gebhart/patrepeval huggingface dataset:
Development and Standardization of an Immuno-Quantified Solid Phase Assay for HIV-1 Aspartyl Protease Activity and Its Application to the Evaluation of Inhibitors (1997)

The catELISA technique was modified and standardized for measuring HIV-1 aspartyl protease activity and evaluating the potency of synthetic peptide inhibitors. This immuno-quantified solid phase assay combines the use of an immobilized C-terminal biotinylated peptide as substrate, a crude enzyme preparation, and a highly specific antiserum elicited against the C-terminal product of the enzyme reaction. A standard curve of this C-terminal product was constructed to determine the enzyme activity. This assay, which requires less enzyme and substrate, is more sensitive than the conventional HPLC method. The amounts of C-terminal peptide produced in solution as determined from ELISA and HPLC standard curves were comparable. Analogues of peptidomimetics designed in our laboratory were assayed for their potency to inhibit the enzyme. One of them, H4, which is a hydroxyethylamine isostere of the Phe-Pro peptide bond, was a powerful inhibitor.
Treatment of Avascular Necrosis of the Femoral HeadWithDrilling and Injection of Concentrated Autologous Bone Marrow (2011)

Surgical treatment of early avascular necrosis of the femoral head remains controversial. The technique presented here involves drilling of the femoral head followed by injection of autologous, concentrated bone marrow stem cells. Preliminary reports using similar techniques show lower rates of collapse when compared with core decompression. This technique is simple, minimally invasive, requires only overnight hospital admission, does not require a period of postoperative nonweightbearing, and is well tolerated by patients. It is important to select patients carefully (ie, those with Association Research Circulation Osseous stage I and II disease). We believe that the mesenchymal stem cells in the concentrated bone marrow are essential for the regeneration of bone within the avascular necrosis lesions but the presence of other hematopoetic lineage cells may also be important to optimize the physiological and cellular milieu for the promotion of both osteogenesis and angiogenesis.
Image coding with windowed modulated filter banks (2003)

Lapped orthogonal transforms (LOT) have been introduced to provide a solution to the problem of blocking that occurs with transform coding at low bit rate. For the purpose of image coding, a more general class of exact reconstruction filter banks, that provides an additional degree of freedom in controlling ringing while relaxing the symmetry constraints of LOTs, is introduced. It is shown that windowed modulated filter banks are a very attractive candidate for image coding, since by allowing almost arbitrary selection of the window, they provide a control of the impulse response of the filters in the filter bank. The outputs of the windowed, modulated filter bank are quantized and entropy-coded in a way analogous to DCT (discrete cosine transform) coefficients. Comparisons are made between the filter bank and the DCT from the point of view of mean square error and subjective quality.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
TTK/hMPS1 Is an Attractive Therapeutic Target for Triple-Negative Breast Cancer (2013)

Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer.
Heterobifunctional Poly(Ethylene Glycol)–Tethered Bone Morphogenetic Protein-2–Stimulated Bone Marrow Mesenchymal Stromal Cell Differentiation and Osteogenesis (2007)

We describe a biomimetic mode of insoluble signaling stimulation to provide target delivery of bone morphogenetic protein-2 (BMP-2), with the aim of prolonging the retention of BMP-2 use in bone tissue engineering and to enable its localized release in response to cellular activity. In our novel localization process, we used heterobifunctional acrylate-N-hydroxysuccinimide poly(ethylene glycol) (PEG) as a spacer to tether BMP-2 onto a poly(lactide-co-glycolide) scaffold. Use of PEG-tethered BMP-2 was feasible because BMP-2 retained its activity after covalent conjugation. The PEG-tethered BMP-2 conjugate sustained stimulation and retained its mitogenic activity, notably affecting pluripotent stem cell proliferation and differentiation. We seeded the scaffolds with bone marrow-derived mesenchymal stromal cells as progenitor cells to evaluate their morphology and phenotypic expression. We also created bilateral, full-thickness cranial defects in rabbits to investigate the osteogenic effect of cultured mesenchymal stromal cells on bone regeneration in vivo. Histomorphometry and histology demonstrated that the PEG-tethered BMP-2 conjugate enhanced de novo bone formation after surgery. Our work revealed the potential for biomimetic surface engineering by entrapping signaling growth factor to stimulate osteogenesis. Our technique may provide a new platform for bone-engineered stem cell therapies.
To flip or not to flip: lipid–protein charge interactions are a determinant of final membrane protein topology (2008)

