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Graphical abstract: The role of acidophilic bacteria in several industrial sectors. Created with BioRender.com.

La meningitis neoplásica (MN) es una complicación metastásica relativamente frecuente en pacientes con cáncer, con alta morbilidad neurológica y en general pobre pronóstico. La prevalencia está en torno al 5-15% de los tumores sólidos, y los más frecuentes son el cáncer de mama, el de pulmón y el melanoma. La clínica se produce por afectación de hemisferios cerebrales, nervios craneales, médula y raíces nerviosas, siendo en muchos casos multifocal, y presenta a menudo síntomas y signos de hipertensión intracraneal. Las principales herramientas diagnósticas son la exploración neurológica, la resonancia magnética cerebral y medular con contraste, y el análisis y la citología del líquido cefalorraquídeo (LCR), aunque recientemente se están investigando técnicas como la detección de células tumorales y ADN circulante en el LCR, que aumentan la sensibilidad diagnóstica. Con las terapias disponibles en la actualidad el objetivo del tratamiento no es curativo, sino retrasar y disminuir los síntomas y preservar la calidad de vida de los pacientes, e implica un enfoque multimodal que puede incluir radioterapia, quimioterapia intratecal y/o sistémica y cirugía. El tratamiento debe ser individualizado y se basa principalmente en guías y opiniones de expertos. Actualmente se están llevando a cabo ensayos clínicos prometedores de fármacos contra dianas moleculares e inmunoterápicos. Este artículo es una revisión actualizada de la MN, e incluye epidemiologia, presentación clínica, diagnóstico, pronóstico, manejo y opciones terapéuticas; se dirige al neurólogo general, y en particular al neurólogo que ejerce su práctica en centros con pacientes oncológicos.

Summary:The relative bioavailability of 2 Met hydroxy analogs (KES and MtS) and a rumen-protected Met (SmT) was determined using the area under the curve method. Relative Met bioavailability was similar between the 3 methionine hydroxy analogs, but the area under the curve was greater for the rumen-protected Met.

La justificación del uso de métodos mixtos es para dar explicación de un fenómeno cuando un enfoque u otro no alcanzan a resolver la problemática planteada. El objetivo es reflexionar sobre los métodos mixtos desde una perspectiva epistemológica y paradigmática de los enfoques que los integran.

ABSTRACTThis work analyses the texture and microstructure gradients emerging in a 316L stainless steel processed by selective laser melting, using an island scan strategy, followed by annealing. Laser processing leads to the alignment of different crystallographic directions with the build direction at the mid and top layers, as well as to gradual structural coarsening. Annealing triggers discontinuous recrystallisation at highly strained regions, such as grain boundaries and laser track centre lines, resulting in the onset of new texture gradients. The development of the mentioned texture gradients is rationalised based on a competition between thermal gradient-driven growth and epitaxial growth.

Eight rumen cannulated Simmental heifers (BW = 281.4 ± 7.28 kg) were randomly assigned to one of four experimental treatments in a 4 × 4 replicated Latin square design to ascertain the effects of increasing levels of alfalfa hay on intake, sorting, and feeding behavior in comparison to barley straw as forage source. Treatments tested were four total mixed rations with: 1) 10% barley straw (10BS)with 7.0% NDF from forage, 2) 13% alfalfa hay (13AH) and less NDF from forage (5.7%) than 10BS, 3) 16% alfalfa hay (16AH) and the same NDF from forage (7.0%) as 10BS, and 4) 19% alfalfa hay (19AH) and more NDF from forage (8.3%) than 10BS. Each experimental period consisted of 3 wk for adaptation and 1 wk for sampling. Increasing the proportion of alfalfa hay in the diet linearly increased (P< 0.05) total DMI, CP intake, water consumption, intake of long, medium and fine particle size, extent of sorting of fine particle size, and time spent rumination, but linearly decreased (P< 0.05) extent of sorting of short particle size. Intake of DM was higher in heifers fed 16AH and 19AH than in heifers fed 10BS (P< 0.001). Intake of NDF and physically effective NDF (peNDF) was greater in 13AH, 16AH, and 19AH than in 10BS (P< 0.01). The DMI of medium and short particle size was greater in 13AH, 16AH, and 19AH than in 10BS (P< 0.05), whereas DMI of long particle size was greater in 16AH and 19AH compared to 10BS (P< 0.001). Heifers fed 13AH, 16AH, and 19AH diets sorted against fine particle size and sorted for or tended to sort for short, medium, and long particle sizes. Meal length was greater in heifers fed 16AH and 19AH than 10BS (P< 0.05). Time spent eating was not affected by diet but time spent ruminating was greater in heifers fed 19AH than in 10BS (P< 0.05). Results indicate that the inclusion of alfalfa hay at 19% of incorporation caused an increase in DM, NDF, and peNDF intake, in comparison to the 10BS diet. In the same way, intake of long, medium, and short particle size was greater in this diet. Moreover, heifers fed 19AH sorted for medium particle size and tended to sort for long and short particles size, and against fine particle size. Sorting behavior and meal length increased in the 19AH diet, which leads us to think that sorting feed ingredients requires time and therefore lengthens the meal. Time spent ruminating was greater in heifers fed 19AH, thus reducing the risk of ruminal acidosis when animals are fed high concentrate diets.

