Reprogramming diminishes retention of Mycobacterium leprae in Schwann cells and elevates bacterial transfer to fibroblasts

Background: Bacterial pathogens can manipulate or subvert host tissue cells to their advantage at different stages during infection, from initial colonization in primary host niches to dissemination. Recently, we have shown that Mycobacterium leprae (ML), the causative agent of human leprosy, reprogrammed its preferred host niche de-differentiated adult Schwann cells to progenitor/stem cell-like cells (pSLC) which appear to facilitate bacterial spread. Here, we studied how this cell fate change influences bacterial retention and transfer properties of Schwann cells before and after reprogramming. Results: Using primary fibroblasts as bacterial recipient cells, we showed that non-reprogrammed Schwann cells, which preserve all Schwann cell lineage and differentiation markers, possess high bacterial retention capacity when co-cultured with skin fibroblasts; Schwann cells failed to transfer bacteria to fibroblasts at higher numbers even after co-culture for 5 days. In contrast, pSLCs, which are derived from the same Schwann cells but have lost Schwann cell lineage markers due to reprogramming, efficiently transferred bacteria to fibroblasts within 24 hours. Conclusions: ML-induced reprogramming converts lineage-committed Schwann cells with high bacterial retention capacity to a cell type with pSLC stage with effective bacterial transfer properties. We propose that such changes in cellular properties may be associated with the initial intracellular colonization, which requires long-term bacterial retention within Schwann cells, in order to spread the infection to other tissues, which entails efficient bacterial transfer capacity to cells like fibroblasts which are abundant in many tissues, thereby potentially maximizing bacterial dissemination. These data also suggest how pathogens could take advantage of multiple facets of host cell reprogramming according to their needs during infection

Natural hydrogel in American lobster: A soft armor with high toughness and strength

Homarus americanus, known as American lobster, is fully covered by its exoskeleton composed of rigid cuticles and soft membranes. These soft membranes are mainly located at the joints and abdomen to connect the rigid cuticles and greatly contribute to the agility of the lobster in swimming and preying. Herein, we show that the soft membrane from American lobster is a natural hydrogel (90% water) with exceptionally high toughness (up to 24.98 MJ/m 3 ) and strength (up to 23.36 MPa), and is very insensitive to cracks. By combining experimental measurements and large-scale computational modeling, we demonstrate that the unique multilayered structure in this membrane, achieved through the ordered arrangement of chitin fibers, plays a crucial role in dissipating energy during rupture and making this membrane tough and damage tolerant. The knowledge learned from the soft membrane of natural lobsters sheds light on designing synthetic soft, yet strong and tough materials for reliable usage under extreme mechanical conditions, including a flexible armor that can provide full-body protection without sacrificing limb mobility. Statement of significance: A body armor to provide protection to people who are at risk of being hurt is only enabled by using a material that is tough and strong enough to prevent mechanical penetration. However, most modern body armors sacrifice limb protection to gain mobility, simply because none of the existing armor materials are flexible enough and they all inhibit movement of the arms and legs. Herein, we focus on the mechanics and mesoscopic structure of American lobsters’ soft membrane and explore how such a natural flexible armor is designed to integrate flexibility and toughness. The knowledge learned from this study is useful to design a flexible armor for full-body protection under extreme mechanical conditions

Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection

SummaryDifferentiated cells possess a remarkable genomic plasticity that can be manipulated to reverse or change developmental commitments. Here, we show that the leprosy bacterium hijacks this property to reprogram adult Schwann cells, its preferred host niche, to a stage of progenitor/stem-like cells (pSLC) of mesenchymal trait by downregulating Schwann cell lineage/differentiation-associated genes and upregulating genes mostly of mesoderm development. Reprogramming accompanies epigenetic changes and renders infected cells highly plastic, migratory, and immunomodulatory. We provide evidence that acquisition of these properties by pSLC promotes bacterial spread by two distinct mechanisms: direct differentiation to mesenchymal tissues, including skeletal and smooth muscles, and formation of granuloma-like structures and subsequent release of bacteria-laden macrophages. These findings support a model of host cell reprogramming in which a bacterial pathogen uses the plasticity of its cellular niche for promoting dissemination of infection and provide an unexpected link between cellular reprogramming and host-pathogen interaction

Primary carcinosarcoma of the liver: imaging features and clinical findings in six cases and a review of the literature

