Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are ...incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, using complementary genetic models of eosinophil deficiency, we demonstrate that in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.
The U.S. broiler industry is trending toward antibiotic-free (ABF) production because of increasing concerns on antimicrobial resistance in human medicinal treatments. Given the differences in ...performance observed between ABF diets and conventional diets, changes in feeding and drinking behaviors may result. The objective of this study was to characterize feeding and drinking behaviors of male broilers fed with ABF diet vs. diet containing antibiotic growth promoter (AGP diet) under 4 stocking densities (SD), that is 27 (27SD), 29 (29SD), 33 (33SD), and kg·m−2 (39SD). Resource allowances ranged from 50 to 72 birds per tube feeder (with 14 feeder slots) and 11 to 12 birds per nipple drinker. Behaviors of 15 broilers in each treatment combination were monitored continuously at 30 to 35 D of age using an ultra-high frequency radio frequency identification system. The results show that feeding time (62.7 min·bird−1 D−1) and feeder visits (52 times·bird−1 D−1) of broilers with ABF diet were significantly less (P≤0.02) than birds with AGP diet (85.1 min·bird−1 D−1 and 62 times·bird−1 D−1). Bird drinking behaviors were similar among treatments. Coefficient of variation of the behaviors was not significantly different among treatments, suggesting unaffected flock uniformity of these behaviors by diet and SD. Feeder and drinker utilization ratios were less than 40% at any diet and SD levels, indicating sufficient resource allowances. It is concluded that 1) changes in diet and management may alter certain broiler behaviors and 2) the results offer benchmark behavioral data for standardization of resource allowances toward efficient, welfare, and healthy broiler production.
Prostate-specific antigen (PSA) and the related kallikrein family of serine proteases are current or emerging biomarkers for prostate cancer detection and progression. Kallikrein 4 (KLK4/hK4) is of ...particular interest, as KLK4 mRNA has been shown to be elevated in prostate cancer. In this study, we now show that the comparative expression of hK4 protein in prostate cancer tissues, compared with benign glands, is greater than that of PSA and kallikrein 2 (KLK2/hK2), suggesting that hK4 may play an important functional role in prostate cancer progression in addition to its biomarker potential. To examine the roles that hK4, as well as PSA and hK2, play in processes associated with progression, these kallikreins were separately transfected into the PC-3 prostate cancer cell line, and the consequence of their stable transfection was investigated. PC-3 cells expressing hK4 had a decreased growth rate, but no changes in cell proliferation were observed in the cells expressing PSA or hK2. hK4 and PSA, but not hK2, induced a 2.4-fold and 1.7-fold respective increase, in cellular migration, but not invasion, through Matrigel, a synthetic extracellular matrix. We hypothesised that this increase in motility displayed by the hK4 and PSA-expressing PC-3 cells may be related to the observed change in structure in these cells from a typical rounded epithelial-like cell to a spindle-shaped, more mesenchymal-like cell, with compromised adhesion to the culture surface. Thus, the expression of E-cadherin and vimentin, both associated with an epithelial-mesenchymal transition (EMT), was investigated. E-cadherin protein was lost and mRNA levels were significantly decreased in PC-3 cells expressing hK4 and PSA (10-fold and 7-fold respectively), suggesting transcriptional repression of E-cadherin, while the expression of vimentin was increased in these cells. The loss of E-cadherin and associated increase in vimentin are indicative of EMT and provides compelling evidence that hK4, in particular, and PSA have a functional role in the progression of prostate cancer through their promotion of tumour cell migration.
A series of hydrogels with both thermoresponsive and completely biodegradable properties was developed for aqueous encapsulation and controlled release of hydrophilic drugs in response to temperature ...change. The hydrogels were prepared in phosphate-buffered saline (pH 7.4) through free radical polymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate−2-hydroxyethyl methacrylate units (Dex−lactateHEMA). Swelling measurement results demonstrated that four gels with feeding weight ratios of NIPAAm:Dex−lactateHEMA = 7:2, 6:3, 5:4, and 4:5 (w/w) were thermoresponsive by showing a lower critical solution temperature at approximately 32 °C. The swelling and degradation of the hydrogels strongly depended on temperature and hydrogel composition. An empirical mathematical model was established to describe the fast water absorption at the early stage and deswelling at the late stage of the hydrogels at 37 °C. Two hydrophilic model drugs, methylene blue and bovine serum albumin, were loaded into the hydrogels during the synthesis process. The molecular size of the drugs, the hydrophilicity and degradation of the hydrogels, and temperature played important roles in controlling the drug release.
β-Amyloid (Aβ), the primary protein component of Alzheimer's plaques, is neurotoxic when aggregated into fibrils. We have devised a modular strategy for generating compounds that inhibit Aβ toxicity. ...These compounds contain a recognition element, designed to bind to Aβ, linked to a disrupting element, designed to interfere with Aβ aggregation. On the basis of this strategy, a hybrid peptide was synthesized with the sequence KLVFF (residues 16−20 of Aβ) as the recognition element and a lysine hexamer as the disrupting element; this compound protects cells in vitro from Aβ toxicity Pallitto, M. M., et al. (1999) Biochemistry 38, 3570. To determine if the length of the disrupting element could be reduced, peptides were synthesized that contained the KLVFF recognition element and a sequence of one to six lysines as disrupting elements. All compounds enhanced the rate of aggregation of Aβ, with the magnitude of the effect increasing as the number of lysines in the disrupting element increased. The greatest level of protection against Aβ toxicity was achieved with compounds containing disrupting elements of three or more lysines in sequence. A peptide with an anionic disrupting element, KLVFFEEEE, had activity similar to that of KLVFFKKKK, in both cellular toxicity and biophysical assays, whereas a peptide with a neutral polar disrupting element, KLVFFSSSS, was ineffective. Protective compounds retained activity even at an inhibitor:Aβ molar ratio of 1:100, making these some of the most effective inhibitors of Aβ toxicity reported to date. These results provide critical insight needed to design more potent inhibitors of Aβ toxicity and to elucidate their mechanism of action.