The objective of this experiment was to compare the effects of using 2 different forage sources on intake and sorting and feeding behavior in growing heifers fed a high-concentrate diet offered as a total mixed ration (TMR). Eight Simmental heifers (initial BW of 148.1 ± 4.83 kg) were used in a crossover design experiment. Treatment diets were a TMR with either barley straw (BS) or alfalfa hay (AH) as forage source. Diets were offered on an ad libitum basis, with a forage to concentrate ratio of 8 to 92. The experiment was performed in two 28-d periods, with 3 wk of diet adaptation and 1 wk of sampling in each period. Heifers were weighed before feeding on 2 consecutive days at the beginning and the end of the experiment, and in the sampling week. Feed and refusal samples were collected daily in the sampling week for DM determination and chemical analysis. Particle size separation was performed using the 3-screen Penn State Particle Separator. Dry matter digestibility was estimated using acid-insoluble ash as internal marker. Feeding behavior was recorded using an automated feeding system. Sorting behavior was measured with the intake of different particle size. Dry matter intake was greater (P< 0.05) in heifers fed BS (6.7 kg/d) than AH (5.8 kg/d) when these animals faced TMR for first time in period 1, but DMI did not differ between diets in period 2 when they were accustomed to the method of feeding. Apparent DM digestibility did not differ between diets (62.7 and 64.3% for BS and AH, respectively). Heifers fed BS sorted in both periods against long particle size (P< 0.01) and against medium particle size in period 2 (P< 0.01), a behavior that did not appear in heifers fed AH. Heifers sorted for short particle size in both diets in period 1, this behavior being maintained in period 2 for heifers fed BS, while it disappeared in heifers fed AH. This sorting behavior preferentially shown in heifers fed BS resulted in a tendency (P= 0.06) for greater length of each meal and a longer feeding time (P= 0.02). In conclusion, at 8% of incorporation, forage source affected intake in only 1 of the 2 experimental periods. Heifers fed BS showed a sorting behavior with preferential consumption for concentrate in the TMR, feeding time being greater in BS than in AH. In contrast, heifers fed AH sorted for short particle size when faced for the first time with a new method of feeding, this sorting behavior disappearing once heifers had got familiar with it.

Continuous recording over 24 h is an accurate method for behavioral measurements in ruminants but is very time-consuming. The aim of this study was to compare different recording rules, in particular continuous recording (CR) with different time samplings (TS) methods, when the behavior of growing heifers housed individually and fed a high-concentrate diet is recorded. Behavior of 8 growing heifers was recorded on 6 non-consecutive days. Continuous recording over 24 h, considered the control treatment, was used to evaluate TS methods by recording all the behaviors that occurred for 60 s at intervals of 2 (S2), 5 (S5), 10 (S10), 15 (S15), 20 (S20) and 30 (S30) min. Three additional TS methods were considered: a sampling of the first 10 min of every h (FS10), and a sampling during 4 h (4PF) and 8 h post-feeding (8PF). Two procedures to assess the accuracy of the relationship between CR and TS methods were used: a) data analysis using the GLIMMIX procedure of SAS together with the Pearson correlation coefficient, and b) linear regression analysis. In this last case, 1-time sampling was considered to accurately reflect true values obtained with CR if the following 3 criteria were met: the coefficient of determination (R2) was greater than 0.76, the intercept did not differ from 0 (P> 0.05), and the slope did not differ from 1 (P> 0.05). The results of the present study suggest that the latter approach provides a much more focused and reliable way of ensuring the accuracy of each TS method. The S5 TS method produced an accurate estimate for all the behavioral activities, except for drinking, social behavior and rummaging in wood shavings, where it would be necessary to consider the S2 TS method, and S10 for self-grooming. Ruminating and resting can be accurately estimated using the S20 and S30 TS methods, respectively. However, FS10, 4PF and 8PF were inadequate TS methods to measure all the activities studied in the present experiment. In conclusion, not all the TS methods tested are adequate for measuring the behaviors recorded.

