Revisiting the genetic architecture of autism spectrum disorders in the genomic era: Insights from East Asian studies.

This review delves into the genetic landscape of Autism Spectrum Disorder (ASD) in the genomic era, with a special focus on insights from East Asian populations. We analyze a spectrum of genetic research, including whole-exome and whole-genome sequencing, to elucidate both the challenges and advancements in comprehending the genetic foundations of ASD. Critical findings from this review highlight the identification of de novo variants, particularly noting the significant role of rare variants that differ from the common variants identified in earlier research.

Adenosine-Dependent Arousal Induced by Astrocytes in a Brainstem Circuit.

Astrocytes play a crucial role in regulating sleep-wake behavior. However, how astrocytes govern a specific sleep-arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep-wake cycles with state-differential Ca activity, peaking during transitions from sleep to wakefulness.

Correction: Li et al. African Swine Fever Virus: A Review. 2022, , 1255.

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Gating of Social Behavior by Inhibitory Inputs from Hippocampal CA1 to Retrosplenial Agranular Cortex.

The retrosplenial cortex has been implicated in processing sensory information and spatial learning, with abnormal neural activity reported in association with psychedelics and in mouse and non-human primate models of autism spectrum disorders (ASDs). The direct role of the retrosplenial cortex in regulating social behaviors remains unclear. In this work, we reveal that neural activity in the retrosplenial agranular cortex (RSA), a subregion of the retrosplenial cortex, is initially activated, then quickly suppressed upon social contact.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.

Downregulation of mGluR1-mediated signaling underlying autistic-like core symptoms in Shank1 P1812L-knock-in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms that consist of social deficits and repetitive behaviors. Unfortunately, no effective medication is available thus far to target the core symptoms of ASD, since the pathogenesis remains largely unknown. To investigate the pathogenesis of the core symptoms in ASD, we constructed Shank1 P1812L-knock-in (KI) mice corresponding to a recurrent ASD-related mutation, SHANK1 P1806L, to achieve construct validity and face validity.

Mitophagy in neurodegenerative disease pathogenesis.

Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.

Engineering of cytosine base editors with DNA damage minimization and editing scope diversification.

Cytosine base editors (CBEs), which enable precise C-to-T substitutions, have been restricted by potential safety risks, including DNA off-target edits, RNA off-target edits and additional genotoxicity such as DNA damages induced by double-strand breaks (DSBs). Though DNA and RNA off-target edits have been ameliorated via various strategies, evaluation and minimization of DSB-associated DNA damage risks for most CBEs remain to be resolved. Here we demonstrate that YE1, an engineered CBE variant with minimized DNA and RNA off-target edits, could induce prominent DSB-associated DNA damage risks, manifested as γH2AX accumulation in human cells.

Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus.

Strong evidence from human genetic studies associates the thousand and one amino acid kinase 1 (TAOK1) gene with autism spectrum disorder (ASD). In this work, we discovered a de novo frameshifting mutation in TAOK1 within a Chinese ASD cohort. We found that Taok1 haploinsufficiency induces autistic-like behaviors in mice.

Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy.

The response rate of pancreatic cancer to chemotherapy or immunotherapy pancreatic cancer is low. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for irresectable pancreatic cancers, the immunosuppressive tumour microenvironment that characterizes this tumour type enables tumour recurrence. Thus, strengthening endogenous adaptive antitumour immunity is critical for improving the outcome of ablation therapy and post-ablation immune therapy.

Discovery and Validation of Novel Genes in a Large Chinese Autism Spectrum Disorder Cohort.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that causes impairments in social communication and stereotypical behaviors, often accompanied by developmental delay or intellectual disability. A growing body of evidence suggests that ASD is highly heritable, and genetic studies have defined numerous risk genes. However, most studies have been conducted with individuals of European and Hispanic ancestry, and there is a lack of genetic analyses of ASD in the East Asian population.

Targeted deep sequencing reveals the genetic heterogeneity in well-differentiated pancreatic neuroendocrine tumors with liver metastasis.

Background: Pancreatic neuroendocrine tumor is a rare and heterogeneous entity, and approximately half of the patients harbored liver metastasis when initially diagnosed, whose prognosis is dismal. High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor, but the genetic alterations in the metastatic cases remain relatively unclear, which we aimed to study.

Methods: Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected.

Identification of de novo Mutations in the Chinese Autism Spectrum Disorder Cohort via Whole-Exome Sequencing Unveils Brain Regions Implicated in Autism.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.

Human MECP2 transgenic rats show increased anxiety, severe social deficits, and abnormal prefrontal neural oscillation stability.

Methylated CpG binding protein 2 (MeCP2) plays an important role in the development and normal function of the neural system. Abnormally high expression of MECP2 leads to a subtype of autism called MECP2 duplication syndrome and MECP2 is considered one of the key pathogenic genes for autism spectrum disorders. However, the effect of MECP2 overexpression on neural activity is still not fully understood.

TadA reprogramming to generate potent miniature base editors with high precision.

Although miniature CRISPR-Cas12f systems were recently developed, the editing efficacy and targeting range of derived miniature cytosine and adenine base editors (miniCBEs and miniABEs) have not been comprehensively addressed. Moreover, functional miniCBEs have not yet be established. Here we generate various Cas12f-derived miniCBEs and miniABEs with improved editing activities and diversified targeting scopes.

TadA orthologs enable both cytosine and adenine editing of base editors.

Cytidine and adenosine deaminases are required for cytosine and adenine editing of base editors respectively, and no single deaminase could enable concurrent and comparable cytosine and adenine editing. Additionally, distinct properties of cytidine and adenosine deaminases lead to various types of off-target effects, including Cas9-indendepent DNA off-target effects for cytosine base editors (CBEs) and RNA off-target effects particularly severe for adenine base editors (ABEs). Here we demonstrate that 25 TadA orthologs could be engineered to generate functional ABEs, CBEs or ACBEs via single or double mutations, which display minimized Cas9-independent DNA off-target effects and genotoxicity, with orthologs B5ZCW4, Q57LE3, E8WVH3, Q13XZ4 and B3PCY2 as promising candidates for further engineering.