Search

The tethered molecule exhibits characteristics of both free and fixed states, with the electrodynamics involved in its diffusion, electrophoresis, and stretching processes still not fully understood. We developed a Single-Molecule Manipulation, Identification, and Length Examination (SMILE) system by integrating piezoelectric devices with nanopipettes. This system enabled successful capture and stretching of tethered double-stranded DNA within the nanopore. Our research unveiled distinct capture (rcapture) and stretch radii (rstretch) surrounding the DNA’s anchor point. Notably, consistent ratios of capture radius for DNA of varying lengths (2k, 4k, and 6k base pairs) were observed across different capturing voltages, approximately 1:1.4:1.83, showing a resemblance to their gyration radius ratios. However, the ratios of stretch radius are consistent to their contour length (L0), with the stretching ratio (rstretch/L0) increasing from 70 to 90% as the voltage rose from 100 to 1000 mV. Additionally, through numerical simulations, we identified the origin of capture and stretch radii, determined by the entropic elasticity-induced capture barrier and the electric field-dominant escape barrier. This research introduces an innovative methodology and outlines research perspectives for a comprehensive exploration of the conformational, electrical, and diffusion characteristics of tethered molecules.

The high incidence and heavy disease burden of prostate cancer (PC) require accurate and comprehensive assessment for appropriate disease management. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) cannot detect PSMA-negative lesions, despite its key role in PC disease management. The overexpression of gastrin-releasing peptide receptor (GRPR) in PC lesions reportedly performs as a complementary target for the diagnosis and therapy of PC. Radiopharmaceuticals derived from the natural ligands of GRPR have been developed. These radiopharmaceuticals enable the visualization and quantification of GRPR within the body, which can be used for disease assessment and therapeutic guidance. Recently developed radiopharmaceuticals exhibit improved pharmacokinetic parameters without deterioration in affinity. Several heterodimers targeting GRPR have been constructed as alternatives because of their potential to detect tumor lesions with a low diagnostic efficiency of single target detection. Moreover, some GRPR-targeted radiopharmaceuticals have entered clinical trials for the initial staging or biochemical recurrence detection of PC to guide disease stratification and therapy, indicating considerable potential in PC disease management. Herein, we comprehensively summarize the progress of radiopharmaceuticals targeting GRPR. In particular, we discuss the impact of ligands, chelators, and linkers on the distribution of radiopharmaceuticals. Furthermore, we summarize a potential design scheme to facilitate the advancement of radiopharmaceuticals and, thus, prompt clinical translation.

Chemical cross-linking combined with mass spectrometry is a technique used to study protein structures and identify protein complexes. Traditionally, chemical cross-linkers contain two reactive groups, allowing them to covalently bond a pair of proximal residues, either within a protein or between two proteins. The output of a cross-linking experiment is a list of interacting site pairs that provide structural constraints for modeling of new structures and complexes. Due to the binary reactive nature of cross-linking reagents, only pairs of interacting sites can be directly observed, and assembly of higher-order structures typically requires prior knowledge of complex composition or iterative docking to produce a putative model. Here, we describe a new tetrameric cross-linker bearing four amine-reactive groups, allowing it to covalently link up to four proteins simultaneously and a real-time instrument method to facilitate the identification of these tetrameric cross-links. We applied this new cross-linker to isolated mitochondria and identified a number of higher-order cross-links in various OXPHOS complexes and ATP synthase, demonstrating its utility in characterizing complex interfaces. We also show that higher-order cross-links can be used to effectively filter models of large protein assemblies generated by using Alphafold. Higher-dimensional cross-linking provides a new avenue for characterizing multiple protein interfaces, even in complex samples such as intact mitochondria.

Cardiac metabolism is vital for heart function. Given that cardiac contraction requires a continuous supply of ATP in large quantities, the role of fuel metabolism in the heart has been mostly considered from the perspective of energy production. However, the consequence of metabolic remodelling in the failing heart is not limited to a compromised energy supply. The rewired metabolic network generates metabolites that can directly regulate signalling cascades, protein function, gene transcription and epigenetic modifications, thereby affecting the overall stress response of the heart. In addition, metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to the development of cardiac pathologies. In this Review, we first summarize how energy metabolism is altered in cardiac hypertrophy and heart failure of different aetiologies, followed by a discussion of emerging concepts in cardiac metabolic remodelling, that is, the non-energy-generating function of metabolism. We highlight challenges and open questions in these areas and finish with a brief perspective on how mechanistic research can be translated into therapies for heart failure.

Coenzyme A, acetyl coenzyme A, coenzymes of cellular energy, coenzymes of redox reactions, and antioxidants mediate biochemical reactions fundamental to the functioning of all living cells. There is an immense interest in measuring them routinely in biological specimens to gain insights into their roles in cellular functions and to help characterize the biological status. However, it is challenging to measure them ex vivo as they are sensitive to specimen harvesting, extraction, and measurement conditions. This challenge is largely underappreciated and carries the risk of grossly inaccurate measurements that lead to incorrect inferences. To date, several efforts have been focused on alleviating this challenge using NMR spectroscopy. However, a comprehensive solution for the measurement of the compounds in a wide variety of biological specimens is still lacking. As a part of addressing this challenge, we demonstrate here that the total pool of each group of unstable metabolites offers a starting place for the representation of labile metabolites in biological specimens. Based on this approach, in this proof-of-concept study, we determine the distribution of the labile compounds in different organs including heart, kidney, liver, brain, and skeletal muscle of a mouse model. The results were independently validated using different specimens and a different metabolite extraction protocol. Further, we show that both stable and unstable metabolites were distributed differentially in different organs, which signifies their differential functional roles, the knowledge of which is currently lacking for many metabolites. Intriguingly, the concentration of taurine, an amino sulfonic acid, in skeletal muscle is >30 mM, which is the highest for any metabolite in a mammalian tissue known to date. To the best of our knowledge, this is the first study to profile the whole body distribution of the labile and other high-concentration metabolites using NMR spectroscopy. The results may pave ways for gaining new insights into cellular functions in health and diseases.

