Distinct Processing of lncRNAs Contributes to Non-conserved Functions in Stem Cells.

Long noncoding RNAs (lncRNAs) evolve more rapidly than mRNAs. Whether conserved lncRNAs undergo conserved processing, localization, and function remains unexplored. We report differing subcellular localization of lncRNAs in human and mouse embryonic stem cells (ESCs). A significantly higher fraction of lncRNAs is localized in the cytoplasm of hESCs than in mESCs. This turns out to be important for hESC pluripotency. FAST is a positionally conserved lncRNA but is not conserved in its processing and localization. In hESCs, cytoplasm-localized hFAST binds to the WD40 domain of the E3 ubiquitin ligase ß-TrCP and blocks its interaction with phosphorylated ß-catenin to prevent degradation, leading to activated WNT signaling, required for pluripotency. In contrast, mFast is nuclear retained in mESCs, and its processing is suppressed by the splicing factor PPIE, which is highly expressed in mESCs but not hESCs. These findings reveal that lncRNA processing and localization are previously under-appreciated contributors to the rapid evolution of function.

Gene regulation by long non-coding RNAs and its biological functions.

Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.

SLERT Regulates DDX21 Rings Associated with Pol I Transcription.

Dysregulated rRNA synthesis by RNA polymerase I (Pol I) is associated with uncontrolled cell proliferation. Here, we report a box H/ACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA) that enhances pre-rRNA transcription (SLERT). SLERT requires box H/ACA snoRNAs at both ends for its biogenesis and translocation to the nucleolus. Deletion of SLERT impairs pre-rRNA transcription and rRNA production, leading to decreased tumorigenesis. Mechanistically, SLERT interacts with DEAD-box RNA helicase DDX21 via a 143-nt non-snoRNA sequence. Super-resolution images reveal that DDX21 forms ring-shaped structures surrounding multiple Pol I complexes and suppresses pre-rRNA transcription. Binding by SLERT allosterically alters individual DDX21 molecules, loosens the DDX21 ring, and evicts DDX21 suppression on Pol I transcription. Together, our results reveal an important control of ribosome biogenesis by SLERT lncRNA and its regulatory role in DDX21 ring-shaped arrangements acting on Pol I complexes.

Mechanisms of Long Noncoding RNA Nuclear Retention.

Long noncoding RNAs (lncRNAs) are crucial regulators in diverse cellular contexts and biological processes. The subcellular localization of lncRNAs determines their modes of action. Compared to mRNAs, however, many mRNA-like lncRNAs are preferentially localized to the nucleus where they regulate chromatin organization, transcription, and different nuclear condensates. Recent studies have revealed the complex mechanisms that govern lncRNA nuclear retention. We review current understanding of how the transcription and processing of lncRNAs, motifs within lncRNAs, and trans-factors coordinately contribute to their nuclear retention in mammalian cells.

[Titin: structure, isoforms and functional regulation].

Titin, the largest known protein in the body expressed in three isoforms (N2A, N2BA and N2B), is essential for muscle structure, force generation, conduction and regulation. Since the 1950s, muscle contraction mechanisms have been explained by the sliding filament theory involving thin and thick muscle filaments, while the contribution of cytoskeleton in force generation and conduction was ignored. With the discovery of insoluble protein residues and large molecular weight proteins in muscle fibers, the third myofilament, titin, has been identified and attracted a lot of interests. The development of single molecule mechanics and gene sequencing technology further contributed to the extensive studies on the arrangement, structure, elastic properties and components of titin in sarcomere. Therefore, this paper reviews the structure, isforms classification, elastic function and regulatory factors of titin, to provide better understanding of titin.

[Effects of alternate-day modified fasting combined exercise on fat reducing and the FNDC5/Irisin-UCP1 pathway].

