Miracle-dz/UniFAR-FTUs huggingface dataset:
A Nucleotide-dependent Molecular Switch Controls Atp Binding at the C-terminal Domain of Hsp90 N-terminal Nucleotide Binding Unmasks a C-terminal Binding Pocket*

In vivo function of the molecular chaperone Hsp90 is ATP-dependent and requires the full-length protein. Our earlier studies predicted a second C-terminal ATP-binding site in Hsp90. By applying direct biochemical approaches, we mapped two ATP-binding sites and unveiled the C-terminal ATP-binding site as the first example of a cryptic chaperone nucleotide-binding site, which is opened by occupancy of the N-terminal site. We identified an N-terminal ␥؊phosphate-binding motif in the middle domain of Hsp90 similar to other GHKL family members. This motif is adjacent to the phosphate-binding region of the C-terminal ATP-binding site. Whereas novobiocin disrupts both C-and N-terminal nucleotide binding, we found a selective C-terminal nucleotide competitor, cisplatin, that strengthens the Hsp90-Hsp70 complex leaving the Hsp90-p23 complex intact. Cisplatin may provide a pharmacological tool to dissect C-and N-terminal nucleotide binding of Hsp90. A model is proposed on the interactions of the two nucleotide binding domains and the charged region of Hsp90. The 90-kDa heat shock protein (Hsp90) 1 is a central part of a chaperone meshwork, the foldosome, specifically chaperoning molecules involved in signal transduction and cell cycle regulation (1–3). Hsp90 is an ATP-binding chaperone (4, 5). Assembly of the Hsp90-client protein complexes requires ATP (6, 7), and ATP binding induces a conformational change in Hsp90 (8, 9). Moreover, ATP binding and hydrolysis are essential for the in vivo function of the chaperone (10, 11). Crystallization of the N-terminal domain uncovered a Bergerat-type ATP-binding fold (12), sharing a similar tertiary structure with the so-called GHKL family members, bacterial type II topoisomerase gyrase B and the mismatch repair protein MutL (13). Geldanamycin (GA) (14) and radicicol (15, 16) are highly specific antagonists of the N-terminal ATP-binding site. These natural antitumor antibiotics abolish Hsp90-dependent folding of immature client proteins and direct them to proteolysis (17, 18). Interestingly, the gyrase inhibitor, novo-biocin (NB), also compromises Hsp90 function similarly to GA (19), but although its binding site in the gyrase overlaps with the N-terminal ATP-binding site (13), that in Hsp90 is located in its C terminus (19, 20). Our earlier studies suggested that a second ATP-binding site exists in the C-terminal domain of Hsp90 (2, 4, 21), and observations with possibly similar explanations have been reported by others (5, 22). During the preparation of this article, a paper by Neckers and co-workers (20) reported that a C-terminal fragment (aa 383–731, to help direct comparison, if not otherwise indicated, all Hsp90 sequences are given as …
Importance of Functional Ingredients in Yak Milk-Derived Food on Health of Tibetan Nomads Living Under High-Altitude Stress: A Review

Tibetan nomads have lived since ancient times in the unique and harsh environment of the Qinghai-Tibetan Plateau with average altitudes over 4000 m. These people have been able to live and multiply healthily over numerous generations under the extreme stress of high-altitude environment, including cold, hypoxia, and strong ultraviolet radiation, and with a simple diet devoid of vegetables and fruits for most of the year. Their survival depends heavily on yak milk, and its products comprise the main portion of their daily diet. In this review, yak milk and its derived products are examined in detail and compared with milk from other ruminant species. Yak milk products seem to be particularly rich in functional and bioactive components, which may play a role in maintaining the health status of Tibetan nomads. This includes particular profiles of amino acids and fatty acids, and high levels of antioxidant vitamins, specific enzymes, and bacteria with probiotic activity (yoghurt is the main food). Based on that, it is proposed that the Tibetan nomads have developed a nutritional mechanism adapted to cope with the specific challenges posed by the environment of the world's highest plateau. Systematic studies are required to demonstrate this in a more mechanistic way.
Thymic transplantation in miniature swine. I. Development and function of the "thymokidney".

