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BACKGROUND: Plague is an acute infectious disease caused by the Yersinia pestis. Historically, it has been a major pandemic with high mortality rates, known as the "Black Death" in the 14th century, which resulted in millions of deaths in Europe. With increasing economic prosperity, more and more people are traveling to Xizang. However, this trend also hides significant safety hazards. Currently, there are few recent reports on plague, especially those with imaging manifestations available. In this study, we report the detailed clinical and radiological data of the patient with pneumonic plague in Xizang, China, in 2023. CASE PRESENTATION: We report a case of pneumonic plague in Xizang, which occurred in a herdsman living in an area where dead marmots were found. The patient presented with symptoms such as fever, hemoptysis, dyspnea and coma. Chest computed tomography (CT) scans showed multiple nodules distributed in the central regions of lung lobes, consolidation distributed in secondary pulmonary lobules, and had a gravity-dependent distribution pattern. These imaging findings were consistent with pulmonary hemorrhage and diffuse alveolar damage. Despite emergency treatment, the patient died within 48 h of admission. Through retrospective medical history investigation, laboratory examination and autopsy, the final diagnosis was confirmed as pneumonic plague. CONCLUSION: Pneumonic plague is the most deadly infectious disease, and its pathological features mainly include damage to the alveoli, pulmonary hemorrhage, and pulmonary edema. Corresponding to CT, it manifests as acute and rapidly progressing pneumonia, alveolar damage, and pulmonary hemorrhage. The value of this article lies in the completeness and typicality of the imaging data, vivid hand-drawn illustrations of transmission pathways, and comprehensive literature review, all of which serve to enhance public understanding of plague and play an important warning role.
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Peste , Tomografia Computadorizada por Raios X , Humanos , Peste/diagnóstico , China , Masculino , Evolução Fatal , Pulmão/diagnóstico por imagem , Pulmão/patologia , Yersinia pestis/isolamento & purificação , Animais , MarmotaRESUMO
Janus monolayers of transition metal dichalcogenides (TMDs) offer versatile applications due to their tunable polymorphisms. While previous studies focused on conventional 2H-phase Janus monolayers, the scalable synthesis of an unconventional 1T' phase remains challenging. We present a novel solution strategy for fabricating Janus 1T'-MoOSe and MoSSe monolayers by growing sandwiched Se-Mo-O/S shells onto Au nanocores. The Janus Au@1T'-MoSSe catalyst exhibits superior electrocatalytic hydrogen evolution reaction (HER) activity compared to 1T'-MoS2, -MoSe2, and -MoOSe, attributed to its unique electronic structure and intrinsic strain. Remarkably, photoexciting the nanoplasmonic Au cores further enhances the HER via a localized surface plasmon (LSP) effect that drives hot electron injection into surface sulfur vacancies of 1T'-MoSSe monolayer shells, accelerating proton reduction. This synergistic activation of anion vacancies by internal strain and external light-induced Au LSPs, coupled with our scalable synthesis, provides a pathway for developing tailorable polymorphic Janus TMDs for specific applications.
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Thioesters are a common class of biologically active fragments and synthetically useful building blocks. An attractive synthetic approach would be to use simple and bench-stable carboxylic acids as a coupling partner. Herein, we present a 4-bromo pyridine-borane complex as a catalyst for the direct coupling of carboxylic acids with thiols. A wide range of thioesters with good functional group compatibility could be prepared via this metal-free approach. The merit of this strategy is exemplified by the modification of carboxylic acid-containing drugs.
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Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncating variants (DSPtvs) and a gene-edited homozygous deletion cell line (DSP-/-). At baseline, DSP-/- EHTs displayed a transcriptomic signature of innate immune activation, which was mirrored by cytokine release. Importantly, DSP-/- EHTs were hypersensitive to Toll-like receptor (TLR) stimulation, demonstrating more contractile dysfunction compared with isogenic controls. Relative to DSP-/- EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits, indicating reduced contractile reserve compared with healthy controls. Colchicine or NF-κB inhibitors improved strain-induced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis, implicating cytokine release as a key part of the myogenic susceptibility to inflammation. The heightened innate immune activation and sensitivity are targets for clinical intervention.
