Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.

Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.

Construction of a prognostic model for lung adenocarcinoma based on m6A/m5C/m1A genes.

BACKGROUND: Developing a prognostic model for lung adenocarcinoma (LUAD) that utilizes m6A/m5C/m1A genes holds immense importance in providing precise prognosis predictions for individuals. METHODS: This study mined m6A/m5C/m1A-related differential genes in LUAD based on public databases, identified LUAD tumor subtypes based on these genes, and further built a risk prognostic model grounded in differential genes between subtypes. The immune status between high- and low-risk groups was investigated, and the distribution of feature genes in tumor immune cells was analyzed using single-cell analysis. Based on the expression levels of feature genes, a projection of chemotherapeutic and targeted drugs was made for individuals identified as high-risk. Ultimately, cell experiments were further verified. RESULTS: The 6-gene risk prognosis model based on differential genes between tumor subtypes had good predictive performance. Individuals classified as low-risk exhibited a higher (P < 0.05) abundance of infiltrating immune cells. Feature genes were mainly distributed in tumor immune cells like CD4+T cells, CD8+T cells, and regulatory T cells. Four drugs with relatively low IC50 values were found in the high-risk group: Elesclomol, Pyrimethamine, Saracatinib, and Temsirolimus. In addition, four drugs with significant positive correlation (P < 0.001) between IC50 values and feature gene expression were found, including Alectinib, Estramustine, Brigatinib, and Elesclomol. The low expression of key gene NTSR1 reduced the IC50 value of irinotecan. CONCLUSION: Based on the m6A/m5C/m1A-related genes in LUAD, LUAD patients were divided into 2 subtypes, and a m6A/m5C/m1A-related LUAD prognostic model was constructed to provide a reference for the prognosis prediction of LUAD.

Harnessing developmental cues for cardiomyocyte production.

Developmental research has attempted to untangle the exact signals that control heart growth and size, with knockout studies in mice identifying pivotal roles for Wnt and Hippo signaling during embryonic and fetal heart growth. Despite this improved understanding, no clinically relevant therapies are yet available to compensate for the loss of functional adult myocardium and the absence of mature cardiomyocyte renewal that underlies cardiomyopathies of multiple origins. It remains of great interest to understand which mechanisms are responsible for the decline in proliferation in adult hearts and to elucidate new strategies for the stimulation of cardiac regeneration. Multiple signaling pathways have been identified that regulate the proliferation of cardiomyocytes in the embryonic heart and appear to be upregulated in postnatal injured hearts. In this Review, we highlight the interaction of signaling pathways in heart development and discuss how this knowledge has been translated into current technologies for cardiomyocyte production.

The structure of the γ-TuRC at the microtubule minus end - not just one solution.

In cells, microtubules (MTs) assemble from α/ß-tubulin subunits at nucleation sites containing the γ-tubulin ring complex (γ-TuRC). Within the γ-TuRC, exposed γ-tubulin molecules act as templates for MT assembly by interacting with α/ß-tubulin. The vertebrate γ-TuRC is scaffolded by γ-tubulin-interacting proteins GCP2-6 arranged in a specific order. Interestingly, the γ-tubulin molecules in the γ-TuRC deviate from the cylindrical geometry of MTs, raising the question of how the γ-TuRC structure changes during MT nucleation. Recent studies on the structure of the vertebrate γ-TuRC attached to the end of MTs came to varying conclusions. In vitro assembly of MTs, facilitated by an α-tubulin mutant, resulted in a closed, cylindrical γ-TuRC showing canonical interactions between all γ-tubulin molecules and α/ß-tubulin subunits. Conversely, native MTs formed in a frog extract were capped by a partially closed γ-TuRC, with some γ-tubulin molecules failing to align with α/ß-tubulin. This review discusses these outcomes, along with the broader implications.

Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell-Derived Cardiac Spheroids.

BACKGROUND: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts. METHODS: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×107 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×107 CMs). RESULTS: Recipients of hiPSC-CSs containing 2×107 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P<0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P<0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P<0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×107 CMs. CONCLUSIONS: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products.

Development of m6A/m5C/m1A regulated lncRNA signature for prognostic prediction, personalized immune intervention and drug selection in LUAD.