Emulsions are popular vehicles in skin care due to their affinity for the skin; however, they are thermodynamically unstable systems. This study investigates zeta potential and particle size distribution as potential screening tools to predict instabilities in emulsion-based cosmetic products, to supplement regular accelerated stability testing. [ABSTRACT FROM AUTHOR]

Fall-calving Angus cows were used to evaluate the effect of ambient temperature on duration of gestation. In Exp. 1, cows were AI and calved in August (n= 14) or October (n= 10). Cows grazed native prairie pasture in Oklahoma and had a BCS of 6.0 ± 0.5 (1 = emaciated, and 9 = obese) at parturition. Commencing 2 wk before the expected calving date, blood samples were taken from the coccygeal vein every 2 to 3 d until calving. Cows that calved in August tended to have shorter gestations (P= 0.07) compared with cows that calved in October. Maximum daily ambient temperature during the last 14 d of gestation was greater for August-calving cows (P< 0.001) compared with October cows. Concentrations of cortisol in plasma during the last 4 d of gestation were greater in cows that calved in August (P< 0.04) compared with cows that calved in October. In Exp. 2, cows were AI and calved in either mid-August (n= 7), late-August (n= 6), September (n= 6), or October (n= 8) to evaluate the effects of elevated ambient temperature on duration of gestation, ruminal temperature at parturition, and plasma cortisol, progesterone, and estradiol. Temperature boluses (SmartStock, LLC, Pawnee, OK) programmed to transmit temperature every hour were place in the rumen at 255 d of gestation. Cows grazed native prairie pasture in Oklahoma and had a BCS of 6.5 ± 0.4 at calving. Maximum ambient temperatures during d 263 to 273 of gestation were influenced by month of calving × day (P< 0.001). Duration of gestation was shorter for mid-August cows (P< 0.05) compared with October cows, but did not differ compared with late-August (P= 0.29) and September (P= 0.50) cows. Ruminal temperature during the 4 d before calving was not influenced by month of calving (P= 0.76). Ruminal temperature was decreased during the 24 h before parturition for cows in all months (P< 0.01) compared with 2 to 4 d before parturition. Concentrations of cortisol in plasma during d 271 to 276 of gestation were less (P< 0.05) for late-August compared with cows that calved during the other months. Concentrations of progesterone were greater during 7 d before parturition in October compared with cows that calved in September. Estradiol in plasma of cows during late gestation was not affected by month of calving (P= 0.76). Exposure of beef cows to elevated ambient temperature resulted in shorter gestations. Ruminal temperature in cows decreased ≥ 0.3°C the day before parturition

Gestating Angus, nonlactating, spring-calving cows were used to determine variation in maintenance energy requirements (MR); to evaluate the relationship among MR and cow and calf performance, plasma concentrations of IGF-I, T4, glucose, insulin, and ruminal temperature; and to describe the LM proteome and evaluate protein abundance in cows with different MR. Cows (4 to 7 yr of age) with a BCS of 5.0 ± 0.2 and BW of 582 ± 37 kg in the second to third trimester of gestation were studied in 3 trials (trial 1, n= 23; trial 2, n= 32; trial 3, n= 38). Cows were individually fed a complete diet in amounts to meet predicted MR (Level 1 Model of NRC), and feed intake was adjusted weekly until constant BW was achieved for at least 21 d (maintenance). Cows were classified on the basis of MR as low (>0.5 SD less than mean, LMR), moderate (±0.5 SD of mean, MMR), or high (>0.5 SD more than mean, HMR) MR. Blood samples were taken at maintenance and at 2 mo postpartum in trial 2. Muscle biopsies were taken from LMR and HMR after cows consumed actual MR for 28 d (trial 2) or 21 d (trial 3). Proteins from LM were separated by 2-dimensional difference gel electrophoresis and were identified, and abundance was quantified and compared. The greatest differences in MR between cows were 29%, 24%, and 25% in trials 1, 2, and 3, respectively. Daily MR (NEm, kcal·BW-0.75·d–1) averaged 89.2 ± 6.3, 93.0 ± 4.9, and 90.4 ± 4.6 in trials 1, 2, and 3, respectively. Postpartum BW and BCS, calf birth and weaning weights, postpartum luteal activity, and ruminal temperature were not influenced by MR of the cows. Concentrations of IGF-I were greater (P= 0.001) in plasma of MMR compared with LMR cows consuming predicted MR diets, and MR was negatively correlated with concentrations of IGF-I in plasma (r= –0.38; P= 0.05) at 2 mo postpartum. A total of 103 proteins were isolated from LM; 52 gene products were identified. Abundance of specific proteins in the LM was not influenced (P> 0.11) by MR. Variation in MR of cows will make it possible to improve feed efficiency by selection. Identification of biomarkers for MR will allow selection of more efficient cows, which consume less feed and produce calves with similar weaning weights. Productive cows that require less feed for maintenance will improve efficiency of production and enhance sustainability of the environment.

