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The recent increase in new technologies to analyze host-pathogen interaction has fostered a race to develop new methodologies to assess these not only on the cellular level, but also on the tissue level. Due to mouse-other mammal differences, there is a desperate need to develop relevant tissue models that can more closely recapitulate the host tissue during disease and repair. Whereas organoids and organs-on-a-chip technologies have their benefits, they still cannot provide the cellular and structural complexity of the host tissue. Here, precision cut tissue slices (PCTS) may provide invaluable models for complex ex-vivo generated tissues to assess host-pathogen interaction as well as potential vaccine responses in a “whole organ” manner. In this mini review, we discuss the current literature regarding PCTS in veterinary species and advocate that PCTS represent remarkable tools to further close the gap between target identification, subsequent translation of results into clinical studies, and thus opening avenues for future precision medicine approaches.

Computational modelling method is an important technique to better understand bone mechanical properties and the relationship between bone structure and its mechanical, as well as biological environment. The chapter first introduces three distinct computational modelling examples of bone, i.e., subject-specific quantitative computed tomography (QCT) image-based nonlinear finite element modelling of proximal femur for bone strength estimation, microfinite element modelling for trabecular bone yield behaviors at the tissue level, and dynamic modelling for the mechanical behaviors of trabecular bone in the intertrochanteric fracture fixation. It then describes computational simulations of bone remodelling and adaptation of trabecular bone to mechanical and biological factors.

Context: Alterations in the plasma sodium concentration ([Na+]p) is predicted based on changes in the mass balance of Na+, K+, and H2O. However, it is well appreciated that Na+ retention results in both osmotically active and osmotically inactive Na+ storage and that only osmotically active Na+ contributes to the modulation of the [Na+]p. Subject of Review: Recent clinical studies suggested that prediction of changes in the [Na+]p based on the mass balance of Na+, K+, and H2O is inaccurate since the osmotically inactive Na+ storage pool is dynamically regulated. In contrast, animal studies demonstrated that changes in the [Na+]p can be predicted if the total body Na+, K+, and H2O were to be accurately accounted for. Second Opinion: Our analysis demonstrated that alterations in the [Na+]p are predictable at the total body level if all sources of input and output of Na+, K+, and H2O can be accurately accounted for despite the paradoxical finding that there are changes in the osmotically inactive Na+ storage pool at the tissue level. However, future prospective clinical studies are needed to corroborate the findings in the animal studies. We proposed that the fundamental question as to whether changes in the [Na+]p can be predicted in the face of osmotically inactive sodium storage is best addressed by serial measurements of total body exchangeable Na+ and K+ and total body water by isotope dilution at different time intervals.

A recent paper in BMC Biology entitled “A tissue level atlas of the healthy human virome” by Kumata et al. describes a meta-transcriptomic analysis of RNA-sequencing datasets from the Genotype-Tissue Expression (GTEx) Project. Using a workflow that maps the GTEx sequences to the human genome, then screens unmapped sequences to detect viral transcripts, the authors present a quantitative analysis of the presence of different viruses in the nondiseased tissues of over 500 individuals and assess the impact of these viruses on host gene expression. Here we draw attention to an issue not acknowledged in this study. Namely, by relying solely on GTEx datasets, which are enriched for transcripts with poly(A) tails, the analysis will have missed non-poly(A) viral transcripts, rendering this tissue level atlas of the virome incomplete, Spanish Ministry of Economy, Industry and Competitiveness (MINECO), European Union (EU) RYC-2016-21199 ENDORE SAF2017-87526-R, FEDER/Junta de Andalucía -Consejería de Economía y Conocimiento: MENDO B-CTS-500-UGR18, University of Granada Plan Propio de Investigacion 2016 -Excellence actions: Unit of Excellence on Exercise and Health (UCEES) SOMM17/6107/UGR, Spanish Ministry of Science, Innovation and Universities PRE2018-0854409 FPU19/01638

Recent advances in omics studies have enabled analysis at the single-cell level; however, methods for analyzing the whole cell of large organs and tissues remain challenging. Here, we developed a method named tsChIL to understand the diverse cellular dynamics at the tissue level using high-depth epigenomic data. tsChIL allowed the analysis of a single tissue section and could reproducibly acquire epigenomic profiles from several types of tissues, based on the distribution of target epigenomic states, tissue morphology, and number of cells. The proposed method enabled the independent evaluation of changes in cell populations and gene activation of cells in regenerating skeletal muscle tissues, using a statistical model of RNA polymerase II distribution on gene loci. Thus, the integrative analysis by tsChIL can elucidate in vivo cell-type dynamics of tissues.

The biological pacemaker was a promising therapy for cardiac diseases such as sick sinus syndrome and atrioventricular block. A lot of experiments showed that pacemaker cells can be transformed from non-rhythmic cardiac cells or stem cells by gene therapy. However, at the tissue level, the electrophysiological properties between rhythmic and non-rhythmic regions are different. For example, the expression of connexin (such as Cx43) reduced in the induced-pacemaker cells which means that the pacemaker cells may have a less electrical coupling with adjacent cells. In addition, some researches indicated that the spatial distribution of pacemaker cells influenced the excitability of cardiac tissue. To the best of our knowledge, it is still unclear how the spatial distribution of bio-pacemaker cells affects the pacemaking behaviour in biological pacemaker tissue. In this study, we constructed a series of two-dimensional pacemaker-ventricle models containing different distributions of pacemaker cells to investigate the effect of spatial distribution on the pacemaking behaviour. Three kinds of models were designed in our simulations: (1) Tight model; (2) Embedded model; (3) Electrically isolated model. The pacemaking ability of cardiac tissue was measured by the least ratio of pacemaker cells needed to drive the whole tissue. Simulation results showed that electrically isolated model was the optimal model as it showed the best pacemaking ability among these three models. This study may guide the clinical use of bio-pacemaker.

Air pollution has been long recognized as a hazardous factor for the human cardiovascular system. Sulfur dioxide $(SO_{2})$ is a common ambient air pollutant that is able to cause detrimental effects on hearts. Though the cardiotoxicity effects by sulfur dioxide were well documented in epidemiological reports, however, the underlying mechanisms remain unclear owing to the technical limitations that exist in traditional experimental measures. In this article, we developed a multi-scale virtual ventricular tissue, which incorporated electrophysiological activities from subcellular to tissue levels and could provide comprehensive records and insightful mechanisms of the SO 2 induced ventricular arrhythmias. Based on the available cellular and molecular experimental data, our findings provide a rationale at tissue level in support of epidemiologic studies pointing to the deleterious effects of SO 2 pollution on cardiac function.

