gebhart/patrepeval huggingface dataset:
Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA (2013)

Due to their immunomodulatory properties, mesenchymal stem cells (MSC) are interesting candidates for cellular therapy for autoimmune disorders, graft-versus-host disease and allograft rejection. MSC inhibit the proliferation of effector T cells and induce T cells with a regulatory phenotype. So far it is unknown whether human MSC-induced CD4(+) CD25(+) CD127(-) forkhead box P3 (FoxP3)(+) T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (nT(reg)). Perirenal adipose-tissue derived MSC (ASC) obtained from kidney donors induced a 2·1-fold increase in the percentage of CD25(+) CD127(-) FoxP3(+) cells within the CD4(+) T cell population from allostimulated CD25(-/dim) cells. Interleukin (IL)-2 receptor blocking prevented this induction. The ASC-induced T cells (iT(reg)) inhibited effector cell proliferation as effectively as nT(reg). The vast majority of cells within the iT(reg) fraction had a methylated FOXP3 gene T(reg)-specific demethylated region (TSDR) indicating that they were not of nT(reg) origin. In conclusion, ASC induce T(reg) from effector T cells. These iT(reg) have immunosuppressive capacities comparable to those of nT(reg). Their induction is IL-2 pathway-dependent. The dual effect of MSC of inhibiting immune cell proliferation while generating de-novo immunosuppressive cells emphasizes their potential as cellular immunotherapeutic agent.
Proteins pinpoint double strand breaks (2013)

Combining green fluorescent protein with a protein that only binds to double strand breaks in DNA allows these breaks-which are an important form of DNA damage-to be detected with high efficiency in living bacteria.
Structure-based model for light-harvesting properties of nucleic acid nanostructures (2013)

Programmed self-assembly of DNA enables the rational design of megadalton-scale macromolecular assemblies with sub-nanometer scale precision. These assemblies can be programmed to serve as structural scaffolds for secondary chromophore molecules with light-harvesting properties. Like in natural systems, the local and global spatial organization of these synthetic scaffolded chromophore systems plays a crucial role in their emergent excitonic and optical properties. Previously, we introduced a computational model to predict the large-scale 3D solution structure and flexibility of nucleic acid nanostructures programmed using the principle of scaffolded DNA origami. Here, we use Förster resonance energy transfer theory to simulate the temporal dynamics of dye excitation and energy transfer accounting both for overall DNA nanostructure architecture as well as atomic-level DNA and dye chemical structure and composition. Results are used to calculate emergent optical properties including effective absorption cross-section, absorption and emission spectra and total power transferred to a biomimetic reaction center in an existing seven-helix double stranded DNA-based antenna. This structure-based computational framework enables the efficient in silico evaluation of nucleic acid nanostructures for diverse light-harvesting and photonic applications.
Preliminary Experience of the Spanish Compassionate Use Registry of Bendamustine in Patients with Relapsed and/or Refractory Multiple Myeloma (2012)

Abstract Abstract 4035 Introduction: Bendamustine is a dual alkylating agent with demonstrated efficacy in de novo multiple myeloma (MM) and in relapsed/refractory (R/R MM). We present the preliminary results from the experience of Spanish compassionate use registry of this agent in different treatment schedules of R/R MM, promoted by the GEM/PETHEMA Group (Benda-MMRR-11). This study has been approved by local ethical committee, CEIC, HUP, Madrid, Spain. Patients and Methods: 72 patients, 42 males and 30 females, with advanced R/R MM after several lines of previous treatment received a schedule containing Bendamustine (Levact®, Mundipharma, UK). Median age was 66 (35–86), with a median of 4 previous salvage lines (1–11). Bendamustine dose used ranged between 60 and 120 mg/m2 iv on days 1 and 2 for each 28 days cycle. The median of cycles was 2 (1–9). The combinations used were: Bendamustine + Prednisone in 27 patients, Bendamustine + Thalidomide + Prednisone in 11 cases, Bendamustine + Dexamethasone in 14 patients, Bendamustine + Bortezomib + Dexamethasone in 7 patients, Bendamustine + Bortezomib + Prednisone in 3 patients, Bendamustine + Thalidomide + Dexamethasone in 2 cases, Bendamustine monotherapy in 5 patients, Bendamustine + Thalidomide in 1 case, Bendamustine with Caelyx in 1 case and Bendamustine with Rituximab in 1 case. Results: In the 69 evaluable patients, the response was: overall response rate (ORR) 30.24%%, with complete response (CR) 11.5%, partial response (PR) 13.04%. Minimal response (MR) was 5.7%, and stable disease (SD) was 17.39%. Progression was documented in 52.1% of patients. In general, treatment was well tolerated; the most common adverse effect was hematological toxicity with grade 3–4 neutropenia in 31.8%, grade 3–4 thrombocytopenia in 30.4% and grade 3–4 anemia in 17.3%. Other toxicities included grade 3–4 infections in 27% of patients and grade 3–4 asthenia in 11.5%. Clinical results will be updated with more details regarding TTP, OS and efficacy and toxicity with each schedule. Comments: Bendamustine is an effective salvage therapy in patients with advanced R/R MM. Our results are consistent with previous published data in larger series of patients. More experience is needed with this agent to define the best combination and to assess its grade of efficacy that will be probably superior in earlier stages of myeloma evolution. Disclosures: Off Label Use: compassionate use.
Apoptosis of Rat Vascular Smooth Muscle Cells Is Regulated by p53-Dependent and -Independent Pathways (1995)