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Imunidade Inata , Células-Tronco Pluripotentes Induzidas , Miocardite , Miócitos Cardíacos , Humanos , Miocardite/genética , Miocardite/imunologia , Miocardite/patologia , Imunidade Inata/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , Masculino , Predisposição Genética para Doença , FemininoRESUMO
Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 µM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.
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Inibidores Enzimáticos , Fibroblastos , Glicosaminoglicanos , Mucopolissacaridose I , Mucopolissacaridose I/tratamento farmacológico , Mucopolissacaridose I/metabolismo , Mucopolissacaridose I/patologia , Humanos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Glicosaminoglicanos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Carboidratos Epimerases/metabolismo , Carboidratos Epimerases/antagonistas & inibidores , Carboidratos Epimerases/genética , Simulação de Acoplamento Molecular , Antígenos de Neoplasias , Proteínas de Ligação a DNA , Proteínas de NeoplasiasRESUMO
The manipulation of oxygen vacancies (OVs) in metal oxides has progressively emerged as a versatile strategy for improving their catalytic performance. In this study, we aim to enhance the oxygen evolution reaction (OER) performance of cerium oxide (CeO2) by doping heteroatoms (Fe, Co, Ni) to generate additional OVs. We systematically analyzed both the morphology and electronic structure of the obtained CeO2 catalysts. The experimental results revealed the self-assembly of two-dimensional (2D) CeO2 nanosheets, with an approximate thickness of â¼1.7 nm, into 2D nanosheet assemblies (NSAs). Moreover, the incorporation of heteroatoms into the CeO2 matrix promoted the formation of OVs, resulting in a significant enhancement of the OER performance of CeO2. Among them, the Co-doped CeO2 NSAs sample displayed the highest activity and durability, with almost negligible activity loss during extended operating periods. The roles of heteroatom doping in improving OER activity were explored by DFT calculations. The produced OVs improve the adsorption of hydroxyl groups (OH-), promote the deprotonation process, and increase more active sites. These findings suggest that doping CeO2 with heteroatoms is a promising strategy for improving electrocatalytic OER activity, with great potential for the development of clean energy technologies, including but not limited to water splitting and fuel cells.
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The spike (S) protein on the surface of the SARS-CoV-2 virus is critical to mediate fusion with the host cell membrane through interaction with angiotensin-converting enzyme 2 (ACE2). Additionally, heparan sulfate (HS) on the host cell surface acts as an attachment factor to facilitate the binding of the S receptor binding domain (RBD) to the ACE2 receptor. Aiming at interfering with the HS-RBD interaction to protect against SARS-CoV-2 infection, we have established a pentasaccharide library composed of 14,112 compounds covering the possible sulfate substitutions on the three sugar units (GlcA, IdoA, and GlcN) of HS. The library was used for virtual screening against RBD domains of SARS-CoV-2. Molecular modeling was carried out to evaluate the potential antiviral properties of the top-hit pentasaccharide focusing on the interactive regions around the interface of RBD-HS-ACE2. The lead pentasaccharide with the highest affinity for RBD was analyzed via drug-likeness calculations, showing better predicted druggable profiles than those currently reported for RBD-binding HS mimetics. The results provide significant information for the development of HS-mimetics as anti-SARS-CoV-2 agents.