Purpose: Advances in surface technology and the understanding of the capabilities of osseointegrating implants have led to the use of shorter implants in a variety of clinical situations. Such implant use offers a number of potential advantages in the posterior maxilla and mandible. The purpose of this retrospective study was to examine the success rates of shorter, tissue-level implants in function for at least 60 months. Materials and Methods: A retrospective study was conducted of all patients treated between January 1, 1998, and December 31, 2012, who received tissue-level endosseous implants 8 mm or less in length, which were restored with abutments and single crowns. Patient age, sex, location of implants, and diameter of implants were examined. Time in function and stability of peri-implant crestal bone were assessed. Results: The retrospective analysis identified 4,251 tissue-level implants that were restored with single abutments and crowns. These implants were followed for up to 228 months in function, with a mean time in function of 127.2 months. Implant success was assessed using commonly utilized metrics combined with bone sounding on the midbuccal and midlingual/ palatal aspects of the implants. The cumulative success rate was 99.5% for all implants. In the posterior mandible, the success rate for regular-neck implants was 99.3% (n = 680, mean time in function: 136.5 months) and was 99.7% for wideneck implants (n = 2,320, mean time in function: 124.5 months). In the posterior maxilla, the success rate for regular-neck implants was 97.8% (n = 211, mean time in function: 169.1 months), and for wide-neck implants, it was 99.2% (n = 1,040, mean time in function: 127.8 months). Conclusion: The use of shorter (8 mm or less in length) tissue-level implants in the maxilla and mandible, restored with single abutments and crowns, offers a viable treatment option, assuming specific criteria and protocols are followed. These criteria and protocols are discussed.

Nowadays, multi-walled carbon nanotubes are considered to be emerging contaminants and their impact in ecosystem has drawn special research attention, while other contaminants, such as caffeine, have more coverage in literature. Despite this, the effects of a combination of the two has yet to be evaluated, especially considering predicted temperature rise. In the present study a typical bioindicator species for marine environment, the clam Ruditapes decussatus, and classical tools, such as biomarkers and histopathological indices, were used to shed light on the species' response to these contaminants, under actual and predicted warming scenarios. The results obtained showed that both contaminants have a harmful effect at tissue level, as shown by higher histopathological index, especially in digestive tubules. Temperatures seemed to induce greater biochemical impacts than caffeine (CAF) and –COOH functionalized multi-walled carbon nanotubes (f-MWCNTs) when acting alone, namely in terms of antioxidant defences and energy reserves content, which were exacerbated when both contaminants were acting in combination (MIX treatment). Overall, the present findings highlight the complex response of clams to both pollutants, evidencing the role of temperature on clams’ sensitivity, especially to mixture of pollutants.

Plants are living information-processing organisms with highly adaptive behavior, allowing them to prosper in a harsh and fluctuating environment in spite of being sessile. Lacking a central nervous system, plants are distributed systems orchestrating complex computational processes performed at the tissue level. Here I consider plant tropisms as a useful input–output system boasting a robust mathematical description, naturally permitting a dialogue between mathematical modeling and biological observations. I propose tropisms as an ideal framework for the study of plant computational processes, allowing us to infer the relationship between observed tropic responses and known stimuli. I concentrate on macroscopic models, and elucidate this approach by presenting recent examples focusing on computational processes involved at different hierarchical levels of interactions: a plant's interaction with itself and its internal state, with the abiotic environment, and with neighboring plants.

Omics approaches for investigating biological systems were introduced in the mid-1990s and quickly consolidated to become a fundamental pillar of modern biology. The idea of measuring the whole complement of genes, transcripts, proteins, and metabolites has since become widespread and routinely adopted in the pursuit of an infinity of scientific questions. Incremental improvements over technical aspects such as sampling, sensitivity, cost, and throughput pushed even further the boundaries of what these techniques can achieve. In this context, single-cell genomics and transcriptomics quickly became a well-established tool to answer fundamental questions challenging to assess at a whole tissue level. Following a similar trend as the original development of these techniques, proteomics alternatives for single-cell exploration have become more accessible and reliable, whilst metabolomics lag behind the rest. This review summarizes state-of-the-art technologies for spatially resolved metabolomics analysis, as well as the challenges hindering the achievement of sensu stricto metabolome coverage at the single-cell level. Furthermore, we discuss several essential contributions to understanding plant single-cell metabolism, finishing with our opinion on near-future developments and relevant scientific questions that will hopefully be tackled by incorporating these new exciting technologies.

Background Many factors play a role in the long-term survival of osseointegrated dental implants. Among these, the preservation of crestal bone remains to be the key principal. The aim of this comparative study was to assess crestal bone loss (CBL) between tissue-level implants restored with platform matching abutments and bone-level implants restored with conical/platform switched hybrid abutments in the posterior molar region. Results All implants in both groups showed a 100% survival and success rate at 1 year. Mean CBL for group I was 0.8 mm (SD 0.85), and mean CBL for group II was 0.18 mm (SD 0.48). There was a statistically significant difference between the CBL in both groups (p Conclusion Within the limitations of the sample size of this study, both implant designs showed minimal CBL at 1-year post-loading. Bone level implants with a platform switched conical hybrid connection showed less CBL compared to tissue level implants.

Cardiac cellular models are utilized as the building blocks for tissue simulation. One of the imprecisions of conventional cellular modeling, especially when the models are used in tissue-level modeling, stems from the mere consideration of cellular properties (e.g., action potential shape) in parameter tuning of the model. In our previous work, we put forward an accurate framework in which membrane resistance (R m ) reflecting inter-cellular characteristics, i.e., electrotonic effects, was considered alongside cellular features in cellular model fitting. This paper, for the first time, examines the hypothesis that considering R m as an additional optimization objective improves the accuracy of tissue-level modeling. To study this hypothesis, after cellular-level optimization of a well-known model, source-sink mismatch configurations in a 2-dimensional model are investigated. The results demonstrate that including R m in the optimization protocol yields a substantial improvement in the relative error of the critical transition border which is defined as the minimum window size between source and sink that wave propagates. Model developers can utilize the proposed concept during parameter tuning to increase the accuracy of models.

