Alternative splicing plays a key role in the expansion of proteomic and regulatory complexity, yet the functions of the vast majority of differentially spliced exons are not known. In this study, we ...observe that brain and other tissue-regulated exons are significantly enriched in flexible regions of proteins that likely form conserved interaction surfaces. These proteins participate in significantly more interactions in protein-protein interaction (PPI) networks than other proteins. Using LUMIER, an automated PPI assay, we observe that approximately one-third of analyzed neural-regulated exons affect PPIs. Inclusion of these exons stimulated and repressed different partner interactions at comparable frequencies. This assay further revealed functions of individual exons, including a role for a neural-specific exon in promoting an interaction between Bridging Integrator 1 (Bin1)/Amphiphysin II and Dynamin 2 (Dnm2) that facilitates endocytosis. Collectively, our results provide evidence that regulated alternative exons frequently remodel interactions to establish tissue-dependent PPI networks.
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▸ Proteins containing tissue-regulated exons have high centrality in PPI networks ▸ Tissue-regulated exons are highly enriched in protein regions that mediate PPIs ▸ LUMIER reveals that one-third of analyzed neural-specific exons modulate PPIs ▸ Exon-resolution functional mapping reveals specific roles for neural AS events
Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. ...Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide “microexons” display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.
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•3–27 nt microexons are highly evolutionarily conserved and neuronal specific•Microexons modulate surfaces of interaction domains of neuronal proteins•Most microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4•Microexons are frequently misregulated in the brains of autistic individuals
Hundreds of 3–27 nt neuronal-specific “microexons” in mammals are identified and characterized. They are frequently misregulated in autistic brains.
Alternative splicing (AS) of pre-mRNA is utilized by higher eukaryotes to achieve increased transcriptome and proteomic complexity. The serine/arginine (SR) splicing factors regulate tissue- or ...cell-type-specific AS in a concentration- and phosphorylation-dependent manner. However, the mechanisms that modulate the cellular levels of active SR proteins remain to be elucidated. In the present study, we provide evidence for a role for the long nuclear-retained regulatory RNA (nrRNA), MALAT1 in AS regulation. MALAT1 interacts with SR proteins and influences the distribution of these and other splicing factors in nuclear speckle domains. Depletion of MALAT1 or overexpression of an SR protein changes the AS of a similar set of endogenous pre-mRNAs. Furthermore, MALAT1 regulates cellular levels of phosphorylated forms of SR proteins. Taken together, our results suggest that MALAT1 regulates AS by modulating the levels of active SR proteins. Our results further highlight the role for an nrRNA in the regulation of gene expression.
► Nuclear speckle-localized MALAT1 interacts with SR splicing factors ► MALAT1 influences the nuclear speckle distribution of splicing factors ► MALAT1 depletion changes alternative splicing of endogenous pre-mRNAs ► MALAT1 regulates the cellular levels of phosphorylated SR proteins
Alternative splicing is crucial for diverse cellular, developmental, and pathological processes. However, the full networks of factors that control individual splicing events are not known. Here, we ...describe a CRISPR-based strategy for the genome-wide elucidation of pathways that control splicing and apply it to microexons with important functions in nervous system development and that are commonly misregulated in autism. Approximately 200 genes associated with functionally diverse regulatory layers and enriched in genetic links to autism control neuronal microexons. Remarkably, the widely expressed RNA binding proteins Srsf11 and Rnps1 directly, preferentially, and frequently co-activate these microexons. These factors form critical interactions with the neuronal splicing regulator Srrm4 and a bi-partite intronic splicing enhancer element to promote spliceosome formation. Our study thus presents a versatile system for the identification of entire splicing regulatory pathways and further reveals a common mechanism for the definition of neuronal microexons that is disrupted in autism.
