Denervation­induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway.

Peripheral nerve injury exacerbates progression of muscle heterotopic ossification (HO) and induces changes in expression of local cytokines in muscle tissue. The objective of the present study was to assess the impact of peripheral nerve injury on muscle HO development and the mechanism of cytokine modulation. A mouse model of gastrocnemius muscle HO was established and the sciatic nerve cut to simulate peripheral nerve injury. To evaluate the underlying factors contributing to the exacerbation of muscle HO resulting from denervation, fresh muscle tissue was collected and micro­computed tomography, histochemical staining, RNA­sequencing, reverse transcription­quantitative PCR, Western blot, muscle tissue chip array were performed to analyze the molecular mechanisms. Sciatic nerve injury exacerbated HO in the gastrocnemius muscle of mice. Moreover the osteogenic differentiation of nerve­injured muscle tissue­derived fibro­adipogenic progenitors (FAPs) increased in vitro. The expression of neuregulin 3 (NRG3) was demonstrated to be increased after nerve injury by muscle tissue chip array. Subsequent transcriptome sequencing analysis of muscle tissue revealed an enrichment of the PI3K/Akt pathway following nerve injury and an inhibitor of the PI3K/Akt pathway reduced the osteogenic differentiation of FAPs. Mechanistically, in vitro, peripheral nerve injury increased secretion of NRG3, which, following binding to ErbB4 on the cell surface of FAPs, promoted expression of osteogenesis­associated genes via the PI3K/Akt signaling pathway, thus contributing to osteogenic differentiation of FAPs. In vivo, inhibition of the PI3K/Akt pathway effectively protected against muscle HO induced by peripheral nerve injury in mice. The present study demonstrated that the regulatory roles of NRG3 and the PI3K/Akt pathway in peripheral nerve injury exacerbated muscle HO and highlights a potential therapeutic intervention for treatment of peripheral nerve injury­induced muscle HO.

Functions and Mechanism of Thyroid Hormone Receptor Action During Amphibian Development.

Thyroid hormones and their receptors (TRs) play critical roles during vertebrate development. One of the most dramatic developmental processes regulated by thyroid hormones is frog metamorphosis, which mimics the postembryonic (perinatal) period in mammals. Here, we review some of the findings on the developmental functions of thyroid hormones and TRs as well as their associated mechanisms of action obtained from this model system. More than 2 decades ago, a dual function model was proposed for TR in anuran development. During larval development, unliganded receptors recruit corepressors to repress thyroid hormone response genes to prevent premature metamorphic changes. Subsequently, when thyroid hormone levels rise, liganded receptors recruit coactivators to activate thyroid hormone response genes, leading to metamorphic changes. Over the years, molecular and genetic approaches have provided strong support for this model and have shown that it is applicable to mammalian development as well as to understanding the diverse effects of thyroid hormones in normal physiology and diseases caused by thyroid hormone signaling dysfunction.

Pde3a and Pde3b regulation of murine pulmonary artery smooth muscle cell growth and metabolism.

A role for metabolically active adipose tissue in pulmonary hypertension (PH) pathogenesis is emerging. Alterations in cellular metabolism in metabolic syndrome are triggers of PH-related vascular dysfunction. Metabolic reprogramming in proliferative pulmonary vascular cells causes a metabolic switch from oxidative phosphorylation to glycolysis. PDE3A and PDE3B subtypes in the regulation of metabolism in pulmonary artery smooth muscle cells (PASMC) are poorly understood. We previously found that PDE3A modulates the cellular energy sensor, AMPK, in human PASMC. We demonstrate that global Pde3a knockout mice have right ventricular (RV) hypertrophy, elevated RV systolic pressures, and metabolic dysfunction with elevated serum free fatty acids (FFA). Therefore, we sought to delineate Pde3a/Pde3b regulation of metabolic pathways in PASMC. We found that PASMC Pde3a deficiency, and to a lesser extent Pde3b deficiency, downregulates AMPK, CREB and PPARγ, and upregulates pyruvate kinase dehydrogenase expression, suggesting decreased oxidative phosphorylation. Interestingly, siRNA Pde3a knockdown in adipocytes led to elevated FFA secretion. Furthermore, PASMC exposed to siPDE3A-transfected adipocyte media led to decreased α-SMA, AMPK and CREB phosphorylation, and greater viable cell numbers compared to controls under the same conditions. These data demonstrate that deficiencies of Pde3a and Pde3b alter pathways that affect cell growth and metabolism in PASMC.

