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1.
Signal Transduct Target Ther ; 6(1): 378, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732694

RESUMO

The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/química , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , COVID-19 , SARS-CoV-2/química , Anticorpos de Cadeia Única/química , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Cristalografia por Raios X , Epitopos/química , Epitopos/imunologia , Humanos , Camundongos , SARS-CoV-2/imunologia , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/uso terapêutico
2.
Nat Plants ; 7(11): 1505-1515, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34782772

RESUMO

Protein homoeostasis in plastids is strategically regulated by the protein quality control system involving multiple chaperones and proteases, among them the Clp protease. Here, we determined the structure of the chloroplast ClpP complex from Chlamydomonas reinhardtii by cryo-electron microscopy. ClpP contains two heptameric catalytic rings without any symmetry. The top ring contains one ClpR6, three ClpP4 and three ClpP5 subunits while the bottom ring is composed of three ClpP1C subunits and one each of the ClpR1-4 subunits. ClpR3, ClpR4 and ClpT4 subunits connect the two rings and stabilize the complex. The chloroplast Cpn11/20/23 co-chaperonin, a co-factor of Cpn60, forms a cap on the top of ClpP by protruding mobile loops into hydrophobic clefts at the surface of the top ring. The co-chaperonin repressed ClpP proteolytic activity in vitro. By regulating Cpn60 chaperone and ClpP protease activity, the co-chaperonin may play a role in coordinating protein folding and degradation in the chloroplast.

3.
BMC Neurol ; 21(1): 451, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34789198

RESUMO

BACKGROUND: The diagnosis of neurosyphilis is challenging due to the requirement of a lumbar puncture and cerebrospinal fluid (CSF) laboratory tests. Therefore, a convenient diagnostic nomogram for neurosyphilis is warranted. This study aimed to construct diagnostic models for diagnosing neurosyphilis. METHODS: This cross-sectional study included data of two patient cohorts from Western China Hospital of Sichuan University between September 2015 and April 2021 and Shangjin Hospital between September 2019 and April 2021 as the development cohort and the external validation cohort, respectively. A diagnostic model using logistic regression analysis was constructed to readily provide the probability of diagnosis at point of care and presented as a nomogram. The clinical usefulness of the diagnostic models was assessed using a receiver operating characteristic (ROC) and Harrell concordance (Harrell C) index for discrimination and calibration plots for accuracy, which adopted bootstrap resampling 500 times. RESULTS: One hundred forty-eight and 67 patients were included in the development and validation cohorts, respectively. Of those, 131 were diagnosed as having reactive neurosyphilis under the criteria of positive results in both CSF treponemal and non-treponemal tests. In the development cohort, male, psychiatric behaviour disorders, and serum toluidine red unheated serum test were selected as diagnostic indicators applying a stepwise procedure in multivariable logistic model. The model reached 80% specificity, 79% sensitivity, and 0·85 area under the curves (AUC) (95% confidence interval, 0·76-0·91). In the validation cohorts, the Harrell C index for the diagnostic possibility of reactive neurosyphilis was 0·71. CONCLUSIONS: A convenient model using gender, presence of psychiatric behaviour disorders, and serum TRUST titre was developed and validated to indicate diagnostic results in patients suspected of neurosyphilis. Checking the model value of factors on nomogram is a feasible way to assist clinicians and primary health servers in updating patients' medical charts and making a quantitatively informed decision on neurosyphilis diagnosis. TRIAL REGISTRATION: This research was retrospectively registered in the Ethics committee on biomedical research, West China Hospital of Sichuan University. The research registration and committee's reference number was 1163 in 2020 approval.


