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Purpose: Several studies have shown that subcutaneous injections of omalizumab can treat chronic idiopathic/spontaneous urticaria (CIU/CSU) patients by only assessing the efficacy on specific endpoints. This study aimed to quantitatively analyze different doses of omalizumab in CIU/CSU and compare it with ligelizumab. Methods: Literature searches were performed in PubMed, Embase, and Web of Science databases. A model-based meta-analysis (MBMA) was utilized to develop a model incorporating time since the initiation of treatment and dose for omalizumab, with the change from baseline in Urticaria Activity Score (CFB-UAS7) as the primary efficacy endpoint. The time-course and dose-effect relationship throughout the omalizumab treatment period was analyzed, and the findings were compared with those of the investigational ligelizumab. Results: The model equation for the CFB-UAS7 was established as E = –Emax × time/(ET50 + time) × (b0 + b1 × dose). The estimated values of the model parameters E max , ET 50 , b 0 , and b 1 were −1.16, 1.26 weeks, −9.90, and −0.0361 mg−1, respectively. At week 12 after the first dose, the model-predicted CFB-UAS7 for 150 mg and 300 mg of omalizumab were −16.0 (95% CI, −17.2 to −14.8) and −21.7 (95% CI, −22.9 to −20.5), respectively. In the PEARL-1 trial, the CFB-UAS7 for 72 mg and 120 mg of ligelizumab were −19.4 (95% CI, −20.7 to −18.1) and −19.3 (95% CI, −20.6 to −18.0), respectively. In the PEARL-2 trial, these values were −19.2 (95% CI, −20.5 to −17.9) and −20.3 (95% CI, −21.6 to −19.0), respectively. Conclusion: Omalizumab showed a significant dose-dependent effect in the treatment of CSU. Both 72 mg and 120 mg ligelizumab might have the potential to outperform 150 mg (but not 300 mg) omalizumab. [ABSTRACT FROM AUTHOR]

Guided by the idea that memory retrieval is selective attention turned inward, we report four experiments examining the time-course of focusing attention on memory. We used a novel episodic flanker task that turns the famous perceptual flanker task inward, presenting memory lists followed by probes that asked whether a cued letter had appeared in the same position in the memory list. Like the perceptual flanker task, we manipulated distance to measure the sharpness of the focus of attention on memory, and compatibility to measure the resistance to distraction. To measure the time-course of focusing, we presented a cue indicating the probed position in the interval between the list and the probe and varied the interval between the cue and the probe (0, 250, 500, 750 ms). The main questions were whether the focus would become sharper and resistance to distraction would become stronger as cue–probe delay increased. Experiments 1a and 1b showed strong distance effects and strong cue–probe interval effects but no reliable interaction between them. Experiments 2a and 2b showed robust compatibility effects and cue–probe interval effects but no interaction between them. Thus, there is no evidence that the sharpness of the focus increases and little evidence that the resistance to distraction improves over time. The robust reduction in response time and slight increase in accuracy with cue–probe interval may reflect the time-course of orienting to the cued position in the memory list prior to focusing on the item it contains. [ABSTRACT FROM AUTHOR]

Bloodstains are crucial pieces of physical evidences found at violent crime scenes, providing valuable information for reconstructing forensic cases. However, there is limited data on how bloodstain lipidomes change over time after deposition. Hence, we deployed a high-throughput high-performance liquid chromatography–mass spectrometry (HPLC–MS) approach to construct lipidomic atlases of bloodstains, whole blood, plasma, and blood cells from 15 healthy adults. A time-course analysis was also performed on bloodstains deposited for up to 6 months at room temperature (~ 25°C). The molecular levels of 60 out of 400 detected lipid species differed dramatically between bloodstain and whole blood samples, with major disturbances observed in membrane glycerophospholipids. More than half of these lipids were prevalent in the cellular and plasmic fractions; approximately 27% and 10% of the identified lipids were uniquely derived from blood cells and plasma, respectively. Furthermore, a subset of 65 temporally dynamic lipid species arose across the 6-month room-temperature deposition period, with decreased triacylglycerols (TAGs) and increased lysophosphatidylcholines (LPCs) as representatives, accounting for approximately 8% of the total investigated lipids. The instability of lipids increased linearly with time, with the most variability observed in the first 10 days. This study sheds light on the impact of air-drying bloodstains on blood components at room temperature and provides a list of potential bloodstain lipid markers for determining the age of bloodstains. [ABSTRACT FROM AUTHOR]