BACKGROUND Previous studies in our laboratory have demonstrated the importance of the thymus for rapid and stable tolerance induction in an allotransplant model. The focus of the present study was to explore the feasibility of autologous thymic transplantation to produce a new transplantable organ (thymokidney) and to examine the function of subsequent vascularized thymokidney transplants in T cell development. MATERIALS AND METHODS Eight juvenile swine received autologous thymic grafts under the renal capsule. Thymic tissue was obtained through a partial (n=6) or complete (n=2) thymectomy, and growth of the autologous thymic graft was compared between partially and completely thymectomized animals. Two of the partially thymectomized animals received irradiated (1000 cGy) as well as non-irradiated autologous thymic grafts. Graft survival, growth and evidence of thymocyte development was determined by (a) macroscopic examination of the implanted tissue, (b) histological examination, and (c) flow cytometry. Naive CD4 SP T cells were identified by CD45RA-expression. RESULTS Growth of transplanted thymic tissue was demonstrated in all thymic graft recipients. No difference was seen between partially and completely thymectomized animals. By POD 60, the thymic grafts exhibited normal macroscopic and microscopic structure, and normal thymocyte composition. Irradiated thymic tissue displayed a similar pattern of development, but growth was markedly delayed. To evaluate thymic function of the graft, a composite thymokidney was transplanted into a recipient which had previously been thymectomized, had few circulating CD4-single positive cells and had lost MLR reactivity. The number of CD4+/CD45RA+ cells in this animal increased steadily from POD 30 to POD 150, indicating that the thymus of the composite thymokidney allograft was functional; in addition, MLR assays demonstrated that the recipient recovered immunocompetence. CONCLUSIONS The establishment of a thymokidney by thymic autografting to the renal subcapsular space results in normal thymic growth and function, and may provide a valuable tool for studying the role of the thymus in tolerance induction. As far as we are aware, we provide the first evidence of functional vascularized thymic graft reconstituting T cells and leading to a return of a immunocompetence in a large animal model.
Na+/H+ Exchange Inhibitor SM‐20220 Attenuates Leukocyte Adhesion Induced By Ischemia‐Reperfusion

&NA; Leukocytes play a key role in ischemia‐reperfusion‐induced tissue injuries. It has been suggested that blocking the Na+/H+ exchanger improves ischemic injuries such as stroke. In this study, we investigated the effect of the Na+/H+ exchanger inhibitor SM‐20220 (N‐[aminoiminomethyl]‐1‐methyl‐1Hindole‐2‐carboxamide methanesulfonate) on leukocyte‐endothelial cell interactions during ischemia‐reperfusion. SM‐20220 (0.3–1.0 mg/kg i.v.) given after ischemia significantly attenuated the leukocyte adhesion in the mesenteric postcapillary venules that was induced by transient superior mesenteric artery occlusion. At 60 min after reperfusion, the numbers of adherent leukocytes in groups treated with vehicle or SM‐20220 (0.3 mg/kg) were 15.1 ± 2.9 cells/100 &mgr;m/3 min and 3.0 ± 0.7 cells/100 &mgr;m/3 min (p < 0.01), respectively. In a transient middle cerebral artery occlusion model, i.v. infusion of SM‐20220 (0.4 mg/kg per hour) for 1 h, beginning 1 h after the start of occlusion, significantly reduced both the infarct size and the increase in brain myeloperoxidase activity, compared with the vehicle group (p < 0.01 and p < 0.05, respectively). In summary, this is the first evidence that the leukocyte adhesion to the endothelium that is induced by ischemia‐reperfusion is attenuated by the inhibition of Na+/H+ exchanger activity in vivo. Our results suggest that Na+/H+ exchanger inhibitors may prevent ischemia‐reperfusion injuries such as stroke partly through the attenuation of leukocyte‐endothelial cell interactions.
The Ubiquitous Distribution of Late Embryogenesis Abundant Proteins across Cell Compartments in Arabidopsis Offers Tailored Protection against Abiotic Stress[C][W][OPEN]

