Miracle-dz/UniFAR-FTUs huggingface dataset:
The Cyc8 (Ssn6)-Tup1 corepressor complex is composed of one Cyc8 and four Tup1 subunits

The Cyc8 (Ssn6)-Tup1 corepressor complex is required for repression in several important regulatory systems in yeast cells, including glucose repression and mating type. Cyc8-Tup1 is recruited to target genes by interaction with diverse repressor proteins that bind directly to DNA. Since the complex has a large apparent molecular mass of 1,200 kDa on nondenaturing gels (F. E. Williams, U. Varanasi, and R. J. Trumbly, Mol. Cell. Biol. 11:3307-3316, 1991), we used a variety of approaches to determine its actual subunit composition. Immunoprecipitation of epitope-tagged complex and reconstitution of the complex from in vitro-translated proteins demonstrated that only the Cyc8 and Tup1 proteins were present in the complex. Hydrodynamic properties showed that these proteins have unusually large Stokes radii, low sedimentation coefficients, and high frictional ratios, all characteristic of asymmetry which partly accounts for the apparent high molecular weight. Calculation of native molecular weights from these properties indicated that the Cyc8-Tup1 complex is composed of one Cyc8 subunit and four Tup1 subunits. This composition was confirmed by reconstitution of the complex from Cyc8 and Tup1 expressed in vitro and analysis by one- and two-dimensional gel electrophoresis.
Therapy of HIV infection

ABSTRACT: HIV is a devastating disease caused by the human immunodeficiency virus. Symptoms of illness can manifest in every organ system, including the skin. Although there is no definitive cure, the creation of antiretroviral drugs and aggressive treatment regimens have dramatically altered disease morbidity and mortality. However, the precise drug selection is often difficult and intimidating given the sheer abundance of drug therapies available. In this article, the HIV disease course is reviewed and different classes of antiretroviral medications are presented with emphasis on initial drug regimens, potential adverse effects, particularly those of dermatologic nature, possible drug interactions, patient compliance, and the emergence of drug resistance.
Primary hyperparathyroidism and the skeleton

Today, primary hyperparathyroidism (PHPT) in the developed countries is typically a disease with few or no obvious clinical symptoms. However, even in the asymptomatic cases the endogenous excess of PTH increases bone turnover leading to an insidious reversible loss of cortical and trabecular bone because of an expansion of the remodelling space and an irreversible loss of cortical bone due to increased endocortical resorption. In contrast trabecular bone structure and integrity to a large extent is maintained and there may be a slight periosteal expansion. Most studies have reported decreased bone mineral density (BMD) in PHPT mainly located at cortical sites, whereas sites rich in trabecular bone only show a modest reduction or even a slight increase in BMD. The frequent occurrence of vitamin D insufficiency and deficiency in PHPT and increased plasma FGF23 levels may also contribute to the decrease in BMD. The effect of smoking is unsolved. Epidemiological studies have shown that the relative risk of spine and nonspine fractures is increased in untreated PHPT starting up to 10 years before the diagnosis is made. Successful surgery for PHPT normalizes bone turnover, increases BMD and decreases fracture risk based on larger epidemiological studies. However, 10 years after surgery fracture risk appears to increase again due to an increase in forearm fractures.
Development of EOG based human machine interface control system for motorized wheelchair

Rehabilitation devices are increasingly being used to improve the quality of the life of differentially-abled persons. Human Machine Interface (HMI) has been extensively studied to control electromechanical rehabilitation aids using biosignals. Electroocculogram (EOG) signal is one of the most commonly studied signals due to the occurrence of definite signal patterns. Even the persons suffering from extremely limited peripheral mobility conditions (e.g. paraplegia or quadriplegia) have the ability to coordinate eye movements. The current project focuses on the development of an EOG based control system for driving a prototype wheelchair model. As a part of this work, an EOG signal acquisition system was developed. The acquired EOG signal was then processed to generate control signals (depending on the amplitude and duration of signals) for the movement of the wheelchair model.
Association of urinary pH with body weight in nephrolithiasis.

