HMGB2 Release Promotes Pulmonary Hypertension and Predicts Severity and Mortality of Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS: Smooth muscle cell (SMC)-specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS: HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS: Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.

Unravelling the impact of RNA methylation genetic and epigenetic machinery in the treatment of cardiomyopathy.

Cardiomyopathy (CM) represents a heterogeneous group of diseases primarily affecting cardiac structure and function, with genetic and epigenetic dysregulation playing a pivotal role in its pathogenesis. Emerging evidence from the burgeoning field of epitranscriptomics has brought to light the significant impact of various RNA modifications, notably N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), 2'-O-methylation (Nm), and 6,2'-O-dimethyladenosine (m6Am), on cardiomyocyte function and the broader processes of cardiac and vascular remodelling. These modifications have been shown to influence key pathological mechanisms including mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, inflammation, immune response, and myocardial fibrosis. Importantly, aberrations in the RNA methylation machinery have been observed in human CM cases and animal models, highlighting the critical role of RNA methylating enzymes and their potential as therapeutic targets or biomarkers for CM. This review underscores the necessity for a deeper understanding of RNA methylation processes in the context of CM, to illuminate novel therapeutic avenues and diagnostic tools, thereby addressing a significant gap in the current management strategies for this complex disease.

Serum PM20D1 levels in patients with idiopathic pulmonary arterial hypertension and its clinical significance.

OBJECTIVE: This study aimed to investigate the serum levels of Peptidase M20 domain containing 1 (PM20D1) in idiopathic pulmonary arterial hypertension (IPAH) patients and examine its association with lipid metabolism, echocardiography, and hemodynamic parameters. METHODS: This prospective observational research enrolled 103 IPAH patients from January 2018 to January 2022. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum PM20D1 levels in all patients before treatment within 24 h of admission. Demographic data, echocardiography, hemodynamic parameters and serum biomarkers were also collected. RESULTS: The IPAH patients in the deceased group had significantly elevated age, right atrial (RA), mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR) and significantly decreased 6 min walking distance (6MWD) and tricuspid annulus peak systolic velocity (TASPV). IPAH patients showed significant decreases in serum PM20D1, low-density lipoprotein cholesterol (LDL-C), and albumin (ALB). Additionally, PM20D1 was negatively correlated with RA, NT-proBNP and positively correlated with PVR, ALB, 6MWD, and TAPSV. Moreover, PM20D1 has the potential as a biomarker for predicting IPAH patients' prognosis. Finally, logistic regression analysis indicated that PM20D1, ALB, NT-proBNP, PVR, TASPV, RA and 6MWD were identified as risk factors for mortality in IPAH patients. CONCLUSION: Our findings indicated that the serum levels of PM20D1 were significantly decreased in IPAH patients with poor prognosis. Moreover, PM20D1 was identified as a risk factor associated with mortality in IPAH patients.

Separate neural subsystems support goal-directed speech listening.

How do humans excel at tracking the narrative of a particular speaker with a distracting noisy background? This feat places great demands on the collaboration between speech processing and goal-related regulatory functions. Here, we propose that separate subsystems with different cross-task dynamic activity properties and distinct functional purposes support goal-directed speech listening. We adopted a naturalistic dichotic speech listening paradigm in which listeners were instructed to attend to only one narrative from two competing inputs. Using functional magnetic resonance imaging with inter- and intra-subject correlation techniques, we discovered a dissociation in response consistency in temporal, parietal and frontal brain areas as the task demand varied. Specifically, some areas in the bilateral temporal cortex (SomMotB_Aud and TempPar) and lateral prefrontal cortex (DefaultB_PFCl and ContA_PFCl) always showed consistent activation across subjects and across scan runs, regardless of the task demand. In contrast, some areas in the parietal cortex (DefaultA_pCunPCC and ContC_pCun) responded reliably only when the task goal remained the same. These results suggested two dissociated functional neural networks that were independently validated by performing a data-driven clustering analysis of voxelwise functional connectivity patterns. A subsequent meta-analysis revealed distinct functional profiles for these two brain correlation maps. The different-task correlation map was strongly associated with language-related processes (e.g., listening, speech and sentences), whereas the same-task versus different-task correlation map was linked to self-referencing functions (e.g., default mode, theory of mind and autobiographical topics). Altogether, the three-pronged findings revealed two anatomically and functionally dissociated subsystems supporting goal-directed speech listening.