Robust and multifunctional polyphenolic hydrogels have been well acknowledged as promising biomaterial candidates due to their various fascinating properties in regulating cell biology. However, the construction of these hydrogels commonly needs multistep fabrication and a sophisticated gelation process. The typical phenol-aldehyde condensation is a facial and in situreaction for industrial resin construction; however, its application in hydrogel fabrication is seldom reported. In this study, we reported the feasibility and modularity of this strategy for in situfabricating various kinds of robust and multifunctional natural polyphenolic hydrogels using natural polyphenol (extracts) and formaldehyde. The physicochemical characterization results demonstrated that the chemical structure (e.g., phenolic hydroxyl groups) of polyphenol molecules could be well maintained after the gelation process, allowing as-prepared hydrogels to inherit the merits of polyphenol molecules, such as good UV shielding, radical scavenging, antibacterial properties, and so forth, as demonstrated by in vitrodata. The in vitroand in vivocellular and animal results further confirmed that the as-prepared hydrogels were able to perform a skin protection and repair role, as demonstrated in UV protection and wound healing models. Collectively, this strategy could allow natural polyphenols as both structural and functional synthons toward more types of robust hydrogels for a wide range of biomedical applications.

Platelet-derived growth factor receptor β (PDGFRβ) has been demonstrated to be an effective biomarker for a variety of malignant cancers, and affibody-based PDGFRβ molecules have potential as positron emission tomography (PET) tracers for the diagnosis of cancers. Based on previous pharmacokinetics studies, short-lived positron emission radionuclides, such as fluorine-18 and gallium-68, would be more suitable for affibody-based PET imaging. Thus, in the present study, we prepared a gallium-68-labeled PDGFRβ-targeting dimeric affibody conjugate and evaluated its capability for visualizing malignant tumors by micro-PET/computed tomography (CT) imaging. The PDGFRβ-targeting ZPDGFRβaffibody was conjugated with the p-NCS-Bn-DOTA macrocyclic ligand and radiolabeled with gallium-68 to generate the 68Ga-DOTA-ZPDGFRβPET probe . Then, several types of malignant carcinoma cells (U-87 MG, LS 174T, A549, H1688, and H446) were used to evaluate the targeted cellular binding capability of the PET probe through in vitro/in vivocellular assays and whole-body imaging by micro-PET/CT. The 68Ga-DOTA-ZPDGFRβwas successfully prepared with a radiochemical yield of 93% and exhibited ideal stability for up to 4 h at room temperature in vitro. This radioactive conjugate demonstrated specific binding ability with PDGFRβ-expressing U-87 MG cells, which was suppressed by PDGFRβ ligands. The biodistribution of 68Ga-DOTA-ZPDGFRβindicated fast liver clearance and a kidney-bladder excretion route. The U-87 MG xenografted tumor was clearly visualized with 68Ga-DOTA-ZPDGFRβat 1 h postinjection using micro-PET/CT imaging. 68Ga-DOTA-ZPDGFRβis a potential radiopharmaceutical for the diagnosis of PDGFRβ-expressing tumors.

A 32-year-old man underwent 18F-FDG PET/CT to evaluate suspicious hepatic metastases, which were revealed by ultrasonography and MRI. The FDG PET/CT images demonstrated only one focus of subtly increased activity in the liver without abnormality elsewhere. The pathological result from hepatic biopsy was consistent with Paragonimus westermaniinfection.

OBJECTIVE--Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice. RESEARCH DESIGN AND METHODS--OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. RESULTS--Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice. CONCLUSIONS--Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy., Autophagy is a physiologic process whereby cytoplasmic components, including long-lived proteins and organelles, are engulfed by a double-membrane structure and targeted for destruction in lysosomes (1). It selectively removes damaged [...]

OBJECTIVE--Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin [...]

High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)β inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and [sup.13]C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCβ or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium., Cardiac failure in diabetic patients can be induced by vascular insufficiency and contractile dysfunction resulting from abnormal levels of metabolites (1,2). For the latter, elevations of plasma glucose and free [...]

