Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope within ...the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, platform technologies based on RNA bacteriophage virus-like particles (VLPs) were used to develop multivalent vaccines targeting the FP8 epitope. Both recombinant MS2 VLPs displaying the FP8 peptide and Qβ VLPs displaying chemically conjugated FP8 peptide induced high titers of FP8-specific antibodies in mice. Moreover, a heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy-inspired by bnAb-guided epitope mapping, VLP bioengineering, and prime-boost immunization approaches-may be a useful strategy for eliciting bnAb responses against HIV.
Transient interactions of platelet-receptor glycoprotein Ibα (GpIbα) and the plasma protein von Willebrand factor (VWF) reduce platelet velocity at sites of vascular damage and play a role in ...haemostasis and thrombosis. Here we present structures of the GpIbα amino-terminal domain and its complex with the VWF domain A1. In the complex, GpIbα wraps around one side of A1, providing two contact areas bridged by an area of solvated charge interaction. The structures explain the effects of gain-of-function mutations related to bleeding disorders and provide a model for shear-induced activation. These detailed insights into the initial interactions in platelet adhesion are relevant to the development of antithrombotic drugs.
N6-methyladenosine (m6A) is among the most abundant post-transcriptional modifications in mRNA, yet its precise cell-type-specific roles in orchestrating gene expression programs remain elusive. ...Although brown and white adipocytes are both considered fat cells, their unique properties underscore the importance of context-specific post-transcriptional regulation for whole-body metabolism. Here, we provide the first evidence that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptomes in brown and white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. We found that human brown and white adipocytes (hBAT and hWAT) display markedly distinct m6A landscapes; besides, in insulin-resistant humans and mice, METTL14 expression differs significantly between the fat depots in the context of correlation with insulin sensitivity. Mettl14-knockout in BAT via Ucp1-cre promotes secretion of specific prostaglandins and improved peripheral insulin sensitivity in mice. Conversely, Mettl14-deficiency in WAT via Adipoq-cre triggers white adipocyte apoptosis, lipodystrophy, and systemic insulin resistance. Integration of m6A-seq and RNA-seq profiling revealed strikingly distinct transcriptomes and m6A methylomes in Mettl14-deficient BAT versus Mettl14-deficient WAT. More specifically, upregulated prostaglandin biosynthesis pathways were enriched in Mettl14-deficient BAT, and TNF-associated and apoptotic pathways were activated in Mettl14-deficient WAT. Using stable METTL14-knockout hBAT or hWAT cell lines, we report that METTL14-mediated m6A negatively regulates gene expression of PTGES2, CBR1, and PGC1a in hBAT, and TRAIL, TNFR1, RIP, and DFFA in hWAT by promoting mRNA decay. These data shed light on the ability of m6A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases. Disclosure L. Xiao: None. D.F. De Jesus: None. C. Ju: None. J. Hu: None. J. Wei: None. A. DiStefano-Forti: None. V.R. Salerno Gonzales: None. T. Tsuji: None. S. Wei: None. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi. Y. Tseng: Other Relationship; Biohaven. Consultant; LyGenesis. C. He: None. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical. Funding This work is supported by NIH grants R01 DK67536 (R.N.K.), UC4 DK116278 (R.N.K. and C.H.), and RM1 HG008935 (C.H.).
Recent developments of transition-edge sensors (TESs), based on extensive experience in ground-based experiments, have been making the sensor techniques mature enough for their application on future ...satellite cosmic microwave background (CMB) polarization experiments. LiteBIRD is in the most advanced phase among such future satellites, targeting its launch in Japanese Fiscal Year 2027 (2027FY) with JAXA’s H3 rocket. It will accommodate more than 4000 TESs in focal planes of reflective low-frequency and refractive medium-and-high-frequency telescopes in order to detect a signature imprinted on the CMB by the primordial gravitational waves predicted in cosmic inflation. The total wide frequency coverage between 34 and 448 GHz enables us to extract such weak spiral polarization patterns through the precise subtraction of our Galaxy’s foreground emission by using spectral differences among CMB and foreground signals. Telescopes are cooled down to 5 K for suppressing thermal noise and contain polarization modulators with transmissive half-wave plates at individual apertures for separating sky polarization signals from artificial polarization and for mitigating from instrumental 1/
f
noise. Passive cooling by using V-grooves supports active cooling with mechanical coolers as well as adiabatic demagnetization refrigerators. Sky observations from the second Sun–Earth Lagrangian point, L2, are planned for 3 years. An international collaboration between Japan, the USA, Canada, and Europe is sharing various roles. In May 2019, the Institute of Space and Astronautical Science, JAXA, selected LiteBIRD as the strategic large mission No. 2.
