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Owing to the inevitable loss in communication channels, the distance of entanglement distribution is limited to approximately 100 kilometres on the ground1. Quantum repeaters can circumvent this problem by using quantum memory and entanglement swapping2. As the elementary link of a quantum repeater, the heralded distribution of two-party entanglement between two remote nodes has only been realized with built-in-type quantum memories3-9. These schemes suffer from the trade-off between multiplexing capacity and deterministic properties and hence hinder the development of efficient quantum repeaters. Quantum repeaters based on absorptive quantum memories can overcome such limitations because they separate the quantum memories and the quantum light sources. Here we present an experimental demonstration of heralded entanglement between absorptive quantum memories. We build two nodes separated by 3.5 metres, each containing a polarization-entangled photon-pair source and a solid-state quantum memory with bandwidth up to 1 gigahertz. A joint Bell-state measurement in the middle station heralds the successful distribution of maximally entangled states between the two quantum memories with a fidelity of 80.4 ± 2.2 per cent (±1 standard deviation). The quantum nodes and channels demonstrated here can serve as an elementary link of a quantum repeater. Moreover, the wideband absorptive quantum memories used in the nodes are compatible with deterministic entanglement sources and can simultaneously support multiplexing, which paves the way for the construction of practical solid-state quantum repeaters and high-speed quantum networks.
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It is well-known that highly reactive hydroxyl radicals (HOâ¢) can be produced by the classic Fenton system and our recently discovered haloquinone/H2O2 system, but rarely from thiol-derivatives. Here, we found, unexpectedly, that HO⢠can be generated from H2O2 and thiourea dioxide (TUO2), a widely used and environmentally friendly bleaching agent. A carbon-centered radical and sulfite were detected and identified as the transient intermediates, and urea and sulfate as the final products, with the complementary application of electron spin-trapping, oxygen-18 isotope labeling coupled with HPLC/MS analysis. Density functional theory calculations were conducted to further elucidate the detailed pathways for HO⢠production. Taken together, we proposed that the molecular mechanism for HO⢠generation by TUO2/H2O2: TUO2 tautomerizes from sulfinic acid into ketone isomer (TUO2-K) through proton transfer, then a nucleophilic addition of H2O2 on the S atom of TUO2-K, forming a S-hydroperoxide intermediate TUO2-OOH, which dissociates homolytically to produce HOâ¢. Our findings represent the first experimental and computational study on an unprecedented new molecular mechanism of HO⢠production from simple thiol-derived sulfinic acids, which may have broad chemical, environmental, and biomedical significance for future research on the application of the well-known bleaching agent and its analogs.
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Microdroplets are a class of soft matter that has been extensively employed for chemical, biochemical, and industrial applications. However, fabricating microdroplets with largely controllable contact-area shape and apparent contact angle, a key prerequisite for their applications, is still a challenge. Here, by engineering a type of surface with homocentric closed-loop microwalls/microchannels, we can achieve facile size, shape, and contact-angle tunability of microdroplets on the textured surfaces by design. More importantly, this class of surface topologies (with universal genus value = 1) allows us to reveal that the conventional Gibbs equation (widely used for assessing the edge effect on the apparent contact angle of macrodroplets) seems no longer applicable for water microdroplets or nanodroplets (evidenced by independent molecular dynamics simulations). Notably, for the flat surface with the intrinsic contact angle ~0°, we find that the critical contact angle on the microtextured counterparts (at edge angle 90°) can be as large as >130°, rather than 90° according to the Gibbs equation. Experiments show that the breakdown of the Gibbs equation occurs for microdroplets of different types of liquids including alcohol and hydrocarbon oils. Overall, the microtextured surface design and topological wetting states not only offer opportunities for diverse applications of microdroplets such as controllable chemical reactions and low-cost circuit fabrications but also provide testbeds for advancing the fundamental surface science of wetting beyond the Gibbs equation.
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Maize and rice were domesticated from their wild progenitors independently. Whether their convergent phenotypic selection was driven by conserved molecular changes remains unclear. We discuss the implications of a recent genome-wide study of convergently selected maize and rice genes showing that maize KERNEL ROW NUMBER2 (KRN2) and its rice ortholog experienced convergent selection.
