Deciphering the Role of Rapidly Evolving Conserved Elements in Primate Brain Development and Exploring Their Potential Involvement in Alzheimer's Disease.

Although previous studies have identified human-specific accelerated regions as playing a key role in the recent evolution of the human brain, the characteristics and cellular functions of rapidly evolving conserved elements (RECEs) in ancestral primate lineages remain largely unexplored. Here, based on large-scale primate genome assemblies, we identify 888 RECEs that have been highly conserved in primates that exhibit significantly accelerated substitution rates in the ancestor of the Simiiformes. This primate lineage exhibits remarkable morphological innovations, including an expanded brain mass. Integrative multiomic analyses reveal that RECEs harbor sequences with potential cis-regulatory functions that are activated in the adult human brain. Importantly, genes linked to RECEs exhibit pronounced expression trajectories in the adult brain relative to the fetal stage. Furthermore, we observed an increase in the chromatin accessibility of RECEs in oligodendrocytes from individuals with Alzheimer's disease (AD) compared to that of a control group, indicating that these RECEs may contribute to brain aging and AD. Our findings serve to expand our knowledge of the genetic underpinnings of brain function during primate evolution.

Integrative Omics Reveals Rapidly Evolving Regulatory Sequences Driving Primate Brain Evolution.

Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease.

Genomic Evidence for the Nonpathogenic State in HIV-1-Infected Northern Pig-Tailed Macaques.

HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research.

Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling.

The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.

Insights into the biocorrosion of Q235A steel influenced by the electron transfer process between iron and methanogenic microbiota.

Anaerobic microbiologically influenced corrosion (MIC) of Fe (0) metals causes great harm to the environment and economy, which depends on the key electron transfer process between anaerobic microorganisms and Fe (0) metals. However, the key electron transfer process in microbiota dominating MIC remains unclear, especially for methanogenic microbiota wildly distributed in the environment. Herein, three different methanogenic microbiota (Methanothrix, Methanospirillum, and Methanobacterium) were acclimated to systematically investigate electron transfer pathways on corroding Q235A steel coupons. Results indicated that microbiota dominated by Methanothrix, Methanospirillum, or Methanobacterium accelerated the steel corrosion mainly through direct electron transfer (DET) pathway, H2 mediated electron transfer (HMET) pathway, and combined DET and HMET pathways, respectively. Compared with Methanospirillum dominant microbiota, Methanothrix or Methanobacterium dominant microbiota caused more methane production, higher weight loss, corrosion pits with larger areas, higher corrosion depth, and smaller corrosion pits density. Such results reflected that the DET process between microbiota and Fe (0) metals decided the biocorrosion degree and behavior of Fe (0) metals. This study insightfully elucidates the mechanisms of methanogenic microbiota on corroding steels, in turn providing new insights for anti-corrosion motives.

The Role of JAK-STAT-SOCS1 Axis in Tumorigenesis, Malignant Progression and Lymphatic Metastasis of Penile Cancer.

Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.

Causal Association of Golgi Protein 73 With Coronary Artery Disease: Evidence from Proteomics and Mendelian Randomization.

Background: Identification of the unknown pathogenic factor driving atherosclerosis not only enhances the development of disease biomarkers but also facilitates the discovery of new therapeutic targets, thus contributing to the improved management of coronary artery disease (CAD). We aimed to identify causative protein biomarkers in CAD etiology based on proteomics and 2-sample Mendelian randomization (MR) design. Methods: Serum samples from 33 first-onset CAD patients and 31 non-CAD controls were collected and detected using protein array. Differentially expressed analyses were used to identify candidate proteins for causal inference. We used 2-sample MR to detect the causal associations between the candidate proteins and CAD. Network MR was performed to explore whether metabolic risk factors for CAD mediated the risk of identified protein. Vascular expression of candidate protein in situ was also detected. Results: Among the differentially expressed proteins identified utilizing proteomics, we found that circulating Golgi protein 73 (GP73) was causally associated with incident CAD and other atherosclerotic events sharing similar etiology. Network MR approach showed low-density lipoprotein cholesterol and glycated hemoglobin serve as mediators in the causal pathway, transmitting 42.1% and 8.7% effects from GP73 to CAD, respectively. Apart from the circulating form of GP73, both mouse model and human specimens imply that vascular GP73 expression was also upregulated in atherosclerotic lesions and concomitant with markers of macrophage and phenotypic switching of vascular smooth muscle cells (VSMCs). Conclusions: Our study supported GP73 as a biomarker and causative for CAD. GP73 may involve in CAD pathogenesis mainly via dyslipidemia and hyperglycemia, which may enrich the etiological information and suggest future research direction on CAD.

