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When The Principles of Humane Experimental Technique was published in 1959, authors William Russell and Rex Burch had a modest goal: to make researchers think about what they were doing in the laboratory – and to do it more humanely. Sixty years later, their groundbreaking book was celebrated for inspiring a revolution in science and launching a new field: The 3Rs of alternatives to animal experimentation. On November 22, 2019, some pioneering and leading scientists and researchers in the field gathered at the Johns Hopkins Bloomberg School of Public Health in Bal­timore for the 60 Years of the 3Rs Symposium: Lessons Learned and the Road Ahead. The event was sponsored by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the Foundation for Chemistry Research and Initiatives, the Alternative Research & Development Foundation (ARDF), the American Cleaning Institute (ACI), the International Fragrance Association (IFRA), the Institute for In Vitro Sciences (IIVS), John “Jack” R. Fowle III, and the Society of Toxicology (SoT). Fourteen pres­entations shared the history behind the groundbreaking publication, international efforts to achieve its aims, stumbling blocks to progress, as well as remarkable achievements. The day was a tribute to Russell and Burch, and a testament to what is possible when people from many walks of life – science, government, and industry – work toward a common goal.

Introduction: There have been relatively few attempts to quantitatively assess if, and in which areas, the use of non-animal methods (NAMs) is increasing in biomedical research and importantly, how this compares to the use of live animals. Methods: We conducted a bibliometric analysis of the relative publication of papers reporting the use of NAMs-only compared to those reporting the use of animals, even if they also reported the use of NAMs, over the period 2003 to 2022 across seven research areas (breast cancer, lung disease, blood cancer, heart disease, neurodegenerative diseases, diabetes and toxicology) and five regions (USA, China, France, Germany, United Kingdom). Results: We found that the relative number of publications of research using NAMs-only has been higher than animal-based research for the last 20 years for all research areas and is growing. Research areas differed in their relative publication of NAMs-only based work, with breast cancer and lung disease having consistently the highest ratio of NAMs-only to animal-based publications and heart disease, diabetes and toxicology showing the greatest change over the time period. A key period of change was 2016--18. By 2022 the UK had the highest NAMs-only to animal-based research ratio than any other country for five of the seven research areas and China the lowest for six, accounting for publication rate. Tissue and in silico-based methods were the most common of all NAMs-only publications; lab-on-a-chip and stem cell models are increasing in their use but at much lower levels and rate of increase. Conclusion: We found that proportionately the reliance on animals in these research areas is decreasing, which will be encouraging to those that support the replacement of animal experiments. [ABSTRACT FROM AUTHOR]

Aging is associated with substantial physiological changes and constitutes a major risk factor for neurological disorders including dementia. Alterations in gene expression upon aging have been extensively studied; however, an in-depth characterization of post-transcriptional regulatory events remains elusive. Here, we profiled the age-related changes of the transcriptome and translatome in the female mouse hippocampus by RNA sequencing of total RNA and polysome preparations at four ages (3-, 6-, 12-, 20-month-old); and we implemented a variety of bioinformatics approaches to unravel alterations in transcript abundance, alternative splicing, and polyadenylation site selection. We observed mostly wellcoordinated transcriptome and translatome expression signatures across age including upregulation of transcripts related to immune system processes and neuroinflammation, though transcripts encoding ribonucleoproteins or associated with mitochondrial functions, calcium signaling and the cell-cycle displayed substantial discordant profiles, suggesting translational control associated with age-related deficits in hippocampal-dependent behavior. By contrast, alternative splicing was less preserved, increased with age and was associated with distinct functionally-related transcripts encoding proteins acting at synapses/dendrites, RNA-binding proteins; thereby predicting regulatory roles for RBM3 and CIRBP. Only minor changes in polyadenylation site selection were identified, indicating pivotal 3'-end selection in young adults compared to older groups. Overall, our study provides a comprehensive resource of age-associated post-transcriptional regulatory events in the mouse hippocampus, enabling further examination of the molecular features underlying age-associated neurological diseases. [ABSTRACT FROM AUTHOR]

Background: Osseointegrated dental implants are widely established as a first-choice treatment for the replacement of missing teeth. Clinical outcomes are however often compromised by short or longer-term biological complications and pathologies. Nanoparticle-coated materials represent a very active research area with the potential to enhance clinical outcomes and reduce complications of implant therapy. This scoping review aimed to summarize current research on various types of nanoparticles (NPs) used as surface modifiers of dental implants and their potential to promote biological and clinical outcomes. Methods: A systematic electronic search was conducted in SCOPUS, PubMed and Google Scholar aiming to identify in vivo, in situ, or in vitro studies published between 2014 and 2024. Inclusion and exclusion criteria were determined and were described in the methods section. Results: A total of 169 articles (44 original papers from Scopus and PubMed, and 125 articles from Google Scholar) were identified by the electronic search. Finally, 30 studies fit the inclusion criteria and were further used in this review. The findings from the selected papers suggest that nanoparticle-coated dental implants show promising results in enhancing bone regeneration and promoting angiogenesis around the implant site. These effects are due to the unique physicochemical properties of nanoparticle-coated implants and the controlled release of bioactive molecules from nanoparticle-modified surfaces. Conclusion: Nanoscale modifications displayed unique properties which could significantly enhance the properties of dental implants and further accelerate revascularization, and osseointegration while facilitating early implant loading. Yet, since many of these findings were based on in-vitro/in-situ systems, further research is required before such technology reaches clinical application. [ABSTRACT FROM AUTHOR]

Open science in its broadest sense can make better science and provide benefits to researchers. When applied to animal experimentation, it can prevent unnecessary use of animals, because knowledge and experiences about past animal experimentation are shared openly to be consulted and used by other researchers. By extension, open science can accelerate the much anticipated transition towards animal-free innovations or New Approach Methodologies (NAMs). The purpose of this paper is to bring together and further share the preparations and findings of a symposium held at Utrecht University on aspects of open science that researchers doing animal experiments can and should take into account to improve their research and benefit themselves. The paper offers a onefigure guideline for that purpose. [ABSTRACT FROM AUTHOR]

Background: Spinal cord compression is a pathology seen in routine clinical practice. However, there remain a number of unanswered questions around both the understanding of the pathogenesis and the best method of treatment of the condition. This is partly due to the issues of the real-life testing of the physical properties of the spinal cord, either through the use of cadaveric human specimens or through animal testing, both of which have methodological, as well as ethical, issues. Design and methods: This paper details a protocol for a systematic review of the literature on the mechanical properties of the spinal cord. We will conduct a literature search of a number of electronic databases, along with the grey literature, as a single-stage search. All literature will be screened for appropriate studies which will then be reviewed fully to extract relevant information on the methodology and mechanics of the reported testing along with the results. Two reviewers will separately screen and extract the data, with a comparison of results to ensure concordance. Conflicts will be resolved through discussion and independent arbitration as required. The methodological quality of the studies will be assessed within the ARRIVE guidelines using the CAMARADES framework and SYRCLE risk of bias tool. A narrative synthesis will be created with the appropriate tables to describe the demographics and findings of the included studies. Discussion: The systematic review described here will form the basis of an understanding of the current literature around the physical properties of the spinal cord. This will allow future work to develop a physical model of the spinal cord, which is translatable to patients for analysis and testing in a controlled and repeatable fashion. Such a model would be the basis for further clinical research to improve outcomes from this condition. Trial registration: Prospero registration number: CRD42022361933. [ABSTRACT FROM AUTHOR]

