Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety, Pharmacokinetics and Immune Effects in Normal Volunteers of CPG 10101 (ACTILON™), an Investigational Synthetic Toll-like Receptor 9 Agonist

CPG 10101 (ACTILON™) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV. Objectives and Methods In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks. Results A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2’,5’-oligoadenylate synthetase were sustained for several days. Conclusion This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
Sensitive periods for developmental toxicity of orally administered artesunate in the rat.

BACKGROUND Artesunate has been reported to cause embryolethality and malformations when administered orally to rats during organogenesis. The purpose of this study was to determine the most sensitive period(s) for the induction of these effects in order to provide clues about possible mechanisms and to identify a short treatment regimen for further studies. METHODS Pregnant rats were orally administered artesunate (10, 17 or 30 mg/kg/day) on single or multiple days of gestation. Cesarean sections and fetal evaluations were conducted on Day 21 postcoitum (pc). RESULTS Embryolethality, cardiovascular malformations and a syndrome of skeletal defects were observed after single doses on days 10 to 14 pc, while no developmental effects were observed before (day 9 pc) or after (days 16 or 17 pc) that period. The most sensitive day for embryo lethality was day 11 pc, where lethality occurred with a very steep dose response (postimplantation loss was approximately 15% at 10 mg/kg and 100% at 17 mg/kg/day). The most sensitive day for the induction of malformations was day 10 pc. Malformations tended to occur in partially resorbed litters and included cardiovascular defects and bent and misshapen long bones and scapulae. CONCLUSIONS The sensitive window for developmental toxicity of artesunate in the rat was identified as days 10 to 14 pc. Single oral doses produced embryolethality and similar cardiovascular and skeletal malformations as previously reported in longer term dosing experiments. These single dose treatment regimens could be useful to further investigate the mechanistic basis for artesunate-induced developmental toxicity.
Exercise and Alzheimer's disease biomarkers in cognitively normal older adults

In addition to the increasingly recognized role of physical exercise in maintaining cognition, exercise may influence Alzheimer's disease (AD) pathology, as transgenic mouse studies show lowered levels of AD pathology in exercise groups. The objective of this study was to elucidate the association between exercise and AD pathology in humans using Pittsburgh compound‐B (PIB), amyloid‐β (Aβ)42, tau, and phosphorylated tau (ptau)181 biomarkers.
An ecological systems approach to examining risk factors for early childhood overweight: findings from the UK Millennium Cohort Study

Objective: To use an ecological systems approach to examine individual-, family-, community- and area-level risk factors for overweight (including obesity) in 3-year-old children. Methods: A prospective nationally representative cohort study conducted in England, Wales, Scotland, Northern Ireland. Participants included 13 188 singleton children aged 3 years in the Millennium Cohort Study, born between 2000 and 2002, who had complete height/weight data. The main outcome measure was childhood overweight (including obesity) defined by the International Obesity TaskForce cut-offs for body mass index. Results: 23.0% of 3-year-old children were overweight or obese. In the fully adjusted model, primarily individual- and family-level factors were associated with early childhood overweight: birthweight z-score (adjusted odds ratio, 1.36, 95% CI 1.30 to 1.42), black ethnicity (1.41, 1.11 to 1.80) (compared with white), introduction to solid foods <4 months (1.12, 1.02 to 1.23), lone motherhood (1.32, 1.15 to 1.51), smoking during pregnancy (1–9 cigarettes daily: 1.34, 1.17 to 1.54; 10–19: 1.49, 1.26 to 1.75; 20+: 1.34, 1.05 to 1.70), parental overweight (both: 1.89, 1.63 to 2.19; father only: 1.45, 1.28 to 1.63; mother only: 1.37, 1.18 to 1.58), prepregnancy overweight (1.28, 1.14 to 1.45) and maternal employment ⩾21 hours/week (1.23, 1.10 to 1.37) (compared with never worked). Breastfeeding ⩾4 months (0.86, 0.76 to 0.97) (compared with none) and Indian ethnicity (0.63, 0.42 to 0.94) were associated with a decreased risk of early childhood overweight. Children from Wales were also more likely to be overweight than children from England. Conclusions: Most risk factors for early childhood overweight are modifiable or would allow at-risk groups to be identified. Policies and interventions should focus on parents and providing them with an environment to support healthy behaviours for themselves and their children.
Long-standing Intrabronchial Foreign Bodies

