Hospital- and Ventilator-associated Pneumonia early after Lung Transplantation: a prospective Study on Incidence, Pathogen Origin and Outcome.

BACKGROUND: Hospital- (HAP) and ventilator-associated pneumonia (VAP) are important complications early (<30 days) after lung transplantation (LT). However, current incidence, associated factors and outcomes are not well reported. METHODS: LT recipients transplanted at our institution (07/2019-01/2020 and 10/2021-11/2022) were prospectively included. We assessed incidence and presentation of pneumonia and evaluated the impact of associated factors using regression models. In addition, we evaluated molecular relatedness of respiratory pathogens collected peri-transplant and at pneumonia occurrence using pulsed-field-gel-electrophoresis (PFGE). RESULTS: In the first 30 days post-LT, 25/270 (9.3%) recipients were diagnosed with pneumonia (68% [17/25] VAP; 32% [8/25] HAP). Median time to pneumonia was 11 days (IQR 7-13). 49% (132/270) of donor and 16% (44/270) of recipient respiratory peri-transplant cultures were positive. However, pathogens associated with pneumonia were not genetically related to either donor or recipient cultures at transplant, as determined by PFGE.Diagnosed pulmonary hypertension (HR 4.42, 95% CI 1.62-12.08) and immunosuppression use (HR 2.87, 95% CI 1.30-6.56) were pre-transplant factors associated with pneumonia.Pneumonia occurrence was associated with longer hospital stay (HR 5.44, 95% CI 2.22-13.37) and VAP with longer ICU stay (HR 4.31, 95% CI: 1.73-10.75) within the first 30 days post-transplant; 30- and 90-day mortality were similar. CONCLUSIONS: Prospectively assessed early pneumonia incidence occurred in around 10% of LT. Populations at increased risk for pneumonia occurrence include LT with pre-transplant pulmonary hypertension and pre-transplant immunosuppression. Pneumonia was associated with increased healthcare use, highlighting the need for further improvements by preferentially targeting higher-risk patients.

RGD Density on Tadpole Nanostructures Regulates Cancer Stem Cell Proliferation and Stemness.

Cancer stem cells (CSCs) make up a small population of cancer cells, primarily responsible for tumor initiation, metastasis, and drug resistance. They overexpress Arg-Gly-Asp (RGD) binding integrin receptors that play crucial roles in cell proliferation and stemness through interaction with the extracellular matrix. Here, we showed that monodisperse polymeric tadpole nanoparticles covalently coupled with different RGD densities regulated colon CSC proliferation and stemness in a RGD density-dependent manner. These tadpoles penetrated deeply and evenly into tumor spheroids and specifically entered cells with cancer stem markers CD24 and CD133. Low RGD density tadpoles triggered integrin α5 expression that further activated TGF-ß3 and TGF-ß2 signaling pathways, confirmed by the increase of pERK and Bcl-2 protein levels. This process is associated with the RGD cluster presentation controlled by the RGD density on the tadpole surface.

A hierarchical cluster analysis for clinical profiling of tofacitinib treatment response in patients with rheumatoid arthritis.

Tofacitinib is the first oral JAK inhibitor approved for treating rheumatoid arthritis (RA). To enhance our understanding of tofacitinib drug response, we used hierarchical clustering to analyse the profiles of patient who responded to the treatment in a real-world setting. Patients who commenced on tofacitinib treatment were selected from 12 major rheumatology centres in Malaysia. The aim was to assess their response to tofacitinib defined as achieving DAS28-CRP/ESR ≤ 3.2 and DAS28 improvement > 1.2 at 12 weeks. A hierarchical clustering analysis was performed using sociodemographic and clinical parameters at baseline. All 163 RA patients were divided into three clusters (Clusters 1, 2 and 3) based on specific clinical factors at baseline including bone erosion, antibody positivity, disease activity and anaemia status. Cluster 1 consisted of RA patients without bone erosion, antibody negative, low baseline disease activity measure and absence of anaemia. Cluster 2 comprised of patients without bone erosion, RF positivity, anti-CCP negativity, moderate to high baseline disease activity score and absence of anaemia. Cluster 3 patients had bone erosion, antibody positivity, high baseline disease activity and anaemia. The response rates to tofacitinib varied among the clusters: Cluster 1 had a 79% response rate, Cluster 2 had a 66% response rate, and Cluster 3 had a 36% response rate. The differences in response rates between the three clusters were found to be statistically significant. This cluster analysis study indicates that patients who are seronegative and have low disease activity, absence of bone erosion and no signs of anaemia may have a higher likelihood of benefiting from tofacitinib therapy. By identifying clinical profiles that respond to tofacitinib treatment, we can improve treatment stratification yielding significant benefits and better health outcomes for individuals with RA.