The molecular details of how lipids influence final topological organization of membrane proteins are not well understood. Here, we present evidence that final topology is influenced by lipid–protein interactions most likely outside of the translocon. The N-terminal half of Escherichia coli lactose permease (LacY) is inverted with respect to the C-terminal half and the membrane bilayer when assembled in mutants lacking phosphatidylethanolamine and containing only negatively charged phospholipids. We demonstrate that inversion is dependent on interactions between the net charge of the cytoplasmic surface of the N-terminal bundle and the negative charge density of the membrane bilayer surface. A transmembrane domain, acting as a molecular hinge between the two halves of the protein, must also exit from the membrane for inversion to occur. Phosphatidylethanolamine dampens the translocation potential of negative residues in favor of the cytoplasmic retention potential of positive residues, thus explaining the dominance of positive over negative amino acids as co- or post-translational topological determinants.
A 3-Hydroxypropionate/4-Hydroxybutyrate Autotrophic Carbon Dioxide Assimilation Pathway in Archaea (2007)

The assimilation of carbon dioxide (CO 2 ) into organic material is quantitatively the most important biosynthetic process. We discovered that an autotrophic member of the archaeal order Sulfolobales, Metallosphaera sedula , fixed CO 2 with acetyl–coenzyme A (acetyl-CoA)/propionyl-CoA carboxylase as the key carboxylating enzyme. In this system, one acetyl-CoA and two bicarbonate molecules were reductively converted via 3-hydroxypropionate to succinyl-CoA. This intermediate was reduced to 4-hydroxybutyrate and converted into two acetyl-CoA molecules via 4-hydroxybutyryl-CoA dehydratase. The key genes of this pathway were found not only in Metallosphaera but also in Sulfolobus, Archaeoglobus , and Cenarchaeum species. Moreover, the Global Ocean Sampling database contains half as many 4-hydroxybutyryl-CoA dehydratase sequences as compared with those found for another key photosynthetic CO 2 -fixing enzyme, ribulose-1,5-bisphosphate carboxylase-oxygenase. This indicates the importance of this enzyme in global carbon cycling.
Mammalian ets-1 and ets-2 genes encode highly conserved proteins. (1988)

Cellular ets sequences homologous to v-ets of the avian leukemia virus E26 are highly conserved. In mammals the ets sequences are dispersed on two separate chromosomal loci, called ets-1 and ets-2. To determine the structure of these two genes and identify the open reading frames that code for the putative proteins, we have sequenced human ets-1 cDNAs and ets-2 cDNA clones obtained from both human and mouse. The human ETS1 gene is capable of encoding a protein of 441 amino acids. This protein is greater than 95% identical to the chicken c-ets-1 gene product. Thus, the human ETS1 gene is homologous to the chicken c-ets-1 gene, the protooncogene that the E26 virus transduced. Human and mouse ets-2 cDNA clones are closely related and contain open reading frames capable of encoding proteins of 469 and 468 residues, respectively. Direct comparison of these data with previously published findings indicates that ets is a family of genes whose members share distinct domains.
Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease (2011)

Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-β (Aβ) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar Aβ oligomers may be the major drivers of Aβ-mediated synaptic dysfunction. Structural information on these Aβ species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18-41 of the Aβ peptide (equivalent to the p3 α/γ-secretase fragment of amyloid precursor protein) presented within the CDR3 loop region of a shark Ig new antigen receptor (IgNAR) single variable domain antibody. The predominant oligomeric species is a tightly associated Aβ dimer, with paired dimers forming a tetramer in the crystal caged within four IgNAR domains, preventing uncontrolled amyloid formation. Our structure correlates with independently observed features of small nonfibrillar Aβ oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in Aβ folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease.
Sequential half-body irradiation in lymphomatoid granulomatosis. Report of a case and an immunohistologic study (1989)

A case is presented of a man with ulcerating skin nodules who was diagnosed by histologic and immunohistologic analysis of skin biopsy specimens as having lymphomatoid granulomatosis (LYG). Phenotypic studies showed the majority of the infiltrating cells to be activated CD4+ T-lymphocytes. The disease followed a rapidly progressive course and did not respond to treatment with cytotoxic chemotherapy. The patient developed life-threatening systemic symptoms and involvement of both upper and lower respiratory tracts. After treatment with sequential half-body irradiation he has been in complete remission for 3.5 years.
NF-κB–Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells (2014)

Essential roles of NF-κB-inducing kinase (NIK) for the development of medullary thymic epithelial cells (mTECs) and regulatory T cells have been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice). However, the exact mechanisms underlying the defect in thymic cross-talk leading to the breakdown of self-tolerance in aly mice remain elusive. In this study, we demonstrated that production of regulatory T cells and the final maturation process of positively selected conventional αβ T cells are impaired in aly mice, partly because of a lack of mature mTECs. Of note, numbers of thymic dendritic cells and their expression of costimulatory molecules were also affected in aly mice in a thymic stroma-dependent manner. The results suggest a pivotal role of NIK in the thymic stroma in establishing self-tolerance by orchestrating cross-talk between mTECs and dendritic cells as well as thymocytes. In addition, we showed that negative selection was impaired in aly mice as a result of the stromal defect, which accounts for the development of organ-specific autoimmunity through a lack of normal NIK.
Cytotoxicity and Cellular Uptake of Amorphous Silica Nanoparticles in Human Cancer Cells (2015)

