Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL-1α.

BACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets. METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment. CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.

Effects of trimetazidine on cardiac function in adult cyanotic congenital heart disease patients: Protocol for a 3-month multicenter, randomized, double-blind controlled trial.

BACKGROUND: Nearly 20% Patients with cyanotic congenital heart disease (CCHD) are not able to receive surgery. These patients experience a decline in cardiac function as they age, which has been demonstrated to be associated with changes in energy metabolism in cardiomyocytes. Trimetazidine (TMZ), a metabolic regulator, is supposed to alleviate such maladaptation and reserve cardiac function in CCHD patients. METHODS: This is a randomized, double-blind, placebo-controlled clinical trial. Eighty adult CCHD patients will be recruited and randomized to the TMZ (20 mg TMZ 3 times a day for 3 months) or placebo group (placebo 3 times a day for 3 months). The primary outcome is the difference in cardiac ejection fractions (EF) measured by cardiac magnetic resonance (MRI) between baseline and after 3 months of TMZ treatment. The secondary outcomes include TMZ serum concentration, rate of cardiac events, NYHA grading, fingertip SpO2, NT-proBNP levels, 6-minute walking test (6MWT), KCCQ-CSS questionnaire score, echocardiography, ECG, routine blood examination, liver and kidney function test, blood pressure and heart rate. DISCUSSION: This trial is designed to explore whether the application of TMZ in adult CCHD patients can improve cardiac function, reduce cardiac events, and improve exercise performance and quality of life. The results will provide targeted drug therapy for CCHD patients with hypoxia and support the application of TMZ in children with CCHD.

Genetic and phenotypic evidence of the predictive validity of preschool parent reports of hyperactivity/impulsivity and inattention.

To determine the validity of parent reports (PRs) of ADHD in preschoolers, we assessed hyperactivity/impulsivity (HI) and inattention (IN) in 1114 twins with PRs at 1.5, 2.5, 4, 5, 14, 15, and 17 years, and teacher-reports at 6, 7, 9, 10, and 12. We examined if preschool PRs (1) predict high HI/IN trajectories, and (2) capture genetic contributions to HI/IN into adolescence. Group-based trajectory analyses identified three 6-17 years trajectories for both HI and IN, including small groups with high HI (N = 88, 10.4%, 77% boys) and IN (N = 158, 17.3%, 75% boys). Controlling for sex, each unit of HI PRs starting at 1.5 years and at 4 years for IN, increased more than 2-fold the risk of belonging to the high trajectory, with incremental contributions (Odds Ratios = 2.5-4.5) at subsequent ages. Quantitative genetic analyses showed that genetic contributions underlying preschool PRs accounted for up to a quarter and a third of the heritability of later HI and IN, respectively. Genes underlying 1.5-year HI and 4-year IN contributed to 6 of 8 later HI and IN time-points and largely explained the corresponding phenotypic correlations. Results provide phenotypic and genetic evidence that preschool parent reports of HI and IN are valid means to predict developmental risk of ADHD.

Association of preoperative neutrophil-lymphocyte ratios with the emergence delirium in pediatric patients after tonsillectomy and adenoidectomy: an observational prospective study.

PURPOSE: The study aimed to investigate potential risk factors for emergence delirium (ED) in pediatric patients after tonsillectomy and adenoidectomy (T&A). METHODS: This prospective, single-center observational study enrolled children aged 3-7 years who underwent T&A under general anesthesia. ED was assessed according to DSM-IV or V criteria. Receiver operating characteristic curve analysis was performed to evaluate the predicative and cut-off values of risk factors, including age, preoperative anxiety level, postoperative pain and neutrophil-lymphocyte ratio (NLR) for ED. Univariate and multivariate logistic regression analyses were performed to investigate risk factors for ED. RESULTS: 94 pediatric patients who underwent T&A were enrolled and 19 developed ED (an incidence of 25.3%). Receiver operating characteristic analysis indicated that preoperative NLR was a significant predictor of ED with a cut-off value of 0.8719 and an area under the curve (AUC) of 0.671 (95% confidence interval (CI) 0.546-0.796, P = 0.022). Preoperative NLR (< 0.8719) and postoperative pain were independent risk factors associated with ED (odds ratio: 0.168, 95% CI 0.033-0.858, P = 0.032; odds ratio: 7.298, 95% CI 1.563-34.083, P = 0.011) according to multivariate logistic regression analysis. CONCLUSIONS: Preoperative NLR level and postoperative pain were independent risk factors for ED in pediatric patients undergoing T&A.

