ABSTRACT
It is self-evident that our chests expand and contract during breathing but, surprisingly, exactly how individual alveoli change shape over the respiratory cycle is still a matter of debate. Some argue that all the alveoli expand and contract rhythmically. Others claim that the lung volume change is due to groups of alveoli collapsing and reopening during ventilation. Although this question might seem to be an insignificant detail for healthy individuals, it might be a matter of life and death for patients with compromised lungs. Past analyses were based on static post-mortem preparations primarily due to technological limitations, and therefore, by definition, incapable of providing dynamic information. In contrast, this study provides the first comprehensive dynamic data on how the shape of the alveoli changes, and, further, provides valuable insights into the optimal lung volume for efficient gas exchange. It is concluded that alveolar micro-dynamics is nonlinear; and at medium lung volume, alveoli expand more than the ducts.
ABSTRACT
As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.
ABSTRACT
Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.
Subject(s)
AMP-Activated Protein Kinases , Acetaminophen , Cell Adhesion Molecules, Neuronal , Chemical and Drug Induced Liver Injury , NF-E2-Related Factor 2 , Animals , Female , Humans , Male , Mice , AMP-Activated Protein Kinases/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Cell Adhesion Molecules, Neuronal/genetics , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/genetics , Hepatocytes/metabolism , Hepatocytes/drug effects , Liver/metabolism , Liver/drug effects , Liver/pathology , Mice, Inbred C57BL , Mice, Knockout , Nerve Growth Factors , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Oxidative Stress/drug effects , Signal Transduction/drug effectsABSTRACT
Many different types of nanoparticles have been suggested for tumor-targeted theranosis. However, most systems were prepared through a series of complicated processes and could not even overcome the blood-immune barriers. For the accurate diagnosis and effective treatment of cancers, herein we suggested the lipid micellar structure capturing quantum dot (QD) for cancer theranosis. The QD/lipid micelles (QDMs) were prepared using a simple self-assembly procedure and then conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for tumor targeting. As a therapeutic agent, Bcl2 siRNA-cholesterol conjugates were loaded on the surface of QDMs. The EGFR-directed QDMs containing Bcl2 siRNA, so-called immuno-QDM/siBcl2 (iQDM/siBcl2), exhibited the more effective delivery of QDs and siBcl2 to target human colorectal cancer cells in cultures as well as in mouse xenografts. The effective in vivo targeting of iQDM/siBcl2 resulted in a more enhanced therapeutic efficacy of siBcl2 to the target cancer in mice. Based on the results, anti-EGFR QDM capturing therapeutic siRNA could be suggested as an alternative modality for tumor-targeted theranosis.
Subject(s)
ErbB Receptors , Proto-Oncogene Proteins c-bcl-2 , Quantum Dots , RNA, Small Interfering , Quantum Dots/chemistry , Animals , ErbB Receptors/genetics , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Humans , RNA, Small Interfering/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Mice , Cell Line, Tumor , Nanoparticles/chemistry , Lipids/chemistry , Theranostic Nanomedicine/methods , Xenograft Model Antitumor Assays , MicellesABSTRACT
Objectives: This research delves into the application of texture analysis in spine computed tomography (CT) scans and its correlation with bone mineral density (BMD), as determined by dual-energy X-ray absorptiometry (DXA). It specifically addresses the discordance between the 2 measurements, suggesting that certain spinal-specific factors may contribute to this discrepancy. Methods: The study involved 405 cases from a single institution collected between May 6, 2012 and June 30, 2021. Each case underwent a spinal CT scan and a DXA scan. BMD values at the lumbar region (T12 to S1) and total hip were recorded. Texture features from axial cuts of T12 to S1 vertebrae were extracted using gray-level co-occurrence matrices, and a regression model was constructed to predict the BMD values. Results: The correlation between CT texture analysis results and BMD from DXA was moderate, with a correlation coefficient ranging between 0.4 and 0.5. This discordance was examined in light of factors unique to the spine region, such as abdominal obesity, aortic calcification, and lumbar degenerative changes, which could potentially affect BMD measurements. Conclusions: Emerging from this study is a novel insight into the discordance between spinal CT texture analysis and DXA-derived BMD measurements, highlighting the unique influence of spinal attributes. This revelation calls into question the exclusive reliance on DXA scans for BMD assessment, particularly in scenarios where DXA scanning may not be feasible or accurate.
