gebhart/patrepeval huggingface dataset:
HIV-1 RNA levels in cerebrospinal fluid and plasma correlate with AIDS dementia. (1998)

Subcutaneous IL-2 in addition to HAART was safe and led to sustained qualitative and quantitative immunological improvements in the majority of patients. Individualisation of therapy intervals further improved the efficacy and tolerance of IL-2.
m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells (2017)

RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.
Broad host range vectors for stable genomic library construction (2006)

We describe the construction of 36 stable vectors for genomic library construction in gram-negative species. These vectors contain the pBBR1 replicon that has been shown to stably replicate in every gram-negative species tested. The plasmids also contain bidirectional, rho-independent transcriptional terminators flanking the multiple cloning site, which allows for greater insert stability, and thus, greater genomic representation. Each vector varies in its antibiotic resistance cassette, mobilization function, and promoter used to express insert sequences. These vectors should prove useful in the screening of highly representational genomic libraries in a broad variety of gram-negative species.
Inflammation, Cytokines, Immune Response, Apolipoprotein E, Cholesterol, and Oxidative Stress in Alzheimer Disease: Therapeutic Implications (2010)

Alzheimer disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for senile dementia. Today many countries have rising aging populations and are facing an increased prevalence of age-related diseases, such as AD, with increasing health-care costs. Understanding the pathophysiology process of AD plays a prominent role in new strategies for extending the health of the elderly population. Considering the future epidemic of AD, prevention and treatment are important goals of ongoing research. However, a better understanding of AD pathophysiology must be accomplished to make this objective feasible. In this paper, we review some hot topics concerning AD pathophysiology that have an important impact on therapeutic perspectives. Hence, we have focused our attention on inflammation, cytokines, immune response, apolipoprotein E (APOE), cholesterol, oxidative stress, as well as exploring the related therapeutic possibilities, i.e., nonsteroidal antiinflammatory drugs, cytokine blocking antibodies, immunotherapy, diet, and curcumin.
Codon optimization of human factor VIII cDNAs leads to high-level expression (2010)

Gene therapy for hemophilia A would be facilitated by development of smaller expression cassettes encoding factor VIII (FVIII), which demonstrate improved biosynthesis and/or enhanced biologic properties. B domain deleted (BDD) FVIII retains full procoagulant function and is expressed at higher levels than wild-type FVIII. However, a partial BDD FVIII, leaving an N-terminal 226 amino acid stretch (N6), increases in vitro secretion of FVIII tenfold compared with BDD-FVIII. In this study, we tested various BDD constructs in the context of either wild-type or codon-optimized cDNA sequences expressed under control of the strong, ubiquitous Spleen Focus Forming Virus promoter within a self-inactivating HIV-based lentiviral vector. Transduced 293T cells in vitro demonstrated detectable FVIII activity. Hemophilic mice treated with lentiviral vectors showed expression of FVIII activity and phenotypic correction sustained over 250 days. Importantly, codon-optimized constructs achieved an unprecedented 29- to 44-fold increase in expression, yielding more than 200% normal human FVIII levels. Addition of B domain sequences to BDD-FVIII did not significantly increase in vivo expression. These significant findings demonstrate that shorter FVIII constructs that can be more easily accommodated in viral vectors can result in increased therapeutic efficacy and may deliver effective gene therapy for hemophilia A.
Microbiology of periodontal disease (1987)

There is a perception of conflicting data and opinions among research laboratories that are studying periodontal microbiology. In response to this perception I was asked to discuss recent literature in this field at the 1986 Annual Meeting of the American Association of Dental Research. This review is based on that discussion which primarily concerned all of the relevant papers that were available to me and that had been published in the last 2 years (1984 and 1985). In order to determine what the data (rather than what our biases) may tell us, accurate comparisons of published reports in this field require an appreciation of the reasons for different results in different laboratories. Therefore, before we compare data, let's consider some of the reasons why results from different laboratories may differ. The periodontal flora is complex. We have found over 325 distinct bacterial species in the human gingival crevice (1). Many of these species have never been formally described, most of them are ignored by some laboratories, identified differently by others, or lumped together in various groups by still others. Some of the predominant species have special growth requirements and are not detected on some media that are widely used. Identification criteria differ among laboratories. Even with rigorous testing, identification of some species is questionable. With minimal testing it is even less reliable.
Coarse-Grained (Multiscale) Simulations in Studies of Biophysical and Chemical Systems (2011)