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Estudio de Asociación del Genoma Completo , Oryza , Alelos , Oryza/genética , Zea mays/genéticaRESUMEN
Bat coronavirus RaTG13 shares about 96.2% nucleotide sequence identity with that of SARS-CoV-2 and uses human and Rhinolophus affinis (Ra) angiotensin-converting enzyme 2 (ACE2) as entry receptors. Whether there are bat species other than R. affinis susceptible to RaTG13 infection remains elusive. Here, we show that, among 18 different bat ACE2s tested, only RaACE2 is highly susceptible to transduction by RaTG13 S pseudovirions, indicating that the bat species harboring RaTG13 might be very limited. RaACE2 has seven polymorphic variants, RA-01 to RA-07, and they show different susceptibilities to RaTG13 S pseudovirions transduction. Sequence and mutagenesis analyses reveal that residues 34, 38, and 83 in RaACE2 might play critical roles in interaction with the RaTG13 S protein. Of note, RaACE2 polymorphisms have minimal effect on S proteins of SARS-CoV-2 and several SARS-CoV-2 related CoVs (SC2r-CoVs) including BANAL-20-52 and BANAL-20-236 in terms of binding, membrane fusion, and pseudovirus entry. Further mutagenesis analyses identify residues 501 and 505 in S proteins critical for the recognition of different RaACE2 variants and pangolin ACE2 (pACE2), indicating that RaTG13 might have not been well adapted to R. affinis bats. While single D501N and H505Y changes in RaTG13 S protein significantly enhance the infectivity and minimize the difference in susceptibility among different RaACE2 variants, an N501D substitution in SARS-CoV-2 S protein displays marked disparity in transduction efficiencies among RaACE2 variants with a significant reduction in infectivity on several RaACE2 variants. Finally, a T372A substitution in RaTG13 S protein not only significantly increases infectivity on all RaACE2 variants, but also markedly enhances entry on several bat ACE2s including R. sinicus YN, R. pearsonii, and R. ferrumeiqunum. However, the T372A mutant is about 4-fold more sensitive to neutralizing sera from mice immunized with BANAL-20-52 S, suggesting that the better immune evasion ability of T372 over A372 might contribute to the natural selective advantage of T372 over A372 among bat CoVs. Together, our study aids a better understanding of coronavirus entry, vaccine design, and evolution.
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COVID-19 , Quirópteros , Animales , Ratones , Humanos , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2 , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). This study aimed to investigate the potential effects of exogenous skeletal stem cells (SSCs) on the necroptosis of subchondral osteoblasts in OA. Human SSCs and subchondral osteoblasts isolated from human tibia plateaus were used for Western blotting, real-time PCR, RNA sequencing, gene editing, and necroptosis detection assays. In addition, the rat anterior cruciate ligament transection OA model was used to evaluate the effects of SSCs on osteoblast necroptosis in vivo. The micro-CT and pathological data showed that intra-articular injections of SSCs significantly improved the microarchitecture of subchondral trabecular bones in OA rats. Additionally, SSCs inhibited the necroptosis of subchondral osteoblasts in OA rats and necroptotic cell models. The results of bulk RNA sequencing of SSCs stimulated or not by tumor necrosis factor α suggested a correlation of SSCs-derived tumor necrosis factor α-induced protein 3 (TNFAIP3) and cell necroptosis. Furthermore, TNFAIP3-derived from SSCs contributed to the inhibition of the subchondral osteoblast necroptosis in vivo and in vitro. Moreover, the intra-articular injections of TNFAIP3-overexpressing SSCs further improved the subchondral trabecular bone remodeling of OA rats. Thus, we report that TNFAIP3 from SSCs contributed to the suppression of the subchondral osteoblast necroptosis, which suggests that necroptotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.
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Osteoartritis , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Animales , Humanos , Ratas , Necroptosis , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/terapia , Osteoblastos/metabolismo , Osteoblastos/patología , Células Madre/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.