The purpose of this paper was to study in vitro atomization properties of the self-developed sodium sivelestat for inhalation, evaluate the feasibility of this preparation as an aerosol inhalation, and provide the guidance for the following animal administration experiment. Firstly, in order to ensure accurate, uniform and stable doses of the self-developed product after administration, its atomization performance was analyzed through the testing of fine particle mass and the total emitted dose, and the results of its atomization parameters meet the requirement of inhalation. Next, Atomization characteristics of two commonly used nebulizers, air compressed nebulizer and mesh nebulizer, were studied and compared. The results showed that mesh atomizers have a smaller and more uniform particle size distribution. And then, the experiment of acute lung injury induced by aerosol inhalation of lipopolysaccharide in mice was used to test the therapeutic effect of our self-developed formulation, and compared with the positive control (sodium sivelestat for injection). The results showed that inhalation had a lower concentration and was equally effective than injection of sodium sivelestat. All the results support that the self-developed sodium sivelestat can be used as an aerosol inhaled drug. [ABSTRACT FROM AUTHOR]

Brody disease (BD) is an "ultra-rare" human genetic disorder of skeletal muscle function due to defects in the atp2a1 gene causing deficiency of the SERCA protein, isoform1. The main clinical signs are exercise-induced stiffness and delayed muscular relaxation after physical exercises, even mild ones. No mouse model nor specific therapies exist for Brody myopathy, which is therefore considered an orphan disease. Bovine congenital pseudomyotonia (PMT) is a muscular disorder characterized by an impairment of muscle relaxation and is the only mammalian model of human BD. The pathogenetic mechanism underlying bovine PMT has been recently clarified. These findings prompted us to purpose a potential pharmacological approach addressing a specific population of BD patients who exhibit reduced expression but still exhibit activity of the SERCA1 pump. Preclinical research involving in vivo studies is essential and necessary before clinical trials can be pursued and SERCA protein shows a high degree of conservation among species. So far, the only animal models available to study BD in vivo are a group of zebrafish mutant lines known as accordion zebrafish (acc). In this paper, we focused on a comprehensive characterization of the "acctq206" zebrafish variant. Our aim was to use this mutant line as an experimental animal model for testing the novel therapeutic approach for BD. [ABSTRACT FROM AUTHOR]

Background: Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, exhibits promising anti-Alzheimer's disease (AD) effects, but its underlying mechanisms remain inadequately investigated. This paper aims to identify potential targets and molecular mechanisms of DAU in AD treatment. Methods: Network pharmacology and molecular docking simulation method were used to screen and focus core targets. Various transgenic Caenorhabditis elegans models were chosen to validate the anti-AD efficacy and mechanism of DAU. Results: There are 66 potential DAU-AD target intersections identified from 100 DAU and 3036 AD-related targets. Subsequent protein-protein interaction (PPI) network analysis identified 16 core targets of DAU for anti-AD. PIK3CA, AKT1 and mTOR were predicted to be the central targets with the best connectivity through the analysis of "compound-target-biological process-pathway network". Molecular docking revealed strong binding affinities between DAU and PIK3CA, AKT1, and mTOR. In vivo experiments demonstrated that DAU effectively reduced paralysis in AD nematodes caused by Aβ aggregation toxicity, downregulated expression of PIK3CA, AKT1, and mTOR homologues (age-1, akt-1, let-363), and upregulated expression of autophagy genes and the marker protein LGG-1. Simultaneously, DAU increased lysosomal content and enhanced degradation of the autophagy-related substrate protein P62. Thioflavin T（Th-T）staining experiment revealed that DAU decreased Aβ accumulation in AD nematodes. Further experiments also confirmed DAU's protein scavenging activity in polyglutamine (polyQ) aggregation nematodes. Conclusion: Collectively, the mechanism of DAU against AD may be related to the activation of the autophagy-lysosomal protein clearance pathway, which contributes to the decrease of Aβ aggregation and the restoration of protein homeostasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Animals are frequently used to determine whether new compounds have the potential to be used as drugs against the parasitic disease leishmaniasis. There is, however, no consensus on the best animal model, and many different ones are used. This review explored the many different models and identified their strengths and weaknesses. The work showed that many papers on animal models for leishmaniasis lack a thorough description of the experimental procedures used, are deficient in appropriate ethical review (to safeguard the welfare of the animals), and measures to reduce, refine or replace animal studies are hardly addressed. Mice and hamsters are most frequently used, but there are many differences in how the animal experiment is set up. We propose a more generalized animal model, in particular to ensure that different experiments can be better compared. Furthermore, we make a plea to report all animal experiments in the same way, and all experiments must be scrutinized by appropriate ethical review committees. Many different animal models are in use for drug development for leishmaniasis, but a universal model does not exist. There is a plethora of models, and this review assesses their design, quality, and limitations, including the attention paid to animal welfare in the study design and execution. A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines of available literature after the year 2000 describing animal models for leishmaniasis. The risk of bias was determined using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias assessment tool. A total of 10,980 records were initially identified after searching the databases PubMed, EMBASE, LILACS, and SciELO. Based on the application of predetermined exclusion and inclusion criteria, a total of 203 papers describing 216 animal experiments were available for full analysis. Major reasons for exclusion were a lack of essential study information or appropriate ethical review and approval. Mice (82.8%; an average of 35.9 animals per study) and hamsters (17.1%; an average of 7.4 animals per study) were the most frequently used animals, mostly commercially sourced, in the included studies. All studies lacked a formal sample size analysis. The promastigote stages of L. amazonensis or L. major were most frequently used to establish experimental infections (single inoculum). Animal welfare was poorly addressed in all included studies, as the definition of a human end-point or consideration of the 3Rs (Replacement, Reduction, Refinement) was hardly addressed. Most animals were euthanized at the termination of the experiment. The majority of the studies had an unknown or high risk of bias. Animal experiments for drug development for leishmaniasis mainly poorly designed and of low quality, lack appropriate ethical review, and are deficient in essential information needed to replicate and interpret the study. Importantly, aspects of animal welfare are hardly considered. This underpins the need to better consider and record the details of the study design and animal welfare. [ABSTRACT FROM AUTHOR]

Simple Summary: Canadian universities and the quasi-regulatory body overseeing animal research (Canadian Council on Animal Care) increasingly use the language of "transparency" to assert that their practices have sufficient public oversight and legitimacy in the eyes of the Canadian public. This paper analyses how this new "transparency" in fact operates to conceal the realities of these animals' lives and inhibit genuine public oversight and ethical engagement. For many years, the lives of animals used for research in Canadian universities have been hidden from public view due both to physical concealment (e.g., security procedures and impenetrable labs) and administrative concealment (non-disclosure of information). Their lives unfold out of sight both physically and discursively, unavailable to the Canadian public for ethical consideration and democratic oversight. Recently, in response to calls by the public to end this secrecy, Canadian universities and the Canadian Council on Animal Care have embraced the language of "transparency" and have begun releasing documentation about animal research practices and procedures. This paper argues that this new "transparency" acts as its own kind of concealment practice, obscuring and displacing meaningful information while constructing highly selective ways of seeing animals in science, and manufacturing acquiescence/consent on the part of the public. [ABSTRACT FROM AUTHOR]

