Miracle-dz/UniFAR-FTUs huggingface dataset:
Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

ABSTRACT Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in Saccharomyces cerevisiae that couples spore morphogenesis to the completion of chromosome segregation. Similar to other MAPKs, Smk1 is controlled by phosphorylation of a threonine (T) and a tyrosine (Y) in its activation loop. However, it is not activated by a dual-specificity MAPK kinase. Instead, T207 in Smk1's activation loop is phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase (Cak1), and Y209 is autophosphorylated in an intramolecular reaction that requires the meiosis-specific protein Ssp2. In this study, we show that Smk1 is catalytically inert unless it is bound by Ssp2. While Ssp2 binding activates Smk1 by a mechanism that is independent of activation loop phosphorylation, binding also triggers autophosphorylation of Y209 in Smk1, which, along with Cak1-mediated phosphorylation of T207, further activates the kinase. Autophosphorylation of Smk1 on Y209 also appears to modify the specificity of the MAPK by suppressing Y kinase and enhancing S/T kinase activity. We also found that the phosphoconsensus motif preference of Ssp2/Smk1 is more extensive than that of other characterized MAPKs. This study therefore defines a novel mechanism of MAPK activation requiring binding of an activator and also shows that MAPKs can be diversified to recognize unique phosphorylation motifs.
Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor γ2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice

ABSTRACT Members of the MiT transcription factor family are pivotal regulators of several lineage-selective differentiation programs. We show that two of these, Tfeb and Tfe3, control the regulator of adipogenesis, peroxisome proliferator-activated receptor γ2 (Pparγ2). Knockdown of Tfeb or Tfe3 expression during in vitro adipogenesis causes dramatic downregulation of Pparγ2 expression as well as adipogenesis. Additionally, we found that these factors regulate Pparγ2 in mature adipocytes. Next, we demonstrated that Tfeb and Tfe3 act directly by binding to consensus E-boxes within the Pparγ transcriptional regulatory region. This transcriptional control also exists in vivo, as we discovered that wild-type mice in the fed state increased their expression of Tfe3, Tf3b, and Pparγ in white adipose tissue. Furthermore, Tfe3 knockout (Tfe3KO) mice in the fed state failed to upregulate Pparγ and the adiponectin gene, a Pparγ-dependent gene, confirming the in vivo role for Tfe3. Lastly, we found that blood glucose is elevated and serum adiponectin levels are suppressed in the Tfe3KO mice, indicating that the Tfe3/Tfeb/Pparγ2 axis may contribute to whole-body energy balance. Thus, we offer new insights into the upstream regulation of Pparγ by Tfe3/Tf3b and propose that targeting these transcription factors may offer opportunities to complement existing approaches for the treatment of diseases that have dysregulated energy metabolism.
Phosphorylation of the Transcription Elongation Factor Spt5 by Yeast Bur1 Kinase Stimulates Recruitment of the PAF Complex

ABSTRACT The Saccharomycescerevisiae kinase Bur1 is involved in coupling transcription elongation to chromatin modification, but not all important Bur1 targets in the elongation complex are known. Using a chemical genetics strategy wherein Bur1 kinase was engineered to be regulated by a specific inhibitor, we found that Bur1 phosphorylates the Spt5 C-terminal repeat domain (CTD) both in vivo and in isolated elongation complexes in vitro. Deletion of the Spt5 CTD or mutation of the Spt5 serines targeted by Bur1 reduces recruitment of the PAF complex, which functions to recruit factors involved in chromatin modification and mRNA maturation to elongating polymerase II (Pol II). Deletion of the Spt5 CTD showed the same defect in PAF recruitment as rapid inhibition of Bur1 kinase activity, and this Spt5 mutation led to a decrease in histone H3K4 trimethylation. Brief inhibition of Bur1 kinase activity in vivo also led to a significant decrease in phosphorylation of the Pol II CTD at Ser-2, showing that Bur1 also contributes to Pol II Ser-2 phosphorylation. Genetic results suggest that Bur1 is essential for growth because it targets multiple factors that play distinct roles in transcription.
A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase

ABSTRACT The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is known as a mediator of toxic responses. Recently, it was shown that the AhR has dual functions. Besides being a transcription factor, it also possesses an intrinsic E3 ubiquitin ligase function that targets, e.g., the steroid receptors for proteasomal degradation. The aim of this study was to identify the molecular switch that determines whether the AhR acts as a transcription factor or an E3 ubiquitin ligase. To do this, we used the breast cancer cell line MCF7, which expresses a functional estrogen receptor alpha (ERα) signaling pathway. Our data suggest that aryl hydrocarbon receptor nuclear translocator (ARNT) plays an important role in the modulation of the dual functions of the AhR. ARNT knockdown dramatically impaired the transcriptional activation properties of the ligand-activated AhR but did not affect its E3 ubiquitin ligase function. The availability of ARNT itself is modulated by another basic helix-loop-helix (bHLH)–Per-ARNT-SIM (PAS) protein, the repressor of AhR function (AhRR). MCF7 cells overexpressing the AhRR showed lower ERα protein levels, reduced responsiveness to estradiol, and reduced growth rates. Importantly, when these cells were used to produce estrogen-dependent xenograft tumors in SCID mice, we also observed lower ERα protein levels and a reduced tumor mass, implying a tumor-suppressive-like function of the AhR in MCF7 xenograft tumors.
The Practice of Instructional Consultation

Re-viewing instructional consultation (IC) from the perspective of its implementation in practice has reaffirmed the importance of the underlying assumptions presented in Instructional Consultation (Rosenfield, 1987). The basic processes have been refined and the results of advances in assessment and intervention continue to be integrated into the structure. More significant has been the evolution of IC-Teams as a more collaborative and systemic approach to service delivery. Several issues have emerged that need to be addressed, including (a) training needs, (b) diversity, (c) the linkage to comprehensive and coordinated service delivery, and (d) the practice of IC in secondary settings.
Efficacy and cost-effectiveness of screening colonoscopy according to the adenoma detection rate

Background The adenoma detection rate of the endoscopist has been related to the post-colonoscopy interval risk of colorectal cancer. Objective The objective of this article is to estimate the impact of adenoma detection rate on the long-term colorectal cancer prevention rate. Methods A Markov model was constructed to simulate the efficacy and cost of colonoscopy screening according to the adenoma detection rate of the endoscopist in 100,000 individuals. Post-colonoscopy interval colorectal cancer risk and the relative risk of interval cancer among endoscopists with different adenoma detection rates were extracted from the literature. A 1.5 relative risk was assumed between endoscopists with low and average adenoma detection rates, and a relative risk of 11 between those with average and high adenoma detection rates. Both efficacy and costs were projected over a steady-state American population. Results Screening colonoscopy performed by endoscopists with low adenoma detection rates resulted in a 7% absolute reduction in the long-term colorectal cancer incidence prevention rate as compared to the same procedure performed by those with an average adenoma detection rate (70% vs. 77%). This difference increased to 21% when comparing endoscopists with an average with those with a high adenoma detection rate. When projected on the US population, this reduced efficacy resulted in an additional 1728 and 16,123 colorectal cancer cases and the loss of $117 million and $906 million per year in the two scenarios, respectively. These estimates were sensitive to the risk of post-colonoscopy interval colorectal cancer. Conclusions A substantial reduction in long-term colorectal cancer prevention rate may be expected when screening colonoscopy is performed by endoscopists with a suboptimal adenoma detection rate. A substantial saving may be expected when implementing policies to improve endoscopist adenoma detection rate.
Evaluating Health Interventions for Older People