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COVID-19 , Humanos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , Domínios Proteicos , Ligação ProteicaRESUMO
2D materials, such as graphene, transition metal dichalcogenides, black phosphorus, layered double hydroxides, and MXene, have exhibited broad application prospects in electrochemical energy conversion due to their unique structures and electronic properties. Recently, the engineering of heterostructures based on 2D materials, including 2D/0D, 2D/1D, 2D/2D, and 2D/3D, has shown the potential to produce synergistic and heterointerface effects, overcoming the inherent restrictions of 2D materials and thus elevating the electrocatalytic performance to the next level. In this review, recent studies are systematically summarized on heterostructures based on 2D materials for advanced electrochemical energy conversion, including water splitting, CO2 reduction reaction, N2 reduction reaction, etc. Additionally, preparation methods are introduced and novel properties of various types of heterostructures based on 2D materials are discussed. Furthermore, the reaction principles and intrinsic mechanisms behind the excellent performance of these heterostructures are evaluated. Finally, insights are provided into the challenges and perspectives regarding the future engineering of heterostructures based on 2D materials for further advancements in electrochemical energy conversion.
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Rational design and controllable synthesis of hollow structures based on transition metal dichalcogenides (TMDs) have gained tremendous attention in the field of clean energy. However, the general synthetic strategies to fabricate single-layer hollow structures of TMDs, especially with unconventional phases (e.g., 1T or 1T'), still pose significant challenges. Herein, a scalable method is reported for the synthesis of single-layer hollow spheres (SLHS) of TMDs with high 1T-phase purity by etching bismuth (Bi) cores from pre-synthesized Bi@TMDs core-shell heterostructures including SLHS-1T-MoS2 , SLHS-1T-MoSe2 , SLHS-1T-WS2 , and SLHS-1T-WSe2 . Additionally, the etched Bi ions can be adsorbed on the single-layer TMDs shells in the form of single atoms (SAs) via the BiâS bond. Due to the benefits of the single-layer hollow structure, high conductivity of 1T phase, and synergistic effect of Bi SAs and TMDs supports, the fabricated SLHS-1T-MoS2 exhibits superior electrocatalytic performance for hydrogen production. This work provides a way to manufacture advanced functional materials based on the single-layer hollow structures of 1T-TMDs and to expand their applications.
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19 compounds, including seven previously undescribed alkaloids ((-)-macleayin K (1), (+)-macleayin K (2), macleayin M (3), macleayin N (4), macleayin L (5), macleayin O (6), oxohydrastinine A (7), one new natural product (8), and 11 known compounds, were isolated from the fruit pods of Macleaya microcarpa. Their structures were defined based on NMR, HRESIMS, and electronic circular dichroism (ECD) data. A network pharmacology approach combined with molecular docking and in vitro validation was performed to determine the bioactivity, key targets of the 19 compounds against breast cancer (BC) and cervical cancer (CC). EGFR and PIK3CA could become potential therapeutic targets based a network pharmacology. Moreover, molecular docking suggested that the 19 compounds combined well with EGFR and PIK3CA, respectively. Their cytotoxicity of selected compounds was tested against the MCF-7 and HeLa cells, and the preliminary structure-activity relationship is discussed. Compounds 1 (IC50: 6.00 µM) and 2 (IC50: 6.82 µM) exhibited strong inhibitory activity against the HeLa cells and are worthy of further study.
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Alcaloides , Antineoplásicos , Papaveraceae , Humanos , Frutas , Células HeLa , Simulação de Acoplamento Molecular , Estrutura Molecular , Papaveraceae/química , Receptores ErbBRESUMO
SARS-CoV-2 infects human epithelial cells through specific interaction with angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate proteoglycans act as the attachment factor to promote the binding of viral spike protein receptor binding domain (RBD) to ACE2 on host cells. Though the rapid development of vaccines has contributed significantly to preventing severe disease, mutated SARS-CoV-2 strains, especially the SARS-CoV-2 Omicron variant, show increased affinity of RBD binding to ACE2, leading to immune escape. Thus, there is still an unmet need for new antiviral drugs. In this study, we constructed pharmacophore models based on the spike RBD of SARS-CoV-2 and SARS-CoV-2 Omicron variant and performed virtual screen for best-hit compounds from our disaccharide library. Screening of 96 disaccharide structures identified two disaccharides that displayed higher binding affinity to RBD in comparison to reported small molecule antiviral drugs. Further, screening PharmMapper demonstrated interactions of the disaccharides with a number of inflammatory cytokines, suggesting a potential for disaccharides with multiple-protein targets.