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Carcinoma Hepatocelular , MicroARNs , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Carcinoma Hepatocelular/patología , Transducción de Señal/fisiología , MicroARNs/genética , MicroARNs/metabolismo , Macrófagos/metabolismo , Línea Celular Tumoral , Microambiente Tumoral/genéticaRESUMEN
Although CRISPR/Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate DNA oligos (PS), one can efficiently deliver single and bi-specific CRISPR/Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.
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The fabrication of solid-state proton-conducting electrolytes possessing both high performance and long-life reusability is significant but challenging. An "all-in-one" composite, H3PO4@PyTFB-1-SO3H, including imidazole, sulfonic acid, and phosphoric acid, which are essential for proton conduction, was successfully prepared by chemical post-modification and physical loading in the rationally pre-synthesized imidazole-based nanoporous covalent organic framework (COF), PyTFB-1. The resultant H3PO4@PyTFB-1-SO3H exhibits superhigh proton conductivity with its value even highly up to 1.15 × 10-1 S cm-1 at 353 K and 98% relative humidity (RH), making it one of the highest COF-based composites reported so far under the same conditions. Experimental studies and theoretical calculations further confirmed that the imidazole and sulfonic acid groups have strong interactions with the H3PO4 molecules and the synergistic effect of these three groups dramatically improves the proton conductivity properties of H3PO4@PyTFB-1-SO3H. This work demonstrated that by aggregating multiple proton carriers into one composite, effective proton-conducting electrolyte can be feasibly achieved.
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Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8 weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2 h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SIRS males. Compared to group-housed counterparts, SIRS males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SIRS males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SIRS male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SIRS). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SIRS males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.
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Agresión , Inhibidores de Histona Desacetilasas , Ratones Endogámicos C57BL , Corteza Prefrontal , Aislamiento Social , Estrés Psicológico , Animales , Masculino , Inhibidores de Histona Desacetilasas/farmacología , Aislamiento Social/psicología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Agresión/efectos de los fármacos , Ratones , Depsipéptidos/farmacología , Piridinas/farmacología , Benzamidas/farmacología , Restricción Física , Transmisión Sináptica/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Células Piramidales/metabolismoRESUMEN
High-altitude pulmonary edema (HAPE) is a fatal threat for sojourners who ascend rapidly without sufficient acclimatization. Acclimatized sojourners and adapted natives are both insensitive to HAPE but have different physiological traits and molecular bases. In this study, based on GSE52209, the gene expression profiles of HAPE patients were compared with those of acclimatized sojourners and adapted natives, with the common and divergent differentially expressed genes (DEGs) and their hub genes identified, respectively. Bioinformatic methodologies for functional enrichment analysis, immune infiltration, diagnostic model construction, competing endogenous RNA (ceRNA) analysis and drug prediction were performed to detect potential biological functions and molecular mechanisms. Next, an array of in vivo experiments in a HAPE rat model and in vitro experiments in HUVECs were conducted to verify the results of the bioinformatic analysis. The enriched pathways of DEGs and immune landscapes for HAPE were significantly different between sojourners and natives, and the common DEGs were enriched mainly in the pathways of development and immunity. Nomograms revealed that the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE in both sojourners and natives, which was further validated in the HAPE rat model. The addition of TNF-α and RPLP0 knockdown activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. In conclusion, TNF-α and RPLP0 are shared biomarkers and molecular bases for HAPE susceptibility during the acclimatization/adaptation/maladaptation processes in sojourners and natives, inspiring new ideas for predicting and treating HAPE.