In recent years there has been a growing emphasis on evidencebased medicine and measuring outcomes of health care. The evaluation of health interventions for older people has increasingly relied upon the use of standardized assessment instruments, which are seen as providing detailed, holistic and patient-centred information. This article argues that such an approach has several drawbacks which may have serious implications for the evaluation and provision of health care. Standardized assessment instruments ignore the social dimensions of interviewing, decontextualize scores and contain an implicitly individualistic biomedical ideology of health. These factors undermine the effective evaluation of interventions. This is particularly significant when health care is purchased on the basis of delivering demonstrable gains. Provision for older people may be under threat if methods of evaluating its efficacy are inadequate.
Effects of preoperative proton pump inhibitor administration on bleeding after gastric endoscopic submucosal dissection: A systematic review and meta-analysis

Background and aim The efficacy of using proton pump inhibitors (PPIs) prior to gastric endoscopic submucosal dissection (ESD) to reduce gastric bleeding remains controversial. This study aimed to systematically review the literature to evaluate the efficacy of preoperative PPI use to reduce post-ESD bleeding. Methods PubMed, the Cochrane library, and the Igaku-Chuo-Zasshi database were searched to identify randomized trials eligible for inclusion in the systematic review. Data from four studies (406 patients) were combined to calculate a pooled risk difference (RD) for developing post-ESD bleeding. Results Compared with patients who received no premedication, the pooled RD for post-ESD bleeding in patients who received preoperavive PPI was –0.027 (95% confidence interval: –0.070–0.017, p = 0.228), without significant heterogeneity. Preoperavive PPI use significantly increased gastric pH (weighted mean difference: 1.289, 95% CI: 0.227–2.352, p = 0.0174). Conclusions This systematic review and meta-analysis showed that premedication with PPI had no advantage for the prevention of post-ESD bleeding, despite increasing gastric pH.
Neuropsychological functioning before and after unilateral thalamic stimulating electrode implantation in Parkinson's disease

One theoretical advantage of chronic thalamic stimulation compared with thalamotomy for the treatment of refractory Parkinson's disease (PD) entails the avoidance and reversibility of potential cognitive morbidity. Support for the cognitive safety of thalamic stimulation remains largely anecdotal; empirical data are limited to the neuropsychological findings published for one small series of patients. The purpose of this study was to supplement those published findings that pertain to the mean changes in neuropsychological test scores and to extend previous findings by evaluating cognitive changes in individual cases from preoperative baseline to 4 months after electrode implantation. Nine patients with tremor-dominant, refractory PD underwent unilateral implantation of a deep brain stimulating electrode in the ventralis intermedius thalamic nucleus (five patients on their left and four patients on their right sides). A neuropsychological test battery was administered to each patient to evaluate attention.
AMP-Activated Protein Kinase Induces p53 by Phosphorylating MDMX and Inhibiting Its Activity

ABSTRACT AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in vitro and in cells, leading to enhanced association between MDMX and 14-3-3. This markedly inhibits p53 ubiquitylation and significantly stabilizes and activates p53. By striking contrast, no phosphorylation of MDM2 by AMPK was noted. AMPK-mediated MDMX phosphorylation, MDMX–14-3-3 binding, and p53 activation were drastically reduced in mouse embryo fibroblasts harboring endogenous MDMX with S341A (mouse homologue of human serine 342), S367A, and S402A (mouse homologue of human serine 403) mutations. Moreover, deficiency of AMPK prevented MDMX–14-3-3 interaction and p53 activation. The activation of p53 through AMPK-mediated MDMX phosphorylation and inactivation was further confirmed by using cell and animal model systems with two AMPK activators, metformin and salicylate (the active form of aspirin). Together, the results unveil a mechanism by which metabolic stresses activate AMPK, which, in turn, phosphorylates and inactivates MDMX, resulting in p53 stabilization and activation.
On the Optimal Switching Probability for a Hybrid Cognitive Radio System