An electrochemical nitric oxide generator for in-home inhalation therapy in pulmonary artery hypertension.

BACKGROUND: Inhaled NO is a selective pulmonary vasodilator proven to be therapeutic for patients with pulmonary artery hypertension (PAH). The most common NO delivery system in clinical practice is cylinder-based, but unfortunately limited by its high costs, complicated delivery, and the requirement of an extensive supply chain, leaving vast unmet medical needs globally. METHODS: To address the need for rapid, affordable, and safe production of nitric oxide (NO) for in-home inhalation therapy in patients with PAH. We developed a novel portable device to derive NO from a nitrite complex solution with a copper(II)-ligand catalyst, and further examined its effectiveness in a porcine model of PAH. This model was established by using female Bama miniature pig and induced by monocrotaline (MCT) administration. RESULTS: This generator could rapidly and safely produce therapeutic NO at concentrations ranging from 0 to 100 parts per million (ppm) with the least disproportionated nitrogen dioxide (NO2) and byproducts. It could effectively alleviate pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in piglets with PAH, without causing major physiologic disruptions. CONCLUSIONS: Our electrochemical NO generator is able to produce the desired NO doses for pulmonary vasodilation in a safe and sustainable way, with low costs, which paves the way for its subsequent clinical trials in the patient with PAH and other common cardiopulmonary conditions with a high disease burden around the world.

Early temperamental and biological predictors of dimensions of social withdrawal in childhood.

Social wariness and preference for solitude, two dimensions of social withdrawal, show unique associations with various socioemotional difficulties in childhood, including internalizing and peer problems. However, their early childhood predictors remain vastly undocumented. The present study aimed to examine whether early indicators of reactivity in situations of unfamiliarity such as behavioral inhibition, affect, and cortisol independently, or in interaction with emotion regulation as indexed by vagal tone, predict later social wariness and preference for solitude. Participants were 1209 children from the Quebec Newborn Twin Study. Vagal tone was assessed at 5 months, and behavioral inhibition, affect, and cortisol were assessed at 19 months in situations of unfamiliarity. Mothers, teachers, and peers evaluated social wariness and preference for solitude repeatedly from 4 to 10 years old. Findings show that three temperamental dimensions, social inhibition, nonsocial inhibition, and affect accounted for the variability in reactions to unfamiliarity. Behavioral inhibition to social unfamiliarity at 19 months predicted social wariness during the preschool years. Poor vagal regulation at 5 months exacerbated the risk associated with negative affect at 19 months to predict preference for solitude during the preschool years. Overall, results show that social wariness and preference for solitude may follow different developmental pathways.

The Intensity of Formal Child-Care Attendance Decreases the Shared Environment Contribution to School Readiness: A Twin Study.

The purpose of this study was to explore if child-care intensity (hours/weeks) and age of onset could moderate genetic and environmental contributions to school readiness. A sample of 648 (85% Whites; 50% Females) pairs of twins was used to compute a GxE, CxE and ExE interaction analyses. The moderation model showed that shared environment explains 48% of individual differences in school readiness for children not attending formal child-care, and decreased gradually to a mere 3% for children attending formal child-care full time, e.g., 40 h per week. Age of onset exerted no moderation effect. The results support the hypothesis that child-care acts as a normalizing environment, possibly buffering negative effects from low-quality home environments on school readiness.