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The Bacteriophage Exclusion (BREX) system is a novel antiphage defense system identified in Bacillus cereus in 2015. The purpose of this study was to investigate the presence of the BREX system defenses against antibiotic-resistant plasmids such as blaKPC and blaNDM invasion in Escherichia coli. The BREX system was present in 5.4% (23/424) of E. coli clinical isolates and 6.5% (84/1283) of E. coli strains with completely sequenced genomes in the GenBank database. All 23 BREX-positive E. coli clinical isolates were susceptible to carbapenems, while all five isolates carrying blaKPC and 11 carrying blaNDM were BREX-negative. For E. coli strains in the GenBank database, 37 of 38 strains carrying blaKPC and 109 of 111 strains carrying blaNDM were BREX negative. The recognition site sequence of methyltransferase PglX in a clinical E. coli 3756 was 5'-CANCATC-3' using PacBio single-molecular real-time sequencing. The transformation efficiency of plasmid psgRNA-ColAori-target with the PglX recognition site was reduced by 100% compared with the plasmid without the recognition site in E. coli DH5α-pHSG398-BREX. The BREX showed lower defense efficacy against plasmid psgRNA-15Aori-target which had the same plasmid backbone but different surrounding sequences of recognition sites with psgRNA-ColAori-target. The conjugation frequency of the KPC-2 plasmid and NDM-5 plasmid in E. coli 3756-ΔBREX was higher than that in E. coli 3756 clinical isolate (1.0 × 10-6 vs 1.3 × 10-7 and 5.5 × 10-7 vs 1.7 × 10-8, respectively). This study demonstrated that the type I BREX system defends against antibiotic-resistant plasmids in E. coli.
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Bacteriófagos , Infecciones por Escherichia coli , Humanos , Escherichia coli , Antibacterianos/farmacología , beta-Lactamasas/genética , Plásmidos/genética , Pruebas de Sensibilidad MicrobianaRESUMEN
Achieving accurate detection of different speciations of heavy metal ions (HMIs) in an aqueous solution is an urgent problem due to the different bioavailabilities and physiological toxicity. Herein, we nominated a novel strategy to detect HCrO4- and Cr(OH)2+ at a trace level via the electrochemical sensitive surface constructed by Co3O4-rGO modified with amino and carboxyl groups, which revealed that the interactions between distinct functional groups and different oxygen-containing groups of target ions are conducive to the susceptible and anti-interference detection. The detection sensitivities of 19.46 counts µg-1 L for HCrO4- and 13.44 counts µg-1 L for Cr(OH)2+ were obtained under optimal conditions, while the limits of detection were 0.10 and 0.12 µg L-1, respectively. Satisfactory anti-interference and actual water sample analysis results were obtained. A series of advanced optical techniques like X-ray photoelectron spectroscopy, X-ray absorption near-edge structure technology, and density functional theory calculations under an electric field demonstrated that chemical interactions between groups contribute more to the fixation of target ions than electrical attraction alone. The presence of oxygen-containing groups distinct from simple ionic forms was a critical factor in the selectivity and anti-interference detection. Furthermore, the valence cycle of Co(II)/(III) synergistically boosted the detection performance. This research provides a promising tactic from the microscopic perspective of groups' interactions to accomplish the precise speciation analysis of HMIs in the water environment.
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Although utilizing nanomaterial-modified electrodes for lead ion detection has achieved great success, most of them are carried out under acidic conditions and ignore the variation of Pb(II) speciation at different pH conditions, leading to the potential inaccuracy of Pb(II) detection in a neutral natural water environment. Thus, designing a novel catalyst with high accuracy for the detection of various forms of the total amount of Pb(II) (Pb2+ and Pb(OH)+) in neutral waters is significant. Herein, Pt nanoclusters (Pt NCs) were elaborately constructed and stabilized on the Co single-atom-doped g-C3N4 with abundant N vacancies (Pt NCs/VN-C3N4), which achieved the ultrasensitive detection (102.16 µM µA-1) of Pb(II) in neutral conditions. The dynamic simulation and theoretical calculations reveal that the parallel deposition of Pb2+ and Pb(OH)+ occurs on the electrode surface modified by Pt NCs/VN-C3N4, and the current peaks of Pb(II) are cocontributed by Pb2+ and Pb(OH)+ species. An "electron inverse" phenomenon in Pt NCs/VN-C3N4 from the VN-C3N4 substrate to Pt NCs endows Pt NCs in an electron-rich state, serving as active centers to promote rapid and efficient reduction for both Pb2+ and Pb(OH)+, facilitating the accurate detection of the total amount of Pb(II) in all forms in the actual water environment.