Research indicates that there are links between m6A, m5C and m1A modifications and the development of different types of tumours. However, it is not yet clear if these modifications are involved in the prognosis of LUAD. The TCGA-LUAD dataset was used as for signature training, while the validation cohort was created by amalgamating publicly accessible GEO datasets including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081. The study focused on 33 genes that are regulated by m6A, m5C or m1A (mRG), which were used to form mRGs clusters and clusters of mRG differentially expressed genes clusters (mRG-DEG clusters). Our subsequent LASSO regression analysis trained the signature of m6A/m5C/m1A-related lncRNA (mRLncSig) using lncRNAs that exhibited differential expression among mRG-DEG clusters and had prognostic value. The model's accuracy underwent validation via Kaplan-Meier analysis, Cox regression, ROC analysis, tAUC evaluation, PCA examination and nomogram predictor validation. In evaluating the immunotherapeutic potential of the signature, we employed multiple bioinformatics algorithms and concepts through various analyses. These included seven newly developed immunoinformatic algorithms, as well as evaluations of TMB, TIDE and immune checkpoints. Additionally, we identified and validated promising agents that target the high-risk mRLncSig in LUAD. To validate the real-world expression pattern of mRLncSig, real-time PCR was carried out on human LUAD tissues. The signature's ability to perform in pan-cancer settings was also evaluated. The study created a 10-lncRNA signature, mRLncSig, which was validated to have prognostic power in the validation cohort. Real-time PCR was applied to verify the actual manifestation of each gene in the signature in the real world. Our immunotherapy analysis revealed an association between mRLncSig and immune status. mRLncSig was found to be closely linked to several checkpoints, such as IL10, IL2, CD40LG, SELP, BTLA and CD28, which could be appropriate immunotherapy targets for LUAD. Among the high-risk patients, our study identified 12 candidate drugs and verified gemcitabine as the most significant one that could target our signature and be effective in treating LUAD. Additionally, we discovered that some of the lncRNAs in mRLncSig could play a crucial role in certain cancer types, and thus, may require further attention in future studies. According to the findings of this study, the use of mRLncSig has the potential to aid in forecasting the prognosis of LUAD and could serve as a potential target for immunotherapy. Moreover, our signature may assist in identifying targets and therapeutic agents more effectively.

Advances in induced pluripotent stem cell-derived cardiac myocytes: technological breakthroughs, key discoveries and new applications.

A transformation is underway in precision and patient-specific medicine. Rapid progress has been enabled by multiple new technologies including induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Here, we delve into these advancements and their future promise, focusing on the efficiency of reprogramming techniques, the fidelity of differentiation into the cardiac lineage, the functional characterization of the resulting cardiac myocytes, and the many applications of in silico models to understand general and patient-specific mechanisms controlling excitation-contraction coupling in health and disease. Furthermore, we explore the current and potential applications of iPSC-CMs in both research and clinical settings, underscoring the far-reaching implications of this rapidly evolving field.

Single-cell ionic current phenotyping elucidates non-canonical features and predictive potential of cardiomyocytes during automated drug experiments.

All new drugs must go through preclinical screening tests to determine their proarrhythmic potential. While these assays effectively filter out dangerous drugs, they are too conservative, often misclassifying safe compounds as proarrhythmic. In this study, we attempt to address this shortcoming with a novel, medium-throughput drug-screening approach: we use an automated patch-clamp system to acquire optimized voltage clamp (VC) and action potential (AP) data from human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) at several drug concentrations (baseline, 3×, 10× and 20× the effective free plasma concentrations). With our novel method, we show correlations between INa block and upstroke slowing after treatment with flecainide or quinine. Additionally, after quinine treatment, we identify significant reductions in current during voltage steps designed to isolate If and IKs. However, we do not detect any IKr block by either drug, and upon further investigation, do not see any IKr present in the iPSC-CMs when prepared for automated patch experiments (i.e. in suspension) - this is in contrast to similar experiments we have conducted with these cells using the manual patch setup. In this study, we: (1) present a proof-of-concept demonstration of a single-cell medium-throughput drug study, and (2) characterize the non-canonical electrophysiology of iPSC-CMs when prepared for experiments in a medium-throughput setting. KEY POINTS: Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model to study the proarrhythmic potential of drugs, but insights from these cells are often limited by the low throughput of manual patch-clamp. In this study, we use a medium-throughput automated patch-clamp system to acquire action potential (AP) and complex voltage clamp (VC) data from single iPSC-CMs at multiple drug concentrations. A correlation between AP upstroke and INa transients was identified and drug-induced changes in ionic currents found. We also characterize the substantially altered physiology of iPSC-CMs when patched in an automated system, suggesting the need to investigate differences between manual and automated patch experiments.