Eight Simmental heifers (initial BW 313.4 ± 13.2 kg) were randomly assigned to 1 of 4 experimental treatments in a 4 × 4 double Latin square design. The experiment was performed in four 28-d periods. Treatments tested were a control diet in which barley straw (BS) was used as a fiber source and 3 diets where the main difference was the nonforage fiber source used: soybean hulls (SH), beet pulp (BP) in pellets, and whole cottonseed (WCS). All ingredients, except the fiber sources, were ground through a 3-mm screen. Fiber ingredients were incorporated at 10, 17, 17, and 16% (on DM basis) in BS, SH, BP, and WCS, respectively. All diets were offered ad libitum as total mixed ration and designed to be isoenergetic (2.95 Mcal ME/kg DM), isonitrogenous (15% CP, DM basis), and with a NDF content of 20% (on DM basis) although there was a discrepancy between the theoretical and the actual chemical composition of the diets. Particle size separation was performed using the 3-screen Penn State Particle Separator. Animals were allotted in 8 individual roofed concrete pens equipped with a feedbunk and water trough. Intake was recorded over 7 d in the last week of each experimental period. Behavior was recorded for 24-h on d 2 and d 6 of each experimental week using a digital video recording device. A digital color camera was set up in front of each pen. Data recorded, except behavioral activities, were statistically analyzed using the MIXED procedure of SAS. To test treatment effect for each behavioral activity, analysis was performed using the GLIMMIX procedure of SAS. Diets ranked from greater to lesser proportion of particles of less than 1.18 mm as follows: SH, BS, WCS, and BP. Dry matter intake of heifers fed WCS was greater than the remaining treatments (P = 0.049). The greatest average ruminal pH was registered in heifers fed BS (6.4) and BP (6.3) whereas the smallest was recorded in SH diet (5.9), with WCS (6.2) occupying an intermediate position (P = 0.006). Total chewing time was greater (P = 0.001) in BS and WCS than in SH and BP. In conclusion, the nonforage fiber sources tested in this experiment can be used in forage-free diets fed to beef heifers as total mixed ration (TMR) without negative consequences in DMI in SH and BP diets and with an increased DMI in WCS diet. The WCS diet promoted rumination and total chewing time to the same degree as BS, which demonstrates that it is equally effective as this forage fiber source.

Aspergillus flavus, a haploid organism found worldwide in a variety of crops, including maize, cottonseed, almond, pistachio, and peanut, causes substantial and recurrent worldwide economic liabilities. This filamentous fungus produces aflatoxins (AFLs) B1and B2, which are among the most carcinogenic compounds from nature, acutely hepatotoxic and immunosuppressive. Recent efforts to reduce AFL contamination in crops have focused on the use of nonaflatoxigenic A. flavus strains as biological control agents. Such agents are applied to soil to competitively exclude native AFL strains from crops and thereby reduce AFL contamination. Because the possibility of genetic recombination in A. flavus could influence the stability of biocontrol strains with the production of novel AFL phenotypes, this article assesses the diversity of vegetative compatibility reactions in isolates of A. flavus to identify heterokaryon self-incompatible (HSI) strains among nonaflatoxigenic isolates, which would be used as biological controls of AFL contamination in crops. Nitrate nonutilizing (nit) mutants were recovered from 25 A. flavus isolates, and based on vegetative complementation between nit mutants and on the microscopic examination of the number of hyphal fusions, five nonaflatoxigenic (6, 7, 9 to 11) and two nontoxigenic (8 and 12) isolates of A. flavus were phenotypically characterized as HSI. Because the number of hyphal fusions is reduced in HSI strains, impairing both heterokaryon formation and the genetic exchanges with aflatoxigenic strains, the HSI isolates characterized here, especially isolates 8 and 12, are potential agents for reducing AFL contamination in crops.

