Miracle-dz/UniFAR-FTUs huggingface dataset:
IKB / MAD-3 Masks the Nuclear Localization Signal of NF-KB p 65 and Requires the Transactivation Domain to Inhibit NF-KB p 65 DNA Binding

The active nuclear form of the NF-KB transcription factor complex is composed of two DNA binding subunits, NF-KB p65 and NF-KB p50, both of which share extensive Nterminal sequence homology with the v-rel oncogene product. The NF-KB p65 subunit provides the transactivation activity in this complex and serves as an intracellular receptor for a cytoplasmic inhibitor of NF-KB, termed IKB. In contrast, NF-KB p50 alone fails to stimulate KB-directed transcription, and based on prior in vitro studies, is not directly regulated by IKB. To investigate the molecular basis for the critical regulatory interaction between NF-KB and IKB/MAD-3, a series of human NF-KB p65 mutants was identified that functionally segregated DNA binding, IKB-mediated inhibition, and IKB-induced nuclear exclusion of this transcription factor. Results from in vivo expression studies performed with these NF-KB p65 mutants revealed the following: 1) IKB/MAD-3 completely inhibits NF-KB p65-dependent transcriptional activation mediated through the human immunodeficiency virus type 1 KB enhancer in human T lymphocytes, 2) the binding of IKB/MAD3 to NF-KB p65 is sufficient to retarget NF-KB p65 from the nucleus to the cytoplasm, 3) selective deletion of the functional nuclear localization signal present in the Rel homology domain of NF-KB p65 disrupts its ability to engage IKB/MAD-3, and 4) the unique Cterminus of NF-KB p65 attenuates its own nuclear localization and contains sequences that are required for IKB-mediated inhibition of NF-KB p65 DNA binding activity. Together, these findings suggest that the nuclear localization signal and transactivation domain of NF-KB p65 constitute a bipartite system that is critically involved in the inhibitory function of IKB/MAD-3. Unexpectedly, our in vivo studies also demonstrate that IKB/MAD-3 binds directly to NF-KB p50. This interaction is functional as it leads to retargeting of NF-KB p50 from the nucleus to the cytoplasm. However, no loss of DNA binding activity is observed, presumably reflecting the unique C-terminal domain that is distinct from that present in NF-KB p65.
Adaptins □ D The Final Recount

Adaptins are subunits of adaptor protein (AP) complexes involved in the formation of intracellular transport vesicles and in the selection of cargo for incorporation into the vesicles. In this article, we report the results of a survey for adaptins from sequenced genomes including those of man, mouse, the fruit ﬂy Drosophila melanogaster , the nematode Caenorhabditis elegans , the plant Arabidopsis thaliana , and the yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe . We ﬁnd that humans, mice, and Arabidopsis thaliana have four AP complexes (AP-1, AP-2, AP-3, and AP-4), whereas D. melanogaster , C. elegans , S. cerevisiae, and S. pombe have only three (AP-1, AP-2, and AP-3). Additional diversiﬁcation of AP complexes arises from the existence of adaptin isoforms encoded by distinct genes or resulting from alternative splicing of mRNAs. We complete the assignment of adaptins to AP complexes and provide information on the chromosomal localization, exon-intron structure, and pseudogenes for the different adaptins. In addition, we discuss the structural and evolutionary relationships of the adaptins and the genetic analyses of their function. Finally, we extend our survey to adaptin-related proteins such as
Brief Family Treatment Intervention to Promote Continuing Care Among Alcoholic Patients in Inpatient Detoxification: A Randomized Pilot Study

Alcoholic patients in inpatient detoxification were randomized to treatment as usual (TAU) or to a brief family treatment (BFT) intervention to promote continuing care post-detox. BFT consisted of meeting with the patient and an adult family member (in person or over the phone) with whom the patient lived, to review and recommend potential continuing care plans for the patient. Results showed that BFT patients (N=24), were significantly more likely than TAU patients (N=21), to enter a continuing care program after detoxification. This was a medium to large effect size. In the 3 months after detoxification, days using alcohol or drugs (a) trended lower for treatment-exposed BFT patients who had an in-person family meeting than TAU counterparts (medium effect), and (b) were significantly lower for patients who entered continuing care regardless of treatment condition (large effect). Meta-analytic reviews indicate that involving the family in the patient's treatment generally but most empirically supported family treatment methods lengthy and intensive still untested, some the most potentially widely family treatment methods brief intervention with family members at key times in the patients' addiction to promote continued use of treatment.
Effect of relative weight group change on NMR spectroscopy derived lipid particle size and concentrations among adolescents