Assuntos
Neurossífilis , Nomogramas , Estudos Transversais , Humanos , Masculino , Neurossífilis/diagnóstico , Sorodiagnóstico da Sífilis , Treponema pallidum
4.
Opt Express ; 29(23): 37703-37711, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34808837

RESUMO

Spot size converter (SSC) plays a role of paramount importance in the silicon photonics integrated circuit. In this article, we report the design of a reconfigurable spot size converter used in the hybrid integration of a DFB laser diode with a silicon photonic waveguide. Our SSC consists of subwavelength gratings and thermal phase shifters. Four subwavelength grating tips are used to improve horizontal misalignment tolerance. Meanwhile, the phase mismatch between two input waveguides is compensated by phase shifters to minimize insertion losses. Our simulated result has yielded a minimum insertion loss of 0.63 dB and an improvement of the horizontal misalignment from ±0.65 µm to ±1.69 µm for 1 dB excess insertion loss at the wavelength of 1310 nm. The phase shifters are designed to compensate any phase error in both the fabrication and bonding processes, which provides a completely new edge-coupling strategy for the silicon photonics integrated circuit.

5.
ACS Catal ; 11(6): 3319-3334, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-34745712

RESUMO

In the anaerobic ergothioneine biosynthetic pathway, a rhodanese domain containing enzyme (EanB) activates tne hercynine's sp2 ε-C-H Dona ana replaces it with a C-S bond to produce ergothioneine. The key intermediate for this trans-sulfuration reaction is the Cys412 persulfide. Substitution of the EanB-Cys412 persulfide with a Cys412 perselenide does not yield the selenium analog of ergothioneine, selenoneine. However, in deuterated buffer, the perselenide-modified EanB catalyzes the deuterium exchange between hercynine's sp2 ε-C-H bond and D2O. Results from QM/MM calculations suggest that the reaction involves a carbene intermediate and that Tyr353 plays a key role. We hypothesize that modulating the pKa of Tyr353 will affect the deuterium-exchange rate. Indeed, the 3,5-difluoro tyrosine containing EanB catalyzes the deuterium exchange reaction with k ex of ~10-fold greater than the wild-type EanB (EanBWT). With regards to potential mechanisms, these results support the involvement of a carbene intermediate in EanB-catalysis, rendering EanB as one of the few carbene-intermediate involving enzymatic systems.

6.
Anal Chim Acta ; 1187: 339146, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34753564

RESUMO

Mitophagy, a specialized form of autophagy, holds the key to cellular metabolism and physiology. Viscosity is a significant marker for visualization of the mitophagy process in real-time. Hence, development of well-performing viscosity probe is beneficial to study mitophagy-related dynamic physiological and pathological processes. Here, a new strategy was proposed by combination of AIE property and molecular rotors to design novel viscosity probe. The probe named TPA-Py was obtained by Knoevenagel condensation reaction of AIE unit and pyridine salt, which giving the probe excellent near-infrared emission, good water-solubility and mitochondrial targeting ability. Most importantly, TPA-Py owns two rotatable parts of triphenylamine and double bond, enabling the probe to equip with AIE property and sensitive recognition units for viscosity. With the environmental viscosity increasing, the rotation of the molecular rotor and the AIE unit is restricted effectively, the probe displayed strong fluorescence. Then, TPA-Py was successfully employed for monitoring the mitophagy process in A549 cells by imaging viscosity alterations. As mitophagy constitutes an important consideration in the pathogenesis of drug-induced liver injury, TPA-Py was also applied to explore the variation of viscosity in production and remediation pathways of APAP-induced liver injury. These results demonstrated that TPA-Py was a highly sensitive viscosity probe which holds great potential of biological applications.


Assuntos
Fígado , Mitofagia , Fluorescência , Corantes Fluorescentes , Células HeLa , Humanos , Viscosidade
7.
Acta Pharm Sin B ; 11(10): 3231-3243, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34729312

RESUMO

Ferroptosis, as a newly discovered cell death form, has become an attractive target for precision cancer therapy. Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione (GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). However, the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported. Herein, novel tumor microenvironments (TME)-activated metal-organic frameworks involving Fe & Cu ions bridged by disulfide bonds with PEGylation (FCSP MOFs) were developed, which would be degraded specifically under the redox TME, simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction, therefore causing ferroptosis. More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs. The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy. Better tumor therapeutic efficiency could be achieved by doxorubicin (DOX) loading since it can not only cause apoptosis, but also indirectly produce H2O2 to amplify Fenton reaction. Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.