BACKGROUND Tissue expansion relies on the ability of skin to grow in response to sustained mechanical strain. This study focuses on correlation of cellular and histologic changes with skin growth and deformation during tissue expansion. METHODS Tissue expanders were placed underneath the skin of five Yucatan minipigs and inflated with one fill of 60 cc of saline 1 hour, 24 hours, 3 days, and 7 days before the animals were killed, or two fills of either 30 cc or 60 cc at 10 and 3 days or 14 and 7 days before the animals were killed. Skin biopsy specimens and three-dimensional photographs were used to calculate skin growth and stretch according to the authors' novel finite element analysis model. RESULTS The mitotic index of keratinocytes in the basal layer increased 1 hour after stimulus was applied (4 percent) (p = 0.022), peaked at approximately day 3 (26 percent) (p < 0.0001), and tapered by day 7 (12.5 percent) (p = 0.012) after tissue expansion. The authors demonstrated that it is the volume per fill rather than the total volume in the expander that scales the magnitude of response. Lastly, the authors demonstrated that the ratio of deformation attributable to growth versus stretch (Fgrowth/Fstretch) after 60 cc of tissue expansion fill was 1.03 at 1 hour, 0.82 at 1 day, 0.85 at day 3, and 0.95 at 7 days. CONCLUSIONS Peak cell proliferation occurred 3 days after tissue expansion fill and is scaled in response to stimulus magnitude. The growth component of deformation equilibrates to the stretch component at day 7, as cell proliferation has started to translate to skin growth.

Cell shape changes are key to observable changes at the tissue level during morphogenesis and organ formation. The major driver of cell shape changes in turn is the actin cytoskeleton, both in the form of protrusive linear or branched dynamic networks and in the form of contractile actomyosin. Over the last 20 years, actomyosin has emerged as the major cytoskeletal system that deforms cells in epithelial sheets during morphogenesis. By contrast, the second major cytoskeletal system, microtubules, have so far mostly been assumed to serve ‘house-keeping' functions, such as directed transport or cell division, during morphogenetic events. Here, I will reflect on a subset of studies over the last 10 years that have clearly shown a major direct role for the microtubule cytoskeleton in epithelial morphogenesis, suggesting that our focus will need to be widened to give more attention and credit to this cytoskeletal system in playing an active morphogenetic role. This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.

Tensile forces influence a variety of important biological processes and force sensors are required to study these processes in vivo. Current force sensors are often tailor-made for a specific application, or activate at much higher forces than those observed at the cellular or tissue level. A versatile force sensor, with tunable mechanical and optical properties, activated at low pN forces will be ideal. In this communication, a new mechanoresponsive fluorescent hydrogen-bonded rotaxane, built around a maleimide dye, is reported. Its force-sensing properties are demonstrated in a polyacrylamide gel, a synthetic model of living tissue.

Nonlinear optical imaging techniques have been widely used to reveal biological structures for accurate diagnosis at the cellular as well as the tissue level. In the present study, polarization-dependent second-harmonic generation (PSHG) was used to determine collagen orientation in breast cancer biopsy tissues (grades 0, I, II and III). The obtained data were processed using fast Fourier transform (FFT) analysis, while second-harmonic generation (SHG) anisotropy and the "ratio parameter" values were also calculated. Such measurements were shown to be able to distinguish collagen structure modifications in different cancer grades tested. The analysis presented herein suggests that PSHG imaging could provide a quantitative evaluation of the tumor state and the distinction of malignant from benign breast tissues. The obtained results also allowed the development of a biophysical model, which can explain the aforementioned differentiations and is in agreement with the simulations relating the SHG anisotropy values with the mechanical tension applied to the collagen during cancer progression. The current approach could be a step forward for the development of new, nondestructive, label free optical diagnostic tools for cancer reducing the need of recalls and unnecessary biopsies, while potentially improving cancer detection rates.

The aim of the studywas analysis of oxygen status of patients with neonatal sepsis during monitoring of premature infants. Materials and methods.Indicators of oxygen status of capillary blood were assessed in premature infants with neonatal sepsis who were treated at the Regional Perinatal Center in Khmelnytsky during 2017–2018. The study included mostly deeply premature babies, including those with extremely low weight. A full range of clinical and laboratory studies, including determination of oxygen status of capillary blood. Research results.Our results allow us to conclude that while such indicators as pH, pO2, BEb3, % SO2do not change significantly, the trouble can be detected using indicators such as AdDO2, RI, PI, which reflect the state of oxygenation with impaired ventilation. -perfusion ratios, increased blood shunting and the processes of delivery and consumption of oxygen at the tissue level. The calculated indicator "PIP×FiO2" was less sensitive to assess changes in the lungs and did not correspond to the clinical picture of the severity of the patient's condition. Conclusion. Thus, the determination of AdDO2, RI, PI capillary blood can be used as informative indicators for determining the oxygen status in premature infants, which is of significant practical importance in terms of limited monitoring of the gas composition of arterial blood

Purpose: to assess any differences on marginal bone loss between bone-level or tissue-level dental implants through a review of literature until September 2019. Materials and methods: MEDLINE, Embase and other database were searched by two independent authors. The search was limited to articles in English. Results: The search provided 1028 records and, after removing the duplicates through titles and abstracts screening, 45 full-text articles were assessed for eligibility. For qualitative analysis 20 articles were included, 17 articles of them for quantitative analysis. A total of 1161 patients (mean age 54,4 years) and 2933 implants were observed, 1427 (Tissue-level) and 1506 (Bone-level). The survival rate and the success rate were more than 90%, except for 2 studies with a success rate of 88% and 86.2%. No studies reported any differences between groups in term of success and survival rates. Three studies showed that BL-implants had statistically less marginal bone loss (P< 0.05). Only one study reported statistically less marginal bone loss in TL-implants (P< 0.05). In the most part of the studies, differences between implant types in marginal bone loss were not statistically significant. Conclusion: Despite to the peri-implant tissue around transmucosal implants has been reported to be inflammation-free because of the absence of bacterial infiltration in the micro-gap between the fixture and abutment, no clinical and radiological differences were highlighted between groups from the included studies after a variable period of follow-up ranged between 1 to 5 years.

