Analysis of RNA translation with a deep learning architecture provides new insight into translation control.

Accurate annotation of coding regions in RNAs is essential for understanding gene translation. We developed a deep neural network to directly predict and analyze translation initiation and termination sites from RNA sequences. Trained with human transcripts, our model learned hidden rules of translation control and achieved a near perfect prediction of canonical translation sites across entire human transcriptome. Surprisingly, this model revealed a new role of codon usage in regulating translation termination, which was experimentally validated. We also identified thousands of new open reading frames in mRNAs or lncRNAs, some of which were confirmed experimentally. The model trained with human mRNAs achieved high prediction accuracy of canonical translation sites in all eukaryotes and good prediction in polycistronic transcripts from prokaryotes or RNA viruses, suggesting a high degree of conservation in translation control. Collectively, we present a general and efficient deep learning model for RNA translation, generating new insights into the complexity of translation regulation.

Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis.

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell-cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.

Melatonin antagonizes oxidative stress-induced apoptosis in retinal ganglion cells through activating the thioredoxin-1 pathway.

This study aimed to explore the role of melatonin in oxidative stress-induced injury on retinal ganglion cells and the underlying mechanisms. The immortalized RGC-5 cells were treated with H2O2 to induce oxidative injury. Cell viability was measured by Cell Counting Kit-8, and apoptosis was determined by flow cytometry and western blot assays. Reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels were examined to evaluate oxidative stress levels. In addition, Thioredoxin-1 (Trx1) was silenced in RGC-5 cells using small interfering RNA followed by signaling pathway examination to explore the underlying mechanisms of melatonin in alleviating oxidative injury. Melatonin pre-treatment significantly alleviated H2O2-induced apoptosis in RGC-5 cells. Melatonin also markedly reversed the upregulation of cleaved-caspase 3, cleaved-caspase 9, and Bax expression and downregulation of Bcl-2 expression induced by H2O2. Further analyses presented that melatonin significantly attenuated the increase of ROS, LDH, and MDA levels in RGC-5 cells after H2O2 treatment. Melatonin also abolished the downregulated expression of Superoxide dismutase type 1, Trx1, and Thioredoxin reductase 1, and the reduced activity of thioredoxin reductase in RGC-5 cells after H2O2 treatment. Notably, Trx1 knockdown significantly mitigated the protective effect of melatonin in alleviating H2O2-induced apoptosis and oxidative stress, while administration of compound C, a common inhibitor of c-Jun N-terminal kinase (JNK) signaling, partially reversed the effect of Trx1 silencing, thereby ameliorating the apoptosis and oxidative injury induced by H2O2 in RGC-5 cells. Melatonin could significantly alleviate oxidative stress-induced injury of retinal ganglion cells via modulating Trx1-mediated JNK signaling pathway.

The lack of homology domain and leucine rich repeat protein phosphatase 2 ameliorates visual impairment in rats with diabetic retinopathy through regulation of the AKT-GSK-3ß-Nrf2 signal cascade.

Pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) is an emerging player in diverse disorders. Our previous findings have documented that reducing PHLPP2 levels in cultured retinal ganglion cells protects against cellular damage caused by high glucose, indicating a possible link between PHLPP2 and diabetic retinopathy (DR). The present work was dedicated to the investigation of PHLPP2 in DR through in vivo experiments with rat models induced by intraperitoneal injection of streptozotocin. Compared to normal rats, the retinas of rats with DR exhibited a notable increase in the level of PHLPP2. The reduction of PHLPP2 levels in the retina was achieved by the intravitreal administration of adeno-associated viruses expressing specific shRNA targeting PHLPP2. Decreasing the expression of PHLPP2 ameliorated visual function impairment and improved the pathological changes of retina in DR rats. Moreover, decreasing the expression of PHLPP2 repressed the apoptosis, oxidative stress and proinflammatory response in the retinas of rats with DR. Reduction of PHLPP2 levels led to an increase in the levels of phosphorylated AKT and glycogen synthase kinase-3ß (GSK-3ß). Decreasing the expression of PHLPP2 resulted in increased activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which was reversed by suppressing AKT. Notably, the protective effect of reducing PHLPP2 on DR was eliminated when Nrf2 was restrained. These observations show that the down-regulation of PHLPP2 has protective effects on DR by preserving the structure and function of the retina by regulating the AKT-GSK-3ß-Nrf2 signal cascade. Therefore, targeting PHLPP2 may hold promise in the treatment of DR.