Apoptosis of vascular smooth muscle cells has recently been described in culture and also in remodeling of the artery after birth. However, the genes that regulate apoptosis in smooth muscle cells are mostly unknown. We studied the regulation of apoptosis in rat smooth muscle cells stably infected with retrovirus constructs containing c-myc, adenovirus E1A, bcl-2, and a temperature-sensitive mutant of the tumor suppressor gene p53. Apoptosis was verified by electron microscopy and quantified by time-lapse videomicroscopy. Death was induced by c-myc and E1A when cells were deprived of serum survival factors, bcl-2 suppressed apoptosis of cells infected with c-myc and E1A and also normal smooth muscle cells. Overexpression of wild-type p53 induced apoptosis of cells infected with E1A and c-myc but not normal cells. In contrast, expression of mutant p53, which blocks wild-type p53 function, suppressed apoptosis of cells infected with E1A or c-myc but not normal cells. Both adenovirus E1A and c-myc increased the expression of endogenous p53 protein but not p53 mRNA. Although bcl-2 suppressed apoptosis induced by E1A and c-myc, upregulation of p53 protein induced by these agents was unaffected. We conclude that apoptosis of vascular smooth muscle cells is regulated by p53-dependent and -independent pathways. Death induced by c-myc and E1A is mediated by, and dependent on, p53. However, the suppression of apoptosis by bcl-2 is not mediated by changes in p53 expression, and the low level of apoptosis seen in normal VSMCs upon removal of survival factors is independent of p53.
Extracellular matrix regulates Sertoli cell differentiation, testicular cord formation, and germ cell development in vitro. (1985)

Sertoli cell preparations isolated from 10-day-old rats were cultured on three different substrates: plastic, a matrix deposited by co-culture of Sertoli and peritubular myoid cells, and a reconstituted basement membrane gel from the EHS tumor. When grown on plastic, Sertoli cells formed a squamous monolayer that did not retain contaminating germ cells. Grown on the matrix deposited by Sertoli-myoid cell co-cultures, Sertoli cells were more cuboidal and supported some germ cells but did not allow them to differentiate. After 3 wk however, the Sertoli cells flattened to resemble those grown on plastic. In contrast, the Sertoli cells grown on top of the reconstituted basement membrane formed polarized monolayers virtually identical to Sertoli cells in vivo. They were columnar with an elaborate cytoskeleton. In addition, they had characteristic basally located tight junctions and maintained germ cells for at least 5 wk in the basal aspect of the monolayer. However, germ cells did not differentiate. Total protein, androgen binding protein, transferrin, and type I collagen secretion were markedly greater when Sertoli cells were grown on the extracellular matrices than when they were grown on plastic. When Sertoli cells were cultured within rather than on top of reconstituted basement membrane gels they reorganized into cords. After one week, tight junctional complexes formed between adjacent Sertoli cells, functionally compartmentalizing the cords into central (adluminal) and peripheral (basal) compartments. Germ cells within the cords continued to differentiate. Thus, Sertoli cells cultured on top of extracellular matrix components assume a phenotype and morphology more characteristic of the in vivo, differentiated cells. Growing Sertoli cells within reconstituted basement membrane gels induces a morphogenesis of the cells into cords, which closely resemble the organ from which the cells were dissociated and which provide an environment permissive for germ cell differentiation.
Tissue‐engineered skin substitutes: from in vitro constructs to in vivo applications (2004)

