RESUMO
Communication in the form of non-verbal, social vocalization, or crying is evolutionary conserved in mammals and is impaired early in human infants that are later diagnosed with autism spectrum disorder (ASD). Defects in infant vocalization have been proposed as an early sign of ASD that may exacerbate ASD development. However, the neural mechanisms associated with early communicative deficits in ASD are not known. Here, we expressed a constitutively active mutant of Rheb (RhebS16H), which is known to upregulate two ASD core pathways, mTOR complex 1 (mTORC1) and ERK1/2, in layer (L) 2/3 pyramidal neurons of the neocortex of mice of either sex. We found that cellular mosaic expression of RhebS16H in L2/3 pyramidal neurons altered the production of isolation calls from neonatal mice. This was accompanied by an expected misplacement of neurons and dendrite overgrowth, along with an unexpected increase in spine density and length, which was associated with increased excitatory synaptic activity. This contrasted with the known decrease in spine density in RhebS16H neurons of one-month-old mice. Reducing the levels of the actin crosslinking and adaptor protein filamin A (FLNA), known to be increased downstream of ERK1/2, attenuated dendrite overgrowth and fully restored spine properties, synaptic connectivity, and the production of pup isolation calls. These findings suggest that upper-layer cortical pyramidal neurons contribute to communicative deficits in a condition known to affect two core ASD pathways and that these mechanisms are regulated by FLNA.Significance Statement An infant's cry is a form of evolutionarily conserved social communication that is altered in ASD and has been proposed as an early sign of ASD. However, the neural substrate of early communicative deficits is not known. We show that cellular mosaic expression of a constitutively active Rheb, known to upregulate two core ASD pathways, selectively in upper-layer neocortical pyramidal neurons, alters the production of pup isolation calls and synaptic connectivity. These defects were prevented by reducing the expression of the adaptor protein FLNA. This underscores the importance of a specific neuronal substrate responsible for communicative deficits and its regulation by FLNA.
RESUMO
Predicting the interaction affinity between drugs and target proteins is crucial for rapid and accurate drug discovery and repositioning. Therefore, more accurate prediction of DTA has become a key area of research in the field of drug discovery and drug repositioning. However, traditional experimental methods have disadvantages such as long operation cycles, high manpower requirements, and high economic costs, making it difficult to predict specific interactions between drugs and target proteins quickly and accurately. Some methods mainly use the SMILES sequence of drugs and the primary structure of proteins as inputs, ignoring the graph information such as bond encoding, degree centrality encoding, spatial encoding of drug molecule graphs, and the structural information of proteins such as secondary structure and accessible surface area. Moreover, previous methods were based on protein sequences to learn feature representations, neglecting the completeness of information. To address the completeness of drug and protein structure information, we propose a Transformer graph-based early fusion research approach for drug-target affinity prediction (GEFormerDTA). Our method reduces prediction errors caused by insufficient feature learning. Experimental results on Davis and KIBA datasets showed a better prediction of drugtarget affinity than existing affinity prediction methods.
Assuntos
Descoberta de Drogas , Reposicionamento de Medicamentos , Sequência de Aminoácidos , Fontes de Energia Elétrica , AprendizagemRESUMO
BACKGROUND: Besides the hallmark of H3K27M mutation, aberrant amplifications of receptor tyrosine kinases (RTKs) are commonly observed in diffuse midline glioma (DMG), a highly malignant brain tumor with dismal prognosis. Here, we intended to evaluate the efficacy and safety of a multitarget RTK inhibitor anlotinib in patients with H3K27M-DMG. METHODS: A total of 40 newly diagnosed H3K27M-DMG patients including 15 with anlotinib and 25 without anlotinib treatment were retrospectively enrolled in this cohort. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed and compared. RESULTS: The median PFS and OS of all patients in this cohort were 8.5 months (95% CI, 6.5-11.3) and 15.5 months (95% CI, 12.6-17.1), respectively. According to the Response Assessment in Neuro-Oncology (RANO) criteria, the disease control rate in the anlotinib group [93.3%, 95% confidence interval (CI), 70.2-98.8] was significantly higher than those without anlotinib (64%, 95% CI: 40.5-79.8, p = 0.039). The median PFS of patients with and without anlotinib was 11.6 months (95% CI, 7.8-14.3) and 6.4 months (95% CI, 4.3-10.3), respectively. Both the median PFS and OS of DMG patients treated with anlotinib were longer than those without anlotinib in the infratentorial patients (PFS: 10.3 vs. 5.4 months, p = 0.006; OS: 16.6 vs. 8.7 months, p = 0.016). Multivariate analysis also indicated anlotinib (HR: 0.243, 95% CI: 0.066-0.896, p = 0.034) was an independent prognosticator for longer OS in the infratentorial subgroup. In addition, the adverse events of anlotinib administration were tolerable in the whole cohort. CONCLUSIONS: This study first reported that anlotinib combined with Stupp regimen is a safe and feasible regimen for newly diagnosed patients with H3K27M-DMG. Further, anlotinib showed significant efficacy for H3K27M-DMG located in the infratentorial region.
Assuntos
Neoplasias Encefálicas , Glioma , Indóis , Mutação , Quinolinas , Temozolomida , Humanos , Masculino , Indóis/uso terapêutico , Indóis/administração & dosagem , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Glioma/genética , Temozolomida/uso terapêutico , Temozolomida/administração & dosagem , Adulto Jovem , Estudos de Coortes , Adolescente , Quimiorradioterapia/métodos , IdosoRESUMO
Intracranial aneurysm (IA) is the most prevalent type of cerebral vascular disease causing life-threatening subarachnoid hemorrhages (SAH). A long-term vascular structure remodeling is considered as the main pathophysiological feature of IAs. However, the causal factors triggering the pathophysiological process are not clear. Recently, the abnormalities of peripheral circulating proteins and metabolites have been found in IAs patients and associated with the ruptures. We comprehensively investigated the potential causal relationship between blood metabolites and proteins and IAs using the mendelian randomization (MR) analysis. We applied two-sample MR to explore the potential causal association between peripheral circulating metabolites (191 blood metabolites) and proteins (1398 proteins) and IAs using data from the FinnGen study and the GWAS datasets published by Bakker et al. We identified palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine as causal contributors of IAs and ruptures. Further two-step mediation MR analysis suggested that hypertension as one of the contributors of IAs and ruptures mediated the causal relationship between palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine and IAs. Together, our study demonstrates that blood metabolic palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine are causally linked to the formation and rupture of IAs. Hypertension partially mediates the causal effects.