Potential antitumor effects of short-chain fatty acids in breast cancer models.

The effects of short-chain fatty acids (SCFAs) have been explored against cancer due to the crosstalk between gut microbiota alterations and the immune system as a crucial role in cancer development. We evaluated the SCFAs effects in both in vitro and in vivo breast cancer models. In vitro, the SCFAs displayed contrasting effects on viability index, according to the evaluation of breast cancer cells with different phenotypes, human MCF-7, SK-BR-3, MDA-MD-231, or the mouse 4T1 lineage. Acetate displayed minimal effects at concentrations up to 100 mM. Alternatively, propionate increases or reduces cell viability depending on the concentration. Butyrate and valerate showed consistent time- and concentration-dependent effects on the viability of human or mouse breast cancer cells. The selective FFA2 4-CMTB or FFA3 AR420626 receptor agonists failed to overtake the SCFA actions, except by modest inhibitory effects on MDA-MB-231 and 4T1 cell viability. The FFA2 CATPB or FFA3 and ß-hydroxybutyrate receptor antagonists lacked significant activity on human cell lines, although CATPB reduced 4T1 cell viability. Butyrate significantly affected cell morphology, clonogenicity, and migration, according to the evaluation of MDA-MB-231 and 4T1 cells. A preliminary examination of in vivo oral effects of butyrate, propionate, or valerate, dosed in prophylactic or therapeutic regimens, on several parameters evaluated in an orthotopic breast cancer model showed a reduction of lung metastasis in post-tumor induction butyrate-treated mice. Overall, the present results indicate that in vitro effects of SCFAs did not rely on FFA2 or FFA3 receptor activation, and they were not mirrored in vivo, at least at the tested conditions. Overall, the present results indicate potential in vitro inhibitory effects of SCFAs in breast cancer, independent of FFA2 or FFA3 receptor activation, and, in the metastatic breast cancer model, the butyrate-dosed therapeutic regimen reduced the number of lung metastases.

Myotonometry and extended field-of-view ultrasound imaging allow reliable quantification of patellar tendon stiffness and length at rest and during maximal load, whereas several restrictions exist for the Achilles tendon.

Introduction: Stiffness and length are well-established tendon parameters in sports and medicine. Myotonometry and ultrasound imaging are the commonly used methods to quantify these parameters. However, further studies are needed to clarify the reliability of these methods, especially when assessing maximally loaded tendons and when conducted by different experienced investigators. This study aimed to determine the intra- and interrater reliabilities of measuring the stiffness and length of the patellar tendon (PT) and Achilles tendon (AT) using the myotonometry method and the extended field-of-view ultrasound (EFOV-US) technique at rest and maximal load performed by different experienced investigators. Methods: Twenty-seven participants were examined on three different days by one experienced investigator and one novice investigator. Primary outcomes were the intraclass correlation coefficient (ICC) and associated 95% confidence interval (95% CI), coefficient of variation (CV), standard error of measurement (SEM), and minimal detectable change (MDC) across the measurement days and investigators. Results: For PT measurements at rest and maximal load, the estimated ICCs for stiffness and length were ≥.867 and ≥.970, respectively, with 95% CIs ranging from poor (.306) to excellent (.973) and good (.897) to excellent (.999). The CV, SEM, and MDC for PT stiffness and length were ≤5.2% and ≤2.0%, ≤39.3 N/m and ≤0.9 mm, and ≤108.9 N/m and ≤2.6 mm, respectively. For AT measurements, some restrictions were evident for stiffness at rest and both parameters at maximal load. However, regarding AT length at rest, the estimated ICC was ≥.996, with an excellent 95% CI (.987-.999). The CV, SEM, and MDC for AT length at rest were 2.8%, ≤1.1 mm, and ≤2.9 mm, respectively. Conclusion: The estimated ICCs show good to excellent reliability for the myotonometry method and the EFOV-US technique for measuring PT stiffness and length at rest and maximal load for experienced and novice investigators. However, some restrictions are evident for the AT, especially for measurements at maximal load.

Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity.

It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.

High-Throughput In Vivo Screening Identifies Differential Influences on mRNA Lipid Nanoparticle Immune Cell Delivery by Administration Route.