For the past few decades, it has been demonstrated that gravity waves (GWs) and neutral winds can drive ionospheric irregularities on Earth. Still, as far as we know, the formation of ionospheric irregularities on Mars due to GWs has not been well studied. In this study, we use data from the NASA's Mars Atmosphere and Volatile Evolution (MAVEN) mission to show evidence of an irregularity event in the Martian ionosphere, potentially seeded by the GWs break (GWB). Statistical findings indicate that the observed ratio of GWB‐related irregularity events varies from ∼0.25 to ∼0.47 each year, and the average ratio in 2015–2020 is ∼0.37. We perform a numerical simulation to provide further insight into the processes behind irregularity formation, which employs neutral wind shear as a source of perturbation in the context of the GWB. The simulations yield results fundamentally aligned with the observed characteristics of ionospheric irregularities in the 2018 event by considering the wind shear as the disturbance source. This study provides supplementary insights into the perturbation sources involved in shaping irregularities within the Martian ionosphere and presents valuable information about the coupling between the Martian ionosphere and the lower atmosphere. Many remote and in situ observations of the Martian ionosphere have been made by landers, orbiting or flyby spacecrafts, for example, Viking, Mars Global Surveyor (MGS), Mars Express (MEX), and Mars Atmosphere and Volatile EvolutioN (MAVEN) missions. It gives us a great opportunity to know the basic ionospheric structure and composition of Mars. However, there are still many scientific questions about the Martian ionosphere that have yet to be studied, for example, the structure of the lower ionosphere, small‐scale ionospheric irregularities, and the role of lower atmospheric effects on the ionosphere. Normally, the ionosphere is a stable stratified structure. However, in some situations, the ionosphere becomes unstable, generating perturbations in the electron density, leading to these so‐called “irregularities.” In this study, we report that the break of gravity waves potentially accounts for the formation of ionospheric irregularities observed in the Martian ionosphere by NASA's MAVEN spacecraft. The results of our statistical study support the notion that gravity waves are a crucial seeding source in the formation of irregularities. This investigation adds to the current understanding of perturbation sources responsible for irregularity formation in the Martian ionosphere, while also contributing to our knowledge of the coupling between the Martian ionosphere and the lower atmosphere. An example of a Martian ionospheric irregularity event potentially seeded by GWB (the break of gravity waves) is presentedStatistical results show that the proportion ratio of GWB‐related irregularities peaked at ∼0.47 in 2018, reached a minimum of ∼0.25 in 2017, and averaged ∼0.37 over the six yearsThe simulation shows that the formation of the irregularities can be fundamentally reproduced using the GWB‐related wind shear as a perturbation source An example of a Martian ionospheric irregularity event potentially seeded by GWB (the break of gravity waves) is presented Statistical results show that the proportion ratio of GWB‐related irregularities peaked at ∼0.47 in 2018, reached a minimum of ∼0.25 in 2017, and averaged ∼0.37 over the six years The simulation shows that the formation of the irregularities can be fundamentally reproduced using the GWB‐related wind shear as a perturbation source

Considering the protective ability of proteins and the potential toxicity of free Cu(II), it was proposed herein that the co-presence of protein could play an important role in suppressing the toxicity of free Cu(II) to the stability of bioactive quercetin if a flavonoid–protein–Cu(II) complex could be formed. In this study, the interaction between quercetin (a major flavonoid in the human diet) and bovine serum albumin (BSA) was investigated in the absence and presence of free Cu(II). The results demonstrated that both quercetin and free Cu(II) had a strong ability to quench the intrinsic fluorescence of BSA through a static procedure (i.e., formation of a BSA–monoligand complex). Site marker competitive experiments illustrated that the binding of both quercetin and Cu(II) to BSA mainly took place in subdomain IIA. The quenching process of free Cu(II) with BSA was easily affected by quercetin, and the increased binding capacity possibly resulted from the generation of a ternary quercetin–BSA–Cu(II) complex. The stability and free radical scavenging activity of bioactive quercetin during incubation was promoted in the BSA–diligand complex relative to a quercetin–Cu(II) complex. A quercetin–Cu(II) system could generate reactive oxygen species such as hydrogen peroxide (H2O2) and hydroxyl radicals (•OH), which were significantly inhibited upon BSA binding. Consistently, the cytotoxicity of the quercetin–Cu(II) system to endothelial cells was decreased in the BSA–diligand complex, where the co-presence of BSA played an important role. These results suggest the possibility and advantage of developing albumin-based carriers for the protection of bioactive components and suppression of Cu(II) toxicity in their biomedical and nutritional applications.

Objective: The occurrence and development of inflammation are closely correlated to the polarization of macrophages. All-trans retinoic acid (ATRA) has been proven to promote the polarization of macrophages from M1 to M2, but this lacks an effective carrier to participate in the biological response. The present study aims to determine whether retinoic acid-incorporated glycol chitosan (RA-GC) nanoparticles can regulate macrophage polarization in Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS)-induced inflammation. Methods: Mouse 264.7 cell lines were treated with 1 µg/mL Pg-LPS to induce inflammation. After the effects of ATRA and RA-GC on the activity of macrophages were detected by CCK-8 assay, cells induced with Pg-LPS were assigned to the blank control group (GC) nanoparticles without ATRA, and experimental groups (GC nanoparticles loaded with different concentrations of ATRA: 1, 10 and 100 µg/mL). The effects of RA-GC on inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-10 and IL-12 in macrophages were detected by enzyme-linked immunosorbent assay (ELISA). Subsequently, the effects of GC nanoparticles loaded with/without ATRA on macrophage polarization in an inflammatory environment were detected by RT-PCR and Western blotting. Results: The results revealed that RA-GC had no significant effect on macrophage activity. However, RA-GC could effectively inhibit the Pg-LPS-induced inflammatory factor expression in macrophages. Meanwhile, the experimental results confirmed that RA-GC could downregulate the expression of inducible nitric oxide synthase (iNOS) (a marker of M1 macrophages) and upregulate the expression of mannose receptor and Arginase-1 (a marker of M2 macrophages) in a dose-dependent manner. Conclusion: The present study confirms that RA-GC can promote the M2 polarization of macrophages in an inflammatory environment, and proposes this as a promising target for the clinical treatment of Pg-LPS-related diseases.

Byline: Rong-Hua. Tian, Xia. Wu, Xia. Liu, Jin-Wang. Yang, Hua-Liang. Ji, Yong-Jin. Yan Purpose: Data on the role of angiogenesis inhibitors (AIs) in the treatment of elderly patients with advanced [...]