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Antivirais , Dissacarídeos , SARS-CoV-2 , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Antivirais/química , Sítios de Ligação , COVID-19 , Dissacarídeos/farmacologia , Ligação Proteica , Receptores Virais/metabolismo , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/química , Ensaios de Triagem em Larga EscalaRESUMO
Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct tumor characterized by intraductal papillary or villous neoplasms covered by neoplastic epithelium with fine fibrovascular stalks in the dilated bile ducts (1). Its true etiology remains unknown. Herein, we report two cases of IPNB that underwent surgical resection. The first case was a 66-year-old male who complained of upper abdominal pain for three years. We found obstruction of the common bile duct and dilation of the intrahepatic and extrahepatic bile ducts after MRCP. Laparoscopic hepatic segmentectomy (S2, S3, S4), resection of the common bile duct, cholecystectomy, and hepaticojejunostomy were performed. The second case was a 67-year-old male with asymptomatic dilation of the intrahepatic duct. The patient underwent robot-assisted laparoscopic hepatic segmentectomy (S5, S6, S7, S8), resection of the common bile duct, hepaticojejunostomy and cholecystectomy.
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1T'-phase MoS2 possesses excellent electrocatalytic performance, but due to the instability of the thermodynamic metastable phase, its actual electrocatalytic effect is seriously limited. Here, we report a wet-chemical synthesis strategy for constructing rGO/1T'-MoS2/CeO2 heterostructures to improve the phase stability of metastable 1T' phase MoS2 monolayers. Importantly, the rGO/1T'-MoS2/CeO2 heterostructure exhibits excellent electrocatalytic hydrogen evolution reaction (HER) performance, which is much better than the 1T'-MoS2 monolayers. The synergistic effects between CeO2 nanoparticles (NPs) and 1T'-MoS2 monolayers were systematically investigated. 1T'-MoS2 monolayers combined with the cocatalyst of CeO2 NPs can produce lattice strain and distortion on 1T'-MoS2 monolayers, which can tune the energy band structure, charge transfer, and energy barriers of hydrogen atom adsorption (ΔEH), leading to promotion of the phase activity and stability of 1T'-MoS2 monolayers for hydrogen production. Our work offers a feasible method for the preparation of efficient HER electrocatalysts based on the engineering phase stability of metastable materials.
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Phase engineering of nanomaterials provides a promising way to explore the phase-dependent physicochemical properties and various applications of nanomaterials. A general bottom-up synthesis method under mild conditions has always been challenging globally for the preparation of the semimetallic phase-transition-metal dichalcogenide (1T'-TMD) monolayers, which are pursued owing to their unique electrochemical property, unavailable in their semiconducting 2H phases. Here, we report the general scalable colloidal synthesis of nanosized 1T'-TMD monolayers, including 1T'-MoS2, 1T'-MoSe2, 1T'-WS2, and 1T'-WSe2, which are revealed to be of high phase purity. Moreover, the surfactant-reliant stacking-hinderable growth mechanism of 1T'-TMD nano-monolayers was unveiled through systematic experiments and theoretical calculations. As a proof-of-concept application, the 1T'-TMD nano-monolayers are used for electrocatalytic hydrogen production in an acidic medium. The 1T'-MoS2 nano-monolayers possess abundant in-plane electrocatalytic active sites and high conductivity, coupled with the contribution of the lattice strain, thus exhibiting excellent performance. Importantly, the catalyst shows impressive endurability in electroactivity. Our developed general scalable strategy could pave the way to extend the synthesis of other broad metastable semimetallic-phase TMDs, which offer great potential to explore novel crystal phase-dependent properties with wide application development for catalysis and beyond.
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Small molecule probes with distinct reactivities are useful tools for the identification and characterization of protein modifications and function. Herein, we show that hydrazone probes with an N-carbamate structural motif react differently from N-carbamates within the human proteome. Mass spectrometry analysis of probe-treated mammalian cell lysates identified several proteins that were covalently modified by the hydrazone probes, including the cytidine deaminase APOBEC3A. We used this enzyme as a model to explore the reactivity of the probes with amino acid residues using LC-MS/MS. Both reactive serine and cysteine residues outside of the enzyme active site were covalently modified. A 1-napthol leaving group provided the most extensive reactivity. These results confirm a unique chemotype for hydrazone probes which can be further optimized to target distinct targets of the human proteome.
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Heparins and sulfated polysaccharides have been recognized as effective clinical anticoagulants for several decades. Heparins exhibit heterogeneity depending on the sources. Meanwhile, the adverse effect in the clinical uses and the adulteration of oversulfated chondroitin sulfate (OSCS) in heparins develop additional attention to analyze the purity of heparins. This review starts with the description of the classification, anticoagulant mechanism, clinical application of heparins and focuses on the existing methods of heparin analysis and detection including traditional detection methods, as well as new methods using fluorescence or gold nanomaterials as probes. The in-depth understanding of these techniques for the analysis of heparins will lay a foundation for the further development of novel methods for the detection of heparins.
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Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle ("myobundle") to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)-induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ-induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ-induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.
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Exercício Físico , Interferon gama , Inibidores de Janus Quinases , Músculo Esquelético , Estimulação Elétrica , Exercício Físico/fisiologia , Humanos , Interferon gama/efeitos adversos , Interferon gama/metabolismo , Inibidores de Janus Quinases/farmacologia , Janus Quinases , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Transdução de Sinais , Engenharia Tecidual/métodosRESUMO
Baicalensines A (1) and B (2) were isolated from the roots of Thalictrum baicalense and structurally characterized using spectroscopic data, 13C NMR calculations, and the CASE algorithm. Compound 1, representing a new class of alkaloid dimers, contains berberine conjugated to a ring-opened isoquinoline. Compound 2 is the first reported natural benzylisoquinoline bearing a formyl group at C-3. Plausible biosynthetic pathways are proposed. Compound 1 exerted moderate cytotoxicity against the Caco-2 and HL-60 cell lines.
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Antineoplásicos Fitogênicos/farmacologia , Berberina/farmacologia , Thalictrum/química , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Berberina/química , Berberina/isolamento & purificação , Células CACO-2 , Células HL-60 , Humanos , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Isoquinolinas/farmacologia , Estrutura Molecular , Raízes de Plantas/químicaRESUMO
BACKGROUND: Extensive bioactivities of alkaloids from the genus Macleaya (Macleaya cordata (Willd.) R. Br. and Macleaya microcarpa (Maxim.) Fedde) have been widely reported, as well as more and more concerned from the scientific communities. However, systematic research on the phytochemical information of M. microcarpa is incomplete. The aim of this study was to rapidly and conveniently qualitative analyze alkaloids from M. microcarpa by ultra-performance liquid chromatography/quadrupole-time-of-fight mass spectrometry (UHPLC-Q-TOF-MS) using accurate mass weight and characteristic fragment ions, furthermore separate and identify the main alkaloids, test antitumor activity in vitro and antiangiogenic activity in vivo. RESULTS: A total of 14 alkaloids from fruits of M. microcarpa were identified by UHPLC-Q-TOF-MS, including 5 protopines, 2 benzophenanthridines, 1 dimer, 1 dihydrobenzophenanthridines and 5 unknown structure compounds. Two major alkaloids were isolated by various column chromatographic methods. Their structures were determined by NMR data and related literatures. The two major alkaloids were evaluated for intro cytotoxic activities against HL-60, MCF-7, A-549, and in vivo antiangiogenic activity using transgenic zebrafish. CONCLUSIONS: Current qualitative method based on UHPLC-Q-TOF-MS technique provided a scientific basis for isolation, structural identification, and in vitro or in vivo pharmacological further study of alkaloids from M. microcarpa in the future.