Changing disturbance regimes and climate can overcome forest ecosystem resilience. Following high-severity fire, forest recovery may be compromised by lack of tree seed sources, warmer and drier ...postfire climate, or short-interval reburning. A potential outcome of the loss of resilience is the conversion of the prefire forest to a different forest type or nonforest vegetation. Conversion implies major, extensive, and enduring changes in dominant species, life forms, or functions, with impacts on ecosystem services. In the present article, we synthesize a growing body of evidence of fire-driven conversion and our understanding of its causes across western North America. We assess our capacity to predict conversion and highlight important uncertainties. Increasing forest vulnerability to changing fire activity and climate compels shifts in management approaches, and we propose key themes for applied research coproduced by scientists and managers to support decision-making in an era when the prefire forest may not return.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone ...contaminated with prions. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-β (Aβ) pathology. The Aβ deposition in the grey matter was typical of that seen in Alzheimer's disease and Aβ in the blood vessel walls was characteristic of cerebral amyloid angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study showed minimal or no Aβ pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aβ pathology and found marked Aβ deposition in multiple cases. Experimental seeding of Aβ pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate. The marked deposition of parenchymal and vascular Aβ in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aβ pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to Aβ and other proteopathic seeds associated with neurodegenerative and other human diseases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•Strain response of additively manufactured piezoelectric PVDF actuators are reported.•The EPAM PVDF measured strain is up to 5.2 times greater than that of a PZT actuator.•Measured EPAM PVDF ...response is orders of magnitude larger than commercial PVDF.•Sample performance varies, and so refinement of the EPAM process is required.
Polyvinyldene fluoride (PVDF) polymer piezoelectric actuators were manufactured using an electric poling-assisted additive manufacturing (EPAM) process and tested for actuation strain in the thickness direction. A heterodyne interferometer was used to measure the strain developed by the actuators as a function of applied voltage. Results were compared to a commercially available ceramic lead–zirconium–titanate (PZT) actuator. The EPAM PVDF samples exhibit strains up to 8.78mϵ, compared to 1.7mϵ developed by PZT samples at their maximum working voltages in linear ramp testing (860V for EPAM PVDF and 200V for PZT). The response of the EPAM PVDF samples to an applied force was tested to measure the piezoelectric effect, although no actual piezoelectric constants are calculated with this method. Results show that strain measurements of EPAM PVDF samples were up to 5.2 times greater than comparable measurements of PZT samples. However, the degree of piezoelectricity between EPAM PVDF samples varies so quality control is required for the EPAM process to ensure sample performance.
A system for naming ribosomal proteins is described that the authors intend to use in the future. They urge others to adopt it. The objective is to eliminate the confusion caused by the assignment of ...identical names to ribosomal proteins from different species that are unrelated in structure and function. In the system proposed here, homologous ribosomal proteins are assigned the same name, regardless of species. It is designed so that new names are similar enough to old names to be easily recognized, but are written in a format that unambiguously identifies them as ‘new system’ names.
To determine if anterior pelvic fracture pattern in lateral compression (LC) sacral fractures correlates with subsequent displacement on examination under anesthesia (EUA) or follow-up in both ...nonoperative and operative cases.
Retrospective cohort study.
Level 1 trauma center.
Two hundred twenty-seven skeletally mature patients with traumatic LC (OTA/AO 61B1.1, 61B2.1-2, and 61B3.1-2) pelvic ring injuries treated nonoperatively, with EUA, or with pelvic fixation were included.
The study intervention included retrospective review of patients' charts and radiographs.
Displacement on EUA or follow-up radiographs (both operative and nonoperative) correlated with anterior pelvic ring fracture pattern.
Independent of sacral fracture pattern (complete or incomplete), risk of subsequent displacement on EUA or at follow-up after both nonoperative and operative treatments correlated strongly with ipsilateral superior and inferior pubic rami fractures that were either comminuted (95.6%, P < 0.001) or oblique (100%, P < 0.001). Patients with transverse or lack of inferior pubic ramus fracture did not displace (0%, P < 0.001). Out of 21 LC injuries treated with posterior-only fixation, displacement at follow-up occurred in all 11 patients (100%) with comminuted and/or oblique superior and inferior pubic rami fractures. Nakatani zone I and II rami fractures correlated most with risk of subsequent displacement.
Unstable anterior fracture patterns are characterized as comminuted and/or oblique fractures of ipsilateral superior and inferior pubic rami. EUA should be strongly considered in these patients to disclose occult instability, for both complete and incomplete sacral fracture patterns. Additionally, these unstable anterior fracture patterns are poor candidates for posterior-only fixation and supplemental anterior fixation should be considered. Irrespective of sacral fracture pattern (complete or incomplete), nonoperative management is successful in patients with transverse or lack of inferior pubic ramus fractures.
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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