Wisdom in self-scrutiny     

Dresser R 《Science (New York, N.Y.)》2004,304(5674):1111

  相似文献   

Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy     

Egan DF  Shackelford DB  Mihaylova MM  Gelino S  Kohnz RA  Mair W  Vasquez DS  Joshi A  Gwinn DM  Taylor R  Asara JM  Fitzpatrick J  Dillin A  Viollet B  Kundu M  Hansen M  Shaw RJ 《Science (New York, N.Y.)》2011,331(6016):456-461

Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.  相似文献   

Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I     

He H  Liyanarachchi S  Akagi K  Nagy R  Li J  Dietrich RC  Li W  Sebastian N  Wen B  Xin B  Singh J  Yan P  Alder H  Haan E  Wieczorek D  Albrecht B  Puffenberger E  Wang H  Westman JA  Padgett RA  Symer DE  de la Chapelle A 《Science (New York, N.Y.)》2011,332(6026):238-240

Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.  相似文献   

A reverse keystone species affects the landscape distribution of woodland avifauna: a case study using the Noisy Miner (<Emphasis Type="Italic">Manorina melanocephala</Emphasis>) and other Australian birds     

Rebecca M. Montague-Drake  David B. Lindenmayer  Ross B. Cunningham  John A. Stein 《Landscape Ecology》2011,26(10):1383-1394

We explored the effects of a purported ‘reverse keystone species’, the Noisy Miner (Manorina melanocephala) using a long-term, large-scale dataset. Specifically, we identify whether this aggressive bird affects the landscape distribution patterns of other avifauna, by displacing them into, or restricting their distribution to, less productive areas, and in so doing, adheres to ‘isoleg theory’. We sought to determine the effect of abundance of the Noisy Miner on the abundance of other birds (individual species and groups), and determine whether that effect was consistent with varying site productivity, using a negative binomial distribution with a logarithmic link function, and an offset variable to account for variations in search effort. Relationships between abundance of Noisy Miners and habitat variables were examined using a Poisson distribution with a logarithmic link function scaled for extra-variation (quasi-Poisson regression). We demonstrate that when Noisy Miner abundance is low, many small passerine species are more abundant on high productivity sites. However, as Noisy Miner abundance increases, small passerine abundance decreases, with this decrease most apparent on productive sites. The same patterns were not evident for birds considered ‘non-competitors’ of the Noisy Miner. We identify that both site productivity and vegetation structure influence the abundance of the Noisy Miner. We reveal that the species increasingly tolerates ‘less desirable’ habitat attributes with increasing site productivity. The preference of the Noisy Miner for productive areas is likely to have deleterious impacts on the long-term survival and reproductive success of other Australian woodland bird species, many of which have already undergone severe declines.  相似文献   

Competencies: a cure for pre-med curriculum     

Anderson WA  Amasino RM  Ares M  Banerjee U  Bartel B  Corces VG  Drennan CL  Elgin SC  Epstein IR  Fanning E  Guillette LJ  Handelsman J  Hatfull GF  Hoy RR  Kelley D  Leinwand LA  Losick R  Lu Y  Lynn DG  Neuhauser C  O'Dowd DK  Olivera T  Pevzner P  Richards-Kortum RR  Rine J  Sah RL  Strobel SA  Walker GC  Walt DR  Warner IM  Wessler S  Willard HF  Zare RN 《Science (New York, N.Y.)》2011,334(6057):760-761

  相似文献   

Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats     

LeVine DN  Papich MG  Gookin JL  Davidson GS  Davis JL  Hayes RB 《Journal of Feline Medicine and Surgery》2011,13(4):244-250

Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2mg/kg) and a 95mg immediate-release RDZ capsule (mean 28.2mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (±16.54)%. The clearance of RDZ following IV administration was 0.82 (±0.07) ml/kg/min. The terminal half-life was 9.80 (±0.35) and 10.50 (±0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats.  相似文献   

Plasma volume and electrolyte changes following intravenous infusion of hypertonic hydroxyethyl starch versus mannitol in healthy dogs     

Robinson R  Schwendenwein I  Wacek S  Nell B  Mosing M 《Veterinary journal (London, England : 1997)》2011,190(2):268-272

In a prospective cross-over study, the duration and magnitude of effect on the electrolyte and plasma volume changes of intravenous (IV) hypertonic hydroxyethyl starch (hyperHES) (7.5%/6%) and mannitol (20%) were compared. Eight Beagle dogs received an IV infusion of 4mL/kg hyperHES (group H) and 4mL/kg mannitol 20% (group M) on separate occasions. Urine and blood samples were taken in the first (T(60)) and second (T(120)) hour after infusion. Significant increases in plasma volume at each time point in group H and M were noted when compared to baseline (start of infusion=T(0)) level. There was no significant difference between groups. Both fluids resulted in diuresis, although no significant difference between groups was noted. A significant increase in plasma sodium (Na) was demonstrated in group H between T(0) and T(60) with a significant increase in the Na and chloride (Cl) fractional excretion (FE) between T(0), T(60) and T(120). In group M no changes in plasma electrolyte concentrations were detected, although FE of Na, Cl and K was increased significantly between T(0) and T(60). In conclusion, hyperHES and mannitol appear to have a volume expanding effect lasting at least 120 min. The hypernatraemia induced by hyperHES was minimal compared to previous reports of hypertonic saline use, and no clinical side effects were noted. HyperHES showed comparable effects to mannitol in increasing plasma volume and diuresis and could be considered for these applications.  相似文献   