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Solid contact (SC) calcium ion-selective electrodes (Ca2+-ISEs) have been widely applied in the analysis of water quality and body fluids by virtue of the unique advantages of easy operation and rapid response. However, the potential drift during the long-term stability test hinders their further practical applications. Designing novel redox SC layers with large capacitance and high hydrophobicity is a promising approach to stabilize the potential stability, meanwhile, exploring the transduction mechanism is also of great guiding significance for the precise design of SC layer materials. Herein, flower-like copper sulfide (CunS-50) composed of nanosheets is meticulously designed as the redox SC layer by modification with the surfactant (CTAB). The CunS-50-based Ca2+-ISE (CunS-50/Ca2+-ISE) demonstrates a near-Nernstian slope of 28.23 mV/dec for Ca2+ in a wide activity linear range of 10-7 to 10-1 M, with a low detection limit of 3.16 × 10-8 M. CunS-50/Ca2+-ISE possesses an extremely low potential drift of only 1.23 ± 0.13 µV/h in the long-term potential stability test. Notably, X-ray absorption fine-structure (XAFS) spectra and electrochemical experiments are adopted to elucidate the transduction mechanism that the lipophilic anion (TFPB-) participates in the redox reaction of CunS-50 at the solid-solid interface of ion-selective membrane (ISM) and redox inorganic SC layer (CunS-50), thereby promoting the generation of free electrons to accelerate ion-electron transduction. This work provides an in-depth comprehension of the transduction mechanism of the potentiometric response and an effective strategy for designing redox materials of ion-electron transduction triggered by lipophilic anions.
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Due to the disadvantages of poor targeting, slow action, and low effectiveness of current commonly used cancer treatments, including surgery, chemotherapy, and radiotherapy, researchers have turned to DNA as a biomaterial for constructing drug delivery nanocarriers. DNA is favored for its biocompatibility and programmability. In order to overcome the limitations associated with traditional drug delivery systems (DDSs), researchers have developed smart-responsive DNA DDSs that can control drug release in response to specific physical or chemical stimuli at targeted sites. In this review, a summary of multiple targeted ligand structures is provided, various shapes of stable DNA nanomaterials, and different stimuli-responsive drug release strategies in DNA DDSs. Specifically, targeted cell recognition, in vivo stable transport, and controlled drug release of smart DDSs are focused. Finally, the further development prospects and challenges of clinical application of DNA nanomaterials in the field of smart drug delivery are discussed. The objective of this review is to enhance researchers' comprehension regarding the potential application of DNA nanomaterials in precision drug delivery, with the aim of expediting the clinical implementation of intelligent DDSs.
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ADN , Sistemas de Liberación de Medicamentos , Neoplasias , Humanos , ADN/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Nanoestructuras/química , AnimalesRESUMEN
Emerging evidence suggests that circular RNA (circRNA) is an important regulator of a variety of pathological processes and serves as a promising biomarker for many complex human diseases. Nevertheless, there are relatively few known circRNA-disease associations, and uncovering new circRNA-disease associations by wet-lab methods is time consuming and costly. Considering the limitations of existing computational methods, we propose a novel approach named MNMDCDA, which combines high-order graph convolutional networks (high-order GCNs) and deep neural networks to infer associations between circRNAs and diseases. Firstly, we computed different biological attribute information of circRNA and disease separately and used them to construct multiple multi-source similarity networks. Then, we used the high-order GCN algorithm to learn feature embedding representations with high-order mixed neighborhood information of circRNA and disease from the constructed multi-source similarity networks, respectively. Finally, the deep neural network classifier was implemented to predict associations of circRNAs with diseases. The MNMDCDA model obtained AUC scores of 95.16%, 94.53%, 89.80% and 91.83% on four benchmark datasets, i.e., CircR2Disease, CircAtlas v2.0, Circ2Disease and CircRNADisease, respectively, using the 5-fold cross-validation approach. Furthermore, 25 of the top 30 circRNA-disease pairs with the best scores of MNMDCDA in the case study were validated by recent literature. Numerous experimental results indicate that MNMDCDA can be used as an effective computational tool to predict circRNA-disease associations and can provide the most promising candidates for biological experiments.