Numerous randomised controlled multicentric studies have investigated various responses to different treatment modalities with dental implants. These studies do not always show the results of daily practice as they are performed under controlled and strict clinical conditions. This multicentric, non-interventionist trial aimed to document the behaviour of implants when used in daily dental practice, without inclusion or exclusion criteria. One hundred and ninety-six screw-shaped, tissue-level implants were placed, and each clinician decided which implant, surgical loading and prosthetic protocol to use. At surgery, data related to the implants were recorded. Additionally, the crestal bone level changes were evaluated for up to two years of follow-up. Two implants were lost before they were loaded. The success rate was 98.31%, and the survival rate was 98.79%. The implant stability quotient (ISQ) at surgery was 68.61 &plusmn, 10.35 and at 2 years was 74.39 &plusmn, 9.64. The crestal&ndash, shoulder distances were 1.25 &plusmn, 1.09 mm and 1.68 &plusmn, 1.07 mm in the mesial and distal aspects on the day of surgery, respectively, and 2.04 &plusmn, 0.91 and 2.16 &plusmn, 0.99 mm at 2 years, respectively. At 2 years, 69.3% of the patients were highly satisfied. The use of implants under standard conditions seemed to have success rates similar to their placement in controlled studies.

Angiotensin converting enzyme 2 (ACE2) is the recognized host cell receptor responsiblefor mediating infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2bound to tissue facilitates infectivity of SARS-CoV-2; thus, one could argue that decreasing ACE2tissue expression would be beneficial. However, ACE2 catalytic activity towards angiotensin I (AngI) and II (Ang II) mitigates deleterious effects associated with activation of the renin-angiotensinaldosteronesystem (RAAS) on several organs, including a pro-inflammatory status. At the tissuelevel, SARS-CoV-2 (a) binds to ACE2, leading to its internalization, and (b) favors ACE2 cleavage toform soluble ACE2: these actions result in decreased ACE2 tissue levels. Preserving tissue ACE2activity while preventing ACE2 shredding is expected to circumvent unrestrained inflammatoryresponse. Concerns have been raised around RAAS modulators and their effects on ACE2expression or catalytic activity. Various cellular and animal models report conflicting results invarious tissues. However, recent data from observational and meta-analysis studies in SARS-CoV-2-infected patients have concluded that RAAS modulators do not increase plasma ACE2 levels orsusceptibility to infection and are not associated with more severe diseases. This review presentsour current but evolving knowledge of the complex interplay between SARS-CoV-2 infection, ACE2levels, modulators of RAAS activity and the effects of RAAS modulators on ACE2 expression.

Cellular and tissue level bioelectrical activity was simulated over structurally realistic 3D interstitial cell of Cajal (ICC) networks reconstructed from confocal images of a wild type (WT) mouse model with a normal ICC distribution and a Spry4 knockout (KO) mouse model with a mild ICC hyperplasia. First, the ICC pixels within the confocal images were segmented. Then, the segmented images were visually inspected and the 3D surface mesh of the ICC tissue network was created from the 90 slices spanning the myenteric plexus ICC network. After two additional concentric meshes (representing the non-ICC and tissue bath regions) surrounding the ICC region were added, a 3D tetrahedral volume mesh containing the three regions was reconstructed. The electrical propagation through the tissue network was simulated using the bidomain continuum model. The results showed that the ICC network of the WT mouse had a smaller volume than the KO mouse (0.008 vs 0.012 mm3). The simulated bioelectrical activity for both mice showed an isotropic propagation from the initial activation region. Mean velocities of 4.2±1.5 and 4.1±1.3 mm/s were reported for the WT and KO mice, respectively. The velocity in the x-direction was higher than the y-direction for the WT mouse with a percent difference of 14.8%. On the other hand, the velocity in the y-direction was higher for the KO mouse with a percent difference of 9.5%. For both cases, there was no propagation in the z-direction as all the solution points along the same z-depth were simultaneously activated.

OBJECTIVE To qualify a 3C approach model of dual-energy X-ray absorptiometry (DXA) to estimate multicomponent resting energy expenditure (REE) referenced by indirect calorimetry (IC). METHODS A sample of 155 college students, of both sexes (18-30 years old) was evaluated. Anthropometric measures, REE by IC, and whole-body DXA-scans were performed. The REE for each body component was determined after transforming the components from the molecular (DXA) to the organ tissue level. Bland-Altman and proportional bias analyses were used to verify agreement between REE measured (REEIC ) and estimated (REEDXA ). RESULTS Statistically significant differences were found for all sex comparisons (P .05). Men also presented greater expenditure (P

Clinical sepsis is a highly dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single cell RNA sequencing revealed the involvement of various cell populations in injury and repair to be temporally organized and highly orchestrated. We identified key changes in gene expression that altered cellular functions and can explain features of clinical sepsis. These changes converged towards a remarkable global cell-cell communication failure and organ shutdown at a well-defined point in the sepsis timeline. Importantly, this time point was also a transition towards the emergence of recovery pathways. This rigorous spatial and temporal definition of murine sepsis will uncover precise biomarkers and targets that can help stage and treat human sepsis.

The new NICE guidelines on thyroid disease and its management do not recommend the routine use of liothyronine, but do not completely rule it out either. Guidelines from the British and European Thyroid Associations are open to a “trial of liothyronine” on an individual basis.Some patients do not feel well on L-thyroxine despite a serum TSH in the reference range. Key issues to consider in such patients include establishing whether the patient had established hypothyroidism initially, and whether the L-thyroxine has been titrated carefully enough, possibly using small increments, to achieve a careful balance between symptoms and serum TSH concentrations. Patients should also be considered for other causes of the symptoms which may be wide-ranging.Meta-analyses of several, but small, randomised control trials show no advantage, or disadvantage of liothyronine over L-thyroxine. However, detailed sub-analysis identifies some tantalising results eg on preferential weight loss, patient preference, and possibly genetic markers. Although linked with plausible theoretical explanations, these results may be over-interpreted. The key questions are whether a short-term trial treatment is worthwhile and safe, and whether in the future sub-groups of patients can be identified who may benefit from liothyronine. These questions remain divisive but require additional focussed research.It could be argued that inflated costs of liothyronine in some countries have either distracted from or helped focus on the science. Costs need to be addressed. However better biomarkers of tissue level thyroid action, and a better understanding of the impact of genetic polymorphisms will help to make progress when choosing if there is a place for liothyronine in the future.(words: 262)

Both biological and engineering approaches have contributed significantly to the recent advance in the field of mechanobiology. Collaborating with biologists, bio-engineers and materials scientists have employed the techniques stemming from the conventional semiconductor industry to rebuild cellular milieus that mimic critical aspects of in vivo conditions and elicit cell/tissue responses in vitro. Such reductionist approaches have help to unveil important mechanosensing mechanism in both cellular and tissue level, including stem cell differentiation and proliferation, tissue expansion, wound healing, and cancer metastasis. In this mini-review, we discuss various microfabrication methods that have been applied to generate specific properties and functions of designer substrates/devices, which disclose cell-microenvironment interactions and the underlying biological mechanisms. In brief, we emphasize on the studies of cell/tissue mechanical responses to substrate adhesiveness, stiffness, topography, and shear flow. Moreover, we comment on the new concepts of measurement and paradigms for investigations of biological mechanotransductions that are yet to emerge due to on-going interdisciplinary efforts in the fields of mechanobiology and microengineering.