The long-standing intrabronchial foreign body presents problems of diagnosis and treatment which are very different from those associated with the recently inhaled foreign body. There may be no history to suggest the original incident; the clinical picture is usually clouded by superadded pathological changes-atelectasis, pneumonitis, bronchiectasis, or lung abscess-and the bronchoscopic appearances are often misleading. Even when correctly diagnosed, the choice of treatment is not always easy. Sixteen such cases are presented in an attempt to find common characteristics, recognition of which may assist correct diagnosis in this not uncommon condition. In addition, the problems of treatment are considered.
Factors Affecting Feed Intake and Its Regulation Mechanisms in Ruminants -A Review -

Feed intake is one of the main determinant factors of ruminant performance. However, it is affected by different sets of factors that can be grouped under three categories; 1) feed related factors (include feed chemical and physical characteristics, associative effects between dietary components, nutrient balance and amount of anti-quality factors), 2) animal related factors (such as physiological status, size and genotype of the animal) and 3) environment related factors (like temperature, housing and prevalence of diseases). Ruminants try to satisfy their nutrient requirements for maintenance and other productive purposes from different feed sources because it is unlikely that feed/s contain the exact amount of nutrients required by animals. This consumption of different feeds to balance nutrient intake by ruminants may lead them to over or under consumption of one or more nutrients. Both under and over feeding are not required by the animals and therefore they should have mechanisms to regulate their intake. Ruminants feed intake regulation mechanisms have been perceived and described differently by scholars—theories of intake regulation. But, these intake regulation theories fall under three categories: 1) physical feed intake regulation—states fill effect from resulted from destination of the gastrointestinal tract causes the animal to stop or start feeding; 2) metabolic or chemostatic feed intake regulation—states the presence of nutrients, metabolites and hormones in the circulating blood signals the animal to stop or continue on feeding); 3) cost benefit model of feed intake regulation—states animals continue feeding to get nutrient they require and stops to avoid the detrimental effect of by-products of metabolism, (free radicals), but this theory have been criticized by different scholars. However, it has been proved that, the different signals in intake regulation are working in integrated way controlled by the central nervous system.
Proteomics of Durum Wheat Grain during Transition to Conservation Agriculture

Nitrogen management in combination with sustainable agronomic techniques can have a great impact on the wheat grain proteome influencing its technological quality. In this study, proteomic analyses were used to document changes in the proportion of prolamins in mature grains of the newly released Italian durum wheat cv Achille. Such an approach was applied to wheat fertilized with urea (UREA) and calcium nitrate (NITRATE), during the transition to no-till Conservation Agriculture (CA) practice in a Mediterranean environment. Results obtained in a two-years field experiment study suggest low molecular weight glutenins (LMW-GS) as the fraction particularly inducible regardless of the N-form. Quantitative analyses of LMW-GS by 2D-GE followed by protein identification by LC-ESI-MS/MS showed that the stable increase was principally due to C-type LMW-GS. The highest accumulation resulted from a physiologically healthier state of plants treated with UREA and NITRATE. Proteomic analysis on the total protein fraction during the active phase of grain filling was also performed. For both N treatments, but at different extent, an up-regulation of different classes of proteins was observed: i) enzymes involved in glycolysis and citric acid cycles which contribute to an enhanced source of energy and carbohydrates, ii) stress proteins like heat shock proteins (HSPs) and antioxidant enzymes, such as peroxidases and superoxide dismutase which protect the grain from abiotic stress during starch and storage protein synthesis. In conclusion N inputs, which combined rate with N form gave high yield and improved quality traits in the selected durum wheat cultivar. The specific up-regulation of some HSPs, antioxidant enzymes and defense proteins in the early stages of grain development and physiological indicators related to fitness traits, could be useful bio-indicators, for wheat genotype screening under more sustainable agronomic conditions, like transition phase to no-till CA in Mediterranean environments.
Fine Mapping and Evolution of the Major Sex Determining Region in Turbot (Scophthalmus maximus)