BACKGROUND The prevalence of kidney stone disease in the United States is progressively increasing, paralleling the growing rate of obesity. Uric acid nephrolithiasis, a condition associated with a low urinary pH, has been linked to obesity and insulin resistance. Based on these observations, we hypothesized that urinary pH may be inversely associated to body weight in nephrolithiasis. METHODS Data were retrieved from 4883 patients with nephrolithiasis who underwent ambulatory evaluation at two established stone clinics in Dallas and Chicago. The patients collected 24-hour urine samples on an outpatient basis, while avoiding any drug that could alter urinary pH. Patients were divided in increasing sextiles of body weight, and urinary pH was adjusted for urinary creatinine and for age. RESULTS Urinary pH had a strong, graded inverse association with body weight. Urinary creatinine and age were both found to be significant covariates of urinary pH, while gender was not a significant independent variable after adjustment for urinary creatinine. Mean 24-hour urinary pH, adjusted for age and urinary creatinine, were 6.09, 6.04, 6.01, 5.99, 5.97, and 5.91 for sextiles of body weight in increasing order from Dallas (P for linear trend <0.0001), and 6.18, 6.10, 6.04, 6.02, 5.97, and 5.88 for the sextiles from Chicago (P for linear trend <0.0001). CONCLUSION We conclude that urinary pH is inversely related to body weight among patients with stones. The results confirm the previously proposed scheme that obesity may sometimes cause uric acid nephrolithiasis by producing excessively acid urine due to insulin resistance.
Brain-computer interface based on high frequency steady-state visual evoked potentials: A feasibility study

Brain-computer interfaces (BCIs) based on steady-state visual evoked potentials (SSVEPs) are systems in which virtual or physical objects are tagged with flicker of different frequencies. When a user focuses on one of the objects its flicker frequency becomes visible in the electroencephalogram (EEG) and so the object on which the user focuses can be determined from brain activity alone. A significant problem inherent to such systems is that typically flicker with frequencies in the range 5 – 30 Hz is used. Flicker in this frequency range is known to elicit easily detectable SSVEPs but is very tiring and annoying for users and can possibly trigger epileptic seizures. In this paper we study the feasibility of using higher frequencies for which the perceived flicker is less intensive. We compare the classification accuracy that can be achieved for stimuli flickering with low frequencies (15 – 20 Hz), medium frequencies (30 – 45 Hz), and high frequencies (50 – 85 Hz). The classification of the data is done with a Bayesian algorithm that learns classification rules and selects optimal electrode pairs. The results show that the medium frequency range can be used to build a high-performance BCI for which the flicker is hardly visible. We also found that for some subjects even high frequency flicker evokes reliably detectable SSVEPs.
Accelerated plasma simulations using the FDTD method and the CUDA Architecture

This letter presents the graphic processor unit (GPU) implementation of the finite-difference time-domain (FDTD) method for the solution of the two-dimensional electromagnetic fields inside dispersive media. An improved Z-transform-based finite-difference time-domain (ZTFDTD) method was presented for simulating the interaction of electromagnetic wave with unmagnetized plasma. By using the newly introduced Compute Unified Device Architecture (CUDA) technology, we illustrate the efficacy of GPU in accelerating the FDTD computations by achieving significant speedups with great ease and at no extra hardware cost. The effect of the GPU-CPU memory transfers on the speedup will be also studied.
How to design an opioid drug that causes reduced tolerance and dependence

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long‐term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply “dialing up” signal transduction at the receptor, designing more potent and efficacious agonists and more long‐lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half‐life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance. ANN NEUROL 2010;67:559–569
Myelin basic protein (MBP) and MBP peptides are mitogens for cultured astrocytes

