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1.
Immunity ; 56(6): 1410-1428.e8, 2023 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-37257450

RESUMO

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.


Assuntos
Plaquetas , COVID-19 , Humanos , SARS-CoV-2 , Infecções Irruptivas , Multiômica , Anticorpos Neutralizantes , Anticorpos Antivirais
2.
Nature ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987597

RESUMO

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

3.
Mol Microbiol ; 121(2): 275-290, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167837

RESUMO

Candida albicans, an opportunistic fungal pathogen, is able to switch between two distinct cell types: white and opaque. While white-to-opaque switching is typically repressed by the a1/α2 heterodimer in MTLa/α cells, it was recently reported that switching can also occur in some natural MTLa/α strains under certain environmental conditions. However, the regulatory program governing white-opaque switching in MTLa/α cells is not fully understood. Here, we collected 90 clinical isolates of C. albicans, 16 of which possess the ability to form opaque colonies. Among the known regulators implicated in white-opaque switching, only OFI1 exhibited significantly higher expression in these 16 strains compared to the reference strain SC5314. Importantly, ectopic expression of OFI1 in both clinical isolates and laboratory strains promoted switching frequency even in the absence of N-acetylglucosamine and high CO2 , the optimal condition for white-to-opaque switching in MTLa/α strains. Deleting OFI1 resulted in a reduction in opaque-formation frequency and the stability of the opaque cell in MTLa/α cells. Ofi1 binds to the promoters of WOR1 and WOR3 to induce their expression, which facilitates white-to-opaque switching. Ofi1 is conserved across the CTG species. Altogether, our study reported the identification of a transcription factor Ofi1 as the critical regulator that promotes white-to-opaque switching in natural MTLa/α isolates of C. albicans.


Assuntos
Candida albicans , Fatores de Transcrição , Candida albicans/genética , Candida albicans/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Regiões Promotoras Genéticas/genética , Fenótipo
4.
Brief Bioinform ; 24(5)2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37605947

RESUMO

Predicting the biological properties of molecules is crucial in computer-aided drug development, yet it's often impeded by data scarcity and imbalance in many practical applications. Existing approaches are based on self-supervised learning or 3D data and using an increasing number of parameters to improve performance. These approaches may not take full advantage of established chemical knowledge and could inadvertently introduce noise into the respective model. In this study, we introduce a more elegant transformer-based framework with focused attention for molecular representation (TransFoxMol) to improve the understanding of artificial intelligence (AI) of molecular structure property relationships. TransFoxMol incorporates a multi-scale 2D molecular environment into a graph neural network + Transformer module and uses prior chemical maps to obtain a more focused attention landscape compared to that obtained using existing approaches. Experimental results show that TransFoxMol achieves state-of-the-art performance on MoleculeNet benchmarks and surpasses the performance of baselines that use self-supervised learning or geometry-enhanced strategies on small-scale datasets. Subsequent analyses indicate that TransFoxMol's predictions are highly interpretable and the clever use of chemical knowledge enables AI to perceive molecules in a simple but rational way, enhancing performance.


Assuntos
Inteligência Artificial , Benchmarking , Redes Neurais de Computação
5.
Nat Mater ; 23(2): 244-251, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38191629

RESUMO

Interface reaction between lithium (Li) and materials at the anode is not well understood in an all-solid environment. This paper unveils a new phenomenon of constriction susceptibility for materials at such an interface, the utilization of which helps facilitate the design of an active three-dimensional scaffold to host rapid plating and stripping of a significant amount of a thick Li metal layer. Here we focus on the well-known anode material silicon (Si) to demonstrate that, rather than strong Li-Si alloying at the conventional solid-liquid interface, the lithiation reaction of micrometre-sized Si can be significantly constricted at the solid-solid interface so that it occurs only at thin surface sites of Si particles due to a reaction-induced, diffusion-limiting process. The dynamic interaction between surface lithiation and Li plating of a family of anode materials, as predicted by our constrained ensemble computational approach and represented by Si, silver (Ag) and alloys of magnesium (Mg), can thus more homogeneously distribute current densities for the rapid cycling of Li metal at high areal capacity, which is important in regard to solid-state battery application.