Fish sex determination (SD) systems are varied, suggesting evolutionary changes including either multiple evolution origins of genetic SD from nongenetic systems (such as environmental SD) and/or turnover events replacing one genetic system by another. When genetic SD is found, cytological differentiation between the two members of the sex chromosome pair is often minor or undetectable. The turbot (Scophthalmus maximus), a valuable commercial flatfish, has a ZZ/ZW system and a major SD region on linkage group 5 (LG5), but there are also other minor genetic and environmental influences. We here report refined mapping of the turbot SD region, supported by comparative mapping with model fish species, to identify the turbot master SD gene. Six genes were located to the SD region, two of them associated with gonad development (sox2 and dnajc19). All showed a high association with sex within families (P = 0), but not at the population level, so they are probably partially sex-linked genes, but not SD gene itself. Analysis of crossovers in LG5 using two families confirmed a ZZ/ZW system in turbot and suggested a revised map position for the master gene. Genetic diversity and differentiation for 25 LG5 genetic markers showed no differences between males and females sampled from a wild population, suggesting a recent origin of the SD region in turbot. We also analyzed associations with markers of the most relevant sex-related linkage groups in brill (S. rhombus), a closely related species to turbot; the data suggest that an ancient XX/XY system in brill changed to a ZZ/ZW mechanism in turbot.
A dual emission mechanism in Sgr A*/L ' ? ⋆

We have collected in 2004 adaptive optics corrected L' images of the Galactic Center region with NAOS-CONICA at VLT. A strong variability was observed as well as a correlation between the photocenter positions and fluxes of the L'-band counterpart of Sgr A*. It is interpreted as the combined emission of a point-like flaring source at the position of Sgr A*/IR itself and an extended dust structure, 75 mas south west of Sgr A*/IR, which we name Sgr A*-f. We examine the different possible mechanisms to explain this dual Sgr A* L' emission and conclude it is likely a flaring emission associated to energetic events in the close environment of the black hole plus a quiescent emission resulting from the collision of Sgr A*-f by a jet from Sgr A*.
Governmental perspectives on evaluating laboratory performance.

The quality of laboratory analytical performance required to support medical decision-making has been defined in four major ways: (a) by the analytical variance of the state of the practice; (b) by the total variance, including analytical and biological variability; (c) by the loss of diagnostic efficiency attributable to analytical error; and (d) by medical-usefulness criteria. From the federal government's perspective, the answer to the question "How good must a laboratory test result be to be medically relevant? " must take into account the clinical context of the test, with accompanying concerns about access, timeliness, and cost, as well as limits for precision and accuracy in the analytical process and the frequency and potential patient-care impact of error in the pre- and postanalytical steps of the total testing process. Therefore, medically relevant goals should encompass not only analytical precision and accuracy but also goals to provide access to clinically effective tests and to reduce errors in the total testing process that can lead to medically misleading information. Development of more appropriate regulatory requirements for laboratories, as well as any needed improvements in instrumentation and methodology, should focus on ensuring that goals for medically relevant results are met by appropriate design and management of the entire process of laboratory testing.
Signature of primordial non-Gaussianity of phi^3-type in the mass function and bias of dark matter haloes

We explore the effect of a cubic correction g{sub NL{phi}}{sup 3} on the mass function and bias of dark matter haloes extracted from a series of large N-body simulations and compare it to theoretical predictions. Such cubic terms can be motivated in scenarios like the curvaton model, in which a large cubic correction can be produced while simultaneously keeping the quadratic f{sub NL{phi}}{sup 2} correction small. The deviation from the Gaussian halo mass function is in reasonable agreement with the theoretical predictions. The scale-dependent bias correction {Delta}b{sub {kappa}}(k,g{sub NL}) measured from the auto- and cross-power spectrum of haloes, is similar to the correction in f{sub NL} models, but the amplitude is lower than theoretical expectations. Using the compilation of LSS data in [A. Slosar et al., J. Cosmol. Astropart. Phys. 08 (2008) 031], we obtain for the first time a limit on g{sub NL} of -3.5x10{sup 5}<g{sub NL}<+8.2x10{sup 5} (at 95% CL). This limit will improve with the future LSS data by 1-2 orders of magnitude, which should test many of the scenarios of this type.
Intrahypothalamic Estradiol Regulates Glucose Metabolism via the Sympathetic Nervous System in Female Rats

Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver.
The compression of morbidity. 1983.