Immune modulation through the intracellular delivery of nucleoside-modified mRNA to immune cells is an attractive approach for in vivo immunoengineering, with applications in infectious disease, cancer immunotherapy, and beyond. Lipid nanoparticles (LNPs) have come to the fore as a promising nucleic acid delivery platform, but LNP design criteria remain poorly defined, making the rate-limiting step for LNP discovery the screening process. In this study, we employed high-throughput in vivo LNP screening based on molecular barcoding to investigate the influence of LNP composition on immune tropism with applications in vaccines and systemic immunotherapies. Screening a large LNP library under both intramuscular (i.m.) and intravenous (i.v.) injection, we observed differential influences on LNP uptake by immune populations across the two administration routes, gleaning insight into LNP design criteria for in vivo immunoengineering. In validation studies, the lead LNP formulation for i.m. administration demonstrated substantial mRNA translation in the spleen and draining lymph nodes with a more favorable biodistribution profile than LNPs formulated with the clinical standard ionizable lipid DLin-MC3-DMA (MC3). The lead LNP formulations for i.v. administration displayed potent immune transfection in the spleen and peripheral blood, with one lead LNP demonstrating substantial transfection of splenic dendritic cells and another inducing substantial transfection of circulating monocytes. Altogether, the immunotropic LNPs identified by high-throughput in vivo screening demonstrated significant promise for both locally- and systemically-delivered mRNA and confirmed the value of the LNP design criteria gleaned from our screening process, which could potentially inform future endeavors in mRNA vaccine and immunotherapy applications.

Ultrabright NIR-IIb Fluorescence Quantum Dots for Targeted Imaging-Guided Surgery.

Pioneering approaches for precise tumor removal involve fluorescence-guided surgery, while challenges persist, including the low fluorescence contrast observed at tumor boundaries and the potential for excessive damage to normal tissue at the edges. Lead/cadmium sulfide quantum dots (PbS@CdS QDs), boasting high quantum yields (QYs) and vivid fluorescence, have facilitated advancements in the second near-infrared window (NIR-II, 900-1700 nm). However, during fluorescent surgical navigation operations, hydrophilic coatings of these inorganic nanoparticles (NPs) guarantee biosafety; it also comes at the expense of losing a significant portion of QY and NIR-II fluorescence, causing heightened damage to normal tissues caused by cutting edges. Herein, we present hydrophilic core-shell PbS@CdS@PEG NPs with an exceptionally small diameter (∼8 nm) and a brilliant NIR-IIb (1500-1700 nm) emission at approximately 1600 nm. The mPEG-SH (MW: 2000) addresses the hydrophobicity and enhances the biosafety of PbS@CdS QDs. In vivo fluorescence-guided cervical tumor resection becomes achievable immediately upon injection of an aqueous solution of PbS@CdS@PEG NPs. Notably, this approach results in a significantly reduced thickness (100-500 µm) of damage to normal tissues at the margins of the resected tumors. With a high QY (∼30.2%) and robust resistance to photobleaching, NIR-IIb imaging is sustained throughout the imaging process.

Synthesis, molecular modeling simulations and anticancer activity of some new Imidazo[2,1-b]thiazole analogues as EGFR/HER2 and DHFR inhibitors.

New imidazo[2,1-b]thiazole analogs were designed, synthesized, and biologically evaluated as anticancer agents. In vitro biological evaluation of the anticancer properties of the compounds was performed against different cancer cell lines. Compounds 23 and 39 showed remarkable broad -spectrum cytotoxic potency on most of the tested cell lines. Compounds 23 and 39 exhibited potent activity against the MCF-7 breast cancer cell line, with IC50 values of 1.81 and 4.95 µM, respectively, compared to DOX and SOR (IC50 values of 4.17 and 7.26 µM, respectively). An enzyme inhibition assay was carried out to clarify the possible mode of action of the tested compounds. Compounds 23 and 39 were identified as possible EGFR, HER-2, and DHFR inhibitors. Cell cycle arrest results indicated that compound 23 caused cell cycle arrest at the G0/G1 phase in the MCF-7 cells and at the G2/M phase in the Hep G2 cells. Compound 39 induced cell cycle arrest at the G2/M phase in Hela cells. In vivo testing of the anticancer activity of the two most promising molecules in this study was conducted, and the results indicated that they possess considerable in vivo anticancer activity in mice. Data obtained from the molecular modeling simulation study were consistent with the biological evaluation results.

