gebhart/patrepeval huggingface dataset:
Cellular Mechanisms for Amyloid β-Protein Activation of Rat Cholinergic Basal Forebrain Neurons (2001)

The deposition of amyloid beta-protein (Abeta) in the brain and the loss of cholinergic neurons in the basal forebrain are two pathological hallmarks of Alzheimer's disease (AD). Although the mechanism of Abeta neurotoxicity is unknown, these cholinergic neurons display a selective vulnerability when exposed to this peptide. In this study, application of Abeta(25-35) or Abeta(1-40) to acutely dissociated rat neurons from the basal forebrain nucleus diagonal band of Broca (DBB), caused a decrease in whole cell voltage-activated currents in a majority of cells. This reduction in whole cell currents occurs through a modulation of a suite of potassium conductances including calcium-activated potassium (I(C)), the delayed rectifier (I(K)), and transient outward potassium (I(A)) conductances, but not calcium or sodium currents. Under current-clamp conditions, Abeta evoked an increase in excitability and a loss of accommodation in cholinergic DBB neurons. Using single-cell RT-PCR technique, we determined that Abeta actions were specific to cholinergic, but not GABAergic DBB neurons. Abeta effects on whole cell currents were occluded in the presence of membrane-permeable protein tyrosine kinase inhibitors, genistein and tyrphostin B-44. Our data indicate that the Abeta actions on specific potassium conductances are modulated through a protein tyrosine kinase pathway and that these effects are selective to cholinergic but not GABAergic cells. These observations provide a cellular basis for the selectivity of Abeta neurotoxicity toward cholinergic basal forebrain neurons that are at the epicenter of AD pathology.
p27Kip1 Directly Represses Sox2 during Embryonic Stem Cell Differentiation (2012)

The mechanisms responsible for the transcriptional silencing of pluripotency genes in differentiated cells are poorly understood. We have observed that cells lacking the tumor suppressor p27 can be reprogrammed into induced pluripotent stem cells (iPSCs) in the absence of ectopic Sox2. Interestingly, cells and tissues from p27 null mice, including brain, lung, and retina, present an elevated basal expression of Sox2, suggesting that p27 contributes to the repression of Sox2. Furthermore, p27 null iPSCs fail to fully repress Sox2 upon differentiation. Mechanistically, we have found that upon differentiation p27 associates to the SRR2 enhancer of the Sox2 gene together with a p130-E2F4-SIN3A repressive complex. Finally, Sox2 haploinsufficiency genetically rescues some of the phenotypes characteristic of p27 null mice, including gigantism, pituitary hyperplasia, pituitary tumors, and retinal defects. Collectively, these results demonstrate an unprecedented connection between p27 and Sox2 relevant for reprogramming and cancer and for understanding human pathologies associated with p27 germline mutations.
Mutations of Keratinocyte Transglutaminase in Lamellar Ichthyosis (1995)

Lamellar ichthyosis is a severe congenital skin disorder characterized by generalized large scales and variable redness. Affected individuals in three families exhibited drastically reduced keratinocyte transglutaminase (TGK) activity. In two of these families, expression of TGK transcripts was diminished or abnormal and no TGK protein was detected. Homozygous or compound heterozygous mutations of the TGK gene were identified in all families. These data suggest that defects in TGK cause lamellar ichthyosis and that intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis.
EMT and Treatment Resistance in Pancreatic Cancer (2017)

Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance.
Vascularized Collagen-Glycosaminoglycan Matrix Provides a Dermal Substrate and Improves Take of Cultured Epithelial Autografts (1998)

