gebhart/patrepeval huggingface dataset:
Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα (2001)

p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the source of the NF-kappaB p50 subunit upon processing. p105 can form various heterodimers with other NF-kappaB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IkappaB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKbeta phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGPsi motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IkappaBalpha, -beta, and -epsilon. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules betaTrCP1 and betaTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKgamma, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.
Human immunodeficiency virus‐associated neurocognitive disorders: Mind the gap (2010)

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HANDs) remain among the most common disorders in people infected with HIV, even in an era when potent antiretroviral therapy is widely deployed. This review discusses the clinical features of HANDs and the implications for more effective treatment. With the improved survival of individuals treated with antiretrovirals, comorbid conditions are increasingly salient, including particularly coinfection with hepatitis C and the effects of aging. This review attempts to answer why there appears to be a therapeutic gap between the salutary effects of antiretroviral regimens and normalization of neurological function. A second gap is found in the understanding of the pathophysiology of HANDs. This review addresses this and discusses the animal models that have helped to elucidate these mechanisms. Although triggered by productive HIV infection of brain macrophages, aberrant and sustained immune activation appears to play a major role in inducing HANDs, and may explain the often incomplete neurological response to highly active antiretroviral therapy. Novel therapies aimed at persistent central nervous system inflammation will be needed to close this gap.
Novel Degradable Poly(ethylene glycol) Esters for Drug Delivery (1997)

In this chapter we describe two applications of new hydrolytically-degradable PEG derivatives. The first involves synthesis of ester-containing PEGs for preparation of soluble PEG-drug conjugates in which the PEG is attached to the drug via a hydrolytically degradable linkage. The second application involves use of these and related PEGs to prepare degradable PEG hydrogels. Degradation rates can be controlled by variation in molecular structure of the esters and in thedegree of branching of the PEGs.
Neuromelanin can protect against iron‐mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease (2008)

In Parkinson's disease (PD), dopamine neurons containing neuromelanin selectively degenerate. Neuromelanin binds iron and accumulates in aging. Iron accumulates in reactive form during aging, PD, and is involved in neurodegeneration. It is not clear how the interaction of neuromelanin and iron can be protective or toxic by modulating redox processes. Here, we investigated the interaction of neuromelanin from human substantia nigra with iron in the presence of ascorbic acid, dopamine, and hydrogen peroxide. We observed that neuromelanin blocks hydroxyl radical production by Fenton's reaction, in a dose-dependent manner. Neuromelanin also inhibited the iron-mediated oxidation of ascorbic acid, thus sparing this major antioxidant molecule in brain. The protective effect of neuromelanin on ascorbate oxidation occurs even in conditions of iron overload into neuromelanin. The blockade of iron into a stable iron-neuromelanin complex prevents dopamine oxidation, inhibiting the formation of neurotoxic dopamine quinones. The above processes occur intraneuronally in aging and PD, thus showing that neuromelanin is neuroprotective. The iron-neuromelanin complex is completely decomposed by hydrogen peroxide and its degradation rate increases with the amount of iron bound to neuromelanin. This occurs in PD when extraneuronal iron-neuromelanin is phagocytosed by microglia and iron-neuromelanin degradation releases reactive/toxic iron.
Binding of Sindbis Virus to Cell Surface Heparan Sulfate (1998)

Alphaviruses are arthropod-borne viruses with wide species ranges and diverse tissue tropisms. The cell surface receptors which allow infection of so many different species and cell types are still incompletely characterized. We show here that the widely expressed glycosaminoglycan heparan sulfate can participate in the binding of Sindbis virus to cells. Enzymatic removal of heparan sulfate or the use of heparan sulfate-deficient cells led to a large reduction in virus binding. Sindbis virus bound to immobilized heparin, and this interaction was blocked by neutralizing antibodies against the viral E2 glycoprotein. Further experiments showed that a high degree of sulfation was critical for the ability of heparin to bind Sindbis virus. However, Sindbis virus was still able to infect and replicate on cells which were completely deficient in heparan sulfate, indicating that additional receptors must be involved. Cell surface binding of another alphavirus, Ross River virus, was found to be independent of heparan sulfate.
Nerve Regeneration through Synthetic Biodegradable Nerve Guides (1984)