The field of skin tissue engineering is a paradigm for the various efforts towards the reconstruction of other tissues and organ substitutes. As skin replacement, this biotechnological approach has evolved from simple cultured autologous epidermal sheets to more complex bilayered cutaneous substitutes. The various types of such substitutes are herein presented with their intended use. However, two integrative characteristics are analysed more specifically because of their critical role: neovascularization and re-innervation. Furthermore, the in vitro use of these various skin substitutes has shed light on various physiological and pathological phenomena. Thus, not only the in vivo application of these skin substitutes as grafts, but also their in vitro value as skin models, are presented.
Chimeric L1-L2 Virus-Like Particles as Potential Broad-Spectrum Human Papillomavirus Vaccines (2009)

The amino (N) terminus of the human papillomavirus (HPV) minor capsid protein L2 can induce low-titer, cross-neutralizing antibodies. The aim of this study was to improve immunogenicity of L2 peptides by surface display on highly ordered, self-assembled virus-like particles (VLP) of major capsid protein L1, and to more completely characterize neutralization epitopes of L2. Overlapping peptides comprising amino acids (aa) 2 to 22 (hereafter, chimera or peptide 2-22), 13 to 107, 18 to 31, 17 to 36, 35 to 75, 75 to 112, 115 to 154, 149 to 175, and 172 to 200 of HPV type 16 (HPV16) L2 were genetically engineered into the DE surface loop of bovine papillomavirus type 1 L1 VLP. Except for chimeras 35-75 and 13-107, recombinant fusion proteins assembled into VLP. Vaccination of rabbits with Freund's adjuvanted native VLP induced higher L2-specific antibody titers than vaccination with corresponding sodium dodecyl sulfate-denatured proteins. Immune sera to epitopes within residues 13 to 154 neutralized HPV16 in pseudovirion neutralization assays, whereas chimera 17-36 induced additional cross-neutralization to divergent high-risk HPV18, -31, -45, -52, and -58; low-risk HPV11; and beta-type HPV5 (titers of 50 to 10,000). Aluminum hydroxide-monophosphoryl lipid A (Alum-MPL)-adjuvanted VLP induced similar patterns of neutralization in both rabbits and mice, albeit with 100-fold-lower titers than Freund's adjuvant. Importantly, Alum-MPL-adjuvanted immunization with chimeric HPV16L1-HPV16L2 (peptide 17-36) VLP induced neutralization or cross-neutralization of HPV16, -18, -31, -45, -52, and -58; HPV6 and -11; and HPV5 (titers of 50 to 100,000). Immunization with HPV16 L1-HPV16 L2 (chimera 17-36) VLP in adjuvant applicable for human use induces broad-spectrum neutralizing antibodies against HPV types evolutionarily divergent to HPV16 and thus may protect against infection with mucosal high-risk, low-risk, and beta HPV types and associated disease.
Controlled Release of Guest Molecules from Mesoporous Silica Particles Based on a pH‐Responsive Polypseudorotaxane Motif (2007)

Stringing them along: The pores of a mesoporous silica particle were filled with guest molecules and then blocked by threading cyclodextrin molecules (CDs) onto the surface-grafted polyethylenimine (PEI) chains at pH 11. At pH 5.5, the guest molecules can be released from the pores of the particle by reversible dethreading of the CDs from the PEI chains. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z603404_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
A Selective Allosteric Potentiator of the M1Muscarinic Acetylcholine Receptor Increases Activity of Medial Prefrontal Cortical Neurons and Restores Impairments in Reversal Learning (2009)

M(1) muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M(1) receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increases M(1) receptor affinity for acetylcholine. We found that activation of the M(1) receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M(1) receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M(1) receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M(1) receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M(1) mAChR subtype may ameliorate impairments in cognitive function.
Potential significance of the cellular immune response against the macaque strain of simian immunodeficiency virus (SIVMAC) in immunized and infected rhesus macaques (1992)

The cellular immune response of seven rhesus macaques immunized with Tween-ether-treated macaque strain of simian immunodeficiency virus (SIVMAC) and three non-vaccinated control animals was investigated. Immunization elicited antigen-specific proliferating CD4+ cells in five of seven monkeys. Proliferating T cells were found in all animals protected from a first virus challenge. Cytotoxic T lymphocytes (CTLs) were not induced by the immunization. After the second challenge, the four formerly protected animals became infected, despite a strong proliferative CD4+ cell activity in three of them. All animals lost their proliferative activity 2 weeks after infection. After the first challenge four of the six infected animals exhibited a CTL response and after the second challenge, one of four newly infected macaques acquired a CTL response. The five animals with a CTL activity against SIVMAC proteins were protected from severe thrombocytopenia, which appeared in the five CTL-negative animals after infection. Our data show the induction of proliferative T cells by immunization with soluble SIVMAC antigen. This T cell reactivity was found in all animals protected from the first virus challenge, but did not confer protection from the second challenge. Interestingly, the proliferative T cell reactivity disappeared 2 weeks after virus infection. Furthermore a CTL response against viral proteins seems to protect infected animals from severe thrombocytopenia which is an early sign of AIDS in monkeys.
Barth syndrome (2013)