Four beef Holstein heifers (BW = 438 ± 71 kg) fitted with a 1-cm i.d. plastic ruminal trocars were used in a 4 × 4 Latin square design to evaluate the effect of 3 doses of capsicum extract (CAP) on intake, water consumption, and ruminal fermentation in heifers fed a high-concentrate diet. Animals were fed (DM basis) 10% barley straw and 90% concentrate (32.2% barley grain, 27.9% ground corn, 7.5% wheat bran, 10.7% soybean meal, 10.7% soybean hulls, 7.2% corn gluten feed, 3.1% mineral-vitamin mix; 16.6% CP, 18.3% NDF). Treatments were no additive (CTR), 125 (CAP125), 250 (CAP250), and 500 (CAP500) mg/d of capsicum oleoresin standardized with 6% of capsaicin and dihydrocapsaicin (XTract 6933, Pancosma, Geneva, Switzerland). Each experimental period consisted of 25 d (15 d for adaptation, 5 d of continuous measurement of DMI, and 3 d for rumen sample collection). Animals had ad libitum access to water and feed offered once daily at 0800 h. Data were analyzed by the MIXED procedure of SAS. The model included the fixed effects of period and treatment, the random effect of heifer, and the residual error. The effects were tested for linear and quadratic effects. A linear response was observed (CTR, CAP125, CAP250, and CAP500, respectively) for DMI (8.56, 9.84, 8.68, and 9.40 kg/d; P < 0.04), ruminal pH (6.03, 5.84, 5.96, and 5.86; P < 0.08) and total VFA (134.3, 144.8, 140.1, and 142.8 mM; P < 0.08). There was a strong correlation between water consumption and DMI (R(2) = 0.98). Dry matter intake in the first 2 h after feeding was reduced (P < 0.05) in all CAP treatments compared with control. The molar proportion of acetate tended to decrease linearly (from 59.6 to 55.5 mol/100 mol; P < 0.06), and ammonia N concentration tended to increase linearly (from 14.4 to 16.0 mg N/dL; P < 0.08). In contrast, the molar proportion of propionate (23.8 mol/100 mol), butyrate (14.2 mol/100 mol), and lactate (0.28 mol/100 mol) were not affected by treatments. Results indicate that capsicum extract stimulated DMI and modified the pattern of DMI in beef cattle fed high concentrate diets.

Spring-calving Angus cows (n = 30) were used to evaluate changes in ruminal temperature (RuT) related to parturition and estrus. Cows were synchronized and artificially inseminated with semen from a single sire. Temperature boluses were placed in the rumen at 7.0 ± 0.2 mo of gestation. Boluses were programmed to transmit RuT every 15 min. Cows (BW = 623 ± 44 kg, BCS = 4.9 ± 0.4) calved during 3 wk, and estrus was synchronized at 77 ± 7 d after calving with PGF2α. Cows were observed every 12 h to detect estrus. Daily average ambient temperatures ranged from 2 to 22°C during parturition (February to March) and 17 to 25°C during estrus (May to June). Ruminal temperature from 7 d before to 3 d after parturition and 2 d before to 2 d after visual detection of estrus was analyzed using the MIXED procedure. Ruminal temperatures <37.72°C were attributed to water consumption and excluded from analyses. Day did not influence (P= 0.36) RuT from d −2 to −7 before parturition (38.94 ± 0.05°C). Ruminal temperature decreased (P< 0.001) from d −2 to d −1 before parturition (38.88 ± 0.05 to 38.55 ± 0.05°C, respectively). Ruminal temperature was not influenced (P= 0.23) by day from 1 d before to 3 d after parturition (38.49 ± 0.05°C). Ruminal temperature at 0 to 8 h after detection of estrus (38.98 ± 0.09°C) was greater (P< 0.001) compared with RuT at the same daily hour of the day before (38.37 ± 0.11°C) or the day after estrus (38.30 ± 0.09°C). Ambient temperature did not influence (P> 0.30) RuT at parturition or estrus. Ruminal temperature decreased the day before parturition and increased at estrus in spring-calving beef cows and has potential use as a predictor of parturition and estrus.

Zirconium at normal conditions (room temperature and atmospheric pressure) has an HCP structure with lattice parameters a= 3.2313 Å and c= 5.1477 Å (α‐phase). During loading under hydrostatic conditions in diamond anvil cells, a transition from the α‐phase to an ω‐phase occurs at a pressure between 2 and 6 GPa and from ωto β(bcc) at 30 GPa. It has been recently reported that the αto ω+ βtransformation might be induced by HPT processing. The resulting microstructures are stable at room temperature and atmospheric pressure. This paper explores the influence of previous processing steps and of composition in the feasibility of the HPT induced αto α+ βtransformation. It will be shown that neither previous quenching nor high temperature HPT processing prevents the transformation from occurring during subsequent room temperature HPT. The addition of elements such as Nb also seems to favor the transformation. Understanding well the potential of HPT to stabilize high‐pressure phases at normal conditions might be critical, as it will open a whole new range of applications for already existing materials.

OBJECTIVE: To analyze mortality due to Hymenoptera stings in Costa Rica during 1985-2006. METHODS: Records of deaths due to Hymenoptera stings in 1985-2006 were retrieved from Instituto Nacional de Estadística y Censos (National Statistics and Census Institute). Mortality rates were calculated on the basis of national population reports, as of 1 July of each year. Information for each case included age, gender, and the province in which the death occurred. In addition, reports of Hymenoptera sting accidents received by the Centro Nacional de Intoxicaciones (National Poison Center, CNI) in 1995-2006 were obtained to assess exposure to these insects. RESULTS: Over the 22-year period analyzed, 52 fatalities due to Hymenoptera stings were recorded. Annual mortality rates varied from 0-1.73 per 1 million inhabitants, with a mean of 0.74 (95% confidence interval: 0.46-0.93). The majority of deaths occurred in males (88.5%), representing a male to female ratio of 7.7:1. A predominance of fatalities was observed in the elderly (50 years of age and older), as well as in children less than 10 years of age. The province with the highest mortality rate was Guanacaste. The CNI documented 1,591 reports of Hymenoptera stings (mostly by bees) in 1995-2006, resulting in an annual average of 133 cases, with only a slight predominance of males over females (1.4:1). CONCLUSIONS: Stings by Hymenoptera, mostly by bees, constitute a frequent occurrence in Costa Rica that can be life-threatening in a small proportion of cases, most often in males and the elderly. The annual number of fatalities fluctuated from 0-6, averaging 2.4 deaths per year. Awareness should be raised not only among the general population, but also among health care personnel that should consider this risk in the clinical management of patients stung by Hymenoptera. [ABSTRACT FROM AUTHOR]