HMGB family proteins: Potential biomarkers and mechanistic factors in cardiovascular diseases.

Cardiovascular disease (CVD) is the most fatal disease that causes sudden death, and inflammation contributes substantially to its occurrence and progression. The prevalence of CVD increases as the population ages, and the pathophysiology is complex. Anti-inflammatory and immunological modulation are the potential methods for CVD prevention and treatment. High-Mobility Group (HMG) chromosomal proteins are one of the most abundant nuclear nonhistone proteins which act as inflammatory mediators in DNA replication, transcription, and repair by producing cytokines and serving as damage-associated molecular patterns in inflammatory responses. The most common and well-studied HMG proteins are those with an HMGB domain, which participate in a variety of biological processes. HMGB1 and HMGB2 were the first members of the HMGB family to be identified and are present in all investigated eukaryotes. Our review is primarily concerned with the involvement of HMGB1 and HMGB2 in CVD. The purpose of this review is to provide a theoretical framework for diagnosing and treating CVD by discussing the structure and function of HMGB1 and HMGB2.

Electrical nerve stimulation for sensory-neural pathway reconstruction in upper-limb amputees.

Introduction: The loss of the neural sensory function pathways between the stump limbs and the brain greatly impacts the rehabilitation of limb function and the daily lives of amputees. Non-invasive physical stressors, such as mechanical pressure and transcutaneous electrical nerve stimulation (TENS), could be potential solutions for recovering somatic sensations in amputees. Previous studies have shown that stimulating the residual or regenerated nerves in the stumps of some amputees can produce phantom hand sensations. However, the results are inconclusive due to unstable physiological responses caused by inaccurate stimulus parameters and positions. Methods: In this study, we developed an optimal TENS strategy by mapping the distribution of the nerves in the stump skin that elicitsphantom sensations known as a "phantom hand map." We evaluated the effectiveness and stability of the confirmed stimulus configuration in a long-term experiment using single- and multi-stimulus paradigms. Additionally, we evaluated the evoked sensations by recording electroencephalograms (EEG) and analyzing brain activities. Results: The results demonstrated that various types of intuitive sensations for amputees could be stably induced by adjusting TENS frequencies, particularly at 5 and 50 Hz. At these frequencies, 100% stability of sensory types was achieved when the stimuli were applied to two specific locations on the stump skin. Furthermore, at these locations, the stability of sensory positions was 100% across different days. Moreover, the evoked sensations were objectively supported by specific patterns of event-related potentials in brain responses. Discussion: This study provides an effective method for developing and evaluating physical stressor stimulus strategies, which could play an important role in the somatosensory rehabilitation of amputees and other patients suffering from somatomotor sensory dysfunction. The paradigm developed in this study can provide effective guidelines for stimulus parameters in physical and electrical nerve stimulation treatments for a variety of symptoms related to neurological disorders.

A plasma proteomic approach in patients with heart failure after acute myocardial infarction: insights into the pathogenesis and progression of the disease.

Aims: The pathogenesis of disease progression targets for patients with heart failure after acute myocardial infarction was investigated by using plasma proteomics. Methods: The plasma proteomes of acute myocardial infarction patients with (MI-HF) and without (MI-WHF) heart failure were compared. Each group consisted of 10 patients who were matched for age and sex. The peptides were analyzed by 2-dimensional liquid chromatography coupled to tandem mass spectrometry in a high definition mode. Parallel reaction monitoring (PRM) verified the selected target proteins. Results: We identified and quantified 2,589 and 2,222 proteins, respectively, and found 117 differentially expressed proteins (DEPs) (≥1.5-fold), when the MI-HF and MI-WHF groups were compared. Of these 51 and 66 were significantly up-regulated and down-regulated, respectively. The significant DEPs was subjected to protein-protein interaction network analysis which revealed a central role of the NF-κB signaling pathway in the MI-HF patients. PRM verified that MB, DIAPH1, VNN1, GOT2, SLC4A1, CRP, CKM, SOD3, F7, DLD, PGAM2, GOT1, UBA7 and HYOU1 were 14 proteins which were highly expressed in MI-HF patients. Conclusions: These findings showed a group of proteins related to the NF-κB signaling pathway in the pathogenesis of patients with poor outcomes after experiencing MI-HF. These proteins may be useful candidate markers for the diagnosis of MI-HF as well as help to elucidate the pathophysiology of this major cause of mortality in older patients.