Purpose: To summarise the methodological quality of systematic reviews used by clinical practice guidelines, focusing on the field of clinical imaging. Methods: We searched PubMed (up to January 2021), EMBASE, and Cochrane Methodology Register (both up to April 2021) for studies quantitatively assessing the methodological quality of systematic reviews referenced in clinical practice guidelines. We summarised the overall quality, methodological areas with low quality, and commonly used assessment tools with their applicability to systematic reviews of diagnostic accuracy studies. Results: 2433 records were retrieved and 12 studies were included, two of which investigated imaging guidelines. The overall methodological quality of systematic reviews was moderate in eight studies (67%), high in one study (8%), and low in one study (8%). One study (8%) assessed merely the risk of bias and found unclear or high risk in general. The Assessment of Multiple Systematic reviews (AMSTAR) tool was used in ten studies, and systematic reviews in imaging guidelines received the lowest AMSTAR scores (mean 4/11, range 0/11–9/11 in an interventional radiology guideline; mean 3/11, range 0/11–11/11 in a mammography screening guideline), correlating to low and borderline moderate quality. Methodological areas frequently found with low quality were financial disclosure, publication bias assessment, and review of grey literature. All commonly used tools are applicable, with or without minor modifications, to assessing diagnostic systematic reviews. Conclusion: The methodological quality of systematic reviews in guidelines for intervention radiology and mammography screening was lower than that in guidelines for other topics. Diagnostic imaging guidelines should also be assessed for the quality of systematic review evidence underlying their recommendations.

We previously demonstrated that apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), is an important target for myeloperoxidase (MPO)-catalyzed tyrosine chlorination in the circulation of subjects with cardiovascular diseases. Oxidation of apoA-I by MPO has been reported to deprive HDL of its protective properties. However, the potential effects of MPO-mediated site-specific tyrosine chlorination of apoA-I on dysfunctional HDL formation and atherosclerosis was unclear. Herein, Tyr192 in apoA-I was found to be the major chlorination site in both lesion and plasma HDL from humans with atherosclerosis, while MPO binding to apoA-I was demonstrated by immunoprecipitation studies in vivo. In vitro, MPO-mediated damage of lipid-free apoA-I impaired its ability to promote cellular cholesterol efflux by the ABCA1 pathway, whereas oxidation to lipid-associated apoA-I inhibited lecithin:cholesterol acyltransferase activation, two key steps in reverse cholesterol transport. Compared with native apoA-I, apoA-I containing a Tyr192 → Phe mutation was moderately resistant to oxidative inactivation by MPO. In high-fat-diet-fed apolipoprotein E-deficient mice, compared with native apoA-I, subcutaneous injection with oxidized apoA-I (MPO treated) failed to mediate the lipid content in aortic plaques while mutant apoA-I (Tyr192 → Phe) showed a slightly stronger ability to reduce the lipid content in vivo. Our observations suggest that oxidative damage of apoA-I and HDL involves MPO-dependent site-specific tyrosine chlorination, raising the feasibility of producing MPO-resistant forms of apoA-I that have stronger antiatherosclerotic activity in vivo.

As an abundant protein in milk and blood serum, bovine serum albumin (BSA) contains various sites to bind a lot of bioactive components, generating BSA–monoligand complex. Demonstration of the interaction between BSA and bioactive components (such as heme, flavonoids) is important to develop effective carrier for the protection of bioactive ligands and to reduce cytotoxicity of heme. Herein, the bindings of BSA to quercetin and/or heme were investigated by multispectroscopic and molecular docking methods. The fluorescence of protein was significantly quenched by both quercetin and heme in a static mode (i.e., generation of BSA–ligand complex). Although quercetin had lower affinity to protein than heme, the interactions of both compounds with protein did locate in site I (i.e., subdomain IIA). BSA–diligand complex was successfully generated after the coaddition of quercetin and heme. The cytotoxicity of free heme to endothelial cells was reduced in the BSA–diligand complex relative to that of heme or BSA–monoligand complex, while the stability of bioactive quercetin was promoted in the complex relative to free flavonoid. The complex provided a better inhibition on the cytotoxicity of heme than BSA–monoligand complex, in which the copresence of quercetin played a vital role.

Pulmonary enteric adenocarcinoma(PEAC) is a rare variant of pulmonary adenocarcinoma. We herein report FDG PET/CT findings of PEAC in a 76-year-old woman. The images showed widespread opacities in both lungs with intense FDG uptake. The pathology revealed pulmonary enteric adenocarcinoma.

A 33-year-old woman presents with cough and hemoptysis for 1 month. Chest CT showed a soft tissue mass in the left upper lobe of the lung. FDG PET/CT showed multiple foci of intense activity not only in the lung but also in the lymph nodes and the bones, which was diagnosed as lung malignancy with metastases. Histopathology revealed desmoplastic small round cell tumor. Our case indicated that, although the incidence is low, desmoplastic small round cell tumor should be considered among differential diagnoses of lung malignancies.