Cardiac Fibroblast Activation Induced by Oxygen-Glucose Deprivation Depends on the HIF-1α/miR-212-5p/KLF4 Pathway.

It is widely accepted that miRNAs play an important role in the pathogenesis of myocardial fibrosis. This study aimed to identify a new pathway of miR-212-5p in the activation of human cardiac fibroblasts (HCFs) induced by oxygen-glucose deprivation (OGD). First, we found that KLF4 protein was markedly decreased in OGD-induced HCFs. Then, bioinformatics analysis and verification experiments were used to identify the existence of an interaction of KLF4 with miR-212-5p. Functional experiments indicated that OGD significantly upregulated the expression of hypoxia inducible factor-1 alpha (HIF-1α) in HCFs, which positively regulated miR-212-5p transcription by binding to its promoter. MiR-212-5p inhibited the expression of Krüppel-like factor 4 (KLF4) protein by binding to the 3' untranslated coding regions (UTRs) of KLF4 mRNA. Inhibition of miR-212-5p effectively inhibited the activation of OGD-induced HCFs by upregulating KLF4 expression and inhibited cardiac fibrosis in vivo and in vitro.

Selective Oxidation of Triethylamine Catalyzed by Mn-Ce/ZSM-5.

The selective catalytic oxidation (SCO) of triethylamine (TEA) to harmless nitrogen (N2), carbon dioxide (CO2), and water (H2O) is of green elimination technology. In this paper, Mn-Ce/ZSM-5 with different proportions of MnOx/CeOx were studied for the selective catalytic combustion of TEA. The catalysts were characterized by XRD, BET, H2-TPR, XPS, and NH3-TPD and their catalytic activities were analyzed. The results showed that MnOx was the main active component. The addition of a small amount of CeOx promotes the generation of high-valence Mn ions, which reduces the reduction temperature of the catalyst and increases the redox capacity of the catalyst. In addition, the synergistic effect between CeOx and MnOx significantly improves the mobility of reactive oxygen species on the catalyst, thus improving the catalytic performance of the catalyst. The catalytic oxidation performance of TEA over 15Mn5Ce/ZSM-5 is the highest. TEA can be completely converted at 220 °C, and the selectivity for N2 is up to 80%. The reaction mechanism was studied by in situ diffuse reflectance infrared Fourier transform spectroscopy (in situ DRIFTS).

Higher serum triglyceride can predict recurrent coronary revascularization events in patients undergoing percutaneous coronary intervention with baseline LDL-C <55 mg/dL.

Patients with low baseline low-density lipoprotein cholesterol (LDL-C) but experiencing recurrent coronary revascularization events have been rarely investigated. In this retrospective cohort study, we enrolled patients undergoing percutaneous coronary intervention (PCI) with baseline LDL-C <55 mg/dL at the First Affiliated Hospital of Xi'an Jiaotong University between January and December 2017. Subsequent ischemia-driven coronary revascularization events and all-cause death were documented during a 4-year follow-up. Cox analysis was used to evaluate the association between baseline clinical characteristics and long-term events. As a result, among 388 patients (mean age 63 years; 79.1% male) enrolled, 32 patients underwent recurrent revascularization events, and 38 patients occurred all-cause death. After adjustment for age, diabetes mellitus, multi-vessel disease, and lipoprotein(a), multivariate Cox analysis showed that baseline serum triglyceride (TG) (HR 1.691, 95% CI 1.178 to 2.428, p=0.004) was an independent predictor of recurrent coronary revascularization events. Kaplan-Meier analysis revealed that a higher TG level (≥1.17 mmol/L, determined by receiver operating characteristic curve) was associated with increased risk of recurrent revascularization events than lower TG level (<1.17 mmol/L) (p=0.021). Female (HR 2.647, 95% CI 1.350 to 5.190, p=0.005) and previous atrial fibrillation (HR 3.163, 95% CI 1.403 to 7.132, p=0.006) were associated with increased risk of all-cause death. In conclusion, for patients undergoing PCI with baseline LDL-C <55 mg/dL, higher baseline TG can predict recurrent coronary revascularization events.

