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1.
Artículo en Inglés | MEDLINE | ID: mdl-39255166

RESUMEN

Multi-objective evolutionary algorithms (MOEAs) have emerged as powerful tools for solving complex optimization problems characterized by multiple, often conflicting, objectives. While advancements have been made in computational efficiency as well as diversity and convergence of solutions, a critical challenge persists: the internal evolutionary mechanisms are opaque to human users. Drawing upon the successes of explainable AI in explaining complex algorithms and models, we argue that the need to understand the underlying evolutionary operators and population dynamics within MOEAs aligns well with a visual analytics paradigm. This paper introduces ParetoTracker, a visual analytics framework designed to support the comprehension and inspection of population dynamics in the evolutionary processes of MOEAs. Informed by preliminary literature review and expert interviews, the framework establishes a multi-level analysis scheme, which caters to user engagement and exploration ranging from examining overall trends in performance metrics to conducting fine-grained inspections of evolutionary operations. In contrast to conventional practices that require manual plotting of solutions for each generation, ParetoTracker facilitates the examination of temporal trends and dynamics across consecutive generations in an integrated visual interface. The effectiveness of the framework is demonstrated through case studies and expert interviews focused on widely adopted benchmark optimization problems.

2.
World J Surg Oncol ; 22(1): 235, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39232762

RESUMEN

BACKGROUND: Micropapillary (MPP) adenocarcinoma is considered one of the most aggressive pathological types of lung adenocarcinoma (LADC). This retrospective study aimed to evaluate the prognostic significance and benefit of postoperative adjuvant therapy (PAT) in stage IA LADC patients with different proportions of MPP components. MATERIALS AND METHODS: We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019. In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH). The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination. RESULTS: Overall, 505 (TPMN, n = 375; TPML, n = 92; TPMH, n = 38) patients harboring EGFR mutations were enrolled in the study. Male sex (P = 0.044), high pathological stage (P < 0.001), and MPP pathological subtype (P < 0.001) were more frequent in the TPM-positive (TPMP) group than in the TPM-negative (TPMN) group. Five-year disease-free survival (DFS) rates were significantly lower in the TPMP group than in the TPMN group (84.5% vs. 93.4%, P = 0.006). In addition, patients with high proportions (greater than 10%) of MPP components had worse overall survival (OS) (91.0% vs. 98.9%, P = 0.025) than those with low proportions (5%≤ TPM ≤ 10%). However, postoperative EGFR tyrosine kinase inhibitors (TKIs) or adjuvant chemotherapy (ACT) cannot improve DFS and OS between EGFR-mutated patients with different proportions of MPP components. CONCLUSION: MPP was related to earlier recurrence and shortened survival time, even in stage IA. Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy.


Asunto(s)
Adenocarcinoma del Pulmón , Receptores ErbB , Neoplasias Pulmonares , Mutación , Estadificación de Neoplasias , Humanos , Masculino , Femenino , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/mortalidad , Estudios Retrospectivos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Persona de Mediana Edad , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/cirugía , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/mortalidad , Pronóstico , Anciano , Tasa de Supervivencia , Estudios de Seguimiento , Quimioterapia Adyuvante/métodos , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Neumonectomía , Adulto
3.
Nat Commun ; 15(1): 8011, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39271660

RESUMEN

Among the fascinating phenomena observed in two-dimensional (2D) magnets, the magneto-exciton effect stands out as a pivotal link between optics and magnetism. Although the excitonic effect has been revealed and exhibits a considerable correlation with the spin structures in certain 2D magnets, the underlying mechanism of the magneto-exciton effect remains underexplored, especially under high magnetic fields. Here we perform a systematic investigation of the spin-exciton coupling in 2D antiferromagnetic NiPS3 under high magnetic fields. When an in-plane magnetic field is applied, the exceptional sharp excitonic emission at ~1.4756 eV exhibits a Zeeman-like splitting with g ≈ 2.0, experimentally identifying the exciton as an excitation of dominant triplet-singlet character. By examining the polarization of excitonic emission and simulating the spin evolution, we further verify the correlation between excitonic emission and Néel vector in NiPS3. Our work elucidates the mechanism behind the spin-exciton coupling in NiPS3 and establishes a strategy for optically probing the spin evolutions in 2D magnets.