8.
Nat Commun ; 12(1): 5796, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608154

RESUMO

The axonemal central pair (CP) are non-centrosomal microtubules critical for planar ciliary beat. How they form, however, is poorly understood. Here, we show that mammalian CP formation requires Wdr47, Camsaps, and microtubule-severing activity of Katanin. Katanin severs peripheral microtubules to produce central microtubule seeds in nascent cilia. Camsaps stabilize minus ends of the seeds to facilitate microtubule outgrowth, whereas Wdr47 concentrates Camsaps into the axonemal central lumen to properly position central microtubules. Wdr47 deficiency in mouse multicilia results in complete loss of CP, rotatory beat, and primary ciliary dyskinesia. Overexpression of Camsaps or their microtubule-binding regions induces central microtubules in Wdr47-/- ependymal cells but at the expense of low efficiency, abnormal numbers, and wrong location. Katanin levels and activity also impact the central microtubule number. We propose that Wdr47, Camsaps, and Katanin function together for the generation of non-centrosomal microtubule arrays in polarized subcellular compartments.


Assuntos
Cílios/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Animais , Axonema/metabolismo , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/metabolismo , Transtornos da Motilidade Ciliar/patologia , Expressão Gênica , Katanina/genética , Katanina/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-34699010

RESUMO

Fully utilizing the energy generated by the explosion of pulverized coal will contribute to realize the clean and efficient exploitation of coal resources. The pulverized coal explosion characteristics will be a far-reaching and important task to explore. In this paper, ten kinds of low-quality coals such as high sulfur, high ash, and low metamorphic degree coals were investigated and the minimum ignition energy (MIE), lower explosion limit (LEL), and explosion intensity (EI) parameters under different particle sizes and coal powder concentration conditions were also analyzed combined with a 1.2-L Hartmann tube and a 20-L explosion sphere experimental system. Finally, the morphological characteristics of the exploded coal powder surface were evaluated by scanning electron microscopy (SEM). The results show that the particle size is positively correlated with MIE. LEL shows an inverted "U"-shaped trend with the increasing degree of coal deterioration. The low-rank coal is more flammable and explosive. The maximum pressure PMax at the LEL concentration and maximum pressure rise rate (dP/dt)Max overall value is small. Here, optimum pulverized coal particle size (75µm) for explosive utilization of low-quality coal was determined. Within 50-225 g/m3 of pulverized coal concentration range, the explosion intensity increases with increasing concentration. The smaller the particle size of pulverized coal, the greater the possibility of agglomeration of pulverized coal particles. The surface of the exploded coal particles produces more developed pores. They are irregularly shaped and have more rounded edges than the original coal.

11.
Reprod Biol Endocrinol ; 19(1): 162, 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715887

RESUMO

BACKGROUND: Decidualization is essential to the successful pregnancy in mice. The molecular mechanisms and effects of Aurora kinase A (Aurora A) remain poorly understood during pregnancy. This study is the first to investigate the expression and role of Aurora A during mouse decidualization. METHODS: Quantitative real time polymerase chain reaction, western blotting and in situ hybridization were used to determine the expression of Aurora A in mouse uteri. Aurora A activity was inhibited by Aurora A inhibitor to explore the role of Aurora A on decidualization via regulating the Aurora A/Stat3/Plk1/Cdk1 signaling pathway. RESULTS: Aurora A was strongly expressed at implantation sites compared with inter-implantation sites. Furthermore, Aurora A was also significantly increased in oil-induced deciduoma compared with control. Both Aurora A mRNA and protein were significantly increased under in vitro decidualization. Under in vitro decidualization, Prl8a2, a marker of mouse decidualization, was significantly decreased by TC-S 7010, an Aurora A inhibitor. Additionally, Prl8a2 was reduced by Stat3 inhibitor, Plk1 inhibitor and Cdk1 inhibitor, respectively. Moreover, the protein levels of p-Stat3, p-Plk1 and p-Cdk1 were suppressed by TC-S 7010. The protein levels of p-Stat3, p-Plk1 and p-Cdk1 were also suppressed by S3I-201, a Stat3 inhibitor). SBE 13 HCl (Plk1 inhibitor) could reduce the protein levels of p-Plk1 and p-Cdk1. Collectively, Aurora A could regulate Stat3/Plk1/Cdk1 signaling pathway. CONCLUSION: Our study shows that Aurora A is expressed in decidual cells and should be important for mouse decidualization. Aurora A/Stat3/Plk1/Cdk1 signaling pathway may be involved in mouse decidualization.