In this c entury w e a re p rogressing t hrough three separate eras with dramatically different characteristics of health and illness. We entered the century in an era of infectious disease, with tuberculosis the number one killer of our population, and smallpox, diphtheria, tetanus, and other infectious illnesses extremely prevalent. A reduction in mortality from these diseases of over 99 percent (Fries and Crapo 1981; Cooper 1982) has led to the present era, where the major burdens of illness of the United States are the chronic diseases. Atherosclerosis and its complications, neoplasia, emphysema, diabetes, cirrhosis, and osteoarthritis have increased in prevalence even as the infectious illnesses which preceded them declined. It is one thesis of this discussion that this chronic disease era in its turn will slowly decline in significance, leaving a third era in which the major health problems of the United States will be directly related to the process of senescence, and where the aging process itself, independent of specific disease, will constitute a major burden of illness for the United States. The ultimate constraint within which we must develop health policy for the future is, of course, the limit of life itself. Man is mortal, and the limits to what presently may be accomplished in decreasing mortality are set by the life span of our species. In the following discussion, we will
Intrarenal Administration of Molsidomine, a Molecule Releasing Nitric Oxide, Reduces Renal Ischemia‐Reperfusion Injury in Rats

Ischemia reperfusion (I‐R)‐induced renal damage is reduced by systemic administration of the NO‐dependent vasodilator molsidomine. The aim of this study was to estimate the effect of direct intrarenal molsidomine administration on renal dysfunction and inflammatory reaction after experimental I‐R in rats, in order to assess only renal NO effects and to obviate its systemic hemodynamic action. Ischemia was induced by renal pedicle ligation (60 min) followed by reperfusion and contralateral nephrectomy. Molsidomine (4 mg/kg) was infused into the renal artery 15 min before reperfusion and its effects were compared with those of the NO‐independent vasodilator hydralazine (2 mg/kg). Survival rates after 7 days were 100% in the sham‐operated group and 75% in the I‐R rats. Molsidomine treatment almost completely prevented the I‐R‐induced renal dysfunction, and survival reached 100%. Molsidomine prevented an I‐R‐induced increase in superoxide anion and reduced plasma levels of pro‐inflammatory cytokines (TNF‐α, IL‐1β and IFN‐γ), whereas it enhanced anti‐inflammatory cytokines (IL‐6 and IL‐10). Inflammatory cell infiltration and cell‐adhesion molecules (ICAM‐1, PECAM‐1, VCAM‐1 and P‐selectin) were lower in the molsidomine‐treated kidneys than in the untreated animals. All these protective effects were not observed after hydralazine administration. In conclusion, intrarenal administration of molsidomine before reperfusion improved renal function and decreased inflammatory responses after I‐R.
New insights into plant glycoside hydrolase family 32 in Agave species

In order to optimize the use of agaves for commercial applications, an understanding of fructan metabolism in these species at the molecular and genetic level is essential. Based on transcriptome data, this report describes the identification and molecular characterization of cDNAs and deduced amino acid sequences for genes encoding fructosyltransferases, invertases and fructan exohydrolases (FEH) (enzymes belonging to plant glycoside hydrolase family 32) from four different agave species (A. tequilana, A. deserti, A. victoriae-reginae, and A. striata). Conserved amino acid sequences and a hypervariable domain allowed classification of distinct isoforms for each enzyme type. Notably however neither 1-FFT nor 6-SFT encoding cDNAs were identified. In silico analysis revealed that distinct isoforms for certain enzymes found in a single species, showed different levels and tissue specific patterns of expression whereas in other cases expression patterns were conserved both within the species and between different species. Relatively high levels of in silico expression for specific isoforms of both invertases and fructosyltransferases were observed in floral tissues in comparison to vegetative tissues such as leaves and stems and this pattern was confirmed by Quantitative Real Time PCR using RNA obtained from floral and leaf tissue of A. tequilana. Thin layer chromatography confirmed the presence of fructans with degree of polymerization (DP) greater than DP three in both immature buds and fully opened flowers also obtained from A. tequilana.