Background: Excessive inflammation is a major cause of implant failure. The surface morphology, hydrophilicity, and loading of biomaterials are major properties modulating anti-inflammatory macrophage activation. This paper investigates the regulatory effects of modifying the surface of Titanium dioxide nanotubes (TNTs) with graphene oxide (GO) on the polarization of mouse monocyte macrophages (RAW264.7). Methods: TNT was produced by the anodic oxidation of titanium. GO was subsequently electrodeposited on the TNT to obtain a TNT–GO composite. The samples were characterised through scanning electron microscopy (SEM), Raman spectroscopy, and X-ray diffraction. RAW264.7 cells were separately seeded onto the surface of three groups of samples: pure Ti, TNT, and TNT–GO. Under the condition of lipopolysaccharide stimulation, the influence of the sample surfaces on the gene expression profiles was investigated through RNA sequence analysis. In addition, cell spreading was observed through SEM, cell adhesion and proliferation were analysed using the CCK8 assay, and the expression of inflammation-related factors was investigated by ELISA and cellular immunofluorescence staining. The production of reactive oxygen species (ROS) in the RAW264.7 cells on the surface of the three groups was detected via immunofluorescence staining. Results: The CCK8 results indicated that the adhesion and proliferation of the RAW264.7 cells were reduced on the TNT and TNT–GO surfaces. ELISA results revealed significant differences in the pro-inflammatory factors tumour necrosis factor-α and interleukin-6 secretion among the three groups at 24 h (p < 0.05). The secretion of pro-inflammatory factors significantly reduced and the expression of anti-inflammatory factor IL-10 increased on the TNT and TNT–GO surfaces. The RNA sequencing, ELISA, and cell immunofluorescence staining test results suggested that the inflammatory response of M1 polarization was reduced and the M2 polarization of macrophages was induced on the TNT–GO surface, which may be attributed to the reduction in ROS production. Conclusions: Under lipopolysaccharide stimulation, the inflammatory response of the RAW264.7 cells was reduced and the M2 polarization of macrophages was promoted on the TNT–GO surface, which may be caused by the reduced ROS production. Consequently, the designed TNT–GO material is promising for implants owing to its excellent inflammation regulation ability. [ABSTRACT FROM AUTHOR]

UV light is a potent mutagen that induces bulky DNA damage in the form of cyclobutane pyrimidine dimers (CPDs). Photodamage and other bulky lesions occurring in nuclear genomes can be repaired through nucleotide excision repair (NER), where incisions on both sides of a damaged site precede the removal of a single-stranded oligonucleotide containing the damage. Mitochondrial genomes (mtDNAs) are also susceptible to damage from UV light, but current evidence suggests that the only way to eliminate bulky mtDNA damage is through mtDNA degradation. Damage-containing oligonucleotides excised during NER can be captured with antidamage antibodies and sequenced (XR-seq) to produce high-resolution maps of active repair locations following UV exposure. We analyzed previously published datasets from Arabidopsis thaliana, Saccharomyces cerevisiae , and Drosophila melanogaster to identify reads originating from the mtDNA (and plastid genome in A. thaliana). In A. thaliana and S. cerevisiae , the mtDNA-mapping reads have unique length distributions compared to the nuclear-mapping reads. The dominant fragment size was 26 nt in S. cerevisiae and 28 nt in A. thaliana with distinct secondary peaks occurring in regular intervals. These reads also show a nonrandom distribution of di-pyrimidines (the substrate for CPD formation) with TT enrichment at positions 7–8 of the reads. Therefore, UV damage to mtDNA appears to result in production of DNA fragments of characteristic lengths and positions relative to the damaged location. The mechanisms producing these fragments are unclear, but we hypothesize that they result from a previously uncharacterized DNA degradation pathway or repair mechanism in mitochondria. [ABSTRACT FROM AUTHOR]

Environmental electromagnetic interference (EMI) has always been a major interference source for multiple-channel neural recording systems, and little theoretical work has been attempted to address it. In this paper, equivalent circuit models are proposed to model both electromagnetic interference sources and neural signals in such systems, and analysis has been performed to generate the design guidelines for neural probes and the subsequent recording circuit towards higher common-mode interference (CMI) rejection performance while maintaining the recorded neural action potential (AP) signal quality. In vivo animal experiments with a configurable 32-channel neural recording system are carried out to validate the proposed models and design guidelines. The results show the power spectral density (PSD) of environmental 50 Hz EMI interference is reduced by three orders from 4.43 × 10−3 V2/Hz to 4.04 × 10−6 V2/Hz without affecting the recorded AP signal quality in an unshielded experiment environment. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell (hiPSC)-derived brain spheroids can recapitulate the complex cytoarchitecture of the brain, as well as the genetic/epigenetic footprint of human brain development. However, hiPSC-derived 3D models such as spheroid and organoids does not have a perfusable microvascular network, which plays a vital role in maintaining homeostasis in vivo. With the critical balance of positive and negative angiogenic modulators, 3D microvascular network can be achieved by angiogenesis. This paper reports on a microfluidic-based three-dimensional, cortical spheroid grafted on the vascular-network. Vascular network was formed by inducing angiogenic sprouting using concentration gradient-driven angiogenic factors in the microfluidic device. We investigate critical factors for angiogenic vascular network formation with spheroid placement, including 1) a PKCα activator, phorbol-12-myristate-13-acetate (PMA); 2) orientation of endothelial cells under perfusion and permeability of vascular network; 3) effect of extracellular matrix (ECM) types and their densities on angiogenesis; and 4) integration with cortical spheroid on vascular network. This paper demonstrates proof of concept for the potential utility of a membrane-free in vitro cortical spheroid tissue construct with perfusable microvascular network that can be scaled up to a high throughput platform. It can provide a cost-effective alternative platform to animal testing by modeling brain diseases and disorders, and screening drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper explores why it is ethical to rehome all healthy laboratory animals after the experiments have finished. We describe our own rehoming experience from the joint Ani-mal Welfare Body of Utrecht University and the University Medical Centre Utrecht, the Nether-lands. During a pilot period, over 350 animals were successfully rehomed. Now, rehoming in our lab is a standard policy and common practice. We discuss several challenges and our responses to those through the continuous evaluation of this adoption program. This paper explores the ethical imperative of rehoming all healthy animals of sentient species after experiments have finished or when they have become otherwise redundant. We take into account disparate perspectives in animal ethics and see how they point in the same direction. We illustrate our case with our own rehoming experience from the joint Animal Welfare Body of Utrecht University and the University Medical Centre Utrecht, the Netherlands. The primary pilot proved successful, after which the principle of rehoming became standing policy and common practice. We discuss several challenges and our responses to those through continuous evaluation of the adoption program. [ABSTRACT FROM AUTHOR]

In order to better demonstrate the relationship between agricultural economic structure growth and environmental pollution, an autoregressive model based on time-varying parameter vector was proposed. In the process of developing the research, this paper introduces the LDMI method, based on the time-varying parameter vector autoregression model, with the help of sampling formula calculation and other methods. Efforts were made to obtain credible conclusions. The experiment result shows that in this study, a total of 10,000 samples were taken. According to this value, 10000/116.15 = 86, which means that at least 86 unrelated samples can be obtained. Therefore, we can determine that each indicator mentioned in this paper has valid samples when it is introduced into the time-varying parameter vector autoregression (TVP-VAR) model for parameter estimation. After sampling detection image analysis and data calculation, the effect of energy structure, energy intensity industrial structure, and scale effect on the emission scale of environmental pollutants was obtained. It is proved that through the research of this paper, two main conclusions are finally obtained, and the influence of the five factors mentioned above is summarized. [ABSTRACT FROM AUTHOR]

This document is a correction to a previously published paper titled "All-Natural Immunomodulatory Bioadhesive Hydrogel Promotes Angiogenesis and Diabetic Wound Healing by Regulating Macrophage Heterogeneity." The correction addresses mistakes in Figure 7A, which included the wrong image due to a computer lag during data processing. The incorrect images have been replaced, and errors in the annotations of other figures have also been corrected. The corrections do not impact the results and conclusions of the original article. [Extracted from the article]