Effects of a competence-based approach for clerkship teaching under alternating clinical placements: An explanatory sequential mixed-methods research.

BACKGROUND: It is unclear whether alternating placements during clinical clerkship, without an explicit emphasis on clinical competencies, would bring about optimal educational outcomes. METHODS: This is an explanatory sequential mixed-methods research. We enrolled a convenience sample of 41 eight-year programme medical students in Sun Yat-sen University who received alternating placements during clerkship. The effects of competence-based approach (n = 21) versus traditional approach (n = 20) to clerkship teaching were compared. In the quantitative phase, course satisfaction was measured via an online survey and academic performance was determined through final scores on summative assessment. Then, in the qualitative phase, students were invited for semi-structured interviews about their learning experiences, and the transcripts were used for thematic analysis. RESULTS: Quantitative findings showed that students in the study group rated high course satisfaction and performed significantly better in their final scores compared with those in the control group. Qualitative findings from thematic analysis showed that students were relatively neutral about their preference on placement models, but clearly perceived, capitalised, and appreciated that their competencies were being cultivated by an instructor who was regarded as a positive role model. CONCLUSION: A competence-based approach to clerkship teaching resulted in better course satisfaction and academic performance, and was perceived, capitalised, and appreciated by students.

Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach.

E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of Vss in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (Cmax) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.

Experimental investigation on the hybrid system of mechanical vapor recompression and hollow fiber vacuum membrane distillation applied for wastewater treatment.

In order to achieve zero discharge and resource utilization of industrial high salt wastewater, a hybrid system of mechanical vapor recompression (MVR) and hollow fiber vacuum membrane distillation (HFVMD) was constructed, and several experiments of air tightness, single working condition and multiple working conditions were carried out with ammonium chloride solution as feed, then thermal economic performance were evaluated via a single factor analysis method. The obtained results showed that the system had excellent airtightness to ensure normal evaporation experiment, and high separation efficiency of 99.9% and lower evaporation energy consumption to achieve high efficient separation by combining the advantages of the hydrophobic membrane evaporation and latent heat recovery in view of MVR and HFVMD technologies. Furthermore, increasing feed temperature and feed flow rate increased evaporation rate and decreased evaporation energy consumption, while increasing feed concentration decreased evaporation rate and increased evaporation energy consumption. Finally, the single factor analysis indicated that total investment cost, annual operation cost and annual evaporation capacity were the main factors while environmental cost and equipment service life were the secondary factors which affected the specific evaporation cost. The above research provides theoretical and experimental bases for the development of the proposed system in the future.

Anlotinib Combined With Toripalimab as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Prospective, Multicenter, Phase II Study.

BACKGROUND: For patients with unresectable hepatocellular carcinoma (HCC), the first-line therapeutic options are still relatively limited, and treatment outcomes remain poor. We aimed to assess the efficacy and safety of anlotinib combined with toripalimab as first-line therapy for unresectable HCC. METHODS: In this single-arm, multicenter, phase II study (ALTER-H-003), patients with advanced HCC without previous systemic anticancer therapy were recruited. Eligible patients were given anlotinib (12 mg on days 1-14) combined with toripalimab (240 mg on day 1) in a 3-week cycle. The primary endpoint was the objective response rate (ORR) by immune-related Response Evaluation Criteria in Solid Tumours (irRECIST)/RECIST v1.1 and modified RECIST (mRECIST). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between January 2020 and Jul 2021, 31 eligible patients were treated and included in the full analysis set. At data cutoff (January 10, 2023), the ORR was 29.0% (95% CI: 12.1%-46.0%) by irRECIST/RECIST v1.1, and 32.3% (95% CI: 14.8%-49.7%) by mRECIST criteria, respectively. Confirmed DCR and median DoR by irRECIST/RECIST v1.1 and mRECIST criteria were 77.4 % (95% CI: 61.8%-93.0%) and not reached (range: 3.0-22.5+ months), respectively. Median PFS was 11.0 months (95% CI: 3.4-18.5 months) and median OS was 18.2 months (95% CI: 15.8-20.5 months). Of the 31 patients assessed for adverse events (AEs), the most common grade ≥ 3 treatment-related AEs were hand-foot syndrome (9.7%, 3/31), hypertension (9.7%, 3/31), arthralgia (9.7%, 3/31), abnormal liver function (6.5%, 2/31), and decreased neutrophil counts (6.5%, 2/31). CONCLUSIONS: Anlotinib combined with toripalimab showed promising efficacy and manageable safety in Chinese patients with unresectable HCC in the first-line setting. This combination therapy may offer a potential new therapeutic approach for patients with unresectable HCC.

