A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.

The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.

Device-Algorithm Co-Optimization for an On-Chip Trainable Capacitor-Based Synaptic Device with IGZO TFT and Retention-Centric Tiki-Taka Algorithm.

Analog in-memory computing synaptic devices are widely studied for efficient implementation of deep learning. However, synaptic devices based on resistive memory have difficulties implementing on-chip training due to the lack of means to control the amount of resistance change and large device variations. To overcome these shortcomings, silicon complementary metal-oxide semiconductor (Si-CMOS) and capacitor-based charge storage synapses are proposed, but it is difficult to obtain sufficient retention time due to Si-CMOS leakage currents, resulting in a deterioration of training accuracy. Here, a novel 6T1C synaptic device using only n-type indium gaIlium zinc oxide thin film transistor (IGZO TFT) with low leakage current and a capacitor is proposed, allowing not only linear and symmetric weight update but also sufficient retention time and parallel on-chip training operations. In addition, an efficient and realistic training algorithm to compensate for any remaining device non-idealities such as drifting references and long-term retention loss is proposed, demonstrating the importance of device-algorithm co-optimization.

Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome.

BACKGROUND: Mutations in the X-linked gene DDX3X account for approximately 2% of intellectual disability in females, often comorbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. METHODS: We generated a Ddx3x haploinsufficient mouse (Ddx3x+/- females) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. RESULTS: Ddx3x+/- females showed physical, sensory, and motor delays that evolved into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments in specific tasks (e.g., contextual fear memory but not novel object recognition memory), and motor deficits. Motor function declined with age but not if mice were previously exposed to behavioral training. Developmental and behavioral changes were associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning was accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. CONCLUSIONS: These data shed new light on the developmental mechanisms driving DDX3X syndrome and support construct and face validity of this novel preclinical mouse model.

Inhibitory effect of esculetin on free-fatty-acid-induced lipid accumulation in human HepG2 cells through activation of AMP-activated protein kinase.

This study aimed to determine the lipid-lowering effect of esculetin (6,7-dihydroxycoumarin), a coumarin derivative, using a cell model of steatosis induced by a mixture of free fatty acids (FFAs). Esculetin dose-dependently inhibited intracellular lipid accumulation by down-regulating the protein expression of lipogenic genes such as sterol regulatory element-binding protein-1c (SREBP1c) and fatty acid synthase (FAS) in FFAs-induced HepG2 cells. Moreover, esculetin significantly elevated the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathways in HepG2 hepatocytes. The anti-lipogenic effects of esculetin mediated by AMPK activation were abolished when FFAs-induced HepG2 cells were treated with a specific inhibitor of AMPK, i.e., compound C. These results suggest that esculetin attenuates hepatic lipid accumulation by inhibiting lipogenesis through the modulation of AMPK signaling pathway on FFAs-induced steatosis in HepG2 cells and may be used for the prevention of nonalcoholic fatty liver disease (NAFLD).