-bearing tissue or from translocating microbiome from distant sites, such as the gut. Despite the increasing number of studies on intratumoral microbiome, it remains unclear whether it is a driver or a bystander of oncogenesis and tumor progression. This review aims to elucidate the intricate role of the intratumoral microbiome in tumor development by exploring its effects on reshaping the multi-leveled ecosystem in which tumors thrive, the TME. To dissect the complexity and the multitude of layers within the TME, we distinguish six specialized tumor microenvironments, namely the immune, metabolic, hypoxic, acidic, mechanical and innervated microenvironments. Accordingly, we attempt to decipher the effects of the intratumoral microbiome on each specialized microenvironment and ultimately decode its tumor-promoting or tumor-suppressive impact. Additionally, we portray the intratumoral microbiome as an orchestrator in the tumor milieu, fine-tuning the responses in distinct, specialized microenvironments and remodeling the TME in a multi-leveled and multi-faceted manner.

Tumor-associated microbiota refers to the community of microorganisms found in tumors and is part of the larger tumor microenvironment (TME). The discovery of the complex relationship between these microbial populations and the growth of cancer has prompted the creation of cutting-edge tailored methods to cancer treatment. In recent years, microbiota profiling's potential as a diagnostic, prognostic, and therapeutic optimization tool has been increasingly apparent. The diagnostic and prognostic use of microbiota profiling is explored in this abstract. Microbiota profiling shows potential for early cancer detection, improved risk stratification, and greater prediction of treatment outcomes by identifying different microbial signatures associated with early-stage tumors, aggressive characteristics, and responses to treatment. In addition, this method provides the way for individualized medicinal approaches based on an individual's specific microbiome.Microbiota profiling is investigated as a means of customizing treatment plans, illuminating how knowledge of an individual's microbiome might direct the development of individualized treatments and multimodal approaches. These kind of interventions have the potential to herald in a new era of patient-centered oncology care by increasing treatment efficacy while decreasing side effects. Despite significant promise, microbiota profiling has obstacles that must be overcome before it can be successfully translated into therapeutic practice. This abstract highlights the revolutionary potential of microbiota-based approaches in cancer care and the need for ongoing research and technology improvements to harness the power of the tumor-associated microbiome for improved patient outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a ravaging disease whose poor prognosis requires a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggested to rather focus on the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer secreted proteins in the complex TME tumor-stroma crosstalk, to sched lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.