Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because ...they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
Metallic glasses (MGs) with the metastable nature and random atomic packing structure have attracted large attention in the catalytic family due to their superior catalytic performance. In contrast, ...their crystalline counterparts are restricted by the highly ordered packing structure, fewer surface active sites, and crystallographic defects for catalytic activity. The uncertainty of the different catalytic mechanisms and the intrinsic characteristics correlated to MGs and their crystalline counterparts become a major impediment to promote their catalytic efficiencies and widespread applications. Herein, it is reported that the excellent catalytic behavior in Fe‐based MGs goes through a detrimental effect with the partial crystallization, but receives a compelling rejuvenation in the full crystallization. Further investigation reveals that multiphase intermetallics with electric potential differences in fully crystallized alloys facilitate the formation of galvanic cells. More importantly, extensively reduced grain boundaries due to grain growth greatly weaken electron trapping and promote inner electron transportation. The relatively homogenous grain‐boundary corrosion in the intermetallics contributes to well‐separated phases after reaction, leading to refreshment of the surface active sites, thereby quickly activating hydrogen peroxide and rapidly degrading organic pollutants. The exploration of catalytic mechanisms in the crystalline counterparts of MGs provides significant insights into revolutionize novel catalysts.
Fully crystallized alloys gained by annealing of metallic glasses show excellent rejuvenated catalytic capabilities for ultrafast activation of peroxide. As galvanic cells form in the fully crystallized alloys, a grain growth contributing to extensively reduced grain boundaries greatly weakens electron trapping and promotes inner electron transportation, providing a significant insight into exploit novel catalysts.
Drug resistance and new therapies in colorectal cancer Van der Jeught, Kevin; Xu, Han-Chen; Li, Yu-Jing ...
World journal of gastroenterology : WJG,
2018-Sep-14, 2018-9-14, 20180914, Volume:
24, Issue:
34
Journal Article
Open access
Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for ...these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.
Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress ...to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients.
From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores.
Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation.
LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.
RIPK3 amyloid complex plays crucial roles during TNF-induced necroptosis and in response to immune defense in both human and mouse. Here, we have structurally characterized mouse RIPK3 homogeneous ...self-assembly using solid-state NMR, revealing a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register β-sheets. This structure differs from previously published human RIPK1/RIPK3 hetero-amyloid complex structure, which adopted a serpentine fold. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for TNF-induced necroptosis. The structural integrity of RIPK3 fibril with three β-strands is necessary for signaling. Molecular dynamics simulations with a mouse RIPK1/RIPK3 model indicate that the hetero-amyloid is less stable when adopting the RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation would provide the missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.
A significant advance toward achieving practical applications of graphene as a two-dimensional material in nanoelectronics would be provided by successful synthesis of both n-type and p-type doped ...graphene. However, reliable doping and a thorough understanding of carrier transport in the presence of charged impurities governed by ionized donors or acceptors in the graphene lattice are still lacking. Here we report experimental realization of few-layer nitrogen-doped (N-doped) graphene sheets by chemical vapor deposition of organic molecule 1,3,5-triazine on Cu metal catalyst. When reducing the growth temperature, the atomic percentage of nitrogen doping is raised from 2.1% to 5.6%. With increasing doping concentration, N-doped graphene sheet exhibits a crossover from p-type to n-type behavior accompanied by a strong enhancement of electron-hole transport asymmetry, manifesting the influence of incorporated nitrogen impurities. In addition, by analyzing the data of X-ray photoelectron spectroscopy, Raman spectroscopy, and electrical measurements, we show that pyridinic and pyrrolic N impurities play an important role in determining the transport behavior of carriers in our N-doped graphene sheets.
An efficient and versatile oxidative coupling reaction was developed for the synthesis of valuable β‐functionalized unsaturated ketones and meta‐substituted phenols. In the case of intramolecular ...reactions, achieving rapid molecular complexity through multiple dehydrogenative couplings is already a well‐established strategy. Herein, we report an intermolecular multiple dehydrogenative coupling between ketones and nucleophilic amines or boronic acids using inexpensive copper(I) oxide as a catalyst. This method provides a facile access to highly desirable chemical products such as α,β‐unsaturated ketones, enaminones, and synthetically relevant meta‐substituted phenols.
•Toujie Quwen Granules play an important role in the treatment of COVID-19.•SARS-CoV-2 3CL hydrolase, RdRP, ACE2, IL-6 and S protein are the crucial enzymes for treating COVID-19.•Molecular docking ...revealed the proposed binding characteristics between five enzymes and quercetin, calycosin, astragaloside IV, rutin, isoquercitrin.•Contrary to rutin and astragaloside IV, quercetin and isoquercitrin bound to Spike protein rather than ACE2.
The Coronavirus disease 2019 pneumonia broke out in 2019 (COVID-19) and spread rapidly, which causes serious harm to the health of people and a huge economic burden around the world.
In this study, the network pharmacology, molecular docking and surface plasmon resonance technology (SPR) were used to explore the potential compounds and interaction mechanism in the Toujie Quwen Granules (TQG) for the treatment of coronavirus pneumonia 2019.