4.
bioRxiv ; 2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39345444

RESUMEN

TP53 , the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seq Ultra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3 - Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

5.
Soft Matter ; 20(37): 7362-7366, 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39268683

RESUMEN

Complex plasmas consist of ionized gas and charged solid microparticles, representing the plasma state of soft matter. We apply machine learning methods to investigate a melting transition in a two-dimensional complex plasma. A convolutional neural network is constructed and trained with the numerical simulation. The hexatic phase is successfully identified and the evolution of topological defects is studied during melting transition in both simulations and experiments.

6.
ACS Med Chem Lett ; 15(8): 1367-1375, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39140070

RESUMEN

Target protein degradation (TPD) has emerged as a revolutionary approach in drug discovery, leveraging the cell's intrinsic machinery to selectively degrade disease-associated proteins. Nanoluciferase (nLuc) fusion proteins and the NanoBiT technology offer two robust and sensitive screening platforms to monitor the subtle changes in protein abundance induced by TPD molecules. Despite these advantages, concerns have arisen regarding potential degradation artifacts introduced by tagging systems due to the presence of lysine residues on them, prompting the development of alternative tools. In this study, we introduce HiBiT-RR and nLucK0, variants devoid of lysine residues, to mitigate such artifacts. Our findings demonstrate that HiBiT-RR maintains a similar sensitivity and binding affinity with the original HiBiT. Moreover, the comparison between nLucWT and nLucK0 constructs reveals variations in degradation patterns induced by certain TPD molecules, emphasizing the importance of choosing appropriate tagging systems to ensure the reliability of experimental outcomes in studying protein degradation processes.

7.
Artículo en Inglés | MEDLINE | ID: mdl-39178071

RESUMEN

Spiking neural networks (SNNs), known for their low-power, event-driven computation, and intrinsic temporal dynamics, are emerging as promising solutions for processing dynamic, asynchronous signals from event-based sensors. Despite their potential, SNNs face challenges in training and architectural design, resulting in limited performance in challenging event-based dense prediction tasks compared with artificial neural networks (ANNs). In this work, we develop an efficient spiking encoder-decoder network (SpikingEDN) for large-scale event-based semantic segmentation (EbSS) tasks. To enhance the learning efficiency from dynamic event streams, we harness the adaptive threshold which improves network accuracy, sparsity, and robustness in streaming inference. Moreover, we develop a dual-path spiking spatially adaptive modulation (SSAM) module, which is specifically tailored to enhance the representation of sparse events and multimodal inputs, thereby considerably improving network performance. Our SpikingEDN attains a mean intersection over union (MIoU) of 72.57% on the DDD17 dataset and 58.32% on the larger DSEC-Semantic dataset, showing competitive results to the state-of-the-art ANNs while requiring substantially fewer computational resources. Our results shed light on the untapped potential of SNNs in event-based vision applications. The source codes are publicly available at https://github.com/EMI-Group/spikingedn.

