The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA ...gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The modular SCF (Skp1, cullin, and F box) ubiquitin ligases feature a large family of F box protein substrate receptors that enable recognition of diverse targets. However, how the repertoire of SCF ...complexes is sustained remains unclear. Real-time measurements of formation and disassembly indicate that SCFFbxw7 is extraordinarily stable, but, in the Nedd8-deconjugated state, the cullin-binding protein Cand1 augments its dissociation by one-million-fold. Binding and ubiquitylation assays show that Cand1 is a protein exchange factor that accelerates the rate at which Cul1-Rbx1 equilibrates with multiple F box protein-Skp1 modules. Depletion of Cand1 from cells impedes recruitment of new F box proteins to pre-existing Cul1 and profoundly alters the cellular landscape of SCF complexes. We suggest that catalyzed protein exchange may be a general feature of dynamic macromolecular machines and propose a hypothesis for how substrates, Nedd8, and Cand1 collaborate to regulate the cellular repertoire of SCF complexes.
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► Cand1 modulates the repertoire of SCF ubiquitin ligase complexes in cells ► Cand1 functions as an F box protein exchange factor ► FRET assay reveals real-time dynamics of SCFFbxw7 assembly and disassembly ► Cand1 accelerates the dissociation rate of SCFFbxw7 one-million-fold
Cand1 accelerates the dissociation of F box proteins from SCF ubiquitin ligases by one-million-fold. It thereby operates as a protein exchange factor to shape the cellular repertoire of SCF complexes.
Although anaesthesiologists strive to avoid hypoxemia during surgery, reliably predicting future intraoperative hypoxemia is not currently possible. Here, we report the development and testing of a ...machine-learning-based system that, in real time during general anaesthesia, predicts the risk of hypoxemia and provides explanations of the risk factors. The system, which was trained on minute-by-minute data from the electronic medical records of over fifty thousand surgeries, improved the performance of anaesthesiologists when providing interpretable hypoxemia risks and contributing factors. The explanations for the predictions are broadly consistent with the literature and with prior knowledge from anaesthesiologists. Our results suggest that if anaesthesiologists currently anticipate 15% of hypoxemia events, with this system's assistance they would anticipate 30% of them, a large portion of which may benefit from early intervention because they are associated with modifiable factors. The system can help improve the clinical understanding of hypoxemia risk during anaesthesia care by providing general insights into the exact changes in risk induced by certain patient or procedure characteristics.
Since 1993, the annual worldwide cost of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), control has been routinely quoted to be US$1 billion. This estimate requires updating ...and incorporation of yield losses to reflect current total costs of the pest to the world economy. We present an analysis that estimates what the present costs are likely to be based on a set of necessary, but reasoned, assumptions. We use an existing climate driven model for diamondback moth distribution and abundance, the Food and Agriculture Organization country Brassica crop production data and various management scenarios to bracket the cost estimates. The “length of the string” is somewhere between US$1.3 billion and US$2.3 billion based on management costs. However, if residual pest damage is included then the cost estimates will be even higher; a conservative estimate of 5% diamondback moth-induced yield loss to all crops adds another US$2.7 billion to the total costs associated with the pest. A conservative estimate of total costs associated with diamondback moth management is thus US$4 billion-US$5 billion. The lower bound represents rational decision making by pest managers based on diamondback moth abundance driven by climate only. The upper estimate is due to the more normal practice of weekly insecticide application to vegetable crops and the assumption that canola (Brassica napus L.) is treated with insecticide at least once during the crop cycle. Readers can decide for themselves what the real cost is likely to be because we provide country data for further interpretation. Our analysis suggests that greater efforts at implementation of even basic integrated pest management would reduce insecticide inputs considerably, reducing negative environmental impacts and saving many hundreds of millions of dollars annually.
The diamondback moth (DBM),
Plutella xylostella
(L.), costs the Chinese economy US$0.77 billion annually, and considerable research has focused on its biology, ecology, and management. Much of this ...research has been published locally and is inaccessible outside China. Since 1990
Brassica
vegetable production has increased 20-fold and production practices have intensified, but losses continue to increase. Insecticide use is widespread and many DBM populations, particularly in southern provinces, are resistant to multiple compounds. The molecular bases of several insecticide resistance mechanisms are well understood, and genetic studies suggest that insecticide-resistant populations migrate northward in spring and that back migrations may occur in southern provinces. Fundamental studies have improved our understanding of the effects of temperature on DBM population dynamics and distributions and of interactions between DBM and its well-established parasitoid fauna. Nationally coordinated research is developing regional management strategies that integrate locally appropriate biological, physical, cultural, and insecticidal control, but sustaining their adoption will prove an enormous challenge.
