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Background: Inflammation serves as a key pathologic mediator in the progression of infections and various diseases, involving significant alterations in the gut microbiome and metabolism. This study aims to probe into the potential causal relationships between gut microbial taxa and human blood metabolites with various serum inflammatory markers (CRP, SAA1, IL-6, TNF-α, WBC, and GlycA) and the risks of seven common infections (gastrointestinal infections, dysentery, pneumonia, bacterial pneumonia, bronchopneumonia and lung abscess, pneumococcal pneumonia, and urinary tract infections). Methods: Two-sample Mendelian randomization (MR) analysis was performed using inverse variance weighted (IVW), maximumlikelihood, MR-Egger, weighted median, and MR-PRESSO. Results: After adding other MRmodels and sensitivity analyses, genus Roseburia was simultaneously associated adversely with CRP (Beta IVW = -0.040) and SAA1 (Beta IVW = -0.280), and family Bifidobacteriaceae was negatively associated with both CRP (Beta IVW = -0.034) and pneumonia risk (Beta IVW = -0.391). After correction by FDR, only glutaroyl carnitine remained significantly associated with elevated CRP levels (Beta IVW = 0.112). Additionally, threonine (Beta IVW = 0.200) and 1-heptadecanoylglycerophosphocholine (Beta IVW = -0.246) were found to be significantly associated with WBC levels. Three metabolites showed similar causal effects on different inflammatory markers or infectious phenotypes, stearidonate (18:4n3) was negatively related to SAA1 and urinary tract infections, and 5-oxoproline contributed to elevated IL-6 and SAA1 levels. In addition, 7-methylguanine showed a positive correlation with dysentery and bacterial pneumonia. Conclusion: This study provides novel evidence confirming the causal effects of the gut microbiome and the plasma metabolite profile on inflammation and the risk of infection. These potential molecular alterations may aid in the development of new targets for the intervention and management of disorders associated with inflammation and infections. [ABSTRACT FROM AUTHOR]

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMPGMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, over expression of cGAS-STING, or SAVI STING mutants. In Trex1−/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease. [ABSTRACT FROM AUTHOR]

The dislocation density in AlGaN epitaxial layers with Al content as high as 45% grown on sapphire substrates has been effectively reduced by introducing an in-situ deposited SiNx nanomask layer in this study. By closely monitoring the evolution of numerous material properties, such as surface morphology, dislocation density, photoluminescence, strain states, and electron mobility of the Si-Al0.45Ga0.55N layers as the functions of SiNx interlayer growth time, the surface coverage fraction of SiNx is found to be a crucial factor determining the strain states and dislocation density. The dependence of the strain states and the dislocation density on the surface coverage fraction of SiNx nanomask supports the very different growth models of Al-rich AlGaN on SiNx interlayer due to the reduced nucleation selectivity compared with the GaN counterpart. Compared with GaN, which can only nucleate at open pores of SiNx nanomask, Al-rich AlGaN can simultaneously nucleate at both open pores and SiNx covered areas. Dislocations will annihilate at the openings due to the 3D growth initiated on the opening area, while 2D growth mode is preserved on SiNx and the threading dislocations are also preserved. During the following growth process, lateral overgrowth will proceed from the Al0.45Ga0.55N islands on the openings towards the regions covered by SiNx, relaxing the compressive strain and bending the dislocations at the same time. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons of the substantia nigra (SN) play a vital role in everyday tasks, such as reward-related behavior and voluntary movement, and excessive loss of these neurons is a primary hallmark of Parkinson's disease (PD). Mitochondrial dysfunction has long been implicated in PD and many animal models induce parkinsonian features by disrupting mitochondrial function. MitoPark mice are a recently developed genetic model of PD that lacks the gene for mitochondrial transcription factor A specifically in dopaminergic neurons. This model mimics many distinct characteristics of PD including progressive and selective loss of SN dopamine neurons, motor deficits that are improved by L-DOPA, and development of inclusion bodies. Here, we used brain slice electrophysiology to construct a timeline of functional decline in SN dopaminergic neurons from MitoPark mice. Dopaminergic neurons from MitoPark mice exhibited decreased cell capacitance and increased input resistance that became more severe with age. Pacemaker firing regularity was disrupted in MitoPark mice and ion channel conductances associated with firing were decreased. Additionally, dopaminergic neurons from MitoPark mice showed a progressive decrease of endogenous dopamine levels, decreased dopamine release, and smaller D2 dopamine receptor-mediated outward currents. Interestingly, expression of ion channel subunits associated with impulse activity (Cavl.2, Cavl.3, HCN1, Navl.2, and NavB3) was upregulated in older MitoPark mice. The results describe alterations in intrinsic and synaptic properties of dopaminergic neurons in MitoPark mice occurring at ages both before and concurrent with motor impairment. These findings may help inform future investigations into treatment targets for prodromal PD. [ABSTRACT FROM AUTHOR]

