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Monocytes are important regulators for the maintenance of homeostasis in innate and adaptive immune system and have been reported to play important role in cancer progression. CD47-SIRPα recognition is a coinhibitory immune signal to inhibit phagocytosis in monocytes and macrophages and has been well-known as the "Don't eat me" signal. By using an approach of integrated sensing and activating proteins (iSNAPs), we have rewired the CD47-SIRPα axis to create iSNAP-M which activates pathways in engineered human monocytes (iSNAP-MC). The mRNA expression levels of the monocyte/macrophage markers CD11b, CD14, and CD31 are upregulated in iSNAP-monocytes (iSNAP-MC). With PMA induction, the iSNAP-MC-derived macrophages (iSNAP-MΦ) showed upregelation in CD86 and CD80, but not CD206. TNFα expression and secretion were also increased in iSNAP-MΦ. Furthermore, the injection of iSNAP-MC into mice bearing human B-lymphoma tumors led to the suppression of tumor progression. Therefore, the engineered monocytes, via blockage of coinhibitory immune signals by rewiring CD47-SIRPα axis, can be applied to suppress target tumors for cancer immunotherapy.

The two main blood flow patterns, namely, pulsatile shear (PS) prevalent in straight segments of arteries and oscillatory shear (OS) observed at branch points, are associated with atheroprotective (healthy) and atheroprone (unhealthy) vascular phenotypes, respectively. The effects of blood flow-induced shear stress on endothelial cells (ECs) and vascular health have generally been studied using human umbilical vein endothelial cells (HUVECs). While there are a few studies comparing the differential roles of PS and OS across different types of ECs at a single time point, there is a paucity of studies comparing the temporal responses between different EC types. In the current study, we measured OS and PS transcriptomic responses in human aortic endothelial cells (HAECs) over 24 h and compared these temporal responses of HAECs with our previous findings on HUVECs. The measurements were made at 1, 4, and 24 h in order to capture the responses at early, mid, and late time points after shearing. The results indicate that the responses of HAECs and HUVECs are qualitatively similar for endothelial function-relevant genes and several important pathways with a few exceptions, thus demonstrating that HUVECs can be used as a model to investigate the effects of shear on arterial ECs, with consideration of the differences. Our findings show that HAECs exhibit an earlier response or faster kinetics as compared to HUVECs. The comparative analysis of HAECs and HUVECs presented here offers insights into the mechanisms of common and disparate shear stress responses across these two major endothelial cell types.

PurposePhthalates are ubiquitous endocrine disruptors that can affect pubertal development in children. The association of fetal and childhood levels of phthalates with pubertal development were explored.MethodsWe conduct a population-based birth cohort study to investigate the association between prenatal and childhood exposure to phthalates and pubertal development. Initially, a total of 445 children were recruited from 2000 to 2001, of which 90 children were followed for 15 years which measurements of urine and development assessed at 2, 5, 8, 11, and 14 years. We defined higher Tanner stage as the 14-year-old Tanner stage ≥ 4 and 5 for boys and girls, respectively. A logistic regression analysis was conducted to estimate the crude and adjusted odds ratio of a higher Tanner stage at 14 years old. The Pearson correlation coefficient and multiple linear regression were used to estimate the association of testicular volume, uterine volume, ovarian volume, and blood hormones at 14 years of age with the log-transformed concentration of phthalates at 2, 5, 8, 11, and 14 years.ResultsIn boys, a significantly different geometric mean of mono-benzyl phthalate (MBzP) was observed in 11-year-olds; 6.82 and 2.96 in the lower Tanner stage group and higher Tanner stage group. In girls, a significant difference in the geometric mean of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in 11-year-olds and mono-ethyl phthalate (MEP) in 2-year-olds was observed; MEHHP was 32.97 and 18.13 in the lower Tanner stage group and higher Tanner stage group, and MEP was 26.54 and 65.74 in the lower Tanner stage group and higher Tanner stage group, respectively. Uterine volume at 14 years old was negatively associated with several phthalate metabolites (MEHP at 8 years old, MnBP at 8 years old, MBzP at 14 years old, MMP prenatally, MMP at 8 years old, and MEP at 8 years old) after adjusting for covariates. However, no significant correlations were found between phthalate metabolites and ovarian or testicular volume.ConclusionPhthalate exposure at certain time points may influence the reproductive development of children during puberty; however, further studies should be conducted to determine the causal nature of this association.