Temporal accuracy is a fundamental characteristic of logging technology and is needed to correlate data streams. Single biologgers sensing animal movement (accelerometers, gyroscope, magnetometers, collectively inertial measurement unit; IMU) have been extensively used to study the ecology of animals. To better capture whole body movement and increase the accuracy of behavior classification, there is a need to deploy multiple loggers on a single individual to capture the movement of multiple body parts. Yet due to temporal drift, accurately aligning multiple IMU datasets can be problematic, especially as deployment duration increases. In this paper we quantify temporal drift and errors in commercially available IMU data loggers using a combination of robotic and animal borne experiments. The variance in drift rate within a tag is over an order of magnitude lower (σ = 0.001 s h−1) than the variance between tags (σ = 0.015 s·h−1), showing that recording frequency is a characteristic of each tag and not a random variable. Furthermore, we observed a large offset (0.54 ± 0.016 s·h−1) between two groups of tags that had differing recording frequencies, and we observed three instances of instantaneous temporal jumps within datasets introducing errors into the data streams. Finally, we show that relative drift rates can be estimated even when deployed on animals displaying various behaviors without the tags needing to be simultaneously moved. For the tags used in this study, drift rates can vary significantly between tags, are repeatable, and can be accurately measured in the field. The temporal alignment of multiple tag datasets allows researchers to deploy multiple tags on an individual animal which will greatly increase our knowledge of movement kinematics and expand the range of movement characteristics that can be used for behavioral classification. [ABSTRACT FROM AUTHOR]

Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs. [ABSTRACT FROM AUTHOR]

This study explored the development of polyvinylpyrrolidone (PVP)–honey-gel (PHG) through 3D printing, aiming to develop a multifunctional bio-tape with adhesive and degradable properties. Based on the potential of honey to promote wound healing due to its antibacterial and anti-inflammatory properties, a PVP–honey-based 3D printing ink was developed by combining honey and PVP to create PHG through 3D printing technology that can form a film with strong adhesion and flexibility. First, the chemical–physical properties of PHG and its 3D printing performance were characterized. The line width achievable in 3D printing for the PHG line can extend to ∼100 µm. In addition, the adhesive properties of the PHG film were evaluated by using a 180° peeling test on various materials (glass, copper, wood, and pig skin), highlighting its potential for diverse applications. Finally, the application of the PHG film as a bio-tape was demonstrated through a successful animal experiment on a rabbit's skin wound. Due to its adhesive and degradable properties, the bio-tape exhibited 3D conformability and ease of removal without residue. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncolytic herpes simplex viruses (oHSVs) employ as natural entry receptors nectin1 or HVEM. In contrast, retargeted oHSVs (ReHVs) employ as an entry receptor a tumor-associated antigen that no longer interacts with nectin1/HVEM and, thus, spares normal cells. Prior to entry, both oHSVs and ReHVs attach to cells by interaction of gC and gB glycoproteins with heparan sulphates and chondroitin sulphates (glycosaminoglycans–GAGs). The systemic delivery of oncolytic viruses would be the ideal route for hard-to-reach or metastatic cancers that constitute unmet clinical needs. In an accompanying paper, we reported that the blood complement and the antiviral neutralizing antibodies represent the major blood factors that inactivate systemically administered ReHVs. Here, we asked whether ReHV adsorption to GAGs acts as a sink and subtracts the virus from circulation. We report that a genetic modification in gC, which reduced its interaction with GAGs, resulted in a longer half-life of circulating ReHV and a higher anticancer efficacy of systemically (but not intratumorally) administered ReHV. The role of the interaction with cell-surface glycosaminoglycans (GAGs) during in vivo HSV infection is currently unknown. The rationale of the current investigation was to improve the anticancer efficacy of systemically administered retargeted oHSVs (ReHVs) by decreasing their binding to GAGs, including those of endothelial cells, blood cells, and off-tumor tissues. As a proof-of-principle approach, we deleted seven amino acids critical for interacting with GAGs from the glycoprotein C (gC) of R-337 ReHV. The modification in the resulting R-399 recombinant prolonged the half-life in the blood of systemically administered R-399 and enhanced its biodistribution to tumor-positive lungs and to the tumor-negative liver. Ultimately, it greatly increased the R-399 efficacy against metastatic-like lung tumors upon IV administration but not against subcutaneous tumors upon IT administration. These results provide evidence that the increased efficacy seen upon R-399 systemic administration correlated with the slower clearance from the circulation. To our knowledge, this is the first in vivo evidence that the partial impairment of the gC interaction with GAGs resulted in a prolonged half-life of circulating ReHV, an increase in the amount of ReHV taken up by tissues and tumors, and, ultimately, an enhanced anticancer efficacy of systemically administered ReHV. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmunity illness, mainly featured with synovitis of the joint. The specificity of ferroptosis is disparate in different diseases, and the mechanism of ferroptosis in RA has some uncertainty yet. Therefore, the mechanism of ferroptosis was deeply observed in RA patients and animal models. In this paper, plasma of RA patients, the tumor necrosis factor-alpha-induced human synovial fibroblasts, and an animal model of arthritis induced by collagen were applied to initially inquire about the therapeutic effect of ferroptosis. For the RA patients, ELISA detected protein expression of glutathione (GSH), GPX4, Nrf2, Keap-1, and ferritin. In cell experiments, erastin or fer-1 regulated the invasion of human synovial fibroblast cells, mitochondrial membrane potential, reactive oxygen species (ROS) expression, marker protein, and so on. For the animal experiments, 32 Sprague–Dawley male rats were randomly separated into four groups with a collagen-induced RA model for 14 days and administered with erastin or fer-1 for 35 days. The expressions of GSH, GPX4, Nrf2, and Keap-1 were lower, and the ferritin was higher in RA patients, and the expressions of these proteins varied significantly after disease remission. In addition, ferroptosis inactivation also reduced the proliferation and migration ability, mitochondrial membrane potential, and ROS in cells. We discovered unexpectedly that activation of ferroptosis meaningfully forbore the foot swelling in animals with CIA, reduced arthritis scores, destruction of bone, and articular synovitis, and also decreased the high expression of inflammatory factors in plasma. There is a nonlinear relationship between human disease manifestations and animal model pathology. Ferroptosis regulating in RA for humans or animals may produce different effects. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluates the effectiveness of a combined regimen involving injectable hydrogels for the treatment of experimental myocardial infarction. Patient concerns: Myocardial infarction is an acute illness that negatively affects quality of life and increases mortality rates. Experimental models of myocardial infarction can aid in disease research by allowing for the development of therapies that effectively manage disease progression and promote tissue repair. Diagnosis: Experimental animal models of myocardial infarction were established using the ligation method on the anterior descending branch of the left coronary artery (LAD). Interventions: The efficacy of intracardiac injection of hydrogels, combined with cells, drugs, cytokines, extracellular vesicles, or nucleic acid therapies, was evaluated to assess the functional and morphological improvements in the post-infarction heart achieved through the combined hydrogel regimen. Outcomes: A literature review was conducted using PubMed, Web of Science, Scopus, and Cochrane databases. A total of 83 papers, including studies on 1332 experimental animals (rats, mice, rabbits, sheep, and pigs), were included in the meta-analysis based on the inclusion and exclusion criteria. The overall effect size observed in the group receiving combined hydrogel therapy, compared to the group receiving hydrogel treatment alone, resulted in an ejection fraction (EF) improvement of 8.87% [95% confidence interval (CI): 7.53, 10.21] and a fractional shortening (FS) improvement of 6.31% [95% CI: 5.94, 6.67] in rat models, while in mice models, the improvements were 16.45% [95% CI: 11.29, 21.61] for EF and 5.68% [95% CI: 5.15, 6.22] for FS. The most significant improvements in EF (rats: MD = 9.63% [95% CI: 4.02, 15.23]; mice: MD = 23.93% [95% CI: 17.52, 30.84]) and FS (rats: MD = 8.55% [95% CI: 2.54, 14.56]; mice: MD = 5.68% [95% CI: 5.15, 6.22]) were observed when extracellular vesicle therapy was used. Although there have been significant results in large animal experiments, the number of studies conducted in this area is limited. Conclusion: The present study demonstrates that combining hydrogel with other therapies effectively improves heart function and morphology. Further preclinical research using large animal models is necessary for additional study and validation. [ABSTRACT FROM AUTHOR]