Recent years have witnessed an explosion in computational power, leading to attempts to model ever more complex systems. Nevertheless, there remain cases for which the use of brute-force computer simulations is clearly not the solution. In such cases, great benefit can be obtained from the use of physically sound simplifications. The introduction of such coarse graining can be traced back to the early usage of a simplified model in studies of proteins. Since then, the field has progressed tremendously. In this review, we cover both key developments in the field and potential future directions. Additionally, particular emphasis is given to two general approaches, namely the renormalization and reference potential approaches, which allow one to move back and forth between the coarse-grained (CG) and full models, as these approaches provide the foundation for CG modeling of complex systems.
Lack of the purinergic receptor P2X7 results in resistance to contact hypersensitivity (2010)

Sensitization to contact allergens requires activation of the innate immune system by endogenous danger signals. However, the mechanisms through which contact allergens activate innate signaling pathways are incompletely understood. In this study, we demonstrate that mice lacking the adenosine triphosphate (ATP) receptor P2X(7) are resistant to contact hypersensitivity (CHS). P2X(7)-deficient dendritic cells fail to induce sensitization to contact allergens and do not release IL-1β in response to lipopolysaccharide (LPS) and ATP. These defects are restored by pretreatment with LPS and alum in an NLRP3- and ASC-dependent manner. Whereas pretreatment of wild-type mice with P2X(7) antagonists, the ATP-degrading enzyme apyrase or IL-1 receptor antagonist, prevents CHS, IL-1β injection restores CHS in P2X(7)-deficient mice. Thus, P2X(7) is a crucial receptor for extracellular ATP released in skin in response to contact allergens. The lack of P2X(7) triggering prevents IL-1β release, which is an essential step in the sensitization process. Interference with P2X(7) signaling may be a promising strategy for the prevention of allergic contact dermatitis.
Targeted Disruption of the Insl3 Gene Causes Bilateral Cryptorchidism (1999)

The sexual dimorphic position of the gonads in mammals is dependent on differential development of two ligaments, the cranial suspensory ligament (CSL) and the gubernaculum. During male embryogenesis, outgrowth of the gubernaculum and regression of the CSL result in transabdominal descent of the testes, whereas in the female, development of the CSL in conjunction with failure of the gubernaculum development holds the ovaries in a position lateral to the kidneys. Several lines of evidence suggest that regression of the CSL and induction of gubernaculum development are mediated by testosterone and a yet unidentified testicular factor, respectively. The Insl3 gene (originally designated Ley I-L), a member of the insulin-like superfamily, is specifically expressed in Leydig cells of the fetal and postnatal testis and in theca cells of the postnatal ovary. Here we show that male mice homozygous for a targeted deletion of the Insl3 locus exhibit bilateral cryptorchidism with free moving testes and genital ducts. These malformations are due to failure of gubernaculum development during embryogenesis. In double-mutant male mice for Insl3 and androgen receptor genes, testes are positioned adjacent to the kidneys and steadied in the abdomen by the CSL. These findings demonstrate, that the Insl3 induces gubernaculum development in an androgen-independent way, while androgen-mediated regression of the CSL occurs independently from Insl3.
Population Dynamics of Bone Marrow B Lymphocytes (1986)

The dynamic concepts of lymphocyte populations which heralded the era of modern cellular immunobiology have been generally substantiated by recent studies and are still being correlated with functional properties. B lineage cells in the bone marrow are dynamically heterogeneous: A large majority are newly-formed, rapidly renewed cells, continuously produced from precursor cells within the bone marrow and disseminated during a terminal maturation phase via the blood stream. These cells develop low densities of sIgM in the extravascular bone marrow parenchyma and may undergo some further maturation within bone marrow sinusoids. The rate of production of bone marrow B cells appears to depend partly on the total load of exogenous agents to which the individual is exposed. Bone marrow lymphocyte production maintains a population of rapidly renewed virgin B cells in the peripheral lymphoid tissues. A small proportion of these cells apparently may be selected to enter a long-lived pool of B cells if suitably activated. By continuously creating novel clonotypes this process potentially can anticipate new antigen challenges and allow the immune system to build up a repertoire of antigen specificities most appropriate to the individual's changing environment throughout life. A minority of B lymphocytes in the bone marrow comprises slowly renewed, long-lived cells which enter and leave the bone marrow parenchyma as a selective part of the recirculating lymphocyte pool in the blood stream. Their role in the bone marrow is unknown. They include antigen-specific B memory cells, yet these are not activated within the bone marrow itself. No regulatory role has yet been directly demonstrated. Recently activated B cells enter from the spleen after secondary antigenic stimulation to develop into antibody-producing cells within the bone marrow. In assessing the significance of any phenotypically or functionally distinct B cell subset in the bone marrow, a basic consideration is to assign the subset to one of the foregoing dynamic categories. Within a given category cells may represent one stage in a time sequence of development. The bone marrow also produces lymphocytes of as yet uncertain lineage and contains selected subsets of T cells. The roles of these cells in cytotoxic, regulatory, or other events remain to be elucidated.
No Evidence for Tumorigenesis of AAV Vectors in a Large-Scale Study in Mice (2005)