6.
Nat Mater ; 23(1): 52-57, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38052935

RESUMO

Although metallic nanostructures have been attracting tremendous research interest in nanoscience and nanotechnologies, it is known that environmental attacks, such as surface oxidation, can easily initiate cracking on the surface of metals, thus deteriorating their overall functional/structural properties1-3. In sharp contrast, here we report that severely oxidized metallic glass nanotubes can attain an ultrahigh recoverable elastic strain of up to ~14% at room temperature, which outperform bulk metallic glasses, metallic glass nanowires and many other superelastic metals hitherto reported. Through in situ experiments and atomistic simulations, we reveal that the physical mechanisms underpinning the observed superelasticity can be attributed to the formation of a percolating oxide network in metallic glass nanotubes, which not only restricts atomic-scale plastic events during loading but also leads to the recovery of elastic rigidity on unloading. Our discovery implies that oxidation in low-dimensional metallic glasses can result in unique properties for applications in nanodevices.

7.
Acc Chem Res ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38963189

RESUMO

ConspectusTwo-dimensional conjugated metal-organic frameworks (2D c-MOFs) have emerged as a novel class of multifunctional materials, attracting increasing attention due to their highly customizable chemistry yielding programmable and unprecedented structures and properties. In particular, over the past decade, the synergistic relationship between the conductivity and porosity of 2D c-MOFs has paved the way toward their widespread applications. Despite their promising potential, the majority of 2D c-MOFs have yet to achieve atomically precise crystal structures, hindering the full understanding and control over their electronic structure and intrinsic charge transport characteristics. When modulating the charge transport properties of two-dimensional layered framework materials, decoupling the charge transport processes within and in between layers is of paramount importance, yet it represents a significant challenge. Unfortunately, 2D c-MOFs systems developed so far have failed to address such a major research target, which can be achieved solely by manipulating charge transport properties in 2D c-MOFs. 2D c-MOFs offer a significant advantage over organic radical molecules and covalent organic frameworks: polymerization through oxidative coordination is a viable route to form "spin-concentrated assemblies". However, the role of these spin centers in charge transport processes is still poorly understood, and the intrinsic dynamics and properties of these spins have seldom been investigated. Consequently, overcoming these challenges is essential to unlock the full potential of 2D c-MOFs in electronics and other related fields, as a new type of quantum materials.In this Account, we summarize and discuss our group's efforts to achieve full control at the atomic level over the structure of 2D c-MOFs and their applications in electronics and spintronics, thereby providing distinct evidence on 2D c-MOFs as a promising platform for exploring novel quantum phenomena. First, we unravel the key role played by the rational design of the ligands to decrease the boundary defects, achieve atomically precise large single crystals, and investigate the intrinsic charge transport properties of 2D c-MOFs. The advantages and disadvantages of the current structural elucidation strategies will be discussed. Second, the fundamental challenge in 2D c-MOF charge transport studies is to decouple the in-plane and interlayer charge transport pathways and achieve precise tuning of the charge transport properties in 2D c-MOFs. To address this challenge, we propose a design concept for the second-generation conjugated ligands, termed "programmable conjugated ligands", to replace the current first-generation ligands which lack modifiability as they mainly consist of sp2 hybridization atoms. Our efforts also extend to controlling the spin dynamics properties of 2D c-MOFs as "spin concentrated assemblies" using a bottom-up strategy.We hope this Account provides enlightening fundamental insights and practical strategies to overcome the major challenges of 2D c-MOFs for electronics and spintronics. Through the rational design of structural modulation within the 2D plane and interlayer interactions, we are committed to making significant steps forward for boosting the functional complexity of this blooming family of materials, thereby opening clear perspectives toward their practical application in electronics with the ultimate goal of inspiring further development of 2D c-MOFs and unleashing their full potential as an emerging quantum material.