Attenuation of Epileptogenesis and Cognitive Deficits by a Selective and Potent Kv7 Channel Opener in Rodent Models of Seizures.

Targeting neuronal Kv7 channels by pharmacological activation has been proven to be an attractive therapeutic strategy for epilepsy. Here, we show that activation of Kv7 channels by an opener SCR2682 dose-dependently reduces seizure activity and severity in rodent models of epilepsy induced by a GABAa receptor antagonist pentylenetetrazole (PTZ), maximal electroshock, and a glutamate receptor agonist kainic acid (KA). Electroencephalographic recordings of rat cerebral cortex confirm that SCR2682 also decreases epileptiform discharges in KA-induced seizures. Nissl and neuronal nuclei staining further demonstrates that SCR2682 also protects neurons from injury induced by KA. In Morris water maze navigation and Y-maze tests, SCR2682 improves PTZ- and KA-induced cognitive impairment. Taken together, our findings demonstrate that pharmacological activation of Kv7 by novel opener SCR2682 may hold promise for therapy of epilepsy with cognitive impairment. SIGNIFICANCE STATEMENT: A neuronal Kv7 channel opener SCR2682 attenuates epileptogenesis and seizure-induced cognitive impairment in rodent models of seizures, thus possessing a developmental potential for effective therapy of epilepsy with cognitive impairment.

Discovery of the covalent SARS-CoV-2 Mpro inhibitors from antiviral herbs via integrating target-based high-throughput screening and chemoproteomic approaches.

The main proteases (Mpro ) are highly conserved cysteine-rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of Mpro from complex herbal matrices. This work begins with biological screening of 60 clinically used antiviral herbal medicines, among which Lonicera japonica Flos (LJF) demonstrated the strongest anti-Mpro effect (IC50 = 37.82 µg/mL). Mass spectrometry (MS)-based chemical analysis and chemoproteomic profiling revealed that LJF extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify Mpro . We subsequently verified the anti-Mpro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit severe acute respiratory syndrome coronavirus 2 Mpro in dose- and time- dependent manners, with the IC50 values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of Mpro from herbal medicines by integrating target-based high-throughput screening and MS-based assays, which would greatly facilitate the discovery of key antiviral constituents from medicinal plants.

[Clinical Outcome and Risk Factors of Treatment Failure of Peritoneal Dialysis Associated Peritonitis Caused by Klebsiella Pneumoniae:A Multicenter Study].

Objective To investigate the treatment outcomes,prognosis,and risk factors of treatment failure of peritoneal dialysis associated peritonitis (PDAP) caused by Klebsiella pneumoniae,and thus provide clinical evidence for the prevention and treatment of this disease. Methods The clinical data of PDAP patients at four peritoneal dialysis centers from January 1,2014 to December 31,2019 were collected retrospectively.The treatment outcomes and prognosis were compared between the patients with PDAP caused by Klebsiella.pneumoniae and that caused by Escherichia coli.Kaplan-Meier method was employed to establish the survival curve of technical failure,and multivariate Logistic regression to analyze the risk factors of the treatment failure of PADP caused by Klebsiella pneumoniae. Results In the 4 peritoneal dialysis centers,1034 cases of PDAP occurred in 586 patients from 2014 to 2019,including 21 cases caused by Klebsiella pneumoniae and 98 cases caused by Escherichia coli.The incidence of Klebsiella pneumoniae caused PDAP was 0.0048 times per patient per year on average,ranging from 0.0024 to 0.0124 times per patient per year during 2014-2019.According to the Kaplan-Meier survival curve,the technical failure rate of Klebsiella pneumoniae caused PDAP was higher than that of Escherichia coli caused PDAP (P=0.022).The multivariate Logistic regression model showed that long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP (OR=1.082,95%CI=1.011-1.158,P=0.023).Klebsiella pneumoniae was highly sensitive to amikacin,meropenem,imipenem,piperacillin,and cefotetan,and it was highly resistant to ampicillin (81.82%),cefazolin (53.33%),tetracycline (50.00%),cefotaxime (43.75%),and chloramphenicol (42.86%). Conclusion The PDAP caused by Klebsiella pneumoniae had worse prognosis than that caused by Escherichia coli,and long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP.