LEA proteins accumulate in plant seeds prior to maturation drying, and some have been shown to protect membranes from desiccation. This work demonstrates the subcellular distribution of each of 51 Arabidopsis LEA proteins and suggests protection against desiccation or cold stress is tailored for each cellular compartment. Late embryogenesis abundant (LEA) proteins are hydrophilic, mostly intrinsically disordered proteins, which play major roles in desiccation tolerance. In Arabidopsis thaliana, 51 genes encoding LEA proteins clustered into nine families have been inventoried. To increase our understanding of the yet enigmatic functions of these gene families, we report the subcellular location of each protein. Experimental data highlight the limits of in silico predictions for analysis of subcellular localization. Thirty-six LEA proteins localized to the cytosol, with most being able to diffuse into the nucleus. Three proteins were exclusively localized in plastids or mitochondria, while two others were found dually targeted to these organelles. Targeting cleavage sites could be determined for five of these proteins. Three proteins were found to be endoplasmic reticulum (ER) residents, two were vacuolar, and two were secreted. A single protein was identified in pexophagosomes. While most LEA protein families have a unique subcellular localization, members of the LEA_4 family are widely distributed (cytosol, mitochondria, plastid, ER, and pexophagosome) but share the presence of the class A α-helix motif. They are thus expected to establish interactions with various cellular membranes under stress conditions. The broad subcellular distribution of LEA proteins highlights the requirement for each cellular compartment to be provided with protective mechanisms to cope with desiccation or cold stress.
The risk factors for herpes zoster in bortezomib treatment in patients with multiple myeloma

Background Bortezomib has significant activity in treating multiple myeloma (MM). The risk of herpes zoster (HZ) has been reported to increase significantly with bortezomib treatment, but the predisposing factors for HZ are not clear. This study is a retrospective analysis of the relevant risk factors for HZ in Korean MM patients treated with bortezomib. Methods Sixty-six patients with refractory or relapsed MM who underwent chemotherapy with bortezomib were included in the study. Prophylactic antiviral drugs were not used for treatment. The following parameters were reviewed: age, gender, stage and type of MM, extent of previous treatment, history of HZ, duration from the time of diagnosis to the time of bortezomib treatment initiation, and absolute lymphocyte counts (ALC) at the time of bortezomib treatment initiation. Results The incidence of HZ was 16.7%. There were no intergroup differences between the HZ-positive and the HZ-negative groups with regard to a history of HZ, number of previous treatments, and exposure to steroids before bortezomib treatment. The median duration from the time of MM diagnosis to the time of bortezomib treatment initiation in the HZ-positive group was significantly shorter than that in the HZ-negative group. The median ALC at the time of bortezomib initiation in the HZ-positive group was significantly lower than that in the HZ-negative group. Conclusion Bortezomib itself might act as a risk factor for HZ by inhibiting cell-mediated immunity, and patients with low ALC at the time of bortezomib treatment initiation were at greater risk of HZ during bortezomib treatment.
Effect of azathioprine or mesalazine therapy on incidence of re-hospitalization in sub-occlusive ileocecal Crohn’s disease patients

Background Although the cost of Crohn’s disease (CD) treatment differs considerably, hospitalization and surgery costs account for most of the total treatment cost. Decreasing hospitalization and surgery rates are pivotal issues in reducing health-care costs. Material/Methods We evaluated the effect of azathioprine (AZA) compared with mesalazine on incidence of re-hospitalizations due to all causes and for CD-related surgeries. In this controlled, randomized study, 72 subjects with sub-occlusive ileocecal CD were randomized for AZA (2–3 mg/kg per day) or mesalazine (3.2 g per day) therapy during a 3-year period. The primary end point was the re-hospitalization proportion due to all causes, as well as for surgical procedures during this period evaluated between the groups. Results On an intention-to-treat basis, the proportion of patients re-hospitalized within 36 months due to all causes was lower in patients treated with AZA compared to those on mesalazine (0.39 vs. 0.83, respectively; p=0.035). The AZA group had also significantly lower proportions of re-hospitalization for surgical intervention (0.25 vs. 0.56, respectively; p=0.011). The number of admissions (0.70 vs. 1.41, p=0.001) and the length of re-hospitalization (3.8 vs. 7.7 days; p=0.002) were both lower in AZA patients. Conclusions Patients with sub-occlusive ileocecal CD treated with AZA had lower re-hospitalization rates due to all causes and for surgical management of CD compared to those treated with mesalazine during a 3-year period. The long-term use of AZA in ileocecal CD patients recovering from a sub-occlusion episode can save healthcare costs.
Very Young Children Use Electronic Paint: A Study of the Beginnings of Drawing with Traditional Media and Computer Paintbox