Background: Coronary artery calcification (CAC) is an independent risk factor of major adverse cardiovascular events; however, the impact of CAC on in-hospital death and adverse clinical outcomes in patients with coronavirus disease 2019 (COVID-19) remains unclear. Objective: To explore the association between CAC and in-hospital mortality and adverse events in patients with COVID-19. Methods: This multicenter retrospective cohort study enrolled 2067 laboratory-confirmed COVID-19 patients with definitive clinical outcomes (death or discharge) admitted from 22 tertiary hospitals in China between January 3, 2020 and April 2, 2020. Demographic, clinical, laboratory results, chest CT findings, and CAC on admission were collected. The primary outcome was in-hospital death and the secondary outcome was composed of in-hospital death, admission to intensive care unit (ICU), and requiring mechanical ventilation. Multivariable Cox regression analysis and Kaplan–Meier plots were used to explore the association between CAC and in-hospital death and adverse clinical outcomes. Results: The mean age was 50 years (SD,16) and 1097 (53.1%) were male. A total of 177 patients showed high CAC level, and compared with patients with low CAC, these patients were older (mean age: 49 vs. 69 years, P< 0.001) and more likely to be male (52.0% vs. 65.0%, P= 0.001). Comorbidities, including cardiovascular disease (CVD) ([33.3%, 59/177] vs. [4.7%, 89/1890], P< 0.001), presented more often among patients with high CAC, compared with patients with low CAC. As for laboratory results, patients with high CAC had higher rates of increased D-dimer, LDH, as well as CK-MB (all P< 0.05). The mean CT severity score in high CAC group was also higher than low CAC group (12.6 vs. 11.1, P= 0.005). In multivariable Cox regression model, patients with high CAC were at a higher risk of in-hospital death (hazard ratio [HR], 1.731; 95% CI 1.010–2.971, P= 0.046) and adverse clinical outcomes (HR, 1.611; 95% CL 1.087–2.387, P= 0.018). Conclusion: High CAC is a risk factor associated with in-hospital death and adverse clinical outcomes in patients with confirmed COVID-19, which highlights the importance of calcium load testing for hospitalized COVID-19 patients and calls for attention to patients with high CAC.

Primary intraosseous squamous cell carcinoma (SCC) is an uncommon malignant cancer involving the jaw bones. We herein reported the imaging findings of a primary intraosseous SCC of the mandible in a 47-year-old man. He was diagnosed as cancer of unknown primary in the cervical node. FDG PET/CT revealed a focal hypermetabolic lesion around the tooth root of the right lower molar. MRI showed the lesion had hyperintensity on T2-weighted imaging and significant enhancement on T1-weighted imaging fat saturate images. The final diagnosis of primary intraosseous SCC of mandible was confirmed pathologically.

Liposarcoma is a soft tissue tumor that commonly appears in the retroperitoneum and the extremities. Herein, we presented the imaging findings of a 68-year-old man with a paravertebral liposarcoma involving the adjacent vertebral bodies, appendices, and ribs. MRI revealed this mass located in the left side of T9 to T10 vertebral bodies. FDG PET/CT demonstrated the mass with intense FDG uptake. Finally, the pathological findings were consistent with a diagnosis of a primary paravertebral liposarcoma.

NADPH oxidase-dependent superoxide (O2·–) production and oxidative stress play important roles in endothelial dysfunction and atherosclerosis. Herein, we investigated the potential effects of dietary quercetin, a flavonoid derived in the diet from vegetables and fruit, on vascular endothelial function and atherosclerosis in the high-fat diet (HFD)-fed apolipoprotein E-deficient (ApoE–/–) mice. Dietary quercetin treatment significantly suppressed endothelial dysfunction and aortic atherosclerosis in HFD-fed ApoE–/–mice (P< 0.05, all cases). Mechanistic studies demonstrated that dietary quercetin significantly attenuated p47phox expression and inhibited NADPH oxidase-derived oxidative stress in the aortas of HFD-fed ApoE–/–mice, while the expression and activity of antioxidant enzyme heme oxygenase-1 (HO-1) was enhanced after quercetin treatment (P< 0.05, all cases). In vitro, it was found that quercetin significantly attenuated NADPH oxidase-derived O2·–formation (75 ± 5.6% for quercetin versus 100 ± 6.0% for the control group, P< 0.01) in endothelial cells through induction of HO-1. In addition, the favorable effects of quercetin on oxidant (i.e., H2O2)-induced endothelial dysfunction could be eliminated by tin protoporphyrin IX (an HO-1 inhibitor) or HO-1-specific siRNA. Our results demonstrated the critical roles of NADPH oxidase and HO-1 for the indirect antioxidant properties of quercetin in vascular diseases.

Supplemental Digital Content is available in the text.

Unexpected extraosseous uptake is common on 99mTc–methylene diphosphonate bone scintigraphy, but accumulation by primary upper gastrointestinal tract malignant melanoma is rarely reported. The present case is a 58-year-old woman with a 10-day history of diffuse bone pain and weakness. Her bone scintigraphy showed unexpected diffuse gastric tracer uptake. Subsequent gastroscopy revealed a number of hyperpigmented lesions in the stomach and duodenal bulb. Malignant melanoma was confirmed by histopathology and immunohistochemistry. Because extensive physical examination failed to identify any other site of ocular and cutaneous melanoma, a diagnosis of primary upper gastrointestinal tract malignant melanoma was established.

Chronic inflammation contributes to cardiovascular disease. Increased levels of the inflammatory cytokine, TNF-α, are often present in conditions associated with cardiovascular disease risk, and TNF-α induces a number of pro-atherogenic effects in macrovascular endothelial cells, including expression of adhesion molecules and chemokines, and lipoprotein uptake and transcytosis to the subendothelial tissue. However, little is known about the roles of acyl-CoA synthetases (ACSLs), enzymes that esterify free fatty acids into their acyl-CoA derivatives, or about the effects of TNF-α on ACSLs in endothelial cells. Therefore, we investigated the effects of TNF-α on ACSLs and downstream lipids in cultured human coronary artery endothelial cells and human umbilical vein endothelial cells. We demonstrated that TNF-α induces ACSL1, ACSL3, and ACSL5, but not ACSL4, in both cell types. TNF-α also increased oleoyl-CoA levels, consistent with the increased ACSL3 expression. RNA-sequencing demonstrated that knockdown of ACSL3 had no marked effects on the TNF-α transcriptome. Instead, ACSL3 was required for TNF-α-induced lipid droplet formation in cells exposed to oleic acid. These results demonstrate that increased acyl-CoA synthesis as a result of ACSL3 induction is part of the TNF-α response in human macrovascular endothelial cells.

68Ga-pentixafor uptake in hemangioma is rare. We report 68Ga-pentixafor PET/MRI findings of a hepatic hemangioma in a 54-year-old woman. The images revealed a hyperintense lesion in the right posterior liver on T2-weighted images, with mild pentixafor uptake. The lesion was consistent with typical presentations of a hemangioma on MRI and contrast-enhanced CT.

Greenhouse gas (GHG) production during ensiling not only causes the nutrient losses of silage but also promotes climate warming. However, there is little information on the production of GHG and strategies for mitigating GHG emissions during ensiling. This work aimed to study the gas production characteristics and techniques for reducing gas emissions during ensiling. Oats and triticale, with Lactiplantibacillus plantarum(LP) or corn meal (CM) addition, were ensiled. The cumulative gas volume rapidly increased and reached to the peak within the first 9 days of ensiling for both forage crops. The highest cumulative gas volume of triticale silage was twice as much as that of oats silage. Triticale silage produced lower carbon dioxide (CO2) concentration, higher methane (CH4) and nitrous oxide (N2O) concentrations than oats silage within the 28 days of ensiling. Adding LP or CM significantly improved the fermentation quality and decreased the gas volume and GHG concentrations of two silages on d56 (except CH4of triticale). At the early stage of ensiling, more Enterobacter, Lactococcusand Leuconostocrelated to gas production were observed, and adding LP increased the abundance of Lactobacillusand decreased the abundance of bacteria like Kosakonia, Pantoea, Enterobacterand Lactococcuspositively correlated with gas volume, CO2and N2O concentrations. These results suggest that gas formation during ensiling mainly occurs in the first 9 days. Adding LP or CM can significantly improve the fermentation quality and decrease the gas volume. This would benefit to reducing GHG emissions in silage production.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitrocells stimulated with H2O2and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivostudies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

Pulmonary sclerosing pneumocytoma is a rare benign neoplasm. Owing to the low incidence, its radiographic features on 18F-FDG PET/MRI are not well-known. Herein, we described findings of pulmonary sclerosing pneumocytoma on 18F-FDG PET/MRI in a 52-year-old woman. It showed moderate FDG uptake and hyperintensity signal on both T1WI and T2WI images.

Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure, and other cardiovascular diseases, as well, but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute convened a group of leading experts in heart failure, cardiovascular diseases, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational, and clinical research focusing on the potential of mitochondria-based therapeutic strategies in heart failure. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of heart failure and cardiovascular diseases by using mitochondria-based approaches.

Platelet-derived growth factor receptor β (PDGFRβ) is overexpressed in a variety of malignant cancers, plays a critical role in tumor angiogenesis, and has been proven as a valuable target for cancer treatment. In this pilot study, a dimeric affibody molecule, ZPDGFRβ, was prepared and radiolabeled with positron emission radionuclide zirconium-89 for PET imaging of colorectal tumors by targeting PDGFRβ expression in vivo. The PDGFRβ-binding capability of dimeric affibody was evaluated by flow cytometry, immunofluorescent staining, and whole-body optical imaging. Then, ZPDGFRβwas conjugated with DFO-Bn-NCS and radiolabeled with 89Zr. Targeted binding capability of 89Zr-DFO-ZPDGFRβto PDGFRβ expressing cells was investigated by cellular assay in vitroand microPET/CT imaging in vivo. Dimeric ZPDGFRβaffibody had specifically higher binding capability with PDGFRβ expressing pericytes rather than LS-174T cancer cells, and well colocalized with tumor neovasculature by flow cytometry and immunofluorescent assay. ZPDGFRβwas successfully labeled with 89Zr by DFO chelating with yield of 94.1 ± 3.53%. 89Zr-DFO-ZPDGFRβindicated preserved specific binding ability with PDGFRβ expressing cells and effective inhibiting capability to PDGF-β ligands (P< 0.05) in vitro. Biodistribution indicated that tumor uptake of 89Zr-DFO-ZPDGFRβreached the peak of 6.93 ± 0.64%ID/g, and the tumor-to-blood ratio was 5.5 ± 0.6 at 2 h post-injection. LS-174T xenografts were clearly visualized by microPET/CT imaging through 1 to 4 h post-injection of 89Zr-DFO-ZPDGFRβaffibody conjugate. In conclusion, the 89Zr-DFO-ZPDGFRβconjugate demonstrated specific and high binding ability with colorectal tumor, which indicated its use as a potential radiopharmaceutical for diagnostic imaging of tumor associate vasculatures with PET/CT.

Objective This study aimed to compare intraoperative lower back pain and leg pain, surgical time, and intraoperative X-ray dose in patients offered local infiltration anesthesia or continuous epidural anesthesia for transforaminal endoscopic spine system (TESSYS) surgery.Methods A total of 98 patients who received TESSYS treatment for single-segmental lumbar disc herniation were included, and were randomly divided into two groups: group A (49 cases; local infiltration anesthesia) and group B (49 cases; continuous epidural anesthesia). Surgical duration, intraoperative X-ray dose, and visual analog scale (VAS) scores of lower back pain and leg pain before surgery, during surgery, and 48 h after surgery were recorded and compared.Results After surgery, the VAS scores of both lower back pain and leg pain decreased in group A, and similar findings were found in group B. Group B had a shorter surgical duration, lower intraoperative X-ray dose, and lower intraoperative VAS scores of lower back pain and leg pain compared with group A.Conclusion Compared with local infiltration anesthesia, continuous epidural anesthesia was more effective for pain relief during TESSYS for single-segmental lumbar disc herniation, and also contributed to a shorter surgical duration and lower X-ray exposure.