D-galactose-induced cardiac ageing: A review of model establishment and potential interventions.

Cardiovascular disease (CVD) is highly prevalent in an ageing society. The increased incidence and mortality rates of CVD are global issues endangering human health. There is an urgent requirement for understanding the aetiology and pathogenesis of CVD and developing possible interventions for preventing CVD in ageing hearts. It is necessary to select appropriate models and treatment methods. The D-galactose-induced cardiac ageing model possesses the advantages of low mortality, short time and low cost and has been increasingly used in the study of cardiovascular diseases in recent years. Therefore, understanding the latest progress in D-galactose-induced cardiac ageing is valuable. This review highlights the recent progress and potential therapeutic interventions used in D-galactose-induced cardiac ageing in recent years by providing a comprehensive summary of D-galactose-induced cardiac ageing in vivo and in vitro. This review may serve as reference literature for future research on age-related heart diseases.

IL-33 in the basolateral amygdala integrates neuroinflammation into anxiogenic circuits via modulating BDNF expression.

Hyper-inflammatory reaction plays a crucial role in the pathophysiology of depression and anxiety disorders. However, the mechanisms underlying inflammation-induced anxiety changes remain poorly understood. Here, we showed that in the lipopolysaccharide (LPS)-induced anxiety model, Interleukin (IL)-33, a member of the IL-1 family, was up-regulated in the basolateral amygdala, and IL-33 deficiency prevent anxiety-like behavior. Overexpression of IL-33 in amygdalar astrocytes led to anxiety-like response via repressing brain-derived neurotrophic factor (BDNF) expression. Mechanically, IL-33 suppressed BDNF expression through NF-κB pathway to impair GABAergic transmission in the amygdala and NF-κB inhibitor abolished the effect of IL-33 on anxiety. Administration of an inverse GABAA receptor agonist increased the anxiety of IL-33- deficient mice. These results reveal that inflammatory response can activate anxiogenic circuits by suppressing BDNF and GABAergic neurons transmission, suggesting that IL-33 in basolateral amygdalar is a linker between inflammation and anxiety.

Programmed cell death 4 as an endogenous suppressor of BDNF translation is involved in stress-induced depression.

Brain-derived neurotrophic factor (BDNF) is a growth factor that plays vital roles in the neuron survival, growth, and neuroplasticity. Alteration to BDNF expression is associated with major depressive disorder. However, the BDNF translational machinery in depression remains unknown. Herein, we pointed that Pdcd4, a suppressor oncogene, acted as an endogenous inhibitor for the translation of BDNF, and selectively repressed the translation of BDNF splice variant IIc mRNA in an eIF4A-dependent manner. Chronic restraint stress (CRS) up-regulated Pdcd4 expression in hippocampus via decreasing mTORC1-mediated proteasomes degradation pathway, which resulted in the reduction of BDNF protein expression. Moreover, over-expression of Pdcd4 in the hippocampus triggered spontaneous depression-like behaviors under the non-stressed conditions in mice, while systemic or neuron-specific knockout of Pdcd4 reverses CRS-induced depression-like behaviors. Importantly, administration of Pdcd4 siRNA or an interfering peptide that interrupts the Pdcd4-eIF4A complex substantially promoted BDNF expression and rescued the behavioral disorders which were caused by CRS. Overall, we have discovered a previously unrecognized role of Pdcd4 in controlling BDNF mRNA translation, and provided a new method that boosting BDNF expression through blocking the function of Pdcd4 in depression, indicating that Pdcd4 might be a new potential target for depressive disorder therapy.

High magnesium mitigates the vasoconstriction mediated by different types of calcium influx from monocrotaline-induced pulmonary hypertensive rats.