The development of graphic representation in the preschool child is examined in relation to the mouse-driven computer paintbox. This has been done through an examination of early drawing and mark-making activity. Detailed observations of children between the ages of 1.10. 16 and 3.10. 5 using the computer paintbox were compared with more 'traditional media' in the form of pencils, felt-tips, crayons and paper. It is argued that the same basic media independent strategies are deployed when children try to establish a relationship between their mark-making actions and resultant ef fects. The observational data suggest that the mark-making strategies employed with elec tronic paint have some similarities to those employed with more traditional media. The work also revealed that much of the early mark-making activity observed was part of a larger scale investigation made by the chil dren of the potentialities of a new device. The extent of the similarities and differences be tween mark-making activities with electronic paint and other media are also discussed in relation to developmental sequence. The wider implications for understanding and symboliza tion are also discussed.
An ICA Algorithm for Separation of Convolutive Mixture of Speech Signals

— This paper describes Independent Component Analysis (ICA) based fixed-point algorithm for the blind separation of the convolutive mixture of speech, picked-up by a linear microphone array. The proposed algorithm extracts independent sources by non-Gaussianizing the Time-Frequency Series of Speech (TFSS) in a deflationary way. The degree of non-Gaussianization is measured by negentropy. The relative performances of algorithm under random initialization and Null beamformer (NBF) based initialization are studied. It has been found that an NBF based initial value gives speedy convergence as well as better separation performance
Gene Knockout and Overexpression Analysis Revealed the Role of N-Acetylmuramidase in Autolysis of Lactobacillus delbrueckii subsp. bulgaricus Ljj-6

Autolysis of lactic acid bacteria (LAB) plays a vital role in dairy processing. During cheese making, autolysis of LAB affects cheese flavor development through release of intracellular enzymes and restricts the proliferation of cells in yogurt fermentation and probiotics production. In order to explore the mechanism of autolysis, the gene for the autolytic enzymes of L. bulgaricus, N-acetylmuramidase (mur), was cloned and sequenced (GenBank accession number: KF157911). Mur gene overexpression and gene knockout vectors were constructed based on pMG76e and pUC19 vectors. Recombinant plasmids were transformed into L. bulgaricus ljj-6 by electroporation, then three engineered strains with pMG76e-mur vector and fifteen engineered strains with pUC19-mur::EryBII were screened. The autolysis of the mur knockout strain was significantly lower and autolysis of the mur overexpressed strain was significantly higher compared with that of the wild type strain ljj-6. This result suggested that the mur gene played an important role in autolysis of L. bulgaricus. On the other hand, autolytic activity in a low degree was still observed in the mur knockout strain, which implied that other enzymes but autolysin encoded by mur were also involved in autolysis of L. bulgaricus.
Evaluation of treatment responsivity in a psychopathic prison treatment sample