In Vivo Confocal Microscopy and Anterior Segment Optical Coherence Tomography Findings of Patients with Iridocorneal Endothelial Syndrome.

This case report aims to present the findings of in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) in three patients with iridocorneal endothelial (ICE) syndrome. Three female patients 37, 50, and 57 years of age presented with complaints of unilateral visual impairment and elevated intraocular pressure (IOP). Biomicroscopy revealed unilateral pupil irregularities and anterior synechiae, and gonioscopy demonstrated synechiae in the iridocorneal angle. IOP was within normal limits with medical treatment in two patients, while one patient had an IOP of 44 mmHg despite maximal antiglaucomatous treatment. IVCM revealed large, polymorphic, and hyperreflective cells in the corneal endothelial layer of the affected eyes and normal corneal epithelium, stroma, and endothelium in the fellow eyes. AS-OCT findings were normal in healthy eyes, while the affected eye showed synechiae in the iridocorneal angle and a hyperreflective, thickened endothelial layer. The patient with refractory glaucoma underwent trabeculectomy surgery with 5-fluorouracil. In conclusion, IVCM and AS-OCT allow a detailed examination of endothelial cell abnormalities and iridocorneal membranes in ICE syndrome, which is characterized by unilateral pupil and iris irregularities and anterior synechiae mainly in women.

Superior In Vivo Wound-Healing Activity of Biosynthesized Silver Nanoparticles with Nepeta cataria (Catnip) on Excision Wound Model in Rat.

Silver nanoparticles were biosynthesized with Nepeta cataria plant extract. It was determined that the synthesized Nc-AgNPs gave a strong absorbance peak at 438 nm wavelength in the UV-vis spectrophotometer. SEM and TEM analyses of Nc-AgNPs showed that the synthesized nanoparticles had a spherical morphology. Based on XRD analysis, the average crystallite size of Nc-AgNPs was calculated at 15.74 nm. At the same time, EDS spectrum analysis exhibited dominant emission energy at 3 keV, indicative of Nc-AgNPs. Nc-AgNPs showed an inhibition zone of 12 nm in gram-negative Escherichia coli, 10 nm in gram-positive Enterococcus faecalis, and 11 nm in Staphylococcus aureus. Nc-AgNPs showed high antioxidant properties, with 63% at 5000 µg/mL. The wound-healing properties of Nc-AgNPs were evaluated in vivo in wound models created in a total of 20 Wistar albino male rats, divided into four groups. After 10 days of treatment, the highest wound closure rate was seen in the Nc-AgNP + Vaseline (Group IV) treatment group, at 94%. It was observed that Nc-AgNP + Vaseline nanoformulation significantly increased wound healing, similar to Silverdin®, and Vaseline alone supported healing but did not result in complete closure. Histopathological examination revealed an increase in mature Type 1 collagen in Group IV and positive control (Group II), with better collagen maturation in vehicle control (Group III) compared to negative control (Group I). Immunohistochemical analysis showed complete epithelialization in Group IV and Group II, with distinct cytokeratin expressions, while Group III exhibited mild expressions.

Progress in experimental models to investigate the in vivo and in vitro antidiabetic activity of drugs.

Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders, and it is a rapidly growing global public health issue. It is characterized by hyperglycemia, a condition involving a high blood glucose level brought on by deficiencies in insulin secretion, decreased activity of insulin, or both. Prolonged effects of diabetes include cardiovascular problems, retinopathy, neuropathy, nephropathy, and vascular alterations in both macro- and micro-blood vessels. In vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis, identifying targets, and reviewing novel treatment options and medications. Fully understanding these models is crucial for the researchers so this review summarizes the different experimental in vivo and in vitro model options used to study diabetes and its consequences. The most popular in vivo studies involves the small animal models, such as rodent models, chemically induced diabetogens like streptozotocin and alloxan, and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals. Other models include virally induced models, diet/nutrition induced diabetic animals, surgically induced models or pancreatectomy models, and non-obese models. Large animals or non-rodent models like porcine (pig), canine (dog), nonhuman primate, and Zebrafish models are also outlined. The in vitro models discussed are murine and human beta-cell lines and pancreatic islets, human stem cells, and organoid cultures. The other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition of α-glucosidase activity.