After CNS demyelination, astrogliosis interferes with axonal regeneration and remyelination. We now provide evidence that myelin basic protein (MBP) can contribute to this observed astrocyte proliferation. We found that astrocytes grown in either serum‐containing or serum‐free medium proliferate in response to MBP. The mitogenic regions of MBP in both media were MBP1–44, MBP88–151 and MBP152–167. The mitogenic effect of these individual peptides was potentiated by simultaneous treatment with microglia conditioned media (CM). MBP‐induced proliferation was inhibited by suramin at concentrations known to block the fibroblast growth factor receptor (FGFR), whereas neither MBP1–44, MBP88–151 nor MBP152–167 were affected. Cholera toxin B, that binds to ganglioside GM1, inhibited the mitogenicity of MBP1–44 and had no significant effect on the mitogenicity of MBP, MBP88–151 or MBP152–167. Treatment of astrocytes with MBP and MBP152–167 caused a modest and transitory elevation of intracellular calcium, whereas treatment with MBP1–44 resulted in a substantial and sustained increase in intracellular calcium. These results suggest that for cultured astrocytes 1) FGFR and extracellular calcium play a major role in MBP mitogenicity; 2) MBP1–44, MBP88–151 and MBP152–167 are the mitogenic regions of MBP; 3) MBP1–44 and MBP152–167 interact with ganglioside GM1 and FGFR, respectively; 4) Component(s) present in microglial CM potentiate the mitogenicity of MBP1–44, MBP88–151 and MBP152–167. These data support the hypothesis that MBP related peptides in conjunction with microglial secreted factors may stimulate astrogliosis after demyelination in vivo. GLIA 29:81–90, 2000. © 2000 Wiley‐Liss, Inc.
Syndromes of nonfluent primary progressive aphasia

Background: Despite recent work, the nosology of nonfluent primary progressive aphasia (PPA) remains unresolved. Methods: We describe a clinical and neurolinguistic cross-sectional analysis of a cohort of 24 patients with nonfluent PPA. Patients were initially classified based on analysis of spontaneous speech into 4 groups: apraxia of speech (AOS)/agrammatism (10 patients); AOS/no agrammatism (4 patients); no AOS/agrammatism (3 patients); no AOS/no agrammatism (7 patients). These groups were further characterized using a detailed neurolinguistic and neuropsychological battery. Parkinsonism was present in 3/10 patients in the AOS/agrammatism group. All patients in the no AOS/agrammatism group had mutations in the progranulin (GRN) gene, while 5/7 cases in the no AOS/no agrammatism group had CSF findings compatible with Alzheimer disease. Results: The groups without AOS showed more severe neurolinguistic impairments for a given disease stage, and sentence comprehension, speech repetition, and reading were impaired in all groups. Prolonged word-finding pauses and impaired single word comprehension were salient features in the no AOS/agrammatism group. Additional impairments of executive function and praxis were present in both groups with agrammatism, and impaired episodic memory was a feature of the no AOS/no agrammatism group. Conclusion: PPA with AOS is aligned with the syndrome previously designated progressive nonfluent aphasia; agrammatism may emerge as the syndrome evolves, or alternatively, the pure AOS group may be pathophysiologically distinct. PPA without AOS resembles the syndrome designated logopenic/phonologic aphasia; however, there is evidence for a distinct subsyndrome of GRN-associated aphasia. The findings provide a rationale for further longitudinal studies with pathologic correlation.
Antigen presentation by naive macrophages, dendritic cells and B cells to primed T lymphocytes and their cytokine production following exposure to immunostimulating complexes