Neuregulin-4 alleviates isoproterenol (ISO)-induced cardial remodeling by inhibiting inflammation and apoptosis via AMPK/NF-κB pathway.

Cardiac remodeling refers to the abnormal changes in cardiac structure and function caused by various pathological conditions. It is an inevitable pathological process in the occurrence and development of heart failure and is related to a variety of cardiovascular diseases. Inflammation and apoptosis are critical pathological processes involved in cardiac remodeling. Neuregulin 4 (Nrg 4) is an adipokine produced primarily by brown adipose tissue that may play a protective role in a variety of inflammatory diseases. The aim of this study was to investigate whether Nrg4 can delay the progression of cardiac remodeling by regulating AMPK/NF-κB pathway, inhibiting inflammation and apoptosis. In our study, we established a model of cardiac remodeling in mice after 14 days of isoproterenol (ISO) intervention, and then gave Nrg4 treatment for another 4 weeks. The cardiac function, the degree of myocardial hypertrophy and myocardial fibrosis of the mice were observed. At the same time, the levels of apoptosis-related proteins (Bax,Bcl-2,Caspase-3), IL-6,IL-Iß and TNF-α, as well as the activation level of AMPK/NF-κB signaling pathway were evaluated.Nrg4 alleviated ISO-induced cardiac dysfunction, cardiac hypertrophy and fibrosis in mice. Nrg4 also attenuated ISO-induced apoptosis and reduces levels of inflammatory factors to protect ISO-induced myocardial damage. At the same time, the effect of Nrg4 on AMPK/NF-κB pathway was measured in vivo and in vitro. The administration of an AMPK inhibitor was found to reverse the anti-hypertrophy, anti-inflammatory, and anti-apoptotic effects of Nrg4. Our findings suggest that Nrg4 may play a protective role in cardiac remodeling by inhibiting inflammation and apoptosis via AMPK/NF-κB pathway.

Impact of zirconia-based oxide on endothelial cell dynamics and extracellular matrix remodeling.

INTRODUCTION: Zirconia (ZrO2) is highly regarded in dental restoration due to its aesthetic compatibility and mechanical properties that align with biological tissues. This study explores the effects of stabilized ZrO2 on endothelial cell function and extracellular matrix (ECM) remodeling, processes critical to successful osseointegration in dental implants. METHODOLOGY: Human Umbilical Vein Endothelial Cells (HUVECs) were cultured in ZrO2 -enriched medium under both static and shear stress conditions. Newly implemented techniques, including detailed zirconia surface characterization using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD), were used to verify material properties. Gene and protein expression related to cell adhesion, proliferation, and ECM remodeling were assessed through RT-qPCR and Western blotting. Zymography was used to evaluate the activity of matrix metalloproteinases (MMP2 and MMP9) involved in ECM remodeling. RESULTS: Characterization data confirmed the stability and structural properties of ZrO2, revealing a tetragonal crystalline structure and rough surface morphology conducive to cell adhesion. ZrO2 exposure led to the downregulation of Src, a key regulator of cell adhesion, while upregulating cell cycle regulators p15, CDK2, and CDK4, indicating enhanced cell proliferation. Under shear stress, ZrO2 modulated TGF-ß and MAPK signaling, affecting cell proliferation and angiogenesis. MMP2 and MMP9 activity increased in static conditions but decreased under shear stress, suggesting ZrO2 dynamic role in ECM remodeling. CONCLUSION: This study shows that stabilized zirconia (ZrO2) modulates endothelial cell dynamics and ECM remodeling, key for osseointegration. ZrO2 downregulated Src expression and upregulated cell cycle regulators, enhancing endothelial proliferation. It also affected TGF-ß and MAPK pathways, influencing angiogenesis, and differentially modulated MMP2 and MMP9 activity depending on mechanical conditions. These findings highlight ZrO2 has potential ability to enhance vascular and tissue integration in dental applications.