Computational Polarization Imaging In Vivo through Surgical Smoke Using Refined Polarization Difference.

In surgery, the surgical smoke generated during tissue dissection and hemostasis can degrade the image quality, affecting tissue visibility and interfering with the further image processing. Developing reliable and interpretable computational imaging methods for restoring smoke-affected surgical images is crucial, as typical image restoration methods relying on color-texture information are insufficient. Here a computational polarization imaging method through surgical smoke is demonstrated, including a refined polarization difference estimation based on the discrete electric field direction, and a corresponding prior-based estimation method, for better parameter estimation and image restoration performance. Results and analyses for ex vivo, the first in vivo animal experiments, and human oral cavity tests show that the proposed method achieves visibility restoration and color recovery of higher quality, and exhibits good generalization across diverse imaging scenarios with interpretability. The method is expected to enhance the precision, safety, and efficiency of advanced image-guided and robotic surgery.

In-situ measurements of dissolved gases in xylem sap as tracers in plant physiology.

Trees transport gases from below ground into the atmosphere through the process of transpiration. Tracing gases transported through this mechanism continuously and under field conditions remains an experimental challenge. Here we measured gases dissolved in tree sap in-situ and in real time, aiming to simultaneously analyse the transport of several gases (He, Ar, Kr, N2, O2, CO2) from the soil, through the trees, into the atmosphere. We constructed and inserted custom-made semi-permeable membrane probes in the xylem of a fir tree and measured gas abundances at different heights using a portable gas equilibrium membrane-inlet mass spectrometer ('miniRUEDI'). With this method we were able to continuously measure the abundances of He, Ar, Kr, N2, O2, CO2 in sap over several weeks. We observed diurnal variations of CO2 and O2 concentrations that reflected tree physiological activities. As a proof of concept that trees do uptake dissolved gases in soil water, we irrigated the tree with He-enriched water in a tracer experiment, and were able to determine upwards sap flow velocity. Measurements of inert gases together with reactive species as CO2 and O2 allows to separate physical transport and exchange of gases derived from the soil or the atmosphere from biological reactions. We discuss the opportunities that our technique provides for continuous in-situ measurements of gases in tree sap.

Preclinical techniques for drug discovery in psoriasis.

Psoriasis is a chronic, inflammatory, papulosquamous, noncontagious disease characterized by scaly, demarcated erythematous plaque, affecting skin, nails, and scalp. The IL-23/Th17 axis is the main operator in the development of psoriasis. Psoriasis is affecting worldwide, and new treatment options are urgently needed. Various local and systemic treatments are available for psoriasis but they only provide symptomatic relief because of numerous unknown mechanisms. Clinical trials demand overwhelming resources; therefore, drug development predominantly depends on the in-vivo, in-vitro, and ex-vivo techniques. Immediate attention is required to develop experimental techniques that completely imitate human psoriasis to assist drug development. This review portrays the various in-vivo, in-vitro, and ex-vivo techniques used in psoriasis research. It describes these techniques' characteristics, pathological presentations, and mechanisms. The experimental techniques of psoriasis provide significant information on disease progression mechanisms and possible therapeutic targets. However, until now, it has been challenging to invent a timely, affordable model that precisely imitates a human disease. Only the xenotransplantation model is reckoned as the closer, that mimics the complete genetic, and immunopathogenic event. Imiquimod-induced psoriasis and HaCat cell lines are popular among researchers because of their convenience, ease of use, and cost-effectiveness. There need to further improve the experimental techniques to best serve the disease imitation and meet the research goal.

A simple calibration routine for small inorganic scintillation detectors for in vivo dosimetry during brachytherapy.

