The complete coding sequence of a rotavirus A strain was determined from a dead racing pigeon in Florida. It was found to be most closely related to a rotavirus A strain isolated from a dead racing ...pigeon in California.
Mutations in the PTEN‐induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and ...phosphorylates serine 65 (Ser65) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1‐dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub‐family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser111) in response to PINK1 activation. Using phospho‐specific antibodies raised against Ser111 of each of the Rabs, we demonstrate that Rab Ser111 phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient‐derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser111 phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser65. We further show mechanistically that phosphorylation at Ser111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser111 may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase‐mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease.
Synopsis
The Parkinson's disease‐mutated PINK1 kinase phosphorylates Parkin and ubiquitin. Phosphoproteomic screening reveals Rab8A, Rab8B and Rab13 GTPases as some of only few additional targets whose phosphorylation depends on PINK1 during mitophagy.
Activated PINK1 indirectly controls phosphorylation of serine 111 of Rab8A and closely related Rab GTPases.
Biochemical and cellular analysis imply an unknown intermediate PINK1‐dependent Rab8A Ser111 kinase or phosphatase.
PINK1‐directed activation of Parkin E3 ligase activity is independent of Rab8A Ser111 phosphorylation
Phosphorylation at Ser111 inhibits Rab8A activation by its guanine exchange factor, Rabin8.
Ser111 modification of Rab8A, Rab8B and Rab13 represent some of only few PINK1‐dependent phosphorylation events and may regulate GTPase function during mitophagy.
Predator effects on prey dynamics are conventionally studied by measuring changes in prey abundance attributed to consumption by predators. We revisit four classic examples of predator—prey systems ...often cited in textbooks and incorporate subsequent studies of nonconsumptive effects of predators (NCE), defined as changes in prey traits (e.g., behavior, growth, development) measured on an ecological time scale. Our review revealed that NCE were integral to explaining lynx—hare population dynamics in boreal forests, cascading effects of top predators in Wisconsin lakes, and cascading effects of killer whales and sea otters on kelp forests in nearshore marine habitats. The relatives roles of consumption and NCE of wolves on moose and consequent indirect effects on plant communities of Isle Royale depended on climate oscillations. Nonconsumptive effects have not been explicitly tested to explain the link between planktonic alewives and the size structure of the zooplankton, nor have they been invoked to attribute keystone predator status in intertidal communities or elsewhere. We argue that both consumption and intimidation contribute to the total effects of keystone predators, and that characteristics of keystone consumers may differ from those of predators having predominantly NCE. Nonconsumptive effects are often considered as an afterthought to explain observations inconsistent with consumption-based theory. Consequently, NCE with the same sign as consumptive effects may be overlooked, even though they can affect the magnitude, rate, or scale of a prey response to predation and can have important management or conservation implications. Nonconsumptive effects may underlie other classic paradigms in ecology, such as delayed density dependence and predator-mediated prey coexistence. Revisiting classic studies enriches our understanding of predator—prey dynamics and provides compelling rationale for ramping up efforts to consider how NCE affect traditional predator—prey models based on consumption, and to compare the relative magnitude of consumptive and NCE of predators.
The molecular mechanisms underlying chemoresistance in some newly diagnosed multiple myeloma (MM) patients receiving standard therapies (lenalidomide, bortezomib, and dexamethasone) are poorly ...understood. Identifying clinically relevant gene networks associated with death due to MM may uncover novel mechanisms, drug targets, and prognostic biomarkers to improve the treatment of the disease. This study used data from the MMRF CoMMpass RNA-seq dataset (N = 270) for weighted gene co-expression network analysis (WGCNA), which identified 21 modules of co-expressed genes. Genes differentially expressed in patients with poor outcomes were assessed using two independent sample
-tests (dead and alive MM patients). The clinical performance of biomarker candidates was evaluated using overall survival via a log-rank Kaplan-Meier and ROC test. Four distinct modules (M10, M13, M15, and M20) were significantly correlated with MM vital status and differentially expressed between the dead (poor outcomes) and the alive MM patients within two years. The biological functions of modules positively correlated with death (M10, M13, and M20) were G-protein coupled receptor protein, cell-cell adhesion, cell cycle regulation genes, and cellular membrane fusion genes. In contrast, a negatively correlated module to MM mortality (M15) was the regulation of B-cell activation and lymphocyte differentiation. MM biomarkers
,
,
,
, and
were co-expressed in positively correlated modules to MM vital status, which was associated with MM's lower overall survival.