ABSTRACT
Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreERT2, that targets PAMs and DAMs in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM and DAM gene expression. Through long-term tracking, we demonstrated microglial state plasticity. Lastly, we specifically depleted DAMs in demyelination, revealing their roles in disease recovery. Together, we provide a versatile genetic tool to characterize microglial states in CNS development and disease.
Subject(s)
Cell Plasticity , Microglia , Remyelination , Microglia/physiology , Animals , Mice , Cell Plasticity/genetics , Demyelinating Diseases/genetics , Mice, Inbred C57BL , Mice, Transgenic , Disease Models, Animal , Brain , Myelin Sheath/metabolism , White Matter/pathologyABSTRACT
In this study, we conduct simulation research on simultaneous desulfurization and denitrification in a multistaggered baffle spray scrubber. By employing two-phase flow simulations within the Euler-Lagrange framework and calculating the gas-liquid mass transfer rate with user-defined functions, we comprehensively analyzed the effects of various operational parameters. Initially, we validated our simulation model by comparing the simulation results with experimental data. Under conditions of a 0.2 mm droplet diameter, a liquid-to-gas ratio (L/G) of 12 L/m3, and a gas flow rate of 5 CMM using a full cone nozzle, the simulation indicated a desulfurization efficiency of 99.90 versus 99.84% obtained experimentally and a denitrification efficiency of 92.01 versus 90.67% obtained experimentally. This comparison confirmed the reliability of the simulation model. Our findings indicate that a droplet size of 2 mm is optimal, enhancing the desulfurization efficiency from 99.90 to 99.98% and the denitrification efficiency from 92.01 to 99.76%. However, when the droplet size exceeds 2 mm, efficiencies marginally decrease. Increasing the liquid-to-gas ratio to 16 L/m3 further improves desulfurization and denitrification efficiencies to 99.98 and 99.80%, respectively. In contrast, higher inlet flue gas flow rates reduce these efficiencies, with a decline observed from 100% to as low as 93.90% for denitrification with 2 mm droplets. Additionally, the use of a swirl cone nozzle, compared to full or hollow cone nozzles, better disperses droplets, enhancing the gas-liquid contact and achieving efficiencies of 99.99% for desulfurization and 99.81% for denitrification with 2 mm droplets. These insights are valuable for optimizing operational conditions in industrial-scale spray scrubbers, significantly contributing to mitigating the environmental impacts of industrial emissions.
ABSTRACT
Exosomal microRNAs (miRNAs) are closely related to drug resistance in patients with breast cancer (BC); however, only a few roles of the exosomal miRNA-target gene networks have been clinically implicated in drug resistance in BC. Therefore, the present study aimed to identify the differential expression of exosomal miRNAs associated with drug resistance and their target mRNAs. In vitro microarray analysis was used to verify differentially expressed miRNAs (DEMs) in drug-resistant BC. Next, tumor-derived exosomes (TDEs) were isolated. Furthermore, it was determined whether the candidate drug-resistant miRNAs were also significant in TDEs, and then putative miRNAs in TDEs were validated in plasma samples from 35 patients with BC (20 patients with BC showing no response and 15 patients with BC showing a complete response). It was confirmed that the combination of five exosomal miRNAs, including miR-125b-5p, miR-146a-5p, miR-484, miR-1246-5p and miR-1260b, was effective for predicting therapeutic response to neoadjuvant chemotherapy, with an area under the curve value of 0.95, sensitivity of 75%, and specificity of 95%. Public datasets were analyzed to identify differentially expressed genes (DEGs) related to drug resistance and it was revealed that BAK1, NOVA1, PTGER4, RTKN2, AGO1, CAP1, and ETS1 were the target genes of exosomal miRNAs. Networks between DEMs and DEGs were highly correlated with mitosis, metabolism, drug transport, and immune responses. Consequently, these targets could be used as predictive markers and therapeutic targets for clinical applications to enhance treatment outcomes for patients with BC.