Evaluation of initial plasma lactate values as a predictor of gastric necrosis and initial and subsequent plasma lactate values as a predictor of survival in dogs with gastric dilatation‐volvulus: 84 dogs (2003–2007)     

Tiffany I. Green DVM  Caroline C. Tonozzi DVM  DACVECC  Rebecca Kirby DVM  DACVIM  DACVECC  Elke Rudloff DVM  DACVECC 《Journal of Veterinary Emergency and Critical Care》2011,21(1):36-44

Objective – To test whether an initial plasma lactate≥6.0 mmol/L is associated with the presence of macroscopic gastric wall necrosis and overall survival in dogs presenting with gastric dilatation‐volvulus (GDV). Additionally, if no association was identified we sought to identify a different predictive initial plasma lactate concentration and to examine whether serial plasma lactate concentrations provide better prediction of survival. Design – Retrospective study over a 5‐year period (2003–2007). Setting – Urban private referral small animal teaching hospital. Animals – Eighty‐four client‐owned dogs with a diagnosis of GDV and plasma lactate measurements. Interventions – None. Measurements and Main Results – There was no statistically significant relationship found between survival and the presence of macroscopic gastric wall necrosis with the initial plasma lactate≥6 mmol/L. There was a significant relationship between the initial plasma lactate >2.9 mmol/L for predicting necrosis and <4.1 mmol/L for predicting survival to discharge. Forty dogs that had an increased initial plasma lactate (>2.5 mmol/L) also had a subsequent plasma lactate measured within 12 hours of presentation, with 37/40 dogs surviving and 70% of these surviving dogs having the subsequent lactate decrease by≥50% within 12 hours. The 3/40 that died failed to decrease their plasma lactate by≥50% from the initial blood lactate. Conclusion – The results of this study indicate that an initial presenting plasma lactate concentration≥6.0 mmol/L is not predictive of macroscopic gastric wall necrosis or survival in dogs presenting with GDV. A decrease in plasma lactate concentrations≥50% within 12 hours may be a good indicator for survival. Limitations to the study include its retrospective nature, the small number of patients, and the number of dogs that were euthanized rather than allowed to progress to a natural outcome.  相似文献   

Bilateral hydronephrosis secondary to endometriosis managed by endoscopic ureteral stent placement in a captive Guinea baboon (Papio papio)     

Dallwig RK  Langan JN  Hatch DA  Terio KA  Demitros C 《Journal of zoo and wildlife medicine》2011,42(4):747-750

Spontaneous endometriosis is an estrogen-dependent, progressive and painful disease that affects a variety of nonhuman primates, including several species of baboons (Papio sp.). This case documents multimodal management of severe endometriosis in a captive female baboon within a zoological institution. An 18-yr-old, intact female Guinea baboon (Papio papio) was found to have an enlarged uterus. Fifteen months post ovariohysterctomy, scarring associated with endometrial tissue resulted in ureteral strictures, bilateral hydronephrosis, and azotemia. Cystoscopic placement of bilateral ureteral stents with fluoroscopy was performed and resulted in short-term clinical improvement. The animal's condition declined and euthanasia was elected 4 mo after ureteral stent placement. Severe endometriosis with secondary inflammation resulting in bilateral hydroureter and hydronephrosis, as well as concurrent cystitis, ureteritis, and pyelonephritis were confirmed at necropsy. Despite possible complications, ureteral stents can be considered a useful therapeutic option in patients with ureteral disease.  相似文献   

Use of pimobendan in 170 cats (2006–2010)     

John M. MacGregor  John E. Rush  Nancy J. Laste  Rebecca L. Malakoff  Suzanne M. Cunningham  Natalie Aronow  Daniel J. Hall  Justin Williams  Lori L. Price 《Journal of Veterinary Cardiology》2011,13(4):251-260

Hypothesis/ObjectivesTo describe the therapeutic use of pimobendan in cats, describe the patient population to which it was administered, document potential side effects and report the clinical course following administration of pimobendan in conjunction with standard heart failure therapy. It is hypothesized that cats with advanced heart disease including congestive heart failure from a variety of causes will tolerate pimobendan with a minimum of side effects when used in treatment in conjunction with a variety of other medications.Animals, materials and methodsOne hundred and seventy client owned cats with naturally occurring heart disease, one hundred and sixty four of which had congestive heart failure. Medical records were reviewed and owners and referring veterinarians were contacted for follow-up data. Data collected included pimobendan dose, other medications administered concurrently, data collected at physical examination, presence or absence of heart failure, adverse effects, classification of heart disease, echocardiographic data and survival time. The data were analyzed for significance between the initial visit and any follow-up visits.ResultsAll cats were treated with pimobendan. The median pimobendan dose was 0.24 mg/kg q 12 h. Pimobendan was used in combination with multiple concurrent medications including angiotensin converting enzyme inhibitors, diuretics and anti-thrombotics. Five cats (3.0%) had potential side effects associated with pimobendan. One cat (0.6%) had presumed side effects severe enough to discontinue pimobendan use. Median survival time for 164 cats with congestive heart failure after initiation of pimobendan was 151 days (range 1–870).ConclusionPimobendan appears to be well tolerated in cats with advanced heart disease when used with a variety of concurrent medications. Randomized controlled studies need to be performed to accurately assess whether it is efficacious for treatment of congestive heart failure in cats.  相似文献