Cardiogenic shock due to Takotsubo cardiomyopathy associated with thyroid crisis: a case report.

Background: The development of cardiogenic shock due to the coexistence of Takotsubo cardiomyopathy and thyroid crisis in patients has been scarcely reported. Case summary: A 46-year-old female presented with chest pain, palpitations, nausea, and vomiting for 8 h. She was initially considered to have acute myocardial infarction due to elevated cardiac markers and abnormal electrocardiogram changes. Immediately after the coronary angiography revealed a normal coronary artery, the patient developed refractory cardiogenic shock. Echocardiography demonstrated a typical apical ballooning type of Takotsubo cardiomyopathy with a left ventricular ejection fraction (LVEF) of 32%. A combination of norepinephrine and dopamine and an intra-aortic balloon pump (IABP) was used to support haemodynamic stability but failed to improve the patient's condition. Immediately after the laboratory tests revealed previously unknown hyperthyroidism on the second hospital day, a rapid atrial fibrillation (AF) suddenly occurred. Nifekalant successfully restored sinus rhythm in a short time. The patient persistently complained of chest tightness, palpitations, and sweating for the first 4 days until levosimendan and antithyroid crisis treatment were used. Discussion: Takotsubo cardiomyopathy and thyroid crisis can co-occur and present as cardiogenic shock. In the presence of severe cardiac dysfunction and untreated hyperthyroidism, nifekalant is an ideal option for the new onset of AF. The combination of heart failure treatment and antithyroid crisis drugs can effectively restore cardiac function and is associated with good clinical outcomes.

Inferior ST-Segment Elevation Can Predict In-Hospital Mortality in Patients with Anterior Myocardial Infarction Complicated by Ventricular Septal Rupture.

Background: Electrocardiogram (ECG) findings in patients with anterior wall myocardial infarction (MI) complicated by ventricular septal rupture (VSR) have rarely been studied. Methods: We conducted a single-center retrospective study among patients with anterior MI complicated by VSR over the past ten years. The presence of ST-segment elevation (STE) in inferior leads and new onset of complete right bundle branch block (RBBB) on ECG were studied for the prediction of in-hospital mortality. Results: Among the 85 patients enrolled, 45 (52.9%) were male, with a median age of 70 years. Sixty-five patients (76.5%) died in the hospital, and the remaining 20 patients (23.5%) had improved conditions and were discharged. Inferior STE was present in 35 patients (41.2%), including 32 patients in the death group and 3 patients in the survival group (P = 0.005). New-onset RBBB was present in 25 patients (29.4%), with 22 patients in the death group and 3 patients in the survival group (P = 0.103). Multivariate logistic regression showed that inferior STE was an independent predictor of in-hospital death in patients with anterior MI and VSR (OR: 14.488; 95% CI: 1.708-122.887; P = 0.014). Conclusions: In patients with anterior MI complicated by VSR, inferior STE was associated with a higher risk of in-hospital mortality.

Pervasive translation of circular RNAs driven by short IRES-like elements.