Six hundred ninety-five mice received adeno-associated virus (AAV) vectors, mostly via portal vein injection. At necropsy, the livers were inspected for tumors, and tissue sections were prepared for histology. We observed only one tumor, a lipoma, resulting in a tumor frequency of 0.14%. This tumor contained fewer vector genomes per total DNA than the surrounding liver tissue, as shown by quantitative PCR. In another mouse we found a macroscopically visible nodule containing lymphocytes. Immunohistochemistry revealed cells not of monoclonal origin, and they contained fewer AAV genomes than the surrounding hepatocytes. There were no macroscopic tumors in 226 control mice. Upon microscopic examination, lymphocytic infiltrates were found in 5% of livers of both control and vector-treated mice; no transgene expression was seen in those infiltrates in AAV-injected animals. Compared to an average frequency of spontaneous liver tumors in C57BL/6 mice (0-10%), and given the absence of high levels of vector DNA in the observed tumor, we conclude that AAV vectors do not predispose these target animals to the formation of liver tumors.
Hybrid Cytomegalovirus Enhancer–H1 Promoter-Based Plasmid and Baculovirus Vectors Mediate Effective RNA Interference (2005)

Plasmid and viral vectors harboring an RNA polymerase (Pol) III promoter would be useful in achieving sustained cellular expression of short interfering RNA (siRNA) to inhibit disease-associated genes. Given that transcription machineries directed by certain Pol II and III promoters may use common factors, we investigated whether the enhancer of the Pol II cytomegalovirus (CMV) immediate-early promoter could improve the efficacy of RNA interference mediated by the Pol III H1 promoter. We constructed a hybrid promoter by appending the CMV enhancer 5' to the H1 promoter. In the context of plasmid vectors, the hybrid promoter provided up to 50% greater inhibition of the expression of target genes than the unmodified H1 promoter and extended the silencing effect beyond that provided by the H1 promoter. Insect baculoviruses can infect a broad range of mammalian cell types. We constructed a baculovector expression cassette in which the synthesis of short hairpin RNA was under the control of the hybrid CMV enhancer-H1 promoter. This recombinant baculovirus vector was capable of suppressing expression of a target gene by 95% in cultured cells and by 82% in vivo in rat brain. These findings indicate that the hybrid CMV enhancer-H1 promoter can be used favorably for RNA interference.
Production of the Escherichia coli betaine‐aldehyde dehydrogenase, an enzyme required for the synthesis of the osmoprotectant glycine betaine, in transgenic plants (1994)

In several organisms osmotic stress tolerance is mediated by the accumulation of the osmoprotective compound glycine betaine. With the ambition to transfer the betaine biosynthetic pathway into plants not capable of synthesizing this osmoprotectant, the Escherichia coli gene betB encoding the second enzyme in the pathway, betaine-aldehyde dehydrogenase was introduced into Nicotiana tabacum. The betB structural gene was fused to the promoter of ats1a, a gene coding for the small subunit of Rubisco in Arabidopsis thaliana. Two types of constructs were made, either encoding the N-terminal transit peptide for chloroplast targeting or without the targeting signal for cytoplasmic localization of the BetB polypeptide. Analysis of transgenic N. tabacum plants harboring these constructs showed that in both cases the transgenes were expressed. Northern analysis of the plants demonstrated the accumulation of betB-related mRNA of the correct size. The production and processing of the corresponding polypeptides could be demonstrated by immunoblotting using polyclonal antisera raised against the BetB polypeptide. The transit peptide encoded by ats1a was able to direct BetB to the chloroplast, as suggested by the presence of the correctly processed BetB polypeptide in the chloroplast fraction. High betaine-aldehyde dehydrogenase activity was detected in transgenic plants, both in those where the chimeric gene product was targeted to the chloroplast and those where it remained in the cytoplasm. The transgenic tobacco acquired resistance to the toxic intermediate, betaine aldehyde, in the betaine biosynthetic pathway indicating that the bacterial enzyme is biologically active in its new host. Furthermore, these transgenic plants were able to convert exogenously supplied betaine aldehyde efficiently to glycine betaine.
Resolution scaling in STED microscopy (2008)

We undertake a comprehensive study of the inverse square root dependence of spatial resolution on the saturation factor in stimulated emission depletion (STED) microscopy and generalize it to account for various focal depletion patterns. We used an experimental platform featuring a high quality depletion pattern which results in operation close to the optimal optical performance. Its superior image brightness and uniform effective resolution <25 nm are evidenced by imaging both isolated and self-organized convectively assembled fluorescent beads. For relevant saturation values, the generalized square-root law is shown to predict the practical resolution with high accuracy.
Genotypic identification of mycobacteria by nucleic acid sequence determination: report of a 2-year experience in a clinical laboratory (1993)

