Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal ...profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.
Display omitted
•Weekly metabolome of maternal blood changes dynamically through healthy pregnancy•A metabolic clock of five blood metabolites accurately predicts gestational age•Two to three metabolites identify labor onset within two, four, and eight weeks•Women with metabolic clocks that outpaced ultrasound evaluation tend to deliver earlier
Identification of blood metabolites in pregnant women that can accurately predict gestational age and provide insights into pregnancy variations undetected by ultrasound.
We report a novel strategy for the regulation of charge transport through single molecule junctions via the combination of external stimuli of electrode potential, internal modulation of molecular ...structures, and optimization of anchoring groups. We have designed redox-active benzodifuran (BDF) compounds as functional electronic units to fabricate metal–molecule–metal (m–M–m) junction devices by scanning tunneling microscopy (STM) and mechanically controllable break junctions (MCBJ). The conductance of thiol-terminated BDF can be tuned by changing the electrode potentials showing clearly an off/on/off single molecule redox switching effect. To optimize the response, a BDF molecule tailored with carbodithioate (−CS2 –) anchoring groups was synthesized. Our studies show that replacement of thiol by carbodithioate not only enhances the junction conductance but also substantially improves the switching effect by enhancing the on/off ratio from 2.5 to 8.
Regioselectivity is of fundamental importance in chemical synthesis. Although many concepts for site-selective reactions are well established for solution chemistry, it is not a priori clear whether ...they can easily be transferred to reactions taking place on a metal surface. A metal will fix the chemical potential of the electrons and perturb the electronic states of the reactants because of hybridization. Additionally, techniques to characterize chemical reactions in solution are generally not applicable to on-surface reactions. Only recent developments in resolving chemical structures by atomic force microscopy (AFM) and scanning tunneling microscopy (STM) paved the way for identifying individual reaction products on surfaces. Here we exploit a combined STM/AFM technique to demonstrate the on-surface formation of complex molecular architectures built up from a heteroaromatic precursor, the tetracyclic pyrazino2,3-f4,7phenanthroline (pap) molecule. Selective intermolecular aryl–aryl coupling via dehydrogenative C–H activation occurs on Au(111) upon thermal annealing under ultrahigh vacuum (UHV) conditions. A full atomistic description of the different reaction products based on an unambiguous discrimination between pyrazine and pyridine moieties is presented. Our work not only elucidates that ortho-hydrogen atoms of the pyrazine rings are preferentially activated over their pyridine equivalents, but also sheds new light onto the participation of substrate atoms in metal–organic coordination bonding during covalent C–C bond formation.
Abstract
N-Glycanase 1 (NGLY1) deficiency is a rare and complex genetic disorder. Although recent studies have shed light on the molecular underpinnings of NGLY1 deficiency, a systematic ...characterization of gene and protein expression changes in patient-derived cells has been lacking. Here, we performed RNA-sequencing and mass spectrometry to determine the transcriptomes and proteomes of 66 cell lines representing four different cell types derived from 14 NGLY1 deficient patients and 17 controls. Although NGLY1 protein levels were up to 9.5-fold downregulated in patients compared with parents, residual and likely non-functional NGLY1 protein was detectable in all patient-derived lymphoblastoid cell lines. Consistent with the role of NGLY1 as a regulator of the transcription factor Nrf1, we observed a cell type-independent downregulation of proteasomal genes in NGLY1 deficient cells. In contrast, genes involved in ribosome biogenesis and mRNA processing were upregulated in multiple cell types. In addition, we observed cell type-specific effects. For example, genes and proteins involved in glutathione synthesis, such as the glutamate-cysteine ligase subunits GCLC and GCLM, were downregulated specifically in lymphoblastoid cells. We provide a web application that enables access to all results generated in this study at https://apps.embl.de/ngly1browser. This resource will guide future studies of NGLY1 deficiency in directions that are most relevant to patients.
Graphical Abstract
Graphical Abstract
Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, ...and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.
Display omitted
•NGLY1 neurons develop ProteoStat-positive aggregates that can be partially rescued•Profiling protein aggregates unveils links to other neurodegenerative diseases•NGLY1 phenotypes appear to be predominantly observed in neurons
Manole et al. employ cutting-edge techniques including laser capture microscopy to scrutinize the protein aggregates accumulating in NGLY1-deficient neurons. Their study unveils a significant enrichment of specific proteins associated with neurodegenerative diseases, providing novel insights into the pathological mechanisms underlying NGLY1 deficiency and shedding light on potential therapeutic targets.