Objective— To examine whether longitudinal changes in relative weight category (as indicated by change in BMI classification group) were associated with changes in nuclear magnetic resonance (NMR) derived lipoprotein particles among US youth. Study design— Secondary analysis of data from clustered RCT. BMI and fasting blood samples were obtained from 2069 participants at the start of 6 th grade and end of 8 th grade. BMI was categorized as normal weight, overweight or obese at both time points. Lipoprotein particle profiles were measured using NMR spectroscopy at both time points. Regression models were used to examine changes in relative weight group and change in lipoprotein variables. Results— 38% of participants changed relative weight category (BMI group) over the 2.5 year study period. Low density lipoprotein cholesterol and non-high density lipoprotein cholesterol decreased almost universally, but more with improved BMI category. There were adverse effects on LDL size and total LDL particles, high density lipoprotein size and cholesterol for participants who remained obese or whose relative weight group worsened. Changes in relative category had no impact on HDL particles. Conclusion— Improvement in relative weight group from 6 th to 8 th grade was associated with favorable changes in non-HDL-C, VLDL size, LDL size, HDL size and LDL particles, but had no effect on HDL particles. Findings indicate that an improvement in relative weight group between 6 th and 8 th grade had an effect on NMR derived particles sizes and concentrations among a large group of adolescents, which overrepresented low-income minorities.
Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP): Development and Validation of a Practical Health- Related Quality of Life Instrument for Use in the Routine Clinical Care of Prostate Cancer Patients

Peter Chang, MD1,2, Konrad M. Szymanski, MD, MPH3, Rodney L. Dunn, MS4, Jonathan J. Chipman, MS5, Mark S. Litwin, MD, MPH6, Paul L. Nguyen, MD7,8, Christopher J. Sweeney, MBBS9, Robert Cook, MD10, Andrew A. Wagner, MD1,11, William C. DeWolf, MD1,11, Glenn J. Bubley, MD11,12, Renee Funches, MD12, Joseph A. Aronovitz, MD, PhD13, John T. Wei, MD, MS3,†, and Martin G. Sanda, MD1,11,† 1Division of Urology, Department of Surgery Beth Israel Deaconess Medical Center, Boston, MA 2Division of Urology, Department of Surgery Brigham and Women’s Hospital, Boston, MA 3Division of Urology, McGill University Health Centre, Montreal, QC, Canada 4Department of Urology, University of Michigan School of Medicine, Ann Arbor, MI 5Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute, Boston, MA 6David Geffen School of Medicine and School of Public Health, University of California-Los Angeles, Los Angeles, CA 7Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA 8Department of Radiation Oncology Dana-Farber Cancer Institute, Boston, MA 9Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 10Seven Hills Urology, Centra Health, Lynchburg, VA 11Harvard School of Medicine, Boston, MA 12Department of Medicine Beth Israel Deaconess Medical Center, Boston, MA 13Department of Radiation-Oncology, Beth Israel Deaconess Medical Center, Boston, MA
Total Energy Shaping for Underactuated Mechanical Systems: Dissipation and Nonholonomic Constraints

This thesis deals with a new systematic design of energy shaping control techniques for underactuated mechanical systems. Thereby, the focus is put on challenges arising from the implementation to practical systems. The first part of the thesis is devoted to dissipation in unactuated coordinates. The second part is devoted to nonholonomic systems.
INVITED EDITORIAL Using Genetics to Dissect Cognition

