Differential expression and analysis of extrachromosomal circular DNAs as serum biomarkers in pulmonary arterial hypertension.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) have been reported to play a key role in the occurrence and development of various diseases. However, the characterization and role of eccDNAs in pulmonary arterial hypertension (PAH) remain unclear. METHODS: In the discovery cohort, we first explored eccDNA expression profiles by Circle-sequencing analysis. The candidate eccDNAs were validated by routine polymerase chain reaction (PCR), TOPO-TA cloning and Sanger sequencing. In the validation cohort, 30 patients with PAH and 10 healthy controls were recruited for qPCR amplification to detect the candidate eccDNAs. Datas at the baseline were collected, including clinical background, biochemical variables, echocardiography and hemodynamic factors. Receiver operating characteristic curve was used to investigate the diagnostic effect of the eccDNA. RESULTS: We identified a total of 21,741 eccDNAs in plasma samples of 3 IPAH patients and 3 individuals in good health, and the expression frequency, GC content, length distribution, and genome distribution of the eccDNAs were thoroughly characterized and analyzed. In the validation cohort, 687 eccDNAs were differentially expressed in patients with IPAH compared with healthy controls (screening threshold: |FC|≥2 and P < 0.05). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the specific eccDNAs in IPAH were significantly enriched in calcium channel activity, the mitogen-activated protein kinase pathway, and the wnt signaling pathway. Verification queue found that the expression of eccDNA-chr2:131208878-131,424,362 in PAH was considerably higher than that in healthy controls and exhibited a high level of accuracy in predicting PAH with a sensitivity of 86.67% and a specificity of 90%. Furthermore, correlation analysis disclosed a significant association between serum eccDNA-chr2:131208878-131,424,362 and mean pulmonary artery pressure (mPAP) (r = 0.396, P = 0.03), 6 min walking distance (6MWD) (r = -0.399, P = 0.029), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (r = 0.685, P < 0.001) and cardiac index (CI) (r = - 0.419, P = 0.021). CONCLUSIONS: This is the first study to identify and characterize eccDNAs in patients with PAH. We revealed that serum eccDNA-chr2:131208878-131,424,362 is significantly overexpressed and can be used in the diagnosis of PAH, indicating its potential as a novel non-invasive biomarker.

Third Harmonic Generation in Thin NbOI2 and TaOI2.

The niobium oxide dihalides have recently been identified as a new class of van der Waals materials exhibiting exceptionally large second-order nonlinear optical responses and robust in-plane ferroelectricity. In contrast to second-order nonlinear processes, third-order optical nonlinearities can arise irrespective of whether a crystal lattice is centrosymmetric. Here, we report third harmonic generation (THG) in two-dimensional (2D) transition metal oxide iodides, namely NbOI2 and TaOI2. We observe a comparable THG intensity from both materials. By benchmarking against THG from monolayer WS2, we deduce that the third-order susceptibility is approximately on the same order. THG resonances are revealed at different excitation wavelengths, likely due to enhancement by excitonic states and band edge resonances. The THG intensity increases for material thicknesses up to 30 nm, owing to weak interlayer coupling. After this threshold, it shows saturation or a decrease, due to optical interference effects. Our results establish niobium and tantalum oxide iodides as promising 2D materials for third-order nonlinear optics, with intrinsic in-plane ferroelectricity and thickness-tunable nonlinear efficiency.

The Role of Prostaglandin E2 Synthesized in Rat Lateral Parabrachial Nucleus in LPS-Induced Fever.

INTRODUCTION: The lateral parabrachial nucleus (LPBN) is considered to be a brain site of the pyrogenic action of prostaglandin (PG) E2 outside of the preoptic area. Yet, the role of the LPBN in fever following a systemic immune challenge remains poorly understood. METHODS: We examined the expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) in the LPBN after the intraperitoneal injection of lipopolysaccharide (LPS). We investigated the effects of LPBN NS-398 (COX-2 inhibitor) on LPS-induced fever, the effects of direct LPBN PGE2 administration on the energy expenditure (EE), brown adipose tissue (BAT) thermogenesis, neck muscle electromyographic activity and tail temperature, and the effects of PGE2 on the spontaneous firing activity and thermosensitivity of in vitro LPBN neurons in a brain slice. RESULTS: The COX-2 and mPGES-1 enzymes were upregulated at both mRNA and protein levels. The microinjection of NS-398 in the LPBN attenuated the LPS-induced fever. Direct PGE2 administration in the LPBN resulted in a febrile response by a coordinated response of increased EE, BAT thermogenesis, shivering, and possibly decreased heat loss through the tail. The LPBN neurons showed a clear anatomical distinction in the firing rate response to PGE2, with the majority of PGE2-excited or -inhibited neurons being located in the external lateral or dorsal subnucleus of the LPBN, respectively. However, neither the firing rate nor the thermal coefficient response to PGE2 showed any difference between warm-sensitive, cold-sensitive, and temperature-insensitive neurons in the LPBN. CONCLUSIONS: PGE2 synthesized in the LPBN was at least partially involved in LPS-induced fever via its different modulations of the firing rate of neurons in different LPBN subnuclei.

Effects of Coupling Agent and Thermoplastic on the Interfacial Bond Strength and the Mechanical Properties of Oriented Wood Strand-Thermoplastic Composites.