The prognostic value of MEK pathway-associated estrogen receptor signaling activity for female cancers.

BACKGROUND: Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness. METHODS: Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data. RESULTS: We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers. CONCLUSION: This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery.

Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator-activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout (MBKO) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced ß-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.

Direct synthesis of CsPbX3 perovskite nanocrystal assemblies.

Inorganic CsPbX3 (X = Cl, Br, I) perovskite nanocrystals (NCs) possess many advantageous optoelectronic properties, making them an attractive candidate for light emitting diodes, lasers, or photodetector applications. Such perovskite NCs can form extended assemblies that further modify their bandgap and emission wavelength. In this article, a facile direct synthesis of CsPbX3 NC assemblies that are 1 µm in size and are composed of 10 nm-sized NC building blocks is reported. The direct synthesis of these assemblies with a conventional hot-injection method of the NCs is achieved through the judicious selection of the solvent, ligands, and reaction stoichiometry. Only under selective reaction conditions where the surface ligand environment is tuned to enhance the hydrophobic interactions between ligand chains of neighbouring NCs is self-assembly achieved. These assemblies possess narrow and red-shifted photoluminescence compared to their isolated NC counterparts, which further expands the colour gamut that can be rendered from inorganic perovskites. This is demonstrated through simple down-converting light emitters.

Origins and functional differences of blood endothelial cells.

The interests in blood endothelial cells arise from their therapeutic potential in vascular repair and regeneration. Our understanding of blood endothelial cells that exist in the circulation has been evolving significantly from the original concept of endothelial progenitor cells. Many studies have uncovered heterogeneities of blood endothelial subtypes where some cells express both endothelial and hematopoietic antigens, and others possess either mature or immature endothelial markers. Due to the lack of definitive cell marker identities, there have been momentums in the field to adopt a technical-oriented labeling system based on the cells' involvement in postnatal neovascularization and cell culture derivatives. Our review streamlines nomenclatures for blood endothelial subtypes and standardizes understanding of their functional differences. Broadly, we will discuss about myeloid angiogenic cells (MACs), endothelial colony-forming cells (ECFCs), blood outgrowth endothelial cells (BOECs) and circulating endothelial cells (CECs). The strategic location of blood endothelial cells confers them essential roles in supporting physiological processes. MACs exert angiogenic effects through paracrine mechanisms, while ECFCs are recruited to sites of vascular injury to participate directly in new vessel formation. BOECs are an in vitro derivative of ECFCs. CECs are shed into the bloodstream from damaged vessels, hence reflective of endothelial dysfunction. With clarity on the functional attributes of blood endothelial subtypes, we present recent advances in their applications in disease modelling, along with serving as biomarkers of vascular tissue homeostasis.

Deep learning-enabled breast cancer endocrine response determination from H&E staining based on ESR1 signaling activity.

Estrogen receptor (ER) positivity by immunohistochemistry has long been a main selection criterium for breast cancer patients to be treated with endocrine therapy. However, ER positivity might not directly correlate with activated ER signaling activity, which is a better predictor for endocrine therapy responsiveness. In this study, we investigated if a deep learning method using whole-slide H&E-stained images could predict ER signaling activity. First, ER signaling activity score was determined using RNAseq data available from each of the 1082 breast cancer samples in the TCGA Pan-Cancer dataset based on the Hallmark Estrogen Response Early gene set from the Molecular Signature Database (MSigDB). Then the processed H&E-stained images and ER signaling activity scores from a training cohort were fed into ResNet101 with three additional fully connected layers to generate a predicted ER activity score. The trained models were subsequently applied to an independent testing cohort. The result demonstrated that ER + /HER2- breast cancer patients with a higher predicted ER activity score had longer progression-free survival (p = 0.0368) than those with lower predicted ER activity score. In conclusion, a convolutional deep neural network can predict prognosis and endocrine therapy response in breast cancer patients based on whole-slide H&E-stained images. The trained models were found to robustly predict the prognosis of ER + /HER2- patients. This information is valuable for patient management, as it does not require RNA-seq or microarray data analyses. Thus, these models can reduce the cost of the diagnosis workflow if such information is required.