The ambitious goal of achieving an integrated, neuroscientific explanation of developmental disorders, like dyslexia, is beginning to be realized because of the collaborative efforts of scientists from different disciplines working at several different levels of analysis. The exciting report by Grigorenko et al. (1997 [in this issue]) represents one such collaboration between neuropsychology and genetics. This report also provides one of the first independent replications of genetic linkage results for a complex human behavior. Shelley Smith and colleagues, including myself, first reported linkage between dyslexia and a centromeric marker on chromosome 15 (Smith et al. 1983) and then linkage between dyslexia and markers on the short arm of chromosome 6 in two separate samples (Cardon et al. 1994). In what follows, I will discuss some of the broader issues raised by this work, including (1) how work in both cognitive science and behavioral genetics prepared the way for these discoveries, (2) the implications of these discoveries for treatment, and (3) how we might begin to think about relations between levels of analysis in an integrated explanation of developmental disorders. One basic point is that dyslexia was a cognitive science success story before it became a success story for modern molecular genetics. Careful analysis of the behavioral phenotype was undertaken before the recent advances were made in understanding the genetics. Although genetic progress will further advance our understanding of the behavioral phenotype, because the relation between disciplines is undoubtedly a reciprocal one, the important first step in analyzing the genetics of complex behavioral phenotypes will often be the analysis of the behavioral phenotype itself. Without such analysis, the phenotype studied for linkage will be much coarser from a cognitive perspective and much more likely to be influenced by numerous underlying cognitive and genetic processes.
Evaluation of sediment transport in the lower part of the Fitzroy River, Queensland

Abstract Comprehensive sediment sampling carried out by the Queensland Department of Natural Resources and Mines (DNRM) at the Laurel Banks site located about 76 km upstream of the Fitzroy River mouth during four flood events in the period 1994 -1999 allowed the evaluation of 14 different sediment transport formulae. The bed material load was accurately predicted by the formula of Bagnold and by the formula of Pacheco-Ceballos. Finally the authors have developed a sediment transport formula best suited to the Fitzroy River conditions. By applying acceptable formulae to hydrograph data for 35 years it was confirmed that approximately 20 million tons of sediment might be eroded from the catchment during the most severe flood events. The mean annual total sediment discharge has been computed to be more than 5 million tons, and the mean bed material discharge sums up to about 260,000 tons.
A novel continuous berth scheduling model at multiple marine container terminals with tidal considerations

Purpose The paper aims to propose a new mathematical model for allocation and scheduling of vessels at multiple marine container terminals of the same port, considering the access channel depth variations by time of day. Design/methodology/approach This paper proposes a new mathematical model for allocation and scheduling of vessels at multiple marine container terminals of the same port, considering the access channel depth variations by time of day. The access channel serves as a gate for vessels entering or leaving the port. During low-depth tidal periods the vessels with deep drafts have to wait until the depth of the access channel reaches the required depth. Findings A number of numerical experiments are performed using the operational data collected from Port of Bandar Abbas (Iran). Results demonstrate that the suggested methodology is able to improve the existing port operations and significantly decrease delayed vessel departures. Originality/value The contribution of this study to the state of the art is a novel mathematical model for allocation and scheduling of vessels at multiple terminals of the same port, taking into consideration channel depth variations by time of day. To the best of the authors’ knowledge, this is the first continuous berth scheduling linear model that addresses the tidal effects on berth scheduling (both in terms of vessel arrival and departure at/from the berth) at multiple marine container terminals.
The same rat ∆6-desaturase not only acts on 18- but also on 24-carbon fatty acids in very-long-chain polyunsaturated fatty acid biosynthesis

The recently cloned ∆6-desaturase is known to catalyse the first step in very-long-chain polyunsaturated fatty acid biosynthesis, i.e. the desaturation of linoleic and α-linolenic acids. The hypothesis that this enzyme could also catalyse the terminal desaturation step, i.e. the desaturation of 24-carbon highly unsaturated fatty acids, has never been elucidated. To test this hypothesis, the activity of rat ∆6-desaturase expressed in COS-7 cells was investigated. Recombinant ∆6-desaturase expression was analysed by Western blot, revealing a single band at 45 kDa. The putative involvement of this enzyme in the ∆6-desaturation of C #% : & n®3 to C #% : ' n®3 was measured by incubating transfected cells with C ## : & n®3. Whereas both transfected and nontransfected COS-7 cells were able to synthesize C #% : & n®3 by
LPS detection across the kingdoms of life

