gebhart/patrepeval huggingface dataset:
Controlled Delivery of Plasmid DNA and siRNA to Intracellular Targets Using Ketalized Polyethylenimine (2008)

A new polyethylenimine (PEI)-derived biodegradable polymer was synthesized as a nonviral gene carrier. Branches of PEI were ketalized, and capabilities of nucleic acid condensation and delivery efficiency of the modified polymers were compared with ones of unketalized PEI. Ketalized PEI was able to efficiently compact both plasmid DNA and siRNA into nucleic acids/ketalized PEI polyplexes with a range of 80-200 nm in diameter. Nucleic acids were efficiently dissociated from the polyplexes made of ketalized PEI upon hydrolysis. In vitro study also demonstrated that ketalization enhanced transfection efficiency of the polyplexes while reducing cytotoxicity, even at high N/ P ratios. Interestingly, transfection efficiency was found to be inversely proportional to molecular weights of ketalized PEI, while RNA interference was observed in the opposite way. This study implies that selective delivery of plasmid DNA and siRNA to the nucleus and the cytoplasm can be achieved by tailoring the structures of polymeric gene carriers.
Toward nonpeptidal substance P mimetic analogues: Design, synthesis, and biological activity (1991)

1,4-Piperazine and 4-hydroxyproline, two small cyclic polyfunctional systems with defined stereochemistry, were introduced as "molecular scaffolds." We define a "bioactive topology," which is a derived putative low-energy conformation obtained through theoretical conformational analysis of substance P. Substitution of these molecular scaffolds by pharmacophors characteristic of the bioactive topology of the C-terminal hexapeptide of substance P resulted in active, partially nonpeptidal substance P mimetic agonists. The study discusses the concepts and tools used to achieve this structural transformation, and points out the need to address flexibility-rigidity issues in an attempt to maintain sufficient molecular plasticity.
Estrogen Biphasically Modifies Hypothalamic GABAergic Function Concomitantly with Negative and Positive Control of Luteinizing Hormone Release (2001)

The principal role of estrogen is its control of the female ovulatory cycle via negative and positive feedback on gonadotropin secretion. However, a detailed, cohesive picture of how the steroid specifically regulates the excitability of hypothalamic neurons involved in the central control of gonadotropin secretion is still emerging. Here, we used an ovariectomized female guinea pig model to test the hypothesis that estrogen acts on GABAergic neurons in the preoptic area (POA) to elicit a biphasic profile of luteinizing hormone (LH) secretion. Intracellular electrophysiological recordings revealed that estradiol benzoate (EB; 25 microgram, s.c.) decreased the hyperpolarizing response of GABAergic neurons to the GABA(B) receptor agonist baclofen 24 hr after treatment. This effect of GABA(B) receptor stimulation in unidentified POA neurons was still depressed 42 hr after EB administration. By the use of a ribonuclease protection assay, however, EB reduced glutamic acid decarboxylase mRNA expression 42 hr but not 24 hr after its administration. Thus, estrogen attenuated the autoinhibition of GABAergic POA neurons during the initial LH suppressive (i.e., negative feedback) phase and subsequently reduced GABAergic function during the LH surge (i.e., positive feedback). These studies demonstrate that the effects of estrogen on hypothalamic GABAergic neurons coincide with the inhibitory and stimulatory actions, respectively, of the steroid on LH secretion. Furthermore, the data provide novel insights into the mechanism by which estrogen regulates hypothalamic GABAergic neurons, which are critical for the biphasic modulation of LH release observed over the course of the female ovulatory cycle.
Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity (1997)

The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.
The Formation of Amphotericin B Ion Channels in Lipid Bilayers (1997)

The ability of amphotericin B (AmB) to form ion-permeable channels in cholesterol containing lipid bilayers was studied by UV/visible absorbance, circular dichroism, and fluorescence spectroscopy. Stable liposomes composed of distearoylphosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, and AmB were prepared so that a wide range of AmB concentrations in the bilayer could be studied. Singular value decomposition analysis (Henry & Hofrichter, 1992) of the circular dichroism spectra of AmB at different AmB/lipid ratios suggests that AmB exists primarily in only two states in the bilayer, a "monomeric" state and an "aggregated" state. The transition from the "monomeric" to the "aggregated" state begins to occur at a critical concentration of 1 AmB per 1000 lipids in the membrane and coincides with the appearance of channel activity. The data support the recent theoretical conclusions of Weakliem et al. (1995) which predict that pore formation in the lipid bilayer will occur when the drug molecule concentration exceeds a critical value. At this critical concentration, it is calculated that a minimum number of 16 AmB molecules per liposome are required to observe channel activity. The results are consistent with the sterol-dependent AmB channel models proposed by de Kruijff and Demel (1974), Andreoli (1974), and Khutorsky (1992). To further elucidate the effects of sterol on AmB-mediated channel formation, liposomes were prepared with varying ratios of cholesterol and AmB. At cholesterol mole percentages greater than 1, channel activity was observed to occur at AmB concentrations just above the critical value. Previous reports show that cholesterol forms "tail-to-tail" dimers at mole percentages greater than 2 (Harris et al., 1995). This suggests that formation of the bilayer-spanning channels by AmB is initiated most efficiently when the tail-to-tail dimer of cholesterol is present. Although the structural nature of the AmB channel could not be unambiguously determined, these experiments provide further evidence in support of the widely held view that AmB's primary mechanism of killing fungal cells occurs by forming ion-permeable channels.
Artificial cloning of domestic animals (2015)