Deep Learning Models for Automatic Upper Airway Segmentation and Minimum Cross-Sectional Area Localisation in Two-Dimensional Images.

OBJECTIVE: To develop and validate convolutional neural network algorithms for automatic upper airway segmentation and minimum cross-sectional area (CSAmin) localisation in two-dimensional (2D) radiographic airway images. MATERIALS AND METHODS: Two hundred and one 2D airway images acquired using cone-beam computed tomography (CBCT) scanning were randomly assigned to a test group (n = 161) to train artificial intelligence (AI) models and a validation group (n = 40) to evaluate the accuracy of AI processing. Four AI models, UNet18, UNet36, DeepLab50 and DeepLab101, were trained to automatically segment the upper airway 2D images in the test group. Precision, recall, Intersection over Union, the dice similarity coefficient and size difference were used to evaluate the performance of the AI-driven segmentation models. The CSAmin height in each image was manually determined using three-dimensional CBCT data. The nonlinear mathematical morphology technique was used to calculate the CSAmin level. Height errors were assessed to evaluate the CSAmin localisation accuracy in the validation group. The time consumed for airway segmentation and CSAmin localisation was compared between manual and AI processing methods. RESULTS: The precision of all four segmentation models exceeded 90.0%. No significant differences were found in the accuracy of any AI models. The consistency of CSAmin localisation in specific segments between manual and AI processing was 0.944. AI processing was much more efficient than manual processing in terms of airway segmentation and CSAmin localisation. CONCLUSIONS: We successfully developed and validated a fully automatic AI-driven system for upper airway segmentation and CSAmin localisation using 2D radiographic airway images.

Can anterior vertebral body tethering provide superior range of motion outcomes compared to posterior spinal fusion in adolescent idiopathic scoliosis? A systematic review.

PURPOSE: Anterior vertebral body tethering (AVBT) was introduced as a fusionless alternative to treating adolescent idiopathic scoliosis (AIS) while preserving range of motion (ROM). This is the first systematic review to compare the ROM outcomes between AVBT and PSF in treating AIS. METHODS: We conducted a comprehensive search on PubMed, EMBASE, MEDLINE, and Cochrane Library. Inclusion criteria were patients with AIS treated with AVBT or PSF or both, and clearly defined ROM outcomes; exclusion criteria were scoliosis other than AIS, biomechanical or cadaveric studies, non-English publications, case reports, conference summaries, unpublished literature, commentaries, and reviews. Primary outcome was ROM. Secondary outcomes included Cobb angle correction, quality of life (QOL), complications, and muscle strength and endurance. RESULTS: Twelve studies were included in this review. We found moderate evidence to support that AVBT results in superior ROM outcomes than PSF while achieving comparable Cobb angle correction with low evidence. The comparison of QOL outcomes between AVBT and PSF remained inconclusive. In addition to the complications noted conventionally in PSF, AVBT could result in over-correction and distal adding-on. We also found very low evidence to support that AIS patients treated with AVBT have superior muscle strength and endurance when compared to those treated with PSF. CONCLUSIONS: AVBT provides better preservation of ROM and muscle strength postoperatively when compared with PSF, while achieving comparable curve correction. Future studies should explore the spinal growth trajectory to determine the window of opportunity for AVBT in AIS.

Innate lymphoid cells: potential targets for cancer therapeutics.

Innate lymphoid cells (ILCs) comprise a number of different subsets, including natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells that express receptors and signaling pathways that are highly responsive to continuously changing microenvironmental cues. In this Review, we highlight the key features of innate cells that define their capacity to respond rapidly to different environments, how this ability can drive both tumor protection (limiting tumor development) or, alternatively, tumor progression, promoting tumor dissemination and resistance to immunotherapy. We discuss how understanding the regulation of ILCs that can detect tumor cells early in a response opens the possibility of exploiting this functional plasticity to develop rational therapeutic strategies to bolster adaptive immune responses and improve patient outcomes.

Src homology 3 domain binding kinase 1 protects against hepatic steatosis and insulin resistance through the Nur77-FGF21 pathway.