Stem cell-derived cardiomyocyte heterogeneity confounds electrophysiological insights.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model for studying drug cardiotoxicity and patient-specific cardiovascular disease. The inherent electrophysiological heterogeneity of these cells limits the depth of insights that can be drawn from well-designed experiments. In this review, we provide our perspective on some sources and the consequences of iPSC-CM heterogeneity. We demonstrate the extent of heterogeneity in the literature and explain how such heterogeneity is exacerbated by patch-clamp experimental artifacts in the manual and automated set-up. Finally, we discuss how this heterogeneity, caused by both intrinsic and extrinsic factors, limits our ability to build digital twins of patient-derived cardiomyocytes.

High-throughput methods for cardiac cellular electrophysiology studies: the road to personalized medicine.

Personalized medicine refers to the tailored application of medical treatment at an individual level, considering the specific genotype or phenotype of each patient for targeted therapy. In the context of cardiovascular diseases, implementing personalized medicine is challenging due to the high costs involved and the slow pace of identifying the pathogenicity of genetic variants, deciphering molecular mechanisms of disease, and testing treatment approaches. Scalable cellular models such as human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) serve as useful in vitro tools that reflect individual patient genetics and retain clinical phenotypes. High-throughput functional assessment of these constructs is necessary to rapidly assess cardiac pathogenicity and test new therapeutics if personalized medicine is to become a reality. High-throughput photometry recordings of single cells coupled with potentiometric probes offer cost-effective alternatives to traditional patch-clamp assessments of cardiomyocyte action potential characteristics. Importantly, automated patch-clamp (APC) is rapidly emerging in the pharmaceutical industry and academia as a powerful method to assess individual membrane-bound ionic currents and ion channel biophysics over multiple cells in parallel. Now amenable to primary cell and hiPSC-CM measurement, APC represents an exciting leap forward in the characterization of a multitude of molecular mechanisms that underlie clinical cardiac phenotypes. This review provides a summary of state-of-the-art high-throughput electrophysiological techniques to assess cardiac electrophysiology and an overview of recent works that successfully integrate these methods into basic science research that could potentially facilitate future implementation of personalized medicine at a clinical level.

In vitro characterization of probiotic potential of Lactobacillus plantarum CM49 against selected cattle mastitogens.

BACKGROUND: Bovine mastitis results in significant economic losses for the dairy industry globally due to milk production losses and decreased herd efficiency. This research aimed to isolate, select, and characterize indigenous lactobacilli with probiotic properties. A total of 40 lactobacilli were isolated from healthy milk samples of cattle and identified at the species level through 16S rDNA sequencing. All isolates were initially screened for antimicrobial activity, and selected isolates underwent in vitro assessment of probiotic properties. RESULTS: Among the lactobacilli isolates, varying levels of activity (9 to 19 mm) against cattle mastitogens; Stapylococcus aureus (Staph. aureus), Escherichia coli (E. coli) and Streptococcus dysgalactiae (Strep. dysgalactiae) were observed in the well diffusion assay. These isolates demonstrated auto-aggregation (ranging from 14.29 ± 0.96% to 62.11 ± 1.09%) and co-aggregate (ranging from 9.21 ± 0.14% to 55.74 ± 0.74%) with mastitogens after 2 h. Lactobacillus (Lb.) plantarum CM49 showed sensitivity to most antibiotics tested and exhibited strong inhibitory effects, with mean log10 reductions of 3.46 for Staph. aureus, 2.82 for E. coli, and 1.45 for Strep. dysgalactiae in co-culture experiments. Furthermore, Lb. plantarum CM49 significantly decreased the adhesion rate of mastitogens on the bovine mammary cell line and mouse model, demonstrating its potential effectiveness in preventing mastitis. CONCLUSION: It is concluded that Lb. plantarum CM49 has remarkable probiotic potential with activity against cattle mastitogens in the laboratory and cell culture and competitively excludes mastitogens from bovine mammary cells and ameliorates Staph. aureus-induced mastitis in mice.

Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues.

INTRODUCTION: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). METHODS: Cryopreserved human induced pluripotent stem cell-derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin-based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. RESULTS: Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation-contraction coupling (i.e., sodium-calcium exchanger, SLC8). CONCLUSION: These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT-based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.

Exploring the extensin gene family: an updated genome-wide survey in plants and algae.