Colorectal cancer (CRC) is the second leading malignancy worldwide. Accurate screening is pivotal to early CRC detection, yet current screening modality involves invasive colonoscopy while non-invasive FIT tests have limited sensitivity. We applied a DNA methylation assay to identify biomarkers for early-stage CRC detection, risk stratification and precancerous lesion screening at tissue level. A model of biomarkers SFMBT2, ITGA4, THBD and ZNF304 showed 96.1% sensitivity and 87.0% specificity in CRC detection, with 100.0% sensitivity for advanced precancerous lesion and stage I CRC. Performances were further validated with TCGA data set, which showed a consistent AUC of 0.99 and exhibited specificity against other cancer types. KCNJ12, VAV3-AS1 and EVC were further identified for stage stratification (stage 0-I versus stage II-IV), with AUC of 0.87, 83.0% sensitivity and 71.2% specificity. Additionally, dual markers of NEUROD1 and FAM72C showed 83.2% sensitivity and 77.4% specificity in differing non-advanced precancerous lesions from inflammatory bowel diseases.

Background It is well known that a severe cell injury after exposure to ionizing radiation is the induction of DNA double-strand breaks (DSBs). After exposure, an early response to DSBs is the phosphorylation of the histone H2AX molecule regions adjacent to the DSBs, referred to as γ-H2AX foci. The γ-H2AX assay after external exposure is a good tool for investigating the link between the absorbed dose and biological effect. However, less is known about DNA DSBs and γ-H2AX foci within the tissue microarchitecture after internal irradiation from radiopharmaceuticals. Therefore, in this study, we aimed to develop and validate a quantitative ex vivo model using γ-H2AX immunofluorescence staining and confocal laser scanning microscopy (CLSM) to investigate its applicability in nuclear medicine dosimetry research. Liver and testis were selected as the organs to study after intravenous administration of 111InCl3. Results In this study, we developed and validated a method that combines ex vivo γ-H2AX foci labeling of tissue sections with in vivo systemically irradiated mouse testis and liver tissues. The method includes CLSM imaging for intracellular cell-specific γ-H2AX foci detection and quantification and absorbed dose calculations. After exposure to ionizing radiation from 111InCl3, both hepatocytes and non-hepatocytes within the liver showed an absorbed dose-dependent elevation of γ-H2AX foci, whereas no such correlation was seen for the testis tissue. Conclusion It is possible to detect and quantify the radiation-induced γ-H2AX foci within the tissues of organs at risk after internal irradiation. We conclude that our method developed is an appropriate tool to study dose–response relationships in animal organs and human tissue biopsies after internal exposure to radiation.

Background. This study aimed to evaluate the effect of bone-level implants in comparison with tissue-level implants on dental papilla dimensions in single-tooth implants. Methods. In the present clinical trial, 50 patients, 24 females (48%) and 26 males (52%), were selected among patients requesting single implants in the posterior area of the jaws. The subjects were divided into two groups (n=25). The subjects in the first group were treated with a bone-level implant (Implantium, Dentium, Korea), and the subjects in the second group were treated with a tissue level implant (Implantium, Dentium, Korea). None of the implants were loaded during this period, and only the healing effect was measured. All the implants underwent one-stage surgery (none-submerged), and healing abutments were placed after implantation. The papilla heights in both the mesial and distal aspects of the adjacent teeth were measured. A periodontal probe was used to measure from the top of the papilla to the CEJ of the adjacent teeth in two time intervals. Descriptive statistics were performed using tables and Shapiro-Wilk, chi-squared, Mann-Whitney, and independent t-tests. Results. The findings showed that the interdental papilla in TL single implants performed better than that in BL implants at the three-month interval. This difference was statistically significant on the mesial aspect but not on the distal aspect. However, the difference was not clinically significant. Conclusion. A comparison of papilla dimensions in two implant types showed that papilla formation in TL implants was better than that in BL implants at the three-month postoperative interval.

Purpose: To evaluate the factors affecting peri-implant marginal bone level of single platform-switched implants with a smooth neck placed at gingival level (tissue level) using a flapless technique. Materials and Methods: Consecutive healthy patients requiring dental implant rehabilitations were enrolled in this study. Titanium implants with a zirconium-oxide-blasted surface and a platform-switch neck tulip configuration were used. Loading was performed 3 months after insertion with a provisional resin crown and after approximately 15 days with a definitive ceramic crown. Peri-implant marginal bone level (MBL) was measured on periapical radiographs at 1, 3, 6, 12, 24, 36, and 48 months by a blinded assessor. The following parameters were evaluated: location (maxillary/mandibular), position (anterior/posterior), sex (male/female), smoke (yes/no), implant placement timing (immediate, early, delayed), gingival thickness (thin/thick), endodontically treated adjacent teeth (yes/no), and diameter (3.8/4.25/5.0 mm). Multilevel analyses exploring factors associated with MBL at 36 and 48 months were performed. Results: A total of 76 patients (42 women, 34 men; mean age: 55.6 ± 10.7 years) received 128 implant rehabilitations. The survival rate was 98.4%. MBL displayed an initial increase during the first months from insertion (preload period). Cumulative mean MBL at T48 was 0.99 ± 0.68, which was not statistically significant from the values at T24 to T36 (P >.05). Mandibular location, delayed implants, and presence of adjacent endodontically treated teeth showed higher bone loss at 36 months (P .05). Conclusion: Platform-switched implants placed nonsubmerged with a flapless approach showed a reduced bone loss progression in the first 4 years, as MBL remained stable at longer times (36 and 48 months). Implants placed with early and immediate timing showed reduced bone loss compared with delayed implants.