Domestic animals can be cloned using techniques such as embryo splitting and nuclear transfer to produce genetically identical individuals. Although embryo splitting is limited to the production of only a few identical individuals, nuclear transfer of donor nuclei into recipient oocytes, whose own nuclear DNA has been removed, can result in large numbers of identical individuals. Moreover, clones can be produced using donor cells from sterile animals, such as steers and geldings, and, unlike their genetic source, these clones are fertile. In reality, due to low efficiencies and the high costs of cloning domestic species, only a limited number of identical individuals are generally produced, and these clones are primarily used as breed stock. In addition to providing a means of rescuing and propagating valuable genetics, somatic cell nuclear transfer (SCNT) research has contributed knowledge that has led to the direct reprogramming of cells (e.g., to induce pluripotent stem cells) and a better understanding of epigenetic regulation during embryonic development. In this review, I provide a broad overview of the historical development of cloning in domestic animals, of its application to the propagation of livestock and transgenic animal production, and of its scientific promise for advancing basic research.
Rat cellular retinol-binding protein II: use of a cloned cDNA to define its primary structure, tissue-specific expression, and developmental regulation. (1986)

The primary structure of rat cellular retinol-binding protein (CRBP) II has been determined from a cloned cDNA. Alignment of this 134-amino acid, 15,580-Da polypeptide with rat CRBP revealed that 75 of 133 comparable residues are identical. Both proteins contain four tryptophan residues, which occupy identical relative positions in the two primary structures, providing a structural explanation for their similar fluorescence spectra when complexed to retinol. Two of the three cysteines in each single-chain protein are comparably positioned. Both polypeptides contain reactive thiol groups, but the rate of disruption of CRBP II-retinol complexes by p-chloromercuribenzoate is greater than that of CRBP-retinol. The small intestine contains the highest concentrations of CRBP II mRNA in adult rats. CRBP II mRNA is first detectable in intestinal RNA during the 19th day of gestation, a time that corresponds to the appearance of an absorptive columnar epithelium. Unlike in intestine, a dramatic fall in liver CRBP II mRNA concentration occurs immediately after birth. The CRBP II gene remains quiescent in the liver during subsequent postnatal development. These data suggest that ligand-protein interactions may be somewhat different for the two rat CRBPs. They also support the concept that CRBP II plays a role in the intestinal absorption or esterification of retinol and suggest that changes in hepatic metabolism of vitamin A occur during development.
Tolerability and immunogenicity of an eleven-valent pneumococcal conjugate vaccine in healthy toddlers (2001)

An 11-valent mixed carrier pneumococcal conjugate vaccine is safe and immunogenic in toddlers. The use of an adjuvant do not seem to offer any significant benefit.
Research advances in oral mucositis (1999)

Oral mucositis is a common toxicity of high-dose chemotherapy and upper mantle head and neck radiation. Published evidence from the past 14 months provides insight into the multiple possible mechanisms. In addition, the data highlight the clinical importance that this lesion exerts relative to infection risk, quality of life, and cost of care. Oral mucositis has emerged as a dose-limiting toxicity in selected cancer therapy models. Thus, it has direct impact on duration of disease remission, cure rates, and long-term survival. Because of its importance in the clinical setting, oral mucositis remains under extensive laboratory and clinical investigation. Advances in the 1980s relative to infection prevention and reduced duration of profound neutropenia via growth factors have elevated oral mucositis to a prominent toxicity of cancer therapy. A contemporary model for mucositis involving four principal phases was published in 1998. Future research will likely add further insight into this model relative to the roles of mucosal immune dysregulation, colonizing microflora, and wound-healing mechanisms. Basic and clinical studies directed to these several components may well lead to effective preventive strategies in the future, with positive impact on quality of life and survival of cancer patients.
Surface area of the digestive tract – revisited (2014)

The total area of the human adult gut mucosa is not in the order of tennis lawn, rather is that of half a badminton court.
Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis (1997)