Extensins (EXTs), a class of hydroxyproline-rich glycoprotein with multiple Ser-Pro3-5 motifs, are known to play roles in cell wall reinforcement and environmental responses. EXTs with repetitive Tyr-X-Tyr (YXY) motifs for crosslinking are referred as crosslinking EXTs. Our comprehensive study spanned 194 algal and plant species, categorizing EXTs into seven subfamilies: classical extensins (EXT I and II), arabinogalactan-protein extensins (AGP-EXTs), proline-rich extensin-like receptor kinases (PERKs), leucine-rich repeat extensins (LRX I and II), formin homology (FH) domain-containing extensins (FH-EXTs), proline-rich, arabinogalactan proteins, conserved cysteines (PAC) domain-containing extensins (PAC I and II), and eight-cysteine motif (8CM)-containing extensins (8CM-EXTs). In the examined dataset, EXTs were detected ubiquitously in plants but infrequently in algae, except for one Coccomyxa and four Chlamydomonadales species. No crosslinking EXTs were found in Poales or certain Zingiberales species. Notably, the previously uncharacterized EXT II, PAC II, and liverwort-specific 8CM-EXTs were found to be crosslinking EXTs. EXT II, featuring repetitive YY motifs instead of the conventional YXY motif, was exclusively identified in Solanaceae. Furthermore, tandem genes encoding distinctive 8CM-EXTs specifically expressed in the germinating spores of Marchantia polymorpha. This updated classification of EXT types allows us to propose a plausible evolutionary history of EXT genes during the course of plant evolution.

Cardiac [99mTc]Tc-hydroxydiphosphonate uptake on bone scintigraphy in patients with hereditary transthyretin amyloidosis: an early follow-up marker?

PURPOSE: There is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments. METHODS: In this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated. RESULTS: Median heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15-34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer. CONCLUSION: A change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.

Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp-3 in anthracycline-induced cardiotoxicity.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline-induced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systems-level transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human-induced pluripotent stem cell-derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of Igfbp-3 in cardiomyocytes. Furthermore, Igfbp-3 reduces DNA damage, impedes topoisomerase IIß expression (Top2ß) which forms Top2ß-Dox-DNA cleavage complex leading to DNA double-strand breaks (DSB), alleviates detyrosinated microtubule accumulation-a hallmark of increased cardiomyocyte stiffness and heart failure-and favorably affects contractility following Dox treatment. These results indicate that Igfbp-3 is induced by cardiomyocytes in an effort to mitigate AIC.

A framework for understanding the human experience of nature through cognitive mapping.

Human behavior is a key driver of the biodiversity crisis, and addressing it requires changing individual choices and actions. Yet, the same processes that imperil biodiversity (e.g., urbanization) also alienate people from the experience of nature, eroding care for the natural world. Although averting this extinction of experience is increasingly recognized as a major contemporary conservation challenge, understanding of what constitutes nature experience remains elusive and few empirical studies have explored it directly. Most researchers have used nature interactions as a stand-in for experience, even though experience extends beyond interactions. We aimed to determine what constitutes the experience of nature and to propose a holistic, empirically derived framework that incorporates the multiple dimensions and components of the experience of nature. Using a mixed-method approach across 3 countries (the United States, Switzerland, and Israel), we conducted a multistage, conceptual content, cognitive mapping (3CM) exercise with 106 participants. This methodology included developing a prompt to capture participants' perceptions of nature experiences and subsequently refining and organizing their input into distinct components and underlying dimensions through an iterative engagement process. Beyond multisensory interactions with nature, experience of nature consisted of 2 dimensions: the circumstances in which interactions occur and the internal responses that encompass various cognitive, affective, and restorative benefits associated with nature interactions. These 3 dimensions had 33 components that occurred consistently across participants in the 3 countries. Frequently mentioned components included seeing animals, landscapes, or scenery; lack of human influence; weather conditions; relaxing, recharging; feeling good; and awe for nature. Fear and nature experienced at home were the least mentioned components. Together, our results showed that nature experience is a combination of nature interactions, circumstances, and internal responses. The emphasized components underscore the significance of offering access to extensive, less human-influenced natural spaces. This in turn can foster a profound nature experience, cultivating feelings of connectedness and care for nature.