Long-term transcranial ultrasound stimulation regulates neuroinflammation to ameliorate post-myocardial infarction cardiac arrhythmia and remodeling.

BACKGROUND: Sympathetic overactivation and neuroinflammation in the paraventricular nucleus (PVN) are crucial factors in post-myocardial infarction (MI) cardiac remodeling and ventricular arrhythmias (VAs). Prior study has indicated that low-intensity focused ultrasound stimulation could attenuate sympathetic neuroinflammation within the PVN to prevent the occurrence of VAs in acute MI model. Meanwhile, the cGAS-STING pathway has shown potential to ameliorate neuroinflammatory response. However, the effect and mechanisms of long-term transcranial ultrasound stimulation (LTUS) for modulating neuroinflammation in the chronic stage of MI remain unclear. OBJECTIVE: The current study aims to ascertain whether LTUS could mitigate post-MI neuroinflammation and improve cardiac arrhythmia and remodeling through the cGAS-STING pathway. METHODS: Thirty-six SD rats were equally randomized to the Sham group (pseudo-MI modeling), CMI group (MI modeling), and LTUS group (MI modeling and long-term ultrasound stimulation). Transcranial ultrasound stimulation (15 min/day) was conducted on the PVN for 4 consecutive weeks. After 4-week intervention, the echocardiography, electrophysiological experiment and histopathological staining were performed to assess the role of LTUS on post-MI neuroinflammation and cardiac remodeling. RESULTS: The results indicated that LTUS significantly facilitated microglial M1-to-M2 polarization via cGAS-STING signaling pathway within the PVN. Furthermore, LTUS inhibited MI-induced sympathetic neuroinflammation, thereby improving cardiac dysfunction, ameliorating cardiac remodeling, and reducing VA inducibility. CONCLUSION: Long-term ultrasound stimulation of the PVN was found to alleviate post-MI neuroinflammation and improve cardiac remodeling, which might inspire novel insights and clinical strategies for non-invasive neuromodulation and the treatment of post-MI VAs.

Three-dimensional anisotropic unified continuum model for simulating the healing of damaged soft biological tissues.

The soft biological tissues have the ability to heal and self-repair after damage or injury. During the healing process, damaged tissues are replaced by newly produced undamaged tissue to restore homeostasis. Computational modeling serves as an effective tool for simulating the healing process and understanding the underlying mechanisms. In previous work, we developed the first unified continuum damage model for the healing of soft biological tissues. However, the initial theory lacked generalizability to more realistic scenarios and applicability to biomechanical problems due to the simplicity of the isotropic constitutive model and two-dimensional simulations. Therefore, we further improve our approach by developing a three-dimensional anisotropic unified healing model to address more realistic challenges. By using the Holzapfel-Gasser-Ogden model as the hyperelastic term, the influence of the collagen fibers is considered and the reorientation of fibers in healing is simulated. Three numerical examples related to hypertension, aneurysm, and restenosis of the atherosclerotic artery after balloon angioplasty are presented to demonstrate the effectiveness of the proposed model. By comparing numerical solutions and reference solutions, we demonstrate the ability of the proposed model in simulating long-term tissue healing process and analyze the impact of anisotropic terms.

Clinical relevance of left atrial structural remodeling and non-pulmonary vein foci in atrial fibrillation.