Cognitive radio (CR) systems are typically classified into two types. In overlay CR, a secondary user opportunistically accesses primary user's spectrum when it is unused, while a secondary user in underlay CR accesses the spectrum at any time as long as the interference power received at a primary user is below a certain level. This paper investigates a hybrid CR system where a secondary user probabilistically changes its spectrum access mode for secondary user's throughput maximization while guaranteeing primary user's target throughput. Basically, the hybrid CR works like overlay CR. The secondary user constantly monitors activity of the primary user and transmits data with maximum transmit power if transmission of the primary user is not detected. However, the only difference from overlay CR is that even when transmission of the primary user is detected, the secondary users are able to access the spectrum with regulated low transmit power with switching rate ε. We show that there is a trade-off of increasing ε due to recursive interactions between primary and secondary users, and optimizing ε is crucial to balance the gain and loss of secondary user's underlay spectrum access. The proposed hybrid CR is shown to achieve higher throughput and be more robust to detection errors than conventional CR systems.
Lymphoma development and survival in refractory coeliac disease type II: Histological response as prognostic factor

Background Refractory coeliac disease type II (RCDII) frequently transforms into an enteropathy-associated T-cell lymphoma (EATL) and therefore requires intensive treatment. Current evaluated treatment strategies for RCDII include cladribine (2-CdA) and autologous stem cell transplantation (auSCT). Objective The purpose of this study was to evaluate long-term survival and define clear prognostic criteria for EATL development comparing two treatment strategies. Methods A total of 45 patients were retrospectively analysed. All patients received 2-CdA, after which they were either closely monitored (monotherapy, n = 30) or a step-up approach was used including auSCT (step-up therapy, n = 15). Results Ten patients (22%) ultimately developed EATL; nine of these had received monotherapy. Absence of histological remission after monotherapy was associated with EATL development (p = 0.010). Overall, 20 patients (44%) died with a median survival of 84 months. Overall survival (OS) within the monotherapy group was significantly worse in those without histological remission compared to those with complete histological remission(p = 0.030). The monotherapy group who achieved complete histological remission showed comparable EATL occurrence and OS as compared to the step-up therapy group (p = 0.80 and p = 0.14 respectively). Conclusion Histological response is an accurate parameter to evaluate the effect of 2-CdA therapy and this parameter should be leading in the decisions whether or not to perform a step-up treatment approach in RCDII.
A New Multilateration System for Ground Surveillance

In the vicinity of buildings and aircraft in airports, conventional multilateration systems sometimes have difficulties in positioning precisely due to reflected signals, so-called multipath. To overcome this problem, ENRI has invented a new multilateration system for ground surveillance, named as Optically ConnecTed PAssive Surveillance System (OCTPASS). OCTPASS uses the same techniques as conventional multilateration systems. For instance, OCTPASS computes target’s positions with Time Differences Of Arrival (TDOA) between ground stations. The major difference from conventional systems is that OCTPASS ground stations directly transmit RF signals to the main processor through Radio On Fiber (ROF) devices and optical fiber cables. This feature enables OCTPASS to position targets with high accuracy under multipath environments. In 2004, to evaluate the performance of OCTPASS, we developed a test system for 1090MHz Mode S signal and conducted tests in an airport. In this paper, we first introduce the test system. Then we show the results of tests. The results show that OCTPASS is capable of positioning targets with high accuracy under multipath environments.
Relationship of anatomic landmarks with occlusal plane.

Purpose : Evaluation of relationship between various anatomical landmarks and the occlusal plane in the natural dentition that could be used for establishing the occlusal plane in complete dentures. Methods : The study comprised of 100 dentulous subjects with all healthy permanent teeth in normal arch form and alignment. Three instruments were custom-made for the purpose : the occlusal plane analyzer to check the parallelism of the ala-tragus lines,and the interpupillary line, the buccinator groove relator and the level analyzer for the level of the linea alba buccalis with the occlusal plane. For the retromolar pad area a metallic scale was used. Results : Within limitations of this study, it was observed that, only 13% subjects showed occlusal plane parallel to the interpupillary line. The posterior reference point of Camper's line was middle point for 72% of males and superior point for 80% of females. Intraorally, 68% of subjects have the occlusal plane at the same level as that of buccinator groove and 77% of the subjects had the occlusal plane at the middle one-third of retromolar pad area. Interpretation and Conclusions : It was concluded that: the occlusal plane is parallel to Camper's plane posterior reference point as the superior point of tragus in females and middle point in males. The occlusal plane is not generally parallel to the interpupillary line. Intra-orally, the level of buccinator groove is reliable, while variations in retromolar pad area make it an unreliable landmark for orienting the occlusal plane.
Iron-Induced Dissociation of the Aft1p Transcriptional Regulator from Target Gene Promoters Is an Initial Event in Iron-Dependent Gene Suppression