8.
Artículo en Inglés | MEDLINE | ID: mdl-39133260

RESUMEN

PURPOSE: Hydrogen sulfide (H2S) secreted by perivascular adipose tissue (PVAT) is a critical vasodilator, which might be involved during the pathogenesis of hypertension. The present study aimed to investigate the exact role of H2S on the regulation of PVAT anti-contraction by long-term exercise in obesity hypertension. METHODS: After the establishment of obesity hypertension (24 weeks) through a high-fat diet, male Sprague-Dawley rats were randomly assigned to control group (HC), exercise group (HE), cystathionine γ-lyase (CSE) blocking group (HCB), and exercise combined with CSE blocking group (HEB). Exercise and CSE inhibitor regimens were performed throughout 13 weeks. RESULTS: After 13 weeks of intervention, blood pressure was significantly decreased by long-term exercise (HC vs. HE, P < 0.05) but not by exercise combined with the CSE inhibitor regimen. Meanwhile, the CSE inhibitor significantly blocked the production of H2S in PVAT even after exercise (HE vs. HEB, P < 0.05). Furthermore, long-term exercise altered the expressions of voltage-dependent K+ (Kv) channel subunits 7 (KCNQs), which were diminished by CSE inhibition in mesenteric arteries. As for vascular tension assessment, after incubation with or without KCNQ opener (retigabine), the anti-contractile effect of PVAT (with or without transferred bath solution of PVAT) was significantly enhanced by long-term exercise and eliminated by the CSE inhibitor regimen (P < 0.05); KCNQ inhibitor (XE991) blunted this effect except for HE. CONCLUSIONS: These results collectively suggest that endogenous H2S is a strong regulator of the anti-contractile effect of PVAT in obesity hypertension by long-term exercise, and KCNQ in the resistance artery might be involved during this process but not the only target channel mediated by H2S.

9.
Cell Rep ; 43(7): 114417, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38980795

RESUMEN

The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. We used gene co-essentiality analysis to identify an unappreciated relationship between TSC22D2, WNK1, and NRBP1 in regulating cell volume homeostasis. All of these genes have paralogs and are functionally buffered for osmo-sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK, and NRBP family members physically associate into biomolecular condensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans revealed that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is accompanied by rapid IDR length expansion in WNK-family kinases. Our study reveals that TSC22D, WNK, and NRBP genes evolved in metazoans to co-regulate rapid cell volume changes in response to osmolarity.


Asunto(s)
Tamaño de la Célula , Proteína Quinasa Deficiente en Lisina WNK 1 , Humanos , Animales , Proteína Quinasa Deficiente en Lisina WNK 1/metabolismo , Proteína Quinasa Deficiente en Lisina WNK 1/genética , Evolución Molecular , Células HEK293 , Unión Proteica , Familia de Multigenes , Presión Osmótica
10.
Anal Methods ; 16(30): 5272-5279, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39016035

RESUMEN

Brown adipose tissue (BAT), characterized by the presence of numerous mitochondria, plays a key role in metabolism and energy expenditure. Accurately reporting the presence and activation of BAT is beneficial to study obesity, diabetes, and other metabolic disorders. Near-infrared (NIR) fluorescence imaging has the advantages of high sensitivity, non-radioactivity, and simple operation. However, most NIR probes for BAT imaging exhibit small Stokes shifts, which may lead to self-quenching, reducing the signal-to-noise ratio, and introducing cross-talk. Herein, we rationally designed and synthesized a series of hemicyanine-based NIR fluorescent probes HCYBAT-1-3. Among them, HCYBAT-1 demonstrated favorable properties such as near-infrared emission (776 nm), large Stokes shift (139 nm), good biocompatibility and specific mitochondrial targeting (Pearson's colocalization coefficient of 0.87). Meanwhile, HCYBAT-1 was successfully employed to differentiate BAT from white adipose tissue (WAT). Quantitative analysis of NIR fluorescent images showed that HCYBAT-1 could be used for real-time monitoring of BAT activation in mice stimulated by norepinephrine (NE) and cold exposure. Overall, probe HCYBAT-1 showcased its efficacy in non-invasive evaluation of BAT metabolism in vivo with high selectivity and sensitivity.


