Highlights • We summarized 977 epilepsy-associated genes, which were divided into 4 categories according to the manifestation of epilepsy in phenotypes. • 84 epilepsy genes, i.e., genes that only ...cause epilepsies or syndromes with epilepsy as the core symptom. • 73 neurodevelopment-associated genes, i.e., genes associated with gross brain developmental malformations and epilepsies. • 536 epilepsy-related genes, i.e., genes associated with gross physical, or other systemic abnormalities and accompanied by epilepsy or seizures. • 284 potential epilepsy-associated genes, i.e., genes that require further verification.
ABSTRACT
Mutations in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and modes of inheritance and in asymptomatic carriers. This raises challenges in ...evaluating the pathogenicity of SCN1A mutations. We systematically reviewed all SCN1A mutations and established a database containing information on functional alterations. In total, 1,257 mutations have been identified, of which 81.8% were not recurrent. There was a negative correlation between phenotype severity and missense mutation frequency. Further analyses suggested close relationships among genotype, functional alteration, and phenotype. Missense mutations located in different sodium channel regions were associated with distinct functional changes. Missense mutations in the pore region were characterized by the complete loss of function, similar to haploinsufficiency. Mutations with severe phenotypes were more frequently located in the pore region, suggesting that functional alterations are critical in evaluating pathogenicity and can be applied to patient management. A negative correlation was found between phenotype severity and familial incidence, and incomplete penetrance was associated with missense and splice site mutations, but not truncations or genomic rearrangements, suggesting clinical genetic counseling applications. Mosaic mutations with a load of 12.5–25.0% were potentially pathogenic with low penetrance, suggesting the need for future studies on less pathogenic genomic variations.
We systematically reviewed SCN1A mutations and established a database with sections detailing functional alteration (funotype) and inheritance. Further analyses indicated a close genotype‐funotype‐phenotype relationship. Mutations located in different sodium channel regions were associated with distinct funotype and subsequently different phenotype severity, suggesting that funotype is critical in evaluating pathogenicity. A negative correlation was found between phenotype severity and familial incidence, incomplete penetrance was associated with missense and splice‐site mutations, but not truncations or genomic rearrangements, suggesting clinical genetic counseling applications.
Abstract
The variational preparation of complex quantum states using the quantum approximate optimization algorithm (QAOA) is of fundamental interest, and becomes a promising application of quantum ...computers. Here, we systematically study the performance of QAOA for preparing ground states of target Hamiltonians near the critical points of their quantum phase transitions, and generating Greenberger–Horne–Zeilinger (GHZ) states. We reveal that the performance of QAOA is related to the translational invariance of the target Hamiltonian: without the translational symmetry, for instance due to the open boundary condition (OBC) or randomness in the system, the QAOA becomes less efficient. We then propose a generalized QAOA assisted by the parameterized resource Hamiltonian (PRH-QAOA), to achieve a better performance. In addition, based on the PRH-QAOA, we design a low-depth quantum circuit beyond one-dimensional geometry, to generate GHZ states with perfect fidelity. The experimental realization of the proposed scheme for generating GHZ states on Rydberg-dressed atoms is discussed. Our work paves the way for performing QAOA on programmable quantum processors without translational symmetry, especially for recently developed two-dimensional quantum processors with OBC.
Lung cancer, the leading cause of cancer deaths worldwide, is characterized with malignant cell growth. Advances in next-generation sequencing has helped us further understand RNA and identify novel ...circular RNAs (circRNAs) that may be useful in the early diagnosis and treatment of lung cancer. Similar to other noncoding RNAs, circRNAs present diverse biological functions in normal and disease states, including various types of cancers. This review focuses mainly on the poorly understood functions of circRNA in lung cancer. This paper also summarizes the recent advances in circRNA biogenesis, analyzes the role of circRNAs in cancers, and discusses the potential mechanisms of circRNAs in lung cancer.
•Classification and underlying mechanisms of circRNA formation.•CircRNA profiles, their cellular effects and corresponding mechanisms in lung cancer.•Possible mechanisms of circRNAs in lung cancer.
This review mainly aims to highlight recent advances on this topic (2013–2019), along with introducing various types of two- and three-component reaction models, organoboron reagents and their ...reactive counterparts, as well as chiral organometallic catalysts. The inherent challenges, mechanistic insights and their applications toward natural products are also discussed.