Viral diseases affecting both humans and animals are a serious public problem. Chemical modifications of the structure of compounds of natural origin, e.g., betulin, seem to be a promising model in the search for new antiviral agents. The subject of our work was to conduct preliminary tests on the antiviral activity of phosphonic derivatives of betulin and betulinic acid and to assess the pharmacokinetic profile of target compounds. Human (HHV-1, HAdV-5) and animal viruses (BEV, VSV) were used in the in vitro tests. Additionally, this paper presents the results of research using in silico methods (ADMET and molecular docking). Two compounds (betulin 29-phosphonate 3 and 3-(3′,3′-dimethylsuccinyl)betulin acid 29-phosphonate 8a) showed antiviral activity against BEV, and compound 3 was also active against HAdV-5. For compound 3, which showed advantageous pharmacokinetic parameters, molecular docking was performed to determine possible interactions with the cellular target HAdV-5 endopeptidase, which plays an important role in various functions of the virus. Selecting the most active derivatives makes it possible to plan tests on an animal model. [ABSTRACT FROM AUTHOR]

Simple Summary: TP is a widely utilized anticancer medication, particularly effective in treating HCC. Thorough investigation into TP's molecular mechanism in HCC treatment is crucial for precise and combination therapy. In this paper, we have unveiled a novel mechanism of TP in HCC treatment, where it inhibits tumor growth by reducing lipid accumulation. While the inhibition of P53 gene activity is commonly thought to be the reason for TP's effectiveness in treating HCC, this new mechanism serves as a significant complement to the current understanding, paving the way for innovative approaches to HCC treatment. Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective therapeutic drug for HCC. However, its precise therapeutic mechanism is still unknown. Understanding the mechanism of action of TP against HCC is crucial for its implementation in the field of HCC treatment. We hypothesize that the anti-HCC actions of TP might be related to its modulation of HCC lipid metabolism given the crucial role that lipid metabolism plays in promoting the progression of HCC. In this work, we first demonstrate that, both in vitro and in vivo, TP significantly reduces lipid accumulation in HCC cells. Additionally, we notice that lipoprotein lipase (LPL) expression is markedly upregulated in HCC, and that its levels are positively connected with the disease's progression. It is interesting to note that TP dramatically reduces LPL activity, which in turn prevents HCC growth and reduces lipid accumulation. Additionally, the effect of TP on LPL is a direct correlation. These results definitely demonstrate that TP protects hepatocytes against abnormal accumulation of lipids by transcriptionally suppressing LPL, which reduces the development of HCC. This newly identified pathway provides insight into the process through which TP exerts its anti-HCC actions. [ABSTRACT FROM AUTHOR]

The American Association for Laboratory Animal Science endorses the United States Government "Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training" and requires that all papers published in Comparative Medicine report research conducted in conformance with these principles. Research for papers submitted from outside the United States must be in conformance with the guidelines of that country's government. The Editor reserves the right to reject papers reporting results of research not adhering to these principles.

The American Association for Laboratory Animal Science endorses the United States Government "Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training" and requires that all papers published in Comparative Medicine report research conducted in conformance with these principles. Research for papers submitted from outside the United States must be in conformance with the guidelines of that country's government. The Editor reserves the right to reject papers reporting results of research not adhering to these principles.

The crucial issue in electrical impedance (EI) measurements lies in the galvanic interaction between the electrodes and the investigated material. This paper brings together the basic and applied research experience and combines their results with excellent properties. Consequently, innovative precise methodologies have emerged, enabling the direct modeling of EI measurements, free from the inaccuracies often associated with numerical approaches. As an outcome of the efficiency and robustness of the applied method, the conductivity of the material and the electrodes are represented by a common piecewise function, which is used to solve the differential equation modeling of the EI measurement. Moreover, this allows the possibility for modeling the conductivity of electrodes with continuous functions, providing an important generalization of the Complete Electrode Model (CEM), which has been widely used so far. The effectiveness of the novel approach was showcased through two distinct case studies. In the first case study, potential functions within both the material and the electrodes were computed using the CEM. In the second case study, calculations were performed utilizing the newly introduced continuous electrode model. The simulation results suggest that the new method is a powerful tool for biological research, from in vitro experiments to animal studies and human applications. [ABSTRACT FROM AUTHOR]

For patients who had testicular tissue cryopreserved before receiving gonadotoxic therapies, transplantation of testicular tissues and cells has been recommended as a potential therapeutic option. There are no studies that indicate the generation of sperm after human immature testicular tissue (ITT) or spermatogonial stem cells (SSCs) transplantation. The use of releasing scaffolds and localized drug delivery systems as well as the optimizing transplantation site can play an effective role in increasing the efficiency and improving the quality of testicular tissue and cell transplantation in animal models. Current research is focused on optimizing ITT and cell transplantation, the use of releasing scaffolds, and the selection of the right transplantation site that might restore sperm production or male infertility treatment. By searching the PubMed and Google Scholar databases, original and review papers were collected. Search terms were relevant for SSCs and tissue transplantation. In this review, we'll focus on the potential advantages of using scaffolds and choosing the right transplantation site to improve transplantation outcomes. [ABSTRACT FROM AUTHOR]

D-allulose, D-sorbose and D-tagatose are D-fructose isomers that are called rare sugars. These rare sugars have been studied intensively in terms of biological production and food application as well as physiological effects. There are limited papers with regard to the transporters mediating the intestinal absorption of these rare sugars. We examined whether these rare sugars are absorbed via sodium-dependent glucose cotransporter 1 (SGLT1) as well as via GLUT type 5 (GLUT5) using rats. High-fructose diet fed rats, which express more intestinal GLUT5, exhibited significantly higher peripheral concentrations, Cmax and AUC0–180 min when D-allulose, D-sorbose and D-tagatose were orally administrated. KGA-2727, a selective SGLT1 inhibitor, did not affect the peripheral and portal vein concentrations and pharmacokinetic parameters of these rare sugars. The results suggest that D-allulose, D-sorbose and D-tagatose are likely transported via GLUT5 but not SGLT1 in rat small intestine. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) generally recurs locally with a dismal median survival of <18 months. Combining thermal therapy with radiation therapy enhances radiation response and improves clinical outcomes. This study evaluates a thermobrachytherapy balloon implant intended for the simultaneous heat and radiation treatment of tumor resection cavities. The data demonstrate that our prototype implant produces spherically symmetric heat and radiation dose distributions around the balloon, while the in vivo experiments confirm our ability to heat ≥40 °C at a 5 mm distance from the balloon surface in highly perfused pig brain tissue. The device is now ready for the finalization of regulatory approvals in anticipation of early-stage clinical investigation. Previous work has reported the design of a novel thermobrachytherapy (TBT) balloon implant to deliver magnetic nanoparticle (MNP) hyperthermia and high-dose-rate (HDR) brachytherapy simultaneously after brain tumor resection, thereby maximizing their synergistic effect. This paper presents an evaluation of the robustness of the balloon device, compatibility of its heat and radiation delivery components, as well as thermal and radiation dosimetry of the TBT balloon. TBT balloon devices with 1 and 3 cm diameter were evaluated when placed in an external magnetic field with a maximal strength of 8.1 kA/m at 133 kHz. The MNP solution (nanofluid) in the balloon absorbs energy, thereby generating heat, while an HDR source travels to the center of the balloon via a catheter to deliver the radiation dose. A 3D-printed human skull model was filled with brain-tissue-equivalent gel for in-phantom heating and radiation measurements around four 3 cm balloons. For the in vivo experiments, a 1 cm diameter balloon was surgically implanted in the brains of three living pigs (40–50 kg). The durability and robustness of TBT balloon implants, as well as the compatibility of their heat and radiation delivery components, were demonstrated in laboratory studies. The presence of the nanofluid, magnetic field, and heating up to 77 °C did not affect the radiation dose significantly. Thermal mapping and 2D infrared images demonstrated spherically symmetric heating in phantom as well as in brain tissue. In vivo pig experiments showed the ability to heat well-perfused brain tissue to hyperthermic levels (≥40 °C) at a 5 mm distance from the 60 °C balloon surface. [ABSTRACT FROM AUTHOR]