International audience; Terahertz radiation offers new contrasts with biological systems, without markers or staining, at the molecular, cellular or tissue level. Thanks to technological advances, it is increasingly emerging as a solution of choice for directly probing the interaction with molecules and biological solutions. Applications range from dynamics of biological molecules to imaging of cancerous tissues, including ion, protein and membrane sensors.

A key goal of aging research was to understand mechanisms underlying healthy aging and develop methods to promote the human healthspan. One approach is to identify gene regulations unique to healthy aging compared with aging in the general population (i.e., “common” aging). Here, we leveraged Genotype‐Tissue Expression (GTEx) project data to investigate “healthy” and “common” aging gene expression regulations at a tissue level in humans and their interconnection with diseases. Using GTEx donors' disease annotations, we defined a “healthy” aging cohort for each tissue. We then compared the age‐associated genes derived from this cohort with age‐associated genes from the “common” aging cohort which included all GTEx donors; we also compared the “healthy” and “common” aging gene expressions with various disease‐associated gene expressions to elucidate the relationships among “healthy,” “common” aging and disease. Our analyses showed that 1. GTEx “healthy” and “common” aging shared a large number of gene regulations; 2. Despite the substantial commonality, “healthy” and “common” aging genes also showed distinct function enrichment, and “common” aging genes had a higher enrichment for disease genes; 3. Disease‐associated gene regulations were overall different from aging gene regulations. However, for genes regulated by both, their regulation directions were largely consistent, implying some aging processes could increase the susceptibility to disease development; and 4. Possible protective mechanisms were associated with some “healthy” aging gene regulations. In summary, our work highlights several unique features of GTEx “healthy” aging program. This new knowledge could potentially be used to develop interventions to promote the human healthspan., A key goal of aging research was to study mechanisms underlying healthy aging and based on them to identify effective methods to promote human healthspan. Here, we leveraged transcriptome data from GTEx to investigate gene expression profiles of both “healthy” and “common” aging in humans and its connection with diseases. Our results highlighted unique features of “healthy” aging and elucidated an intimate intertwined relationship among “healthy” aging, “common” aging, and age‐related diseases.

Iron is an essential element for multiple fundamental biological processes required for life; yet iron overload can be cytotoxic. Consequently, iron concentrations at the cellular and tissue level must be exquisitely governed by mechanisms that complement and fine-tune systemic control. It is well appreciated that macrophages are vital for systemic iron homeostasis, supplying or sequestering iron as needed for erythropoiesis or bacteriostasis, respectively. Indeed, recycling of iron through erythrophagocytosis by splenic macrophages is a major contributor to systemic iron homeostasis. However, accumulating evidence suggests that tissue-resident macrophages regulate local iron availability and modulate the tissue microenvironment, contributing to cellular and tissue function. Here, we summarize the significance of tissue-specific regulation of iron availability and highlight how resident macrophages are critical for this process. This tissue-dependent regulation has broad implications for understanding both resident macrophage function and tissue iron homeostasis in health and disease.

Delay differential equations (DDEs) recently have been used in models of cardiac electrophysiology, particularly in studies focusing on electrical alternans, instabilities, and chaos. A number of processes within cardiac cells involve delays, and DDEs can potentially represent mechanisms that result in complex dynamics both at the cellular level and at the tissue level, including cardiac arrhythmias. However, DDE-based formulations introduce new computational challenges due to the need for storing and retrieving past values of variables at each spatial location. Cardiac tissue simulations that use DDEs may require over 28 GB of memory if the history of variables is not managed carefully. This paper addresses both computational and dynamical issues. First, we present new methods for the numerical solution of DDEs in tissue to mitigate the memory requirements associated with the history of variables. The new methods exploit the different time scales of an action potential to dynamically optimize history size. We find that the proposed methods decrease memory usage by up to 95% in cardiac tissue simulations compared to straightforward history-management algorithms. Second, we use the optimized methods to analyze for the first time the dynamics of wave propagation in two-dimensional cardiac tissue for models that include DDEs. In particular, we study the effects of DDEs on spiral-wave dynamics, including wave breakup and chaos, using a canine myocyte model. We find that by introducing delays to the gating variables governing the calcium current, DDEs can induce spiral-wave breakup in 2D cardiac tissue domains.

Imaging modalities have developed rapidly in recent decades. In addition to improved resolution as well as whole-body and faster image acquisition, the possibilities of functional and molecular examination of tissue pathophysiology have had a decisive influence on imaging diagnostics and provided ground-breaking knowledge. Many promising approaches are currently being pursued to increase the application area of devices and contrast media and to improve their sensitivity and quantitative informative value. These are complemented by new methods of data processing, multiparametric data analysis, and integrated diagnostics. The aim of this article is to provide an overview of technological innovations that will enrich clinical imaging in the future, and to highlight the resultant diagnostic options. These relate to the established imaging methods such as CT, MRI, ultrasound, PET, and SPECT but also to new methods such as magnetic particle imaging (MPI), optical imaging, and photoacoustics. In addition, approaches to radiomic image evaluation are explained and the chances and difficulties for their broad clinical introduction are discussed. The potential of imaging to describe pathophysiological relationships in ever increasing detail, both at whole-body and tissue level, can in future be used to better understand the mechanistic effect of drugs, to preselect patients to therapies, and to improve monitoring of therapy success. Consequently, the use of interdisciplinary integrated diagnostics will greatly change and enrich the profession of radiologists.

Mammalian heart valves are soft tissue assemblies with multi-scale material properties. This is because they are constructs comprising both muscle and non-contractile extracellular matrix proteins (such as collagens and proteoglycans) and transition regions where one form of tissue structure becomes another, significantly different form. The leaflets of the mitral and tricuspid valves are connected to chordae tendinae which, in turn, bind through papillary muscles to the cardiac wall of the ventricle. The transition regions between these tissue subsets are complex and diffuse. Their material composition and mechanical properties have not been previously described with both micro and nanoscopic data recorded simultaneously, as reported here. Annotating the mechanical characteristics of these tissue transitions will be of great value in developing novel implants, improving the state of the surgical simulators and advancing robot-assisted surgery. We present here developments in multi-scale methodology that produce data that can relate mechanical properties to molecular structure using scanning X-ray diffraction. We correlate these data to corresponding tissue level (macro and microscopic) stress and strain, with particular emphasis on the transition regions and present analyses to indicate points of possible failure in these tissues.