Thin organic coated steels have been widely used in the building industry due to their formability, anticorrosive and antifinger print characteristics. In this work paintability properties of these coated steels were studied. Several thin organic coated steel sheets were treated by means of a roll coater following standard procedures (primer + topcoat) and only with topcoat (in this case, the thin organic coating was used as a primer). Characterization tests were carried out in terms of gloss, hardness, adherence and corrosion resistance.

Abstract: The ascomycete Fusarium fujikuroi produces carotenoids by means of the enzymes encoded by three car genes. The enzymes encoded by carRA and carB are responsible of the synthesis of β-carotene and torulene, respectively, while the product encoded by carT cleaves torulene to produce the acidic xanthophyll neurosporaxanthin. carRA and carB are found in a cluster with a third gene, carO, which codes for an opsin-like protein. However, no information is available on the sequence or chromosomal location of carT, which has been identified only by mutant analysis. Transcription of the three clustered genes is stimulated by light and by mutations in a regulatory gene, leading to overproduction of carotenoids. We have now identified a fourth gene in the car cluster, called carX, which codes for a protein similar to known carotenoid-cleaving oxygenases. carX is transcribed divergently from carRA, and exhibits the same transcriptional pattern as carRA, carB and carO. Targeted deletion of carX resulted in a phenotype characterized by a significant increase in the overall carotenoid content. In the dark, the carX mutants accumulate at least five times more carotenoids than the wild type, and exhibit partial derepression of carRA and carB transcription. The mutants also show more intense pigmentation in the light, but the increase in the carotenoid content relative to the wild type is less than twofold. Under these conditions, the mutants also show a relative increase in the amounts of phytoene and cyclic carotenoids formed, suggesting that CarRA activity is enhanced.

This study sought to assess the effect of giardiasis on growth of young children. In Salvador, northeast Brazil, 597 children initially aged 6 to 45 months were followed for a year in 1998/9, measured anthropometrically thrice, every 6 months, and monitored for diarrhoea prevalence twice weekly. Stool samples were collected and examined during the second round of anthropometry, and infected children were treated 39 days later, on average (S.D. 20 days). For each 6-month interval, the gains in z-scores of infected and uninfected children were compared, after adjustment for potential confounding factors, including longitudinal prevalence of diarrhoea. No significant difference was found for the first interval but in the second, the gain in adjusted height-for-age z-score was 0·09 less in infected than uninfected children, equivalent to a difference in height gain of 0·5 cm. The shortfall in growth was greater in children who remained free of diarrhoea, and was significantly correlated with the proportion of the second interval during which the child had remained untreated. We conclude that Giardia can impede child growth even when asymptomatic, presumably through malabsorption. This finding challenges the view that young children found to have asymptomatic giardiasis in developing countries should not be treated.

Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain:  reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.

We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38α inhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFα release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.

A cross-sectional study of 694 children aged 2 to 45 months selected from 30 clusters throughout the city of Salvador, Bahia (pop. 2·3 million) was carried out as part of a longitudinal study of diarrhoea in order to identify risk factors for infection with Giardia duodenalis. Variables studied included three social and demographic factors (such as mother's education and marital status), five relating to the peri-domestic environment (rubbish disposal, open sewers, paving of the street), seven relating to the home itself (house construction, susceptibility to flooding, water supply and sanitation) as well as a score for hygiene behaviour based on structured observation. After multivariate analysis using a hierarchical model, only four significant risk factors were found: (a) number of children in the household under five years (b) rubbish not collected from the house (c) presence of visible sewage nearby, and (d) absence of a toilet. All four were significant at the 1% level.