NASA’S Origins, Spectral Interpretation, Resource Identification and Security-Regolith Explorer (OSIRIS-REx) spacecraft recently arrived at the near-Earth asteroid (101955) Bennu, a primitive body ...that represents the objects that may have brought prebiotic molecules and volatiles such as water to Earth1. Bennu is a low-albedo B-type asteroid2 that has been linked to organic-rich hydrated carbonaceous chondrites3. Such meteorites are altered by ejection from their parent body and contaminated by atmospheric entry and terrestrial microbes. Therefore, the primary mission objective is to return a sample of Bennu to Earth that is pristine—that is, not affected by these processes4. The OSIRIS-REx spacecraft carries a sophisticated suite of instruments to characterize Bennu’s global properties, support the selection of a sampling site and document that site at a sub-centimetre scale5,6,7,8,9,10,11. Here we consider early OSIRIS-REx observations of Bennu to understand how the asteroid’s properties compare to pre-encounter expectations and to assess the prospects for sample return. The bulk composition of Bennu appears to be hydrated and volatile-rich, as expected. However, in contrast to pre-encounter modelling of Bennu’s thermal inertia12 and radar polarization ratios13—which indicated a generally smooth surface covered by centimetre-scale particles—resolved imaging reveals an unexpected surficial diversity. The albedo, texture, particle size and roughness are beyond the spacecraft design specifications. On the basis of our pre-encounter knowledge, we developed a sampling strategy to target 50-metre-diameter patches of loose regolith with grain sizes smaller than two centimetres4. We observe only a small number of apparently hazard-free regions, of the order of 5 to 20 metres in extent, the sampling of which poses a substantial challenge to mission success.
Radiofrequency catheter ablation (RFCA) is a promising intervention to treat atrial fibrillation. However, pulmonary vein (PV) stenosis after RFCA has been reported. The aim of this study was to ...investigate the incidence and time course of pulmonary vein stenosis after RFCA within a period of 3 months. Contrast-enhanced magnetic resonance angiography (MRA) was used to visualize pulmonary veins and was compared with radiographic angiography.
Forty-six consecutive patients with symptomatic paroxysmal atrial fibrillation had RFCA in the orifice of 138 pulmonary veins. Comparison of diameters measured in 44 untreated vessels either by radiographic angiography or with MRA established the reliability of MRA (r=0.934). MRA measurements revealed an incidence of relevant diameter reductions of > or =25% or stenosis of > or =50% after RFCA of 25 of 138 (18.1%) treated vessels 1 day and/or 3 months after ablation. A progression of diameter reduction after RFCA was observed in 8.3% (maximum 75%), whereas a regression was observed in 6.3% of treated PVs. Ablation at a radial angle of >180 degrees of a pulmonary vein orifice increased the risk of diameter reduction significantly compared with ablation at a radial angle < or =180 degrees (P=0.002).
The occurrence and progression of PV stenosis is a potential significant complication of RFCA in the orifice of pulmonary veins. These findings may have an impact on the technical performance of this intervention. In addition, long-term studies will be necessary to evaluate lumen reduction over time. MRA is a noninvasive, reproducible imaging modality for this purpose.
Architecture validation for processors Ho, Richard C.; Yang, C. Han; Horowitz, Mark A. ...
International Symposium on Computer Architecture: Proceedings of the 22nd annual international symposium on Computer architecture : S. Margherita Ligure, Italy; 22-24 June 1995,
05/1995
Conference Proceeding
Modem, high performance microprocessors are extremely complex machines which require substantial validation effort to ensure functional correctness prior to tapeout. Generating the corner cases to ...test these designs is a mostly manual process, where completion is hard to judge. Experience shows that the errors that are caught late in the design, many post-silicon, are interactions between different components in very improbable corner case situations. In this paper we present a technique that targets such error-causing interactions by automatically generat- ing test vectors that will cause the processor to exercise all transitions of the control logic in simulation. We use techniques from formal verification to derive transition tours of a fully enumerated state graph of the control logic of the processor. Our system works from a Verilog description of the original machine and is currently being used to validate an embedded dual-issue processor in the node controller of the Stanford FLASH Multiprocessor. Modeling the processor control results in 200K states and an 8M instruction trace to check all transitions of control arcs.
Purpose: Cauda equina syndrome (CES) is a spinal emergency with clinical symptoms and signs that have low diagnostic accuracy. National guidelines in the United Kingdom (UK) state that all patients ...should undergo an MRI prior to referral to specialist spinal units and surgery should be performed at the earliest opportunity. We aimed to evaluate the current practice of investigating and treating suspected CES in the UK.
Materials and Methods: A retrospective, multicentre observational study of the investigation and management of patients with suspected CES was conducted across the UK, including all patients referred to a spinal unit over 6 months between 1st October 2016 and 31st March 2017.