Advances in single cell genomics and transcriptomics have shown that at tissue level there is complex cellular heterogeneity. To understand the effect of this inter-cell heterogeneity on metabolism it is essential to develop a single cell lipid profiling approach that allows the measurement of lipids in large numbers of single cells from a population. This will provide a functional read out of cell activity and membrane structure. Using liquid extraction surface analysis (LESA) coupled with high-resolution mass spectrometry we have developed a new high-throughput method for untargeted single cell lipid profiling. This technological advance revealed new insights into the importance of cellular heterogeneity in the functional metabolism of individual human dopamine neurons, suggesting that A53T alpha-synuclein ( SNCA ) mutant neurons have impaired membrane function. These results demonstrate that this novel single cell lipid profiling platform can provide robust data that will open new frontiers in biomedical research.

The premature infant is to some extent protected from hypoxia, however defense against hyperoxia is poorly developed. The optimal assessment of oxygenation is to measure oxygen delivery and extraction. At the bedside PaO2 and SpO2 are approximations of oxygenation at the tissue level. After birth asphyxia it is crucial to know whether or not to give oxygen supplementation, when, how much, and for how long. Oxygen saturation targets in the delivery room have been studied, but the optimal targets might still be unknown because factors like gender and delayed cord clamping influence saturation levels. However,SpO2 > 80% at 5 minutes of age is associated with favorable long term outcome in preterm babies. Immature infants most often need oxygen supplementation beyond the delivery room. Predefined saturation levels, and narrow alarm limits might together with the total oxygen exposure may impact on development of oxygen related diseases like ROP and BPD. Hyperoxia is a strong trigger for genetic and epigenetic changes, contributing to the development of these conditions and perhaps lifelong changes.

International audience; A sustained exposure to Hand-Arm transmitted-Vibration may cause various vascular pathologies such as the vibration-induced Raynaud’s Syndrome. This disorder is characterized at the tissue level by an arterial growth and remodelling potentially induced by an intimal hyperplasia phenomenon. The proliferation and migration of the Vascular Smooth Muscle Cells (VSMCs) are the keystone of this intimal hyperplasia phenomenon. Wall Shear Stress (WSS) alterations play a key role in inducing such mechanisms. Moreover, finger-transmitted-vibration is likely to be responsible for a WSS decrease (Noel and Settembre 2017). So, the aim of our work is to develop an Agent-Based Model (ABM) of the WSS-modulated arterial growth induced by finger-transmitted vibration. This study is intended for the agent-based migration model.

In mammals, the central pacemaker that coordinates 24‐hr rhythms is located in the suprachiasmatic nucleus (SCN). Individual neurons of the SCN have a molecular basis for rhythm generation and hence, they function as cell autonomous oscillators. Communication and synchronization among these neurons are crucial for obtaining a coherent rhythm at the population level, that can serve as a pace making signal for brain and body. Hence, the ability of single SCN neurons to produce circadian rhythms is equally important as the ability of these neurons to synchronize one another, to obtain a bona fide pacemaker at the SCN tissue level. In this chapter we will discuss the mechanisms underlying synchronization, and plasticity herein, which allows adaptation to changes in day length. Furthermore, we will discuss deterioration in synchronization among SCN neurons in aging, and gain in synchronization by voluntary physical activity or exercise., All our bodily functions show 24‐hr patters, in order to increase fitness in an everchanging environment. It is phenomenal that these global rhythms rely on a handful of tiny oscillating neurons in the suprachiasmatic nuclei (SCN) that synchronize to the environmental cycle via a primitive retinal pathway. The neurons of the SCN have the extraordinary capacity to function as a pacemaker, and by their responsiveness to internal cues, they form an integrated circadian system subserving health.

Statement of problem Whether increasing the space for peri-implant soft tissues by using implant systems with conical or convergent transmucosal components would improve tissue stability and esthetics is unclear. Purpose The purpose of this prospective clinical study was to evaluate the clinical and esthetic outcomes of using tissue-level implants with a convergent collar in the esthetic zone that had been rehabilitated following the biological oriented preparation technique (BOPT) approach after a 3-year follow-up period. Material and methods Sixteen participants with at least 1 nonrestorable tooth in the maxillary anterior region or with congenitally missing maxillary lateral incisors were enrolled, and tissue-level implants with a convergent collar were inserted 3 months after extraction. The implants were restored with cemented single crowns designed according to the BOPT protocol. Bone resorption and the pink esthetic score were evaluated over a 3-year period. Results Fifteen participants (mean age: 54.6 years) were evaluated over the 3-year period (total: 16 implants). One participant with 1 implant relocated dropped out of the study. The 3-year implant cumulative survival rate was 100%. The mean ±standard deviation bone-level change was 0.071 ±0.11 mm. The mean pink esthetic score was 8.5 ±1.59, range 4-10. Conclusions The use of the BOPT protocol to restore tissue-level implants with a convergent collar achieved good esthetic results and maintained stable soft and hard peri-implant tissues.

The function of ligaments and tendons is to support and transmit loads applied to the musculoskeletal system. These tissues are often able to perform their function for many decades; however, connective tissue disease and injury can compromise ligament and tendon integrity. A range of protein and non-protein constituents, combined in a complex structural hierarchy from the collagen molecule to the tissue and covering nanometer to centimeter length scales, govern tissue function, and impart characteristic non-linear material behavior. This review summarizes the structure of ligaments and tendons, the roles of their constituent components for load transfer across the hierarchy of structure, and the current understanding of how damage occurs in these tissues. Disease and injury can alter the constituent make-up and structural organization of ligaments and tendons, affecting tissue function, while also providing insight to the role and interactions of individual constituents. The studies and techniques presented here have helped to understand the relationship between tissue constituents and the physical mechanisms (e.g., stretching, sliding) that govern material behavior at and between length scales. In recent years, new techniques have been developed to probe ever smaller length scales and may help to elucidate mechanisms of load transfer and damage and the molecular constituents involved in the in the earliest stages of ligament and tendon damage. A detailed understanding of load transfer and damage from the molecular to the tissue level may elucidate targets for the treatment of connective tissue diseases and inform practice to prevent and rehabilitate ligament and tendon injuries. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3093-3104, 2018.