Some circular RNAs (circRNAs) were found to be translated through IRES-driven mechanism, however the scope and functions of circRNA translation are unclear because endogenous IRESs are rare. To determine the prevalence and mechanism of circRNA translation, we develop a cell-based system to screen random sequences and identify 97 overrepresented hexamers that drive cap-independent circRNA translation. These IRES-like short elements are significantly enriched in endogenous circRNAs and sufficient to drive circRNA translation. We further identify multiple trans-acting factors that bind these IRES-like elements to initiate translation. Using mass-spectrometry data, hundreds of circRNA-coded peptides are identified, most of which have low abundance due to rapid degradation. As judged by mass-spectrometry, 50% of translatable endogenous circRNAs undergo rolling circle translation, several of which are experimentally validated. Consistently, mutations of the IRES-like element in one circRNA reduce its translation. Collectively, our findings suggest a pervasive translation of circRNAs, providing profound implications in translation control.

Inhibition of Human Sulfotransferases by Phthalate Monoesters.

Objective: This study aimed to investigate the inhibition of human important phase II metabolic enzyme sulfotransferases (SULTs) by phthalate monoesters, which are important metabolites of phthalate esters (PAEs). Method: Recombinant SULT-catalyzed metabolism of p-nitrophenol (PNP) was employed as the probe reactions of SULTs to investigate the inhibition of 8 kinds of phthalate monoesters towards SULT isoforms. An in vitro incubation system was utilized for preliminary screening, and 100 µM of phthalate monoesters was used. Inhibition kinetics were carried out to determine the inhibition of SULTs by phthalate monoesters. Result: Multiple phthalate monoesters have been demonstrated to exert strong inhibition potential towards SULT1A1, SULT1B1, and SULT1E1, and no significant inhibition of phthalate monoesters towards SULT1A3 was found. The activity of SULT1A1 was strongly inhibited by mono-hexyl phthalate (MHP), mono-octyl phthalate (MOP), mono-benzyl phthalate (MBZP), and mono-ethylhexyl phthalate (MEHP). Monobutyl phthalate (MBP), MHP, MOP, mono-cyclohexyl phthalate (MCHP), and MEHP significantly inhibited the activity of SULT1B1. MHP, MOP, and MEHP significantly inhibited the activity of SULT1E1. MOP was chosen as the representative phthalate monoester to determine the inhibition kinetic parameters (Ki) towards SULT1B1 and SULT1E1. The inhibition kinetic parameters (Ki) were calculated to be 2.23 µM for MOP-SULT1B1 and 5.54 µM for MOP-SULT1E1. In silico docking method was utilized to understand the inhibition mechanism of SULT1B1 by phthalate monoesters. Conclusions: All these information will be beneficial for understanding the risk of phthalate monoester exposure from a new perspective.

Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway.

Y-box-binding protein 1 (YB-1) is a multifunctional RNA binding protein involved in virtually every step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we found that YB-1 protein was markedly overexpressed in glioblastoma and acted as a critical activator of both mTORC1 and mTORC2 signaling. Mechanistically, YB-1 bound the 5'UTR of CCT4 mRNA to promote the translation of CCT4, a component of the CCT chaperone complex, that in turn activated the mTOR signaling pathway by promoting mLST8 folding. In addition, YB-1 autoregulated its own translation by binding to its 5'UTR, leading to sustained activation of mTOR signaling. In patients with glioblastoma, high protein expression of YB-1 correlated with increased expression of CCT4 and mLST8 and activated mTOR signaling. Importantly, the administration of RNA decoys specifically targeting YB-1 in a mouse xenograft model resulted in slower tumor growth and better survival. Taken together, these findings uncover a disrupted proteostasis pathway involving a YB-1/CCT4/mLST8/mTOR axis in promoting glioblastoma growth, suggesting that YB-1 is a potential therapeutic target for the treatment of glioblastoma.