A novel structural class of picornavirus inhibitors comprising an imidazo[1,2-b]pyridazine nucleus was discovered. 2-Aminoimidazo[1,2-b]pyridazines (6d, (E/Z)-7b, (E)-7d, (Z)-7d, (E/Z)-8b, (E)-10b, (E)-13a, (Z)-13a, (E)-13b, (Z)-13b, (E)-13c, and (Z)-13c) were designed and synthesized in an effort to identify potent broad spectrum antirhinoviral agents. A practical synthetic route to this chemical scaffold has been developed. The target compounds were evaluated in a plaque reduction assay and in a cytopathic effect assay. Our preliminary SAR studies highlight the minimum structural features required for antirhinovirus activity. Our data suggest that the nature of the linker between the phenyl and the imidazopyridazine moieties has a significant influence on the activity of these compounds. Oximes are slightly better than vinyl carboxamides at this position. The oximes are the most potent analogues against human rhinovirus 14 (HRV-14), and at the concentrations evaluated, no apparent cellular toxicity is noted. Furthermore, the E geometry appears to be a key element for activity; the Z isomer leads to a considerable loss in potency. Of particular interest, analogue 7b exhibits potent broad-spectrum antirhinoviral and antienteroviral activity when evaluated against a panel of seven additional rhino- and enteroviruses. The chemistry and the biological evaluations are discussed.

Abstract: Pure aluminum deformed in pure shear at elevated temperature reaches a broad “peak” stress and then undergoes about a 17 pct decrease in flow stress with deformation with, roughly, 1 to 2 equivalent uniaxial strain. Beyond this strain, the flow stress is approximately constant. The sources for this softening are unclear. The suggested basis includes texture softening, microstructural softening, enhanced dynamic recovery, and discontinuous dynamic recrystallization. Experiments were performed in which specimens were deformed in torsion to various strains within the softening regime followed by compression tests at ambient and elevated temperature. Analysis of the compressive yield strengths indicate that the softening is most likely substantially explained by a decrease in the average Taylor factor.

Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine:  the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.

The calcitonin-gene-related peptide (CGRP) receptor component protein (RCP) is a 148-amino-acid intracellular protein that is required for G-protein-coupled signal transduction at receptors for the neuropeptide CGRP. RCP works in conjunction with two other proteins to constitute a functional CGRP receptor: calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein 1 (RAMP1).CRLR has the stereotypical seven-transmembrane topology of a G-protein-coupled receptor; it requires RAMP1 for trafficking to the cell surface and for ligand specificity, and requires RCP for coupling to the cellular signal transduction pathway. We have made cell lines that expressed an antisense construct of RCP and determined that CGRP-mediated signal transduction was reduced, while CGRP binding was unaffected. Furthermore, signalling at two other endogenous G-protein-coupled receptors was unaffected, suggesting that RCP was specific for a limited subset of receptors.

Abstract. Phytoene synthase, phytoene dehydrogenase and carotene cyclase are three of the four enzyme activities needed to produce the acidic carotenoid neurosporaxanthin from the precursor geranylgeranyl pyrophosphate. In the filamentous fungus Fusarium fujikuroi, these three enzyme activities are encoded by two closely linked genes, carRA and carB, oriented in the same direction in the genome. The two genes are separated by 548 bp and code for two polypeptides of 612 and 541 amino acids, respectively, which are highly similar to the homologous proteins from other filamentous fungi. The ORF of carRA contains a 96-bp insertion that is absent in the other fungal homologues. The 32 additional residues are located in one of the two repeated domains responsible for the cyclase activity in the homologous fungal proteins. We have determined the function of carRA by gene disruption. The resulting mutants were albino and had lost the ability to produce phytoene, as expected from the simultaneous loss of phytoene synthase and carotene cyclase. In the same experiments, we also found transformants in which carB had been deleted. These mutants accumulate phytoene, confirming the function of the gene previously shown by gene-targeted mutagenesis. Expression of carRA and carB is strongly induced by light. Loss of carB or disruption of the carRA ORF led to enhanced expression of the carRA gene, suggesting the existence of a feedback regulatory mechanism.

Abstract: Superplastic aluminum alloys are often classified according to the mechanism of microstructural transformation during annealing after deformation processing. In Al-Cu-Zr materials, such as Supral 2004, the presence of fine (10 to 50 nm) second-phase particles retards dislocation rearrangement and the formation and migration of boundaries during either annealing or elevated temperature deformation after thermomechanical processing. This leads to predominance of recovery in the evolution of microstructure, although high-angle boundaries must still form in order to account for the superplastic response of such materials. The mechanisms of high-angle boundary formation in such circumstances have remained unclear. The term “continuous recrystallization” (CRX) has been used as a phenomenological description of recovery-dominated processes that take place uniformly throughout the microstructure and lead to the formation of fine grains with high-angle boundaries. Orientation imaging microscopy (OIM) methods have been employed to assess the as-processed microstructure of this alloy and its evolution during annealing at 450 C, as well as during superplastic deformation at this temperature. Orientation images demonstrate the presence of deformation bands of alternating lattice orientations that corresponds to the symmetric variants of the brass, or B, texture component (〈112〉{110} in rolled material). During annealing, the high-angle grain boundaries (disorientation of 50 to 62.8 deg) develop from transition regions between such bands while the lower-angle boundaries (i.e., up to 20 deg) separate an evolving cell structure within the bands. Further OIM results show that the bands remain distinct features of the microstructure during either annealing alone or during deformation under superplastic conditions.