12.
Oncol Rep ; 46(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34643248

RESUMO

Glucose transporter 1 (GLUT1) plays a primary role in the glucose metabolism of cancer cells. However, to the best of our knowledge, there are currently no anticancer drugs that inhibit GLUT1 function. The present study aimed to investigate the antineoplastic activity of berberine (BBR), the main active ingredient in numerous Traditional Chinese medicinal herbs, on HepG2 and MCF7 cells. The results of Cell Counting Kit­8 assay, colony formation assay and flow cytometry revealed that BBR effectively inhibited the proliferation of tumor cells, and induced G2/M cell cycle arrest and apoptosis. Notably, the results of luminescence ATP detection assay and glucose uptake assay showed that BBR also significantly inhibited ATP synthesis and markedly decreased the glucose uptake ability, which suggested that the antitumor effect of BBR may occur via reversal of the Warburg effect. In addition, the results of reverse transcription­quantitative PCR, western blotting and immunofluorescence staining indicated that BBR downregulated the protein expression levels of GLUT1, maintained the cytoplasmic internalization of GLUT1 and suppressed the Akt/mTOR signaling pathway in both HepG2 and MCF7 cell lines. Augmentation of Akt phosphorylation levels by the Akt activator, SC79, abolished the BBR­induced decrease in ATP synthesis, glucose uptake, GLUT1 expression and cell proliferation, and reversed the proapoptotic effect of BBR. These findings indicated that the antineoplastic effect of BBR may involve the reversal of the Warburg effect by downregulating the Akt/mTOR/GLUT1 signaling pathway. Furthermore, the results of the co­immunoprecipitation assay demonstrated that BBR increased the interaction between ubiquitin conjugating enzyme E2 I (Ubc9) and GLUT1, which suggested that Ubc9 may mediate the proteasomal degradation of GLUT1. On the other hand, BBR decreased the interaction between Gα­interacting protein­interacting protein at the C­terminus (GIPC) and GLUT1, which suggested that the retention of GLUT1 in the cytoplasm may be achieved by inhibiting the interaction between GLUT1 and GIPC, thereby suppressing the glucose transporter function of GLUT1. The results of the present study provided a theoretical basis for the application of the Traditional Chinese medicine component, BBR, for cancer treatment.

13.
J Clin Invest ; 131(22)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34609966

RESUMO

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.

14.
Int J Gen Med ; 14: 5527-5535, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531678

RESUMO

Purpose: Recurrent patellar dislocation (RPD) is the most common complication of patellar instability and the medial patellofemoral ligament (MPFL) reconstruction has become its reference treatment. Lateral patellar retinaculum (LPR) release used to be performed in association with MPFL reconstruction. The aim of this study was to investigate the added values of MPFL reconstruction plus LPR release for RPD. Methods: After Institutional Review Board approval, RPD patients from October 2014 to April 2019 were randomly assigned into two groups (isolated MPFL reconstruction [Group I] and MPFL reconstruction plus LPR release [Group II]) and prospectively assessed until 12 months after surgery. Knee joints with flexion of 20° were scanned by a 64-row CT scanner. Congruence angle (CA), patella tilt angle (PTA), lateral patellofemoral angle (LPFA), tibial tuberosity-trochlear groove distance and patellar tilt with the quadriceps relaxed and contracted were measured. Knee function was assessed by Lysholm knee score and International Knee Documentation Committee (IKDC) score. Patients were followed up for at least 12 months. Results: A total of 87 RPD patients (45 for Group I and 42 for Group II) were selected in this study. Preoperative clinical characteristics were not significantly different across groups. No serious complications were noted in either group. It was statistically insignificant between the two group patients in terms of postoperative patella associated measurements (P > 0.05 for all). The Lysholm score and IKDC score of Group I (84.5 ± 7.1 and 87.9 ± 7.2) were significantly less than that of Group II (89.7 ± 8.7 and 93.1 ± 7.7), which indicated the better knee function of Group II. Conclusion: LPR release plus MPFL reconstruction provides additional benefits compared with isolated MPFL reconstruction in knee function. A combination of surgical treatments for RPD should be recommended.