The synthetic amino acid copolymer copolymer 1 (Cop 1) suppresses experimental autoimmune encephalomyelitis (EAE) and is beneficial in multiple sclerosis. To further understand Cop 1 suppressive activity, we studied the cytokine secretion profile of various Cop 1-induced T cell lines and clones. Unlike T cell lines induced by myelin basic protein (MBP), which secreted either T cell helper type 1 (Th1) or both Th1 and Th2 cytokines, the T cell lines/clones induced by Cop 1 showed a progressively polarized development toward the Th2 pathway, until they completely lost the ability to secrete Th1 cytokines. Our findings indicate that the polarization of the Cop 1-induced lines did not result from the immunization vehicle or the in vitro growing conditions, but rather from the tendency of Cop 1 to preferentially induce a Th2 response. The response of all of the Cop 1 specific lines/clones, which were originated in the (SJL/JxBALB/c)F1 hybrids, was restricted to the BALB/c parental haplotype. Even though the Cop 1-induced T cells had not been exposed to the autoantigen MBP, they crossreacted with MBP by secretion of interleukin (IL)-4, IL-6, and IL-10. Administration of these T cells in vivo resulted in suppression of EAE induced by whole mouse spinal cord homogenate, in which several autoantigens may be involved. Secretion of anti-inflammatory cytokines by Cop 1-induced suppressor cells, in response to either Cop 1 or MBP, may explain the therapeutic effect of Cop 1 in EAE and in multiple sclerosis.
Characterization of a Time-Resolved Diffuse Optical Spectroscopy Prototype Using Low-Cost, Compact Single Photon Avalanche Detectors for Tissue Optics Applications (2018)

Time-resolved diffuse optical spectroscopy (TR-DOS) is an increasingly used method to determine the optical properties of diffusive media, particularly for medical applications including functional brain, breast and muscle measurements. For medical imaging applications, important features of new generation TR-DOS systems are low-cost, small size and efficient inverse modeling. To address the issues of low-cost, compact size and high integration capabilities, we have developed free-running (FR) single-photon avalanche diodes (SPADs) using 130 nm silicon complementary metal-oxide-semiconductor (CMOS) technology and used it in a TR-DOS prototype. This prototype was validated using assessments from two known protocols for evaluating TR-DOS systems for tissue optics applications. Following the basic instrumental performance protocol, our prototype had sub-nanosecond total instrument response function and low differential non-linearity of a few percent. Also, using light with optical power lower than the maximum permissible exposure for human skin, this prototype can acquire raw data in reflectance geometry for phantoms with optical properties similar to human tissues. Following the MEDPHOT protocol, the absolute values of the optical properties for several homogeneous phantoms were retrieved with good accuracy and linearity using a best-fitting model based on the Levenberg-Marquardt method. Overall, the results of this study show that our silicon CMOS-based SPAD detectors can be used to build a multichannel TR-DOS prototype. Also, real-time functional monitoring of human tissue such as muscles, breasts and newborn heads will be possible by integrating this detector with a time-to-digital converter (TDC).
Nevoid basal cell carcinoma syndrome: Review of 118 affected individuals (1994)

One hundred eighteen cases of nevoid basal cell carcinoma syndrome (NBCCS, Gorlin's syndrome or basal cell nevus syndrome) are presented in this study. In aiming to ascertain all the affected families in Australia, we have examined the largest series to date. Relative frequencies of associated complications are presented and compared with those of the recent English survey by Evans et al. [J Med Genet 30:460-464, 1993]. The frequencies of most manifestations are similar. However, one major difference is that the multiple basal cell carcinomas are manifest from an earlier age in the Australian population, which probably reflects greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented simplex cases, and, accordingly, the apparent new mutation rate is surprisingly high (14-81%) given the lack of impact of NBCCS on reproductive capabilities. There is some evidence to suggest that this may be attributable to anticipation.
Comparison of recombinant Escherichia coli strains for synthesis and accumulation of poly‐(3‐hydroxybutyric acid) and morphological changes (1994)

A stable high-copy-number plasmid pSYL105 containing the Alcaligenes eutrophus polyhydroxyalkanoic acid (PHA) biosynthesis genes was constructed. This plasmid was transferred to seven Escherichia coli strains (K12, B, W, XL1-Blue, JM109, DH5alpha, and HB101), which were subsequently compared for their ability to synthesize and accumulate ploy- (3-hydroxybutyric acid) (PHB). Growth of recombinant cells and PHB synthesis were investigated in detail in Luria-Bertani (LB) medium containing 20 g/L glucose. Cell growth, the rate of PHB synthesis, the extent of PHB accumulation, the amount of glucose utilized, and the amount of acetate formed varied from one strain to another. XL1-Blue (pSYL105) and B (pSYL105) synthesized PHB at the fastest rate, which was ca. 0.2 g PHB/g true cell mass-h, and produced PHB up to 6-7 g/L. The yields of cell mass, true cell mass, and PHB varied considerably among the strains. The PHB yield of XL1-Blue (pSYL105) in LB plus 20 g/L glucose was as high as 0.369 g PHB/g glucose. Strains W (pSYL105) and K12 (pSYL105) accumulated the least amount of PHB with the lowest PHB yield at the lowest synthesis rate. JM109 (pSYL105) accumulated PHB to the highest extent (85.6%) with relatively low true cell mass (0.77 g/L). Considerable filamentation of cells accumulating PHB was observed for all strains except for K12 and W, which seemed to be due either to the overexpression of the foreign PHA biosynthesis enzymes or to the accumulation of PHB.
Fc Receptors as Targets for Immunotherapy (1997)