For the diagnosis of pediatric osteomyelitis, the sensitivity, specificity, and predictive value of erythrocyte sedimentation rate (ESR) were evaluated in this study.Methods: A systematic computer-based search was performed for relevant articles focusing on the ESR diagnosis of pediatric osteomyelitis in PubMed, Embase, and the Cochrane Library with an inclusion criteria: 1) the diagnostic utility of ESR for diagnosing osteomyelitis patients under the age of 18;2) two-by-two contingency tables can be obtained. Case reports, review papers, and animal experiments were excluded.Results: The diagnostic meta-analysis included 8 studies involving 348 children with osteomyelitis, all of whom were tested for ESR. Diagnostic meta-analysis revealed a sensitivity and specificity of 0.90, 95% confidence interval (CI) (0.86– 0.93), and 0.50 (95% CI,0.47– 0.54) for ESR in pediatric osteomyelitis diagnosis, respectively. The positive likelihood ratio (LR), negative LR, and diagnostic odds ratio were 1.38,(95% CI,1.08– 1.78), 0.46, (95% CI,0.26– 0.73), and 3.20, (95% CI,1.33– 7.69), respectively. The area under the curve (AUC) was determined to be 0.80 based on the summary receiver operating characteristic curve (SROC).Conclusion: The literature on the use of ESR in pediatric osteomyelitis diagnosis was thoroughly reviewed in this study. It was also found that ESR may be useful as a biomarker for pediatric osteomyelitis diagnosis. Due to its low specificity, it should be used in combination with other markers such as C-reactive protein, neutrophil percentage, and white blood cell count. [ABSTRACT FROM AUTHOR]

This review outlines the function of oxidative stress in DR and discusses therapeutic strategies to treat DR with antioxidants. Published papers on oxidative stress in DR and therapeutic strategies to treat DR with antioxidants were collected and reviewed via database searching on PubMed. The abnormal development of DR is a complicated process. The pathogenesis of DR has been reported to involve oxidative stress, despite the fact that the mechanisms underlying this are still not fully understood. Excessive reactive oxygen species (ROS) accumulation can damage retina, eventually leading to DR. Increasing evidence have demonstrated that antioxidant therapy can alleviate the degeneration of retinal capillaries in DR. Oxidative stress can play an important contributor in the pathogenesis of DR. Furthermore, animal experiments have shown that antioxidants are a beneficial therapy for treating DR, but more clinical trial data is needed. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA), characterized by inflammation and articular cartilage degradation, is a prevalent arthritis among geriatric population. This paper was to scrutinize the novel mechanism of long noncoding RNA (lncRNA) NEAT1 in OA etiology. Methods: A total of 10 OA patients and 10 normal individuals was included in this study. Cell model of OA was built in human normal chondrocytes induced by lipopolysaccharide (LPS). An OA Wistar rat model was established through intra-articular injection of L-cysteine and papain mixtures (proportion at 1:2) into the right knee. Quantitative reverse transcription-polymerase chain reaction was employed to ascertain the expression levels of NEAT1, microRNA (miR)-374b-5p and post-GPI attachment to protein 1 (PGAP1), while dual-luciferase reporter experiments were used for the validation of target relationship among them. Cell cycle and apoptosis were calculated by flow cytometry analysis. CCK-8 assay was done to evaluate the proliferative potentials of chondrocytes. The levels of cell cycle-related proteins (Cyclin A1, Cyclin B1 and Cyclin D2) and pro-apoptotic proteins (Caspase3 and Caspase9) were measured by western blotting. Tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6 levels were determined via ELISA. Hematoxylin & eosin (HE) Staining was used for pathological examination in OA rats. Results: Pronounced downregulation of NEAT1 and PGAP1 and high amounts of miR-374b-5p were identified in OA patients, LPS-induced chondrocytes and OA rats. NEAT1 targeted miR-374b-5p to control PGAP1 expression. Loss of NEAT1 or upregulation of miR-374b-5p dramatically accelerated apoptosis, led to the G1/S arrest and promoted the secretion of inflammatory cytokines in LPS-induced chondrocytes, while ectopic expression of PGAP1 exhibited the opposite influences on chondrocytes. Additionally, we further indicated that upregulation of miR-374b-5p attenuated the effects of PGAP1 overexpression on LPS-induced chondrocytes. Conclusions: Reduced NEAT1 induces the development of OA via miR-374b-5p/PGAP1 pathway. This suggests that the regulatory axis NEAT1/miR-374b-5p/PGAP1 is a novel and prospective target for OA treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic tumours present significant treatment challenges due to their resistance to chemotherapy and complex tumour microenvironment. Choosing the appropriate preclinical models and understanding how their characteristics affect drug delivery to the tumours is essential for designing clinically relevant experiments. This study investigates pancreatic tumours growing orthotopically or subcutaneously and presents the properties of their tumour microenvironments and their impacts on drug delivery. Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper presents an experimental study on a brachytherapy multi-needle insertion device, manipulated using a collaborative robot, to assess a set of characteristics: accuracy, needle deflection due to resistance forces, instrument and needle wear and the influence of insertion speed and rotation during needle manipulation inside the liver parenchyma. This paper presents a study regarding the design and the experimental setup of a medical robotic system for brachytherapy using tribology analysis. The robotic system is composed of a collaborative robotic arm and a multi-needle brachytherapy instrument controlled using a unified control system embedding a haptic device and force-feedback. This work is oriented towards identifying the technical characteristics of the system components to determine the accuracy of the procedure, as well as using different scenarios for needle insertion in ex vivo porcine liver tissue in order to determine the forces required for insertion and extraction of the needle and the friction coefficient that accompanies the previously mentioned forces. Subsequent to the computation of the friction forces, the normal forces and the wear during the needle insertion are determined with the scope of predicting the lifecycle of some components of the medical device. [ABSTRACT FROM AUTHOR]