ABSTRACT
mRNA vaccines have emerged as a pivotal tool in combating COVID-19, offering an advanced approach to immunization. A key challenge with these vaccines is their need for extremely-low-temperature storage, which affects their stability and shelf life. Our research addresses this issue by enhancing the stability of mRNA vaccines through a novel cationic lipid, O,O'-dimyristyl-N-lysyl aspartate (DMKD). DMKD effectively binds with mRNA, improving vaccine stability. We also integrated phosphatidylserine (PS) into the formulation to boost immune response by promoting the uptake of these nanoparticles by immune cells. Our findings reveal that DMKD-PS nanoparticles maintain structural integrity under long-term refrigeration and effectively protect mRNA. When tested, these nanoparticles containing green fluorescent protein (GFP) mRNA outperformed other commercial lipid nanoparticles in protein expression, both in immune cells (RAW 264.7 mouse macrophage) and non-immune cells (CT26 mouse colorectal carcinoma cells). Importantly, in vivo studies show that DMKD-PS nanoparticles are safely eliminated from the body within 48 h. The results suggest that DMKD-PS nanoparticles present a promising alternative for mRNA vaccine delivery, enhancing both the stability and effectiveness of these vaccines.
Subject(s)
Liposomes , Nanoparticles , Vaccines , Animals , Mice , RNA, Messenger/chemistry , mRNA Vaccines , Transfection , Antigen-Presenting Cells , Nanoparticles/chemistryABSTRACT
The importance of evaluating the cardiotoxicity potential of common chemicals as well as new drugs is increasing as a result of the development of animal alternative test methods using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Bisphenol A (BPA), which is used as a main material in plastics, is known as an endocrine-disrupting chemical, and recently reported to cause cardiotoxicity through inhibition of ion channels in CMs even with acute exposure. Accordingly, the need for the development of alternatives to BPA has been highlighted, and structural analogues including bisphenol AF, C, E, F, and S have been developed. However, cardiotoxicity data for analogues of bisphenol are not well known. In this study, in order to evaluate the cardiotoxicity potential of analogues, including BPA, a survival test of hiPSC-CMs and a dual-cardiotoxicity evaluation based on a multi-electrode array were performed. Acute exposure to all bisphenol analogues did not affect survival rate, but spike amplitude, beat period, and field potential duration were decreased in a dose-dependent manner in most of the bisphenols except bisphenol S. In addition, bisphenols, except for bisphenol S, reduced the contractile force of hiPSC-CMs and resulted in beating arrest at high doses. Taken together, it can be suggested that the developed bisphenol analogues could cause cardiotoxicity even with acute exposure, and it is considered that the application of the MEA-based dual-cardiotoxicity evaluation method can be an effective help in the development of safe alternatives.
Subject(s)
Benzhydryl Compounds , Induced Pluripotent Stem Cells , Myocytes, Cardiac , Animals , Humans , Cardiotoxicity/etiology , Induced Pluripotent Stem Cells/physiology , Phenols/toxicityABSTRACT
BACKGROUND: Predicting tumor responses to neoadjuvant chemotherapy (NAC) is critical for evaluating prognosis and designing treatment strategies for patients with breast cancer; however, there are no reliable biomarkers that can effectively assess tumor responses. Therefore, we aimed to evaluate the clinical feasibility of using extracellular vesicles (EVs) to predict tumor response after NAC. METHODS: Drug-resistant triple-negative breast cancer (TNBC) cell lines were successfully established, which developed specific morphologies and rapidly growing features. To detect resistance to chemotherapeutic drugs, EVs were isolated from cultured cells and plasma samples collected post-NAC from 36 patients with breast cancer. RESULTS: Among the differentially expressed gene profiles between parental and drug-resistant cell lines, drug efflux transporters such as MDR1, MRP1, and BCRP were highly expressed in resistant cell lines. Drug efflux transporters have been identified not only in cell lines but also in EVs released from parental cells using immunoaffinity-based EV isolation. The expression of drug resistance markers in EVs was relatively high in patients with residual disease compared to those with a pathological complete response. CONCLUSIONS: The optimal combination of drug-resistant EV markers was significantly efficient in predicting resistance to NAC with 81.82% sensitivity and 92.86% specificity.