BACKGROUND AND AIMS: Metabolism in the liver is dysregulated in obesity, contributing to various health problems including steatosis and insulin resistance. While the pathogenesis of lipid accumulation has been extensively studied, the protective mechanism against lipid challenge in the liver remains unclear. Here, we report that Src homology 3 domain binding kinase 1 (SBK1) is a regulator of hepatic lipid metabolism and systemic insulin sensitivity in response to obesity. APPROACH AND RESULTS: Enhanced Sbk1 expression was found in the liver of high-fat diet (HFD)-induced obese mice and fatty acid (FA)-challenged hepatocytes. SBK1 knockdown in mouse liver cells augmented FA uptake and lipid accumulation. Similarly, liver-specific SBK1 knockout ( Lsko ) mice displayed more severe hepatosteatosis and higher expression of genes in FA uptake and lipogenesis than the Flox/Flox ( Fl/Fl ) control mice when fed the HFD. The HFD-fed Lsko mice also showed symptoms of hyperglycemia, poor systemic glucose tolerance, and lower insulin sensitivity than the Fl/Fl mice. On the other hand, hepatic Sbk1 overexpression alleviated the high-fructose diet-induced hepatosteatosis, hyperlipidemia, and hyperglycemia in mice. White adipose tissue browning was also observed in hepatic SBK1 -overexpressed mice. Moreover, we found that SBK1 was a positive regulator of FGF21 in the liver during energy surplus conditions. Mechanistically, SBK1 phosphorylates the orphan nuclear receptor 4A1 (Nur77) on serine 344 to promote hepatic FGF21 expression and inhibit the transcription of genes involved in lipid anabolism. CONCLUSIONS: Collectively, our data suggest that SBK1 is a regulator of the metabolic adaption against obesity through the Nur77-FGF21 pathway.

Fostering a High-Functioning Team in Cancer Care Using the 4R Oncology Model: Assessment in a Large Health System and a Blueprint for Other Institutions.

PURPOSE: Delivering cancer care by high-functioning multidisciplinary teams promises to address care fragmentation, which threatens care quality, affects patient outcomes, and strains the oncology workforce. We assessed whether the 4R Oncology model for team-based interdependent care delivery and patient self-management affected team functioning in a large community-based health system. METHODS: 4R was deployed at four locations in breast and lung cancers and assessed along four characteristics of high-functioning teams: recognition as a team internally and externally; commitment to an explicit shared goal; enablement of interdependent work to achieve the goal; and engagement in regular reflection to adapt objectives and processes. RESULTS: We formed an internally and externally recognized team of 24 specialties committed to a shared goal of delivering multidisciplinary care at the optimal time and sequence from a patient-centric viewpoint. The team conducted 40 optimizations of interdependent care (22 for breast, seven for lung, and 11 for both cancers) at four points in the care continuum and established an ongoing teamwork adaptation process. Half of the optimizations entailed low effort, while 30% required high level of effort; 78% resulted in improved process efficiency. CONCLUSION: 4R facilitated development of a large high-functioning team and enabled 40 optimizations of interdependent care along the cancer care continuum in a feasible way. 4R may be an effective approach for fostering high-functioning teams, which could contribute to improving viability of the oncology workforce. Our intervention and taxonomy of results serve as a blueprint for other institutions motivated to strengthen teamwork to improve patient-centered care.

Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors.

BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. METHODS: Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. RESULTS: We identified single-nucleotide variants (SNVs) (range: 5688-14,833 per sample), insertion and deletion variants (indels) (range: 880-1065), and regions with copy number variants (CNVs) (range: 62-335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. CONCLUSIONS: This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC.

Single-Cell Transcriptome of Wet AMD Patient-Derived Endothelial Cells in Angiogenic Sprouting.

Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. 'Wet' AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our 'activated' BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research.

6-O-angeloylplenolin inhibits anti-IgE-stimulated human mast cell activation via suppressing calcium influx and ERK phosphorylation.

Objectives: Mast cells are important immune cells that primarily localize in the interface between the host and external environment, and protect us from pathogen infection. However, they are also involved in the pathology of allergic diseases such as asthma and atopic dermatitis. A novel S phase kinase-associated protein 1 (SKP1) inhibitor 6-O-angeloylplenolin (6-OAP), was studied with its potential ability to alleviate the anti-IgE-induced inflammatory responses of primary human cultured mast cells (HCMCs) and LAD2 cell line. Materials and Methods: We isolated the HCMCs from the buffy coat of voluntary blood donors. The effects of 6-OAP on mast cell activation were evaluated by measuring degranulation, cytokine release, migration, calcium influx, and ERK phosphorylation using spectro-fluorescence assay, multiplex cytometric bead assay/ELISA, migration assay, Fluo-4 calcium flux assay, and western blot, respectively. Results: It was found that 6-OAP exerted anti-inflammatory effects on human mast cells by dose-dependently suppressing the anti-IgE-mediated degranulation and release of cytokines such as proinflammatory cytokines (IL-8 and TNF-α), growth factors (GM-CSF, VEGF, and FGF), and chemokines (CCL2 and CCL3) in HCMC and LAD2 cells. It also suppressed the migration of immature HCMCs induced by CXCL12. Moreover, the process of calcium influx and ERK phosphorylation in activated HCMC cells were inhibited by 6-OAP administration. Conclusion: Our results showed that 6-OAP inhibited anti-IgE-induced inflammatory responses of human mast cells via suppressing calcium influx and ERK phosphorylation.