Abstract: Creep experiments were conducted on aluminum single crystals and copper polycrystals deformed within the five-power-law regime. The dislocation structure of copper, which has not been extensively characterized in the past, consists of less-well-defined subgrain walls of relatively low misorientation, typically between 0.1 and 0.3 deg, with a Frank network of dislocations within the subgrains. The aluminum, as expected, consisted of well-defined subgrain boundaries with a typical misorientation between 1.0 and 2.0 deg. The subgrains were probed from one boundary to another in copper and aluminum using convergent-beam electron diffraction (CBED). This allowed a determination of any changes in the lattice parameter, which would indicate the presence of any internal stresses. Earlier investigations by others suggested that internal stresses may be high in the vicinity of the “hard” subgrain boundaries in both loaded and unloaded specimens, based on a variety of techniques including X-ray diffraction (XRD), stress-dip tests, as well as some preliminary CBED. It was determined in this work that the lattice parameter was unchanged at the equilibrium or stress-free value within the interior of the subgrains and along (within a one-beam diameter) the subgrain boundaries.

Single crystals of copper were cyclically deformed, in single slip, to presaturation at 298 K. The dislocation substructure was analyzed using conventional bright-field and dark-field transmission electron microscopy with particular attention directed towards the dislocation dipole spacing. It was found that, in both metals, the dipole spacing and statistical distribution of spacings were independent of the location in the heterogeneous substructure, which consisted of dense dipole bundles (or veins) and channels with relatively low dislocation density. Furthermore, the stress to separate the dipoles with largest spacing (upper-bound separation for stable dipoles) can be used to calculate the stress at the dipole location. This stress is within a factor of about two of the applied stress in both channels and veins. The stress necessary to pass dislocations through the dense veins was calculated to also be within a factor of about two of the applied stress. Convergent-beam electron diffraction (CBED) experiments were also performed at several locations very near the dipole bundles and within the channels. The lattice parameter measurements also suggested an absence of long-range internal stresses. The observations and calculations suggest a uniform state of stress throughout the heterogeneous dislocation substructure, without the presence of significant internal stresses.

In this paper the shrinkage of Dates (Phoenix dactilyfera L.) during drying was observed. Samples were dried in a convective tray dryer under three different conditions (60°C-11.1%RH, 70°C-7.2%RH and 80°C-4.7%RH) and three different air velocities (0.5m/s, l.0m/s and 1.5m/s). Sample shrinkage was directly (using a caliper) and indirectly measured (snapshot area measured). The indirect manner shows a higher precision. The geometry applied in the shrinkage solution proved that the ellipsoidal geometry of the dates, may be successfully approached to a cylinder. Three mathematical models developed by Suzuki et al. (1976) were applied to correlate the dates surface to its moisture content. The core model presented the best fit to the experimental data.

Two distinct microstructural transformation processes have been observed to enable superplastic response in aluminium alloys, depending upon the composition and thermomechanical history. Continuous recrystallization has been used to describe the transformation leading to a superplastically enabled state in alloys that respond to processing, as does the commercial alloy Supral 2004. Such a transformation is characterized by significant retention of the deformation microstructure and texture. Microtexture analysis methods have been employed to examine the grain–boundary misorientation distribution in as–processed Supral 2004, and its evolution during annealing of this alloy. A bimodal boundary misorientation distribution is observed in as–processed material and is seen to persist through subsequent annealing. Comparison of correlated (nearest neighbour) and uncorrelated (predicted by the texture) grain–boundary misorientation data reveals that the populations of boundaries in the misorientation ranges of 0–15° and 55–62.8° exceed those predicted. A model is presented describing high–angle boundaries as interfaces between symmetric variants of the deformation texture components. The misorientation distribution of lower angle boundaries can be fitted by a probability density function. It is concluded that grain subdivision into deformation bands during severe straining leads to the formation of high–angle grain boundaries as interfaces between symmetric variants of deformation texture components, while lower angle boundaries develop by dislocation reaction within these variants, leading to observed bimodal grain–boundary misorientation distributions. During post–processing static annealing, stable coarsening of deformation–induced features occurs gradually and homogeneously throughout the microstructure without recrystallization involving the formation of new grains by the migration of high–angle grain boundaries. The ability to quantify and model the reactions that occur during thermomechanical processing, and that lead to the microstructures present in Supral 2004, will facilitate processing for similar reactions in a wider family of aluminium alloys for enhanced formability.