The animal‐centric approach so far predominantly employed in risk assessment has been questioned in recent years due to a number of shortcomings regarding performance, consistency, transferability of results, sustainability, costs and ethical reasons. Alternatives to animal testing, collectively termed NAMs, may have the potential to deliver sound, cost‐effective, prompt and reliable information, but their regulatory acceptance has not been established yet. The main reasons behind this are mostly related to actual methodological obstacles, with particular reference to addressing complex endpoints such as repeated‐dose toxicity, the issue of translating the concept of adversity to NAMs, and doubts of stakeholders about the level of chemical safety ensured by NAMs. With the aim of providing an updated view on major conceptual and methodological developments in the field of toxicology, a symposium and a workshop were organised by the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) and Helmholtz Centre for Environmental Research on 15–17 November 2021 in Berlin. The conference, entitled 'Challenges in Public Health Protection in the 21st Century: New Methods, Omics and Novel Concepts in Toxicology' brought together eminent scientists with representatives from industry and regulatory authorities. The organisation, day‐to‐day operations and the reporting of the event main outcomes in a position paper were the main focus of the present EFSA EU‐FORA work programme. Tasks pertaining to 'The use of NAMs and omics data in risk assessment' were implemented under the shared supervision of units 'Testing and Assessment Strategies Pesticides' and 'Effect‐based Analytics and Toxicogenomics' of the German Federal Institute for Risk Assessment. [ABSTRACT FROM AUTHOR]

Biomaterials with osteoinductivity are widely used for bone defect repair due to their unique structures and functions. Machine learning (ML) is pivotal in analyzing osteoinductivity and accelerating new material design. However, challenges include creating a comprehensive database of osteoinductive materials and dealing with low-quality, disparate data. As a standard for evaluating the osteoinductivity of biomaterials, ectopic ossification has been used. This paper compiles research findings from the past thirty years, resulting in a robust database validated by experts. To tackle issues of limited data samples, missing data, and high-dimensional sparsity, a data enhancement strategy is developed. This approach achieved an area under the curve (AUC) of 0.921, a precision of 0.839, and a recall of 0.833. Model interpretation identified key factors such as porosity, bone morphogenetic protein-2 (BMP-2), and hydroxyapatite (HA) proportion as crucial determinants of outcomes. Optimizing pore structure and material composition through partial dependence plot (PDP) analysis led to a new bone area ratio of 14.7 ± 7 % in animal experiments, surpassing the database average of 10.97 %. This highlights the significant potential of ML in the development and design of osteoinductive materials. This study leverages machine learning to analyze osteoinductive biomaterials, addressing challenges in database creation and data quality. Our data enhancement strategy significantly improved model performance. By optimizing pore structure and material composition, we increased new bone formation rates, showcasing the vast potential of machine learning in biomaterial design. [Display omitted] [ABSTRACT FROM AUTHOR]

The number of genome assemblies has rapidly increased in recent history, with NCBI databases reaching over 41,000 eukaryotic genome assemblies across about 2,300 species. Increases in read length and improvements in assembly algorithms have led to increased contiguity and larger genome assemblies. While this number of assemblies is impressive, only about a third of these assemblies have corresponding genome size estimations for their respective species on publicly available databases. In this paper, genome assemblies are assessed regarding their total size compared to their respective publicly available genome size estimations. These deviations in size are assessed related to genome size, kingdom, sequencing platform, and standard assembly metrics, such as N50 and BUSCO values. A large proportion of assemblies deviate from their estimated genome size by more than 10%, with increasing deviations in size with increased genome size, suggesting nonprotein coding and structural DNA may be to blame. Modest differences in performance of sequencing platforms are noted as well. While standard metrics of genome assessment are more likely to indicate an assembly approaching the estimated genome size, much of the variation in this deviation in size is not explained with these raw metrics. A new, proportional N50 metric is proposed, in which N50 values are made relative to the average chromosome size of each species. This new metric has a stronger relationship with complete genome assemblies and, due to its proportional nature, allows for a more direct comparison across assemblies for genomes with variation in sizes and architectures. [ABSTRACT FROM AUTHOR]

This paper presents a novel, cost-effective multisensory system designed for animal monitoring in research settings. The system aims to objectively assess animal welfare and discomfort during experiments, addressing the need for affordable monitoring solutions in research laboratories. Developed and validated in compliance with European regulations on animal experimentation and in accordance with the requirements of the Animal Research Centre at the University of Alcala´ in Madrid. The system integrates Raspberry Pi 4 Model B and Arduino Uno boards with various sensors, including temperature, humidity, ammonia, airborne particles, and an RGB camera. A user-friendly web interface allows remote monitoring and management of the system. This innovation promises to improve the efficiency and feasibility of animal research, enabling more precise and ethical experimentation while advancing scientific knowledge and animal welfare. [ABSTRACT FROM AUTHOR]

The relevance of the study is that pathological and morphological changes with feline infectious peritonitis have been studied by few authors and are not fully described. The purpose of this study was to investigate the effect of the causative agent of infectious peritonitis on the structure of the spleen in cats. The paper highlights the results of histological studies of sections obtained from distinct parts of the spleen of cats of different ages who died from mixed (26 animals) and dry (7 animals) forms of infectious peritonitis. Sections were stained with haematoxylin and eosin according to the generally accepted method. The paper describes the details of microscopic changes in the spleen in dry and mixed forms of feline infectious peritonitis. It was found that these changes are not affected by the form of the disease but are characterized by features depending on the duration of its course. In cats in which the disease lasted up to three weeks before death, the red pulp of the spleen was unevenly swollen, infiltrated by lymphocytes and monocytes, in some places contained foci of necrotic cells, and red blood cells were absent. Changes in the white pulp were represented by hyperplasia of lymphoid nodules. These nodules were of varied sizes and were located eccentrically relative to the central arteries. There are no distinct lymphoid nodules around part of the central arteries. On the surface of the capsule, fibrinous-necrotic overlays are present in places, under which there is no mesothelium, and the capsule is infiltrated with lymphocytes and monocytes. In other areas, mesotheliocytes underwent distinct metaplasia from flat cells, they turned into columnar cells. In some areas of the spleen, some animals have no serous membrane. In cats with the disease lasting over three weeks, the red pulp is noticeably more swollen, and the lymphoid nodules are single and small. Other microscopic changes were the same as in animals that were ill for less than three weeks. The results of the study are of practical value for pathologists, as well as for scientists investigating the pathogenesis of feline infectious peritonitis [ABSTRACT FROM AUTHOR]

Almost a decade after the stipulated deadline in the 7th amendment to the EU Cosmetics Directive, which bans the marketing of animal-tested cosmetics in the EU from 2013, animal experimentation for cosmetic-related purposes remains a topic of animated debate. Cosmetic industry continues to be scrutinised for the practice, despite its leading role in funding and adopting innovation in this field. This paper aims to provide a state-of-the-art review of the field on alternative testing methods, also known as New Approach Methodologies (NAMs), with the focus on assessing the safety of cosmetic ingredients and products. It starts with innovation drivers and global regulatory responses, followed by an extensive, endpoint-specific overview of accepted/prospective NAMs. The overview covers main developments in acute toxicity, skin corrosion/irritation, serious eye damage/irritation, skin sensitisation, repeated dose toxicity, reproductive toxicity/endocrine disruption, mutagenicity/genotoxicity, carcinogenicity, photo-induced toxicity, and toxicokinetics. Specific attention was paid to the emerging in silico methodology. This paper also provides a brief overview of the studies on public perception of animal testing in cosmetics. It concludes with a view that educating consumers and inviting them to take part in advocacy could be an effective tool to achieve policy changes, regulatory acceptance, and investment in innovation. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment (TME) and play a key role in TME, participating in the process of tumor occurrence, growth, invasion, and metastasis. Among them, metastasis to tumor tissue is the key step of malignant development of tumor. In this paper, the latest progress in the role of TAMs in the formation of tumor microenvironment is summarized. It is particularly noteworthy that cell and animal experiments show that TAMs can provide a favorable microenvironment for the occurrence and development of tumors. At the same time, clinical pathological experiments show that the accumulation of TAMs in tumor is related to poor clinical efficacy. Finally, this paper discusses the feasibility of TAMs-targeted therapy as a new indirect cancer therapy. This paper provides a theoretical basis for finding a potentially effective macrophage-targeted tumor therapy. [ABSTRACT FROM AUTHOR]