Influenza virus envelope proteins incorporated into immunostimulating complexes (iscoms) are taken up and processed by various kinds of antigen‐presenting cells (APC), encompassing peritoneal cells (PEC), unfractionated splenocytes, splenic dendritic cells (DC) or B cells. The iscom‐pulsed naive APC stimulated primed T cells to proliferate and produce cytokine in vitro. In contrast, only DC and B cells pulsed with the same antigen (Ag) in the micelle form functioned as accessory cells stimulating the primed T cells to proliferate and produce cytokine. In general, iscoms were better inducers of cell proliferation than micelles, Iscoms stimulated more secretion of IL‐2 and interferon‐gamma (IFN‐γ) than the micelles, but both antigenic forms stimulated secretion of IL‐4. DC and B cells pulsed with iscoms stimulated most efficiently the secretion of IL‐2 and IFN‐γ, DC were superior to the other APC in stimulating primed T cells to secrete IFN‐γ. On the other hand, micelles stimulated more efficiently than iscoms splenic T cells from micelle‐primed as well as iscom‐primed mice to secrete IL‐10, These data indicate that influenza virus envelope proteins incorporated in iscoms stimulate a broad T cell response, possibly emphasizing a Thl type of response. The same Ag in a micelle form induce a more prominent Th2 type of T cell response. The results indicate that the administration of an Ag in an adjuvant formulation can superimpose a different cytokine profile on the immune response than that induced by the protein Ag alone.
Haemophilus ducreyi Outer Membrane Determinants, Including DsrA, Define Two Clonal Populations

ABSTRACT The Haemophilus ducreyi outer membrane component DsrA (for ducreyi serum resistance A) is necessary for complete resistance to normal human serum (NHS). When DsrA expression in 19 temporally and geographically diverse clinical isolates of H. ducreyi was examined by Western blotting, 5 of the strains expressed a different immunotype of the DsrA protein (DsrAII) than the well-characterized prototypical strain 35000HP (DsrAI). The predicted DsrA proteins expressed by the DsrAII strains were 100% identical to each other but only 48% identical to that of strain 35000HP. In addition to the DsrAII protein, class II strains also expressed variant forms of other outer membrane proteins (OMPs) including NcaA (necessary for collagen adhesion A), DltA (ducreyi lectin A), Hlp (H. ducreyi lipoprotein), major OMP, and/or OmpA2 (for OMP A2) and synthesized a distinct, faster-migrating lipooligosaccharide. Based on these data, strains expressing DsrAI were termed class I, and those expressing DsrAII were termed class II. Expression of dsrAII from strain CIP 542 ATCC in the class I dsrAI mutant FX517 (35000HP background), which does not express a DsrA protein, rendered this strain resistant to 50% NHS. This demonstrates that DsrAII protein is also critical to serum resistance. Taken together, these results indicate that there are two clonal populations of H. ducreyi. The implications of two classes of H. ducreyi strains differing in important antigenic outer membrane components are discussed.
Novelty‐evoked elevations of nucleus accumbens dopamine: dependence on impulse flow from the ventral subiculum and glutamatergic neurotransmission in the ventral tegmental area

In vivo microdialysis in freely moving rats was used to monitor novelty‐evoked elevations in extracellular dopamine in the nucleus accumbens septi (NAS) and to examine the role of the ventral subiculum of the hippocampus and glutamatergic transmission in the ventral tegmental area (VTA) on these elevations. Exposure to novel stimuli evoked investigatory activity and increased nucleus accumbens dopamine. Unilateral injections of the sodium channel blocker tetrodotoxin (0.16 ng/0.5 µL) into the ventral subiculum ipsilateral to the dialysed NAS abolished novelty‐evoked elevations in dopamine. Injections of tetrodotoxin into the contralateral VS did not prevent novelty‐evoked elevations in nucleus accumbens dopamine. Unilateral perfusion (via microdialysis) of the ionotropic glutamate receptor antagonists kynurenic acid (1 mm) into the ipsilateral but not the contralateral VTA blocked novelty‐evoked elevations in nucleus accumbens dopamine. Neither unilateral injections of tetrodotoxin nor unilateral perfusion of kynurenic acid disrupted investigatory behaviour. These data indicate that phasic elevations in nucleus accumbens dopamine evoked by exposure to unconditioned novel stimuli are dependent on impulse flow from the hippocampus and glutamatergic transmission in the VTA.
Molecular analysis of restriction endonuclease EcoRII from Escherichia coli reveals precise regulation of its enzymatic activity by autoinhibition