Targeted metabolomic analysis of plasma fatty acids in acute myocardial infarction in young adults.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) in young adults has distinct clinical features and risk profile as compared with that in elder adults. The pathophysiologic mechanism of AMI in young adults remains unclear. In this study, we used targeted metabolomics to measure metabolic profile and analyzed plasma fatty acids levels in young adults with AMI, seeking to determine whether circulating fatty acid metabolism was correlated with the occurrence of AMI in young adults. METHODS AND RESULTS: Consecutive young and elder patients admitted to hospital for AMI were enrolled. Plasma samples of all participants were obtained after overnight fast and then measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) based targeted metabolomic platform. A total of 201 plasma metabolites were measured using UPLC-MS/MS. Several plasma fatty acids were significantly altered in young AMI patients compared with control or elder AMI patients, which also showed significant prediction value for AMI in young adults. Percentage of short chain fatty acids (SCFAs) was decreased and long chain increased in AMI as compared with control. Moreover, alpha-linolenic acid and linoleic acid metabolism (ALALAM) pathway metabolites were gradually increased in control, young, and elder AMI patients. Altered fatty acid correlation network further identified fatty acid metabolism disorder in AMI in young adults. CONCLUSION: By utilizing targeted metabolomic technique, we have found several altered fatty acids and respective pathways that show diagnostic value for AMI in young adults. SCFA and long-chain fatty acid (LCFA) were differentially altered in AMI patients.

SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B.

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.

All cells in the brain start life as stem cells which are yet to have a defined role in the body. A wide range of molecules and chemical signals guide stem cells towards a neuronal fate, including a group of molecules called sphingolipids. These molecules sit in the membrane surrounding the cell and play a pivotal role in a number of processes which help keep the neuronal cell healthy. Various enzymes work together to break down sphingolipids and remove them from the membrane. Defects in these enzymes can result in excess levels of sphingolipids, which can lead to neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's disease. But how these enzymes are used and controlled during neuronal development is still somewhat of a mystery. To help answer this question, Fan et al. studied an enzyme called SIRT1 which has been shown to alleviate symptoms in animal models of neurodegenerative diseases. Stem cells were extracted from a mouse embryo lacking the gene for SIRT1 and cultured in the laboratory. These faulty cells were found to have superfluous amounts of sphingolipids, which made their membranes more fluid and reduced their ability to develop into neuronal cells. Further investigation revealed that SIRT1 regulates the degradation of sphingolipids by promoting the production of another enzyme called SMPDL3B. Fan et al. also found that when female mice were fed a high-fat diet, this caused sphingolipids to accumulate in their embryos which lacked the gene for SIRT1; this, in turn, impaired the neural development of their offspring. These findings suggest that targeting SIRT1 may offer new strategies for treating neurological diseases. The discovery that embryos deficient in SIRT1 are sensitive to high-fat diets implies that activating this enzyme might attenuate some of the neonatal complications associated with maternal obesity.

Sleep fragmentation and incidence of congestive heart failure: the Sleep Heart Health Study.

STUDY OBJECTIVES: Sleep fragmentation (SF) has been reported to be associated with cardiovascular risk. The aim of this study was to explore the relationship between SF and congestive heart failure (CHF). METHODS: A total of 4,887 participants (2,256 males and 2,631 females; mean age of 63.6 ± 11.0 years) from the Sleep Heart Health Study were included in this study. Incident CHF was defined as the first occurrence of CHF between baseline in-home polysomnography (PSG) and the end of follow-up. Objective assessments for SF, including sleep fragmentation index (SFI), arousal index (ArI), sleep efficiency (SE), and wake after sleep onset (WASO), were determined based on in-home PSG records. Multivariate Cox regression analysis was used to investigate the relationship between SF and incident CHF. RESULTS: During an average of 10 years of follow-up, 543 participants with CHF (11.1%) were observed. Individuals with CHF had a significantly higher SFI, total ArI, and WASO and a lower SE than controls. After multivariate Cox regression analysis, SE (odds ratio [OR], 0.967; 95% confidence interval [CI], 0.955-0.978; P < .001), WASO (OR, 1.009; 95% CI, 1.006-1.012; P < .001), SFI (OR, 1.046; 95% CI, 1.007-1.086; P = .021), and total ArI (OR, 1.018; 95% CI, 1.000-1.035; P = .044) were found to be associated with the incidence of CHF in participants without hypertension. CONCLUSIONS: Objectively measured SF was associated with the incidence of CHF. The role of SFI, total ArI, SE, and WASO deserves further investigation. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Sleep Heart Health Study (SHHS) Data Coordinating Center (SHHS); URL: https://clinicaltrials.gov/ct2/show/NCT00005275; Identifier: NCT00005275. CITATION: Yan B, Wu Y, Fan X, Lu Q, Ma X, Bai L. Sleep fragmentation and incidence of congestive heart failure: the Sleep Heart Health Study. J Clin Sleep Med. 2021;17(8):1619-1625.