15.
Sci Adv ; 7(33)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34389544

RESUMO

The recruitment of Unc-51-like kinase and TANK-binding kinase 1 complexes is essential for Nuclear dot protein 52-mediated selective autophagy and relies on the specific association of NDP52, RB1-inducible coiled-coil protein 1, and Nak-associated protein 1 (5-azacytidine-induced protein 2, AZI2). However, the underlying molecular mechanism remains elusive. Here, we find that except for the NDP52 SKIP carboxyl homology (SKICH)/RB1CC1 coiled-coil interaction, the LC3-interacting region of NDP52 can directly interact with the RB1CC1 Claw domain, as that of NAP1 FIP200-binding region (FIR). The determined crystal structures of NDP52 SKICH/RB1CC1 complex, NAP1 FIR/RB1CC1 complex, and the related NAP1 FIR/Gamma-aminobutyric acid receptor-associated protein complex not only elucidate the molecular bases underpinning the interactions of RB1CC1 with NDP52 and NAP1 but also reveal that RB1CC1 Claw and Autophagy-related protein 8 family proteins are competitive in binding to NAP1 and NDP52. Overall, our findings provide mechanistic insights into the interactions of NDP52, NAP1 with RB1CC1 and ATG8 family proteins.

16.
Analyst ; 146(18): 5668-5674, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34382632

RESUMO

Monitoring the concentration of dopamine (DA) is vital for preventing and diagnosing DA related diseases. In contrast to the traditional sensing methods for DA, in which direct or indirect effects on the optical probes are often recorded, a novel sensing concept is disclosed based on as a result of the in situ formation of polydopamine (PDA) originating from the synergetic effect between boron nitride quantum dots (BNQDs) and Cu2+. In the co-presence of BNQDs and Cu2+, DA was catalytically oxidized to PDA, accompanied by an obvious color change from colorless to brown. In contrast to previous reports, in which BNQDs have been employed as an optical probe, herein, the BNQDs not only acted as the optical energy donor, but also as the catalysts for the formation of PDA. The quenching efficiency resulting from the inner filter effect and the electron transfer between the BNQDs and PDA was directly proportional to the concentration of DA, ranging linearly from 2 to 80 µM with a limit of detection of 0.49 µM. The present system exhibited an outstanding selectivity for DA among other interfering coexisting biomolecules. Furthermore, the practical application of the proposed platform was verified by assaying DA in human plasma samples, and satisfactory recoveries ranging from 101.24% to 111.98% were obtained. With the satisfactory reliability, repeatability and stability, the proposed simple sensor showed significant potential for use in DA detection in other biomedical applications.


Assuntos
Pontos Quânticos , Compostos de Boro , Dopamina , Humanos , Limite de Detecção , Reprodutibilidade dos Testes
17.
J Chem Phys ; 155(2): 024114, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34266248

RESUMO

Progress in electrochemical technologies, such as automotive batteries, supercapacitors, and fuel cells, depends greatly on developing improved charged interfaces between electrodes and electrolytes. The rational development of such interfaces can benefit from the atomistic understanding of the materials involved by first-principles quantum mechanical simulations with Density Functional Theory (DFT). However, such simulations are typically performed on the electrode surface in the absence of its electrolyte environment and at constant charge. We have developed a new hybrid computational method combining DFT and the Poisson-Boltzmann equation (P-BE) capable of simulating experimental electrochemistry under potential control in the presence of a solvent and an electrolyte. The charged electrode is represented quantum-mechanically via linear-scaling DFT, which can model nanoscale systems with thousands of atoms and is neutralized by a counter electrolyte charge via the solution of a modified P-BE. Our approach works with the total free energy of the combined multiscale system in a grand canonical ensemble of electrons subject to a constant electrochemical potential. It is calibrated with respect to the reduction potential of common reference electrodes, such as the standard hydrogen electrode and the Li metal electrode, which is used as a reference electrode in Li-ion batteries. Our new method can be used to predict electrochemical properties under constant potential, and we demonstrate this in exemplar simulations of the differential capacitance of few-layer graphene electrodes and the charging of a graphene electrode coupled to a Li metal electrode at different voltages.