Bacterial restriction endonuclease EcoRII requires two recognition sites to cleave DNA. Proteolysis of EcoRII revealed the existence of two stable domains, EcoRII‐N and EcoRII‐C. Reduction of the enzyme to its C‐terminal domain, EcoRII‐C, unleashed the enzyme activity; this truncated form no longer needed two recognition sites and cleaved DNA much more efficiently than EcoRII wild‐type. The crystal structure of EcoRII showed that probably the N‐terminal domain sterically occludes the catalytic site, thus apparently controlling the cleavage activity. Based on these data, EcoRII was the first restriction endonuclease for which an autoinhibition mechanism as regulatory strategy was proposed. In this study, we probed this assumption and searched for the inhibitory element that mediates autoinhibition. Here we show that repression of EcoRII‐C is achieved by addition of the inhibitory domain EcoRII‐N or by single soluble peptides thereof in trans. Moreover, we perturbed contacts between the N‐ and the C‐terminal domain of EcoRII by site‐directed mutagenesis and proved that β‐strand B1 and α‐helix H2 are essential for autoinhibition; deletion of either secondary structural element completely relieved EcoRII autoinhibition. This potent regulation principle that keeps EcoRII enzyme activity controlled might protect bacteria against suicidal restriction of rare unmodified recognition sites in the cellular genome.
“What's Character Got to Do with It?”*

Do you trust your wife? Your husband? Your friend? Your colleague? Your editor? Your students? On what basis does anyone trust anyone? Do we really trust them? Or do we only predict their future behavior? Or, perhaps, we simply assume the stability of their circumstances and predict that those circumstances won't change. But this last has nothing to do with trust, as it has nothing to do with the person's character. Perhaps neither does prediction of behavior, which involves what I have called reliance as opposed to trust. But even reliance depends on some sort of stability in a person's character. There is a line in an Elmore Leonard novel, Rum Punch, which was turned into the Hollywood film Jackie Brown. The character played by Samuel Jackson says, "I don't need to trust Melanie. I know her. " But trust or knowledge, the presumption is that there is a basis for this in the person, a stability or regularity of character. Confidence in the stability of circumstances is not at all the same thing, and given the nature of life, betting on the stability of circumstances is probably a bad bet. I trust my wife because I know her. True, I don't know what she might do in extraordinary circumstances, during a terrorist attack or a Latin American kidnapping. But I trust her thoroughly, not just because I know her, but because I recognize in her a character that is robust and resolute, that has withstood many challenges and temptations, that remains more or less constant throughout an enormous range of different circumstances. I want to think about what an enormous loss it would be if any such concept of character turned out to be an illusion. Many young philosophers seem content travelling safely in the well-worn ruts of their established field, its problems, and its already exhausted literature. How delightful, then, to meet a still rather young philosopher who refuses to play it safe and stay in the ruts but instead takes a jack-hammer to the ruts and, perhaps, even to the road. The rather young philosopher is John Doris, who has written an impressive book with the ominous title, Lack of
P2X receptor channels in chronic pain pathways

Chronic pain is a highly prevalent debilitating condition for which treatment options remain limited for many patients. Ionotropic ATP signalling through excitatory and calcium‐permeable P2X receptor channels is now rightfully considered as a critical player in pathological pain generation and maintenance; therefore, their selective targeting represents a therapeutic opportunity with promising yet untapped potential. Recent advances in the structural, functional and pharmacological characterization of rodent and human ATP‐gated P2X receptor channels have shed brighter light on the role of specific subtypes in the pathophysiology of chronic inflammatory, neuropathic or cancer pain. Here, we will review the contribution of P2X3, P2X4 and P2X7 receptors to chronic pain and discuss the opportunities and challenges associated with the pharmacological manipulation of their function.