This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction ...of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.
Since its discovery in the 1970s, surface-enhanced Raman scattering (SERS) has been primarily associated with substrates composed of nanostructured noble metals. Here we investigate chemically ...synthesized nanocrystal aggregates of aluminum, an inexpensive, highly abundant, and sustainable metal, as SERS substrates. Al nanocrystal aggregates are capable of substantial near-infrared SERS enhancements, similar to Au nanoparticles. The intrinsic nanoscale surface oxide of Al nanocrystals supports molecule–substrate interactions that differ dramatically from noble metal substrates. The preferential affinity of the single-stranded DNA (ssDNA) phosphate backbone for the Al oxide surface preserves both the spectral features and nucleic acid cross sections relative to conventional Raman spectroscopy, enabling quantitative ssDNA detection and analysis.
Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the ...developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ∼25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.
In phase-change memory devices, a material is cycled between glassy and crystalline states. The highly temperature-dependent kinetics of its crystallization process enables application in memory ...technology, but the transition has not been resolved on an atomic scale. Using femtosecond x-ray diffraction and ab initio computer simulations, we determined the time-dependent pair-correlation function of phase-change materials throughout the melt-quenching and crystallization process. We found a liquid-liquid phase transition in the phase-change materials Ag
In
Sb
Te
and Ge
Sb
at 660 and 610 kelvin, respectively. The transition is predominantly caused by the onset of Peierls distortions, the amplitude of which correlates with an increase of the apparent activation energy of diffusivity. This reveals a relationship between atomic structure and kinetics, enabling a systematic optimization of the memory-switching kinetics.
BACKGROUND:The ATTRACT trial (Acute Venous ThrombosisThrombus Removal with Adjunctive Catheter-Directed Thrombolysis) previously reported that pharmacomechanical catheter–directed thrombolysis (PCDT) ...did not prevent postthrombotic syndrome (PTS) in patients with acute proximal deep vein thrombosis. In the current analysis, we examine the effect of PCDT in ATTRACT patients with iliofemoral deep vein thrombosis.
METHODS:Within a large multicenter randomized trial, 391 patients with acute deep vein thrombosis involving the iliac or common femoral veins were randomized to PCDT with anticoagulation versus anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes.
RESULTS:Between 6 and 24 months, there was no difference in the occurrence of PTS (Villalta scale ≥5 or ulcer49% PCDT versus 51% No-PCDT; risk ratio, 0.95; 95% CI, 0.78–1.15; P=0.59). PCDT led to reduced PTS severity as shown by lower mean Villalta and Venous Clinical Severity Scores (P<0.01 for comparisons at 6, 12, 18, and 24 months), and fewer patients with moderate-or-severe PTS (Villalta scale ≥10 or ulcer18% versus 28%; risk ratio, 0.65; 95% CI, 0.45–0.94; P=0.021) or severe PTS (Villalta scale ≥15 or ulcer8.7% versus 15%; risk ratio, 0.57; 95% CI, 0.32–1.01; P=0.048; and Venous Clinical Severity Score ≥86.6% versus 14%; risk ratio, 0.46; 95% CI, 0.24–0.87; P=0.013). From baseline, PCDT led to greater reduction in leg pain and swelling (P<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease–specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life unit difference 5.6 through 24 months, P=0.029), but no difference in generic quality of life (P>0.2 for comparisons of SF-36 mental and physical component summary scores through 24 months). In patients having PCDT versus No-PCDT, major bleeding within 10 days occurred in 1.5% versus 0.5% (P=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% versus 9.2% (P=0.21).
CONCLUSIONS:In patients with acute iliofemoral deep vein thrombosis, PCDT did not influence the occurrence of PTS or recurrent venous thromboembolism. However, PCDT significantly reduced early leg symptoms and, over 24 months, reduced PTS severity scores, reduced the proportion of patients who developed moderate-or-severe PTS, and resulted in greater improvement in venous disease–specific quality of life.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT00790335.
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