OBJECTIVE: The effects of Alternate-day modified fasting combined exercise on fat mass, muscle mass, and serum Irisin, FNDC5 and UCP1 proteins were investigated in rats with 4 weeks of aerobic exercise and modified alternate-day fasting intervention. METHODS: Thirty-two healthy 8-week-old SPF male SD rats were randomly divided into control group, exercise group, alternate-day modified fasting and alternate-day modified fasting combined with exercise group, 8 rats in each group. The exercise group performed treadmill exercise with moderate exercise intensity(60 min/d,5 d/w), the alternate-day modified fasting group alternated between fasting and free feeding every other day, and fed 25% basal energy feed on fasting days, and the alternate-day modified fasting combined exercise group received two combined interventions. After 4 weeks of intervention, the body fat rate of rats was measured by apical blood sampling and abdominal aortic blood sampling, and the serum was preserved and centrifuged, and the wet weights of bilateral gastrocnemius, bilateral perirenal fat and brown fat at the scapula were weighed, and samples were collected for paraffin sectioning and HE staining, and the cell areas were counted; serum Irisin levels were measured by ELISA, and FNDC5 protein expression in gastrocnemius and UCP1 protein expression in adipose tissue were detected by Western blot. RESULTS: After 4 weeks of intervention, compared with the Con group, energy intake, body weight and body fat were decreased significantly in the Exer, ADMF and ADMF-Exer groups (P＜0.05), the wet weight/body weight and adipocyte area of white fat were reduced significantly (P＜0.01), and there was no significant difference in scapular fat wet weight/body weight (P＞0.05). Compared with the Con group, the gastrocnemius wet weight/body weight in the ADMF group was reduced significantly (P＜0.05), while that in the ADMF-Exer group was increased significantly (P＜0.05), the muscle cross-sectional areas in the Exer group and the ADMF-Exer group were increased (P＜0.05), and the content of gastrocnemius FNDC5 protein, serum Irisin level and expression of adipose UCP1 protein in the ADMF-Exer group were increased significantly (P＜0.05). After 4 weeks of intervention, energy intake was reduced significantly in both ADMF and ADMF-Exer groups (P＜0.01) and body weight of ADMF-Exer group was decreased (P＜0.05) compared with the Exer group. Compared with the Exer group, there were no significant differences in body fat content, white fat wet weight/body weight and scapular fat wet weight/body weight between ADMF group and ADMF-Exer group (P＞0.05), and adipocyte area in ADMF-Exer group was reduced significantly (P＜0.05). Compared with the Exer group, the gastrocnemius muscle wet weight/body weight was reduced significantly in the ADMF group (P＜0.05), and the expression of FNDC5 protein, serum Irisin and adipose UCP1 protein in the ADMF-Exer group were increased significantly compared with the Exer group (P＜0.05). CONCLUSION: Alternate-day modified fasting combined with exercise intervention can effectively control body weight and reduce body fat in rats, and the mechanism may be through the FNDC5/Irisin-UCP1 pathway to induce browning of white adipose tissue and increase thermogenesis of brown fat.

[Effect of 4-week electroacupuncture intervention on "Browning" of white fat in rats and its mechanism].