Un marco de trabajo para entender la experiencia humana de la naturaleza a través del mapeo cognitivo Resumen El comportamiento humano es un factor clave en la crisis de la biodiversidad, por lo que abordarlo requiere cambios en las acciones y elecciones individuales. Aun así, los mismos procesos que ponen en peligro la biodiversidad (p. ej.: la urbanización) también alejan a las personas de experimentar la naturaleza, lo que disminuye el cuidado por la naturaleza. Aunque cada vez se reconoce más que evitar la extinción de las experiencias es un reto importante para la conservación, todavía no está claro qué constituye una experiencia de la naturaleza y pocos estudios empíricos lo han estudiado directamente. La mayoría de los investigadores ha usado las interacciones con la naturaleza como un sustituto para las experiencias, aunque éstas van más allá de las interacciones. Buscamos determinar qué constituye a las experiencias de la naturaleza y proponer un marco holístico y empírico que incorpore las múltiples dimensiones y componentes de la experiencia de la naturaleza. Usamos una estrategia de método mixto en tres países (EUA, Suiza e Israel) para realizar un ejercicio de un mapeo cognitivo de contenido conceptual en varias fases (3CM) con 106 participantes. Esta metodología incluyó el desarrollo de una entrada para capturar la percepción de los participantes con respecto a las experiencias de la naturaleza y con ello refinar y organizar sus contribuciones en diferentes componentes y dimensiones subyacentes por medio de un proceso iterativo de participación. Más allá de las interacciones multisensoriales con la naturaleza, las vivencias de la naturaleza consistieron en dos dimensiones: las circunstancias en las que ocurren las interacciones y las respuestas internas que engloban varios beneficios cognitivos, afectivos y restauradores asociados con las interacciones con la naturaleza. Estas dos dimensiones contaron con 33 componentes que aparecieron constantemente entre los participantes de los tres países. Con frecuencia mencionaron componentes que incluían avistamiento de animales o paisajes; la ausencia de influencia humana; las condiciones del clima; relajarse, recargarse; sentirse bien; y asombro por la naturaleza. El miedo y la naturaleza vivida en casa fueron los componentes menos mencionados. En conjunto, nuestros resultados mostraron que las vivencias de la naturaleza son una combinación de interacciones con la naturaleza, circunstancias y respuestas internas. Los componentes enfatizados resaltan la importancia de ofrecer acceso a los espacios naturales extensos con menos influencia humana. Esto a la vez puede promover una experiencia profunda de la naturaleza, lo que genera sentimientos de conexión y cuidado de la naturaleza.

Building a cm2scale CVD graphene-based gas sensor: modelling the kinetic with a three-site adsorption/desorption Langmuir model.

In this article, we aim to develop and study a highly sensitive and selective cm2scale graphene-based gas sensor. We present the technology used to fabricate sensors which integrate monolayer chemical vapour deposition graphene: photolithography and transfer of layers. Characterization techniques (optical microscopy, AFM, micro-Raman spectroscopy, transport electrical measurements) ensure a diagnosis of graphene ribbons and allow good reproducibility of technological processes. We present the results of gas characterizations after a 200 ppm NO2exposure. We propose a novel approach for the modelling of the sensor response with a three-site adsorption/desorption Langmuir model. This innovative way of modelling the sensor response should provide a better understanding of the sensor's kinetic and help to overcome the long response time observed with graphene gas sensors.

The effect of human umbilical cord mesenchymal stem cells conditioned medium combined with tamoxifen drug on BRCA1 and BRCA2 expression in breast cancer mouse models.

BACKGROUND: A growing number of studies has indicated that the expression of Breast Cancer Susceptibility Genes 1 (BRCA1) and BRCA2 contribute to the resistance to DNA-damaging chemotherapies. Tamoxifen induces tumor cell death by suppressing estrogen receptor (ER) signaling and inducing DNA damage, and BRCA1 upregulation causes Tamoxifen chemoresistance in breast cancer cells. Consequently, this research study aimed to investigate the possible therapeutic effect of Human Umbilical Cord Mesenchymal Stem Cells Conditioned Medium (UCMSCs-CM) on sensitizing breast cancer cells to Tamoxifen by regulating BRCA1 and BRCA2 expression in vivo. METHODS: Forty female mice, 4-8 weeks old, with weight of 150 g, were used for this study. Mouse 4T1 breast tumor models were established and then treated with UCMSCs-CM and Tamoxifen alone or in combination. After 10 days, the tumor masses were collected and the expression levels of BRCA1 and BRCA2 were evaluated using qRT-PCR assay. RESULTS: The results obtained from qRT-PCR assay illustrated that UCMSCs-CM, either alone or in combination with Tamoxifen, significantly downregulated the mRNA expression levels of BRCA1 in breast cancer mouse models. However, both UCMSCs-CM and Tamoxifen indicated no statistically significant impact on BRCA2 mRNA expression compared to controls. CONCLUSION: Our findings evidenced that UCMSCs-CM could be considered as a potential therapeutic option to modulate Tamoxifen chemosensitivity by regulating BRCA1 in breast cancer.

