TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis.

The patho-mechanism of apolipoprotein variant, APOE4, the strongest genetic risk for late-onset Alzheimer's disease (AD) and longevity, remains unclear. APOE's neighboring gene, TOMM40 (mitochondria protein transport channel), is associated with brain trauma outcome and aging-related cognitive decline, however its role in AD APOE4-independently is controversial. We report that TOMM40 is prone to transcription readthrough into APOE that can generate spliced TOMM40-APOE mRNA chimera (termed T9A2) detected in human neurons and other cells and tissues.

Integrative annotation scores of variants for impact on RNA binding protein activities.

Motivation: The ENCODE project generated a large collection of eCLIP-seq RNA binding protein (RBP) profiling data with accompanying RNA-seq transcriptomes of shRNA knockdown of RBPs. These data could have utility in understanding the functional impact of genetic variants, however their potential has not been fully exploited. We implement INCA (Integrative annotation scores of variants for impact on RBP activities) as a multi-step genetic variant scoring approach that leverages the ENCODE RBP data together with ClinVar and integrates multiple computational approaches to aggregate evidence.

Palliative care and Chinese medicine in a centenarian with primary hepatocellular carcinoma and 27-month follow-up: A case report.

The number of centenarians with cancer is increasing as the global population ages. The diagnosis and treatment for centenarians with tumor sometimes are specific, and there are currently less appropriate guidelines as references. We report a 104-year-old man with asymptomatic primary liver cancer (PLC) whose family decided to receive conservative and palliative care.

Understanding online self-directed learning using point of care information systems (POCIS): A plot study using a capability approach perspective.

Purpose Of The Study: Understanding self-directed learning (SDL) when using point of care information systems (POCIS) can inform educational providers of the usefulness of the system for continuing medical education (CME). Sen's capability approach can offer a unique perspective to understand SDL, which considers the extent to which individual valued learning needs can be achieved. The aim of the study was to pilot the use of a questionnaire informed by the capability approach for understanding SDL when using POCIS in the context of CME.

Individualized Treatment and Palliative Care for A 90-Year-Old Patient with Primary Gastric Diffuse Large-B Cell Lymphoma: 4 Year Follow-up and Inspiration.

A 90-year-old man was diagnosed with primary gastric diffuse large B-cell lymphoma (PGDLBL) by PET/CT examination, gastroscopy, biopsy and histopathological analysis at a regular physical check in April, 2016. The patient received R-CO chemotherapy (rituximab, cyclophosphamide, and vincristine) and radiotherapy subsequently, with enteral nutritional treatment through 3-cavity nasogastric tube due to development of pyloric obstruction. To satisfy patient's strong desire of eating by himself, we performed surgery of exploratory laparotomy and Roux-en-Y gastric bypass (RGB) to relieve pylorus obstruction.

U1 snRNP Telescripting Roles in Transcription and Its Mechanism.

Telescripting is a fundamental cotranscriptional gene regulation process that relies on U1 snRNP (U1) to suppress premature 3'-end cleavage and polyadenylation (PCPA) in RNA polymerase II (Pol II) transcripts, which is necessary for full-length transcription of thousands of protein-coding (pre-mRNAs) and long noncoding (lncRNA) genes. Like U1 role in splicing, telescripting requires U1 snRNA base-pairing with nascent transcripts. Inhibition of U1 base-pairing with U1 snRNA antisense morpholino oligonucleotide (U1 AMO) mimics widespread PCPA from cryptic polyadenylation signals (PASs) in human tissues, including PCPA in introns and last exons' 3'-untranslated regions (3' UTRs).

U1 snRNP regulates cancer cell migration and invasion in vitro.

Stimulated cells and cancer cells have widespread shortening of mRNA 3'-untranslated regions (3'UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in introns and last exons. U1 snRNP (U1), vertebrates' most abundant non-coding (spliceosomal) small nuclear RNA, silences proximal PASs and its inhibition with antisense morpholino oligonucleotides (U1 AMO) triggers widespread premature transcription termination and mRNA shortening. Here we show that low U1 AMO doses increase cancer cells' migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect.

A U1 snRNP-specific assembly pathway reveals the SMN complex as a versatile hub for RNP exchange.

Despite equal snRNP stoichiometry in spliceosomes, U1 snRNP (U1) is typically the most abundant vertebrate snRNP. Mechanisms regulating U1 overabundance and snRNP repertoire are unknown. In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins.

Kinetic and thermodynamic characterization of the reaction pathway of box H/ACA RNA-guided pseudouridine formation.

The box H/ACA RNA-guided pseudouridine synthase is a complicated ribonucleoprotein enzyme that recruits substrate via both the guide RNA and the catalytic subunit Cbf5. Structural studies have revealed multiple conformations of the enzyme, but a quantitative description of the reaction pathway is still lacking. Using fluorescence correlation spectroscopy, we here measured the equilibrium dissociation constants and kinetic association and dissociation rates of substrate and product complexes mimicking various reaction intermediate states.

Structure of the Shq1-Cbf5-Nop10-Gar1 complex and implications for H/ACA RNP biogenesis and dyskeratosis congenita.

Shq1 is a conserved protein required for the biogenesis of eukaryotic H/ACA ribonucleoproteins (RNPs), including human telomerase. We report the structure of the Shq1-specific domain alone and in complex with H/ACA RNP proteins Cbf5, Nop10 and Gar1. The Shq1-specific domain adopts a novel helical fold and primarily contacts the PUA domain and the otherwise disordered C-terminal extension (CTE) of Cbf5.

Reconstitution and structural analysis of the yeast box H/ACA RNA-guided pseudouridine synthase.

Box H/ACA ribonucleoprotein particles (RNPs) mediate pseudouridine synthesis, ribosome formation, and telomere maintenance. The structure of eukaryotic H/ACA RNPs remains poorly understood. We reconstituted functional Saccharomyces cerevisiae H/ACA RNPs with recombinant proteins Cbf5, Nop10, Gar1, and Nhp2 and a two-hairpin H/ACA RNA; determined the crystal structure of a Cbf5, Nop10, and Gar1 ternary complex at 1.

Structural mechanism of substrate RNA recruitment in H/ACA RNA-guided pseudouridine synthase.

H/ACA RNAs form ribonucleoprotein complex (RNP) with proteins Cbf5, Nop10, L7Ae, and Gar1 and guide site-specific conversion of uridine into pseudouridine in cellular RNAs. The crystal structures of H/ACA RNP with substrate bound at the active site cleft reveal that the substrate is recruited through sequence-specific pairing with guide RNA and essential protein contacts. Substrate binding leads to a reorganization of a preset pseudouridylation pocket and an adaptive movement of the PUA domain and the lower stem of the H/ACA RNA.