In this review, we explored the potential of a zebrafish model to investigate the antioxidant effects of key components of the Mediterranean diet, namely, olive oil and wine, in the context of preventing age-related diseases, particularly cardiovascular conditions. This paper explores the spectrum of observational studies to preclinical investigations and ultimately converges toward potential translational insights derived from animal experimentation. This review highlights the potential and underutilization of zebrafish as an experimental model in this domain. We highlighted the genetic proximity of zebrafish to humans, offering a unique opportunity for translational insights into the health benefits of olive oil and wine. Indeed, we wanted to focus on the potential of zebrafish to elucidate the health benefits of olive oil and wine while calling for continued exploration to unlock its full potential to advance our knowledge of age-related disease prevention within the Mediterranean diet framework. [ABSTRACT FROM AUTHOR]

Background: Stroke is a major contributor to disability and death worldwide. Studies have demonstrated that inflammasome/pyroptosis and its mediated inflammatory response are important factors aggravating brain injury after stroke. We aimed to investigate and map the knowledge structure and global trends on inflammasome/pyroptosis in stroke. Methods: All relevant documents were obtained from the Web of Science on 5 June 2023. Bibliometric visualization diagrams were created using VOSviewer and CiteSpace. Excel was used for statistical analysis and drawing graphs. Results: A total of 1106 publications were included, with more articles published each year, especially since 2014. China (740 papers), Zhejiang University (57 papers), Wang J (25 papers), and the Journal of Neuroinflammation (45 papers) were the most productive countries, institutions, authors, and journals, respectively. The United States was the country with highest centrality (0.56) and total link strength (171), and all of the top 10 institutions were in China. China and the U.S. cooperated closely. The centralities of the top 10 authors were all lower than 0.01; no leader has yet emerged in this field. "NLRP3 inflammasome" ranked first with 447 occurrences among 2136 keywords, of which 56 terms appeared more than 10 times when categorized into four clusters: cluster 1 (inflammation), cluster 2 (pyroptosis), cluster 3 (NLRP3 inflammasome), and cluster 4 (neuroinflammation). The studies focused on the mechanisms of inflammasome/pyroptosis in stroke were mainly limited to cell and animal experiments. Conclusion: Interest in inflammasome/pyroptosis in stroke is progressively increasing. The NLRP3 inflammasome is the most extensively studied and has been a research hotspot. The mechanisms of cell death in stroke are complex and future studies are needed to strengthen the clinical research on the relationship between pyroptosis-related processes and stroke, determine at which stage NLRP3 inflammasome activation, and clarify the detailed mechanism of NLRP3 in stroke. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper, we report on the inhibition of glioblastoma (GBM) cell growth and migration by the putative S1PR1 modulator ACT-2009905, using appropriate in vitro models. This work is based on our previously published finding that S1PR1 expression is strongly up-regulated in human glioblastoma samples and the fact that there is an association between S1PR1 with patients' survival times. We now show that pharmacological modulation by the putative S1PR1 modulator ACT-209905 inhibits GBM cell growth and migration. Furthermore, we investigated the influence of co-culture of GBM cells with THP-1 cells as a model for human monocytes, showing pro-tumoral effects and arguing for a complex interplay between GBM cells, immune cells and underlying signaling pathways. We believe that this manuscript fits the interests of the readership of the journal Cancers as it addresses the impact of alternative therapeutic options using ACT-209905 for improving GBM therapy. Glioblastoma (GBM) is still a deadly tumor due to its highly infiltrative growth behavior and its resistance to therapy. Evidence is accumulating that sphingosine-1-phosphate (S1P) acts as an important tumor-promoting molecule that is involved in the activation of the S1P receptor subtype 1 (S1PR1). Therefore, we investigated the effect of ACT-209905 (a putative S1PR1 modulator) on the growth of human (primary cells, LN-18) and murine (GL261) GBM cells. The viability and migration of GBM cells were both reduced by ACT-209905. Furthermore, co-culture with monocytic THP-1 cells or conditioned medium enhanced the viability and migration of GBM cells, suggesting that THP-1 cells secrete factors which stimulate GBM cell growth. ACT-209905 inhibited the THP-1-induced enhancement of GBM cell growth and migration. Immunoblot analyses showed that ACT-209905 reduced the activation of growth-promoting kinases (p38, AKT1 and ERK1/2), whereas THP-1 cells and conditioned medium caused an activation of these kinases. In addition, ACT-209905 diminished the surface expression of pro-migratory molecules and reduced CD62P-positive GBM cells. In contrast, THP-1 cells increased the ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905. In conclusion, our study suggests the role of S1PR1 signaling in the growth of GBM cells and gives a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells. [ABSTRACT FROM AUTHOR]

The drug development process involves a variety of drug activity evaluations, which can determine drug efficacy, strictly analyze the biological indicators after the drug action, and use these indicators as the preclinical drug evaluation criteria. At present, most of the screening of preclinical anticancer drugs mainly relies on traditional 2D cell culture. However, this traditional technology cannot simulate the tumor microenvironment in vivo, let alone reflect the characteristics of solid tumors in vivo, and has a relatively poor ability to predict drug activity. 3D cell culture is a technology between 2D cell culture and animal experiments, which can better reflect the biological state in vivo and reduce the consumption of animal experiments. 3D cell culture can link the individual study of cells with the study of the whole organism, reproduce in vitro the biological phenotype of cells in vivo more greatly, and thus predict the activity and resistance of anti-tumor drugs more accurately. In this paper, the common techniques of 3D cell culture are discussed, with emphasis on its main advantages and application in the evaluation of anti-tumor resistance, which can provide strategies for the screening of anti-tumor drugs. [ABSTRACT FROM AUTHOR]

Background: Sepsis poses a serious threat to human life and health, with limited options for current clinical treatments. Acupuncture plays an active role in treating sepsis. However, previous studies have focused on the neuromodulatory effect of acupuncture, neglecting its network modulatory effect. Exosomes, as a new way of intercellular communication, may play an important role in transmitting acupuncture information. This paper explores the possibility of electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs as a potential treatment for sepsis. Methods: The sepsis mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS) (12 mg/kg, 24 mg/kg), and EA (continuous wave, 10 Hz, intensity 5) or intraperitoneal injection of Acupuncture Exosomes (Acu-exo) were performed before the model establishment. The therapeutic effect was evaluated by survival rate, ELISA, H&E staining and lung wet/dry weight ration (W/D). In vivo imaging of small animals was used to observe the accumulation of Acu-exo in various organs of sepsis mice. LPS was used to induce macrophages in cell experiments, and the effect of Acu-exo on macrophage inflammatory cytokines was observed. In addition, The miRNA sequencing method was further used to detect the serum exosomes of normal and EA-treated mice, and combined with network biology analysis methods to screen possible key targets. Results: EA and Acu-exo reduced the W/D and lung tissue damage in sepsis mice, down-regulated the expression of serum inflammatory cytokines TNF-α and IL-6, and increased the survival rate of sepsis mice. In vivo imaging of small animals found that Acu-exo were accumulated in the lungs of sepsis mice. Cell experiments proved that Acu-exo down-regulated the expression of inflammatory cytokines TNF-α, IL-6 and IL-1β to alleviate the inflammatory response induced by LPS in macrophages. MiRNA sequencing revealed 53 differentially expressed miRNAs, and network biology analysis revealed the key targets of Acu-exo in sepsis treatment. Conclusion: Electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs may be a potential treatment for sepsis. [ABSTRACT FROM AUTHOR]