Molecular Mechanism of Aluminum-Induced Oxidative Damage and Apoptosis in Rat Cardiomyocytes.

Aluminum exposure can mediate either acute toxicity or chronic toxicity. Aluminum exerts toxic effects on the cardiovascular system, but there are few studies on its related mechanisms. In this study, we investigated the molecular mechanism of aluminum-induced oxidative damage and apoptosis in rat cardiomyocytes. Thirty-two male Wistar rats were randomly divided into four groups, including the control group (GC), low-dose group of aluminum exposure (GL), medium-dose group (GM), and high-dose group (GH), with eight rats in each group. The GL, GM, and GH groups were given 5, 10, and 20 mg/(kg·d) of AlCl3 solution by intraperitoneal injection, and the GC group received intraperitoneal injection of the same volume of normal saline (2 ml/rat/day), 5 times a week for 28 days. At the end of the experiment, the levels of aluminum, malondialdehyde (MDA), plasma lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CKMB), and alpha-hydroxybutyrate dehydrogenase (HBDH) were measured. The pathological changes of myocardium were observed by H&E staining. The apoptosis of cardiomyocytes was detected by TUNEL staining, and the expression of apoptosis-related proteins was determined by western blot. The results showed that the levels of CKMB and HBDH in the GM and GH groups were significantly higher than those in the GC group (P < 0.05). The content of aluminum in the myocardium and serum of the aluminum exposure groups was significantly higher than that of the GC group (P < 0.05). The level of MDA in the GM and GH groups was significantly higher than that in the GC group (P < 0.05). The pathological results showed that vacuolated and hypertrophied cardiomyocytes were found in aluminum exposure groups, especially in the GM and GH groups. The TUNEL staining showed that the apoptosis rate of the aluminum exposure groups was considerably higher than that of the GC group (P < 0.05). Western blot showed that the expression of Bcl-2, an anti-apoptotic protein, in cardiomyocytes of aluminum exposure groups was lower than that of the GC group (P < 0.05), while the levels of Bax and caspase-3 in the cardiomyocytes of the GM and GH groups were higher than those of the GC group (P < 0.05). The experimental results showed that aluminum could accumulate in myocardial tissues and cause damage to cardiomyocytes. It could induce oxidative stress damage by increasing the content of MDA in cardiomyocytes and trigger cardiomyocyte apoptosis by activating the pro-apoptotic proteins caspase-3 and Bax and reducing the anti-apoptotic protein Bcl-2.

Twofold advantages of face processing with or without visual awareness.

The advantages of face processing over processing items in other object categories have been found in conditions both with and without visual awareness. This study examined the possible mechanisms underlying the advantages of processing visible and invisible faces. Specifically, contributions from face-like configurations and face-specific local attributes were evaluated by comparing perceptual processes of three image types: genuine faces, face-like objects, and non-face-like objects. Illusory face perception induced from face-like objects largely depended on information from a global configuration level, with a high tolerance for variations in local features. Comparable processing advantages for real faces and face-like objects were observed in invisible conditions using interocular rivalry and crowding paradigms. However, the visible face advantage seemed to be exclusive to genuine faces. These results suggest that the face processing privilege is twofold: It is strongly triggered by global configuration without visual awareness, but with awareness, it relies on facial local attributes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Multiomics Analysis of Transcriptome, Epigenome, and Genome Uncovers Putative Mechanisms for Dilated Cardiomyopathy.