Blood flow and vascular shear stress patterns play a significant role in inducing and modulating physiological responses of endothelial cells (ECs). Pulsatile shear (PS) is associated with an atheroprotective endothelial phenotype, while oscillatory shear (OS) is associated with an atheroprone endothelial phenotype. Although mechanisms of endothelial shear response have been extensively studied, most studies focus on characterization of single molecular pathways, mainly at fixed time points after stress application. Here, we carried out a longitudinal time-series study to measure the transcriptome after the application of PS and OS. We performed systems analyses of transcriptional data of cultured human vascular ECs to elucidate the dynamics of endothelial responses in several functional pathways such as cell cycle, oxidative stress, and inflammation. By combining the temporal data on differentially expressed transcription factors and their targets with existing knowledge on relevant functional pathways, we infer the causal relationships between disparate endothelial functions through common transcriptional regulation mechanisms. Our study presents a comprehensive temporally longitudinal experimental study and mechanistic model of shear stress response. By comparing the relative endothelial expressions of genes between OS and PS, we provide insights and an integrated perspective into EC function in response to differential shear. This study has significant implications for the pathogenesis of vascular diseases.

The “Emergency Department Pathology Order Support Tool” (EDPOST) is an electronic laboratory test ordering decision support tool that aims to decrease variation in test ordering practices. As part of a larger project on the codesign, development, and evaluation of ED-POST, this study aimed to explore the workflow nuances that might affect the intended use of the digital decision support tool. Semi-structured, in-depth interviews were conducted with 15 ED clinicians involved in the laboratory test ordering process across the development and evaluation phases of ED-POST. Participants identified the expanded role of registered nurses in test ordering and the practice of ordering tests that are outside the ED’s scope as contextual characteristics that can affect the use and perceived utility of the proposed ED-POST tool. Reconciling “work-as-imagined” with “work-as-done” in the design and development of electronic interventions is important in achieving interventions to improve the safe and effective use of pathology tests. [ABSTRACT FROM AUTHOR]

Introduction: Our earlier analysis during the COVID-19 surges in 2020 showed a reduction in general practitioner (GP) in-person visits to residential aged care facilities (RACFs) and increased use of telehealth. This study assessed how sociodemographic characteristics affected telehealth utilisation. Methods: This retrospective cohort consists of 27,980 RACF residents aged 65 years and over, identified from general practice electronic health records in Victoria and New South Wales during March 2020-August 2021. Residents' demographic characteristics, including age, sex, region, and pension status, were analysed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the associations with telehealth utilisation (telephone/video vs. in-person consultations) and with video versus telephone consultations, in mixed-effects multiple level regression models. Results: Of 32,330 median monthly GP consultations among 21,987 residents identified in 2020, telehealth visits accounted for 17% of GP consultations, of which 93% were telephone consults. In 2021, of 32,229 median monthly GP consultations among 22,712 residents, telehealth visits accounted for 11% of GP consultations (97% by telephone). Pension holders (OR: 1.14; 95% CI: 1.10, 1.17) and those residing in rural areas (OR: 1.72; 95% CI: 1.57, 1.90) were more likely to use telehealth. However, residents in rural areas were less likely to use video than telephone in GP consultations (OR: 0.41; 95% CI: 0.29, 0.57). Results were similar in separate analyses for each COVID surge. Discussion: Telephone was primarily used in telehealth consultations among pension holders and rural residents in RACFs. Along with the limited use of video in virtual care in rural RACFs, the digital divide may imply potential healthcare disparities in socially disadvantaged patients. [ABSTRACT FROM AUTHOR]