Identification of miRNA-mRNA network and immune-related gene signatures in IgA nephropathy by integrated bioinformatics analysis.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and its diagnosis depends mainly on renal biopsy. However, there is no specific treatment for IgAN. Moreover, its causes and underlying molecular events require further exploration. METHODS: The expression profiles of GSE64306 and GSE93798 were downloaded from the Gene Expression Omnibus (GEO) database and used to identify the differential expression of miRNAs and genes, respectively. The StarBase and TransmiR databases were employed to predict target genes and transcription factors of the differentially expressed miRNAs (DE-miRNAs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict biological functions. A comprehensive analysis of the miRNA-mRNA regulatory network was constructed, and protein-protein interaction (PPI) networks and hub genes were identified. CIBERSORT was used to examine the immune cells in IgAN, and correlation analyses were performed between the hub genes and infiltrating immune cells. RESULTS: Four downregulated miRNAs and 16 upregulated miRNAs were identified. Forty-five and twelve target genes were identified for the upregulated and downregulated DE-miRNAs, respectively. CDKN1A, CDC23, EGR1, HIF1A, and TRIM28 were the hub genes with the highest degrees of connectivity. CIBERSORT revealed increases in the numbers of activated NK cells, M1 and M2 macrophages, CD4 naive T cells, and regulatory T cells in IgAN. Additionally, HIF1A, CDC23, TRIM28, and CDKN1A in IgAN patients were associated with immune cell infiltration. CONCLUSIONS: A potential miRNA-mRNA regulatory network contributing to IgAN onset and progression was successfully established. The results of the present study may facilitate the diagnosis and treatment of IgAN by targeting established miRNA-mRNA interaction networks. Infiltrating immune cells may play significant roles in IgAN pathogenesis. Future studies on these immune cells may help guide immunotherapy for IgAN patients.

A Genetic Cross-Lagged Study of the Longitudinal Association Between Anxiety and Depressive Symptoms During Childhood.

This study documented the etiology contributions between anxiety symptoms (AS) and depressive symptoms (DS) from ages 6-12 years. Teachers assessed AS and DS in 1112 twins at 5 time points. A genetic cross-lagged model was used to estimate genetic/environmental contributions to cross-sectional, cross-age and cross-lag associations. The variance in AS and DS was largely time-specific and more genetic in nature for DS than for AS. Previous DS predicted subsequent DS better than cross-lag or previous common effects, and AS up to age 9 better than previous AS or previous common effects. Thereafter, previous AS predicted subsequent AS. All predictions involved both genetic and unique environment. Suppression effects were found and, when controlled, AS marginally predicted DS from age 7 onward through genetic influences. AS and DS are associated throughout childhood. DS are more stable than AS, and more central to both subsequent AS and DS. AS marginally contribute to subsequent DS.

Contribution of genes and environment to the longitudinal association between childhood impulsive-aggression and suicidality in adolescence.

BACKGROUND: Population-based and family studies showed that impulsive-aggression predicts suicidality; however, the underlying etiological nature of this association is poorly understood. The objective was to determine the contribution of genes and environment to the association between childhood impulsive-aggression and serious suicidal ideation/attempt in young adulthood. METHODS: N = 862 twins (435 families) from the Quebec Newborn Twin Study were followed up from birth to 20 years. Repeated measures of teacher-assessed impulsive-aggression were modeled using a genetically informed latent growth model including intercept and slope parameters reflecting individual differences in the baseline level (age 6 years) and in the change (increase/decrease) of impulsive-aggression during childhood (6 to 12 years), respectively. Lifetime suicidality (serious suicidal ideation/attempt) was self-reported at 20 years. Associations of impulsive-aggression intercept and slope with suicidality were decomposed into additive genetic (A) and unique environmental (E) components. RESULTS: Additive genetic factors accounted for an important part of individual differences in impulsive-aggression intercept (A = 90%, E = 10%) and slope (A = 65%, E = 35%). Genetic (50%) and unique environmental (50%) factors equally contributed to suicidality. We found that 38% of the genetic factors accounting for suicidality were shared with those underlying impulsive-aggression slope, whereas 40% of the environmental factors accounting for suicidality were shared with those associated with impulsive-aggression intercept. The genetic correlation between impulsive-aggression slope and suicidality was 0.60, p = .027. CONCLUSIONS: Genetic and unique environmental factors underlying suicidality significantly overlap with those underlying childhood impulsive-aggression. Future studies should identify putative genetic and environmental factors to inform prevention.

Trajectories of pain and anxiety in a longitudinal cohort of adolescent twins.