8.
Chem Rev ; 123(24): 14119-14184, 2023 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-38055201

RESUMO

Solid-state phase transformation is an intriguing phenomenon in crystalline or noncrystalline solids due to the distinct physical and chemical properties that can be obtained and modified by phase engineering. Compared to bulk solids, nanomaterials exhibit enhanced capability for phase engineering due to their small sizes and high surface-to-volume ratios, facilitating various emerging applications. To establish a comprehensive atomistic understanding of phase engineering, in situ transmission electron microscopy (TEM) techniques have emerged as powerful tools, providing unprecedented atomic-resolution imaging, multiple characterization and stimulation mechanisms, and real-time integrations with various external fields. In this Review, we present a comprehensive overview of recent advances in in situ TEM studies to characterize and modulate nanomaterials for phase transformations under different stimuli, including mechanical, thermal, electrical, environmental, optical, and magnetic factors. We briefly introduce crystalline structures and polymorphism and then summarize phase stability and phase transformation models. The advanced experimental setups of in situ techniques are outlined and the advantages of in situ TEM phase engineering are highlighted, as demonstrated via several representative examples. Besides, the distinctive properties that can be obtained from in situ phase engineering are presented. Finally, current challenges and future research opportunities, along with their potential applications, are suggested.

9.
Chem Rev ; 123(12): 7421-7497, 2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37232480

RESUMO

Polymer semiconductors composed of a carbon-based π conjugated backbone have been studied for several decades as active layers of multifarious organic electronic devices. They combine the advantages of the electrical conductivity of metals and semiconductors and the mechanical behavior of plastics, which are going to become one of the futures of modulable electronic materials. The performance of conjugated materials depends both on their chemical structures and the multilevel microstructures in solid states. Despite the great efforts that have been made, they are still far from producing a clear picture among intrinsic molecular structures, microstructures, and device performances. This review summarizes the development of polymer semiconductors in recent decades from the aspects of material design and the related synthetic strategies, multilevel microstructures, processing technologies, and functional applications. The multilevel microstructures of polymer semiconductors are especially emphasized, which plays a decisive role in determining the device performance. The discussion shows the panorama of polymer semiconductors research and sets up a bridge across chemical structures, microstructures, and finally devices performances. Finally, this review discusses the grand challenges and future opportunities for the research and development of polymer semiconductors.

10.
Proc Natl Acad Sci U S A ; 119(45): e2211228119, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36322742

RESUMO

Magnetic targeting is one of the most promising approaches for improving the targeting efficiency by which magnetic drug carriers are directed using external magnetic fields to reach their targets. As a natural magnetic nanoparticle (MNP) of biological origin, the magnetosome is a special "organelle" formed by biomineralization in magnetotactic bacteria (MTB) and is essential for MTB magnetic navigation to respond to geomagnetic fields. The magnetic targeting of magnetosomes, however, can be hindered by the aggregation and precipitation of magnetosomes in water and biological fluid environments due to the strong magnetic attraction between particles. In this study, we constructed a magnetosome-like nanoreactor by introducing MTB Mms6 protein into a reverse micelle system. MNPs synthesized by thermal decomposition exhibit the same crystal morphology and magnetism (high saturation magnetization and low coercivity) as natural magnetosomes but have a smaller particle size. The DSPE-mPEG-coated magnetosome-like MNPs exhibit good monodispersion, penetrating the lesion area of a tumor mouse model to achieve magnetic enrichment by an order of magnitude more than in the control groups, demonstrating great prospects for biomedical magnetic targeting applications.


Assuntos
Magnetossomos , Magnetospirillum , Nanopartículas , Neoplasias , Camundongos , Animais , Proteínas de Bactérias/metabolismo , Magnetossomos/química , Bactérias Gram-Negativas/metabolismo , Nanopartículas/química , Campos Magnéticos , Neoplasias/metabolismo , Magnetospirillum/metabolismo
11.
Nano Lett ; 24(1): 424-432, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38153402

RESUMO

Applying high pressure to effectively modulate the electronic and lattice structures of materials could unravel various physical properties associated with phase transitions. In this work, high-pressure-compatible femtosecond pump-probe microscopy was constructed to study the pressure-dependent ultrafast dynamics in black phosphorus (BP) thin films. We observed pressure-driven evolution of the electronic topological transition and three structural phases as the pressure reached ∼22 GPa, which could be clearly differentiated in the transient absorption images containing spatially resolved ultrafast carrier and coherent phonon dynamics. Surprisingly, an anomalous coherent acoustic phonon mode with pressure softening behavior was observed within the range of ∼3-8 GPa, showing distinct laser power and time dependences. Density functional theory calculations show that this mode, identified as the shear mode along the armchair orientation, gains significant electron-phonon coupling strength from out-of-plane compression that leads to decreased phonon frequency. Our results provide insights into the structure evolution of BP with pressure and hold potential for applications in microelectromechanical devices.

12.
Nano Lett ; 24(23): 7108-7115, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38722094

RESUMO

Diamond is considered the most promising next-generation semiconductor material due to its excellent physical characteristics. It has been more than three decades since the discovery of a special structure named n-diamond. However, despite extensive efforts, its crystallographic structure and properties are still unclear. Here, we show that subdisordered structures in diamond provide an explanation for the structural feature of n-diamond. Monocrystalline diamond with subdisordered structures is synthesized via the chemical vapor deposition method. Atomic-resolution scanning transmission electron microscopy characterizations combined with the picometer-precision peak finder technology and diffraction simulations reveal that picometer-scale shifts of atoms within cells of diamond govern the subdisordered structures. First-principles calculations indicate that the bandgap of diamond decreases rapidly with increasing shifting distance, in accordance with experimental results. These findings clarify the crystallographic structure and electronic properties of n-diamond and provide new insights into the bandgap adjustment in diamond.

13.
Genes Chromosomes Cancer ; 63(1): e23210, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37870859

RESUMO

COL1A1::PDGFB fusion uterine sarcoma is a rare uterine mesenchymal tumor with some clinicopathological features that overlap with those of soft tissue dermatofibrosarcoma protuberans. However, the varied clinicopathologic and genetic characteristics have not been fully revealed, which may be a potential pitfall for diagnosis. Here, we present a case of COL1A1::PDGFB fusion-positive uterine sarcoma in a 49-years-old female. Histologically, the tumor from the initial marginal excision predominantly exhibited high-grade fibrosarcomatous and myxofibrosarcoma-like appearances, while a low-grade focal area displaying storiform growth was identified in the residual tumor after subsequently extended resection. Immunohistochemically, the high-grade components mainly exhibited focal positivity for CD34 and mutated-type p53 immunoreactivity, whereas the low-grade component showed diffuse positivity for CD34 and wild-type p53 staining. The COL1A1::PDGFB fusion was confirmed by fluorescence in situ hybridization and next-generation sequencing. In addition, the TERT-124 C > T mutation was further identified in this lesion's fibrosarcomatous and classic storiform components. To the best of our knowledge, this is the first described case of COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation, which might be a novel genetic finding associated with tumorigenesis of this rare tumor.


Assuntos
Dermatofibrossarcoma , Fibrossarcoma , Neoplasias Pélvicas , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Telomerase , Neoplasias Uterinas , Feminino , Humanos , Pessoa de Meia-Idade , Dermatofibrossarcoma/genética , Fibrossarcoma/genética , Hibridização in Situ Fluorescente , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Neoplasias Cutâneas/genética , Telomerase/genética , Proteína Supressora de Tumor p53/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/cirurgia
14.
Lancet Oncol ; 25(5): 658-667, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38608693

RESUMO

BACKGROUND: Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. METHODS: The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. FINDINGS: From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. INTERPRETATION: Cabozantinib shows promising activity in patients with MPPGs. FUNDING: Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.


Assuntos
Neoplasias das Glândulas Suprarrenais , Anilidas , Paraganglioma , Feocromocitoma , Piridinas , Humanos , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Feocromocitoma/tratamento farmacológico , Feocromocitoma/patologia , Feocromocitoma/genética , Paraganglioma/tratamento farmacológico , Paraganglioma/patologia , Adulto , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/secundário , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos
15.
J Neurosci ; 43(40): 6760-6778, 2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37607820

RESUMO

Unconscious acquisition of sequence structure from experienced events can lead to explicit awareness of the pattern through extended practice. Although the implicit-to-explicit transition has been extensively studied in humans using the serial reaction time (SRT) task, the subtle neural activity supporting this transition remains unclear. Here, we investigated whether frequency-specific neural signal transfer contributes to this transition. A total of 208 participants (107 females) learned a sequence pattern through a multisession SRT task, allowing us to observe the transitions. Session-by-session measures of participants' awareness for sequence knowledge were conducted during the SRT task to identify the session when the transition occurred. By analyzing time course RT data using switchpoint modeling, we identified an increase in learning benefit specifically at the transition session. Electroencephalogram (EEG)/magnetoencephalogram (MEG) recordings revealed increased theta power in parietal (precuneus) regions one session before the transition (pretransition) and a prefrontal (superior frontal gyrus; SFG) one at the transition session. Phase transfer entropy (PTE) analysis confirmed that directional theta transfer from precuneus → SFG occurred at the pretransition session and its strength positively predicted learning improvement at the subsequent transition session. Furthermore, repetitive transcranial magnetic stimulation (TMS) modulated precuneus theta power and altered transfer strength from precuneus to SFG, resulting in changes in both transition rate and learning benefit at that specific point of transition. Our brain-stimulation evidence supports a role for parietal → prefrontal theta signal transfer in igniting conscious awareness of implicitly acquired knowledge.SIGNIFICANCE STATEMENT There exists a pervasive phenomenon wherein individuals unconsciously acquire sequence patterns from their environment, gradually becoming aware of the underlying regularities through repeated practice. While previous studies have established the robustness of this implicit-to-explicit transition in humans, the refined neural mechanisms facilitating conscious access to implicit knowledge remain poorly understood. Here, we demonstrate that prefrontal activity, known to be crucial for conscious awareness, is triggered by neural signal transfer originating from the posterior brain region, specifically the precuneus. By employing brain stimulation techniques, we establish a causal link between neural signal transfer and the occurrence of awareness. Our findings unveil a mechanism by which implicit knowledge becomes consciously accessible in human cognition.


Assuntos
Conscientização , Aprendizagem , Feminino , Humanos , Conscientização/fisiologia , Aprendizagem/fisiologia , Córtex Pré-Frontal/fisiologia , Tempo de Reação/fisiologia , Eletroencefalografia
16.
Am J Physiol Cell Physiol ; 326(6): C1697-C1709, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38586875

RESUMO

Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal apoptosis. Although sirtuin 4 (SIRT4) has been implicated in regulating apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study used APP/PS1 mice as an animal model of AD and amyloid-ß (Aß)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine Aß deposition in mice and apoptosis, respectively. Protein expression was assessed by Western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of Sirt4. Subsequently, the binding of transcription factors to Sirt4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and Aß-treated HT-22 cells compared with their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced apoptosis, decreased Aß deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD.NEW & NOTEWORTHY The study reveals that in Alzheimer's disease models, SIRT4 expression increases, contributing to neuronal apoptosis and amyloid-ß deposition. Reducing SIRT4 lessens apoptosis and amyloid-ß accumulation, improving memory in mice. This process involves the mTOR pathway, regulated by STAT2 transcription factor. These findings suggest targeting the STAT2-SIRT4-mTOR axis as a potential Alzheimer's treatment strategy.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Apoptose , Modelos Animais de Doenças , Camundongos Transgênicos , Neurônios , Fator de Transcrição STAT2 , Transdução de Sinais , Sirtuínas , Serina-Treonina Quinases TOR , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Sirtuínas/metabolismo , Sirtuínas/genética , Serina-Treonina Quinases TOR/metabolismo , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Fator de Transcrição STAT2/metabolismo , Fator de Transcrição STAT2/genética , Peptídeos beta-Amiloides/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem Celular , Proteínas Mitocondriais
17.
J Am Chem Soc ; 146(4): 2574-2582, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38231138

RESUMO

Two-dimensional conjugated metal-organic frameworks (2D c-MOFs) have attracted increasing interest in electronics due to their (semi)conducting properties. Charge-neutral 2D c-MOFs also possess persistent organic radicals that can be viewed as spin-concentrated arrays, affording new opportunities for spintronics. However, the strong π-interaction between neighboring layers of layer-stacked 2D c-MOFs annihilates active spin centers and significantly accelerates spin relaxation, severely limiting their potential as spin qubits. Herein, we report the precise tuning of the charge transport and spin dynamics in 2D c-MOFs via the control of interlayer stacking. The introduction of bulky side groups on the conjugated ligands enables a significant dislocation of the 2D c-MOFs layers from serrated stacking to staggered stacking, thereby spatially weakening the interlayer interactions. As a consequence, the electrical conductivity of 2D c-MOFs decreases by 6 orders of magnitude, while the spin density achieves more than a 30-fold increase and the spin-lattice relaxation time (T1) is increased up to ∼60 µs, hence being superior to the reference 2D c-MOFs with compact stackings whose spin relaxation is too fast to be detected. Spin dynamics results also reveal that spinless polaron pairs or bipolarons play critical roles in the charge transport of these 2D c-MOFs. Our strategy provides a bottom-up approach for enlarging spin dynamics in 2D c-MOFs, opening up pathways for developing MOF-based spintronics.

18.
Mol Microbiol ; 119(1): 112-125, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36545847

RESUMO

Candida albicans is a normal resident of humans and also a prevalent fungal pathogen. Lactate, a nonfermentative carbon source available in numerous anatomical niches, can be used by C. albicans as a carbon source. However, the key regulator(s) involved in this process remain unknown. Here, through a genetic screen, we report the identification of a transcription factor Zcf24 that is specifically required for lactate utilization in C. albicans. Zcf24 is responsible for the induction of CYB2, a gene encoding lactate dehydrogenase that is essential for lactate catabolism, in response to lactate. Chromatin immunoprecipitation showed a significantly higher signal of Zcf24 on the CYB2 promoter in lactate-grown cells than that in glucose-grown cells. Genome-wide transcription profiling indicates that, in addition to CYB2, Zcf24 regulates genes involved in the ß-oxidation of fatty acids, iron transport, and drug transport. Surprisingly, deleting ZCF24 confers enhanced commensal fitness. This could be attributed to Crz1-activated ß-glucan masking in the zcf24 mutant. The orthologs of Zcf24 are distributed in species most closely to C. albicans and some filamentous fungal species. Altogether, Zcf24 is the first transcription factor identified to date that regulates lactate catabolism in C. albicans and it is also involved in the regulation of commensalism.


Assuntos
Candida albicans , Proteínas Fúngicas , Ácido Láctico , Fatores de Transcrição , Candida albicans/metabolismo , Carbono/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Ácido Láctico/metabolismo , Simbiose , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Dedos de Zinco
19.
Clin Immunol ; 261: 110163, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38401659

RESUMO

Rowell's syndrome is an autoimmune disease characterized by lupus erythematosus, erythema multiforme skin lesions, and speckled antinuclear antibody. We report the case of a woman who presented with erythema multiforme with target-type skin lesions and vulvar vegetation who fulfilled the criteria for Rowell's syndrome and condyloma acuminatum. The simultaneous occurrence of both conditions has rarely been reported in the literature.


Assuntos
Eritema Multiforme , Lúpus Eritematoso Sistêmico , Feminino , Humanos , Síndrome , Eritema Multiforme/diagnóstico , Eritema Multiforme/patologia , Anticorpos Antinucleares
20.
Small ; : e2311185, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38616775

RESUMO

The layer-by-layer stacked van der Waals structures (termed vdW hetero/homostructures) offer a new paradigm for materials design-their physical properties can be tuned by the vertical stacking sequence as well as by adding a mechanical twist, stretch, and hydrostatic pressure to the atomic structure. In particular, simple twisting and stacking of two layers of graphene can form a uniform and ordered Moiré superlattice, which can effectively modulate the electrons of graphene layers and lead to the discovery of unconventional superconductivity and strong correlations. However, the twist angle of twisted bilayer graphene (tBLG) is almost unchangeable once the interlayer stacking is determined, while applying mechanical elastic strain provides an alternative way to deeply regulate the electronic structure by controlling the lattice spacing and symmetry. In this review, diverse experimental advances are introduced in straining tBLG by in-plane and out-of-plane modes, followed by the characterizations and calculations toward quantitatively tuning the strain-engineered electronic structures. It is further discussed that the structural relaxation in strained Moiré superlattice and its influence on electronic structures. Finally, the conclusion entails prospects for opportunities of strained twisted 2D materials, discussions on existing challenges, and an outlook on the intriguing emerging field, namely "strain-twistronics".

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