The successful regeneration of a multifascicular, complete peripheral nerve through a tubular synthetic biodegradable nerve guide across a gap of 10 mm in the rat sciatic nerve is reported. The importance of the distal nerve as a source of target-derived neuronotrophic factors necessary for the successful regeneration of the proximal regenerating nerve is emphasized. A simplified research model for further investigation into and manipulation of the biological processes of nerve regeneration is described. The potential clinical utilization of this model in the management of peripheral nerve injuries and, ultimately, central nervous system lesions is mentioned.
Facile One-Pot Synthesis of N-Difluoromethyl-2-pyridone Derivatives (2006)

[reaction: see text] A novel one-pot synthesis of N-difluoromethyl-2-pyridones is described. N-(Pyridin-2-yl)acetamide derivatives were excellent precursors for the preparation of N-difluoromethyl-2-pyridone derivatives. Difluoromethylation of 2-acetaminopyridine derivatives was achieved with sodium chlorodifluoroacetate as a difluorocarbene source in the presence of a catalytic amount of 18-crown-6. Subsequent in situ hydrolysis of resultant 1,2-dihydro-2-acetimino-1-difluoromethylpyridines proceeded under mild acidic conditions to afford the corresponding N-difluoromethyl-2-pyridones in moderate to good yields.
pvFPGA: accessing an FPGA-based hardware accelerator in a paravirtualized environment (2013)

In this paper we present pvFPGA, the first system design solution for virtualizing an FPGA-based hardware accelerator on the x86 platform. Our design adopts the Xen virtual machine monitor (VMM) to build a paravirtualized environment, and a Xilinx Virtex-6 as an FPGA accelerator. The accelerator communicates with the x86 server via PCI Express (PCIe). In comparison to the recent accelerator virtualization solutions which primarily intercept and redirect API calls to the hosted or privileged domain's user space, pvFPGA virtualizes an FPGA accelerator directly at the lower device driver level. This gives rise to higher efficiency and lower overhead. In pvFPGA, each unprivileged domain allocates a shared data pool for both user-kernel and inter-domain data transfer. In addition, we propose a new component, the coprovisor, which enables multiple domains to simultaneously access an FPGA accelerator. The experimental results have shown that 1) pvFPGA achieves close-to-zero overhead compared to accessing the FPGA accelerator without the VMM layer, 2) the FPGA accelerator is successfully shared by multiple domains, and 3) distributing different maximum data transfer bandwidths to different domains is achieved by regulating the size of the shared data pool at the split driver loading time.
Did the world really change on 9/11? (2002)

In setting myself the question 'Did the world really change an 9/11 ?', I tie myself into two discussions. The first is an exercise in comparing and contrasting perceptions around the pivotal date of September 11, 2001: what was the world 'really' like prior to the attacks on America (as they came to be called) and what is it 'really' like now? The use of the word 'really' here flags the operation of value judgements; any estimation of change around this event is laden with personal perspectives. The second discussion is the one I deal with first: is there a body of opinion asserting that the events of 9/11 were world-changing events? I propose to offer four examples, centred in the US media, but exported thence to western audiences, which variously assert that the events of September 11 changed the world.
Unopposed Production of Granulocyte-Macrophage Colony-Stimulating Factor by Tumors Inhibits CD8+ T Cell Responses by Dysregulating Antigen-Presenting Cell Maturation (1999)