Purpose: Although research on how the downstream calculations of a patent's profit potential influence invention renewal decisions is extensive, the impact of the upstream knowledge creation stages is overlooked. The purpose of this study is to address this theoretical vacuum by examining the intra-organizational configuration of knowledge networks and collaboration networks. Design/methodology/approach: The data consist of 491 global pharmaceutical firms that patent in the USA. Drawing on patent records, the authors simultaneously construct intra-organizational knowledge networks and collaboration networks and identify network cohesion features (i.e. local and global). The authors employ panel fixed-effects models to test the hypotheses. Findings: The results show that local knowledge cohesion and local social cohesion decrease invention renewals, while global knowledge cohesion and global social cohesion increase renewals. Moreover, the marginal effects of local and global social cohesion are stronger than those of local and global knowledge cohesion, respectively. Research limitations/implications: The hypotheses are tested using the pharmaceutical industry as a research setting, which limits the generalizability of our findings. In addition, potential formal and informal contingencies are not considered. Practical implications: Despite its limitations, this study provides valuable implications. First, managers are cautioned against the adverse effects of local cohesion structures on invention renewal. Second, firms can dynamically adjust their local and global network configuration strategies to harmonize the generation of valuable inventions and the retention of good ideas. Originality/value: Complementary to previous research that focused on inventions' performance feedback, this study delves into upstream knowledge creation stages to understand invention renewals. [ABSTRACT FROM AUTHOR]

Laboratory tests play an integral role in the delivery of quality health care. However, evidence indicates variations in diagnostic testing, which can lead to patient safety risks. Electronic decision support systems are often identified as key to reducing diagnostic error. However, such tools are often introduced into a clinical setting with little understanding of clinician workflow and how tools are likely to impact this. This study reports a qualitative co-design methodology and results from the first phase in the design and development of an analytics-driven, dashboard approach to supporting clinician test ordering in the Emergency Department. [ABSTRACT FROM AUTHOR]

Focal adhesions (FAs) are dynamic subcellular structures crucial for cell adhesion, migration and differentiation. It remains an enigma how enzymatic activities in these local complexes regulate their structural remodeling in live cells. Utilizing biosensors based on fluorescence resonance energy transfer (FRET), we developed a correlative FRET imaging microscopy (CFIM) approach to quantitatively analyze the subcellular coordination between the enzymatic Src activation and the structural FA disassembly. CFIM reveals that the Src kinase activity only within the microdomain of lipid rafts at the plasma membrane is coupled with FA dynamics. FA disassembly at cell periphery was linearly dependent on this raft-localized Src activity, although cells displayed heterogeneous levels of response to stimulation. Within lipid rafts, the time delay between Src activation and FA disassembly was 1.2 min in cells seeded on low fibronectin concentration ([FN]) and 4.3 min in cells on high [FN]. CFIM further showed that the level of Src-FA coupling, as well as the time delay, was regulated by cell-matrix interactions, as a tight enzyme-structure coupling occurred in FA populations mediated by integrin αvβ₃, but not in those by integrin α₅β₁. Therefore, different FA subpopulations have distinctive regulation mechanisms between their local kinase activity and structural FA dynamics.

Single-molecule experiments indicate that integrin affinity is cation-type-dependent, but in spread cells integrins are engaged in complex focal adhesions (FAs), which can also regulate affinity. To better understand cation-type-dependent adhesion in fully spread cells, we investigated attachment strength by application of external shear. While cell attachment strength is indeed modulated by cations, the regulation of integrin-mediated adhesion is also exceedingly complex, cell specific, and niche dependent. In the presence of magnesium only, fibroblasts and fibrosarcoma cells remodel their cytoskeleton to align in the direction of applied shear in an α5-integrin/fibronectin-dependent manner, which allows them to withstand higher shear. In the presence of calcium or on collagen in modest shear, fibroblasts undergo piecewise detachment but fibrosarcoma cells exhibit increased attachment strength. These data augment the current understanding of force-mediated detachment by suggesting a dynamic interplay in situ between cell adhesion and integrins depending on local niche cation conditions.