BACKGROUND: Adolescence is critical to intercept chronic/persistent pain and decipher its association with anxiety. We ascertained adolescent pain trajectories, their demographic and clinical correlates, the longitudinal association with opiate prescriptions at age 19, and the etiology of the covariation between adolescent pain problems and anxiety symptoms. METHODS: Longitudinal assessment of: 6 common pain problems at age 12, 13, 14, 15, and 17 years; 7 common anxiety symptoms at age 12, 13, and 14 years; opiates' prescriptions at age 19, in the Quebec Newborn Twin Study birth cohort of 667 twin pairs born between 1995-1998. RESULTS: Analyses yielded three trajectories of: "none-to-minimal" (34.3%), "sporadic" (56.7%), and "frequent" (9.0%) pain problems between age 12-17. Anxiety (odds ratios [OR] ORage12 : 2.38; confidence interval [CI]: 1.26-4.47; ORage13 : 3.96; CI: 1.73-9.05; ORage14 : 5.45; CI: 2.67-11.11), the female sex (OR: 3.69; CI: 2.20-6.21), and lower socioeconomic status (OR: 0.87; CI: 0.77-0.98) were associated with the "frequent" compared to the "none-to-minimal" pain trajectory. Only the "frequent" pain trajectory predicted opioid prescriptions at age 19 (OR: 4.14; CI: 1.16-14.55). A twin bivariate latent growth curve model and a cross-lagged model showed that genetic factors and non-shared environmental factors common to both phenotypes influence the longitudinal association between anxiety and adolescent pain problems. CONCLUSIONS: The relatively common, adolescent "frequent pain" trajectory predicts early opioid prescriptions, and anxiety and adolescent pain share multiple etiological components. These data can inform diagnostic reasoning, clinical practice, and help reducing opioid prescriptions and abuse.

The Genetic and Environmental Etiology of Shyness Through Childhood.

The objective of this study was to examine the genetic and environmental contributions to shyness throughout the school-age period. Participants were 553 twin pairs from the ongoing prospective longitudinal Quebec Newborn Twin Study. Teacher-rated measures of shyness were collected at five time-points from age 6-12 years. On average, shyness was moderately stable over time (r = 0.23-0.33) and this stability was almost entirely accounted for by genetic factors. Genetic factors at age 6 accounted for 44% of individual differences and these early genetic factors also explained individual differences at all subsequent ages (6-22%). Non-shared environmental factors explained most of individual differences at single time-points (51-63%), and did not account for stability in shyness. Contributions of shared environment were not significant. Our results suggest that the stability in shyness is mostly accounted for by early and persistent genetic contributions.

Development of a bio-MEMS device for electrical and mechanical conditioning and characterization of cell sheets for myocardial repair.

Here we propose a bio-MEMS device designed to evaluate contractile force and conduction velocity of cell sheets in response to mechanical and electrical stimulation of the cell source as it grows to form a cellular sheet. Moreover, the design allows for the incorporation of patient-specific data and cell sources. An optimized device would allow cell sheets to be cultured, characterized, and conditioned to be compatible with a specific patient's cardiac environment in vitro, before implantation. This design draws upon existing methods in the literature but makes an important advance by combining the mechanical and electrical stimulation into a single system for optimized cell sheet growth. The device has been designed to achieve cellular alignment, electrical stimulation, mechanical stimulation, conduction velocity readout, contraction force readout, and eventually cell sheet release. The platform is a set of comb electrical contacts consisting of three-dimensional walls made of polydimethylsiloxane and coated with electrically conductive metals on the tops of the walls. Not only do the walls serve as a method for stimulating cells that are attached to the top, but their geometry is tailored such that they are flexible enough to be bent by the cells and used to measure force. The platform can be stretched via a linear actuator setup, allowing for simultaneous electrical and mechanical stimulation that can be derived from patient-specific clinical data.

Distinct prognostic values of YAP1 in gastric cancer.