Subject(s)
Extracellular Vesicles , Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Neoadjuvant Therapy , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Neoplasm Proteins/metabolism , Extracellular Vesicles/metabolismABSTRACT
The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.
Subject(s)
Arachnoid , Brain , Dura Mater , Animals , Humans , Mice , Arachnoid/anatomy & histology , Arachnoid/blood supply , Arachnoid/immunology , Arachnoid/metabolism , Biological Transport , Brain/anatomy & histology , Brain/blood supply , Brain/immunology , Brain/metabolism , Dura Mater/anatomy & histology , Dura Mater/blood supply , Dura Mater/immunology , Dura Mater/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Gene Expression Profiling , Magnetic Resonance Imaging , Mice, Transgenic , Subarachnoid Space/anatomy & histology , Subarachnoid Space/blood supply , Subarachnoid Space/immunology , Subarachnoid Space/metabolism , Cerebrospinal Fluid/metabolism , Veins/metabolismABSTRACT
Combining standard surgical procedures with personalized chemotherapy and the continuous monitoring of cancer progression is necessary for effective NSCLC treatment. In this study, we developed liposomal nanoparticles as theranostic agents capable of simultaneous therapy for and imaging of target cancer cells. Copper-64 (64Cu), with a clinically practical half-life (t1/2 = 12.7 h) and decay properties, was selected as the radioisotope for molecular PET imaging. An anti-epidermal growth factor receptor (anti-EGFR) antibody was used to achieve target-specific delivery. Simultaneously, the chemotherapeutic agent doxorubicin (Dox) was encapsulated within the liposomes using a pH-gradient method. The conjugates of 64Cu-labeled and anti-EGFR antibody-conjugated micelles were inserted into the doxorubicin-encapsulating liposomes via a post-insertion procedure (64Cu-Dox-immunoliposomes). We evaluated the size and zeta-potential of the liposomes and analyzed target-specific cell binding and cytotoxicity in EGFR-positive cell lines. Then, we analyzed the specific therapeutic effect and PET imaging of the 64Cu-Dox-immunoliposomes with the A549 xenograft mouse model. In vivo therapeutic experiments on the mouse models demonstrated that the doxorubicin-containing 64Cu-immunoliposomes effectively inhibited tumor growth. Moreover, the 64Cu-immunoliposomes provided superior in vivo PET images of the tumors compared to the untargeted liposomes. We suggest that nanoparticles will be the potential platform for cancer treatment as a widely applicable theranostic system.
Subject(s)
Copper Radioisotopes , Doxorubicin , Liposomes , Neoplasms , Animals , Humans , Mice , Cell Line, Tumor , Copper , Doxorubicin/therapeutic use , Doxorubicin/analogs & derivatives , Drug Delivery Systems/methods , ErbB Receptors/metabolism , Neoplasms/diagnostic imaging , Neoplasms/drug therapy , Polyethylene Glycols , Positron-Emission Tomography , Precision MedicineABSTRACT
BACKGROUND: Femoral neck fractures are effectively treated with bipolar hemiarthroplasty (BHA) surgery, yet postoperative pain management remains a challenge. This study explores the efficacy of multimodal pain management in minimizing opioid use and enhancing recovery. METHODS: A retrospective analysis of 87 patients who underwent BHA between September 2016 and September 2020 was conducted. Patients were analyzed in two groups: Group I (n = 42), receiving serial-injection nerve blocks (SINBs) before and after surgery, and Group II (n = 41), with no SINB. Notably, all nerve blocks for Group I were performed after November 2017, following the implementation of this technique in our protocol. Pain and analgesic medication usage were assessed over 72 h post-surgery, along with hospitalization duration and perioperative complications. RESULTS: Group I patients exhibited significantly lower pain scores at 6, 12, 24, and 48 h post-surgery, alongside reduced incidences of postoperative nausea and vomiting (PONV) and delirium compared with Group II (p < 0.05). CONCLUSIONS: Utilizing sequential lower limb nerve blocks under ultrasound guidance in BHA surgeries effectively reduces early postoperative pain and associated adverse effects. This approach demonstrates potential benefits in pain management, leading to diminished narcotic usage and lower risks of PONV and delirium.