Tumor cells gene-modified to produce GM-CSF potently stimulate antitumor immune responses, in part, by causing the growth and differentiation of dendritic cells (DC). However, GM-CSF-modified tumor cells must be gamma-irradiated or they will grow progressively, killing the host. We observed that 23 of 75 (31%) human tumor lines and two commonly used mouse tumor lines spontaneously produced GM-CSF. In mice, chronic GM-CSF production by tumors suppressed Ag-specific CD8+ T cell responses. Interestingly, an inhibitory population of adherent CD11b(Mac-1)/Gr-1 double-positive cells caused the observed impairment of CD8+ T cell function upon direct cell-to-cell contact. The inhibitory cells were positive for some markers associated with Ag presenting cells, like F4/80, but were negative for markers associated with fully mature DC like DEC205, B7. 2, and MHC class II. We have previously reported that a similar or identical population of inhibitory "immature" APC was elicited after immunization with powerful recombinant immunogens. We show here that these inhibitory cells can be elicited by the administration of recombinant GM-CSF alone, and, furthermore, that they can be differentiated ex vivo into "mature" APC by the addition of IL-4 and GM-CSF. Thus, tumors may be able to escape from immune detection by producing "unopposed" GM-CSF, thereby disrupting the balance of cytokines needed for the maturation of fully functional DC. Further, CD11b/Gr-1 double-positive cells may function as "inhibitory" APC under the influence of GM-CSF alone.
Direct Measurement of Hepatic Blood Flow in Surgical Patients (1962)

Schenk, Worthington G. Jr. M.D.; McDonald, John C. M.D.; McDonald, Khlar M.D.; Drapanas, Theodore M.D. Author Information
Safingol (l-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway (2009)

Safingol, the synthetic L-threo-stereoisomer of endogenous (D-erythro-) sphinganine, is an inhibitor of protein kinase C and sphingosine kinase in vitro, and in some cell types has been implicated in ceramide generation and induction of apoptosis. Utilizing electron microscopy, acridine orange staining, and immunoblot and fluorescent localization studies of the myosin light chain-associated protein (LC3), we determined that safingol induces cell death of an exclusively autophagic character and lacking any of the hallmarks of apoptosis. Safingol inhibited PKCbeta-I, PKC delta and PKC epsilon, and inhibited phosphorylation of critical components of the PI3k/Akt/mTOR pathway (Akt, p70S6k and rS6) and the MAPk pathway (ERK). Inhibition of PI3k with LY294002 or suppression of PKC delta and PKC epsilon with siRNA in HCT-116 cells induced autophagy, though not to the extent caused by safingol. Conversely, activation of PKCs with phorbol 12,13-dibutyrate (PDBu) or transient transfection of a constitutively active form of Akt each reduced safingol's autophagic induction, but not completely, indicating that Akt- and PKC-dependent pathways both contribute partially and independently to safingol-induced autophagy. Accordingly, combining siRNA depletion of PKC epsilon with LY294002 inhibition of PI3k induced autophagy to a degree comparable to safingol. Liquid chromatography, electrospray tandem mass spectrometry analysis indicated that safingol did not elevate levels of any endogenous sphingolipids previously shown to induce autophagy (ceramide, sphingosine-1-phosphate and dihydroceramide); therefore, these effects may be due to safingol per se or another metabolite. Thus, our studies establish that safingol induces autophagy through inhibition of PKCs and PI3k by safingol directly rather than via changes in endogenous sphingolipids.
Localization and controls of aromatase in the quail spinal cord (2000)

In adult male and female Japanese quail, aromatase-immunoreactive cells were identified in the spinal dorsal horns from the upper cervical segments to the lower caudal area. These immunoreactive cells are located mostly in laminae I-III, with additional sparse cells being present in the medial part of lamina V and, at the cervical level exclusively, in lamina X around the central canal. Radioenzyme assays based on the measurement of tritiated water release confirmed the presence of substantial levels of aromatase activity throughout the rostrocaudal extent of the spinal cord. Contrary to what is observed in the brain, this enzyme activity and the number of aromatase-immunoreactive cells in five representative segments of the spinal cord are not different in sexually mature males or females and are not influenced in males by castration with or without testosterone treatment. The aromatase activity and the numbers of aromatase-immunoreactive cells per section are higher at the brachial and thoracic levels than in the cervical and lumbar segments. These experiments demonstrate for the first time the presence of local estrogen production in the spinal cord of a higher vertebrate. This production was localized in the sensory fields of the dorsal horn, where estrogen receptors have been identified previously in several avian and mammalian species, suggesting an implication of aromatase in the modulation of sensory (particularly nociceptive) processes.
Solid wastes management in sulphide mines: from waste characterisation to safe closure of disposal sites (2003)