Abstract Cefiderocol (formerly S-649266) is a new catechol-substituted parenteral siderophore cephalosporin with potent in vitro antibacterial activity against Gram-negative isolates including ...multidrug-resistant strains. A recent study following CLSI M23-A4 quality control guidelines established cefiderocol MIC QC ranges against Escherichia coli ATCC 25922 (0.06–0.5 μg/mL) and Pseudomonas aeruginosa ATCC 27853 (0.06–0.5 μg/mL).
Rheumatoid arthritis is one of the most critical diseases that impair the quality of life of patients, but its pathogenesis has not yet been fully understood. Osteopontin (OPN) is an extracellular ...matrix protein containing Arg-Gly-Asp (RGD) sequence, which interacts with αvβ3 integrins, promotes cell attachment, and cell migration and is expressed in both synovial cells and chondrocytes in rheumatoid arthritis; however, its functional relationship to arthritis has not been known. Therefore, we investigated the roles of OPN in the pathogenesis of inflammatory process in a rheumatoid arthritis model induced by a mixture of anti-type II collagen mAbs and lipopolysaccharide (mAbs/LPS). mAbs/LPS injection induced OPN expression in synovia as well as cartilage, and this expression was associated with joint swelling, destruction of the surface structures of the joint based on scanning electron microscopy, and loss of toluidine blue-positive proteoglycan content in the articular cartilage in wild-type mice. In contrast, OPN deficiency prevented the mice from such surface destruction, loss of proteoglycan in the articular joint cartilage, and swelling of the joints even when the mice were subjected to mAbs/LPS injection. Furthermore, mAbs/LPS injection in wild-type mice enhanced the levels of CD31-positive vessels in synovia and terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive chondrocytes in the articular cartilage, whereas such angiogenesis as well as chondrocyte apoptosis was suppressed significantly in OPN-deficient mice. These results indicated that OPN plays a critical role in the destruction of joint cartilage in the rheumatoid arthritis model in mice via promotion of angiogenesis and induction of chondrocyte apoptosis.
Commercial purity Al was severely deformed by equal channel angular pressing (ECAP) up to eight passes using route B
C. The deformation microstructure was characterized quantitatively by ...electron-backscattered diffraction (EBSD) and transmission electron microscopy (TEM). The microstructural homogeneity was investigated by EBSD at various locations from center to surface of the samples on a longitudinal section parallel to the pressing direction. Structural parameters including mean boundary spacing, boundary misorientation angle and fraction of high angle grain boundaries were measured and characterized through the section of the ECAP samples. EBSD scans revealed a homogeneous ultrafine grained microstructure after 8 passes. The analysis showed that the fraction of high angle grain boundaries was more than 70% at most locations of the sample section. Also, an average boundary spacing of 380 nm was obtained by the linear intercept method. TEM analysis was used for more detailed characterization of the microstructure, such as low angle boundaries with misorientation angles smaller than 2°. Using the structural parameters–flow stress relationship, the flow stress was estimated based on the EBSD and TEM/Kikuchi-line analyses and compared with measured values.
Antioxidant genes such as ferritin are transcriptionally activated in oxidative stress via the antioxidant responsive element (ARE), to which nuclear factor‐E2‐related factor 2 (Nrf2) binds and ...activates transcription. Histone modification plays a cooperative and essential role in transcriptional regulation; however, its role in antioxidant gene transcription remains elusive. Arsenic exposure activated ferritin transcription via the ARE concomitant with increased methylation of histones H4Arg3 (H4R3) and H3Arg17 (H3R17). To test our hypothesis that histone H4R3 and H3R17 methylation regulates ferritin transcription, H4R3 and H3R17 protein arginine (R) methyltransferases 1 and 4 (PRMT1 and PRMT4) were investigated. Arsenic exposure of human HaCaT keratinocytes induced nuclear accumulation of PRMT1 and PRMT4, histone H4R3 and H3R17 methylation proximal to the ARE, but not to the non‐ARE regions of ferritin genes. PRMT1 or PRMT4 knockdown did not block Nrf2 nuclear accumulation but inhibited Nrf2 binding to the AREs by ~40% (P<0.05), thus diminishing ferritin transcription in HaCaT and human primary keratinocytes and fibroblasts, causing enhanced cellular susceptibility to arsenic toxicity as evidenced by 2‐fold caspase 3 activation. Focused microarray further characterized several oxidative stress response genes are subject to PRMT1 or PRMT4 regulation. Collectively, PRMT1 and PRMT4 regulate the ARE and cellular antioxidant response to arsenic.—Huang, B.‐W., Ray, P. D., Iwasaki, K., Tsuji, Y., Transcriptional regulation of the human ferritin gene by coordinated regulation of Nrf2 and protein arginine methyltransferases PRMT1 and PRMT4. FASEB J. 27, 3763–3774 (2013). www.fasebj.org
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