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Redes Neurales de la Computación , ARN Circular , Humanos , AlgoritmosRESUMEN
BACKGROUND AND AIMS: Hepatocyte keratin polypeptides 8/18 (K8/K18) are unique among intermediate filaments proteins (IFs) in that their mutation predisposes to, rather than causes, human disease. Mice that overexpress human K18 R90C manifest disrupted hepatocyte keratin filaments with hyperphosphorylated keratins and predisposition to Fas-induced liver injury. We hypothesized that high-throughput screening will identify compounds that protect the liver from mutation-triggered predisposition to injury. APPROACH AND RESULTS: Using A549 cells transduced with a lentivirus K18 construct and high-throughput screening, we identified the SRC-family tyrosine kinases inhibitor, PP2, as a compound that reverses keratin filament disruption and protects from apoptotic cell death caused by K18 R90C mutation at this highly conserved arginine. PP2 also ameliorated Fas-induced apoptosis and liver injury in male but not female K18 R90C mice. The PP2 male selectivity is due to its lower turnover in male versus female livers. Knockdown of SRC but not another kinase target of PP2, protein tyrosine kinase 6, in A549 cells abrogated the hepatoprotective effect of PP2. Phosphoproteomic analysis and validation showed that the protective effect of PP2 associates with Ser/Thr but not Tyr keratin hypophosphorylation, and differs from the sex-independent effect of the Ser/Thr kinase inhibitor PKC412. Inhibition of RAF kinase, a downstream target of SRC, by vemurafenib had a similar protective effect to PP2 in A549 cells and male K18 R90C mice. CONCLUSIONS: PP2 protects, in a male-selective manner, keratin mutation-induced mouse liver injury by inhibiting SRC-triggered downstream Ser/Thr phosphorylation of K8/K18, which is phenocopied by RAF kinase inhibitor vemurafenib. The PP2/vemurafenib-associated findings, and their unique mechanisms of action, further support the potential role of select kinase inhibition as therapeutic opportunities for keratin and other IF-associated human diseases.
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Queratinas , Familia-src Quinasas , Ratones , Masculino , Humanos , Animales , Queratinas/metabolismo , Familia-src Quinasas/metabolismo , Vemurafenib/metabolismo , Vemurafenib/farmacología , Ratones Transgénicos , Hígado/metabolismo , Queratina-8/genética , Queratina-8/metabolismo , Mutación , Queratina-18RESUMEN
In this work, genetic algorithm (GA) is employed to optimize convolutional neural networks (CNNs) for predicting the confinement loss (CL) in anti-resonant fibers (ARFs), achieving a prediction accuracy of CL magnitude reached 90.6%, which, to the best of our knowledge, represents the highest accuracy to date and marks the first instance of using a single model to predict CL across diverse ARF structures. Different from the previous definition of ARF structures with parameter groups, we use anchor points to describe these structures, thus eliminating the differences in expression among them. This improvement allows the model to gain insight into the specific structural characteristics, thereby enhancing its generalization capabilities. Furthermore, we demonstrate a particle swarm optimization algorithm (PSO), driven by our model, for the design of ARFs, validating the model's robust predictive accuracy and versatility. Compared with the calculation of CL by finite element method (FEM), this model significantly reduces the cost time, and provides a speed-up method in fiber design driven by numerical calculation.
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In recent decades, rapid advances in astronomical imaging campaigns have generated an urgent need for detailed spectroscopic surveys with increased speed and efficiency. The 6.5 m MUltiplexed Survey Telescope (MUST) aims to address these current demands. The performance of the multi-object fiber-fed spectrograph (MOFS) plays a critical role for spectroscopic survey telescopes, directly influencing the realization of scientific aims. In this paper, we demonstrate a high-resolution and highly-multiplexed option for MOFS of MUST. The system is believed to be first to apply a 92 mm × 92 mm large-size detector in a Schmidt-like camera and reduces the average central obscuration to 14%. Thanks to the F/1.25 camera design with excellent image quality, the spectrograph achieves up to 800 150µm-large-core optical fibers integration. It can obtain the broadband spectral information (395 nm-435â nm, 520 nm-570â nm, 610 nm-680â nm) of 800 objects with a high resolution of >16,000 within one exposure. The spectrograph theory, design method, and final system scheme of the MOFS can offer good reference and guidance for the spectrograph design in the spectroscopic survey.