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•Tandem reactions involving several sequential CC or CX (X = B, F or N) bond formations in one operation.•Initial reactive intermediates obtained from the transmetalation of organoboron reagents.•Reactions ended with the reductive coupling reaction of organoboron reagents.•A single chiral transition-metal catalyst or cooperative dual chiral catalysts were applied.•Asymmetric difunctionalization of alkenes with aryl- and diboronate reagents.
The in-depth research on merging organoboron reagents with unique characteristics and asymmetric tandem reaction strategy has inspired particular interest on account of the synthetic power for a wide array of chiral complicated molecules that may otherwise be difficult to obtain. Found on the well-established transition-metal-catalyzed Suzuki-Miyaura cross coupling reactions and asymmetric nucleophilic addition of CX (X = C, O or N) double bonds with organoboron reagents, single or dual chiral catalysts can enable generating reactive intermediates to initiate subsequent multiple CC or CY (Y = B, F, N or Sn) bond formations in one operation involving the use of organoboron reagents. This review mainly aims to highlight recent advances on transition-metal-catalyzed asymmetric tandem reactions with organoboron reagents (2013–2019), along with introducing various types of two- and three-component reaction models, organoboron reagents and their reactive counterparts, as well as chiral transition metal catalysts. The inherent challenges, mechanistic insights and synthetic applications toward natural products are also discussed.
2‐Pyridylsulfone‐ and fluoroalkylated group‐activated olefins underwent highly efficient diastereo‐ and enantioselective 1,3‐dipolar cycloadditions across various aromatic and aliphatic nitrones in ...the presence of a chiral NiII/bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α‐trifluoromethylated γ‐amino alcohol in gram‐scale and a trifluoromethylated derivative of 1,3‐oxazinan‐2‐one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo‐ and enantioselectivity.
Synthetically useful: The Ni(ClO4)2/L1‐catalyzed asymmetric cycloaddition of nitrones and β‐fluoroalkylated vinyl 2‐pyridylsulfones is described. Enantioenriched fluoroalkylated isoxazolidines were afforded in high yields with excellent diastereo‐ and enantioselectivities, and then converted into an α‐trifluoromethylated γ‐amino alcohol and a 1,3‐oxazinan‐2‐one derivative.
Circulating tumor DNA (ctDNA) provides a potential non‐invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in ...hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real‐time track the therapeutic responses in the longitudinal monitoring.
What's new?
Hepatocellular carcinoma (HCC) is a heterogenous disease, with significant variability in morphology, molecular alterations, and progression. Accurately evaluating the prognosis of this complicated disease is challenging but could potentially overcome through the use of circulating tumor DNA (ctDNA), according to the present study. Analysis of mutation profiles in HCC patients showed that more than 98% of subclonal mutations are captured in ctDNA. The majority of changes in circulating levels of subclonal mutations were correlated to tumor burden. By providing real‐time information on tumor lesions, the screening of somatic ctDNA alterations could facilitate tumor burden tracking and enable earlier prognostic determination.
This paper explores whether duality in the chief financial officer's (CFO's) job role (i.e. also serving as board secretary) reduces information asymmetry through higher levels of information ...transparency, focusing on Chinese publicly listed companies from 2001 to 2018. Our findings reveal that CFOs serving as board secretaries contribute to greater information transparency. The positive effect of CFO duality on information transparency appears to be more pronounced in state-owned enterprises (SOEs) and in firms whose CFO is female and have had a longer tenure. Knowledge of these impacts is critical to building appropriate investment strategies.
Hawking radiation is one of the quantum features of a black hole that can be understood as a quantum tunneling across the event horizon of the black hole, but it is quite difficult to directly ...observe the Hawking radiation of an astrophysical black hole. Here, we report a fermionic lattice-model-type realization of an analogue black hole by using a chain of 10 superconducting transmon qubits with interactions mediated by 9 transmon-type tunable couplers. The quantum walks of quasi-particle in the curved spacetime reflect the gravitational effect near the black hole, resulting in the behaviour of stimulated Hawking radiation, which is verified by the state tomography measurement of all 7 qubits outside the horizon. In addition, the dynamics of entanglement in the curved spacetime is directly measured. Our results would stimulate more interests to explore the related features of black holes using the programmable superconducting processor with tunable couplers.
IMPORTANCE: Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. OBJECTIVE: To investigate ...the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. DESIGN, SETTING, AND PARTICIPANTS: This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. INTERVENTIONS: Liver resection for HCC. MAIN OUTCOMES AND MEASURES: Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. RESULTS: Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio HR, 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence. CONCLUSIONS AND RELEVANCE: Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence.
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