The cytotoxic effects of silica nanoparticles (SNPs) on different human cancer cells, as well as the uptake kinetics and pathways of SNPs have been studied here. SNPs with the diameter of ≈20 nm induced a dose-dependent cytotoxicity in both gastric cancer cells (MGC80–3) and cervical adenocarcinoma epithelial cells (HeLa), but MGC80–3 cells were more susceptible to the cytotoxic effect induced by SNPs. Changes in the nuclear morphology and flow cytometric analysis with annexin V/PI double staining show that SNPs induced a higher degree of apoptosis in MGC80–3 cells. Accordingly, more remarkable reactive oxygen species (ROS) burst is detected in SNP-treated MGC80–3 cells. Using fluorescein isothiocyanate (FITC)-labeled SNPs and flow cytometry, it is found that the uptake of SNPs is more efficient in MGC80–3 than in HeLa cells. SNPs are internalized into both cancer cells through energy-dependent pathway. Inhibitor studies with dynasore and methyl-β-cyclodextrin show that these cancer cells took up 20 nm SNPs mainly through the caveolin-mediated endocytosis, while in HeLa cells SNPs internalization was also via dynamin-dependent clathrin-mediated pathway. These findings indicate that SNPs cause differential cytotoxic effects in different human cancer cells, which might be related to the uptake process and efficiency toward these cancer cells.
Identification of T cell epitopes occurring in a meningococcal class 1 outer membrane protein using overlapping peptides assembled with simultaneous multiple peptide synthesis. (1992)

The meningococcal class 1 outer membrane protein (OMP) plays an important role in the development of protective immunity against meningococcal infection, and is therefore considered to be a promising candidate antigen (Ag) for a meningococcal vaccine. The induction of an effective antibody response entirely depends upon T helper cells. To identify T cell epitopes of the OMP, we prepared 45 overlapping synthetic peptides representing the entire sequence of the class 1 protein of reference strain H44/76. Fully automated simultaneous multiple peptide synthesis (SMPS) was used to assemble the 45 twenty mer which overlapped by 12 amino acid residues on a 12 mumol scale. The peptides were tested for recognition by peripheral blood mononuclear cells (PBMC) obtained from 34 volunteers. Surprisingly, all synthetic peptides induced proliferative responses of PBMC isolated from one or more human histocompatibility leukocyte antigen (HLA)-typed immune adults. With PBMC from seven nonimmune donors, no proliferative response was observed. Immunodominant regions were found, recognized by PBMC from many volunteers, irrespective of their HLA type. Most of the immunodominant T cell epitopes are located outside the variable regions and, thus, will be conserved among different meningococcal (and gonococcal) strains. Furthermore, the overlapping peptides could be used to identify the epitopes recognized by OMP-specific T cell clones with known HLA restriction. It is interesting that the epitopes defined with the clones occur in highly conserved areas, shared by all neisserial porin proteins. In summary, this analysis of the T cell response to the meningococcal class 1 OMP constitutes a complete study of reactivity to a foreign protein, and illustrates some important features of Ag recognition by T cells. Our data demonstrate unexpected diversity in the T cell recognition of the OMP, and imply that the T cell repertoire against foreign Ag may be greater than previously assumed. This observation is supported by recent data on the interaction of peptide and major histocompatibility complex (MHC) class II, the latter being much less selective than MHC class I. Finally, a comparative analysis pointed out the limitations of algorithms predicting T cell determinants, and the importance of the empirical methodology provided by SMPS.
Adeno-associated virus Rep protein inhibits human immunodeficiency virus type 1 production in human cells (1991)

The adeno-associated virus (AAV) rep gene encodes four proteins (Rep78, Rep68, Rep52, and Rep40) required for AAV DNA replication and AAV gene regulation. In addition, the Rep proteins may have pleiotropic regulatory effects in heterologous systems, and in particular Rep78 may mediate a negative regulatory effect. We analyzed the effects of the AAV rep gene on human immunodeficiency virus type 1 (HIV-1) gene expression. The rep gene proteins of AAV type 2 (AAV2) inhibited the trans-activating ability of HIV-1. Constructs containing the AAV2 rep gene (pHIVrep) or a CAT gene (pBennCAT) expressed from the 5' HIV-1 long terminal repeat were inducible for Rep78 and Rep68 or CAT expression, respectively, when cotransfected with a plasmid containing the HIV-1 tat gene (pARtat). When equivalent amounts of pHIVrep and pBennCAT were cotransfected with increasing amounts of pARtat, expression of CAT activity was decreased. The pHIVrep construct was more inhibitory than plasmids expressing rep from the wild-type AAV2 p5 transcription promoter. rep expression from pHIVrep almost completely inhibited the replication of an HIV-1 proviral clone as measured by reverse transcriptase activity and p24 protein levels. Inhibition of HIV-1 production by Rep protein was also seen at the transcriptional level in that all HIV-1 transcripts were decreased when pHIVrep was present. The inhibitory effects of pHIVrep appear to be mediated primarily by Rep78 and perhaps Rep68. These results suggest that a trans-acting protein from a heterologous virus might be used to inhibit HIV-1 growth.
Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia (2010)

Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.
Understanding transmitted HIV resistance through the experience in the USA (2009)

Transmitted drug resistance is an emerging phenomenon with important clinical and public health implications. It has been reported in 3.4% to 26% of HIV-infected persons in the USA. Most cases affect non-nucleoside reverse transcriptase inhibitors or nucleos(t)ide reverse transcriptase inhibitors. Transmitted protease inhibitor or multi-class resistance is uncommon, occurring in <5% of cases. The genital tract may function as a reservoir of transmissible drug-resistant variants or a site for low-level viral replication at a time plasma HIV is suppressed. Transmitted drug-resistant HIV variants, including those that exist in very low titers (minority populations), are associated with suboptimal virologic response to initial antiretroviral therapy. Baseline resistance testing, preferably genotype, appears to be cost-effective and is recommended for all treatment-naïve patients in the USA, although prospective trials have not been performed. It appears transmitted drug resistance is still relatively low in developing countries, but there is a dearth of information.
Reflex Changes in Sympathetic Activity and Arterial Blood Pressure Evoked by Afferent Stimulation of the Renal Nerve (1970)

Abstract The effects of afferent stimulation of renal nerves on efferent sympathetic activity and systemic blood pressure were studied in anesthetized rabbits. In most animals, afferent impulses pro duced reduction or abolition of sympathetic activity and a fall in blood pressure. High fre quencies of stimulation (20–30 pulses/sec or more) caused a more marked and long‐lasting depression of efferent activity and blood pressure than low frequencies. The highest sensitivity of blood pressure to variations in stimulation frequency was found in the range of 1–10 pulseslsec. Stimulation of the renal afferents had qualitatively the same effect on sympathetic activity and blood pressure as aortic nerve stimulation, but for the aortic nerve, higher stimu lation frequencies were required to obtain the same reduction in blood pressure. It is con cluded that afferent activity in renal nerves has a predominantly inhibitory effect on vasomotor activity, resulting in a fall in blood pressure.
Experimental allergic encephalomyelitis in cobra venom factor—treated and C4‐deficient guinea pigs (1978)

Experimental allergic encephalomyelitis (EAE) was studied in guinea pigs with an inherited deficiency of the fourth component of complement (C4) and in guinea pigs injected with cobra venom factor to deplete the third component and late-acting components of complement. EAE was elicited by immunization with homologous spinal cord or purified basic protein. Administration of cobra factor after the injection of encephalitogenic emulsion delayed the onset and reduced the intensity of the clinical manifestations of EAE. In addition, cobra factor markedly reduced mortality during the sixty days of observation. However, pathological changes of perivascular infiltration and demyelination were similar in cobra factor-treated and untreated animals. Clinical signs of EAE an mortality in C4-deficient guinea pigs were no different from those in normocomplementemic controls. Thus, although activation of the classic complement pathway does not appear to be involved in the production of EAE in guinea pigs, our results suggest a possible role of the alternative complement pathway in the pathogenesis of EAE.
Extracellular ATP Mediates Necrotic Cell Swelling in SN4741 Dopaminergic Neurons through P2X7 Receptors (2007)

Extracellular ATP has recently been identified as an important regulator of cell death in response to pathological insults. When SN4741 cells, which are dopaminergic neurons derived from the substantia nigra of transgenic mouse embryos, are exposed to ATP, cell death occurs. This cell death is associated with prominent cell swelling, loss of ER integrity, the formation of many large cytoplasmic vacuoles, and subsequent cytolysis and DNA release. In addition, the cleavage of caspase-3, a hallmark of apoptosis, is induced by ATP treatment. However, caspase inhibitors do not overcome ATP-induced cell death, indicating that both necrosis and apoptosis are associated with ATP-induced cell death and suggesting that a necrotic event might override the apoptotic process. In this study we also found that P2X(7) receptors (P2X(7)Rs) are abundantly expressed in SN4741 cells, and both ATP-induced swelling and cell death are reversed by pretreatment with the P2X(7)Rs antagonist, KN62, or by knock-down of P2X(7)Rs with small interfering RNAs. Therefore, extracellular ATP release from injured tissues may act as an accelerating factor in necrotic SN4741 dopaminergic cell death via P2X(7)Rs.