Results: A total of 28 UK spinal units submitted data on 4441 referrals. Over half of referrals were made without any previous imaging (n = 2572, 57.9%). Of all referrals, 695 underwent surgical decompression (15.6%). The majority of referrals were made out-of-hours (n = 2229/3517, 63.4%). Patient location and pre-referral imaging were not associated with time intervals from symptom onset or presentation to decompression. Patients investigated outside of the spinal unit experienced longer time intervals from referral to undergoing the MRI scan.
Conclusions: This is the largest known study of the investigation and management of suspected CES. We found that the majority of referrals were made without adequate investigations. Most patients were referred out-of-hours and many were transferred for an MRI without subsequently requiring surgery. Adherence to guidelines would reduce the number of referrals to spinal services by 72% and reduce the number of patient transfers by 79%.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The percutaneous infrainguinal stent (PSI) register study aimed to collate all percutaneous endovascular procedures for infrainguinal peripheral arterial occlusive disease (PAOD) conducted ...in 74 German vascular centers between September and November 2015 (3 months). In order to obtain representative results all consecutive treatment procedures had to be submitted by the participating trial centers.
Material and methods
This was a prospective, nonrandomized multicenter study design. All patients suffering from intermittent claudication (IC, Fontaine stage II) or critical limb ischemia (CLI, Fontaine stages III and IV) were included. Trial centers with less than 5 cases reported within the 3‑month trial period or centers that could not ensure the submission of all treated patients were excluded.
Results
In the final assessment 2798 treated cases from 74 trial centers were reported of which 65 (87.8 %) centers were under the leadership of a vascular surgeon. Approximately 33 % of the interventions in centers under the leadership of vascular surgeons were conducted by radiologists. Risk factors, especially chronic renal disease, diabetes and cardiac risk factors were significantly different between patients with IC and CLI. Of the patients with Fontaine stage II PAOD 41.3 % had 3 patent crural vessels compared to only 10.8 % of patients with Fontaine stage IV. With respect to peri-interventional complications, percutaneous endovascular treatment of IC was a safe procedure with severe complications in less than 1 % and no fatalities. Only 4.5 % of the procedures were conducted under ambulatory conditions. In the supragenual region self-expanding bare metal stents, standard percutaneous transluminal angioplasty (PTA) and drug-coated balloons were the most frequently used procedures. For interventions below the knee, standard PTA was the most commonly employed treatment.
Conclusion
The main aim of the PSI study was to obtain a realistic picture of percutaneous endovascular techniques used to treat suprapopliteal and infrapopliteal PAOD lesions and to describe the treatment procedures used by vascular specialists in Germany. To investigate the change in trends for treatment over time, this study has to be repeated in the future in order to test how quickly the results of randomized studies can be implemented in practice.
The investigations involved geophysical, sedimentological, palynological, chemical and mineralogical studies, supported by field-based infrared spectrometry. The Baganuur Basin, Central Mongolia, is ...among the rift or pull-apart-basins, which subsided at the boundary between the Jurassic and the Lower Cretaceous in East Asia. During the Berriasian, peat accumulation began in the area under study in Central Mongolia. The palynoflora is akin to the Siberian palynological province. Based on the phytoclast assemblages and the ratios of total sulfur content to total organic content, marine transgressions into this intermontane basin may be ruled out. The coal interseam sediments were laid down prevalently under neutral to slightly alkaline conditions; only in some carbonaceous sediments, the pH of intrastratal solutions was lowered. Suboxic to anoxic conditions persisted during almost the entire Lower Cretaceous period in the Baganuur Basin. Based on the distribution of fining- and coarsening-upward sequences and the organic matter, the basin fill has been subdivided into seven depositional units (A: fluvial–swamp, B: fluvial–lacustrine, C: deltaic–fluvial, D: fluvial, E: fluvial–deltaic–lacustrine/floodplain (?), F: lacustrine–deltaic–swamp, G: swamp–fluvial). A conspicuous change in the fluvial–lacustrine regime and an increase in the sediment supply may be observed at the boundary between depositional units B and C. A strong uplift triggered the onset of an intensive delta sedimentation. Lithoclasts, heavy minerals (e.g., apatite, zircon, garnet, anatase, brookite, epidote, sphene, tourmaline) and phyllosilicates (e.g., kaolinite, smectite, mica, chlorite) attest to a mixing of detrital material. One provenance area was abundant in acidic plutonic rocks as shown by the granitic lithoclasts, the other in volcanic rocks, which produced the vitroclastic debris deposited as tephra fallout. Post-depositional alteration of the siliciclastic interseam sediments was favored by a distinctive facies association of transmissive and sealing horizons. It led to a re-deposition of Ca, U and Sr in the siliciclastics. Post-depositional alteration of the organic material converted it into lignite to subbituminous C coal.
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