Studies in recent years have uncovered a diverse set of eukaryotic receptors that recognize lipopolysaccharide (LPS), the major outer-membrane component of gram-negative bacteria. Indeed, Toll-like Receptors, G-protein coupled receptors, Integrins, Receptor-like kinases, and caspases have emerged as important LPS-interacting proteins. In this Review, the mammalian receptors that detect LPS are described. I highlight how no host protein is involved in all LPS responses, but a single lipid (phosphatidylinositol 4,5-bisphosphate) regulates many LPS responses, including endocytosis, phagocytosis, inflammation and pyroptosis. I further describe LPS response systems that operate specifically in plants, and discuss potentially new LPS response systems that await discovery. This diversity of receptors for a single microbial product underscores the importance of host-microbe interactions in multiple kingdoms of life.
Postsynaptic clustering of g-aminobutyric acid type A receptors by the g3 subunit in vivo

Synaptic localization of g-aminobutyric acid type A (GABAA) receptors is a prerequisite for synaptic inhibitory function, but the mechanism by which different receptor subtypes are localized to postsynaptic sites is poorly understood. The g2 subunit and the postsynaptic clustering protein gephyrin are required for synaptic localization and function of major GABAA receptor subtypes. We now show that transgenic overexpression of the g3 subunit in g2 subunit-deficient mice restores benzodiazepine binding sites, benzodiazepine-modulated whole cell currents, and postsynaptic miniature currents, suggesting the formation of functional, postsynaptic receptors. Moreover, the g3 subunit can substitute for g2 in the formation of GABAA receptors that are synaptically clustered and colocalized with gephyrin in vivo. These clusters were formed even in brain regions devoid of endogenous g3 subunit, indicating that the factors present for clustering of g2 subunit-containing receptors are sufficient to cluster g3 subunit-containing receptors. The GABAA receptor and gephyrin-clustering properties of the ectopic g3 subunit were also observed for the endogenous g3 subunit, but only in the absence of the g2 subunit, suggesting that the g3 subunit is at a competitive disadvantage with the g2 subunit for clustering of postsynaptic GABAA receptors in wild-type mice.
Reevaluation of the role of DNA polymerase θ in somatic hypermutation of immunoglobulin genes

DNA polymerase θ has been implicated in the process of somatic hypermutation in immunoglobulin variable genes based on several reports of alterations in the frequency and spectra of mutations from Polq − / − mice. However, these studies have contrasting results on mutation frequencies and the types of nucleotide substitutions, which question the role of polymerase θ in hypermutation. DNA polymerase η has a dominant effect on mutation and may substitute in the absence of polymerase θ to affect the pattern. Therefore, we have examined mutation in mice deficient for both polymerases θ and η . The mutation frequencies in rearranged variable genes from Peyer’s patches were similar in wild type, Polq − / − , Polh − / − , and Polq − / − Polh − / − mice. The types of substitutions were also similar between wild type and Polq − / − clones, and between Polh − / − and Polq − / − Polh − / − clones. Furthermore, there was no difference in heavy chain class switching in splenic B cells from the four groups of mice. These results indicate that polymerase θ does not play a significant role in the generation of somatic mutation in immunoglobulin genes. then TA-cloned into pGEM-T Easy vector (Promega, WI)
Development of a Patient-Reported Outcome Instrument to Evaluate Symptoms of Advanced NSCLC: Qualitative Research and Content Validity of the Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ)

PURPOSE— To describe the process and results of the preliminary qualitative development of a new symptom-based PRO measure intended to assess treatment benefit in advanced non-small cell lung cancer (NSCLC) clinical trials. METHODS— Individual qualitative interviews were conducted with adult NSCLC (Stage I–IV) patients in the US. Experienced interviewers conducted concept elicitation (CE) and cognitive interviews using semi-structured interview guides. The CE interview guide was used to elicit spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. Interview transcripts were coded and analyzed by professional qualitative coders using Atlas.ti software, and were summarized by like-content using an iterative coding framework. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to development of a preliminary version of the NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ). Three waves of cognitive interviews were conducted to evaluate concept relevance, item interpretability, and structure of the draft items to facilitate further instrument refinement. FINDINGS— Fifty-one patients (mean age 64.9 [SD=11.2]; 51.0% female) participated in the CE interviews. A total of 1,897 expressions of NSCLC-related symptoms were identified and coded in interview transcripts, representing approximately 42 distinct symptom concepts. A 9-item initial draft instrument was developed for testing in three waves of cognitive interviews with additional NSCLC patients (n=20), during which both paper and electronic versions of the instrument were evaluated and refined. Participant responses and feedback during cognitive interviews led to the removal of 2 items and substantial modifications to others.
Blood Alcohol Concentrations Rise Rapidly and Dramatically Following Roux-en-Y Gastric Bypass