Cultured epithelial autografts are an important adjunct in treating severely burned patients, greatly expanding the epidermis using a small donor site. Problems with cultured epithelial autografts include the time delay to culture cells to confluence and variable take on full-thickness wounds. Dermal allografts have been used as a substrate to improve the take of cultured epithelial autografts. This study examined the effect of a vascularized collagen-glycosaminoglycan matrix as a substrate for cultured epithelial autografts. The matrix was grafted onto 12 full-thickness wounds in Yorkshire pigs and allowed to vascularize for 10 days. The cultured epithelial autografts were applied over the vascularized collagen-glycosaminoglycan matrix (n = 12) or onto freshly excised full-thickness wounds (n = 10). Gross and histologic observations were made over a 3-week period. Gross observations at 7 days indicated cultured epithelial autografts to have nearly complete confluence when applied to wounds treated by collagen-glycosaminoglycan, whereas cultured epithelial autografts applied to freshly excised wounds did not take. Gross determination of epithelial confluence was verified by histologic analysis of randomly selected wounds. Histologic epithelial confluence of cultured epithelial autografts on collagen-glycosaminoglycan (98 +/- 4 percent) was significantly greater than that on full-thickness wounds (4 +/- 10 percent). Electron microscopy of the cultured epithelial autografts/collagen-glycosaminoglycan construct demonstrated anchoring fibrils at the dermal-epidermal junction at day 7. The neoepidermis of wounds treated by cultured epithelial autografts/collagen-glycosaminoglycan was hyperplastic at day 7 but developed a normal maturation sequence by 21 days. Results from this study suggest that vascularized collagen-glycosaminoglycan matrices produce a favorable substrate for cultured epithelial autografts and may improve cultured epithelial autografts take in burn patients.
Classical and Quantum Algorithms for the Boolean Satisfiability Problem (2015)

This paper presents a complete algorithmic study of the decision Boolean Satisfiability Problem under the classical computation and quantum computation theories. The paper depicts deterministic and probabilistic algorithms, propositions of their properties and the main result is that the problem has not an efficient algorithm (NP is not P). Novel quantum algorithms and propositions depict that the complexity by quantum computation approach for solving the Boolean Satisfiability Problem or any NP problem is lineal time.
Expanded-Size Bases in Naturally Sized DNA:  Evaluation of Steric Effects in Watson−Crick Pairing (2004)

We describe physicochemical properties in DNA of altered-size nucleobases that retain Watson-Crick analogous hydrogen-bonding ability. Size-expanded analogues of adenine and thymine (xA and xT, respectively, which are expanded by benzo-fusion) were incorporated into natural DNA oligonucleotides, and their effects on helix stability were measured. Base stacking studies revealed that the two stretched analogues stack much more strongly than do their naturally sized counterparts. In contrast to this, pairing studies showed that single substitutions of the new bases are destabilizing to the natural helix as compared to A or T in standard A-T pairs in the same context, unless multiple adjacent substitutions are used. Interestingly, the size-expanded bases displayed selective recognition of the hydrogen-bonding complementary partners, suggesting that Watson-Crick analogous pairs were still formed despite local backbone strain. In an attempt to compensate for the added size of the expanded adenine, we tested a formamide deoxynucleoside, which Leonard proposed as a shortened thymine analogue (F(o)). Data showed, however, that this compound adopts a conformation unfavorable for pairing. On the basis of the combined thermodynamic data, we estimate the energetic cost of the 2.4 A stretching of an isolated base pair in DNA at ca. +1 to 2 kcal/mol. Notably, during the pairing studies, the two size-expanded nucleobases were found to display significant changes in fluorescence on formation of stacked versus unstacked structures, suggesting possible applications in probing nucleic acid structures and biochemical mechanisms.
Fast seismic modeling and Reverse Time Migration on a GPU cluster (2009)

We have designed a fast parallel simulator that solves the acoustic wave equation on a GPU cluster. Solving the acoustic wave equation in an oil exploration industrial context aims at speeding up seismic modeling and Reverse Time Migration. We consider a finite difference approach on a regular mesh, in both 2D and 3D cases. The acoustic wave equation is solved in either a constant density or a variable density domain. All the computations are done in single precision, since double precision is not required in our context. We use CUDA to take advantage of the GPUs computational power. We study different implementations and their impact on the application performance. We obtain a speed up of 10 for Reverse Time Migration and up to 30 for the modeling application over a sequential code running on general purpose CPU.
Human Papillomavirus Type 16 E6/E7-specific Cytotoxic T Lymphocytes for Adoptive Immunotherapy of HPV-associated Malignancies (2012)