Asunto(s)
Tejido Adiposo Pardo , Colorantes Fluorescentes , Imagen Óptica , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Pardo/metabolismo , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Animales , Ratones , Imagen Óptica/métodos , Carbocianinas/química , Carbocianinas/síntesis química , Ratones Endogámicos C57BL , Espectroscopía Infrarroja Corta/métodos , Mitocondrias/metabolismo , Masculino
11.
Nanoscale ; 16(30): 14441-14447, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39012338

RESUMEN

The electrocatalytic nitrogen reduction reaction (NRR) enables the production of ammonia by the use of renewable energy, providing a direct method for nitrogen fixation. Nevertheless, the NRR process under ambient conditions is often impeded by inertness of N2 and the occurrence of hydrogen evolution as a byproduct in aqueous electrolytes, resulting in a diminished reaction rate and reduced efficiency. In this study, we synthesized Cu6(SMPP)6 nanoclusters (Cu6 NCs for short) and immobilized them on graphene oxide (GO) to investigate their electrocatalytic nitrogen reduction reaction (ENRR) using an H-cell setup. The GO-supported Cu6 NCs exhibit enhanced catalysis with a high NH3 yield rate of 4.8 µg h-1 cm-2 and a high faradaic efficiency up to 30.39% at -1.1 V. Quantum chemistry calculations reveal that the Cu6S6 cluster on GO support facilitates the N2 adsorption and NN bond activation with a surmountable energy barrier for the potential-determining step (N2* → NNH*).

12.
Nano Lett ; 24(27): 8320-8326, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38935843

RESUMEN

Magnetic topological materials with coexisting magnetism and nontrivial band structures exhibit many novel quantum phenomena, including the quantum anomalous Hall effect, the axion insulator state, and the Weyl semimetal phase. As a stoichiometric layered antiferromagnetic topological insulator, thin films of MnBi2Te4 show fascinating even-odd layer-dependent physics. In this work, we fabricate a series of thin-flake MnBi2Te4 devices using stencil masks and observe the Chern insulator state at high magnetic fields. Upon magnetic field training, a large exchange bias effect is observed in odd but not in even septuple layer (SL) devices. Through theoretical calculations, we attribute the even-odd layer-dependent exchange bias effect to the contrasting surface and bulk magnetic properties of MnBi2Te4 devices. Our findings reveal the microscopic magnetic configuration of MnBi2Te4 thin flakes and highlight the challenges in replicating the zero magnetic field quantum anomalous Hall effect in odd SL MnBi2Te4 devices.

13.
Artículo en Inglés | MEDLINE | ID: mdl-38874521

RESUMEN

Aims: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on sirtuin (SIRT)3-induced optic atrophy protein 1 (OPA1) deacetylation. Results: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3-(1H-1, 2, 3-triazol-4-yl) pyridine (3TYP)-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI. Innovation: Our study revealed, for the first time, the regulation of mitochondrial dynamics and AM polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease. Conclusions: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury.

14.
mSystems ; 9(7): e0008924, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38940519

RESUMEN

The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors (Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori-positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula, Streptococcus oralis, and Prevotella intermedia, was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori-negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori-positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori-negative GCs. IMPORTANCE: Our study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori-negative GCs.


Asunto(s)
Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Helicobacter pylori/genética , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/patogenicidad , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/patología , Microbioma Gastrointestinal/genética , Boca/microbiología , Microbiota/genética
15.
Int Endod J ; 57(9): 1315-1325, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38923421

RESUMEN

AIM: Autophagy is involved in human apical periodontitis (AP). However, it is not clear whether autophagy is protective or destructive in bone loss via the receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) axis. This study aimed to investigate the involvement of autophagy via the RANKL/RANK/OPG axis during the development of AP in an experimental rat model. METHODOLOGY: Twenty-four female Sprague-Dawley rats were divided into control, experimental AP (EAP) + saline, and EAP + 3-methyladenine (An autophagy inhibitor, 3-MA) groups. The control group did not receive any treatment. The EAP + saline group and the EAP + 3-MA group received intraperitoneal injections of saline and 3-MA, respectively, starting 1 week after the pulp was exposed. Specimens were collected for microcomputed tomography (micro-CT) scanning, histological processing, and immunostaining to examine the expression of light chain 3 beta (LC3B), RANK, RANKL, and OPG. Data were analysed using one-way analysis of variance (p < .05). RESULTS: Micro-CT showed greater bone loss in the EAP + 3-MA group than in the EAP + saline group, indicated by an elevated trabecular space (Tb.Sp) (p < .05). Inflammatory cell infiltration was observed in the EAP + saline and EAP + 3-MA groups. Compared with EAP + saline group, the EAP + 3-MA group showed weaker expression of LC3B (p < .01) and OPG (p < .05), more intense expression of RANK (p < .01) and RANKL (p < .01), and a higher RANKL/OPG ratio (p < .05). CONCLUSION: Autophagy may exert a protective effect against AP by regulating the RANKL/RANK/OPG axis, thereby inhibiting excessive bone loss.