Background— This study provides new information on how rapidly and extensively alcohol is absorbed following Roux-en-Y Gastric Bypass (RYGB). Prior alcohol pharmacokinetic research in RYGB patients has not reported blood alcohol concentrations in this early time-period following ingestion. Objectives— The objective of this study was to examine the rate and extent of alcohol absorption, particularly in the first ten minutes following a dose of alcohol. Setting— The study was conducted at a nonprofit research organization within the United States. Methods— Five female participants who had undergone RYGB three to four years prior completed the study. Participants were given 0.3 grams/kilogram of actual body weight of ethanol. Following the dose of alcohol, blood samples were collected through an indwelling intravenous catheter every minute for the first five minutes and at 7.5, 10, 20, and 60 minutes. Results— The observed mean Cmax was 138.4 ± 28.6 mg/dl (range 98.0–170.0 mg/dl) and the observed mean Tmax was 5.4 ± 3.1 minutes (range 2–10 minutes) following alcohol consumption. Conclusions— Within minutes following consumption of a beverage containing a modest amount of alcohol, post-RYGB patients achieve disproportionately high blood alcohol concentrations. All five patients in this study reached blood alcohol concentrations above 0.08%, the legal driving limit in the United States, within ten minutes following a dose of alcohol. Clinicians are encouraged to educate patients about the marked changes in alcohol pharmacokinetics that are they are likely to experience post-RYGB and to guide patients in making modifications to alcohol intake following surgery accordingly.
Imaging of Nitroxides at 250 MHz using Rapid-Scan Electron Paramagnetic Resonance

Projections for 2D spectral-spatial images were obtained by continuous wave and rapid-scan electron paramagnetic resonance using a bimodal cross-loop resonator at 251 MHz. The phantom consisted of three 4 mm tubes containing different 15N,2H-substituted nitroxides. Rapid-scan and continuous wave images were obtained with 5 min total acquisition times. For comparison, images also were obtained with 29 s acquisition time for rapid scan and 15 min for continuous wave. Relative to continuous wave projections obtained for the same data acquisition time, rapid-scan projections had significantly less low-frequency noise and substantially higher signal-to-noise at higher gradients. Because of the improved image quality for the same data acquisition time, linewidths could be determined more accurately from the rapid-scan images than from the continuous wave images.
Organ Specificity and Lactate-Dehydrogenase Activity

The preceding paper confirms the earlier finding of Rosalki & Wilkinson (1960) that the slow- and fast-migrating lactate-dehydrogenase isoenzymes of human serum differ considerably in their relative activities towards pyruvate and 2-oxobutyrate as substrate. in and the rabbit the fastest isoenzymes (peak almost exclusively the heart, the slowest (peak 5) principally tests upon relative of of these keto acids by for in heart and liver dehydrogenases
Effects of Various Medical and Social Practices on the Frequency of Genetic Disorders

In the past many workers have studied the effects of various factors on the human gene pool [1-4]. The emphasis has usually been on single factors with dysgenic (deleterious) effects and on the long-term changes and time to reach new equilibria. However, short-term changes and the combined effects of several factors are of more interest and practical importance. In recent years a number of new medical practices, such as improved treatments for affected individuals, genetic counseling, and population screening, and social customs, such as family limitation or selective abortion, have been introduced and are being widely adopted. Not all of these are dysgenic, and some have eugenic (beneficial) effects on the gene pool. In this paper we will study the effects of a variety of such practices and the net effect of their combination and use in practice.