18.
Front Bioeng Biotechnol ; 9: 673691, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295880

RESUMO

Intestinal tuberculosis (ITB) and Crohn's disease (CD) are chronic inflammatory bowel disorders that are associated with dysregulated mucosal immunity. The gut microbiota plays an important role in the regulation of host immunity and inflammatory response. Although mounting evidence has linked CD with the dysbiosis of gut microbiota, the characteristic profiles of mucosal bacteria in ITB remain unclear. The aim of this study was to assess the alterations of the gut microbiota in ITB and compare the microbial structure of ITB with CD. A total of 71 mucosal samples were collected from patients with ITB, CD, and healthy controls (HC), and then, 16S rRNA gene sequencing was performed. The overall composition of gut microbiota in ITB was strikingly different from HC, with the dominance of Proteobacteria and reduction of Firmicutes. Of note, the short-chain fatty acids (SCFAs)-producing bacteria such as Faecalibacterium, Roseburia, and Ruminococcus were decreased in ITB relative to HC, while Klebsiella and Pseudomonas were enriched. Multiple predictive functional modules were altered in ITB, including the over-representation of lipopolysaccharide biosynthesis, bacterial invasion of epithelial cells, and pathogenic Escherichia coli infection that can promote inflammation. Additionally, the microbial structure in CD was distinctly different from ITB, characterized by lower alpha diversity and increased abundance of Bacteroides, Faecalibacterium, Collinsella, and Klebsiella. These four bacterial markers distinguished ITB from CD with an area under the curve of 97.6%. This study established the compositional and functional perturbation of the gut microbiome in ITB and suggested the potential for using gut microbiota as biomarkers to differentiate ITB from CD.

19.
BMC Ecol Evol ; 21(1): 137, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229631

RESUMO

BACKGROUND: Understanding how island ecosystems change across habitats is a major challenge in ecological conservation under the conditions of habitat degradation. According to a 2-year investigation on Dong Island of the Paracel Islands, South China Sea, we assessed the roles of different habitats at the species level and community level of birds using topological and network analysis. RESULTS: In addition to the thousands of Sula sula (a large-sized arboreal seabird) inhabiting the forests, there were 56 other bird species were recorded, representing 23 families and 12 orders, ranging in habitats of wetlands, forests, shrublands, grasslands, and/or beaches. The bird-habitat network had high nestedness, and bird species showed obvious clustering distribution. Integrated topological and network analysis showed that wetlands had a high contribution to species diversity and network structure, and it was a cluster center of migrant birds. Forests and grasslands were species hub and connector respectively, and forests were also the key habitat for residents. Beaches and shrublands were peripherals. The loss of wetlands and forests will result in a sharp reduction of species richness, and even make the S. sula, and most of the resident birds, become locally extinct. CONCLUSIONS: These results suggest that the wetland and forest habitats on the focal island are key important for migrant birds and resident birds respectively, and therefore much more attention should be paid to conservation of the focal island ecosystems.


Assuntos
Antozoários , Ecossistema , Animais , Aves , China , Florestas , Humanos
20.
Nat Commun ; 12(1): 4635, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330908

RESUMO

SARS-CoV-2, the causative agent of COVID-191, features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein1-6. Neutralizing antibodies that block RBD-ACE2 interaction are candidates for the development of targeted therapeutics7-17. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (KD = 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.42 µg mL-1). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log10. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Anticorpos de Domínio Único/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/farmacologia , Anticorpos Antivirais/ultraestrutura , Sítios de Ligação/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Microscopia Crioeletrônica , Cristalografia por Raios X , Feminino , Humanos , Espectrometria de Massas/métodos , Mesocricetus , Camundongos Endogâmicos C57BL , Testes de Neutralização , Ligação Proteica/efeitos dos fármacos , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/metabolismo
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