Human mast cells induce osteoclastogenesis through cell surface RANKL.

OBJECTIVES: We employed the co-culture of CD34+ stem cell-derived human mast cells (HMC) and human monocyte-derived osteoclast precursors to evaluate if mast cells contribute to the pathogenesis of osteoporosis through regulation of osteoclast proliferation and activation. METHODS: Mature HMC and osteoclast precursors were cultured from monocytes isolated from human buffy coat. The osteoclast precursors were incubated with HMC or receptor activator of nuclear factor kappa-B ligand (RANKL) for a week prior to determination of osteoclast maturation through characterization by their morphology and tartrate resistant acid phosphatase (TRAP) expression. The bone absorption activity was determined by pit formation on osteo-assay plate. RESULTS: Mature osteoclasts were identified following co-culture of osteoclast precursors with HMC for one week in the absence of RANKL and they were capable of bone resorption. These actions of HMC on osteoclasts were not affected by mast cell activators such anti-IgE or substance P but could be reversed by osteoprotegerin (OPG) in the co-culture system suggesting the involvement of RANKL. The expression of RANKL on the cell surface of HMC was confirmed by flow cytometry and the density was not affected by activation of HMC. CONCLUSION: Our study provided direct evidence confirming the initiation of osteoclast proliferation and activation by mast cells through cell surface RANKL suggesting that mast cells may contribute to bone destruction in pathological conditions such as osteoporosis.

Macroporous perovskite nanocrystal composites for ultrasensitive copper ion detection.

Accumulation of heavy metal ions, including copper ions (Cu2+), presents a serious threat to human health and to the environment. A substantial amount of research has focused on detecting such species in aqueous solutions. However, progress towards ultrasensitive and easy-to-use sensors for non-aqueous solutions is still limited. Here, we focus on the detection of copper species in hexane, realising ultra-sensitive detection through a fluorescence-based approach. To achieve this, a novel macroporous composite material has been developed featuring luminescent CsPbBr3 nanocrystals (NCs) chemically adhered to a polymerized high internal phase emulsion (polyHIPE) substrate through surface thiol groups. Due to this thiol functionality, sub-monolayer NC formation is realised, which also renders outstanding stability of the composite in the ambient environment. Copper detection is achieved through a direct solution based immersion of the CsPbBr3-(SH)polyHIPE composite, which results in concentration-dependent quenching of the NC photoluminescence. This newly developed sensor has a limit of detection (LOD) for copper as low as 1 × 10-16 M, and a wide operating window spanning 10-2 to 10-16 M. Moreover, the composite exhibits excellent selectivity among different transition metals.

Generating human artery and vein cells from pluripotent stem cells highlights the arterial tropism of Nipah and Hendra viruses.

Stem cell research endeavors to generate specific subtypes of classically defined "cell types." Here, we generate >90% pure human artery or vein endothelial cells from pluripotent stem cells within 3-4 days. We specified artery cells by inhibiting vein-specifying signals and vice versa. These cells modeled viral infection of human vasculature by Nipah and Hendra viruses, which are extraordinarily deadly (∼57%-59% fatality rate) and require biosafety-level-4 containment. Generating pure populations of artery and vein cells highlighted that Nipah and Hendra viruses preferentially infected arteries; arteries expressed higher levels of their viral-entry receptor. Virally infected artery cells fused into syncytia containing up to 23 nuclei, which rapidly died. Despite infecting arteries and occupying ∼6%-17% of their transcriptome, Nipah and Hendra largely eluded innate immune detection, minimally eliciting interferon signaling. We thus efficiently generate artery and vein cells, introduce stem-cell-based toolkits for biosafety-level-4 virology, and explore the arterial tropism and cellular effects of Nipah and Hendra viruses.