Abstract Background Carcinosarcoma of the liver is a very rare tumor composed of a mixture of carcinomatous and sarcomatous elements. Less than 25 adequately documented cases have been reported, with inadequate description of imaging features. In order to improve the awareness of this rare tumor, this study aimed to analyze the clinicopathologic and imaging features of six cases of hepatic carcinosarcoma (HCS) confirmed by surgical pathologic evaluation. Methods We retrospectively studied the clinicopathologic and imaging features of six cases of HCS (matching the World Health Organization definition) and discussed the differential diagnosis on the basis of imaging findings. The patients, including five men and one woman, were 38 to 69 years of age. Five patients underwent CT scans, one underwent MRI scans. Results While 3 patients were positive for hepatitis-B surface antigen, 2 had cirrhosis. The largest tumor diameter ranged from 5.0 to 21.0 cm. Satellite nodules, venous thrombi, and organ invasion (gastric wall, gallbladder, and right adrenal gland) were identified. Pathologically, the carcinomatous components corresponded to hepatocellular carcinoma in three cases, cholangiocellular carcinoma in one case, and adenocarcinoma in two cases. The sarcomatous components exhibited complex features, with undifferentiated spindle cells in five cases and a leiomyosarcoma in one. All tumors showed heterogeneous density/intensity with extensive cystic change and necrosis; spot calcification was observed in one case. Capsule was not identified. While four tumors showed heterogeneous hypervascular enhancement, two showed hypovascular enhancement. All patients underwent surgical resection. The follow-up period ranged from 2 to 18 months. Four patients died from recurrence and metastasis. Conclusions The clinical and imaging features of HCS are heterogeneous. Due to the heterogenous nature and very low morbidity of HCS, combination of careful analysis of imaging findings and clinical features might be useful for a more accurate diagnosis of HCS

3.0T MRI for long-term observation of lung nodules post cryoablation: a pilot study

Abstract Background The purpose of this study was to use serial magnetic resonance imaging (MRI) examinations to observe changes in malignant lung tumors over time post-cryoablation. Methods The study protocol was approved by Institutional Review Board, and written informed consent was obtained from each participant in accordance with the Declaration of Helsinki. Patients with primary or metastatic lung tumors eligible for cryoablation were included in this prospective study. Cryoablation was performed according to standard procedures. Unenhanced and dynamic contrast-enhanced MRI scans were performed pre-cryoablation and at 1 day, 1 week, and 3-, 6-, and 12 months after cryoablation. At each time point, the signal intensity of the ablated zone on both T1WI and T2WI images, and volume and characteristics of the ablation zone were examined, and changes over time analyzed. Results A total of 26 nodules in 23 patients were included in the study. The mean patient age was 53.7 ± 13.6 years, and 57.7% were males. Ablation zone volume increased to 1 week after the procedure, and then returned to baseline by 3 months. Cavitation post-cryoablation was found in 34.6% (9/26) of the nodules 1 month after treatment. Two types of time-signal intensity curves post-cryoablation were found: a straight line representing no definite enhancement from 1-day to 1-month, and an inflow curve representing mild delayed enhancement from month 3 to month 12. Local progression was associated with an incomplete hypointense rim around the ablation zone and absence of cavitation post-treatment. Conclusions Characteristic changes are present on MRI after cryoablation of lung tumors. A complete hypointense rim and cavitation may be signs of adequate treatment and that local tumor progression is less likely

Injectable Alginate Hydrogel Cross-Linked by Calcium Gluconate-Loaded Porous Microspheres for Cartilage Tissue Engineering

A great interest has been shown in the injectable scaffolds for cartilage tissue regeneration because it can fill irregularly shaped defects easily through minimally invasive surgical treatments. Herein, we developed a new injectable three-dimensional (3D) alginate hydrogel loaded with biodegradable porous poly­(ε-caprolactone)–<i>b</i>-poly­(ethylene glycol)–<i>b</i>-poly­(ε-caprolactone) microspheres (MPs/Alg) as the calcium gluconate container to cross-link alginate. Suspensions of chondrocytes/alginate and porous microspheres turned into a gel because of the release of calcium gluconate; thus, the injectable composite hydrogels give a 3D scaffold to fit the defects perfectly and integrate the extracellular-matrix-mimicking architecture to efficiently accommodate cartilage cells in situ. Tissue repair in a full-thickness cartilage defect model was controlled at 6, 12, and 18 weeks after the implant by micro-CT and immunohistochemistry to evaluate the healing status. The defect in the MPs/Alg+ cells group achieved an almost complete repair at 18 weeks, and the repaired chondrocytes regained a normal tissue structure. Moreover, the MPs/Alg+ cells-treated group increased the quality of tissue formed, including the accumulated glycosaminoglycan and the uniformly deposited type II collagen. The results point out the promising application of the injectable MPs/Alg-chondrocytes system for cartilage tissue engineering

Super-Resolution Fluorescence Imaging of Spatial Organization of Proteins and Lipids in Natural Rubber

Natural rubber (NR) with proteins and lipids has superior mechanical properties to its synthetic counterpart, polyisoprene rubber. However, it is a challenge to unravel the morphology of proteins and lipids. Here we used two-color stochastic optical reconstruction microscopy (STORM) to directly visualize the spatial organization of proteins and lipids in NR. We found that the proteins and lipids form an interdispersed stabilizing layer on the surface of NR latex particles. After drying, the proteins and lipids form aggregates of up to 300 nm in diameter. The aggregates physically interact with the terminal groups of polyisoprene chains, leading to the formation of a network, which contributes to the high elasticity and mechanical property of NR. If we remove proteins in NR, the large phospholipid aggregates disintegrate into small ones. However, it does not decompose the network but rather reduces the effective cross-linking density, thus the deproteinized NR is still elastic-like with decreased mechanical property. Removing both proteins and lipids wholly decomposes the network, thus, results in a liquid-like behavior of the rubber. The STORM measurements in this paper enable more insight into the structure–property relationship of NR, which also shows a great potential of STORM in studying the fine structure of polymeric materials and nanocomposites