The Hippo pathway regulates intrinsic organ sizes by regulating apoptosis and cell proliferation. YAP1 (yes-associated protein 1) is a transcriptional effector of the Hippo pathway. YAP1 expression is reported to be associated with gastric cancer carcinogenesis and malignancy. In this study, we compared the expression of YAP1 in gastric cancer and normal stomach tissues. Tissue microarray analysis was performed in 156 gastric cancer samples, 8 adjacent normal stomach tissues, and 4 normal stomach tissues. We also analyzed the association between YAP1 protein expression and clinicopathological features, such as age, gender, histological differentiation, and clinical stages. We used the ONCOMINE database and the Kaplan-Meier plotter to analyze YAP1 expression status in different clinicopathological parameters of gastric cancer. We also used the Kaplan-Meier plotter to summarize the survival information of YAP1 from a total of 631 gastric cancer patients. YAP1 expression was found to be elevated in gastric cancer tissues compared to normal stomach tissues. YAP1 messenger RNA was found to be upregulated in gastric intestinal-type adenocarcinoma and gastric mixed adenocarcinoma compared to gastric mucosa. YAP1 high expression was found to be correlated to worse overall survival for all gastric cancer patients followed for 20 years. These results indicate that YAP1 can be used to predict the prognosis of gastric cancer. And YAP1 maybe a potential drug target for gastric cancer patients.

Persistent Genetic and Family-Wide Environmental Contributions to Early Number Knowledge and Later Achievement in Mathematics.

This study investigated the stable and transient genetic and environmental contributions to individual differences in number knowledge in the transition from preschool (age 5) to Grade 1 (age 7) and to the predictive association between early number knowledge and later math achievement (age 10-12). We conducted genetic simplex modeling across these three time points. Genetic variance was transmitted from preschool number knowledge to late-elementary math achievement; in addition, significant genetic innovation (i.e., new influence) occurred at ages 10 through 12 years. The shared and nonshared environmental contributions decreased during the transition from preschool to school entry, but shared and nonshared environment contributed to the continuity across time from preschool number knowledge to subsequent number knowledge and math achievement. There was no new environmental contribution at time points subsequent to preschool. Results are discussed in light of their practical implications for children who have difficulties with mathematics, as well as for preventive intervention.

Isolation and characterization of a Sca-1+/CD31- progenitor cell lineage derived from mouse heart tissue.

BACKGROUND: Myocardial infarction remains the leading cause of mortality in developed countries despite recent advances in its prevention and treatment. Regenerative therapies based on resident cardiac progenitor cells (CPCs) are a promising alternative to conventional treatments. However, CPCs resident in the heart are quite rare. It is unclear how these CPCs can be isolated and cultured efficiently and what the effects of long-term culture in vitro are on their 'stemness' and differentiation potential, but this is critical knowledge for CPCs' clinical application. RESULTS: Here, we isolated stem cell antigen-1 positive cells from postnatal mouse heart by magnetic active cell sorting using an iron-labeled anti-mouse Sca-1 antibody, and cultured them long-term in vitro. We tested stemness marker expression and the proliferation ability of long-term cultured Sca-1+ cells at early, middle and late passages. Furthermore, we determined the differentiation potential of these three passages into cardiac cell lineages (cardiomyocytes, smooth muscle and endothelial cells) after induction in vitro. The expression of myocardial, smooth muscle and endothelial cell-specific genes and surface markers were analyzed by RT-PCR and IF staining. We also investigated the oncogenicity of the three passages by subcutaneously injecting cells in nude mice. Overall, heart-derived Sca-1+ cells showed CPC characteristics: long-term propagation ability in vitro, non-tumorigenic in vivo, persistent expression of stemness and cardiac-specific markers, and multipotent differentiation into cardiac cell lineages. CONCLUSIONS: Our research may bring new insights to myocardium regeneration, for which even a small number of biopsy-derived CPCs could be enriched and propagated long term in vitro to obtain sufficient seed cells for cell injection or cardiac tissue engineering.

A case of peritoneal Burkitt's lymphoma mimic of peritoneal tuberculosis.

Peritoneal lymphomatosis is a rare presentation of lymphoma that can mimic peritoneal tuberculosis. The computed tomography findings in both conditions include omental caking, thickening, and nodularity. We report the case of a 41-year-old man who presented with intermittent abdominal pain and distension. Abdominal CT initially suggested peritoneal tuberculosis due to the thickening of the peritoneum and greater omentum with multiple nodules. However, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images showed diffuse metabolic activity increase in the thickened peritoneum, omentum, and mesentery. An omental biopsy was performed under ultrasonography guidance, and histopathological examination revealed a high-grade Burkitt lymphoma. It is crucial to distinguish peritoneal lymphomatosis from tuberculosis, as the prognosis and management of the two conditions are vastly different.