Vaccines prevent human papillomavirus (HPV)-associated cancer but, although these tumors express foreign, viral antigens (E6 and E7 proteins), they have little benefit in established malignancies, likely due to negative environmental cues that block tumor recognition and induce T-cell anergy in vivo. We postulated that we could identify mechanisms by which ex vivo stimulation of T cells could reactivate and expand tumor-directed T-cell lines from HPV cancer patients for subsequent adoptive immunotherapy. A total of 68 patients with HPV-associated cancers were studied. Peripheral blood T cells were stimulated with monocyte-derived dendritic cells loaded with pepmixes [peptide libraries of 15-mers overlapping by 11 amino acids (aa)] spanning E6/E7, in the presence or absence of specific accessory cytokines. The resulting T-cell lines were further expanded with pepmix-loaded activated B-cell blasts. Interferon-γ release and cytotoxic responses to E6/E7 were assessed. We successfully reactivated and expanded (>1200-fold) E6-specific/E7-specific T cells from 8/16 cervical and 33/52 oropharyngeal cancer patients. The presence of the cytokines interleukin (IL)-6, IL-7, IL-12, and IL-15 is critical for this process. These T-cell lines possess the desirable characteristics of polyclonality, multiple T-cell subset representation (including the memory compartment) and a TH1 bias, and may eliminate E6/E7 targets. In conclusion, we have shown it is possible to robustly generate HPV16 E6/E7-directed T-cell lines from patients with HPV16-associated cancers. Because our technique is scalable and good-manufacturing procedures-compliant, these lines could be used for adoptive cellular immunotherapy of patients with HPV16 cancers.
Pharmacokinetics of intravitreal injection. Assessment of a gentamicin model by ocular dialysis. (1989)

Intravitreal drug administration is the treatment of choice for bacterial endophtalmitis, but improved knowledge of vitreal pharmacokinetics is essential for the development of optimal antibiotic regimes. We used our recently developed sampling device to estimate vitreal gentamicin concentrations for up to 30 hr after an intravitreal bolus injection of gentamicin. The device is based on the principle of dialysis, whereby a constant flow rate of dialysate through a loop of dialysis fiber in the vitreous attains a gentamicin concentration proportional to the intravitreal gentamicin level around the fiber. The dialysate is continuously recovered and the collected samples then assayed for gentamicin. Normal cat eyes and those with induced bacterial endophthalmitis formed the two groups tested. Concentration-time data fitted well to an open single compartment pharmacokinetic model that incorporated the processes of transfer of drug from the injection site to the sampling site (a function of diffusion within the vitreous), and the elimination from the sampling site (a function of elimination from the vitreous). The initial phase of transfer between the injection and sampling site was rapid and rates were comparable in the two groups. Elimination rate constants were uniformly greater in infected eyes than in controls (0.107 hr-1 compared to 0.055 hr-1). Aqueous humor gentamicin concentrations in control eyes varied between 3 and 6 times those found in fellow infected eyes at the end of each experiment. Accelerated elimination of gentamicin from the vitreous body of eyes with endophthalmitis may be explained by increased permeability of the blood-retinal barrier.
A more cost effective and rapid high percentage germ‐line transmitting chimeric mouse generation procedure via microinjection of 2‐cell, 4‐cell, and 8‐cell embryos with ES and iPS cells (2010)

The long-standing traditional method of delivering embryonic stem (ES) cells adjacent to the inner cell mass (ICM) of blastocysts to generate chimeras improved with the advent of laser- or Piezo assisted 8-cell embryo microinjection. Building on this technology but omitting either the laser or the Piezo to penetrate the zona pellucida and making use of earlier embryonic stages (2-cell and 4-cell), we were able to significantly speed up and economize our ES cell microinjection and chimera production throughput. We demonstrate here that embryonic (ES) and induced pluripotent stem (iPS) cells can stay fully pluripotent when delivered into 2-cell- and 4-cell-stage embryos, long before they would naturally be incorporated into the ICM of a blastocyst (E3.5) and give rise to high percentage and germline transmitting chimeras.
Computer Aided Drug Design Strategies Used in the Discovery of Fructose 1, 6-Bisphosphatase Inhibitors (2005)

