The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver

Noise Can Reduce Disorder in Chaotic Dynamics

We evoke the idea of representation of the chaotic attractor by the set of unstable periodic orbits and disclose a novel noise-induced ordering phenomenon. For long unstable periodic orbits forming the strange attractor the weights (or natural measure) is generally highly inhomogeneous over the set, either diminishing or enhancing the contribution of these orbits into system dynamics. We show analytically and numerically a weak noise to reduce this inhomogeneity and, additionally to obvious perturbing impact, make a regularizing influence on the chaotic dynamics. This universal effect is rooted into the nature of deterministic chaos.Comment: 11 pages, 5 figure

CREB is a critical regulator of normal hematopoiesis and leukemogenesis

The cAMP-responsive element binding protein (CREB) is a 43-kDa nuclear transcription factor that regulates cell growth, memory, and glucose homeostasis. We showed previously that CREB is amplified in myeloid leukemia blasts and expressed at higher levels in leukemia stem cells from patients with myeloid leukemia. CREB transgenic mice develop myeloproliferative disease after 1 year, but not leukemia, suggesting that CREB contributes to but is not sufficient for leukemogenesis. Here, we show that CREB is most highly expressed in lineage negative hematopoietic stem cells (HSCs). To understand the role of CREB in hematopoietic progenitors and leukemia cells, we examined the effects of RNA interference (RNAi) to knock down CREB expression in vitro and in vivo. Transduction of primary HSCs or myeloid leukemia cells with lentiviral CREB shRNAs resulted in decreased proliferation of stem cells, cell- cycle abnormalities, and inhibition of CREB transcription. Mice that received transplants of bone marrow transduced with CREB shRNA had decreased committed progenitors compared with control mice. Mice injected with Ba/F3 cells expressing either Bcr-Abl wild-type or T315I mutation with CREB shRNA had delayed leukemic infiltration by bioluminescence imaging and prolonged median survival. Our results suggest that CREB is critical for normal myelopoiesis and leukemia cell proliferation

Opioid Doses and Acute Care Utilization Outcomes for Adults with Sickle Cell Disease: Emergency Department versus Acute Care Unit

Background Acute care units (ACUs) with focused sickle cell disease (SCD) care have been shown to effectively address pain and limit hospitalizations compared to emergency departments (ED), the reason for differences in admission rates is understudied. Our aim was compare effects of usual care for adult SCD pain in ACU and ED on opioid doses and discharge pain ratings, hospital admission rates and lengths of stay. Methods In a retrospective, comparative cohort, single academic tertiary center study, 148 adults with sickle cell pain received care in the ED, ACU or both. From the medical records we documented opioid doses, unit discharge pain ratings, hospital admission rates, and lengths of stay. Findings Pain on admission to the ED averaged 8.7 ± 1.5 and to the ACU averaged 8.0 ± 1.6. The average pain on discharge from the ED was 6.4 ± 3.0 and for the ACU was 4.5 ± 2.5. 70% of the 144 ED visits resulted in hospital admissions as compared to 37% of the 73 ACU visits. Admissions from the ED or ACU had similar inpatient lengths of stay. Significant differences between ED and ACU in first opioid dose and hourly opioid dose were noted. Conclusions Applying guidelines for higher dosing of opioids for acute painful episodes in adults with SCD in ACU was associated with improved pain outcomes and decreased hospitalizations, compared to ED. Adoption of this approach for SCD pain in ED may result in improved outcomes, including a decrease in hospital admissions

Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues

Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy approximate to 4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter

A linguistic analysis of lying in negative evaluations: The speech act performance of Chinese learners of Korean

이 논문은 중국인 한국어 학습자와 한국어 화자들 사이의 ‘거짓말’ 화행 양상을 언어학적으로 분석한 연구이다. 여기서 말하는 ‘거짓말’이란 요청, 사과, 거절 등과 같은 화행의 일종으로서 ‘부정적 평가’에 속하며 대화 참여자나 상황을 고려한 소위 ‘선의의 거짓말’을 가리키는 것으로 이해할 수 있을 것이다. 우리는 중국인 한국어 학습자 15명과 한국어 화자 15명을 대상으로 담화완성테스트(DCT)와 부연설명질문지(QFE)를 사용하여 피실험자들의 화행을 분석하였다. 피실험자 자신들의 설명과 한국어교육 전문가 다섯 명의 판정을 종합해 ‘거짓말’ 화행을 가려내고 통계 처리를 바탕으로 다음과 같은 결론에 도달했다. 한국어 화자들이 중국인 한국어 학습자들보다 (선의의) 거짓말을 더 많이 수행하는 것으로 나타났다. 그리고 두 집단 모두 부정적 평가가 사물에 관련된 경우보다 사람에 관련된 경우에 ‘거짓말’ 화행을 더 많이 사용한다. 그러나 화자와 청자 사이의 친소관계(distance)나 상하관계(power)는 거짓말 사용에 직접적 상관 관계를 보여주지 않았다. 이 연구는 지금까지 화행 연구 중에서 상대적으로 연구가 부진했던 부정평가와 ‘거짓말’ 화행에 대한 분석을 시도했다는 점에서 의미가 있다. 또한 한국어 화자와 중국인 한국어 학습자 사이에 보이는 화행 수행의 차이를 문화인식(cultural awareness)의 관점에서 해석해 볼 수 있는 가능성도 열어 주었다

Risk Score, Causes, and Clinical Impact of Failure of Transradial Approach for Percutaneous Coronary Interventions

ObjectivesTo study the causes of and to develop a risk score for failure of transradial approach (TRA) for percutaneous coronary intervention (PCI).BackgroundTRA-PCI failure has been reported in 5% to 10% of cases.MethodsTRA-PCI failure was categorized as primary (clinical reasons) or crossover failure. Multivariate analysis was performed to determine independent predictors of TRA-PCI failure, and an integer risk score was developed.ResultsFrom January to June 2010, TRA-PCI was attempted in 1,609 (97.3%) consecutive patients, whereas 45 (2.7%) had primary TRA-PCI failure. Crossover TRA-PCI failure occurred in 30 (1.8%) patients. Causes of primary TRA-PCI failure included chronic radial artery occlusion (11%), previous coronary artery bypass graft (27%), and cardiogenic shock (20%). Causes for crossover TRA-PCI failure included: inadequate puncture in 17 patients (57%); radial artery spasm in 5 (17%); radial loop in 4 (13%); subclavian tortuosity in 2 (7%); and inadequate guide catheter support in 2 (7%) patients. Female sex (odds ratio [OR]: 3.2; 95% confidence interval [CI]: 1.95 to 5.26, p < 0.0001), previous coronary artery bypass graft (OR: 6.1; 95% CI: 3.63 to 10.05, p < 0.0001), and cardiogenic shock (OR: 11.2; 95% CI: 2.78 to 41.2, p = 0.0011) were independent predictors of TRA-PCI failure. Risk score values from 0 to 7 predicted a TRA-PCI failure rate from 2% to 80%.ConclusionsIn a high-volume radial center, 2.7% of patients undergoing PCI are excluded from initial TRA on clinical grounds, whereas crossover to femoral approach is required in only 1.8% of the cases. A new simple clinical risk score is developed to predict TRA-PCI failure