Asunto(s)
Pérdida de Hueso Alveolar , Autofagia , Modelos Animales de Enfermedad , Osteoprotegerina , Periodontitis Periapical , Ligando RANK , Ratas Sprague-Dawley , Receptor Activador del Factor Nuclear kappa-B , Microtomografía por Rayos X , Animales , Femenino , Ratas , Adenina/análogos & derivados , Adenina/farmacología , Pérdida de Hueso Alveolar/metabolismo , Pérdida de Hueso Alveolar/patología , Osteoprotegerina/metabolismo , Periodontitis Periapical/metabolismo , Periodontitis Periapical/patología , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo
16.
JCEM Case Rep ; 2(6): luae092, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38803508

RESUMEN

Desmopressin is increasingly used for the diagnosis of Cushing disease (CD) since corticotropin-releasing hormone became unavailable. We report the case a 32-year-old man who presented with overt Cushing syndrome. Morning blood cortisol, ACTH, 1 mg dexamethasone suppression test, 24-hour urinary free cortisol, and bedtime salivary cortisol were highly variable, reaching markedly elevated values. Intravenous desmopressin administration produced no ACTH or cortisol increase. Pituitary magnetic resonance imaging, thoracic computed tomography, and DOTATATE positron emission tomography scan identified no lesion. Inferior petrosal sinus sampling (IPSS) with desmopressin stimulation resulted in elevated central-to-peripheral ACTH ratio and prolactin co-secretion, while peripheral ACTH remained stable. No corticotroph tumor was identified on pituitary surgery pathology. Hypercortisolism persisted postoperatively. Cabergoline was initiated, after which the patient rapidly developed transient severe adrenal insufficiency (AI). Bilateral adrenalectomy was performed in view of persistent hypercortisolism. This is an unusual case of petrosal sinus ACTH response to desmopressin without any peripheral response, suggesting a central source of ACTH. Thus, desmopressin should still be used during IPSS in patients with no peripheral response. It is unclear whether the AI episode resulted from a combination of nadir of cyclic hypercortisolism, partial apoplexy, and response to cabergoline of an occult corticotroph tumor.

17.
Artículo en Inglés | MEDLINE | ID: mdl-38771689

RESUMEN

Advancements in adapting deep convolution architectures for spiking neural networks (SNNs) have significantly enhanced image classification performance and reduced computational burdens. However, the inability of multiplication-free inference (MFI) to align with attention and transformer mechanisms, which are critical to superior performance on high-resolution vision tasks, imposes limitations on these gains. To address this, our research explores a new pathway, drawing inspiration from the progress made in multilayer perceptrons (MLPs). We propose an innovative spiking MLP architecture that uses batch normalization (BN) to retain MFI compatibility and introduce a spiking patch encoding (SPE) layer to enhance local feature extraction capabilities. As a result, we establish an efficient multistage spiking MLP network that blends effectively global receptive fields with local feature extraction for comprehensive spike-based computation. Without relying on pretraining or sophisticated SNN training techniques, our network secures a top-one accuracy of 66.39% on the ImageNet-1K dataset, surpassing the directly trained spiking ResNet-34 by 2.67%. Furthermore, we curtail computational costs, model parameters, and simulation steps. An expanded version of our network compares with the performance of the spiking VGG-16 network with a 71.64% top-one accuracy, all while operating with a model capacity 2.1 times smaller. Our findings highlight the potential of our deep SNN architecture in effectively integrating global and local learning abilities. Interestingly, the trained receptive field in our network mirrors the activity patterns of cortical cells.