Objective: To investigate the effects of 4-week electroacupuncture intervention on "Browning" of white fat in rats, and to explore its molecular mechanisms. Methods: Twenty-four 8-week-old male SD rats were randomly divided into sedentary group (Sed), aerobic exercise group (Exe) and electroacupuncture group (ElA), 8 rats in each group. Exe group used 65% Max oxygen uptake intensity treadmill exercise, 1 h/d,6 d/w, while the ElA group used electric acupuncture to stimulate "zusanli" and "tianshu" points, 20 min/d,6 d/w, and the weight of rats was recorded every week. After 4 weeks of intervention, blood samples were collected from the apex and abdominal aorta. The wet weight of scapular fat and perirenal fat of rats was detected and the body fat and the serum levels of Irisin were determined. What's more, the expressions of adenosine 5'-monophosphate activated protein kinase-α (AMPKα), phosphorylation of adenosine 5'-monophosphate activated protein kinase-α (p-AMPKα), peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α), fibronectin type III domain containing 5 (FNDC5) and uncoupling protein (UCP1) and brown adipose tissue lipid droplets in rats were detected. Results: Compared with the Sed group, the weight gain of rats in the Exe and ElA groups was decreased significantly from the second week. After 4 weeks, the body weight and body fat of the Exe and ElA groups were decreased significantly (P＜0.01), while there was no significant difference between the Exe and ElA groups (P＞0.05). ②After 4 weeks of intervention, the white fat wet weight of ElA group and Exe group was significantly was reduced (P＜0.05 or P＜0.01). ③The serum levels of Irisin in Exe and ElA groups were significantly increased (P＜0.05), and the expressions of p-AMPKα/AMPKα, PGC-1α, FNDC5 in the gastrocnemius and the expressions of UCP1 in white fat and brown adipose tissue of Exe and ElA groups were increased (P＜0.05). ④The area of lipid droplets in white and brown adipose tissue of Exe and ElA groups was significantly reduced (P＜ 0.01). Conclusion: 4 weeks of electroacupuncture intervention can effectively control the weight of rats and induce "browning" of white fat, and its effect was similar to aerobic exercise, which may be release Irisin through the AMPKα-PGC-1α-FNDC5-Irisin signaling pathway, and then "crosstalk" with adipose tissue, up-regulate the expression of UCP1, and induce "browning" of white adipose tissue.

Distinct subtypes of Alzheimer's disease based on patterns of brain atrophy: longitudinal trajectories and clinical applications.

Atrophy patterns on MRI can reliably predict three neuropathological subtypes of Alzheimer's disease (AD): typical, limbic-predominant, or hippocampal-sparing. A method to enable their investigation in the clinical routine is still lacking. We aimed to (1) validate the combined use of visual rating scales for identification of AD subtypes; (2) characterise these subtypes at baseline and over two years; and (3) investigate how atrophy patterns and non-memory cognitive domains contribute to memory impairment. AD patients were classified as either typical AD (n = 100), limbic-predominant (n = 33), or hippocampal-sparing (n = 35) by using the Scheltens' scale for medial temporal lobe atrophy (MTA), the Koedam's scale for posterior atrophy (PA), and the Pasquier's global cortical atrophy scale for frontal atrophy (GCA-F). A fourth group with no atrophy was also identified (n = 30). 230 healthy controls were also included. There was great overlap among subtypes in demographic, clinical, and cognitive variables. Memory performance was more dependent on non-memory cognitive functions in hippocampal-sparing and the no atrophy group. Hippocampal-sparing and the no atrophy group showed less aggressive disease progression. Visual rating scales can be used to identify distinct AD subtypes. Recognizing AD heterogeneity is important and visual rating scales may facilitate investigation of AD heterogeneity in clinical routine.

Deterioration of palatal myoclonus after acute thalamic hemorrhage.

BACKGROUND: Palatal myoclonus (PM) is the hallmark of hypertrophic olivary degeneration (HOD); however, little is known regarding the association of thalamic lesions and PM. Case presentation: Here, we report a case of deteriorative PM after an acute small ventrolateral thalamic hemorrhage in a female Chinese patient with HOD. The sudden and severe deterioration of PM was preceded by at least 10 days of an occasionally occurring PM, which was related to an acute cerebellar hemorrhage 8 months earlier. A computed tomography scan upon admission showed a small intracerebral hematoma in the left ventrolateral thalamus, and a magnetic resonance imaging scan revealed the typical signs of HOD as well as a remote lesion in the dentate nucleus. Symptoms of PM were controlled by carbamazepine and clonazepam. CONCLUSION: These findings indicated that the damaged dentatothalamic tract might be due to a unique pathogenic mechanism involving a lesion of the ventrolateral thalamus and Guillain-Mollaret triangle.