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design (CADD) paradigms. The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this review, the FEP method is compared with molecular mechanics (MM) methods to assess the advantages of each in the estimation of relative binding affinities of inhibitors to an enzyme. Qualitative predictions of relative binding free energies of fructose 1, 6-bisphosphatase inhibitors using MM methods are discussed and compared with the corresponding FEP results. The results indicate that the MM based methods and the FEP method are useful in the qualitative and quantitative assessment of relative binding affinities of enzyme inhibitors, respectively, prior to synthesis.
Versatile and Efficient Genome Editing in Human Cells by Combining Zinc-Finger Nucleases With Adeno-Associated Viral Vectors (2011)

Zinc-finger nucleases (ZFNs) have become a valuable tool for targeted genome engineering. Based on the enzyme's ability to create a site-specific DNA double-strand break, ZFNs promote genome editing by activating the cellular DNA damage response, including homology-directed repair (HDR) and nonhomologous end-joining. The goal of this study was (i) to demonstrate the versatility of combining the ZFN technology with a vector platform based on adeno-associated virus (AAV), and (ii) to assess the toxicity evoked by this platform. To this end, human cell lines that harbor enhanced green fluorescence protein (EGFP) reporters were generated to easily quantify the frequencies of gene deletion, gene disruption, and gene correction. We demonstrated that ZFN-encoding AAV expression vectors can be employed to induce large chromosomal deletions or to disrupt genes in up to 32% of transduced cells. In combination with AAV vectors that served as HDR donors, the AAV-ZFN platform was utilized to correct a mutation in EGFP in up to 6% of cells. Genome editing on the DNA level was confirmed by genotyping. Although cell cycle profiling revealed a modest G2/M arrest at high AAV-ZFN vector doses, platform-induced apoptosis could not be detected. In conclusion, the combined AAV-ZFN vector technology is a useful tool to edit the human genome with high efficiency. Because AAV vectors can transduce many cell types relevant for gene therapy, the ex vivo and in vivo delivery of ZFNs via AAV vectors will be of great interest for the treatment of inherited disorders.
New Advances in the Treatment of Metastatic Pancreatic Cancer (2015)

In this study, recent advances in the chemotherapeutic options available to treat metastatic PDAC and their implications for today’s treatment choices are reviewed.
Pilot Study of phoP/phoQ -Deleted Salmonella enterica Serovar Typhimurium Expressing Helicobacter pylori Urease in Adult Volunteers (2000)

Attenuated Salmonella enterica serovar Typhi has been studied as an oral vaccine vector. Despite success with attenuated S. enterica serovar Typhimurium vectors in animals, early clinical trials of S. enterica serovar Typhi expressing heterologous antigens have shown that few subjects have detectable immune responses to vectored antigens. A previous clinical study of phoP/phoQ-deleted S. enterica serovar Typhi expressing Helicobacter pylori urease from a multicopy plasmid showed that none of eight subjects had detectable immune responses to the vectored antigen. In an attempt to further define the variables important for engendering immune responses to vectored antigens in humans, six volunteers were inoculated with 5 x 10(7) to 8 x 10(7) CFU of phoP/phoQ-deleted S. enterica serovar Typhimurium expressing the same antigen. Two of the six volunteers had fever; none had diarrhea, bacteremia, or other serious side effects. The volunteers were more durably colonized than in previous studies of phoP/phoQ-deleted S. enterica serovar Typhi. Five of the six volunteers seroconverted to S. enterica serovar Typhimurium antigens and had strong evidence of anti-Salmonella mucosal immune responses by enzyme-linked immunospot studies. Three of six (three of five who seroconverted to Salmonella) had immune responses in the most sensitive assay of urease-specific immunoglobulin production by blood mononuclear cells in vitro. One of these had a fourfold or greater increase in end-point immunoglobulin titer in serum versus urease. Attenuated S. enterica serovar Typhimurium appears to be more effective than S. enterica serovar Typhi for engendering immune responses to urease. Data suggest that this may be related to a greater stability of antigen-expressing plasmid in S. enterica serovar Typhimurium and/or prolonged intestinal colonization. Specific factors unique to nontyphoidal salmonellae may also be important for stimulation of the gastrointestinal immune system.
Clinical Decision Making in a Patient with Stage 5 CKD—Is eGFR Good Enough? (2015)