OBJECTIVE: Multiple genes have been identified to cause dilated cardiomyopathy (DCM). Nevertheless, there is still a lack of comprehensive elucidation of the molecular characteristics for DCM. Herein, we aimed to uncover putative molecular features for DCM by multiomics analysis. METHODS: Differentially expressed genes (DEGs) were obtained from different RNA sequencing (RNA-seq) datasets of left ventricle samples from healthy donors and DCM patients. Furthermore, protein-protein interaction (PPI) analysis was then presented. Differentially methylated genes (DMGs) were identified between DCM and control samples. Following integration of DEGs and DMGs, differentially expressed and methylated genes were acquired and their biological functions were analyzed by the clusterProfiler package. Whole exome sequencing of blood samples from 69 DCM patients was constructed in our cohort, which was analyzed the maftools package. The expression of key mutated genes was verified by three independent datasets. RESULTS: 1407 common DEGs were identified for DCM after integration of the two RNA-seq datasets. A PPI network was constructed, composed of 171 up- and 136 downregulated genes. Four hub genes were identified for DCM, including C3 (degree = 24), GNB3 (degree = 23), QSOX1 (degree = 21), and APOB (degree = 17). Moreover, 285 hyper- and 321 hypomethylated genes were screened for DCM. After integration, 20 differentially expressed and methylated genes were identified, which were associated with cell differentiation and protein digestion and absorption. Among single-nucleotide variant (SNV), C>T was the most frequent mutation classification for DCM. MUC4 was the most frequent mutation gene which occupied 71% across 69 samples, followed by PHLDA1, AHNAK2, and MAML3. These mutated genes were confirmed to be differentially expressed between DCM and control samples. CONCLUSION: Our findings comprehensively analyzed molecular characteristics from the transcriptome, epigenome, and genome perspectives for DCM, which could provide practical implications for DCM.

Attentional effect on contrast appearance: From enhancement to attenuation.

Does attention alter appearance? Recent studies have shown that an exogenous cue tends to increase the perceived contrast of a low-contrast stimulus. In the present study we systematically studied the attentional effect over a wide range of contrast levels (15% to 60%). Besides replicating the enhancement at lower contrast levels with higher comparative tasks (Experiment 1), the data revealed a cue-induced attenuation in apparent contrast at higher contrast levels with lower comparative tasks (Experiment 2) and same/different judgment task (Experiment 3). This attenuation effect was robust at the individual level, and it was not due to response bias or sensory interactions (Experiments 3 and 4). These results suggest that attention modulates contrast appearance and this effect depends on both the contrast level and the type of judgment task used. We propose that our findings can be understood through contrast gain mechanism on supersatuating neurons, whose response increases first as the stimulus intensity increases, but decrease the responses after the peak. This surprising phenomenon offers insights for the underlying neural mechanisms of visual processing. (PsycINFO Database Record

Distribution of radionuclides between atmosphere and ash during combustion of contaminated vegetation.

A series of laboratory-scale combustion tests were conducted under well-controlled conditions to measure the release of 90Sr and 137Cs nuclides to the atmosphere (air) from combustion of vegetation and organic soil samples contaminated with radioactivity. These vegetation and soil samples were collected from a controlled contaminated forest area within the Canadian Nuclear Laboratories - Chalk River site. The combustion products including ash and smoke particulates, along with gaseous emissions, were collected and then analyzed for 137Cs and 90Sr concentrations by radiometric techniques. The experimental results reveal that the releases of 90Sr to the atmosphere (air) from combustion of vegetation are very low with most of the 90Sr activity remaining in ash residues, even at a temperature of 800 °C. The detailed combustion experiments with surface litter and twigs, alder twigs, alder leaves, and organic soil indicate that 0.5 ± 0.1%, 0.3 ± 0.1%, 0.9 ± 0.1%, and 0.3 ± 0.1% of 90Sr is released to the atmosphere (air), respectively. On the other hand, the releases of 137Cs are found to be highly dependent on the combustion temperature as well as the nature of vegetation. The releases of 137Cs obtained at 800 °C are 45 ± 7%, 77 ± 9%, 92 ± 5%, and 2.4 ± 0.5% for surface litter and twigs, alder twigs, alder leaves, and organic soil, respectively. The mechanism associated with the high release of 137Cs at a high temperature of 800 °C was explored.