Environmentally compatible Waste Management schemes employed by the European extractive industry for the development of new projects, and applied in operating sulphide mines, are presented in this study. Standard methodologies used to assess the geotechnical and geochemical properties of the solid wastes stemming from mining and processing of sulphidic metal ores are firstly given. Based on waste properties, the measures applied to ensure the environmentally safe recycling and disposal of sulphidic wastes are summarised. Emphasis is given on the novel techniques developed to effectively prevent and mitigate the acid drainage phenomenon from sulphidic mine wastes and tailings. Remediation measures taken to minimise the impact from waste disposal sites in the post‐closure period are described.
The Mechanism of Insertion of a Segment of Heterologous DNA into the Chromosome of Bacillus subtilis (1983)

An Escherichia coli plasmid, p1949, that is derived from pMB9 and pC194, and unable to replicate in Bacillus subtilis, can give rise to stable CmR transformants of the latter species if it is inserted into the bacterial chromosome. A purified segment of the B. subtilis chromosome, with transforming activity against pheA1 and nic-38 recipients, was used to direct the insertion of p1949 into the B. subtilis chromosome. Insertion of the ligated DNA segments occurred in the region of the chromosome from which the purified phe-nic segment was derived. Many of the properties of the resulting CmR transformants of B. subtilis are consistent with the occurrence of a Campbell recombination mechanism leading to integration. However, certain of these properties are more easily explained if it is proposed that integration occurs by a reciprocal recombination event involving a linear ligation product. Evidence is presented suggesting that the inserted sequences may be tandemly duplicated. This may effectively vitiate the use of p1949 as a convenient means for complementation analysis of recessive mutations in B. subtilis.
Structures of Human ALKBH5 Demethylase Reveal a Unique Binding Mode for Specific Single-stranded N6-Methyladenosine RNA Demethylation (2014)

N(6)-Methyladenosine (m(6)A) is the most prevalent internal RNA modification in eukaryotes. ALKBH5 belongs to the AlkB family of dioxygenases and has been shown to specifically demethylate m(6)A in single-stranded RNA. Here we report crystal structures of ALKBH5 in the presence of either its cofactors or the ALKBH5 inhibitor citrate. Catalytic assays demonstrate that the ALKBH5 catalytic domain can demethylate both single-stranded RNA and single-stranded DNA. We identify the TCA cycle intermediate citrate as a modest inhibitor of ALKHB5 (IC50, ∼488 μm). The structural analysis reveals that a loop region of ALKBH5 is immobilized by a disulfide bond that apparently excludes the binding of dsDNA to ALKBH5. We identify the m(6)A binding pocket of ALKBH5 and the key residues involved in m(6)A recognition using mutagenesis and ITC binding experiments.
Primary Total Knee Arthroplasty in Patients With Severe Varus Deformity (1991)