Human membrane and soluble Fc epsilon receptors (Fc epsilon RI, Fc epsilon RII/CD23) and Fc gamma receptors (Fc gamma RI/CD64, Fc gamma RII/CD32, Fc gamma RIII/CD16) have been implicated in a number of diseases. Their functional roles such as capture and clearance of immune complexes, antibody-dependent cell cytotoxicity, or cytokine or inflammatory mediator release, make them potential targets for immuno-intervention. In the present review, we will describe how membrane and soluble human Fc epsilon R and Fc gamma R have been already used as targets/tools for immuno-interventions by using monoclonal and bispecific engineered antibodies. Some therapeutic uses of these molecules both in cancer, infectious, and auto-immune diseases are presented.
Aging-related Deficiency of CD28 Expression in CD4+ T Cells Is Associated with the Loss of Gene-specific Nuclear Factor Binding Activity (1998)

Changes in T cell populations and concomitant perturbation of T cell effector functions have been postulated to account for many aging-related immune dysfunctions. Here, we report that high frequencies of CD28(null) CD4+ T cells were found in elderly individuals. Because deviations in the function of these unusual CD4+ T cells might be directly related to CD28 deficiency, we examined the molecular basis for the loss of CD28 expression in CD4+ T cells. In reporter gene bioassays, the minimal promoter of the CD28 gene was mapped to the proximal 400 base pairs (bp) of the 5' untranslated region. CD28 deficiency was associated with the loss of two noncompeting binding activities within a 67-bp segment of the minimal promoter. These binding activities were not competed by consensus Ets, Elk, or AP3 motifs that were found within the sequence stretch. The DNA-protein complexes were also not recognized by antibodies to Ets-related transcription factors. Furthermore, introduction of mutations into the 67-bp segment at positions corresponding to the two DNA-protein interaction sites, i.e. nucleotides spanning -206 to -179 and -171 to -148, resulted in the loss of specific nuclear factor binding activities and the abrogation of promoter activity. These observations implicate at least two regulatory motifs in the constitutive expression of CD28. The loss of binding activity of trans-acting factors specific for these sequences may contribute to the accumulation CD4+CD28(null) T cells during aging.
Efficacy and Safety of Catheter-Based Radiofrequency Renal Denervation in Stented Renal Arteries (2014)

Radiofrequency ablation of previously stented RA demonstrated that RDN provides equally safe experimental procedural outcomes in a porcine model whether the radiofrequency treatment is delivered within, adjacent, or without the stent struts being present in the RA. However, efficacious RDN is only achieved when radiofrequency ablation is delivered to the nonstented RA segment distal to the stent.
Single Amino Acid Modification of Adeno-Associated Virus Capsid Changes Transduction and Humoral Immune Profiles (2012)

Adeno-associated virus (AAV) vectors have the potential to promote long-term gene expression. Unfortunately, humoral immunity restricts patient treatment and in addition provides an obstacle to the potential option of vector readministration. In this study, we describe a comprehensive characterization of the neutralizing antibody (NAb) response to AAV type 1 (AAV1) through AAV5 both in vitro and in vivo. These results demonstrated that NAbs generated from one AAV type are unable to neutralize the transduction of other types. We extended this observation by demonstrating that a rationally engineered, muscle-tropic AAV2 mutant containing 5 amino acid substitutions from AAV1 displayed a NAb profile different from those of parental AAV2 and AAV1. Here we found that a single insertion of Thr from AAV1 into AAV2 capsid at residue 265 preserved high muscle transduction, while also changing the immune profile. To better understand the role of Thr insertion at position 265, we replaced all 20 amino acids and evaluated both muscle transduction and the NAb response. Of these variants, 8 mutants induced higher muscle transduction than AAV2. Additionally, three classes of capsid NAb immune profile were defined based on the ability to inhibit transduction from AAV2 or mutants. While no relationship was found between transduction, amino acid properties, and NAb titer or its cross-reactivity, these studies map a critical capsid motif involved in all steps of AAV infectivity. Our results suggest that AAV types can be utilized not only as templates to generate mutants with enhanced transduction efficiency but also as substrates for repeat administration.