Coenzyme A (CoA) and acetyl-coenzyme A (acetyl-CoA) are ubiquitous cellular molecules, which mediate hundreds of anabolic and catabolic reactions including energy metabolism. Highly sensitive methods including absorption spectroscopy and mass spectrometry enable their analysis, albeit with many limitations. To date, however, NMR spectroscopy has not been used to analyze these important molecules. Building on our recent efforts, which enabled simultaneous analysis of a large number of metabolites in tissue and blood including many coenzymes and antioxidants (Anal. Chem.2016,88, 4817–24; ibid2017, 89, 4620–4627), we describe here a new method for identification and quantitation of CoA and acetyl-CoA ex vivo in tissue. Using mouse heart, kidney, liver, brain, and skeletal tissue, we show that a simple 1H NMR experiment can simultaneously measure these molecules. Identification of the two species involved a comprehensive analysis of the different tissue types using 1D and 2D NMR, in combination with spectral databases for standards, as well as spiking with authentic compounds. Time dependent studies showed that while the acetyl-CoA levels remain unaltered, CoA levels diminish by more than 50% within 24 h, which indicates that CoA is labile in solution; however, degassing the sample with helium gas halted its oxidation. Further, interestingly, we also identified endogenous coenzyme A glutathione disulfide (CoA–S–S–G) in tissue for the first time by NMR and show that CoA, when oxidized in tissue extract, also forms the same disulfide metabolite. The ability to simultaneously visualize absolute concentrations of CoA, acetyl-CoA, and endogenous CoA–S–S–G along with redox coenzymes (NAD+, NADH, NADP+, NADPH), energy coenzymes (ATP, ADP, AMP), antioxidants (GSH, GSSG), and a vast pool of other metabolites using a single 1D NMR spectrum offers a new avenue in the metabolomics field for investigation of cellular function in health and disease.

Equatorial plasma bubbles (spread F/ionospheric irregularities) are plasma density irregularities or depletion in the ionosphere. It can be observed by radio waves, optical and in situ instruments during postsunset in equatorial and low‐latitude regions. Severe scintillations in radio waves can be caused by the presence of plasma bubbles. Therefore, studies of plasma bubbles become one of the most important and hot topics. Many studies have been devoted to the physical mechanism and characteristics of plasma bubbles in the ionosphere. However, some critical issues (e.g., day‐to‐day variability, complex structures, and ions composition) are still not well known. In this study, a new two‐dimensional model of multi‐ion (H+, He+, N+, O+, N2+, NO+, and O2+) plasma bubbles was developed. The photoionization, chemical reaction, and recombination processes of multiple ions have been added to the new model. The present model was used to simulate the nonlinear evolutions of multiple plasma bubbles in the equatorial region. Results show that the merging, disconnection and connection processes of plasma bubbles can be reproduced in this simulation. In addition, simulations first present morphological structures of molecular ions (NO+, O2+) of multiple plasma bubbles, which are significantly different from plasma bubbles. Molecular ion NO+is manifested as plasma blobs. However, molecular ion O2+is manifested as bubbles at low altitudes but blobs at high altitudes. The complex structures of multiple plasma bubbles and morphological structures of molecular ions in the present simulation are mostly consistent with observations. Plasma bubbles are plasma density irregularities or depletion in the ionosphere. It is also named spread F/ionospheric irregularities. Plasma bubbles can be observed frequently by radar, optical imager, and satellite in situ measurements during postsunset in equatorial and low‐latitude regions. Severe scintillations in radio waves can be caused by the presence of plasma bubbles. Studies of plasma bubbles become one of the most important and hot topics in ionospheric communities. Plasma bubbles/ionospheric irregularities have been studied for a long time. However, some critical issues (e.g., day‐to‐day variability, complex structures, and ions composition) still need to be further studied in plasma bubbles. In this study, a two‐dimensional model of multi‐ion plasma bubbles was developed to study the complex structures and ions composition in the development of multiple plasma bubbles. The complex structures of multiple plasma bubbles can be reproduced by the model. Moreover, morphological structures of molecular ions in the low ionosphere are first presented in the simulation of multiple plasma bubbles. The present model also can be used to study the day‐to‐day variability of plasma bubbles in future studies. A new two‐dimensional model of equatorial plasma bubbles, including photochemical and recombination processes, was developed in this studyThe bifurcation, reconnected, and disconnected processes of multiple plasma bubbles can be simulated in the new modelMorphological structures of molecular ions (NO+, O2+) are first presented in multiple plasma bubbles A new two‐dimensional model of equatorial plasma bubbles, including photochemical and recombination processes, was developed in this study The bifurcation, reconnected, and disconnected processes of multiple plasma bubbles can be simulated in the new model Morphological structures of molecular ions (NO+, O2+) are first presented in multiple plasma bubbles

To evaluate whether nicotinamide adenine dinucleotide-positive (NAD+) boosting modulates adaptive immunity, primary CD4+T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. NR administration increases sqstm1and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2and the Nrf2-dependent gene, sqstm1, diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD+boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4+T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1, and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD+boosting in CD4+T cell-linked inflammation.

Diabetics with coronary artery disease are more likely to develop heart failure, following cardiac ischemia when compared to non-diabetics. One proposed mechanism is downregulation of cardiac GLUT4 and GLUT1 which [...]