Varus deformity is a common finding in candidates for total knee arthroplasty (TKA), but very little has been written concerning the problems encountered in correcting these deformities at the time of arthroplasty. Compared to patients without deformities, this group of patients require more attention to the technical aspects of the arthroplasty, especially bony alignment and ligament balancing. Specific operative techniques used to correct severe varus deformities at primary TKA were evaluated, and the clinical and roentgenographic results were compared with those of a control group of patients without preoperative angular deformity. Operative findings and clinical results in 27 knees (20 patients) with a minimum preoperative varus deformity of 20 degrees (average follow-up period, 58.7 months; range, 24-102 months) were compared with those of 40 knees (31 patients) with a preoperative angulatory deformity of less than 5 degrees varus or valgus (average follow-up period, 50.0 months; range, 24-90 months), in whom a minimally constrained, posterior-cruciate-ligament-sparing prosthesis was implanted. Operative time was an average of 30 minutes longer in the varus deformity group. The average knee evaluation score in the varus group was 89 points, and for the nondeformity group it was 92 points (p less than 0.02). There were no fair or poor results in the varus deformity group; there was one poor result in the nondeformity group. Postoperative knee are of motion was 98 degrees in the varus deformity group and 107 degrees in the nondeformity group. After arthroplasty, the average angle between the mechanical axis of the femur and the tibia was 3 degrees varus in the varus deformity group and 0 degree varus in the nondeformity group (p less than 0.006). Postoperative functional scores of patients in the varus deformity group approached, but were not equal to, the nondeformity group. Greater variability in results and longer operative times were needed in the varus deformity group. Postoperative alignment of the varus deformity group tended to be in residual varus.
Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine (1991)

The combined cytotoxicity of zidovudine and ganciclovir in three cell lines of human origin was examined. The data were generated by a new rapid cell proliferation assay and a more sensitive plating efficiency assay. A three-dimensional analytical approach was used to evaluate the drug-drug interactions, and the results were compared with those obtained by two conventional methods of analysis. Synergistic cytotoxicity was observed in all cell lines examined and by both assays. Moreover, this synergistic cytotoxicity was statistically significant at physiologically relevant concentrations. It is not known whether these drug-drug interactions manifest themselves in vivo as granulocytopenia or other untoward side effects. These results, however, indicate that further investigation is warranted and that the coadministration of zidovudine and ganciclovir may be contraindicated.
An Efficient Switching Technique for NoCs with Reduced Buffer Requirements (2008)

Networks on chip (NoCs) communicate the components located inside a chip. Overall system performance depends on NoC performance, that is affected by several factors. One of them is the network clock frequency, imposed by the critical path delay. Recent works show that switch critical path includes buffer control logic. Consequently, by removing switch buffers, switch frequency can be doubled. In this paper, we exploit this idea, proposing a new switching technique for NoCs which requires a reduced amount of storage at the switches. It is based on replacing switch port buffers by single latches. By doing so, network cycle can be reduced, which reduces packet latency. On the other hand, power and area consumption requirements can be reduced. However, since there are no buffers at the switch ports, packets can not be stopped. Stopped packets due to contention are dropped and reinjected from their senders via negative acknowledgments. Packet dropping is strongly reduced by exploiting NoCs wiring capability.
Identification of Chelerythrine as an Inhibitor of BclXL Function (2003)

The identification of small molecule inhibitors of antiapoptotic Bcl-2 family members has opened up new therapeutic opportunities, while the vast diversity of chemical structures and biological activities of natural products are yet to be systematically exploited. Here we report the identification of chelerythrine as an inhibitor of BclXL-Bak Bcl-2 homology 3 (BH3) domain binding through a high throughput screening of 107,423 extracts derived from natural products. Chelerythrine inhibited the BclXL-Bak BH3 peptide binding with IC50 of 1.5 micro m and displaced Bax, a BH3-containing protein, from BclXL. Mammalian cells treated with chelerythrine underwent apoptosis with characteristic features that suggest involvement of the mitochondrial pathway. While staurosporine, H7, etoposide, and chelerythrine released cytochrome c from mitochondria in intact cells, only chelerythrine released cytochrome c from isolated mitochondria. Furthermore BclXL-overexpressing cells that were completely resistant to apoptotic stimuli used in this study remained sensitive to chelerythrine. Although chelerythrine is widely known as a protein kinase C inhibitor, the mechanism by which it mediates apoptosis remain controversial. Our data suggest that chelerythrine triggers apoptosis through a mechanism that involves direct targeting of Bcl-2 family proteins.