BACKGROUND: The mechanistic role of left atrial (LA) structural remodeling as a non-pulmonary vein (PV) trigger in the initiation of atrial fibrillation (AF) remains uncertain. This study is aimed at prospectively evaluating the association between non-PV triggers and LA structural remodeling. METHODS: A total of 517 patients undergoing catheter ablation for AF were included. After PV isolation, a standardized protocol was implemented to reveal non-PV triggers, which included burst pacing into AF followed by cardioversion during isoproterenol infusion. If pacing-induced atrial tachycardia (AT) was observed, mapping and catheter ablation were performed. RESULTS: The mean percentage of LA low-voltage area (LVA) < 0.5 mV incrementally increased during right atrial pacing among the no induction (n = 470), AF (n = 21), and AT (n = 26) groups (2.6 ± 5.7%, 5.5 ± 6.4%, and 18.0 ± 21.5%, respectively; P < 0.001). In the AF induction group, non-PV foci originated from the left atrium in 13 of 25 foci (52%), and 8 of 13 LA non-PV foci (62%) were located in the septal region. All except 1 focus originated from the non-LVA < 0.5 mV (8%), but 8 of the 13 LA foci originated from the LVA < 1.0 mV (62%). There were no differences in AF recurrence among the groups (log-rank, P = 0.160). CONCLUSION: The majority of non-PV foci in the LA originated outside regions with advanced structural remodeling, thus suggesting the limited effectiveness of adjunctive ablation guided by the LVA < 0.5 mV during sinus rhythm in eliminating non-PV triggers.

Conservative management of malpositioned maxillary anterior implant. Technique description and case report.

This case report presents the conservative management of a malposed implant in the maxillary anterior region caused by craniofacial bone remodeling. The patient expressed dissatisfaction with the position and shade of an implant that was placed almost three decades previously. After evaluating different treatment options, the patient opted to replace the implant prosthesis. The selected treatment consisted of a zirconia crown layered with feldspathic porcelain (including pink porcelain) cemented onto a screw-retained customized zirconia abutment with an angled screw channel for the single-unit permanent fixed implant prosthesis. The report highlights the importance of informed decision making and patient preferences in treatment option selection. It emphasizes the conservative approach of replacing a malposed implant prosthesis with pink porcelain to address the patient's esthetic concerns. Dental photographs and shade-matching protocols were crucial in achieving satisfactory esthetic outcomes. The report also underscores the potential for infraocclusion as well as proclination caused by craniofacial growth in implant therapy, and emphasizes the significance of patient education regarding long-term considerations.

Embryonic macrophages support endocrine commitment during human pancreatic differentiation.

Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.

Three-dimensional changes in the mandibular condyle in skeletal class III patients treated with orthognathic surgery: a systematic review.

This systematic review aimed to evaluate the available evidence on the incidence and quantification of 3-dimensional changes in mandibular condyles after orthognathic surgery by bilateral sagittal split osteotomy (BSSO), with or without maxillary surgery, in class III symmetrical or asymmetrical individuals. The databases PubMed, Lilacs, Web of Science, Embase, SciELO, Scopus, EBSCO, Cochrane, and Google Scholar were surveyed and the study was registered on the PROSPERO (CRD42022383594). The selected studies met the criteria established by the PICO model: 1: Population - individuals over 18 years of age with class III dentofacial skeletal deformities; 2: Intervention - orthognathic surgery using BSSO; 3: Comparison - condylar tomographic measurements (volume, thickness, height, and width) prior to the surgical procedure; and 4: Results - condylar tomographic measurements (volume, thickness, height, and width) at least 12 months after surgery. Initially, 800 articles were identified. After excluding 694 duplicates and screening 153, nine studies met the inclusion criteria for data extraction and analysis. Six evaluated class III symmetrical individuals, and three assessed those with mandibular asymmetry. A total of 233 patients (92 males and 141 females) were studied. Analysis of 466 condyles revealed minimal bone remodelling, with resorption averaging from -0.03 to -0.94 mm and apposition from 0.01 to 0.34 mm. Data analysis showed minimal changes in condylar morphology post BSSO with or without maxillary surgery, indicating predictable skeletal stability. Bias (ACROBAT-NRSI guidelines) did not affect data reliability, and no occlusal changes were observed. The main limitations of the study were heterogeneous imaging techniques, varied study designs, diverse populations, and inconsistent protocols. Further trials with standardised cone-beam computed tomography are needed to enhance remodelling and volume measurement reliability. This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The protective role of brown adipose tissue in cardiac cell damage after myocardial infarction and heart failure.