Clinical isolates of Mycobacterium spp. were identified by direct sequence determination of 16S rRNA gene fragments amplified by polymerase chain reaction. Identification was based on a hypervariable region within the 16S rRNA gene in which mycobacterial species are characterized by species-specific nucleotide sequences. A manually aligned data base including the signature sequences of 52 species of mycobacteria easily allowed rapid and correct identification. The results of this study demonstrate that polymerase chain reaction-mediated direct sequence determination can be used as a rapid and reliable method for the identification of mycobacteria in the clinical laboratory. In addition, the prompt recognition of previously undescribed species is now feasible.
Tumor Necrosis Factor α and Interleukin-1α Stimulate Late Shedding of p75 TNF Receptors but Not p55 TNF Receptors from Human Monocytes (1995)

Soluble receptors for TNF (sTNF-R) are present at elevated concentrations in the synovial fluid of patients with rheumatoid arthritis. They are presumably released by cells of the synovial membrane, including the monocyte-derived synovial macrophages. Cytokines from the synovium, including IL-1 and TNF-alpha, may stimulate release. We therefore examined the release of sTNF-R from monocytes exposed to IL-1 and TNF-alpha. Elutriator-purified human blood monocytes spontaneously released both the p75 and the p55 sTNF-R (1011 +/- 199 and 177 +/- 20 pg/10(6) cells, respectively, mean +/- SEM) during 48 h of in vitro culture. TNF-alpha and IL-1 alpha induced time- and concentration-dependent increases in the release of sTNF-R75 from monocytes, but neither had a measurable effect on the release of sTNF-R55. The release of sTNF-R75 was inhibited by cycloheximide. Neither lymphocytes nor polymorphonuclear leukocytes (PMN) released measurable sTNF-R spontaneously or in response to stimulation with IL-1 alpha, but TNF-alpha stimulated the release of small amounts of sTNF-R75 by PMN. The timing, cycloheximide sensitivity, and selectivity of stimulated release of TNF-R75 by monocytes are consistent with previous observations on other cell types of late (8-20 h) increased synthesis and turnover of cell surface TNF-R75, but not TNF-R55, after stimulation with TNF-alpha or IL-1. These observations help to explain why elevated levels of sTNF-R in synovial fluid coexist with enhanced expression of cell surface TNF-R on synovial macrophages in rheumatoid arthritis.
The Koch monopole: a small fractal antenna (2000)

Fractal objects have some unique geometrical properties. One of them is the possibility to enclose in a finite area an infinitely long curve. The resulting curve is highly convoluted being nowhere differentiable. One such curve is the Koch curve. In this paper, the behavior the Koch monopole is numerically and experimentally analyzed. The results show that as the number of iterations on the small fractal Koch monopole are increased, the Q of the antenna approaches the fundamental limit for small antennas.
Future hepatitis C virus treatment: interferon‐sparing combinations (2011)

An estimated million people have chronic hepatitis C virus (HCV) infection. With current treatment success rates, by 2030, more than 40% will be cirrhotic and the number of cases with end-stage liver disease is projected to treble. Current standard-of-care is the combination of pegylated interferon plus ribavirin for 24-48 weeks. Unfortunately this is associated with poor efficacy (45% in HCV GT1; 75% in GT2 and 65% in GT 3) and tolerability. Many patients are either unsuitable for or decline current treatment infection because of the significant side-effects associated with this treatment, including those with decompensated cirrhosis or sever psychiatric illness. It is hoped that the development of direct acting antiviral agents (DAAs) will address this huge unmet medical need. The addition of a protease inhibitor to pegylated interferon plus ribavirin is associated with increase in efficacy and shortened duration of therapy in patients with HCV GT1 and is likely to become the new standard-of-care. However, triple therapy will not be suitable for patients with non-1 HCV infection, or contraindications to interferon. It is hoped that the combination of multiple DAAs which target different steps of HCV replication should provide interferon-free treatment regimen. Current and planned studies will determine which combination (protease, nonnucleoside polymerase, nucleoside polymerase, NS5A, cyclophyllin B inhibitors), how many DAAs and duration of therapy will be required to optimise cure. It will also be important to minimise the emergence of multi-resistance, which would jeopardise future retreatment options.
Cardiac Dyssynchrony Analysis Using Circumferential Versus Longitudinal Strain (2005)

Dyssynchrony assessed by longitudinal motion is less sensitive to dyssynchrony, follows different time courses than those from circumferential motion, and may manifest CRT benefit during specific cardiac phases depending on pacing mode. These results highlight potential limitations to epsilonll-based analyses and support further efforts to develop noninvasive synchrony measures based on circumferential deformation.