Barth syndrome (BTHS) is an X-linked recessive disorder that is typically characterized by cardiomyopathy (CMP), skeletal myopathy, growth retardation, neutropenia, and increased urinary levels of 3-methylglutaconic acid (3-MGCA). There may be a wide variability of phenotypes amongst BTHS patients with some exhibiting some or all of these findings. BTHS was first described as a disease of the mitochondria resulting in neutropenia as well as skeletal and cardiac myopathies. Over the past few years, a greater understanding of BTHS has developed related to the underlying genetic mechanisms responsible for the disease. Mutations in the TAZ gene on chromosome Xq28, also known as G4.5, are responsible for the BTHS phenotype resulting in a loss-of-function in the protein product tafazzin. Clinical management of BTHS has also seen improvement. Patients with neutropenia are susceptible to life-threatening bacterial infections with sepsis being a significant concern for possible morbidity and mortality. Increasingly, BTHS patients are suffering from heart failure secondary to their CMP. Left ventricular noncompaction (LVNC) and dilated CMP are the most common cardiac phenotypes reported and can lead to symptoms of heart failure as well as ventricular arrhythmias. Expanded treatment options for end-stage myocardial dysfunction now offer an opportunity to change the natural history for these patients. Herein, we will provide a current review of the genetic and molecular basis of BTHS, the clinical features and management of BTHS, and potential future directions for therapeutic strategies.
From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements (2006)

The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous--in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known artemisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t(1/2) 26 min, and at pH 7.4, t(1/2) is about 10 hours. With a pK(a) of 4.6, over 99% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of artemisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the 'druggability' of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristic of the current derivatives, and enhance absorption, by and large has not been considered. A review of the various types of newer derivatives is given together with a consideration of medicinal chemistry aspects.
Syk Protein-tyrosine Kinase Is Regulated by Tyrosine-phosphorylated Iga/Ig/3 Immunoreceptor Tyrosine Activation Motif Binding and Autophosphorylation (1995)

Syk is a cytoplasmic protein-tyrosine kinase containing two amino-terminal Src homology 2 domains that is activated following ligation of the B cell antigen receptor. Syk activation in B cells correlates with Syk tyrosine phosphorylation as well as with Syk SH2-mediated association with the tyrosine-phosphorylated Ig alpha and Ig beta B cell antigen receptor subunits. Tyrosine-phosphorylated peptide 20-mers representing Ig alpha and Ig beta immunoreceptor tyrosine activation motifs were synthesized and found to stimulate the specific activity of Syk by as much as 10-fold in vitro. Maximal phosphopeptide-induced Syk activation required both Syk SH2 domains and phosphorylation of both tyrosine residues present in the immunoreceptor tyrosine activation motif. The biochemical mechanism responsible for the phosphopeptide-induced Syk enzyme activation appears to be a function of Syk autophosphorylation. Our observations suggest the association of Syk tandem SH2 domains with the tyrosine-phosphorylated Ig alpha and/or Ig beta immunoreceptor tyrosine activation motifs in B cells stimulates Syk autophosphorylation leading to Syk enzyme activation.
Modular structure of genes encoding multifunctional peptide synthetases required for non-ribosomal peptide synthesis (1995)

Peptide synthetases are large multienzyme complexes that catalyze the non-ribosomal synthesis of a structurally diverse family of bioactive peptides. They possess a multidomain structure and employ the thiotemplate mechanism to activate, modify and link together by amide or ester bonds the constituent amino acids of the peptide product. The domains, which represent the functional building units of peptide synthetases, appear to act as independent enzymes whose specific linkage order forms the protein-template that defines the sequence of the incorporated amino acids. Two types of domains have been characterized in peptide synthetases of bacterial and fungal origin: type I comprises about 600 amino acids and contains at least two modules involved in substrate recognition, adenylation and thioester formation, whereas type II domains carry in addition an insertion of about 430 amino acids that may function as a N-methyltransferase module. The role of other genes associated with bacterial opérons encoding peptide synthetases is also discussed.