Acute myocardial infarction (AMI) and related cardiovascular disease complications are the leading causes of mortality worldwide. Brown adipose tissue (BAT) is thermogenic and characterized by the uncoupling protein expression. Recent studies have found that in cardiovascular diseases, activated BAT can effectively improve the prognosis of AMI and concurrent heart failure through intercellular communication. However, a clear and systematic understanding of the myocardial protective mechanism of BAT after AMI is lacking, especially in the endocrine function of BAT. This review describes the effects of BAT on various cells in the heart after AMI. BAT plays a protective role on cardiac cells and fibroblasts during ischemia/reperfusion (I/R), myocardial remodeling, and myocardial fibrosis. This review also discusses the changes caused by BAT activation in different stages of heart failure. Finally, this review summarizes the treatment methods that target BAT to improve AMI. Further in-depth researches are still needed to clarify the underlying mechanism of the connection between BAT and different cells in cardiac tissue in order to identify potential therapeutic targets.

Effects of repetitive transcranial magnetic stimulation at different targets on brain function in stroke patients: a randomized controlled trial.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) can improve post stroke motor function. However, there is little research on targets. The purpose of this study is to investigate the effects of rTMS therapy with different targets on post stroke motor function and neural plasticity. Methods: Fifty-four subjects were randomly divided into M1 (Primary motor area) group, SMA (supplementary motor area) group and Sham group, and were given 10 Hz on the affected M1 area, SMA area and sham stimulation rTMS. The primary outcomes included Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE), Fugl-Meyer Assessment Lower Extremity Scale (FMA-LE) and Berg balance scale (BBS). Secondary outcomes: amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were analyzed by functional magnetic resonance imaging (fMRI) to evaluate brain functional activation and functional connectivity changes. Results: The 2-way repeated-measures ANOVA revealed a significant group × time interaction (F = 23.494, p < 0.001; F = 10.801, p < 0.001; F = 17.812, p < 0.001) in the FMA-UE, FMA-LE and BBS scores. Post hoc analysis indicated that 4 weeks of SMA rTMS resulted in an increase in FMA-UE, FMA-LE and BBS scores compared with Sham group (p = 0.006; p = 0.033; p = 0.012), SMA group was significantly increased in BBS compared with M1 group (p = 0.034). Moreover, there were significant effects of time in all 3 groups in the FMA-UE, FMA-LE and BBS scores (p < 0.001). In addition, the increase of ALFF in the supramarginal gyrus on the affected side was correlated with better FMA-UE recovery, the increase of ALFF in the middle temporal gyrus and the middle frontal gyrus on the affected side was positively correlated with the improvement of BBS, and the ALFF in the cerebellum on the healthy side was negatively correlated with the improvement of BBS. There was a positive correlation between FC (SMA - ipsilateral cerebellum) changes and BBS changes in SMA group. Discussion: In conclusion, SMA-rTMS intervention has a better recovery effect on motor dysfunction after stroke than Sham-rTMS. SMA-rTMS led to similar improvement on motor function but significantly greater improvement on balance compared to M1-rTMS, and this may pave a new way for stroke rehabilitation. Clinical trial registration: Registration number: ChiCTR2200060955, https://www.chictr.org.cn/.

Importance of environmental signals for cardiac morphological development in Atlantic salmon.

The hearts of salmonids display remarkable plasticity, adapting to various environmental factors that influence cardiac function and demand. For instance, in response to cold temperature, the salmonid heart undergoes growth and remodeling to counterbalance the reduced contractile function associated with dropping temperatures. Alongside heart size, the distinct pyramidal shape of the wild salmonid heart is essential for optimal cardiac performance, yet the environmental drivers behind this optimal cardiac morphology remain to be fully understood. Intriguingly, farmed salmonids often have rounded, asymmetrical ventricles and misaligned bulbi from an early age. These deformities are noteworthy given that farmed salmon are often not exposed to natural cues, such as a gradual temperature increase and changing day lengths, during critical developmental stages. In this study, we investigated whether natural environmental conditions during early life stages are pivotal for proper cardiac morphology. Atlantic salmon were raised under simulated natural conditions (low temperature with a natural photoperiod; SimNat) and compared with those reared under simulated farming conditions (SimFarm). Our findings reveal that the ventricle shape and bulbus alignment in SimNat fish closely resemble those of wild salmon, while functional analyses indicate significant differences between SimNat and SimFarm hearts, suggesting diastolic dysfunction and higher cardiac workload in SimFarm hearts. These findings highlight the profound influence of environmental factors such as water temperature and photoperiod on the structural development of the salmonid heart, underscoring the importance of early environmental conditions for cardiac health.

Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells.

BACKGROUND: The transformation of airway smooth muscle cells (ASMCs) from a quiescent phenotype to a hypersecretory and hypercontractile phenotype is a defining feature of asthmatic airway remodeling. Fisetin, a flavonoid compound, possesses anti-inflammatory characteristics in asthma; yet, its impact on airway remodeling and ASMCs phenotype transition has not been investigated. OBJECTIVES: This research seeked to assess the impact of fisetin on ovalbumin (OVA) induced asthmatic airway remodeling and ASMCs phenotype transition, and clarify the mechanisms through network pharmacology predictions as well as in vivo and in vitro validation. METHODS: First, a fisetin-asthma-ASMCs network was constructed to identify potential targets. Subsequently, cellular and animal studies were carried out to examine the inhibitory effects of fisetin on airway remodeling in asthmatic mice, and to detemine how fisetin impacts the phenotypic transition of ASMCs. RESULTS: Network analysis indicated that fisetin might affect asthma via mediating the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) pathway. Intraperitoneal administration of fisetin in vivo reduced airway inflammation and remodeling, as shown by reduced inflammatory cells, decreased T helper type 2 (Th2) cytokine release, diminished collagen accumulation, mitigated airway smooth muscle thickening, and decreased expression of osteopontin (OPN), collagen-I and α-smooth muscle actin (α-SMA). Moreover, fisetin suppressed the PI3K/AKT pathway in asthmatic lung tissue. According to the in vitro data, fisetin downregulated the expression of the synthetic phenotypic proteins OPN and collagen-I, contractile protein α-SMA, and inhibited cellular migration, potentially through the PI3K/AKT pathway. CONCLUSION: These results suggest that fisetin inhibits airway remodeling in asthma by regulating ASMCs phenotypic shift, emphasizing that fisetin is a promising candidate for the treatment of airway smooth muscle remodeling.

The spatial impact of a Western diet in enriching Galectin-1-regulated Rho, ECM, and SASP signaling in a novel MASH-HCC mouse model.

BACKGROUND: Hepatocellular carcinoma (HCC) arising from metabolic dysfunction-associated steatohepatitis (MASH) presents a significant clinical challenge, particularly given the prevalence of the Western diet (WD). The influence of diet on the tumor microenvironment remains poorly understood. Galectin-1 (Gal-1) is a biomarker for HCC and has a crucial role in liver carcinogenesis. Our previous studies demonstrated that silencing Gal-1 effectively treats mouse HCC. However, the impacts of a WD on Gal-1 signaling on MASH to HCC progression are unknown, and this study addresses these knowledge gaps. METHODS: We developed a novel MASH-HCC mouse model. Using spatial transcriptomics and multiplex immunohistochemistry (IHC), we studied the effects of a WD on the liver and tumor microenvironment. By modulating Gal-1 expression through silencing and overexpression, we explored the location-specific impacts of WD on Gal-1 signaling. RESULTS: Pathways such as Rho signaling, extracellular matrix (ECM) remodeling, and senescence-associated secretory phenotypes (SASP) were prominently activated in WD-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and MASH-HCC, compared to healthy livers controls. Furthermore, Rho GTPase effectors, ECM remodeling, neutrophil degranulation, cellular stress, and cell cycle pathways were consistently enriched in human and mouse MASH-HCC. Spatially, these pathways were enriched in the tumor and tumor margins of mouse MASH-HCC. Additionally, there was a notable increase in CD11c and PD-L1-positive cells from non-tumor tissues to the tumor margin and inside the tumor of MASH-HCC, suggesting compromised immune surveillance due to WD intake. Moreover, MASH-HCC exhibited significant Gal-1 induction in N-Cadherin-positive cells, indicating enhanced epithelial-to-mesenchymal transition (EMT). Modulating Gal-1 expression in MASH-HCC further established its specific roles in regulating Rho signaling and SASP in the tumor margin and non-tumor tissues in MASH-HCC. CONCLUSION: WD intake significantly influences vital cellular processes involved in Gal-1-mediated signaling, including Rho signaling and ECM remodeling, in the tumor microenvironment, thereby contributing to the development of MASH-HCC.