Single-Cell Transcriptome Analysis Decipher New Potential Regulation Mechanism of ACE2 and NPs Signaling Among Heart Failure Patients Infected With SARS-CoV-2.

Aims: COVID-19 patients with comorbidities such as hypertension or heart failure (HF) are associated with poor clinical outcomes. The cellular distribution of Angiotensin-converting enzyme 2 (ACE2), the critical enzyme for SARS-CoV-2 infection, in the human heart is unknown. We explore the underlying mechanism that leads to increased susceptibility to SARS-CoV-2 in patients with cardiovascular diseases and patients of cardiac dysfunction have increased risk of multi-organ injury compared with patients of normal cardiac function. Methods and Results: We analyzed single-cell RNA sequencing (scRNA-seq) data in both normal and failing hearts. The results demonstrated that ACE2 is present in cardiomyocytes (CMs) and non-CMs, while the number of ACE2-postive (ACE2+) CMs and ACE2 gene expression in these CMs are significantly increased in the failing hearts. Interestingly, both brain natriuretic peptides (BNP) and atrial natriuretic peptide (ANP) are significantly up-regulated in the ACE2+ CMs, which is consistent with other studies that ACE2, ANP, and BNP increased in HF patients. We found that genes related to virus entry, virus replication and suppression of interferon-gamma signaling are all up-regulated in failing CMs, and the increase was significantly higher in ACE2+ CMs, suggesting that these CMs may be more vulnerable to virus infection. As the level of expression of both ACE2 and BNP in CMs were up-regulated, we further performed retrospective analysis of the plasma BNP levels and clinical outcomes of 91 COVID-19 patients from a single-center. Patients with higher plasma BNP were associated with significantly higher mortality and expression levels of inflammatory and infective markers. Conclusion: In the failing heart, the upregulation of ACE2 and virus infection associated genes could potentially facilitate SARS-CoV-2 virus entry and replication in these vulnerable cardiomyocyte subsets. COVID-19 patients with higher plasma BNP levels had poorer clinical outcomes. These observations may allude to a potential regulatory association between ACE2 and BNP in mediating myocarditis associated with COVID-19.

Coupling loss characteristics of N-P-C through runoff and sediment in the hilly region of SE China under simulated rainfall.

Soil total carbon (TC), phosphorus (P), and nitrogen (N) exports from the weathered granite slopes are greatly influenced by the complex hydrological processes and terrain factors. In this study, the coupling loss characteristics of N-P-C via runoff and sediment were studied with two soil tanks under simulated rainfalls. Three soils respectively derived from the tillage layer (T-soil), laterite layer (L-soil), and sand layer (S-soil) were employed to determine the interactions of hydrology and topography on N-P-C exports under three rainfall intensities (1.5, 2.0, and 2.5 mm/min). The erosion degree of different soils displayed an order of S-soil > L-soil > T-soil. The results showed that surface flow was the main runoff form for L- and T-soil, while underground flow was predominant for S-soil. There was a linear correlation between sediment and surface flow (R2 > 0.78). Surface flow was the dominant pathway of P loss via runoff with underground flow being an important supplementation, and the main P loss pattern switched between dissolved phosphorus (DP) and particle phosphorus (PP) during the experiment. However, P lost via eroded sediment accounted for more than 94% of the TP loss amount. N presented an opposite trend to P and was mainly lost via underground flow. The main N loss form in surface and underground flow was NO3--N. Underground flow was the predominant total nitrogen (TN) loss pathway for S- and L-soil, followed by sediment and surface flow. For T-soil, TN lost via runoff was much greater than that carried by eroded sediment. TC for S-soil was mainly lost via underground flow while that for L- and T-soil was mostly lost via surface flow. Both N-P loss loads in surface flow and P loss load in underground flow were positively correlated with TC loss load (p < 0.05), indicating that the presence of organic matter brings about more nutrient losses. These results expand our understanding of the combined effects of rainfall intensity and erosion degree on runoff and sediment yields as well as N-P-C losses from the bare weathered granite slopes of SE China.