We describe a case of Langerhans cell histiocytosis involving the bilateral pleura on FDG PET/CT. Multiple pleural nodules were detected by CT in a 38-year-old woman with chest pain and night sweats. Malignant tumors were suspected. PET/CT showed abnormal FDG uptake in those pleural lesions. No other abnormal foci were seen in the rest of the whole body. A primary pleural disease was considered. Then the histopathologic findings after biopsy confirmed the diagnosis of Langerhans cell histiocytosis.

Characterization of brown adipose tissue (BAT) 18F-FDG uptake has been well reported; however, 68Ga-DOTA–conjugated somatostatin receptor targeting peptides uptake in BAT is rarely documented. Herein, we report an interesting case of increased 68Ga-DOTATATE uptake in supraclavicular BAT in a young boy with paroxysmal hypertension. The low body mass index and increased perfusion of BAT in response to cold may be significant influencing factors.

A 52-year-old man had shortness of breath and chest discomfort for 2 months. Chest CT and MRI showed a mass in the left atrium attached to the mitral annulus without obvious enhancement. Initial diagnosis was suspected of myxoma. Preoperative FDG PET/CT demonstrated the corresponding lesion with abnormal FDG uptake, indicating a malignancy. Finally, histopathologic examination revealed primary undifferentiated sarcoma.

A 24-year-old woman with left hip pain for 4 months was admitted. Radiographs of the left hip showed a radiolucent lesion in the proximal femur. The lesion demonstrated hypointensity on T1-weighted and high intensity on T2-weighted fat saturated images. 99mTc-MDP bone scan and 18F-FDG PET/CT illustrated intense radiotracer accumulation at the osteolytic lesion. Postoperative pathology confirmed a low-grade myofibroblastic sarcoma (LGMS). LGMS is a rare neoplasm, which often occurred in the head and neck region. Our case suggested that LGMS should be considered in the differential diagnosis of proximal femur lesion on 99mTc-MDP bone scan and 18F-FDG PET/CT.

Multimodality imaging was performed on a 53-year-old woman who was suspected with malignant bone tumor in her left femoral midshaft on radiograph. An MRI demonstrated the lesion showed hypointensity on T1-weighted and high intensity on T2-weighted fat-saturated images. It was more extensive on MRI than that on radiograph, especially in bone marrow and parosteal soft tissue. The lesion accumulated radiotracer on bone scan and 18F-FDG PET/CT. Finally, a Langerhans cell histiocytosis was confirmed after surgery. The case cautions us Langerhans cell histiocytosis should be in the differential diagnosis spectrum in an adult with unexplained unifocal bone lesion on 18F-FDG PET/CT.

Proteins in the bloodstream bind to carbon nanotubes (CNTs) through noncovalent interactions to form a protein corona, thereby effectively influencing the biological properties and blood biocompatibility of the CNTs. Here, we investigated the binding of common plasma proteins (i.e., human immunoglobulin G (IgG), human serum albumin (HSA), and fibrinogen (FG)) to carboxylated single-walled CNTs (SWCNTs), and evaluated the effects of these different protein coronas on cytotoxicity to endothelial cells and immune response to neutrophils in the bloodstream. Measurements of adsorption parameters revealed tight binding of proteins to SWCNTs, and the SWCNTs adsorption capacities followed the order FG > HSA > IgG. In addition, the basic residues (Arg, Lys, His) were found to play an important role in the formation of protein–SWCNTs corona complexes and determine their adsorption capacity. Consistent with the higher protein adsorption capacity, FG more significantly reduced the cytotoxicity of CNTs to human umbilical vein endothelial cells than the other two proteins. However, only treatment of SWCNTs with IgG resulted in the enhancement of CNT-induced myeloperoxidase (MPO) release (i.e., neutrophil activation) in neutrophils, while MPO-dependent degradation of CNTs induced less cytotoxicity than initial nanomaterials. Consistent with these effects of protein coronas, the presence of serum attenuated the cytotoxicity of CNTs and CNTs could induce neutrophil activation in human blood plasma. Our study demonstrates the ability of adsorbed plasma proteins to influence cytotoxicity and neutrophil response caused by CNTs in the bloodstream.

The interactions between proteins and bioactive ligands (such as flavonoids and nanomaterials) are vital to the design of effective protein carriers for the protection of bioactive molecules and reduction of the cytotoxicity of nanotubes. Bovine serum albumin (BSA) can bind various bioactive components and subsequently form protein–ligand complexes. Herein, the binding of BSA to quercetin and single-walled carbon nanotubes (SWCNTs) was investigated by using experimental and molecular-docking methods. The fluorescence intensity of BSA was decreased by both quercetin and SWCNTs in static quenching mode (i.e., compound formation), which was authenticated by Stern–Volmer calculations. Although quercetin showed a higher affinity for BSA than SWCNTs, the binding of both components to BSA was located in site I (subdomain IIA). BSA–diligand complexes were successfully generated when SWCNTs and quercetin, in that sequence, were added. The cytotoxicity of SWCNTs and the formation of reactive oxygen species in endothelial cells were decreased with the BSA–diligand complexes relative to those of SWCNTs or BSA–SWCNT corona, whereas the stability problems of quercetin were ameliorated in the BSA–diligand complex relative to in the free flavonoid. The BSA–diligand complex showed a better inhibitive effect on the cytotoxicity of SWCNTs than the BSA–SWCNT complex, and thus the coexistence of quercetin played a crucial role. These data demonstrate the advantages and possibility of designing BSA carriers for the protection of bioactive ligands and reduction of the cytotoxicity of nanotubes in functional-food and biomedical applications.