Efficacy, Safety and Mechanistic Impact of a Heart Failure Guideline-Directed Medical Therapy Clinic.

BACKGROUND: Although clinical evidence supports rapid institution of guideline-directed medical therapy (GDMT) for heart failure (HF), in actual practice, there remain large gaps in adherence to guideline recommendations. Recent data support safety and efficacy of rapid GDMT implementation; however, rapid GDMT deployment within a general cardiology environment remains unexplored. OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of a GDMT clinic within a general cardiology practice relative to usual care, the impact on prescription of GDMT, HF symptoms, N-terminal pro-B-type natriuretic peptide concentrations and echocardiographic parameters of remodeling. METHODS: Individuals with HF with an abnormal ejection fraction (<50%) referred to the GDMT clinic underwent rapid GDMT titration with close monitoring of clinical data. Rates of GDMT prescription were compared with a matched reference group. Patients underwent echocardiography at baseline and after GDMT clinic completion. RESULTS: A total of 114 persons were treated in GDMT clinic. The mean age was 67.6 ± 14.6 years, and 32 (28%) were women. Among those referred, 100 (87.7%) had no contraindications for 4-drug GDMT. From baseline to clinic completion (median 15.8 weeks [Q1-Q3: 10.7-23.0 weeks]), patients without medication contraindications experienced significant increases in 4-drug GDMT use (from 21% to 88%; P < 0.001); of 4-drug GDMT recipients, 92% received angiotensin receptor neprilysin inhibitor. GDMT clinic participants achieved higher medication doses than those in usual care, with greater achievement of ≥50% target dose of angiotensin receptor neprilysin inhibitor (52% vs 8%), beta-blocker (78% vs 6.2%), mineralocorticoid receptor antagonist (98% vs 15.6%), and sodium-glucose cotransporter 2 inhibitors (92% vs 6.2%). Target doses of all 4 drugs were reached in nearly 1 in 4 participants. HF symptoms improved (94% to 75% NYHA functional class II/III; P < 0.001) and N-terminal pro-B-type natriuretic peptide concentration decreased (median 587 to 534 ng/L; P = 0.03) despite loop diuretic reduction. Additionally, we observed an absolute 6% LVEF increase (from 37% [Q1-Q3: 31%-41%] to 43% [Q1-Q3: 38%-53%]; P < 0.001) and substantial decrease in moderate or severe mitral regurgitation. GDMT titration was well-tolerated. CONCLUSIONS: Rapid GDMT implementation via an outpatient GDMT clinic was effective, safe, and associated with improvement in key clinical parameters. The more widespread role of GDMT clinics to improve HF care warrants further study.

Retinal waves in adaptive rewiring networks orchestrate convergence and divergence in the visual system.

Spontaneous retinal wave activity shaping the visual system is a complex neurodevelopmental phenomenon. Retinal ganglion cells are the hubs through which activity diverges throughout the visual system. We consider how these divergent hubs emerge, using an adaptively rewiring neural network model. Adaptive rewiring models show in a principled way how brains could achieve their complex topologies. Modular small-world structures with rich-club effects and circuits of convergent-divergent units emerge as networks evolve, driven by their own spontaneous activity. Arbitrary nodes of an initially random model network were designated as retinal ganglion cells. They were intermittently exposed to the retinal waveform, as the network evolved through adaptive rewiring. A significant proportion of these nodes developed into divergent hubs within the characteristic complex network architecture. The proportion depends parametrically on the wave incidence rate. Higher rates increase the likelihood of hub formation, while increasing the potential of ganglion cell death. In addition, direct neighbors of designated ganglion cells differentiate like amacrine cells. The divergence observed in ganglion cells resulted in enhanced convergence downstream, suggesting that retinal waves control the formation of convergence in the lateral geniculate nuclei. We conclude that retinal waves stochastically control the distribution of converging and diverging activity in evolving complex networks.