The development and widespread use of serum creatinine concentration-based prediction equations to calculate eGFR have been major advances for detection of patients with CKD and the epidemiologic study of CKD and its outcomes. However, these equations as well as those that also incorporate serum cystatin C concentration provide GFR estimates that, although reasonably precise on average, can differ markedly and in clinically important ways from actual GFR. Thus, it is important that clinicians who use these equations for clinical decision-making be familiar with their strengths and weaknesses and have an appreciation of their potential for error. More precise knowledge of actual GFR is important in certain clinical circumstances, including, as presented in this Attending Rounds, patients with stage 5 CKD, in whom decisions regarding dialysis initiation are necessary. Nephrologists should have the ability to accurately determine GFR when needed if clinical circumstances suggest inaccuracy of the calculated eGFR reported by the clinical laboratory.
Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 Gene Fusions in Prostate Cancer (2008)

Recurrent gene fusions involving oncogenic ETS transcription factors (including ERG, ETV1, and ETV4) have been identified in a large fraction of prostate cancers. The most common fusions contain the 5' untranslated region of TMPRSS2 fused to ERG. Recently, we identified additional 5' partners in ETV1 fusions, including TMPRSS2, SLC45A3, HERV-K_22q11.23, C15ORF21, and HNRPA2B1. Here, we identify ETV5 as the fourth ETS family member involved in recurrent gene rearrangements in prostate cancer. Characterization of two cases with ETV5 outlier expression by RNA ligase-mediated rapid amplification of cDNA ends identified one case with a TMPRSS2:ETV5 fusion and one case with a SLC45A3:ETV5 fusion. We confirmed the presence of these fusions by quantitative PCR and fluorescence in situ hybridization. In vitro recapitulation of ETV5 overexpression induced invasion in RWPE cells, a benign immortalized prostatic epithelial cell line. Expression profiling and an integrative molecular concepts analysis of RWPE-ETV5 cells also revealed the induction of an invasive transcriptional program, consistent with ERG and ETV1 overexpression in RWPE cells, emphasizing the functional redundancy of ETS rearrangements. Together, our results suggest that the family of 5' partners previously identified in ETV1 gene fusions can fuse with other ETS family members, suggesting numerous rare gene fusion permutations in prostate cancer.
Robust H.263 compatible video transmission for mobile access to video servers (2002)

For interactive video storage applications that retrieve video data over low bit-rate networks, precoded bit-streams have to be transmitted to the receiver with low latency. Besides random access, fast forward and reverse, the scalability of the bit-stream is an important requirement for the above application. In this paper, we investigate a standard compatible approach that avoids the overhead involved in the transmission of periodic I-frames. We propose to store multiple bit-streams of different rates at the video server, which can be selected for transmission. Especially encoded P-frames are used to switch between the stored bit-streams. During normal-speed playback only P-frames are transmitted, providing increased efficiency. The approach is evaluated in the framework of the H.263 video compression standard. Based on the Salesman test sequence encoded at 12.5 fps in QCIF format, the resulting frame jitter is investigated when an error control protocol is used to transmit the bit-streams over a wireless DECT channel. Compared to periodic I-frames at an interval of 800 ms, a gain of 2 dB PSNR can be observed at the same frame jitter.