ABSTRACT
Beyond single cell two-dimensional (2D) culture, research on organoids that can mimic human organs is rapidly developing. However, there are still problems in commercialization and joint research using organoids due to the lack of technology to safely store organoids. Since organoids are 3D complex structures with a certain size (0.1-5 mm) beyond the size of cells, the conventional cell-level cryopreservation method using cryoprotectant (CPA) cannot overcome the damage caused by volume change due to osmotic pressure difference and ice nucleation. Herein, we attempted to solve such limitations by applying a nanowarming system using CPA with high cell permeability and Fe3 O4 nanoparticles. By performing beat rate measurement, histological analysis, contractility analysis, and multi-electrode array, it was verified that the developed method could significantly improve functional recovery and survival of heart organoids after freezing and thawing. In this study, we demonstrated a successful organoid cryopreservation method based on a Fe3 O4 nanowarming system. The developed technology will provide clues to the field of tissue cryopreservation and spur the application of organoids.
Subject(s)
Cryopreservation , Nanoparticles , Humans , Cryopreservation/methods , Freezing , Cryoprotective Agents/pharmacology , OrganoidsABSTRACT
BACKGROUND: This research explores the application of morphometric texture analysis in chest Computed Tomography (CT) scans for determining Bone Mineral Content (BMC) and its temporal changes, both crucial in diagnosing osteoporosis. The study establishes an innovative approach to osteoporosis screening by leveraging Hounsfield Units (HUs) in CT scans to evaluate BMC, offering a comparison with dual-energy X-ray absorptiometry (DXA)-based BMC. METHODS: A total of 806 instances (encompassing 379 individuals) were meticulously compiled from a sole institution, during the period stretching from 6 May 2012 to 30 June 2020. In this detailed analysis, each participant was subjected to a pair of chest CT scans, sequentially pursued by a DXA scan, spread over two years. Focused records of BMC values at the inaugural lumbar vertebra (L1) were secured from both the DXA and CT axial slices across all instances. A meticulous selection process pinpointed the largest trabecular section from the L1 vertebral body, whereupon 45 distinctive texture attributes were harvested utilizing gray-level co-occurrence matrix methodologies. Utilizing these amassed 45 attributes, a regression architecture was devised, aiming to forecast the precise BMC values individually. Moreover, an alternative regression framework was engaged, leveraging 90 distinct features, to gauge the BMC fluctuations observed between the duo of scans administered to each participant. RESULTS: The precision of the cultivated regression frameworks was scrupulously assessed, benchmarking against the correlation coefficient (CC) and the mean absolute deviation (MAE) in comparison to the DXA-established references. The regression apparatus employed for estimating BMC unveiled a CC of 0.754 and an MAE of 1.641 (g), respectively. Conversely, the regression mechanism devoted to discerning the variations in BMC manifested a CC of 0.680, coupled with an MAE of 0.528 (g), respectively. CONCLUSION: The innovative methodology utilizing morphometric texture analysis in CT HUs offers an indirect, yet promising, approach for osteoporosis screening by providing estimations of BMC and its temporal changes. The estimations demonstrate moderate positive correlations with DXA measures, suggesting a potential alternative in circumstances where DXA scanning is limited.
ABSTRACT
Tissue-specific gene expression generates fundamental differences in the function of each tissue and affects the characteristics of the tumors that are created as a result. However, it is unclear how much the tissue specificity is conserved during grafting of the primary tumor into an immune-compromised mouse model. Here, we performed a comparative RNA-seq analysis of four different primary-patient derived xenograft (PDX) tumors. The analysis revealed a conserved RNA biotype distribution of primary-PDX pairs, as revealed by previous works. Interestingly, we detected significant changes in the splicing pattern of PDX, which was mainly comprised of skipped exons. This was confirmed by splicing variant-specific RT-PCR analysis. On the other hand, the correlation analysis for the tissue-specific genes indicated overall strong positive correlations between the primary and PDX tumor pairs, with the exception of gastric cancer cases, which showed an inverse correlation. These data propose a tissue-specific change in splicing events during PDX formation as a variable factor that affects primary-PDX integrity.