The intake of ultra-processed foods and homocysteine levels in women with(out) overweight and obesity: The Rotterdam Periconceptional Cohort.

PURPOSE: Today's diet consists of a substantial proportion of ultra-processed foods (UPF), especially in women with overweight and obesity in the reproductive period. High UPF intake results in an inadequate and unbalanced diet leading to derangements of several metabolic pathways detrimental to pregnancy and birth outcomes. Therefore, we aim to investigate whether UPF intake in the periconceptional period affects total homocysteine plasma levels (tHcy). METHODS: 1532 participants were included from the prospective Rotterdam Periconceptional Cohort. UPF intake was calculated using Food Frequency Questionnaires including items classified as 4 in the Nova classification, and tHcy was measured by using liquid chromatography-tandem mass spectrometry system, with an interassay coefficient of variation of < 5.5%. Multivariable linear regression modeling was used and adjusted for covariates and significant interaction terms. RESULTS: Women with overweight or obesity showed significantly higher percentage of UPF intake (respectively, 50.3 and 51.3%) and higher tHcy (respectively, 6.6 and 6.3 µmol/L, Kruskal-Wallis test; respectively, p < 0.001 and p = 0.04) compared to women with normal BMI (UPF intake: 46.8%, tHcy: 6.1 µmol/L). A 10% higher intake of UPF was associated with an increase in tHcy (adjusted: ß = 1.31, 95% CI = 0.38-2.23). Analysis stratified for BMI classification showed comparable associations in normal weight participants (adjusted: ß = 1.07, 95% CI = 0.06-2.07); however, no significant association in participants with overweight (adjusted: ß = 0.06, 95% CI = - 0.95-1.07) and obesity (adjusted: ß = 1.70, 95% CI = - 0.52-3.92) was shown. CONCLUSION: This study showed that a higher intake of UPF is associated with increased tHcy. Better knowledge and awareness of the nutritional quality of the diet in the periconceptional period may contribute to 1-CM and subsequently improve pregnancy course and outcome. TRIAL REGISTRATION NUMBER AND DATE: NTR4356, November 2010.

Validity of ICD-10-based algorithms to identify patients with influenza in inpatient and outpatient settings.

PURPOSE: To evaluate the validity of ICD-10-CM code-based algorithms as proxies for influenza in inpatient and outpatient settings in the USA. METHODS: Administrative claims data (2015-2018) from the largest commercial insurer in New Jersey (NJ), USA, were probabilistically linked to outpatient and inpatient electronic health record (EHR) data containing influenza test results from a large NJ health system. The primary claims-based algorithms defined influenza as presence of an ICD-10-CM code for influenza, stratified by setting (inpatient/outpatient) and code position for inpatient encounters. Test characteristics and 95% confidence intervals (CIs) were calculated using test-positive influenza as a reference standard. Test characteristics of alternative outpatient algorithms incorporating CPT/HCPCS testing codes and anti-influenza medication pharmacy claims were also calculated. RESULTS: There were 430 documented influenza test results within the study period (295 inpatient, 135 outpatient). The claims-based influenza definition had a sensitivity of 84.9% (95% CI 72.9%-92.1%), specificity of 96.3% (95% CI 93.1%-98.0%), and PPV of 83.3% (95% CI 71.3%-91.0%) in the inpatient setting, and a sensitivity of 76.7% (95% CI 59.1%-88.2%), specificity of 96.2% (95% CI 90.6%-98.5%), PPV of 85.2% (95% CI 67.5%-94.1%) in the outpatient setting. Primary inpatient discharge diagnoses had a sensitivity of 54.7% (95% CI 41.5%-67.3%), specificity of 99.6% (95% CI 97.7%-99.9%), and PPV of 96.7% (95% CI 83.3%-99.4%). CPT/HCPCS codes and anti-influenza medication claims were present for few outpatient encounters (sensitivity 3%-10%). CONCLUSIONS: In a large US healthcare system, inpatient ICD-10-CM codes for influenza, particularly primary inpatient diagnoses, had high predictive value for test-positive influenza. Outpatient ICD-10-CM codes were moderately predictive of test-positive influenza.