Although punishment still dominates the criminal justice system, the progression of research on offending and imprisonment has led to a general consensus that rehabilitation programmes are the appropriate method to effectively reduce both recidivism and prison populations. Hence, many effective offender treatment programmes have been developed. This thesis evaluated phase one of a 10 month pilot treatment programme which used the theories and principles of effective programming to develop an effective programme for male high risk violent offenders assessed with elevated psychopathic personality (High Risk Personality Programme; HRPP), a population of offenders that is often regarded as treatment resistant. Specifically, phase one of the HRPP was designed to address the participants‟ responsivity barriers (namely, antisocial interpersonal style) in order to increase self-efficacy, therapeutic alliance, treatability, and readiness, and to reduce perceived coercion in order to aid engagement and success in treatment. A sample of 11 male HRPP inmates had data collected before and after their 17week first phase of the 10 month three-phase programme. Treatment contact comprised four sessions per week, including three group sessions of 2.5 hours, and 1 individual session of one hour, as well as a two-hour group cultural session that focused on Maori cultural identity (10 of the 11 men were Maori). The battery of tests employed included the Self-Efficacy Questionnaire; the responsivity and readiness scales of the Treatment Readiness Responsivity and Gain Scale; the Corrections Victoria Treatment Readiness Questionnaire, the Paulhus Deception Scale, and the therapist and client versions of the Working Alliance Inventory Short Form, the Perceived Coercion Scale, and an evaluation questionnaire. Demographic data was also collected. The results indicated that the majority of the participants came to the intervention ready or motivated to change. Perceived coercion remained low throughout the programme, representing the participant‟s voluntary status. On average participants‟ levels of self-efficacy and treatability (except callousness) improved significantly over the course of the treatment. Differing levels of improvement were found for the client and therapist perspective of the therapeutic alliance, indicating they interpreted the alliance differently. Participants with high PCL-R factor one scores showed a decrease in coercion, compared to an increase by their counterparts with low PCL-R factor
Information-Theoretic Characterization and Undersampling Ratio Determination for Compressive Radar Imaging in a Simulated Environment

Assuming sparsity or compressibility of the underlying signals, compressed sensing or compressive sampling (CS) exploits the informational efficiency of under-sampled measurements for increased efficiency yet acceptable accuracy in information gathering, transmission and processing, though it often incurs extra computational cost in signal reconstruction. Shannon information quantities and theorems, such as source rate-distortion, trans-information and rate distortion theorem concerning lossy data compression, provide a coherent framework, which is complementary to classic CS theory, for analyzing informational quantities and for determining the necessary number of measurements in CS. While there exists some information-theoretic research in the past on CS in general and compressive radar imaging in particular, systematic research is needed to handle issues related to scene description in cluttered environments and trans-information quantification in complex sparsity-clutter-sampling-noise settings. The novelty of this paper lies in furnishing a general strategy for information-theoretic analysis of scene compressibility, trans-information of radar echo data about the scene and the targets of interest, respectively, and limits to undersampling ratios necessary for scene reconstruction subject to distortion given sparsity-clutter-noise constraints. A computational experiment was performed to demonstrate informational analysis regarding the scene-sampling-reconstruction process and to generate phase transition diagrams showing relations between undersampling ratios and sparsity-clutter-noise-distortion constraints. The strategy proposed in this paper is valuable for information-theoretic analysis and undersampling theorem developments in compressive radar imaging and other computational imaging applications.
Controllable Tuning Plasmonic Coupling with Nanoscale Oxidation

The nanoparticle on mirror (NPoM) construct is ideal for the strong coupling of localized plasmons because of its simple fabrication and the nanometer-scale gaps it offers. Both of these are much harder to control in nanoparticle dimers. Even so, realizing controllable gap sizes in a NPoM remains difficult and continuous tunability is limited. Here, we use reactive metals as the mirror so that the spacing layer of resulting metal oxide can be easily and controllably created with specific thicknesses resulting in continuous tuning of the plasmonic coupling. Using Al as a case study, we contrast different approaches for oxidation including electrochemical oxidation, thermal annealing, oxygen plasma treatments, and photo-oxidation by laser irradiation. The thickness of the oxidation layer is calibrated with depth-mode X-ray photoemission spectroscopy (XPS). These all consistently show that increasing the thickness of the oxidation layer blue-shifts the plasmonic resonance peak while the transverse mode remains constant, which is well matched by simulations. Our approach provides a facile and reproducible method for scalable, local and controllable fabrication of NPoMs with tailored plasmonic coupling, suited for many applications of sensing, photochemistry, photoemission, and photovoltaics.
Majority Logic Gate for Magnetic Quantum-Dot Cellular Automata

We describe the operation of, and demonstrate logic functionality in, networks of physically coupled, nanometer-scale magnets designed for digital computation in magnetic quantum-dot cellular automata (MQCA) systems. MQCA offer low power dissipation and high integration density of functional elements and operate at room temperature. The basic MQCA logic gate, that is, the three-input majority logic gate, is demonstrated.