Subject(s)
Alternative Splicing , Stomach Neoplasms , Animals , Mice , Humans , Stomach Neoplasms/pathology , RNA Splicing/genetics , Sequence Analysis, RNAABSTRACT
Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative region-associated microglia (PAM) in developing white matter and disease-associated microglia (DAM) prevalent in various neurodegenerative conditions. PAM and DAM share a similar core gene signature and other functional properties. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we report the generation of an inducible Cre driver line, Clec7a-CreERT2, designed to target PAM and DAM in the brain parenchyma. Utilizing this tool, we profile labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM/DAM gene expression. Through long-term tracking, we demonstrate surprising levels of plasticity in these microglial states. Lastly, we specifically depleted DAM in cuprizone-induced demyelination, revealing their roles in disease progression and recovery.
ABSTRACT
BACKGROUND: Recent research underscores the clinical relevance of muscle conditions such as sarcopenia and their links to bone mineral density (BMD), yet notable gaps persist in the understanding of their interconnections. Our study addresses this by introducing a novel approach to decipher the correlation between BMD and the texture of the multifidus muscle, utilizing spinal computed tomography (CT) and dual-energy X-ray absorptiometry (DXA) to evaluate muscle texture, BMD, and bone mineral content (BMC) at the total lumbar vertebra and total hip. METHODS: Our single-institution study examined 395 cases collected from 6 May 2012 to 30 November 2021. Each patient underwent a spinal CT scan and a DXA scan within a one-month interval. BMD and BMC at the total lumbar vertebra and total hip were measured. The texture features of the multifidus muscle from the axial cuts of T12 to S1 vertebrae were assessed via gray-level co-occurrence matrices. CT texture analysis values at angles of 45 + 45 and 90 degrees were calculated and correlated with BMD and BMC. A regression model was then constructed to predict BMD values, and the precision of these correlations was evaluated using mean square error (MSE) analysis. RESULTS: Total lumbar BMC showed a correlation of 0.583-0.721 (MSE 1.568-1.842) and lumbar BMD of 0.632-0.756 (MSE 0.068-0.097). Total hip BMC had a correlation of 0.556-0.690 (MSE 0.448-0.495), while hip BMD ranged from 0.585 to 0.746 (MSE 0.072-0.092). CONCLUSIONS: The analysis of spinal CT texture alongside BMD and BMC measures provides a new approach to understanding the relationship between bone and muscle health. The strong correlations expected from our research affirm the importance of integrating bone and muscle measures in the prevention, diagnosis, and management of conditions such as sarcopenia and osteoporosis.
ABSTRACT
Perovskite nanowire arrays with large surface areas for efficient charge transfer and continuous highly crystalline domains for efficient charge transport exhibit ideal morphologies for solar-cell active layers. Here, we introduce a room temperature two-step method to grow dense, vertical nanowire arrays of formamidinium lead iodide (FAPbI3). PbI2 nanocrystals embedded in the cylindrical nanopores of anodized titanium dioxide scaffolds were converted to FAPbI3 by immersion in a FAI solution for a period of 0.5-30 min. During immersion, FAPbI3 crystals grew vertically from the scaffold surface as nanowires with diameters and densities determined by the underlying scaffold. The presence of butylammonium cations during nanowire growth stabilized the active α polymorph of FAPbI3, precluding the need for a thermal annealing step. Solar cells comprising α-FAPbI3 nanowire arrays exhibited maximum solar conversion efficiencies of >14%. Short-circuit current densities of 22-23 mA cm-2 were achieved, on par with those recorded for the best-performing FAPbI3 solar cells reported to date. Such large photocurrents are attributed to the single-crystalline, low-defect nature of the nanowires and increased interfacial area for photogenerated charge transfer compared with thin films.