The cyanobacterium Synechocystis sp. strain FS 78 was recently isolated from chromium polluted paddy fields in the North of Iran. In the present work, the effect of chromium (VI) was studied at extreme alkaline conditions (pH 11) on the growth, pigment composition, function of photosystems and phycobilisomes. We monitored the cyanobacterium viability in the presence of chromium (VI) from 0.5 to 5 µM every hour up to 6 h inoculation time. An increase in growth, pigment production, photosystems and phycobilisomes activities was observed in cells grown at low concentration (0.5 µM) of chromium (VI). The toxicity of higher chromium concentrations (3.5 and 5 µM) was observed after 1 h of inoculation. Confocal laser microscopy analysis showed the toxic effect of elevated chromium (VI) concentration on viability, probably due to the damage of the photosystem and phycobilisome structures, which on the long-term was able to recover. We concluded that the combination of the three factors (extreme alkaline pH, different concentrations of Cr(VI) and time) can affect cyanobacterial behaviours individually or in combination. [ABSTRACT FROM AUTHOR]

Introduction: Manganese is important for the endocarditis pathogen Streptococcus sanguinis. Little is known about why manganese is required for virulence or how it impacts the metabolome of streptococci. Objectives: We applied untargeted metabolomics to cells and media to understand temporal changes resulting from manganese depletion. Methods: EDTA was added to a S. sanguinis manganese-transporter mutant in aerobic fermentor conditions. Cell and media samples were collected pre- and post-EDTA treatment. Metabolomics data were generated using positive and negative modes of data acquisition on an LC–MS/MS system. Data were subjected to statistical processing using MetaboAnalyst and time-course analysis using Short Time series Expression Miner (STEM). Recombinant enzymes were assayed for metal dependence. Results: We observed quantitative changes in 534 and 422 metabolites in cells and media, respectively, after EDTA addition. The 173 cellular metabolites identified as significantly different indicated enrichment of purine and pyrimidine metabolism. Further multivariate analysis revealed that the top 15 cellular metabolites belonged primarily to lipids and redox metabolites. The STEM analysis revealed global changes in cells and media in comparable metabolic pathways. Glycolytic intermediates such as fructose-1,6-bisphosphate increased, suggesting that enzymes that utilize them require manganese for activity or expression. Recombinant enzymes were confirmed to utilize manganese in vitro. Nucleosides accumulated, possibly due to a blockage in conversion to nucleobases resulting from manganese-dependent regulation. Conclusion: Differential analysis of metabolites revealed the activation of a number of metabolic pathways in response to manganese depletion, many of which are connected to carbon catabolite repression. [ABSTRACT FROM AUTHOR]

Hexaploid spring wheat (Triticum aestivum) may exhibit significant crown rot disease responses to infection by Fusarium pseudograminearum, with a range of susceptibility levels available in commercial cultivars. Dry conditions during grain-fill may lead to the expression of prematurely senescing culms, which typically fail to set grain. Assessment of hexaploid spring wheat plants exhibiting both non-senescent and prematurely senescent culms was performed using visual discolouration, F. pseudograminearum biomass and vascular colonisation in culm sections sampled at three different heights above the crown and at the peduncle. Samples from six commercial cultivars were collected at milk development in 2014 from Narrabri and Tamworth, New South Wales and Wellcamp, Queensland. Prematurely senescent culms exhibited greater visual discolouration, F. pseudograminearum biomass and vascular colonisation than non-senescent culms in each cultivar. A further comparison of the parameters across four time points from milk development, when senescent culms are first observed, to maturity was conducted for cultivar Sunlin. F. pseudograminearum biomass and vascular colonisation were significantly different between culm conditions prior to maturation, while visual discolouration was not significantly different between culm conditions at any single time point. Colonisation of xylem and phloem tissue was extensive in the basal portions of prematurely senescent culms (36 to 99%) prior to maturation, and suggests significant impacts on water and nutrient movement during crown rot disease. Despite a range of resistance ratings being assessed, cultivars were not reliably separated based upon responses to severe disease pressure, demonstrating the continuing need for improved crown rot resistance in commercial wheat. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to establish a pharmacodynamic model to quantitatively compare the efficacy characteristics of seven kinds of triptans and their different dosage forms in the treatment of acute migraines. Methods: Clinical studies of triptans in the treatment of acute migraines were comprehensively searched in the public databases. Pharmacodynamic models were established to describe the dose-effect and time-course of each kind of triptan for the proportion of patients who became pain free or had pain relief. Results: A total of 92 articles involving 47,376 subjects were included in the analysis. After eliminating the placebo effect, oral eletriptan (40 mg) had the highest efficacy among all oral drugs at the maximum approved dose, and the proportion of patients who became pain free and had pain relief were 30.9% and 37.9% at 2 h, respectively. However, oral naratriptan (2.5 mg) had the lowest efficacy, and the proportion of patients who became pain free and had pain relief was 10.3% and 21.6% at 2 h, respectively. The efficacy of subcutaneous administration was significantly higher than that of oral administration, and the efficacy of nasal spray administration was comparable to that of oral administration. Regarding the dose-effect, the efficacy of the sumatriptan nasal spray significantly increased within the FDA (Food and Drug Administration)-approved dose range. When the dose was increased from 5 to 20 mg of sumatriptan nasal spray, the proportion of patients who became pain free and had pain relief increased by 16.8% and 18.3% at 2 h, respectively. Regarding the time-course, the time of onset of subcutaneous sumatriptan (6 mg) was the fastest, and the fraction of patients who were pain free at 2 h accounted for 90.6% of that at 4 h. Conclusions: This study evaluated the efficacy characteristics of seven kinds of triptans and their different dosage forms. The present findings provide necessary quantitative information for migraine medication guidelines. [ABSTRACT FROM AUTHOR]