Can99mTc-MDP-SPECT/CT Differentiate Loosening and Infection After Hip and Knee Replacements?

Background: Prosthetic loosening and infection are still common complications after joint replacement. Over the past few years, single-photon emission computed tomography-computed tomography (SPECT/CT) was widely used and showed unique value based on the combination of anatomic and metabolic information of foci. However, its performance in differentiating between prosthetic loosening and periprosthetic infection after joint replacement is still the focus of clinicians and deserves further investigation. Purpose: This retrospective study was aimed to determine whether bone scintigraphy combined with SPECT/CT still can differentiate prosthetic infection from loosening in patients after joint replacement. The differential efficacy in hip and knee prosthesis was also analyzed. Blood biomarkers for the diagnosis of periprosthetic infection were also evaluated. Patients and methods: Data sets of 74 prosthetic joints (including knees and hips), with suspected prosthetic loosening or infection between 2015 and 2021, were evaluated. Besides the results of nuclear imaging, X-ray images and serum biomarker were also recorded. Telephone follow-up and revision surgery after SPECT/CT were used as a gold standard. The sensitivity and accuracy of different imaging modalities were calculated by Chi-square test. The diagnostic efficacy of imaging methods and serum biomarkers were then analyzed by the area under curve (receiver operating characteristic curves, ROC) in SPSS 26. Results: In all, 47 joints (14 knees and 33 hips) were confirmed as aseptic loosening, while 25 joints (18 knees and 7 hips) were confirmed as infection. The sensitivity and accuracy of SPECT combined with SPECT/CT imaging were the highest (92.86% and 87.84%, respectively). The differential efficacy of bone scintigraphy combined with SPECT/CT imaging was also better than any other single imaging modality. In the analysis of involved prosthesis, prosthetic loosening occurred more in hip prosthesis and knee prosthesis was easily infected (P < 0.05). Finally, the sensitivity of ESR and CRP were 80% and 84%, respectively. Conclusions: Bone scintigraphy with hybrid SPECT/CT remains encouraging in differentiating prosthetic infection from loosening after joint replacement. The diagnostic efficacy of differentiation in hip prosthesis was better than knee. Serum biomarkers cannot be used alone to differentiate prosthetic infection from loosening.

Fiber configuration determines foreign body response of electrospun scaffolds:in vitroandin vivoassessments.

Biomaterial scaffolds boost tissue repair and regeneration by providing physical support, delivering biological signals and/or cells, and recruiting endogenous cells to facilitate tissue-material integration and remodeling. Foreign body response (FBR), an innate immune response that occurs immediately after biomaterial implantation, is a critical factor in determining the biological outcomes of biomaterial scaffolds. Electrospinning is of great simplicity and cost-effectiveness to produce nanofiber scaffolds with well-defined physicochemical properties and has been used in a variety of regenerative medicine applications in preclinical trials and clinical practice. A deep understanding of causal factors between material properties and FBR of host tissues is beneficial to the optimal design of electrospun scaffolds with favorable immunomodulatory properties. We herein prepared and characterized three electrospun scaffolds with distinct fiber configurations and investigated their effects on FBR in terms of immune cell-material interactions and host responses. Our results show that electrospun yarn scaffold results in greater cellular immune reactions and elevated FBR inin vivoassessments. Although the yarn scaffold showed aligned fiber bundles, it failed to induce cell elongation of macrophages due to its rough surface and porous grooves between yarns. In contrast, the aligned scaffold showed reduced FBR compared to the yarn scaffold, indicating a smooth surface is also a contributor to the immunomodulatory effects of the aligned scaffold. Our study suggests that balanced porousness and smooth surface of aligned fibers or yarns should be the key design parameters of electrospun scaffolds to modulate host responsein vivo.

Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2.

Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese family with ARS and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between paired-like homeodomain transcription factor 2 (PITX2) and family with sequence similarity 241 member A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-Seq and real-time quantitative PCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while forkhead box C1 expression remained unchanged. ChIP-Seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a substantial downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) that is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence that is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent.