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1.
Nature ; 625(7994): 276-281, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38200300

RESUMEN

In the field of semiconductors, three-dimensional (3D) integration not only enables packaging of more devices per unit area, referred to as 'More Moore'1 but also introduces multifunctionalities for 'More than Moore'2 technologies. Although silicon-based 3D integrated circuits are commercially available3-5, there is limited effort on 3D integration of emerging nanomaterials6,7 such as two-dimensional (2D) materials despite their unique functionalities7-10. Here we demonstrate (1) wafer-scale and monolithic two-tier 3D integration based on MoS2 with more than 10,000 field-effect transistors (FETs) in each tier; (2) three-tier 3D integration based on both MoS2 and WSe2 with about 500 FETs in each tier; and (3) two-tier 3D integration based on 200 scaled MoS2 FETs (channel length, LCH = 45 nm) in each tier. We also realize a 3D circuit and demonstrate multifunctional capabilities, including sensing and storage. We believe that our demonstrations will serve as the foundation for more sophisticated, highly dense and functionally divergent integrated circuits with a larger number of tiers integrated monolithically in the third dimension.

2.
Mol Cell ; 81(13): 2736-2751.e8, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33932349

RESUMEN

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias Colorrectales/metabolismo , Ácido Mevalónico/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Ratones , Ratones Transgénicos , Proteínas Supresoras de Tumor/genética , Proteínas Señalizadoras YAP
3.
PLoS Pathog ; 20(4): e1012123, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38607975

RESUMEN

RAB GTPases (RABs) control intracellular membrane trafficking with high precision. In the present study, we carried out a short hairpin RNA (shRNA) screen focused on a library of 62 RABs during infection with porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), a member of the family Arteriviridae. We found that 13 RABs negatively affect the yield of PRRSV-2 progeny virus, whereas 29 RABs have a positive impact on the yield of PRRSV-2 progeny virus. Further analysis revealed that PRRSV-2 infection transcriptionally regulated RAB18 through RIG-I/MAVS-mediated canonical NF-κB activation. Disrupting RAB18 expression led to the accumulation of lipid droplets (LDs), impaired LDs catabolism, and flawed viral replication and assembly. We also discovered that PRRSV-2 co-opts chaperone-mediated autophagy (CMA) for lipolysis via RAB18, as indicated by the enhanced associations between RAB18 and perlipin 2 (PLIN2), CMA-specific lysosomal associated membrane protein 2A (LAMP2A), and heat shock protein family A (Hsp70) member 8 (HSPA8/HSC70) during PRRSV-2 infection. Knockdown of HSPA8 and LAMP2A impacted on the yield of PRRSV-2 progeny virus, implying that the virus utilizes RAB18 to promote CMA-mediated lipolysis. Importantly, we determined that the C-terminal domain (CTD) of HSPA8 could bind to the switch II domain of RAB18, and the CTD of PLIN2 was capable of associating with HSPA8, suggesting that HSPA8 facilitates the interaction between RAB18 and PLIN2 in the CMA process. In summary, our findings elucidate how PRRSV-2 hijacks CMA-mediated lipid metabolism through innate immune activation to enhance the yield of progeny virus, offering novel insights for the development of anti-PRRSV-2 treatments.


Asunto(s)
Autofagia Mediada por Chaperones , Virus del Síndrome Respiratorio y Reproductivo Porcino , Porcinos , Animales , Lipólisis , Regulación hacia Arriba , Proteínas de Unión al GTP rab/genética , Proteínas de Membrana de los Lisosomas , ARN Interferente Pequeño
4.
Nat Mater ; 23(2): 271-280, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37957270

RESUMEN

Interfacing molecular machines to inorganic nanoparticles can, in principle, lead to hybrid nanomachines with extended functions. Here we demonstrate a ligand engineering approach to develop atomically precise hybrid nanomachines by interfacing gold nanoclusters with tetraphenylethylene molecular rotors. When gold nanoclusters are irradiated with near-infrared light, the rotation of surface-decorated tetraphenylethylene moieties actively dissipates the absorbed energy to sustain the photothermal nanomachine with an intact structure and steady efficiency. Solid-state nuclear magnetic resonance and femtosecond transient absorption spectroscopy reveal that the photogenerated hot electrons are rapidly cooled down within picoseconds via electron-phonon coupling in the nanomachine. We find that the nanomachine remains structurally and functionally intact in mammalian cells and in vivo. A single dose of near-infrared irradiation can effectively ablate tumours without recurrence in tumour-bearing mice, which shows promise in the development of nanomachine-based theranostics.


Asunto(s)
Nanopartículas , Neoplasias , Estilbenos , Animales , Ratones , Fototerapia/métodos , Nanopartículas/química , Oro/química , Mamíferos
5.
Hepatology ; 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38537130

RESUMEN

BACKGROUND AND AIMS: Tumor microenvironment (TME) heterogeneity leads to a discrepancy in survival prognosis and clinical treatment response for patients with HCC. The clinical applications of documented molecular subtypes are constrained by several issues. APPROACH AND RESULTS: We integrated 3 single-cell data sets to describe the TME landscape and identified 6 prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and the Xiangya HCC cohort. TME features were estimated using single-cell immune repertoire sequencing, mass cytometry, and multiplex immunofluorescence. The prognosis-related score was constructed based on a machine-learning algorithm. Comprehensive single-cell analysis described TME heterogeneity in HCC. The 5 transcriptomic subtypes possessed different clinical prognoses, stemness characteristics, immune landscapes, and therapeutic responses. Class 1 exhibited an inflamed phenotype with better clinical outcomes, while classes 2 and 4 were characterized by a lack of T-cell infiltration. Classes 5 and 3 indicated an inhibitory tumor immune microenvironment. Analysis of multiple therapeutic cohorts suggested that classes 5 and 3 were sensitive to immune checkpoint blockade and targeted therapy, whereas classes 1 and 2 were more responsive to transcatheter arterial chemoembolization treatment. Class 4 displayed resistance to all conventional HCC therapies. Four potential therapeutic agents and 4 targets were further identified for high prognosis-related score patients with HCC. CONCLUSIONS: Our study generated a clinically valid molecular classification to guide precision medicine in patients with HCC.

6.
Mol Psychiatry ; 2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-39003414

RESUMEN

Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.

7.
Mol Psychiatry ; 29(3): 730-741, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38221548

RESUMEN

Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.


Asunto(s)
Complejo Nuclear Basolateral , Cocaína , Consolidación de la Memoria , Neuronas , Corteza Prefrontal , Animales , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Cocaína/farmacología , Masculino , Ratas , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Señales (Psicología) , Ratas Sprague-Dawley , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Autoadministración , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Espinas Dendríticas/fisiología , Trastornos Relacionados con Cocaína/metabolismo , Trastornos Relacionados con Cocaína/fisiopatología , Memoria/efectos de los fármacos , Memoria/fisiología
8.
Chem Rev ; 123(24): 14119-14184, 2023 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-38055201

RESUMEN

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.
Nature ; 575(7782): 336-340, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31723273

RESUMEN

Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials1. The discovery of simpler, milder and more efficient approaches to organoborons can open additional routes to diverse substances2-5. Here we show a general method for the directed C-H borylation of arenes and heteroarenes without the use of metal catalysts. C7- and C4-borylated indoles are produced by a mild approach that is compatible with a broad range of functional groups. The mechanism, which is established by density functional theory calculations, involves BBr3 acting as both a reagent and a catalyst. The potential utility of this strategy is highlighted by the downstream transformation of the formed boron species into natural products and drug scaffolds.


Asunto(s)
Compuestos de Boro/química , Compuestos de Boro/síntesis química , Boro/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Teoría Funcional de la Densidad , Descubrimiento de Drogas , Indoles/química , Compuestos Organometálicos/química , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química
10.
J Med Genet ; 61(2): 176-181, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-37798098

RESUMEN

BACKGROUND: Expanded genetic screening before conception or during prenatal care can provide a more comprehensive evaluation of heritable fetal diseases. This study aimed to provide a large cohort to evaluate the significance of expanded carrier screening and to consolidate the role of expanded genetic screening in prenatal care. METHODS: This multicentre, retrospective cohort study was conducted between 31 December 2019 and 21 July 2022. A screening panel containing 302 genes and next-generation sequencing were used for the evaluation. The patients were referred from obstetric clinics, infertility centres and medical centres. Genetic counsellors conducted consultation for at least 15 min before and after screening. RESULTS: A total of 1587 patients were screened, and 653 pairs were identified. Among the couples who underwent the screening, 62 (9.49%) had pathogenic variants detected on the same genes. In total, 212 pathogenic genes were identified in this study. A total of 1173 participants carried at least one mutated gene, with a positive screening rate of 73.91%. Among the pathogenic variants that were screened, the gene encoding gap junction beta-2 (GJB2) exhibited the highest prevalence, amounting to 19.85%. CONCLUSION: Next-generation sequencing carrier screening provided additional information that may alter prenatal obstetric care by 9.49%. Pan-ethnic genetic screening and counselling should be suggested for couples of fertile age.


Asunto(s)
Consejo , Pruebas Genéticas , Embarazo , Femenino , Humanos , Tamización de Portadores Genéticos , Estudios Retrospectivos , Estudios Prospectivos
11.
Proc Natl Acad Sci U S A ; 119(36): e2205629119, 2022 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-36037365

RESUMEN

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.


Asunto(s)
Apoptosis , Tolerancia Inmunológica , Proteínas de la Membrana , Células Precursoras de Linfocitos B , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína Forkhead Box O1/metabolismo , Humanos , Lisosomas/metabolismo , Proteínas de la Membrana/genética , Fosfohidrolasa PTEN/metabolismo , Células Precursoras de Linfocitos B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
12.
J Cell Mol Med ; 28(9): e18286, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38742843

RESUMEN

Osteosarcoma, the primary bone cancer in adolescents and young adults, is notorious for its aggressive growth and metastatic potential. Our study delved into the prognostic impact of inflammasome-related gene signatures in osteosarcoma patients, employing comprehensive genetic profiling to uncover signatures linked with patient outcomes. We identified three patient subgroups through consensus clustering, with one showing worse survival rates correlated with high FGFR3 and RARB expressions. Immune profiling revealed significant immune cell infiltration differences among these subgroups, affecting survival. Utilising advanced machine learning, including StepCox and gradient boosting machine algorithms, we developed a prognostic model with a notable c-index of 0.706, highlighting CD36 and MYD88 as key genes. Higher inflammasome risk scores from our model were associated with poorer survival, corroborated across datasets. In vitro experiments validated CD36 and MYD88's roles in promoting osteosarcoma cell proliferation, invasion and migration, emphasising their therapeutic potential. This research offers new insights into inflammasomes' role in osteosarcoma, introducing novel biomarkers for risk assessment and potential therapeutic targets. Our findings suggest a pathway towards personalised treatment strategies, potentially improving patient outcomes in osteosarcoma.


Asunto(s)
Biomarcadores de Tumor , Neoplasias Óseas , Regulación Neoplásica de la Expresión Génica , Inflamasomas , Osteosarcoma , Humanos , Osteosarcoma/genética , Osteosarcoma/patología , Osteosarcoma/inmunología , Osteosarcoma/mortalidad , Inflamasomas/metabolismo , Inflamasomas/genética , Biomarcadores de Tumor/genética , Pronóstico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/mortalidad , Neoplasias Óseas/inmunología , Neoplasias Óseas/diagnóstico , Perfilación de la Expresión Génica , Femenino , Masculino , Transcriptoma/genética , Línea Celular Tumoral , Proliferación Celular/genética , Adolescente , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo
13.
Neuroimage ; 290: 120577, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38490585

RESUMEN

The extent to which brain responses are less distinctive across varying cognitive loads in older adults is referred to as neural dedifferentiation. Moment-to-moment brain signal variability, an emerging indicator, reveals not only the adaptability of an individual's brain as an inter-individual trait, but also the allocation of neural resources within an individual due to ever-changing task demands, thus shedding novel insight into the process of neural dedifferentiation. However, how the modulation of intra-individual brain signal variability reflects behavioral differences related to cognitively demanding tasks remains unclear. In this study, we employed functional near-infrared spectroscopy (fNIRS) imaging to capture the variability of brain signals, which was quantified by the standard deviation, during both the resting state and an n-back task (n = 1, 2, 3) in 57 healthy older adults. Using multivariate Partial Least Squares (PLS) analysis, we found that fNIRS signal variability increased from the resting state to the task and increased with working memory load in older adults. We further confirmed that greater fNIRS signal variability generally supported faster and more stable response time in the 2- and 3-back conditions. However, the intra-individual level analysis showed that the greater the up-modulation in fNIRS signal variability with cognitive loads, the more its accuracy decreases and mean response time increases, suggesting that a greater intra-individual brain signal variability up-modulation may reflect decreased efficiency in neural information processing. Taken together, our findings offer new insights into the nature of brain signal variability, suggesting that inter- and intra-individual brain signal variability may index distinct theoretical constructs.


Asunto(s)
Encéfalo , Imagen por Resonancia Magnética , Humanos , Anciano , Encéfalo/fisiología , Memoria a Corto Plazo/fisiología , Mapeo Encefálico/métodos , Cognición/fisiología
14.
J Am Chem Soc ; 146(7): 4320-4326, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38335536

RESUMEN

A highly efficient palladium-catalyzed asymmetric tandem aza-Heck/Sonogashira coupling reaction of O-phenyl hydroxamic ethers with terminal alkynes is described. This protocol enables versatile access to challenging chiral isoindolinone derivatives bearing a quaternary stereogenic center. The palladium-catalyzed aminoalkynylation reaction shows broad functional group tolerance and allows the straightforward preparation of isoindolinones with high efficiency and excellent enantioselectivity under mild conditions. DFT calculations were performed to disclose the reaction mechanism and the origins of the enantioselectivity.

15.
J Am Chem Soc ; 146(3): 2275-2285, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38215226

RESUMEN

The construction of structurally well-defined supramolecular hosts to accommodate catalytically active species within a cavity is a promising way to address catalyst deactivation. The resulting supramolecular catalysts can significantly improve the utilization of catalytic sites, thereby achieving a highly efficient chemical conversion. In this study, the Co-metalated phthalocyanine (Pc-Co) was successfully confined within a tetragonal prismatic metallacage, leading to the formation of a distinctive type of supramolecular photocatalyst (Pc-Co@Cage). The host-guest architecture of Pc-Co@Cage was unambiguously elucidated by single-crystal X-ray diffraction (SCXRD), NMR, and ESI-TOF-MS, revealing that the single cobalt active site can be thoroughly isolated within the space-restricted microenvironment. In addition, we found that Pc-Co@Cage can serve as a homogeneous supramolecular photocatalyst that displays high CO2 to CO conversion in aqueous media under visible light irradiation. This supramolecular photocatalyst exhibits an obvious improvement in activity (TONCO = 4175) and selectivity (SelCO = 92%) relative to the nonconfined Pc-Co catalyst (TONCO = 500, SelCO = 54%). The present strategy provided a rare example for the construction of a highly active, selective, and stable photocatalyst for CO2 reduction through a cavity-confined molecular catalyst within a discrete metallacage.

16.
Artículo en Inglés | MEDLINE | ID: mdl-38972436

RESUMEN

BACKGROUND: There are limited clinical data regarding the additional yields of random biopsies (RBs) during colorectal cancer surveillance in patients with inflammatory bowel disease. To assess the additional yield of RB, a systematic review and meta-analysis was conducted. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies investigating the preferred colonoscopy surveillance approach for inflammatory bowel disease patients. The additional yield, detection rate, procedure time, and withdrawal time were pooled. RESULTS: Thirty-seven studies (48 arms) were included in the meta-analysis with 9051 patients. The additional yields of RB were 10.34% in per-patient analysis and 16.20% in per-lesion analysis. The detection rates were 1.31% and 2.82% in per-patient and per-lesion analysis, respectively. Subgroup analysis showed a decline in additional yields from 14.43% to 0.42% in the per-patient analysis and from 19.20% to 5.32% in the per-lesion analysis for studies initiated before and after 2011. In per-patient analysis, the additional yields were 4.83%, 10.29%, and 56.05% for primary sclerosing cholangitis (PSC) proportions of 0% to 10%, 10% to 30%, and 100%, respectively. The corresponding detection rates were 0.56%, 1.40%, and 19.45%. In the per-lesion analysis, additional yields were 11.23%, 21.06%, and 45.22% for PSC proportions of 0% to 10%, 10% to 30%, and 100%, respectively. The corresponding detection rates were 2.09%, 3.58%, and 16.24%. CONCLUSIONS: The additional yields of RB were 10.34% and 16.20% for per-patient and per-lesion analyses, respectively. Considering the decreased additional yields in studies initiated after 2011, and the influence of PSC, endoscopy centers lacking full high-definition equipment should consider incorporating RB in the standard colonoscopy surveillance for inflammatory bowel disease patients, especially in those with PSC.

17.
Clin Gastroenterol Hepatol ; 22(6): 1265-1274.e19, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38354969

RESUMEN

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.


Asunto(s)
Hipercolesterolemia , Metabolismo de los Lípidos , Cirrosis Hepática Biliar , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Cirrosis Hepática Biliar/metabolismo , Cirrosis Hepática Biliar/complicaciones , Hipercolesterolemia/epidemiología , Anciano , Adulto , Lipidómica , Colesterol/sangre
18.
Hum Brain Mapp ; 45(1): e26566, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38224535

RESUMEN

Both plasma biomarkers and brain network topology have shown great potential in the early diagnosis of Alzheimer's disease (AD). However, the specific associations between plasma AD biomarkers, structural network topology, and cognition across the AD continuum have yet to be fully elucidated. This retrospective study evaluated participants from the Sino Longitudinal Study of Cognitive Decline cohort between September 2009 and October 2022 with available blood samples or 3.0-T MRI brain scans. Plasma biomarker levels were measured using the Single Molecule Array platform, including ß-amyloid (Aß), phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The topological structure of brain white matter was assessed using network efficiency. Trend analyses were carried out to evaluate the alterations of the plasma markers and network efficiency with AD progression. Correlation and mediation analyses were conducted to further explore the relationships among plasma markers, network efficiency, and cognitive performance across the AD continuum. Among the plasma markers, GFAP emerged as the most sensitive marker (linear trend: t = 11.164, p = 3.59 × 10-24 ; quadratic trend: t = 7.708, p = 2.25 × 10-13 ; adjusted R2 = 0.475), followed by NfL (linear trend: t = 6.542, p = 2.9 × 10-10 ; quadratic trend: t = 3.896, p = 1.22 × 10-4 ; adjusted R2 = 0.330), p-tau181 (linear trend: t = 8.452, p = 1.61 × 10-15 ; quadratic trend: t = 6.316, p = 1.05 × 10-9 ; adjusted R2 = 0.346) and Aß42/Aß40 (linear trend: t = -3.257, p = 1.27 × 10-3 ; quadratic trend: t = -1.662, p = 9.76 × 10-2 ; adjusted R2 = 0.101). Local efficiency decreased in brain regions across the frontal and temporal cortex and striatum. The principal component of local efficiency within these regions was correlated with GFAP (Pearson's R = -0.61, p = 6.3 × 10-7 ), NfL (R = -0.57, p = 6.4 × 10-6 ), and p-tau181 (R = -0.48, p = 2.0 × 10-4 ). Moreover, network efficiency mediated the relationship between general cognition and GFAP (ab = -0.224, 95% confidence interval [CI] = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA) or NfL (ab = -0.224, 95% CI = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA). Our findings suggest that network efficiency mediates the association between plasma biomarkers, specifically GFAP and NfL, and cognitive performance in the context of AD progression, thus highlighting the potential utility of network-plasma approaches for early detection, monitoring, and intervention strategies in the management of AD.


Asunto(s)
Enfermedad de Alzheimer , Conectoma , Sustancia Blanca , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Estudios Retrospectivos , Péptidos beta-Amiloides , Biomarcadores , Proteínas tau
19.
Small ; : e2311185, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38616775

RESUMEN

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".

20.
Acc Chem Res ; 56(10): 1213-1227, 2023 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-37126765

RESUMEN

ConspectusAs versatile, modular, and strongly coordinating moieties in organometallic compounds, N-heterocyclic carbenes (NHCs) have led to numerous breakthroughs in transition-metal catalysis, main group chemistry, and organocatalysis. In contrast, the chemistry of NHC-based metallosupramolecular assemblies, in which discrete individual components are held together via metal (M)-CNHC bonds, has been underdeveloped. Integrating NHCs into supramolecular assemblies would endow them with some unforeseen functions. However, one of the most critical challenges is seeking an appropriate combination of the rigid CNHC-M-CNHC units with the resulting topologies and applications. Toward this goal, for the last decade we have focused on the development of M-NHC directed toward metallosupramolecular synthesis. This Account aims to summarize our contributions to the application of M-NHC chemistry toward supramolecular synthesis from structural design to postassembly modification (PAM) and their functional applications since integrating NHCs into supramolecular assemblies has garnered much attention among organometallic, photochemical, and supramolecular researchers. While presenting representative examples of NHC-based architectures, we try to illustrate the purposes and concepts behind the systems developed to aid the rational approach to the design and fabrication of complex assemblies and M-NHC-templated photochemical reactions.We present synthetic approaches for new architectures by the rational design of starting NHC precursors, including the poly-NHC-based mechanically interlocked metallacages and the heteroleptic architectures based on electronic complementary and self-sorting mechanisms. The structural regulation of poly-NHC-based architectures with increasing topological complexity is elaborated on by selective combinations of tetraphenylethylene (TPE) units, NHC backbones, and N-wingtip substituents in a controllable manner.Subsequently, we move to elucidating an M-NHC-templated PAM approach that leads to functional organic cages featuring polyimidazolium/triazolium groups of different shapes and sizes that are difficult to access using alternative organic approaches. These organic cages possess well-defined cavities, and their in situ-generated NHC sites are ideal platforms for stabilizing metal nanoparticles (MNPs) within their cavities for improved catalytic performance.Finally, we demonstrate how to design supramolecular M-NHC templates to synthesize cyclobutane derivatives in homogeneous solutions in a catalytic fashion. Selected examples of M-NHC template-dependent structural transformations and photoreactions are discussed. Their applications in molecular recognition, aggregation-induced emission (AIE), cell imaging, anticancer activity, radical chemistry, and stimuli-responsive materials are also described.Taken together, M-NHC-templated approaches have proven to be powerful methods for constructing diverse architectures with functional applications. The development of this methodology is still in its infancy, with tremendous growth potential and a promising future. We believe that this Account will guide researchers to design fascinating and valuable M-carbene species for diverse applications.

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