18.
BMC Oral Health ; 24(1): 592, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38778368

RESUMEN

BACKGROUND: Treating the coronal dens invaginatus (CDI) with pulp infection commonly involves the removal of invagination, which increases the risk of perforation and fracture, and compromises the tooth structure. Minimally invasive endodontic management of CDI is highly recommended. This report describes two cases of type II CDI with the application of personalized templates. CASE PRESENTATION: Two cases of type II CDI, affecting the main root canal in a maxillary canine and a lateral incisor, were diagnosed. A guided endodontics (GE) approach was applied. Cone-beam computed tomography and intraoral scans were imported and aligned in a virtual planning software to design debridement routes and templates. The MICRO principle (which involves the aspects of Mechanical (M) debridement, Irrigation (I), Access cavities (C), Rectilinear routes (R), and Obstruction (O)) was proposed for designing optimal debridement routes for future applications. The templates were innovatively personalized and designed to preserve the tooth structure maximally while effectively debriding the root canal. Root canal treatment with supplementary disinfection was then performed. The follow-up of the two patients revealed favorable clinical and radiographic outcomes. CONCLUSIONS: The GE approach could be a feasible method for preserving healthy dental structure while effectively debriding the root canal, thereby achieving successful and minimally invasive endodontic treatment for CDI.


Asunto(s)
Tomografía Computarizada de Haz Cónico , Dens in Dente , Tratamiento del Conducto Radicular , Humanos , Desbridamiento/métodos , Dens in Dente/terapia , Dens in Dente/complicaciones , Dens in Dente/diagnóstico por imagen , Incisivo/anomalías , Incisivo/diagnóstico por imagen , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Tratamiento del Conducto Radicular/métodos
19.
J Asian Nat Prod Res ; 26(9): 1094-1105, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38753582

RESUMEN

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 µg/ml) and 7a (38.15 µg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 µg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 µg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.


Asunto(s)
Alternaria , Benzaldehídos , Fusarium , Pruebas de Sensibilidad Microbiana , Oxadiazoles , Oxadiazoles/farmacología , Oxadiazoles/química , Benzaldehídos/química , Benzaldehídos/farmacología , Estructura Molecular , Fusarium/efectos de los fármacos , Alternaria/efectos de los fármacos , Tiazolidinas/farmacología , Tiazolidinas/química , Botrytis/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Humanos , Relación Estructura-Actividad
20.
bioRxiv ; 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38798562

RESUMEN

Target protein degradation (TPD) has emerged as a revolutionary approach in drug discovery, leveraging the cell's intrinsic machinery to selectively degrade disease-associated proteins. Proteolysis-Targeting Chimeras (PROTACs) exemplify this strategy, exploiting heterobifunctional molecules to induce ubiquitination and subsequent degradation of target proteins. The clinical advancement of PROTACs underscores their potential in therapeutic intervention, with numerous projects progressing through clinical stages. However, monitoring subtle changes in protein abundance induced by TPD molecules demands highly sensitive assays. Nano-luciferase (nLuc) fusion proteins, or the NanoBiT technology derived from it, offer a robust screening platform due to their high sensitivity and stability. Despite these advantages, concerns have arisen regarding potential degradation artifacts introduced by tagging systems due to the presence of lysine residues on them, prompting the development of alternative tools. In this study, we introduce HiBiT-RR and nLuc K0 , variants devoid of lysine residues, to mitigate such artifacts. Our findings demonstrate that HiBiT-RR maintains similar sensitivity and binding affinity with the original HiBiT. Moreover, the comparison between nLuc WT and nLuc K0 constructs reveals variations in degradation patterns induced by certain PROTAC molecules, emphasizing the importance of choosing appropriate tagging systems to ensure the reliability of experimental outcomes in studying protein degradation processes.

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