Retinal waves consist of spontaneous neural activity that propagates across the retina during neural development. We simulate the intermittent spread of retinal waveforms originating from a designated node in an adaptively rewiring neural network model. Adaptive rewiring models simulate, in a highly abstracted manner, how brains may achieve their complex topologies during development. This way, we aim to uncover basic principles of neural maturation in the visual system. Namely, we seek to shed light onto how retinal waves might be responsible for the differentiation of immature neurons into specific cell types (e.g., retinal ganglion cells, amacrine cells) and how these waves shape the connectivity structure in the visual system.

Therapeutic potential of a novel hybrid protein: Mitigating allergy and airway remodeling in chronic asthma models induced by Dermatophagoides pteronyssinus.

BACKGROUND: The house-dust mite Dermatophagoides pteronyssinus is a key trigger of allergic asthma. Therefore, it is essential to develop new vaccines that can alter inflammatory processes and airway remodeling. The goal of this study was to test the hypoallergenic and immunogenic characteristics of the hypoallergen rDer p 2231 in a murine model of chronic asthma induced by D. pteronyssinus. METHODS: For this, we measured the levels of IgE, IgG1, IgG2a, and cytokines produced by mice receiving the rDer p 2231 protein. Histopathological parameters of the chronic inflammatory response were also investigated by assessing inflammation and airway remodeling. RESULTS: rDer p 2231 given as a therapeutic vaccine, led to a reduction in the production of IgE, eosinophils, and neutrophils, a lower activity of eosinophilic peroxidase in the airways, and an increase in the production of IgG1 and IgG2a antibodies. IgG antibodies blocked IgE binding to parental allergens in sera from atopic patients. Splenocytes, BALF, and lung from mice treated with rDer p 2231 secreted higher levels of Th1 and regulatory cytokines, as well as reduced levels of Th2 cytokines. Histopathological investigation of the lower airways demonstrated reductions in the thickness of the bronchiolar smooth muscle layer, in the subepithelial fibrosis, and in the goblet cells hyperplasia. CONCLUSIONS: Our preclinical studies suggest that rDer p 2231 is a promising candidate for the treatment of D. pteronyssinus allergy, as the hypoallergen has demonstrated the ability to reduce IgE production, induce specific blocking antibodies, restore and balance Th1/Th2 immune responses, and significantly reduce airway remodeling factors. However, additional clinical studies are needed to more accurately assess the efficacy and safety of rDer p 2231 as a vaccine against D. pteronyssinus-induced allergy.

Antiproliferative agent attenuates post-thrombotic vein wall remodeling in murine and human subjects.

BACKGROUND: Despite appropriate treatment, up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Once PTS occurs, there is no specific treatment, and some patients constantly suffer from intolerable symptoms. How to prevent PTS is important. OBJECTIVES: Characterize vein wall remodeling after thrombus and investigate the effects of antiproliferative agent on post-thrombotic vein wall remodeling in murine and human subjects. METHODS: Features of post-thrombotic vein wall remodeling in murine and human subjects were characterized using imaging and histological examinations. Paclitaxel-loaded hydrogels were used to assess the effects of antiproliferative agent on the remodeling in murine model. Based on the above results, a pilot study was conducted to assess the effects of paclitaxel-coated balloon dilation in severe PTS patients suffering from intolerable symptoms. The control cohort was obtained by 1:1 propensity score matching from a prospective database. RESULTS: Structural and functional alterations in post-thrombotic vein wall were verified by imaging and histological examinations, and predominant active α-SMA+ cells and FSP-1+ cells proliferation was observed. In the murine model, the application of paclitaxel-loaded hydrogels inhibited the remodeling. In the pilot clinical study, patients receiving DCB demonstrated benefits in Villalta scores and VCSS scores compared with those not receiving DCB, and no severe adverse events reported except for thrombosis recurrence. CONCLUSION: Cell proliferation plays an important role in post-thrombotic vein wall remodeling. Inhibition of cell proliferation inhibits the remodeling in murine model, and may reduce signs and symptoms in severe PTS patients.