Although there exists increasing knowledge about brain correlates underlying creative ideation in general, the specific neurocognitive mechanisms implicated in different stages of the creative thinking process are still under-researched. Some recent EEG studies suggested that alpha power during creative ideation varies as a function of time, with the highest levels of alpha power after stimulus onset and at the end of the creative thinking process. The main aim of the present study was to replicate and extend this finding by applying an individual differences approach, and by investigating functional coupling between long distance cortical sites during the process of creative ideation. Eighty-six participants performed the Alternate Uses (AU) task during EEG assessment. Results revealed that more original people showed increased alpha power after stimulus onset and before finalizing the process of idea generation. This U-shaped alpha power pattern was accompanied by an early increase in functional communication between frontal and parietal-occipital sites during the creative thinking process, putatively indicating activation of top-down executive control processes. Participants with lower originality showed no significant time-related variation in alpha power and a delayed increase in long distance functional communication. These findings are in line with dual process models of creative ideation and support the idea that increased alpha power at the beginning of the creative ideation process may indicate more associative modes of thinking and memory processes, while the alpha increases at later stages may indicate executive control processes, associated with idea elaboration/evaluation. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic degenerative disease that leads to joint failure, pain, and disability. Gene regulation is implicated as a driver of the imbalance between the expression of catabolic and anabolic factors that eventually leads to the degeneration of osteoarthritic cartilage. In our model, knee-joint OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate (MIA) injections. Whole-genome microarrays were used to analyse the alterations in gene expression during the time-course of OA development (at 2, 14, and 28 days post-injection) in rat knee joints. The identified co-expressed groups of genes were analysed for enriched regulatory mechanisms, functional classes, and cell-type-specific expression. This analysis revealed 272 regulated transcripts (ANOVA FDR < 0.1% and fold > 2). Functionally, the five major gene expression patterns (A-E) were connected to PPAR signalling and adipogenesis (in cluster A), WNT signalling (in cluster B), endochondral ossification (in cluster C), matrix metalloproteinases and the ACE/RAGE pathway (in cluster D), and the Toll-like receptor, and IL-1 signalling pathways (in cluster E). Moreover, the dynamic profiles of these transcriptional changes were assigned to cellular compartments of the knee joint. Classifying the molecular processes associated with the development of cartilage degeneration provides novel insight into the OA disease process. Our study identified groups of co-regulated genes that share functional relationships and that may play an important role in the early and intermediate stages of OA. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the impact of dynamic distractors on the time-course of oculomotor selection using saccade trajectory deviations. Participants were instructed to make a speeded eye movement (pro-saccade) to a target presented above or below the fixation point while an irrelevant distractor was presented. Four types of distractors were varied within participants: (1) static, (2) flicker, (3) rotating apparent motion and (4) continuous motion. The eccentricity of the distractor was varied between participants. The results showed that saccadic trajectories curved towards distractors presented near the vertical midline; no reliable deviation was found for distractors presented further away from the vertical midline. Differences between the flickering and rotating distractor were found when distractor eccentricity was small and these specific effects developed over time such that there was a clear differentiation between saccadic deviation based on apparent motion for long-latency saccades, but not short-latency saccades. The present results suggest that the influence on performance of apparent motion stimuli is relatively delayed and acts in a more sustained manner compared to the influence of salient static, flickering and continuous moving stimuli. [ABSTRACT FROM AUTHOR]

Gadolinium (Gd) enhancement of multiple sclerosis (MS) lesions on MRI scans is a commonly used outcome measure in therapeutic trials. However, enhancement depends on MRI acquisition parameters that might significantly alter detectability. We investigated how the difference in blood-brain barrier (BBB) permeability threshold between MRI protocols affects lesion detection and apparent enhancement time using dynamic-contrast-enhanced (DCE) MRI. We examined fourty-four relapsing-remitting MS patients with two MRI protocols: 'standard sensitivity' (SS) (1.5 T, single-dose Gd) and 'high sensitivity' (HS) (3 T, triple-dose Gd, delayed acquisition). Eleven patients had at least one enhancing lesion and completed the 1-month follow-up. We acquired DCE-MRI during the HS protocol and calculated BBB permeability. Sixty-five lesions were enhanced with the SS vs. 135 with the HS protocol. The detection threshold of the HS was significantly lower than that of the SS protocol ( K = 2.64 vs. 4.00E−3 min, p < 0.01). Most lesions (74 %) were in the recovery phase; none were in the onset phase and 26 % were at the peak of enhancement. The estimated duration of detectability with the HS protocol was significantly longer than for the SS protocol (6-12 weeks vs. 3 weeks). Our observations on the protocol-dependent threshold for detection and time-course help explain discrepancies in the observed effects of anti-inflammatory therapies on MS lesions. [ABSTRACT FROM AUTHOR]

Rationale: The notion that the onset of action of antidepressant drugs (ADs) takes weeks is widely accepted; however, the sequence of events necessary for therapeutic effects still remains obscure. Objective: We aimed to evaluate a time-course of ADs-induced alterations in the expression of 95 selected genes in 4 regions of the rat brain: the prefrontal and cingulate cortices, the dentate gyrus of the hippocampus, and the amygdala. Methods: We employed RT-PCR array to evaluate changes during a time-course (1, 3, 7, 14, and 21 days) of treatments with desipramine (DMI) and citalopram (CIT). In addition to repeated treatment, we also conducted acute treatment (a single dose of drug followed by the same time intervals as the repeated doses). Results: Time-dependent and structure-specific changes in gene expression patterns allowed us to identify spatiotemporal differences in the molecular action of two ADs. Singular value decomposition analysis revealed differences in the global gene expression profiles between treatment types. The numbers of characteristic modes were generally smaller after CIT treatment than after DMI treatment. Analysis of the dynamics of gene expression revealed that the most significant changes concerned immediate early genes, whose expression was also visualized by in situ hybridization. Transcription factor binding site analysis revealed an over-representation of serum response factor binding sites in the promoters of genes that changed upon treatment with both ADs. Conclusions: The observed gene expression patterns were highly dynamic, with oscillations and peaks at various time points of treatment. Our study also revealed novel potential targets of antidepressant action, i.e., Dbp and Id1 genes. [ABSTRACT FROM AUTHOR]

Rationale: Discovery of an endocannabinoid signaling system launched the development of the blocker rimonabant, a cannabinoid CB1 receptor (CBR) antagonist/inverse agonist. Due to untoward effects, this medication was withdrawn and efforts have been directed towards discovering chemicals with more benign profiles. Objective: This study aims to comparatively evaluate new ligands using a rimonabant discriminated drinking aversion procedure. Methods: Rats discriminated between rimonabant (5.6 mg/kg) and vehicle. The 30 min saccharin (0.1%) drinking after rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental animals. After vehicle pretreatment, experimental animals were given i.p. NaCl (10 ml/kg). Postdrinking treatment for controls was NaCl, irrespective of pretreatment condition (rimonabant or vehicle). Results: The centrally acting neutral CBR antagonist AM4113, but not the limited brain penetrating CBR neutral antagonist AM6545, substituted for rimonabant. The CBR agonists THC (1-10 mg/kg), AM1346 (1-10 mg/kg) did not substitute. The rimonabant-induced conditioned suppression of saccharin drinking was attenuated when CBR agonists AM5983 (0.01-1 mg/kg) and THC (10 mg/kg), but not the CBR agonist AM1346 (0.1-18 mg/kg), were combined with rimonabant (5.6 mg/kg). By varying the injection-to-test interval, we gauged the relative duration of the cueing effects of rimonabant, and the in vivo functional half-life was estimated to be approximately 1.5 h. Conclusion: A neutral CBR antagonist (AM4113) produced cueing effects similar to those of rimonabant and generalization likely was centrally mediated. The functional cueing effects of rimonabant are relatively short-acting, pharmacologically selective, and differentially blocked by cannabinergics. [ABSTRACT FROM AUTHOR]

Despite the evidence describing the rapid vascular function modifications to commencement and cessation of large muscle exercises (i.e. cycling), no studies examined the time-course vascular modifications to localized training and detraining. This study aimed to examine the effects of 4-week rhythmic handgrip exercise training and 2-week detraining on reactive hyperemic forearm blood flow and vascular resistance in 11 young men. Rhythmic handgrip exercise was performed in the non-dominant forearm for 20 min/day, 5 days/week, at 60% of maximum voluntary contraction for 4 weeks, followed by 2 weeks of no training. Forearm blood flow and vascular resistance were evaluated, in both arms, at rest and following arterial occlusion. These vascular function indices were obtained in five visits; before, after 1 and 4 week(s) of training as well as after 1 and 2 week(s) of training cessation. Resting cardiovascular measures were not altered during the study period. A 2 (arms) x 5 (visits) ANOVA revealed significant arms-by-visits interactions for reactive hyperemic forearm blood flow (p = 0.02) and vascular resistance (p = 0.02). Subsequent comparison demonstrated increased trained forearm reactive hyperemic blood flow 1 week after training, then returned to pre-training values 1 week following training cessation. In contrast, vascular resistance decreased 1 week after training commencement, only to return to pretraining level 1 week after training cessation. These results indicate a rapid, unilateral improvement in regional reactive hyperemic blood flow and vascular resistance following localized exercise-training. However, the improvements are transient and return to pretraining levels 1 week after detraining. [ABSTRACT FROM AUTHOR]

Since its invasion to the North American waters 20 years ago, the zebra mussel ( Dreissena polymorpha) has negatively impacted the ecosystems through its firm underwater adhesion. The molecular mechanisms governing the functions of the zebra mussel byssus, the main structure responsible for maintaining the underwater adhesion, have received little attention. Our previously developed zebra mussel foot byssus cDNA microarray was applied in this study to identify the genes involved in different stages of the byssal threads generation. Byssal threads of zebra mussels were manually severed under laboratory conditions and the formation of new byssal threads was followed over a 3 week course. By comparing the gene expression profiles in different stages of byssal threads generation (byssogenesis) to their baseline values, we found that the number of unique byssus genes differentially expressed at 12-h, 1, 2, 3, 4, 7, and 21 days post-treatment was 13, 13, 20, 17, 16, 20, and 29, respectively. Comparisons were also made between two subsequent samples (e.g., 12 h vs. 1, 1 vs. 2 days, 2 vs. 3 days, and so on). Seven differentially expressed genes were selected for validation by using quantitative reverse transcription PCR (qRT-PCR) and the results were consistent with those from the microarray analysis. By using fluorescent in situ hybridization, we found that two microarray identified genes, BG15_F03-DPFP and BG16_H05-EGP, were expressed in two major byssus glands located in the zebra mussel foot: the stem-forming gland and plaque-forming gland, respectively. Moreover, the qRT-PCR of seven microarray identified genes with different zebra mussel samples suggested that they were also expressed in other mussel tissues beside the foot, albeit at much lower levels. This suggested that the microarray identified genes were produced primarily by the foot, and were likely associated with byssogenesis. The differentially expressed genes identified in this study indicated that multiple molecules are involved in byssogenesis, most likely performing multiple functions during the generation of byssal threads. These results obtained herein represent the first logical step toward understanding underwater attachment mechanisms employed by this invasive species. [ABSTRACT FROM AUTHOR]

In order to determine the sensitivity and specificity of the test and to optimize experimental conditions utilizing the SBT in a rat model of chemotherapy-induced small intestinal damage. Initially, a 13C-sucrose dose-response study was performed in rats to determine an optimal sucrose concentration for the SBT; then applied to assess chemotherapy-induced intestinal damage. A further study was conducted to establish a SBT time-course of methotrexate-induced small intestinal damage and repair. Animals were killed at 96 or 144 h. A sucrose concentration of 0.25 g/ml was optimal (20% CV) for reproducibility and detection of intestinal damage. Maximal damage occurred at 72 h, small intestinal repair was initiated by 96 h and continued at 144 h post-MTX, as determined by the SBT and confirmed by biochemical analyses. Levels of sensitivity and specificity for the SBT were 98 and 94%, respectively. The SBT is a reliable non-invasive marker of small intestinal health and damage with a high degree of sensitivity and specificity. [ABSTRACT FROM AUTHOR]

During early visual processing the eyes can be captured by salient visual information in the environment. Whether a salient stimulus captures the eyes in a purely automatic, bottom-up fashion or whether capture is contingent on task demands is still under debate. In the first experiment, we manipulated the relevance of a salient onset distractor. The onset distractor could either be similar or dissimilar to the target. Error saccade latency distributions showed that early in time, oculomotor capture was driven purely bottom-up irrespective of distractor similarity. Later in time, top-down information became available resulting in contingent capture. In the second experiment, we manipulated the saliency information at the target location. A salient onset stimulus could be presented either at the target or at a non-target location. The latency distributions of error and correct saccades had a similar time-course as those observed in the first experiment. Initially, the distributions overlapped but later in time task-relevant information decelerated the oculomotor system. The present findings reveal the interaction between bottom-up and top-down processes in oculomotor behavior. We conclude that the task relevance of a salient event is not crucial for capture of the eyes to occur. Moreover, task-relevant information may integrate with saliency information to initiate saccades, but only later in time. [ABSTRACT FROM AUTHOR]

Rationale: Positron emission tomography (PET) has been utilized for determining the dosage of antipsychotic drugs. To evaluate the dosage of antidepressants such as selective serotonin reuptake inhibitors, serotonin transporter occupancy (5-HTT) is also a useful index. Objectives: We investigated the degree of 5-HTT occupancy with different doses of the antidepressant duloxetine and the time-course of 5-HTT occupancy using PET. Methods: PET scans with [11C]DASB were performed before and after a single administration of duloxetine (5--60 mg), and three consecutive scans were performed after a single dose or repeated doses of 60 mg of duloxetine. Results: 5-HTT occupancies by duloxetine were increased by 35.3 to 86.5% with dose and plasma concentration increments. The ED50 value of 5-HTT occupancy was 7.9 mg for dose and 3.7 ng/ml for plasma concentration. In the time-course of 5-HTT occupancy, mean occupancies were 81.8% at 6 h, 71.9% at 25 h, and 44.9% at 53 h after a single administration, and 84.3% at 6 h, 71.9%at 49 h, and 47.1% at 78 h after repeated administrations. Conclusions: Based on 5-HTT occupancy, 40 mg and more of duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of 5-HTT occupancy with a once-a-day administration schedule. [ABSTRACT FROM AUTHOR]

A meiotic time-course for Arabidopsis pollen mother cells has been established based on BrdU pulse-labelling of nuclear DNA in the meiotic S-phase. Labelled flower buds were sampled at intervals and the progress of labelled cells through meiosis assessed by anti-BrdU antibody detection. The overall duration of meiosis from the end of meiotic S-phase to the tetrad stage, at 18.5°C, was 33 h, which is about three times longer than the mitotic cell cycle in seedlings. The onset of leptotene was defined by reference to the loading of the axis-associated protein Asy1, and this permitted the detection of a definite G2 stage, having a maximum duration of 9 h. It is likely, from two independent sources of evidence, that the meiotic S-phase has a duration similar to that of G2. The durations of leptotene and zygotene/pachytene are 6 h and 15.3 h, respectively, but the remaining meiotic division stages are completed very rapidly, within 3 h. The establishment of a meiotic time-course provides a framework for determining the relative timing and durations of key molecular events of meiosis in Arabidopsis in relation to cytologically defined landmarks. In addition, it will be important in a broader developmental context for determining the timing of epigenetic mechanisms that are known or suspected to occur during meiosis. [ABSTRACT FROM AUTHOR]

One reason the electrophysiological correlates of hippocampal neurons are of interest is the possibility that they reflect their representational properties, presumably spatial/relational ones. Stable spatial representations, based on activity of ensembles of hippocampal place cells, initially develop through a series of short-episodic spatial tunings. Hence these short-episodic spatial tunings are important for understanding the establishment of stable place fields. Studies of age-related changes in place cell activities traditionally focus on place fields. In the present study, we characterized the short-episodic spatial tunings (1-min bins) of hippocampal CA1 place cells of freely moving mice in a familiar cylinder arena, and compared these functions in young and old mice. Spatial tuning was expressed by spatial selectivity, which we found fluctuated across a 16-min recording session in both young and old mice. High spatial selectivity, which is mainly due to the low firing of a place cell out of the place field in young mice, was significantly higher in old mice. The high firing rate out of the place field was the main factor contributing to significantly lower spatial selectivity in old mice. In addition, young mice showed a broad peak in the spatial selectivity between 4 and 10 min. In contrast old mice showed no peak in the spatial selectivity during this time period. The stability of place fields after a 24-h interval was also lower in old mice than in young mice. The low spatial tuning and unstable place fields suggest that a hippocampal-based spatial representation was impaired in the old mice. Furthermore, we speculate that the age-related impairment in hippocampal inhibition system may be involved in the impaired spatial representation of hippocampal CA1 place cells in old mice. [ABSTRACT FROM AUTHOR]

Oral administration of inorganic arsenic has been shown to lead to an accumulation of copper in the kidneys of rats and guinea pigs. However, nothing is known about the characteristics and mechanisms of this organ-specific renal copper accumulation. Many heavy metals accumulate in the kidney, either after environmental or occupational exposure. An additional accumulation of any other trace metals, even essential ones, may therefore be critical for that organ. This prompted us to follow the course of the renal copper accumulation. Rats were given daily subcutaneous doses of sodium arsenite for 12 d. Each second day, three rats were killed by exsanguination and the liver, kidneys, and blood removed and analysed for As, Cu, and other trace elements by atomic emission spectrometry. Results indicate that arsenic and copper accumulate in the kidney cortex synchroneously over time. Arsenic also accumulated in the liver and red blood cells (RBC). Copper levels in the RBC and liver as well as copper excretion into the urine were unaffected. After terminating arsenite administration, there was a slow decline in tissue levels of both arsenic and copper, a phenomenon which was parallel for both metals. Because the copper level in the liver was not affected, it is concluded from this study that renal processes and not hepatic or biliary mechanisms might be responsible for the renal copper accumulation. Furthermore, the strong linear correlation ( r=0.85) between arsenic and copper levels in the kidney during and after arsenite administration suggests a functional relationship between arsenic and copper with respect to their retention in the kidney. [ABSTRACT FROM AUTHOR]

Learning-induced changes of the spectro-temporal characteristics of primary auditory cortex (AI) units were studied by response plane analysis of recordings from the AI in unanaesthetized Mongolian gerbils. Using response planes obtained prior to and after auditory discrimination training bins of significant change were identified and their spectro-temporal distribution was studied. Bins of significant changes were generally found to be distributed over the entire spectro-temporal receptive field but occurred most frequently within the first 100 ms of response in the spectral neighbourhood (1.5 octaves) of the frequency of the reinforced conditioned stimulus. Training-induced response decreases occurred early after 10 ms for reinforced conditioned tones and tones in the frequency neighbourhood. Response increases occurred so early only for non-reinforced tones in the neighbourhood of the reinforced frequency and occurred later (after 40 ms) for the reinforced tones. The results are discussed in the light of dynamic disinhibition. [ABSTRACT FROM AUTHOR]

The course and determinants of insulin action were investigated in 8 newly diagnosed Type 1 (insulin-dependent) diabetic patients, who were studied every 3 months for one year, and in three groups of 8 patients each with 5, 10 and 20 years diabetes, studied once. Fifteen healthy subjects matched for age, sex and body weight served as control subjects. Dose-response curves were constructed using sequential euglycaemic (5.0 mmol/l) clamps (insulin infusion rates: 0.5, 1.0, 2.0 and 5.0 mU·kg·min in periods of 2h). After 1/2 month of insulin treatment, insulin responsiveness was normal, but sensitivity was decreased (ED 70±7 mU/l (SEM) vs 54±4mU/l in control subjects, p<0.05). After 6 months, insulin sensitivity was improved (ED 57±4 mU/l, p<0.01 vs 1/2 month and not significant (NS) vs control subjects); but after 9 and 12 months, it was reduced again, similarly to 0.5 month. Insulin responsiveness remained normal at all time-points. In the three groups of patients with longstanding diabetes, impaired insulin sensitivity with normal responsiveness was noted also (ED 73±9 mU/l, p<0.02 vs control subjects). At 6, 9 and 12 months, glycaemic control (HbA) and insulin dose were inverse correlates for insulin action; in patients with longstanding disease, this was noted for HbA and body weight, in control subjects for body weight. In conclusion, decreased insulin sensitivity re-develops in Type 1 diabetes within the first year following an initial improvement. Presumably, hyperglycaemia plays a role in the pathogenesis of this recurrence. [ABSTRACT FROM AUTHOR]

Rats received subcutaneous injections of either nicotine (NIC; 0.05-0.8 mg/kg) or vehicle [VEH (phosphate buffer); 1 ml/kg] immediately after conditioning sessions in a place-conditioning paradigm (delay conditioning). NIC was paired for three delay-conditioning sessions with one environment of a three-compartment place-conditioning apparatus; VEH was paired with another environment. The subjects were then tested for place preference or aversion by determining the proportion of time spent in each compartment during a 15-min test session. Delay conditioning with NIC only produced a dose-related place aversion (greater time was spent in the VEH-paired chamber on test day). Place aversion was evident when NIC, 0.8 mg/kg, was administered either immediately or 5 min after conditioning sessions but not when given 15 min after conditioning. Chlorisondamine (5 μg, lateral ventricle), but not saline, administered 2 weeks prior to delay conditioning with 0.8 mg/kg NIC completely blocked the NIC-induced place aversion. These data suggest that delay conditioning with NIC produces place aversion by a central mechanism. Since standard conditioning (NIC injection immediately before the place-conditioning sessions) with NIC only produced dose-related place preferences (Fudala et al. 1985; Fudala and Iwamoto 1986), the time of administration of the unconditioned stimulus is a strong determinant of the place-conditioning effects of NIC. [ABSTRACT FROM AUTHOR]

Four male rats performed during 35-min sessions under a schedule that arranged water delivery (0.04 ml) after every fortieth response. Cocaine (1.0-16.0 mg per rat, i.p.) was administered 15 min, 30 min, 60 min or 120 min prior to a session. When given 15 min prior to a session, cocaine (1.0-8.0 mg) in all rats produced dose-related decreases in responding. The largest dose, when given 15 min pre-session to two rats, almost completely suppressed responding. Lengthening the time between drug injection and test session attenuated the rate-decreasing effects of cocaine (1.0-8.0 mg), but did not affect the almost complete suppression of performance seen with the largest dose. Small doses (1.0-4.0 mg) had no effect on the pause in responding that occurred after water delivery. The 8.0-mg dose lengthened the pause by approximately 9000% and 650% when given 15 and 30 min prior to a session, respectively, but by less than 50% when given 60 or 120 min pre-session. Cocaine effects depend on the dose as well as the time of its administration prior to testing. [ABSTRACT FROM AUTHOR]

Introduction: Zinc is a heavy metal commonly detected in urban estuaries around Australia. Boscalid is a fungicide found in estuaries, both in water and sediment, it enters the system predominantly through agricultural run-off. Zinc is persistent while boscalid breaks down, with a half-life of 108 days. Both contaminants are widely distributed and their effects on ecosystems are not well understood. Objectives: The aim of this study was to determine the metabolite changes in Simplisetia aequisetis (an estuarine polychaete) following laboratory exposure to a sub-lethal concentration of zinc or boscalid over a 2-week period. Methods: Individuals were collected at six time points over a 2-week period. Whole polychaete metabolites were extracted and quantified using a multi-platform approach. Polar metabolites were detected using a semi-targeted GC–MS analysis and amine containing compounds were analysed using a targeted LC–MS analysis. Total lipid energy content was also analysed for Simplisetia aequisetis. Results: The pathways that responded to zinc and boscalid exposure were alanine, aspartate and glutamate metabolism (AAG); glycine, serine and threonine metabolism (GST) and metabolites associated with the tricarboxylic acid cycle (TCA). Results showed that changes in total abundance of some metabolites could be detected as early as 24-h exposure. Changes were detected in the metabolites before commonly used total lipid energy assays identified effects. Conclusion: A multi-platform approach provided a holistic overview of the metabolomic response to contaminants in polychaetes. This approach shows promise to be used in biomonitoring programs to provide early diagnostic indicators of contamination and exposure. [ABSTRACT FROM AUTHOR]

In rats trained to eat during a five-hour daily period, cocaine (10, 15, and 25 mg/kg) depressed food intake. The anorexia was seen during the 1st h only, with no effect on total food intake. [ABSTRACT FROM AUTHOR]