BACKGROUND: In vivo dosimetry (IVD) is rarely performed in brachytherapy (BT), allowing potential dose misadministration to go unnoticed. This study presents a clinical routine-calibration method of detectors for IVD in high (HDR) and pulsed dose rate (PDR) Ir-192 BT. PURPOSE: To evaluate the dosimetric precision and feasibility of an in-clinic calibration routine of detectors for IVD in afterloading BT. METHODS: Calibrations were performed in a PMMA phantom with two needles inserted 20 mm apart. The source was loaded in one of the needles at 15 dwells for 10 s. The detector was placed in the other needle, and its signal was recorded. The mean signal at each dwell position was fitted to the expected dose rate with the calibration factor and the detector's longitudinal position being free parameters. The method was tested with an inorganic scintillation detector using one Ir-192 FlexiSource HDR and two Ir-192 GammaMedPlus PDR sources and followed by validation measurements in water. RESULTS: The standard measurement uncertainty (k = 1) of the calibration factor in absolute terms (Gy/s) was 3.2/3.4% for the HDR/PDR source. The uncertainty was dominated by source strength uncertainty, and the precision of the method was <1%. The mean ± 1SD of the difference in measured and expected dose rate during validation was 1.5 ± 4.7% (HDR) and 0.0 ± 4.1% (PDR) with a positional uncertainty in the setup of 0.33/0.23 mm (HDR/PDR) (k = 1). CONCLUSION: A precise and feasible in-clinic calibration method for IVD and source strength consistency tests in BT was presented.

Decoding changes in tumor-infiltrating leukocytes through dynamic experimental models and single-cell technologies.

The ability to characterize immune cells and explore the molecular interactions that govern their functions has never been greater, fueled in recent years by the revolutionary advance of single-cell analysis platforms. However, precisely how immune cells respond to different stimuli and where differentiation processes and effector functions operate remain incompletely understood. Inferring cellular fate within single-cell transcriptomic analyses is now omnipresent, despite the assumptions typically required in such analyses. Recently developed experimental models support dynamic analyses of the immune response, providing insights into the temporal changes that occur within cells and the tissues in which such transitions occur. Here we will review these approaches and discuss how these can be combined with single-cell technologies to develop a deeper understanding of the immune responses that should support the development of better therapeutic options for patients.

Astrocyte coverage of excitatory synapses correlates to measures of synapse structure and function in ferret primary visual cortex.

Most excitatory synapses in the mammalian brain are contacted or ensheathed by astrocyte processes, forming tripartite synapses. Astrocytes are thought to be critical regulators of the structural and functional dynamics of synapses. While the degree of synaptic coverage by astrocytes is known to vary across brain regions and animal species, the reason for and implications of this variability remains unknown. Further, how astrocyte coverage of synapses relates to in vivo functional properties of individual synapses has not been investigated. Here, we characterized astrocyte coverage of synapses of pyramidal neurons in the ferret visual cortex and, using correlative light and electron microscopy, examined their relationship to synaptic strength and sensory-evoked Ca2+ activity. Nearly, all synapses were contacted by astrocytes, and most were contacted along the axon-spine interface. Structurally, we found that the degree of synaptic astrocyte coverage directly scaled with synapse size and postsynaptic density complexity. Functionally, we found that the amount of astrocyte coverage scaled with how selectively a synapse responds to a particular visual stimulus and, at least for the largest synapses, scaled with the reliability of visual stimuli to evoke postsynaptic Ca2+ events. Our study shows astrocyte coverage is highly correlated with structural metrics of synaptic strength of excitatory synapses in the visual cortex and demonstrates a previously unknown relationship between astrocyte coverage and reliable sensory activation.

Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases.

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.

Maximum in-vivo joint contact forces double during active compared to assisted motion in the glenohumeral joint and decline long-term due to rotator cuff pathologies.