NEW FINDINGS: What is the central question of this study? What is the involvement of Mg2+ in mitigating the vasoconstriction in pulmonary arteries and smaller pulmonary arteries in the monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model? What are the main finding and its importance? Both store-operated Ca2+ entry- and receptor-operated Ca2+ entry-mediated vasoconstriction were enhanced in the MCT-PAH model. High magnesium inhibited vasoconstriction by directly antagonizing Ca2+ and increasing NO release, and this was more notable in smaller pulmonary arteries. ABSTRACT: Increased extracellular magnesium concentration has been shown to attenuate the endothelin-1-induced contractile response via the release of nitric oxide (NO) from the endothelium in proximal pulmonary arteries (PAs) of chronic hypoxic mice. Here, we further examined the involvement of Mg2+ in the inhibition of vasoconstriction in PAs and distal smaller pulmonary arteries (sPAs) in a monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model. The data showed that in control rats vasoconstriction in sPAs is more intense than that in PAs. In MCT-PAH rats, store-operated Ca2+ entry (SOCE)- and receptor-operated Ca2+ entry (ROCE)-mediated contraction were significantly strengthened. However, there was no upregulation of the vasoconstriction mediated by voltage-dependent calcium entry (VDCE). Furthermore, high magnesium greatly inhibited VDCE-mediated contraction in PAs rather than sPAs, which was the opposite of the ROCE-mediated contraction. Moreover, monocrotaline pretreatment partly eliminated the endothelium-dependent vasodilatation in PAs, which in sPAs, however, was still promoted by magnesium due to the increased NO release in pulmonary microvascular endothelial cells (PMVECs). In conclusion, the findings suggest that both SOCE- and ROCE-mediated vasoconstriction in the MCT-PAH model are enhanced, especially in sPAs. The inhibitory effect of high magnesium on vasoconstriction can be achieved partly by its direct role as a Ca2+ antagonist and partly by increasing NO release in PMVECs.

Diagnosis of left anterior descending branch-right ventricular fistula with giant coronary artery aneurysm by contrast echocardiography: A case report.

BACKGROUND: Coronary fistulae are communications between a coronary artery and a heart chamber or vessel. The final diagnosis is usually made by coronary angiography or computed tomographic (CT) angiography. Here we report a case by employing contrast echocardiography in diagnosis of a giant coronary aneurysm with right ventricle (RV) fistula. CASE PRESENTATION: The patient, a 29-year-old woman, referred to our institution with a complaint of palpitation occasionally. Transthoracic echocardiogram showed a spherical, echogenic structure in the apex of RV. Proximal to the aneurysm, the left anterior descending branch (LAD) remained enlarged (8-9 mm) and showed a fistulous communication with the echogenic structure. A contrast echocardiography was performed, and 4-5 cardiac cycle after the left ventricle was enhanced, the echogenic structure started to become more prominent and several fistulae were seen between RV and the echogenic structure. Computed tomography (CT) angiography and coronary angiography confirmed the dilation (9 mm in diameter) of the LAD with an aneurysm at the distal segment of the LAD, with a small amount of iodinated contrast agent flowing into the subsequent region of the RV, thereby characterizing a LAD-to-RV fistula. CONCLUSION: The final diagnosis of fistula is usually made by coronary angiography or CT angiography. However, contrast echocardiography is also a well-established method for the demonstration of intracardiac shunting. In this case, the contrast echocardiography clearly revealed one of the fistulae between the aneurysm and RV.

A Novel κ-Carrageenase from Marine Bacterium Rhodopirellula sallentina SM41: Heterologous Expression, Biochemical Characterization and Salt-Tolerance Mechanism Investigation.

κ-carrageenases are members of the glycoside hydrolase family 16 (GH16) that hydrolyze sulfated galactans in red algae, known as κ-carrageenans. In this study, a novel κ-carrageenase gene from the marine bacterium Rhodopirellula sallentina SM41 (RsCgk) was discovered via the genome mining approach. There are currently no reports on κ-carrageenase from the Rhodopirellula genus, and RsCgk shares a low identity (less than 65%) with κ- carrageenase from other genera. The RsCgk was heterologously overexpressed in Escherichia coli BL21 and characterized for its enzymatic properties. RsCgk exhibited maximum activity at pH 7.0 and 40 °C, and 50% of its initial activity was retained after incubating at 30 °C for 2 h. More than 70% of its activity was maintained after incubation at pH 6.0-8.0 and 4 °C for 24 h. As a marine derived enzyme, RsCgk showed excellent salt tolerance, retaining full activity in 1.2 M NaCl, and the addition of NaCl greatly enhanced its thermal stability. Mass spectrometry analysis of the RsCgk hydrolysis products revealed that the enzyme had high degradation specificity and mainly produced κ-carrageenan disaccharide. Comparative molecular dynamics simulations revealed that the conformational changes of tunnel-forming loops under salt environments may cause the deactivation or stabilization of RsCgk. Our results demonstrated that RsCgk could be utilized as a potential tool enzyme for efficient production of κ-carrageenan oligosaccharides under high salt conditions.