Wood-plastic composites (WPC) with good mechanical and physical properties are desirable products for manufacturers and customers, and interfacial bond strength is one of the most critical factors affecting WPC performance. To verify that a higher interfacial bond strength between wood and thermoplastics improves WPC performance, wood veneer-thermoplastic composites (VPC) and oriented strand-thermoplastic composites (OSPC) were fabricated using hot pressing. The effects of the coupling agent (KH550 or MDI) and the thermoplastic (LDPE, HDPE, PP, or PVC) on the interfacial bond strength of VPC, and the mechanical and physical properties of OSPC, were investigated. The results showed that coupling agents KH550 and MDI improved the interfacial bond strength between wood and thermoplastics under dry conditions. MDI was better than KH550 at improving the interfacial bond strength and the mechanical properties of OSPC. Better interfacial bonding between plastic and wood improved the OSPC performance. The OSPC fabricated using PVC film as the thermoplastic and MDI as the coupling agent displayed the highest mechanical properties, with a modulus of rupture of 91.9 MPa, a modulus of elasticity of 10.9 GPa, and a thickness swelling of 2.4%. PVC and MDI are recommended to fabricate WPCs with desirable performance for general applications.

[Role of oxotremorine in arginine vasopressin-induced hypothermia and its effects on behavioral thermoregulatory response in rats].

OBJECTIVE: To investigate the role of oxotremorine in arginine vasopressin (AVP)-induced hypothermia and its effects on the behavioral thermoregulatory response. METHODS: Core temperature (Tc), brown adipose tissue (BAT) temperature and motor activities were monitored in undisturbed female SD rats using radiotelemetry. The behavioral thermoregulatory response was monitored in rats using radiotelemetric temperature gradient apparatus. Effect of AVP (10 microg/kg) and oxotremorine (0.25 mg/kg) on Tc, motor activities, BAT temperature (T(BAT)), grooming activities and the behavioral thermoregulatory response were observed in rats. RESULTS: Administration of AVP and oxotremorine caused a significant drop in Tc, T(BAT), and an increases in grooming activities, respectively. The hypothermic responses were accompanied with a preference for cooler ambient temperature. Oxotremorine augmented the reduction of Tc, T(BAT), and the elevation of grooming activities resulting from AVP, and lasting a longer time. Administration of oxotremorine followed immediately by AVP injection in rats was also shown to induce a preference for cooler ambient temperature, but there was no significant difference compared with AVP. CONCLUSION: AVP-induced hypothermia was related with the set point temperature reduction, inhibiton of BAT thermogenesis and an increases in grooming activities. Oxotremorine could participate in peripheral AVP-induced hypothermia by affecting BAT thermogenesis and behavioral thermoregulation.

[Simultaneous telemetric analyzing of the temporal relationship for the changes of the circadian rhythms of brown adipose tissue thermogenesis and core temperature in the rat].

OBJECTIVE: To measure simultaneously the time course for the circadian rhythm of brown adipose tissue(BAT) thermogenesis and core temperature, and analyzing their temporal relationship. METHODS: The circadian rhythm of core temperature (Tc), BAT temperature (T(BAT)), axillary temperature (Tax) and motor activity were simultaneously measured by telemetry in adult male Sprague-Dawley rats at an ambient temperature of 22 degrees C during a 12-h light:12-h dark photoperiod (lights on at 06:00 h and lights off at 18:00 h). RESULTS: (1) T(BAT) was 0.67 degrees C lower than Tc group under the light phase, but it was similar to that Tc during the dark phase. The rate of increase in T(BAT) was higher than corresponding increases in Tc at the start of transition from the light to dark phase, and increase in T(BAT) commenced approximately 8 min before Tc increases. Whereas at the start of transition from the dark to light phase, decrease in T(BAT) commenced approximately 4 min before Tc decreases. (2) The amplitude of the circadian Tax rhythm was similar to that of Tc. During either the light phase or dark phase, Tax was lower than simultaneous measurement of Tc. (3) Increases in behavioral activity commenced before increases in T(BAT) and Tc at the start of transition from the light to dark phase. CONCLUSION: BAT thermogenesis contributes to increase in core temperature during the dark phase, indicating that circadian changes of BAT thermogenesis does indeed play significant role in the overall maintenance of the circadian rhythm of core temperature.

Physostigmine-induced hypothermic response in rats and its relationship with endogenous arginine vasopressin.

AIMS: It is well known that physostigmine (PHY) and other anticholinesterase (anti-ChE) agents induce hypothermia in rodents but little is known about the mechanism of action. Because arginine vasopressin (AVP) has been found to be an endogenous antipyretic molecule in the CNS, we determined if PHY-induced hypothermia is linked to the endogenous release of AVP. MAIN METHODS: Core temperature and motor activity were monitored by telemetry in rats maintained at an ambient temperature of 25 degrees C. Tail skin temperature was also measured at 30min intervals to estimate nonevaporative heat loss. The central cholinergic antagonist, scopolamine (1mg/kg; ip) and an AVP V(1) receptor antagonist (30microg/kg; ip) were administered during the period of PHY (200microg/kg; sc) induced hypothermia at 10am. Plasma AVP concentration and plasma cholinesterase (ChE) activity were measured at 50min after administration of PHY or scopolamine, respectively. KEY FINDINGS: PHY led to a rapid reduction in core temperature concomitant with a marked increase in heat loss from the tail. The hypothermic response of PHY was blocked by the AVP V(1) receptor antagonist. Administration of scopolamine also reversed the hypothermic responses and led to marked elevations in motor activity. Plasma AVP levels increased markedly at 50min after PHY and plasma ChE activity was significantly reduced by PHY. SIGNIFICANCE: The results clearly demonstrate that PHY-induced hypothermia was blocked by the AVP V(1) antagonist and associated with elevations in plasma AVP, suggesting a novel role for AVP in the mechanism of action of anti-ChE agents.