Copper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deicient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1 mice show that Atox1-/- in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease. [ABSTRACT FROM AUTHOR]

Spherical Bi2S3 nanoparticles (NPs) were prepared by a facile in situ thermal sulfuration method. Different Bi2S3 samples were obtained by controlling the sulfuration time. The products were characterized by X-ray diffractometer (XRD), scanning electron microscopy (SEM), Raman and Fourier-transform infrared (FT-IR) methods. The optical properties were examined by UV-visible-near-infrared (UV-Vis–NIR) and photoluminescence (PL) techniques. The results show that the phase of the products after sulfuration is pure and the spherical shape of Bi NPs has been successfully transmitted to Bi2S3 samples. The light absorption edges exhibit red shift to 1060 nm while the light emission displays blue shift to 868 nm, compared with the energy bandgap of bulk Bi2S3. The reason for the special optical properties of Bi2S3 NPs by this in situ sulfuration route is considered to associate with the defects and quantum size effect of NPs. [ABSTRACT FROM AUTHOR]

Mutations in parkin, an E3 ubiquitin ligase, are the most common cause of autosomal-recessive Parkinson's disease (PD). Here, we show that the stress-signaling non-receptor tyrosine kinase c-Abl links parkin to sporadic forms of PD via tyrosine phosphorylation. Under oxidative and dopaminergic stress, c-Abl was activated in cultured neuronal cells and in striatum of adult C57BL/6 mice. Activated c-Abl was found in the striatum of PD patients. Concomitantly, parkin was tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activities, and the accumulation of parkin substrates,AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2) (p38/JTV-1) and FBP-1.STI-571, a selective c-Abl inhibitor, prevented tyrosine phosphorylation of parkin and restored its E3 ligase activity and cytoprotective function both in vitro and in vivo. Our results suggest that tyrosine phosphorylation of parkin by c-Abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic PD. Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression. [ABSTRACT FROM AUTHOR]

In pituitary cells, c-fos transcription induced by releasing hormones and growth factors results from enhanced initiation of transcription, and sustained elongation of transcripts beyond the first intron. We studied the regulatory role of the first intron of the mouse c-fos gene for the control of its transcription in rat pituitary cells. We showed that the intron contains a block to elongation which is relieved by physiological activators TRH and EGF. By expressing luciferase under the control of the c-fos promoter including the first intron in reporter gene constructs, we demonstrate enhancement of TRH and EGF transcriptional stimulation by intron sequences. Further analysis of Ca[sup 2+] signalling-depending transcription showed that the intron contains control elements in addition to the block to elongation, and that sequences in the first intron can mediate Ca[sup 2+] -stimulated transcription also with a minimal or the SV40 promoter, irrespective of the presence or absence of the intronic block site. Within the c-fos promoter the serum response element and the cAMP response element play a permissive role in Ca[sup 2+] - and cAMP-enhanced transcription of intron containing reporter genes. Specific binding of nuclear proteins to a consensus enhancer binding site (Sp1) within the first intron of c-fos was demonstrated, which might reflect one of the mechanisms that link Ca[sup 2+] and intron sequences to c-fos expression. These findings point towards important functions of intronic sequences in gene transcription control.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

An effective approach for growing large-scale, uniformly aligned ZnO nanorods arrays is demonstrated. The synthesis uses a GaN quantum dot (QD) template produced by a self-assembled Stranski–Krastanow mode in metal organic chemical vapor deposition, which serves as a nucleation site for ZnO owing to the QD’s high surface free energy. The resultant ZnO nanorods with uniform shape and length align vertically on the template, while their density is easily tunable by adjusting the density of GaN QDs, which can be adjusted by simply varying growth interruption. By controlling the density of ZnO nanorod arrays, their optical performance can also be improved. This approach opens the possibility of combining one-dimensional (1D) with 0D nanostructures for applications in sensor arrays, piezoelectric antenna arrays, optoelectronic devices, and interconnects. [ABSTRACT FROM AUTHOR]

Low defect concentration few-layer graphene (FLG) sheets were fabricated by a two-step electrochemical intercalation exfoliation, including a graphite foil pretreatment in sodium hydroxide solution and a subsequent further exfoliation in sulfuric acid solution. During the process, the pretreatment results in the expansion of the graphite foil and in turn facilitates the final exfoliation in sulfuric acid solution. The results show that the ID/IG of the obtained FLG sheets is as low as 0.29 while maintaining relatively high yield, more than 56%. In addition, the oxygen content in the FLG sheets is 8.32% with the C/O ratio of 11.02. [ABSTRACT FROM AUTHOR]