Oral squamous cell carcinoma is one of the most common neoplasm in the world. Despite the improvements in diagnosis and treatment, the outcome is still poor now. Thus, the development of novel ...therapeuticapproaches is needed. The aim of this study is to assess the synergistic anti-tumor effect of andrographolide with cisplatin (DDP) in oral squamous cell carcinoma CAL-27 cells in vitro and in vivo. We performed Cell Counting Kit-8 proliferation assay, apoptosis assay, and western blotting on CAL-27 cells treated with andrographolide, DDP or the combination in vitro. In vivo, we also treated CAL-27 xenografts with andrographolide or the combination, and performed terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay and immunohistochemical analysis of Ki-67. The results showed the combination of andrographolide and DDP synergistically inhibited CAL-27 cell proliferation in vitro and caused tumor regression in vivo in the CAL-27 xenografts. In addition, the synergistic anti-tumor effect of andrographolide with synergistic was due to an enhanced apoptosis. Moreover, the combination therapy upregulated the expression level of p-p53 in vitro and decreased Ki-67 expression in vivo. Our data indicate that the combination treatment of andrographolide and DDP results in synergistic anti-tumor growth activity against oral squamous cell carcinoma CAL-27 in vitro and in vivo. These results demonstrated that combination of andrographolide with DDP was likely to represent a potential therapeutic strategy for oral squamous cell carcinoma.
The Zika virus is responsible for neurological diseases such as microcephaly, Guillain-Barré syndrome, neuropathy, and myelitis in human adults and children. Previous studies have shown that the Zika ...virus can infect nerve progenitor cells and interfere with neural development. However, it is unclear how the immune system responds to infection with Zika viruses with variable pathogenicity. Here, we used two Zika strains with relatively different pathogenicity, the Asian ancestral strain CAM/2010 and the America pandemic strain GZ01/2016, to infect the brains of mice. We found that both strains elicited a strong immune response. Notably, the strain with relatively high pathogenicity, GZ01/2016, caused more intense immune regulation, with stronger CD8+ T cell and macrophage activation at 14 days post infection (dpi), as well as a greater immune gene disturbance. Notably, several TNF family genes were upregulated at 14 dpi, including Tnfrsf9, Tnfsf13, Tnfrsf8, Cd40, and Tnfsf10. It was notable that GZ01/2016 could maintain the survival of nerve cells at 7dpi but caused neurological disorders at 14dpi. These results indicate that Zika viruses with high pathogenicity may induce sustained activation of the immune system leading to nerve tissue damage.
Benzodifuran (BDF) single-molecule transistors have been fabricated in electromigration break junctions for electronic measurements. The inelastic electron tunneling spectrum validates that the BDF ...molecule is the pathway of charge transport. The gating effect is analyzed in the framework of a single-level tunneling model combined with transition voltage spectroscopy (TVS). The analysis reveals that the highest occupied molecular orbital (HOMO) of the thiol-terminated BDF molecule dominates the charge transport through Au-BDF-Au junctions. Moreover, the energy shift of the HOMO caused by the gate voltage is the main reason for conductance modulation. In contrast, the electronic coupling between the BDF molecule and the gold electrodes, which significantly affects the low-bias junction conductance, is only influenced slightly by the applied gate voltage. These findings will help in the design of future molecular electronic devices.
In order to solve the problems of grouting diffusion and invisible formation process in shield slurry film forming test, transparent soil and transparent slurry were introduced to carry out shield ...mud film test based on shield grouting model. Using laser imaging combined with CCD camera (high-speed industrial camera) rapid capture photography technology, through a series of visible physical model tests of slurry diffusion and mud film development under different working conditions, the temporal and spatial conditions of slurry diffusion were observed and recorded in real time to explore the slurry diffusion law and the formation mechanism of mud film in slurry shield excavation face.The phenomenon shows that the smaller the grouting pressure is, the more favorable the formation of mud film is.The mud penetration distance is generally proportional to the grouting pressure.The infiltration distance of the grout increases with time, and the infiltration distance of the grout is similar at each moment under the same grouting pressure. The leachate volume and time show a quadratic function roughly under the same density and mud pressure, and the increase rate of the leachate volume begins to slow down with time.
A tandem directed metalation has been successfully applied to the preparation of thieno2,3-fbenzofuran-4,8-dione, providing an efficient and facile approach to symmetrically and unsymmetrically ...functionalize the thieno2,3-fbenzofuran core at the 2,6 positions as well as to introduce the electron-withdrawing or -donating groups (EWG or EDG) at its 4,8 positions. The presence of various functional groups makes late-stage derivatization attainable.
PDF