The tissue-level Young's modulus of trabecular bone is important for detailed mechanical analysis of bone and bone-implant mechanical interactions. However, the heterogeneity and small size of the trabecular struts complicate an accurate determination. Methods such as micro-mechanical testing of single trabeculae, ultrasonic testing, and nanoindentation have been used to estimate the trabecular Young's modulus. This review summarizes and classifies the trabecular Young's moduli reported in the literature. Information on species, anatomic site, and test condition of the samples has also been gathered. Advantages and disadvantages of the different methods together with recent developments are discussed, followed by some suggestions for potential improvement for future work. In summary, this review provides a thorough introduction to the approaches used for determining trabecular Young's modulus, highlights important considerations when applying these methods and summarizes the reported Young's modulus for follow-up studies on trabecular properties.The spongy trabecular bone provides mechanical support while maintaining a low weight. A correct measure of its mechanical properties at the tissue level, i.e. at a single-trabecula level, is crucial for analysis of interactions between bone and implants, necessary for understanding e.g. bone healing mechanisms. In this study, we comprehensively summarize the Young's moduli of trabecular bone estimated by currently available methods, and report their dependency on different factors. The critical review of different methods with recent updates is intended to inspire improvements in estimating trabecular Young's modulus. It is strongly suggested to report detailed information on the tested bone to enable statistical analysis in the future.

Purpose The esthetic outcome of dental implants can be compromised when some degree of bone loss occurs around the implant. This may particularly affect the tissue-level (TL) design. Therefore, bone-level (BL) design implants may be preferable if a natural emergence profile is important. Notwithstanding the implant design, the gingival biotype has been identified as a crucial factor in the stability of crestal bone. The objective of this study was to investigate bone loss in patients with different gingival biotypes at TL and BL implant sites in the esthetic zone. Materials and methods In 41 patients, 20 TL and 22 BL implant procedures were carried out. Intraoral radiographs of all of the 42 sites were taken immediately after implant insertion as well as during the follow-up examination. The analysis of bone height was conducted using a computerized technique. The TRAN method was used to determine the gingival biotype. Results After a mean in situ period of 4.9 years in the TL group, 12 implants with a thick biotype had a mean bone loss of 0.21 mm (SD: 0.43 mm). The eight implants with a thin biotype had a loss of 0.05 mm (SD: 0.47 mm; P = .31). After a mean in situ period of 1.9 years, the 14 BL sites with a thick biotype showed a mean bone change of -0.03 mm (SD: 0.38 mm). In the eight implants with a thin biotype, a change of +0.09 mm (SD: 0.32 mm; P = .84) was noted. Conclusion Analysis of the obtained results did not reveal a dependency of bone height on implant design or on gingival biotype. However, prior to choosing an implant design, it may nevertheless be beneficial to screen for transparent soft tissues, where the BL design offers a more natural emergence profile. For this purpose, the TRAN method is clearly the fastest and easiest.

Several in vitro and in vivo investigations have already proved that cells and tissues, when pre-exposed to low oxidative stress by different stimuli such as chemical, physical agents and environme...

Background It is well known that a severe cell injury after exposure to ionizing radiation is the induction of DNA double-strand breaks (DSBs). After exposure, an early response to DSBs is the phosphorylation of the histone H2AX molecule regions adjacent to the DSBs, referred to as γ-H2AX foci. The γ-H2AX assay after external exposure is a good tool for investigating the link between the absorbed dose and biological effect. However, less is known about DNA DSBs and γ-H2AX foci within the tissue microarchitecture after internal irradiation from radiopharmaceuticals. Therefore, in this study, we aimed to develop and validate a quantitative ex vivo model using γ-H2AX immunofluorescence staining and confocal laser scanning microscopy (CLSM) to investigate its applicability in nuclear medicine dosimetry research. Liver and testis were selected as the organs to study after intravenous administration of 111InCl3. Results In this study, we developed and validated a method that combines ex vivo γ-H2AX foci labeling of tissue sections with in vivo systemically irradiated mouse testis and liver tissues. The method includes CLSM imaging for intracellular cell-specific γ-H2AX foci detection and quantification and absorbed dose calculations. After exposure to ionizing radiation from 111InCl3, both hepatocytes and non-hepatocytes within the liver showed an absorbed dose-dependent elevation of γ-H2AX foci, whereas no such correlation was seen for the testis tissue. Conclusion It is possible to detect and quantify the radiation-induced γ-H2AX foci within the tissues of organs at risk after internal irradiation. We conclude that our method developed is an appropriate tool to study dose–response relationships in animal organs and human tissue biopsies after internal exposure to radiation.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

Tissue-level properties of bone play an important role when characterising apparent-level bone biomechanical behaviour and yet little is known about its effect at this hierarchical level. In combination with trabecular morphological data these properties can be used to predict bone strength, which becomes an invaluable tool for clinicians in patient treatment planning. This study developed specimen-specific micro-finite element (μFE) models using validated continuum-level models, containing grayscale-derived material properties, to indirectly establish tissue-level properties of porcine talar subchondral bone. Specimen-specific continuum finite element (hFE) models of subchondral trabecular bone were setup using μCT data of ten cylindrical specimens extracted from juvenile porcine tali. The models were validated using quasi-static uniaxial compression testing. Validated hFE models were used to calibrate the tissue modulus of corresponding μFE models by minimising the difference between the μFE and hFE stiffness values. Key trabecular morphological indices (BV/TV, DA, Conn.D, Tb.Th, EF) were evaluated. Good agreement was observed between hFE models and experiment (CCC = 0.66). Calibrated Etiss was 504 ± 37.65 MPa. Average BV/TV and DA for μFE specimens were 0.37 ± 0.05 and 0.68 ± 0.11, respectively. BV/TV (r2 = 0.667) correlated highly with μFE stiffness. The small intra-specimen variation to tissue-level properties suggests that variations to apparent-level stiffness originate from variations to microarchitecture rather than tissue mechanical properties.

The spongy mesophyll layer in leaves is ubiquitous among vascular plants, yet its structure is relatively unknown and typically described as a disordered assemblage of isodiametric cells. We characterized spongy mesophyll structure among diverse taxa using X-ray microCT imaging and found that leaves with small cell sizes, high cell packing densities, and close vein spacing were congruent with the isodiametric paradigm. When these structural traits exceeded well-defined thresholds, the spongy mesophyll domain was instead tessellated with an emergent topological motif of an irregular honeycomb that minimizes cellular investment and obeys Euler’s Law of space filling. Our data suggest spongy mesophyll is governed by allometric scaling laws, with two distinct topologies optimized for either photosynthetic performance or minimal resource investment.One Sentence SummaryConserved topological motifs in the spongy mesophyll are coordinated with leaf photosynthetic performance.