Rehabilitation programs advocate early passive and assisted motion after rotator cuff repair to induce healing und maintaining range of motion while avoiding excessive strain on the repaired tendons. In-vivo glenohumeral joint contact forces reflect the compressive forces generated by the rotator muscles. In the present study, maximum in-vivo joint contact forces (FresMax) were determined to compare active and assisted execution of a single movement and the long-term development of joint compression forces. FresMax were measured in six patients who received instrumented, telemetric modified anatomical hemi endoprostheses of the shoulder joint between 2006 and 2008. Data were gathered 23 months postoperatively (2006-2010), were analysed and compared with measurements 133 months postoperatively. Additional imaging was obtained as x-rays and ultrasound examination. Data analysis was conducted by synchronizing video tapes and measured force curves. New imaging showed a rupture of the M. supraspinatus and progressive joint degeneration. FresMax nearly doubled during active compared to assisted execution of each of the four chosen movements. Over the course of 133 months post-surgery, the studied movements showed a decrease of active compression force, probably due to a ruptured supraspinatus, resulting in a lower active/assisted ratio. A long term follow up after eleven years, eight out of ten measured movements showed a decrease of FresMax. These results support current rehabilitation protocols recommending early passive and assisted motion to limit activation of the rotator muscles generating compressive forces. Following degeneration of the rotator cuff, active joint contact forces decrease over time.Level of evidence: III.

Changes in protein fluxes in skeletal muscle during sequential stages of muscle regeneration after acute injury in male mice.

Changes in protein turnover play an important role in dynamic physiological processes, including skeletal muscle regeneration, which occurs as an essential part of tissue repair after injury. The inability of muscle tissue to recapitulate this regenerative process can lead to the manifestation of clinical symptoms in various musculoskeletal diseases, including muscular dystrophies and pathological atrophy. Here, we employed a workflow that couples deuterated water (2H2O) administration with mass spectrometry (MS) to systematically measure in-vivo protein turnover rates across the muscle proteome in 8-week-old male C57BL6/J mice. We compared the turnover kinetics of over 100 proteins in response to cardiotoxin (CTX) induced muscle damage and regeneration at unique sequential stages along the regeneration timeline. This analysis is compared to gene expression data from mRNA-sequencing (mRNA-seq) from the same tissue. The data reveals quantitative protein flux signatures in response to necrotic damage, in addition to sequential differences in cell proliferation, energy metabolism, and contractile gene expression. Interestingly, the mRNA changes correlated poorly with changes in protein synthesis rates, consistent with post-transcriptional control mechanisms. In summary, the experiments described here reveal the signatures and timing of protein flux changes during skeletal muscle regeneration, as well as the inability of mRNA expression measurements to reveal changes in directly measured protein turnover rates. The results of this work described here provide a better understanding of the muscle regeneration process and could help to identify potential biomarkers or therapeutic targets.

Soft tissue material properties based on human abdominal in vivo macro-indenter measurements.

Simulations of human-technology interaction in the context of product development require comprehensive knowledge of biomechanical in vivo behavior. To obtain this knowledge for the abdomen, we measured the continuous mechanical responses of the abdominal soft tissue of ten healthy participants in different lying positions anteriorly, laterally, and posteriorly under local compression depths of up to 30 mm. An experimental setup consisting of a mechatronic indenter with hemispherical tip and two time-of-flight (ToF) sensors for optical 3D displacement measurement of the surface was developed for this purpose. To account for the impact of muscle tone, experiments were conducted with both controlled activation and relaxation of the trunk muscles. Surface electromyography (sEMG) was used to monitor muscle activation levels. The obtained data sets comprise the continuous force-displacement data of six abdominal measurement regions, each synchronized with the local surface displacements resulting from the macro-indentation, and the bipolar sEMG signals at three key trunk muscles. We used inverse finite element analysis (FEA), to derive sets of nonlinear material parameters that numerically approximate the experimentally determined soft tissue behaviors. The physiological standard values obtained for all participants after data processing served as reference data. The mean stiffness of the abdomen was significantly different when the trunk muscles were activated or relaxed. No significant differences were found between the anterior-lateral measurement regions, with exception of those centered on the linea alba and centered on the muscle belly of the rectus abdominis below the intertubercular plane. The shapes and areas of deformation of the skin depended on the region and muscle activity. Using the hyperelastic Ogden model, we identified unique material parameter sets for all regions. Our findings confirmed that, in addition to the indenter force-displacement data, knowledge about tissue deformation is necessary to reliably determine unique material parameter sets using inverse FEA. The presented results can be used for finite element (FE) models of the abdomen, for example, in the context of orthopedic or biomedical product developments.

Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer's disease.

Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking. Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß status and tau-PET were included. Forty-one EOAD individuals aged ≤65 years and, as comparison, late-onset AD (LOAD, ≥70 years, n=154) and Aß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found. Conclusions: We found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies.