Changes In Architecture Research Articles

Exploring the regenerative capacity of the spleen following irradiation

IntroductionHaematopoietic stem cell transplantation (HSCT) is commonly used to treat patients with haematological disorders. Myeloablative conditioning is an important preparation for patients receiving haematopoietic stem cells (HSC) or haematopoietic stem and progenitor cells (HSPC). While widely successful, HSCT is still associated with high rates of mortality. The recovery time between complete myeloablation and haematopoietic recovery is a large factor in the recovery rate. Successful engraftment of HSC is also directly correlated with the number of HSC niches available. This highlights the importance of the haematopoietic niche and its recovery from myeloablation as an important therapeutic target.MethodsThis murine model study specifically considers changes in spleen tissue architecture and cellular composition involving stromal and vascular cells that occur following lethal irradiation.ResultsSpleen recovered fully between 4- and 8-weeks after irradiation due to reconstitution by HSPC from bone marrow. Specific temporal changes in spleen architecture were identified, and these were linked to the cell types that constitute the white pulp, red pulp and marginal zones. Mesenchymal stromal cells returned before endothelial cells, and reticular cell types recovered more quickly in spleen following irradiation. Losses in gp38+ fibroblastic reticular cells and MAdCAM-1+ marginal reticular cells were associated with loss of the white pulp in the first 4 weeks following irradiation. White pulp was restored following recovery of supporting reticular cells.DiscussionThis study tests how spleen regeneration following a lethal dose of irradiation can be influenced by co-infusion of bone marrow HSPC together with either neonatal spleen stromal cells, or cells of the stromal STX3 line. Both the infusion of neonatal spleen stromal cells and STX3 stromal cells hastened recovery of both mesenchymal and vascular compartments. Following neonatal spleen stromal cell infusion, endothelial cells increased early, but a delay in structural reformation of distinct red and white pulp areas was found. Results from this study show that spleen regeneration can be influenced and even hastened through cellular therapy. Neonatal spleen stromal cells, co-infused together with HSPC following irradiation conditioning, represent a potential therapeutic opportunity for hastening spleen regeneration.

More than a wink and a nudge: examining the choice architecture of online government budget simulations

Abstract Following the growing interest in using behavioral theory and choice architecture in the public sector, several new studies have looked at how changes in the choice architecture of budget simulations influence the participants’ budgetary decisions. These studies have also introduced the possible problem that participants may make inappropriate choices in the budget simulation, like creating a budget with unacceptably high budget surpluses. Building on Thaler and Sunstein’s NUDGES framework, we seek to answer the question, ‘How can budgetary choice architects correct for errors such as large ending surpluses at the end of the budget simulation?’ We replicate earlier results on budget starting conditions. Additionally, we test a budget treatment that encourages participants to reduce ending budget surpluses. The budget treatment works as intended and suggests that the large ending budget surpluses stem from errors made by participants in the simulation rather than loss aversion. The need to both nudge and budge participants is important for practicing choice architects, like public budgeters who have to design and implement tools that inform citizens and reveal accurate preferences that conform with legal requirements.

A Simple Method to Dissect, Orientate, and Visualize the Murine Limbal Stem Cell Niche with Cornea and Conjunctiva Attached.

The limbus is a narrow tissue intersection between the cornea and conjunctiva which is purported to harbor stem cells (SCs) that replenish the corneal epithelium throughout life. Damage to these cells can result in debilitating visual consequences. To date, various immunohistochemical methods have been employed to investigate limbal morphology and identify SC location to improve their isolation for therapeutic use. However, none of these methods preserve tissue integrity and orientation, nor do they incorporate adjacent conjunctiva as a contiguous ocular surface for analyses. In this chapter, we provide a methodology to overcome these limitations by integrating a unique dissection technique along with a tissue clearing strategy to enable the detection of morphological features within the limbal SC niche in different locations across its circumference. The morphological and biochemical details acquired from such investigations will heighten the current understanding of changes in tissue architecture in healthy and diseased corneas and in those that have been treated with biologicals, pharmacological, and/or surgical interventions.

Rescaling the contributed sphere: sociocultural processes in temple reconstruction in Taiwan

ABSTRACT This paper explores temple reconstruction as a symbolic action within traditional Han Chinese society, emphasizing the evolution of this expression in the architectural history of temples. Simultaneously, it underscores the sociocultural process of converting economic capital into symbolic capital. We utilize the “rescaling the contribution sphere” approach to clarify these processes, emphasizing people’s contribution culture in reconstruction. It proposes examining how the spatial accessibility of this culture influences the materialization of symbolic capital. Based on the archives from the reconstruction of “Tongshan Guan”, a temple in Magung City, between 1932 and 1951, we analyze how its architectural action transitioned from communitarianism, emphasizing the process of rescaling the ideal scale of the contributed sphere within the “architecture-history-politics” nexus. We found that the Han Chinese relieve social conflicts and tensions through temple architectural actions, hence, the value of temple architectural changes lies not only in technical history and aesthetics but also in their role as both the material outcomes and specific symbols of social change.

Geographies of transimperial religion: the transformation of religious space in a world of empires

ABSTRACT This article uses the concept of ‘transimperial’ history to show how religious transformations within then between different empires led to the development of new religious geographies and the alteration of existing religious centres. Combining examples from Asian, African, European and American empires, the article points to common patterns across four categories of religious space: steam ports (such as Bombay), railway towns (such as Harbin), preexisting pilgrimage places (such as Bodhgaya), and imperial borderlands (such as Hawaii). These transimperial sites spaces enabled doctrinal, ritual, linguistic, and organizational changes to Christianity, Islam, and Buddhism, enabling the propagation of such new religions as Theosophy and Baha’ism. Further attention is paid to architectural and organizational change, as well as the use of printing and translation in promoting new versions of these religions to different population groups. In this way, transimperial tranformation paved the way for more familiar globalized forms of religiosity in the later 20th century.

Response of transient soil waterlogging on shoot growth pattern and root architecture of finger millet and barnyard millet seedlings

Millets, as key crops in semi-arid and arid tropical regions, are gaining recognition for their nutritional benefits and resilience to challenging conditions. Finger millet and barnyard millet, in particular, stand out for their nutrient profiles and adaptability. However, research on their response to waterlogging, a major abiotic stress, remains limited. This study aimed to examine the immediate response of finger millet and barnyard millet seedlings to transient waterlogging conditions, focusing on their growth patterns and changes in root architecture to understand their morpho-physiological adaptive strategy. Seedlings were subjected to varying durations of waterlogging: control, 48, 74, and 120 hours to assess parameters such as shoot and root characteristics, leaf growth, and tolerance indices. Results showed a decrease in root length and an increase in shoot length with prolonged waterlogging. Root and shoot biomass, along with seedling dry weight, rose as waterlogging durations increased. Significant increases were observed in root surface area, volume, and the number of root tips and forks. Leaf area initially expanded but declined after 72 hours of waterlogging, accompanied by changes in specific leaf area and chlorophyll concentration. Tolerance indices, such as root-to-shoot ratio, decreased under waterlogging conditions, with finger millet exhibiting higher tolerance than barnyard millet. These findings provide insights into the adaptive strategies of millets under waterlogging, which is valuable for crop management and breeding for enhanced stress tolerance.

Abstract I008: Antisense Oligonucleotides as Therapeutics for Difficult-to-Drug Targets in Oncology

Abstract Many potential oncology targets are difficult to modulate by conventional classes of agents. Interfering with these targets at the level of RNA is a novel approach for difficult-to target proteins, as well as for non-coding RNAs, emerging targets that are part of the “dark matter’ of the genome. Antisense oligonucleotide (ASO) therapeutics are short sequences of 12- 30 DNA/RNA residues, designed to bind the cognate transcribed RNA. The ASO is chemically modified to increase stability, improve binding affinity, optimize pharmacokinetic properties and reduce immunostimulatory potential. The hybridization of ASO to cognate RNA results in cleavage of bound RNA by RNAse H1 and subsequent degradation. Several ASOs are marketed for treatment of rare diseases, but to date none have been approved for oncology indications. The long-noncoding RNA (lncRNA) MALAT1 is an example of an oncology target uniquely suited for an ASO therapeutic. This lncRNA is not translated and resides mostly in the nucleus, limiting access for most therapeutic approaches. MALAT1 is highly upregulated in various cancers, appears to play a role in epithelial to mesenchymal transition, and is associated with disease progression in patients. Inhibition of MALAT1 in preclinical breast cancer models, either genetic or pharmacologic using a murine ASO, leads to changes in tumor architecture and reduction in metastasis. FLM-7523 is a 16-mer ASO designed to bind to human MALAT1. It is a generation 2.5 design based on the constrained ethyl (cEt) modification to the 3 residues on the 3’ and 5’ ends of the ASO, and administered in a saline solution without any delivery vehicle. Preclinical studies have shown that FLM-7523 effectively inhibits MALAT1 expression in in vitro and in vivo models, and GLP toxicology studies have been completed to support a First-in-Human clinical trial. The signal transduction molecule STAT3 is another oncology target of interest that has, to date, been difficult to modulate. Danvatirsen is a 16-mer generation 2.5 ASO targeting human STAT3 mRNA and is currently in clinical trials. Preclinical in vivo studies in murine tumor models have demonstrated a reduction in STAT3 mRNA and protein following treatment with a STAT3 targeting ASO, along with tumor growth inhibition. Combination treatments with immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1, demonstrate improved tumor growth inhibition relative to monotherapy. In clinical trials, tumor uptake of danvatirsen is observed in post-treatment biopsies, with corresponding reduction in STAT3 protein. Danvatirsen is generally well tolerated with the most common adverse events being increased liver function tests and decreased myeloid hematologic parameters, both of which are easily monitored, manageable, and reversible. Clinical responses have been observed with the most robust being in combination with a PD-L1 inhibitor in recurrent/metastatic head and neck squamous cell carcinoma. In conclusion, ASOs are novel therapies that can inhibit oncology targets not tractable by traditional approaches. Citation Format: Andrew Denker. Antisense Oligonucleotides as Therapeutics for Difficult-to-Drug Targets in Oncology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I008.

Effects of horizontally versus vertically loaded resistance exercises on performance and muscle architecture.

The aim of this study was to compare a training program based on horizontally (HT) versus vertically (VT) loaded exercises on performance and muscle architecture of the lower body muscles. Nineteen resistance trained individuals were randomly assigned to HT (N.=10; age: 25.9±4.2 y; body mass: 72.7±11.4 kg; height: 174.0±6.0 cm) or VT group (N.=9; age: 26.9±4.4 y; body mass: 76.2±10.8 kg; height: 174.2.0±5.8 cm). Both 6-week training programs included 4 training sessions per week and were equated for the total number of repetitions. One repetition maximum (1RM) was assessed for squat and hip thrust, together with vertical and horizontal jumps and sprint. Muscle thickness (MT) and echo intensity (EI) of vastus lateralis, vastus medialis and gluteus were also evaluated pre- and post-training period. A significantly greater increase in 1RM hip thrust was detected in HT (+17.9%; P=0.004) while greater increases in 1RM squat were found in VT (+10.5%; P=0.007). A greater increase (P=0.009) in vastus medialis MT was detected in VT (4.1%) compared to HT (-7.9%). Similar increases in MT of gluteus were registered in both groups (P<0.05). A greater improvement in standing long jump (P=0.004) was detected in HT (+7.6%) compared to VT (+1.6%), while both groups significantly improved vertical jump performance. Combining both groups, strong correlations were detected between gluteus EI and 20-m sprint (r=0.79; P<0.001). Results indicate that HT was more effective than VT for horizontal jumps while both HT and VT were equally effective on vertical jumps. Both HT and VT promoted similar changes in muscle architecture of the gluteus, but not of the vastus medialis.

Root System Architecture Reorganization Under Decreasing Soil Phosphorus Lowers Root System Conductance of Zea mays.

The global supply of phosphorus is decreasing. At the same time, climate change reduces the availability of water in most regions of the world. Insights on how decreasing phosphorus availability influences plant architecture are crucial to understanding its influence on plant functional properties, such as the root system's water uptake capacity. In this study, we investigated the structural and functional responses of Zea mays to varying phosphorus fertilization levels focusing especially on the root system's conductance. A rhizotron experiment with soils ranging from severe phosphorus deficiency to sufficiency was conducted. We measured the architectural parameters of the whole plant and combined them with root hydraulic properties to simulate time-dependent root system conductance of growing plants under different phosphorus levels. We observed changes in the root system architecture, characterised by decreasing crown root elongation and reduced axial root radii with declining phosphorus availability. Modeling revealed that only plants with optimal phosphorus availability sustained a high root system conductance, while all other phosphorus levels led to a significantly lower root system conductance, both under light and severe phosphorus deficiency. We postulate that phosphorus deficiency decreases root system conductance, which could mitigate drought conditions through a more conservative water use strategy, but ultimately reduces biomass and impairs root development and overall water uptake capacity. Our results also highlight that the organisation of the root system, rather than its overall size, is critical for estimating important root functions.

RBIO-01. CHARACTERIZING THE TEMPORAL EVOLUTION OF BRAIN ARCHITECTURE DURING RADIOTHERAPY FOR GLIOBLASTOMA USING NONLINEAR IMAGE REGISTRATION

Abstract BACKGROUND Previous serial MRI studies following glioblastoma (GBM) resection reveal dynamic changes in the tumor cavity and surrounding tissue. However, the time course of these dynamics is unclear, especially in the immediate postoperative period. METHODS GBM patients (n=8) received three MRIs: within 72 hours post-resection, immediately preceding RT (RTstart), and at the RT midpoint (RTmid). The radiation field (RF) was based on the resection cavity (RC) and surrounding T2-FLAIR hyperintensities at the 72 hour MRI. Nonlinear image registration was performed across the two time intervals, allowing comparison between the intended radiation targets and the actual irradiated tissue. Dice coefficients (DRF and DRC), the relative volume of the RC (RCvol), and the volume of unintended iatrogenic radiation (IRvol) were measured at each timepoint, and IRvol was fitted to an exponential decay. RESULTS DRF showed modest reduction, with mean±SD of 0.97±0.02 at both RTstart and RTmid. In contrast, the RC showed more change, with mean DRC 0.63±0.13 and 0.60±0.12, and mean RCvol of 0.74±0.27 and 0.72±0.25 at RTstart and RTmid, respectively. DRF, DRC, and RCvol showed greater change during the first interval than the second (p=3.5x10-4, 4.1x10-4, and 0.1, respectively). The mean IRvol was 16.7±12.6 at RTstart and 21.7±12.8 at RTmid, with a time constant of -0.031 (95% CI=[-0.017, -0.060]), indicating that 80% of all voxels that receive unintended iatrogenic radiation moved into the radiation field by postoperative day 57, and 95% will have moved in by day 125. CONCLUSIONS Nonlinear registration demonstrated significant postoperative architectural changes, with most occurring in the first two months after surgery near the RC. This potentially suggests a role for adaptive planning during RT, particularly for protocols that focus on the RC rather than T2-FLAIR hyperintensities. Future prospective studies are needed to assess the role of adaptive radiotherapy for GBM.

NIMG-13. CHANGES IN CORTICAL ARCHITECTURE ASSOCIATED WITH GLIOBLASTOMA ASSOCIATED EPILEPSY

Abstract BACKGROUND Emerging evidence suggests both local hyper-excitability promoting epilepsy, and synaptic and paracrine mediated integration of Glioblastoma into brain-wide neural networks. In this study we sought clinical evidence of disease progression, and concurrent radiological evidence of differences in remote cortical architecture, in Glioblastoma patients with and without epilepsy. METHODS 55 patients with biopsy-confirmed Glioblastoma, mean-age 59.4yrs±10.9yrs, were studied. 23 patients had a diagnosis of Glioblastoma-related epilepsy on presentation. We compared clinical markers of disease progression in individuals with and without epilepsy. Further, we explored differences in cortical architecture between both groups. Utilising pre-operative T1-weighted, contrast-enhanced MRI scans (n=45), we performed vertex-wise measurements of cortical thickness (CT) and cortical surface area (CSA) using the Virtual Brain Grafting Toolbox and FreeSurfer v.7.0. Radiologically-identifiable tumour and oedema was masked and excluded from analysis. Scans with right-hemispheric tumours were flipped to the left. Linear mixed-effects models were applied to pre-processed imaging-data. RESULTS Individuals with epilepsy had shorter progression-free survival (median 4.2 months) than those without seizures (9.3 months, p&amp;lt;0.05) with gold-standard treatment. No significant difference between lesion volumes (tumour and oedema) existed between the two groups (unpaired t-test, p&amp;gt;0.05). Controlling for age and tumour location, significant increases (p&amp;lt;0.01) in CT and CSA were observed in patients with Glioblastoma-related epilepsy in lesion-ipsilateral supramarginal gyrus, superior parietal lobule, precuneus/cuneus and temporal lobe compared to those without epilepsy. Interestingly, significant (p&amp;lt;0.05) increases in CT in lesion-contralateral supramarginal gyrus were additionally observed in those with epilepsy compared to those without. CONCLUSIONS Glioblastoma-related epilepsy was associated with poorer survival outcomes and changes in remote cortical architecture. Implicated regions form part of the default mode network, which has previously been identified as a crucial hub for epilepsy. Biological underpinnings of cortical network alterations, and their possible role in promoting not only hyper-excitability but also Glioblastoma progression, require correlation with histopathological characteristics and validation in larger study cohorts.

Hedgehog Signalling Pathway and Its Role in Shaping the Architecture of Intestinal Epithelium.

The hedgehog (Hh) signalling pathway plays a key role in both embryonic and postnatal development of the intestine and is responsible for gut homeostasis. It regulates stem cell renewal, formation of the villous-crypt axis, differentiation of goblet and Paneth cells, the cell cycle, apoptosis, development of gut innervation, and lipid metabolism. Ligands of the Hh pathway, i.e., Indian hedgehog (Ihh) and Sonic hedgehog (Shh), are expressed by superficial enterocytes but act in the mesenchyme, where they are bound by a Patched receptor localised on myofibroblasts and smooth muscle cells. This activates a cascade leading to the transcription of target genes, including those encoding G1/S-specific cyclin-D2 and -E1, B-cell lymphoma 2, fibroblast growth factor 4, and bone morphogenetic protein 4. The Hh pathway is tightly connected to Wnt signalling. Ihh is the major ligand in the Hh pathway. Its activation inhibits proliferation, while its blocking induces hyperproliferation and triggers a wound-healing response. Thus, Ihh is a negative feedback regulator of cell proliferation. There are data indicating that diet composition may affect the expression of the Hh pathway genes and proteins, which in turn, induces changes in mucosal architecture. This was shown for fat, vitamin A, haem, berberine, and ovotransferrin. The Hh signalling is also affected by the intestinal microbiota, which affects the intestinal barrier integrity. This review highlights the critical importance of the Hh pathway in shaping the intestinal mucosa and summarises the results obtained so far in research on the effect of dietary constituents on the activity of this pathway.

Nucleosome repositioning in cardiac reprogramming.

Early events in the reprogramming of fibroblasts to cardiac muscle cells are unclear. While various histone undergo modification and re-positioning, and these correlate with the activity of certain genes, it is unknown if these events are causal or happen in response to reprogramming. Histone modification and re-positioning would be expected to open up chromatin on lineage-specific genes and this can be ascertained by studying nucleosome architecture. We have recently developed a set of tools to identify significant changes in nucleosome architecture which we used to study skeletal muscle differentiation. In this report, we have applied these tools to understand nucleosome architectural changes during fibroblast to cardiac muscle reprogramming. We found that nucleosomes surrounding the transcription start sites of cardiac muscle genes induced during reprogramming were insensitive to reprogramming factors as well as to agents which enhance reprogramming efficacy. In contrast, significant changes in nucleosome architecture were observed distal to the transcription start site. These regions were associated with nucleosome build-up. In summary, investigations into nucleosome structure do not support the notion that fibroblasts to cardiac muscle cell reprogramming involves chromatin opening and suggests instead long-range effects such as breaking closed-loop inhibition.

Can letrozole be repurposed for the treatment of visceral leishmaniasis?

Visceral leishmaniasis, caused by Leishmania infantum in New World countries, is the most serious and potentially fatal form of leishmaniasis, if left untreated. There are currently no effective prophylactic measures, and therapeutic options are limited. Therefore, we investigated whether the aromatase inhibitor letrozole (LET), which is already used to treat breast cancer, has an antileishmanial activity and/or immunomodulatory potential and therefore may be used to treat L. infantum infection. LET was active against L. infantum promastigote and amastigote life cycle stages in an in vitro infection model using human THP-1 cell-derived macrophages. In human peripheral blood leukocytes ex vivo, LET reduced the internalized forms of L. infantum by classical monocytes and activated neutrophils. Concomitantly, LET stimulated the production of IL-12/TNF-α and decreased the production of IL-10/TGF-β by peripheral blood phagocytes, while in T and B cells, it promoted the production of TNF-α/IFN-γ and decreased that of IL-10. In a murine infection model, LET significantly reduced the parasite load in the liver after just 5 days and in the spleen after 15 days. During in vivo treatment with LET, the production of TNF-α/IFN-γ also increased. In addition, the proportion of developing granulomas decreased and that of mature granulomas increased in the liver, while there was no significant change in organ architecture in the spleen. Based on these data, repositioning of LET may be promising for the treatment of visceral leishmaniasis in humans.

Genomic architecture in social insects is more strongly associated with phylogeny than social behavior

Abstract The evolution of sociality in insects has been predicted to reduce effective population sizes, in turn leading to changes in genome architecture, including higher recombination rates, larger genomes, increased GC-biased gene conversion (gBGC), and greater intragenomic variation in GC content to maintain castes through differential methylation. As the number of sequenced insect genomes continues to grow, it remains an open question which, if any, of these genomic features are consistent across social insect genomes. A major challenge to determining such commonalities has been the lack of phylogenetically controlled analyses across independent origins of sociality. Of the 15 Hymenoptera species for which recombination rate was available, social species had higher rates of recombination. Next, we conducted a broader analysis of genome architecture by analyzing genome assemblies for 435 species of Hymenoptera and 8 species of Blattodea to test if GC content, genome size, distribution of CpG sites or codon bias repeatedly differed between social and nonsocial species. Overall, there was little support for predictable changes in genome architecture associated with sociality across Hymenoptera, after accounting for phylogenetic relationships. However, we found a significant negative relationship between sociality and GC content within the family Apidae and a significant negative relationship between sociality and genome size within the family Halictidae. In all, these results suggest that unique origins of social behavior may produce unique trends in genomic architecture. Our study highlights the need to examine genome architecture across independent origins of social behavior.

YAP signaling orchestrates the endothelin-1-guided invadopodia formation in high-grade serous ovarian cancer.

The high-grade serous ovarian cancer (HG-SOC) is a notoriously challenging disease, characterized by a rapid peritoneal dissemination. HG-SOC cells leverage actin-rich membrane protrusions, known as invadopodia, to degrade the surrounding extracellular matrix (ECM) and invade, initiating the metastatic cascade. In HG-SOC, the endothelin-1 (ET-1)/endothelin A receptor (ETAR)-driven signaling coordinates invadopodia activity, however how this axis integrates pro-oncogenic signaling routes, as YAP-driven one, impacting on the invadopodia-mediated ECM degradation and metastatic progression, deserves a deeper investigation. Herein, we observed that downstream of the ET-1/ET-1R axis, the RhoC and Rac1 GTPases, acting as signaling intermediaries, promote the de-phosphorylation and nuclear accumulation of YAP. Conversely, the treatment with the dual ETA/ETB receptor antagonist, macitentan, inhibits the ET-1-driven YAP activity. Similarly, RhoC silencing, or cell transfection with a dominant inactive form of Rac1, restore the YAP phosphorylated and inhibited state. Mechanistically, the ET-1R/YAP signal alliance coordinates invadopodia maturation into ECM-degrading structures, indicating how such ET-1R-guided protein network represents a route able to enhance the HG-SOC invasive potential. At functional level, we found that the interconnection between the ET-1R/RhoC and YAP signals is required for MMP-2 and MMP-9 proteolytic functions, cell invasion, and cytoskeleton architecture changes, supporting the HG-SOC metastatic strength. In HG-SOC patient-derived xenografts (PDX) macitentan, turning-off the invadopodia regulators RhoC/YAP, halt the metastatic colonization. ET-1R targeting, hindering the YAP activity, weakens the invadopodia machinery, embodying a promising therapeutic avenue to prevent peritoneal dissemination in HG-SOC.

Intestinal epithelial Gasdermin C is induced by IL-4R/STAT6 signaling but is dispensable for gut immune homeostasis

Gasdermin C is one of the least studied members of the gasdermin family of proteins, known for their critical involvement in pyroptosis and host defense. Furthermore, evidence for the role of Gasdermin C in the intestine is scarce and partly controversial. Here, we tested the functional role of Gasdermin C in intestinal homeostasis, inflammation and tumorigenesis. : We studied Gasdermin C in response to cytokines in intestinal organoids. We evaluated epithelial differentiation, cell death and immune infiltration under steady state conditions in a new mouse line deficient in Gasdermin C. The role of Gasdermin C was analyzed in acute colitis, infection and colitis-associated cancer. Gasdemin C is highly expressed in the intestinal epithelium and strongly induced by the type 2 cytokines IL-4 and IL-13 in a STAT6-dependent manner. Gasdermin C-deficient mice show no changes in tissue architecture and epithelial homeostasis. Epithelial organoids deficient in Gasdermin C develop normally and show no alterations in proliferation or cell death. No changes were found in models of acute colitis, type 2 intestinal infection and colitis-associated cancer. Gasdermin C genes are upregulated by type 2 immunity, yet appear dispensable for the development of intestinal inflammation, infection and colitis-associated cancer.

Longitudinal changes in Achilles tendon and triceps surae muscle architecture during a 156-km mountain ultramarathon.

This study aimed to assess the longitudinal changes in triceps surae muscle-tendon architecture during a mountain ultramarathon. Experienced trail runners [n = 55, 78% men, age: 45.2 (13.5) yr] participated in a 156-km trail run (6,000 m climbing) consisting of six 26-km laps. The resting architectural properties of triceps surae muscle-tendon were measured using ultrasound imaging for Achilles tendon cross-sectional area (AT CSA), medial gastrocnemius muscle pennation angle, thickness, length, and fiber length. Measurements were performed the day before the race (baseline), at 52 km (T1), at 104 km (T2), at 156 km (T3), and 12 h after the race (H12). Among finishers (n = 41), there was a significant biphasic change in AT CSA during the race (P = 0.001). First, a significant decrease in AT CSA occurred between baseline and T1 (P = 0.006), with a greater decrease for participants averaging speed >8 km/h (P = 0.014). Second, there was a significant increase in AT CSA especially between T2 and T3 (P = 0.006) that was correlated with a decrease in average speed (P = 0.001) and alteration of spaciotemporal running parameters (P < 0.05). Changes in muscle-tendon architecture were not significantly different between finishers (n = 41) and nonfinishers (n = 14). In 47 participants (85.5%) who completed the follow-up, AT CSA at H12 was greater compared with baseline (P = 0.010). The main finding is the significant and biphasic modification of the AT CSA during a 156-km mountain ultramarathon with an initial decrease corresponding to mechanical stress followed by a secondary increase suggesting adaptive mechanotransduction persisting after 12 h.NEW & NOTEWORTHY Achilles tendon cross-sectional area (AT CSA) demonstrated significant adaptive modifications during a 156 km mountain ultramarathon in trained athletes. Initially, a decrease in AT CSA, especially at higher running speeds, is consecutive to the biomechanical stress on the plantar flexor muscle-tendon unit (MTU). Subsequently, there is a significant increase in AT CSA persisting up to 12 h after the race, which likely corresponds to an adaptive process to limit the compressive and tensile load on the tendon.

Laser NIR Irradiation Enhances Antimicrobial Photodynamic Inactivation of Biofilms of Staphylococcus aureus.

Photodynamic inactivation (PDI) is a powerful technique for eradicating microorganisms, and our group previously demonstrated its effectiveness against planktonic cultures of Staphylococcus aureus bacteria using 5,10,15,20-tetrakis[4-(3-N,N-dimethylaminopropoxy)phenyl]porphyrin (TAPP) and visible light irradiation. However, biofilms exhibit a lower sensitivity to PDI, mainly due to limited penetration of the photosensitizer (PS). In the context of emerging antibacterial strategies, near-infrared treatments (NIRTs) have shown promise, especially for combating resistant strains. NIRT can act either through photon absorption by water, causing a thermal effect on bacteria, or by specific chromophores without a significant temperature increase. Our objective was to enhance biofilm sensitivity to TAPP-PDI by pretreatment with NIRT. This combined approach aims to disrupt biofilms and increase the efficacy of TAPP-PDI against bacterial biofilms. In vitro biofilm models of S. aureus RN6390 were utilized. NIRTs involved a 980 nm laser (continuous mode, 7.5 W/cm2, 30 s, totaling 225 J/cm2) post-TAPP exposure to enhance photosensitizer accumulation. Subsequent visible light irradiation at 180 J/cm2 was employed to perform PDI. Colony-forming unit counts evaluated the synergistic effect on bacterial viability. Scanning electron microscopy visualized the architectural changes in the biofilm structure. TAPP was extracted from bacteria to estimate the impact of NIRT on biofilm penetration. Using in vitro biofilm models, NIRT application following biofilm exposure to TAPP increased PS accumulation per bacteria. Under these conditions, NIRT induced a transient increase in the temperature of PBS to 46.0 ± 2.6°C (ΔT = 21.5°C). Following exposure to visible light, a synergistic effect emerged, yielding a substantial 4.4 ± 0.1-log CFU reduction. In contrast, the PDI and NIRT treatments individually caused a decrease in viability of 0.9 ± 0.1 and 0.8 ± 0.2-log respectively. Interestingly, preheating TAPP-PBS to 46°C had no significant impact on TAPP-PDI efficacy, suggesting the involvement of thermal and nonthermal effects of NIR action. In addition to the enhanced TAPP penetration, NIRT dispersed the biofilms and induced clefts in the biofilm matrix. Our findings suggest that NIR irradiation serves as a complementary treatment to PDI. This combined strategy reduces bacterial numbers at lower PS concentrations than standalone PDI treatment, highlighting its potential as an effective and resource-efficient antibacterial approach.

Building the social. A query into the societal impact of the Pompeian water supply

This study explores the importance of the means of ensuring water supply in the formation of the architectural profile and basic social organization of Pompeii. It sees the city’s domestic water supply, for over two centuries ensured through rainwater-harvesting areas, basins and cisterns situated mainly in and below the many atria, as a stabilizing factor of both cityscape and household. Through the introduction of the city aqueduct in the 1st century AD and the creation of a generous network of public fountains this situation changes and the need to maintain the traditional organization of the “houseful”, comprising enlarged family, slaves and dependents of various kind including shopkeepers, is lessened; the physical proximity between those of different status renegotiated. This development, witnessed in adaptations of the architecture, can be followed through close study of the standing structures in Insula V 1. The hallmarks are the creation of upperfloor living quarters seemingly independent from the life of the large households of the atrium houses, and in parallel the introduction of private water lines from the city aqueduct. The remodelling that resulted in the creation of the double-atrium house of Caecilius Iucundus is focal to the discussion since it offers a coeval chronological fix point in the AD 40s for both remodelling and obtention of piped water. Given that the change in the domestic architecture observed was merely in its embryonic state in AD 79, the tenability to attribute a lower dating than that traditionnaly attributed not just to the private lines, but to the city’s distribution system of public aqueduct water as well, is reasoned. The particularities of Pompeii’s geomorphological situation and political status and how they impacted the discussed change in social relationships are also raised.