Aqueous humor monocyte chemoattractant protein-1 predicted long-term visual outcome of proliferative diabetic retinopathy undergone intravitreal injection of bevacizumab and vitrectomy.

PURPOSE: We aim to investigate the risk factors associated with the prognosis of proliferative diabetic retinopathy (PDR) after a sequential treatment of intravitreal injection of bevacizumab (IVB) and pars plana vitrectomy (PPV). METHODS: In this cohort study, 63 eyes from 55 patients (21 females) diagnosed with PDR, who needed PPV for non-clearing vitreous hemorrhage or fibrovascular membrane proliferation were enrolled. All the eyes underwent IVB followed by PPV. Anterior chamber tap was performed at the beginning of both procedures to evaluate the concentration of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. RESULTS: Forty-seven patients (54 eyes) were followed over six months, averaging 12±5 (6-19) months. The concentration of VEGF significantly decreased after IVB (P<0.001), while other cytokines did not change significantly. The aqueous humor level of IL-8 after IVB (R = 0.378, P = 0.033), MCP-1 before (R = 0.368, P = 0.021) and after (R = 0.368, P = 0.038) IVB, and combined phacoemulsification (R = 0.293, P = 0.032) was correlated with the logMAR visual acuity at the last follow-up. Multivariate analysis showed that MCP-1 was the predictor for a worse visual outcome (B = 0.108, 95% CI 0.013-0.202; P = 0.027). CONCLUSIONS: MCP-1 was a predictor for the unfavorable visual outcome of PDR after IVB pretreatment and PPV.

Dilated retinal large vessels and capillaries associated with diabetic macular edema and photoreceptor loss respectively.

PURPOSE: Previously, we measured retinal large vessels and capillaries separately on optical coherence tomography angiography (OCTA). In the present study, we aim to evaluate the role of these parameters in association to diabetic macular edema (DME) and ellipsoid zone disruption (EZD). METHODS: In this cross-sectional study, 54 eyes from 31 patients (10 females, 31 Asians) with severe non-proliferative diabetic retinopathy (25 eyes) or proliferative diabetic retinopathy (PDR, 29 eyes) were enrolled. All eyes underwent 3 × 3 mm OCTA scans centered on the fovea. Perfusion density (PD), vessel length density (VLD), and vessel diameter index (VDI) were calculated for retinal large vessels and superficial capillaries separately. Other OCTA findings included suspended scattering particles in motion (SSPiM), number of microaneurysms (MA) in all retinal layers, and the area of foveal avascular zone (FAZ) of superficial capillary plexus. DME and EZD were evaluated on B-scans. Both univariate and multivariate analysis were performed. RESULTS: Of the 54 study eyes, 31 (57%) had DME and 21 (40%) had EZD. Multivariate regression model showed that PDR (ß = 27.8, 95% confidence interval (CI): 2.7-282.8, p = 0.005), more MA (ß = 2.5, 95% CI: 1.3-4.5, p = 0.003), and increased VDI of larger vessels (ß = 1.9, 95% CI: 1.0-3.5, p = 0.047) were risk factors for DME. As for EZD, presence of SSPiM (ß = 5.5, 95% CI: 1.2-26.1, p = 0.032) and increased VDI of capillaries (ß = 3.9, 95% CI: 1.1-13.8, p = 0.034) were risk factors. CONCLUSIONS: In eyes with diabetic retinopathy, dilation of retinal larger vessels was associated with macular edema, while dilation of retinal capillaries was associated with ellipsoid zone disruption.