The implosion efficiency in inertial confinement fusion depends on the degree of stagnated fuel compression, density uniformity, sphericity, and minimum residual kinetic energy achieved. Compton ...scattering-mediated 50–200 keV x-ray radiographs of indirect-drive cryogenic implosions at the National Ignition Facility capture the dynamic evolution of the fuel as it goes through peak compression, revealing low-mode 3D nonuniformities and thicker fuel with lower peak density than simulated. By differencing two radiographs taken at different times during the same implosion, we also measure the residual kinetic energy not transferred to the hot spot and quantify its impact on the implosion performance.
Four high-resolution regional climate models (RCMs) have been set up for the area of Greenland, with the aim of providing future projections of Greenland ice sheet surface mass balance (SMB), and its ...contribution to sea level rise, with greater accuracy than is possible from coarser-resolution general circulation models (GCMs). This is the first time an intercomparison has been carried out of RCM results for Greenland climate and SMB. Output from RCM simulations for the recent past with the four RCMs is evaluated against available observations. The evaluation highlights the importance of using a detailed snow physics scheme, especially regarding the representations of albedo and meltwater refreezing. Simulations with three of the RCMs for the 21st century using SRES scenario A1B from two GCMs produce trends of between −5.5 and −1.1 Gt yr−2 in SMB (equivalent to +0.015 and +0.003 mm sea level equivalent yr−2), with trends of smaller magnitude for scenario E1, in which emissions are mitigated. Results from one of the RCMs whose present-day simulation is most realistic indicate that an annual mean near-surface air temperature increase over Greenland of ~ 2°C would be required for the mass loss to increase such that it exceeds accumulation, thereby causing the SMB to become negative, which has been suggested as a threshold beyond which the ice sheet would eventually be eliminated.
The medicinal use of cacao, or chocolate, both as a primary remedy and as a vehicle to deliver other medicines, originated in the New World and diffused to Europe in the mid 1500s. These practices ...originated among the Olmec, Maya and Mexica (Aztec). The word cacao is derived from Olmec and the subsequent Mayan languages (kakaw); the chocolate-related term cacahuatl is Nahuatl (Aztec language), derived from Olmec/Mayan etymology. Early colonial era documents included instructions for the medicinal use of cacao. The Badianus Codex (1552) noted the use of cacao flowers to treat fatigue, whereas the Florentine Codex (1590) offered a prescription of cacao beans, maize and the herb tlacoxochitl (Calliandra anomala) to alleviate fever and panting of breath and to treat the faint of heart. Subsequent 16th to early 20th century manuscripts produced in Europe and New Spain revealed >100 medicinal uses for cacao/chocolate. Three consistent roles can be identified: 1) to treat emaciated patients to gain weight; 2) to stimulate nervous systems of apathetic, exhausted or feeble patients; and 3) to improve digestion and elimination where cacao/chocolate countered the effects of stagnant or weak stomachs, stimulated kidneys and improved bowel function. Additional medical complaints treated with chocolate/cacao have included anemia, poor appetite, mental fatigue, poor breast milk production, consumption/tuberculosis, fever, gout, kidney stones, reduced longevity and poor sexual appetite/low virility. Chocolate paste was a medium used to administer drugs and to counter the taste of bitter pharmacological additives. In addition to cacao beans, preparations of cacao bark, oil (cacao butter), leaves and flowers have been used to treat burns, bowel dysfunction, cuts and skin irritations.
We investigated whether a rejection episode in one graft was associated with rejection in the other graft, in recipients with bilateral corneal transplants. In a prospectively maintained, national ...register of 14 865 followed corneal grafts, 1476 patients with bilateral penetrating corneal grafts were identified. Occurrence of rejection was a risk factor for graft failure (p < 0.0001). Logistic regression was used to calculate the adjusted odds ratio for rejection in one eye following rejection in the other eye. In the subset of 1118 patients with bilateral grafts but no history of previous grafts or rejections in either eye, the adjusted odds ratio for a rejection episode in the first eye following rejection in the second was 3.27 (95% confidence interval, CI 1.85, 5.79; p < 0.001). The adjusted odds ratio was 2.04 (95% CI 1.07, 3.91; p = 0.03) for rejection in the second eye following rejection in the first. The median time between the first rejection episode in one eye and the first rejection episode in the other eye was 15 months. Patients with bilateral corneal grafts who suffer a graft rejection episode in one eye are at significantly greater odds of suffering a rejection episode in the other corneal transplant.
Analyses of outcomes in 1,476 recipients of bilateral corneal transplants followed in a national register indicate that a patient who suffers a rejection episode in either graft is then at significantly greater odds of suffering a rejection episode in the corneal graft in the other eye.
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