The chemical constituents and compound targets of Lonicerae Japonicae Flos, Pseudostellariae Radix, Artemisia Annua L, Peucedani Radix, Forsythiae Fructus, Scutellariae Radix, Hedysarum Multijugum Maxim, Isatidis Folium, Radix Bupleuri, Fritiliariae Irrhosae Bulbus, Cicadae Periostracum, Poria Cocos Wolf, Pseudobulbus Cremastrae Seu Pleiones, Mume Fructus, Figwort Root and Fritillariae Thunbrgii Bulbus in TQG were searched. The target name was translated to gene name using the UniProt database and then the Chinese medicine-compound-target network was constructed. Protein-protein interaction network (PPI), Gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the core targets were performed in the Metascape to predict its mechanism. The top 34 compounds in the Chinese medicine-compound-target network were docked with SARS-CoV-2 3CL enzyme and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and then the 13 compounds with lowest affinity score were docked with angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 Spike protein and interleukin 6 to explore its interaction mechanism. Lastly, SPR experiments were done using the quercetin, astragaloside IV, rutin and isoquercitrin, which were screened from the Chinese medicine-compound-target network and molecular docking.
The Chinese medicine-compound-target network includes 16 medicinal materials, 111 compounds and 298 targets, in which the degree of PTGS2, TNF and IL6 is higher compared with other targets and which are the disease target exactly. The result of GO function enrichment analysis included the response to the molecule of bacterial origin, positive regulation of cell death, apoptotic signaling pathway, cytokine-mediated signaling pathway, cytokine receptor binding and so on. KEGG pathway analysis enrichment revealed two pathways: signaling pathway IL-17 and signaling pathway TNF. The result of molecular docking showed that the affinity score of compounds including quercetin, isoquercitrin, astragaloside IV and rutin is higher than other compounds. In addition, the SPR experiments revealed that the quercetin and isoquercitrin were combined with SARS-CoV-2 Spike protein rather than Angiotensin-converting enzyme 2, while astragaloside IV and rutin were combined with ACE2 rather than SARS-CoV-2 Spike protein.
TQG may have therapeutic effects on COVID-19 by regulating viral infection, immune and inflammation related targets and pathways, in the way of multi-component, multi-target and multi-pathway.
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The specific states of aggregation of metal atoms in sub‐nanometer‐sized gold clusters are related to the different quantum confinement volumes of electrons, leading to novel optical and electronic ...properties. These volumes can be tuned by changing the relative positions of the gold atoms to generate isomers. Studying the isomeric gold core and the electron coupling between the basic units is fundamentally important for nanoelectronic devices and luminescence; however, appropriate cases are lacking. In this study, the structure of the first staggered di‐superatomic Au25‐S was solved using single‐crystal X‐ray diffraction. The optical properties of Au25‐S were studied by comparing with eclipsed Au25‐E. From Au25‐E to Au25‐S, changes in the electronic structures occurred, resulting in significantly different optical absorptions originating from the coupling between the two Au13 modules. Au25‐S shows a longer electron decay lifetime of 307.7 ps before populating the lowest triplet emissive state, compared to 1.29 ps for Au25‐E. The experimental and theoretical results show that variations in the geometric isomerism lead to distinct photophysical processes owing to isomerism‐dependent electronic coupling. This study offers new insights into the connection between the geometric isomerism of nanosized building blocks and the optical properties of their assemblies, opening new possibilities for constructing function‐specific nanomaterials.
The first completely staggered configuration of a di‐superatomic Au25 cluster was solved with atomic precision. The significant torsion angle induces changes in electron coupling and complicates the relaxation pathway of electrons in the excited state when compared with the parallel eclipsed configuration.
Fabricating high-performance MXene-based polymer nanocomposites is a huge challenge because of the poor dispersion and interfacial interaction of MXene nanosheets in the polymer matrix. To address ...the issue, MXene nanosheets were successfully exfoliated and subsequently modified by long-chain cationic agents with different chain lengths, i.e., decyltrimethylammonium bromide (DTAB), octadecyltrimethylammonium bromide (OTAB), and dihexadecyldimethylammonium bromide (DDAB). With the long-chain groups on their surface, modified Ti
C
(MXene) nanosheets were well dispersed in
,
-dimethylformamide (DMF), resulting in the formation of uniform dispersion and strong interfacial adhesion within a polystyrene (PS) matrix. The thermal stability properties of cationic modified Ti
C
/PS nanocomposites were improved considerably with the temperatures at 5% weight loss increasing by 20 °C for DTAB-Ti
C
/PS, 25 °C for OTAB-Ti
C
/PS and 23 °C for DDAB-Ti
C
/PS, respectively. The modified MXene nanosheets also enhanced the flame-retardant properties of PS. Compared to neat PS, the peak heat release rate (PHRR) was reduced by approximately 26.4%, 21.5% and 20.8% for PS/OTAB-Ti
C
, PS/DDAB-Ti
C
and PS/DTAB-Ti
C
, respectively. Significant reductions in CO and CO
productions were also obtained in the cone calorimeter test and generally lower pyrolysis volatile products were recorded by PS/OTAB-Ti
C
compared to pristine PS. These property enhancements of PS nanocomposites are attributed to the superior dispersion, catalytic and barrier effects of Ti
C
nanosheets.
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