ABSTRACT Aft1p is an iron-responsive transcriptional activator that plays a central role in the regulation of iron metabolism in Saccharomyces cerevisiae. Aft1p is regulated by accelerated nuclear export in the presence of iron, mediated by Msn5p. However, the transcriptional activity of Aft1p is suppressed under iron-replete conditions in the Δmsn5 strain, although Aft1p remains in the nucleus. Aft1p dissociates from its target promoters under iron-replete conditions due to an interaction between Aft1p and the monothiol glutaredoxin Grx3p or Grx4p (Grx3/4p). The binding of Grx3/4p to Aft1p is induced by iron repletion and requires binding of an iron-sulfur cluster to Grx3/4p. The mitochondrial transporter Atm1p, which has been implicated in the export of iron-sulfur clusters and related molecules, is required not only for iron binding to Grx3p but also for dissociation of Aft1p from its target promoters. These results suggest that iron binding to Grx3p (and presumably Grx4p) is a prerequisite for the suppression of Aft1p. Since Atm1p plays crucial roles in the delivery of iron-sulfur clusters from the mitochondria to the cytoplasm and nucleus, these results support the previous observations that the mitochondrial iron-sulfur cluster assembly machinery is involved in cellular iron sensing.
Expanded Endoscopic Endonasal Approach to Anterior and Ventral Skull Base: An Evolving Paradigm

The transition from external approaches to an endonasal corridor has seen a significant decline in patient morbidity and inpatient care. Our Rhinology and Cranial Base Surgery Group has been able to focus on the management of certain pathologies, endoscopic access to various areas in the skull base, reconstruction of the defect, ensuring that clear anatomical landmarks can be identified during the surgery, and improving the quality of life/function after treatment. The focus on surgical treatment is always to control disease and cure patients by not only reducing recovery time and perioperative morbidity, but also decreasing the long-term impact of having a tumour removed. With a dedicated combined operating theater setting with updated instrumentation, the Neuro-ENT team is able to continue to expand and develop endoscopic care for a greater number of patients and wider range of pathologies. The collaborative Neuro-ENT to work closely via the nose using the two-hole and four-hand technique when performing the operation simultaneously is of added advantage in the diverse and expanding field of cranial base surgery. Our skull base team is joined by expert radiation and medical oncologists who provide essential adjunctive care in the multidisciplinary management of these patients.
Maximum Likelihood Frequency Estimation and Preamble Identification in OFDMA-based WiMAX Systems

In multi-cellular WiMAX systems based on orthogonal frequency-division multiple-access (OFDMA), the training preamble is chosen from a set of known sequences so as to univocally identify the transmitting base station. Therefore, in addition to timing and frequency synchronization, preamble index identification is another fundamental task that a mobile terminal must successfully complete before establishing a communication link with the base station. In this work we investigate the joint maximum likelihood (ML) estimation of the carrier frequency offset (CFO) and preamble index in a multicarrier system compliant with the WiMAX specifications, and derive a novel expression of the relevant Cramer-Rao bound (CRB). Since the exact ML solution is prohibitively complex in its general formulation, suboptimal algorithms are developed which can provide a reasonable trade-off between estimation accuracy and processing load. Specifically, we show that the fractional CFO can be recovered by combining the ML estimator with an existing algorithm that attains the CRB in all practical scenarios. The integral CFO and preamble index are subsequently retrieved by a suitable approximation of their joint ML estimator. Compared to existing alternatives, the resulting scheme exhibits improved accuracy and reduced sensitivity to residual timing errors. The price for these advantages is a certain increase of the system complexity.