Conclusions: This study shows that the SN abnormality observed by

Conclusions: This study shows that the SN abnormality observed by TCS

is a specific feature, which can be helpful in the process of PD diagnosing.”
“The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus(1). In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity(2). However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine(3). This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells(4). www.selleckchem.com/products/ag-881.html However, different studies have suggested either a requirement(5)

or a lack of function(6) for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target LY3023414 clinical trial genes. Recent studies identified a late step of reprogramming associated with methylation status(7), and implicated a secondary

set of pluripotency network components(8). AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.”
“Here, U0126 in vitro we present LNCipedia (http://www.lncipedia.org), a novel database for human long non-coding RNA (lncRNA) transcripts and genes. LncRNAs constitute a large and diverse class of non-coding RNA genes. Although several lncRNAs have been functionally annotated, the majority remains to be characterized. Different high-throughput methods to identify new lncRNAs (including RNA sequencing and annotation of chromatin-state maps) have been applied in various studies resulting in multiple unrelated lncRNA data sets. LNCipedia offers 21 488 annotated human lncRNA transcripts obtained from different sources. In addition to basic transcript information and gene structure, several statistics are determined for each entry in the database, such as secondary structure information, protein coding potential and microRNA binding sites. Our analyses suggest that, much like microRNAs, many lncRNAs have a significant secondary structure, in-line with their presumed association with proteins or protein complexes.

Applications of

Applications of Cediranib in vitro these models have been made within the field of toxicology, most notably for the screening of mutagenic and carcinogenic potential and for the characterization of toxic mechanisms of action. It has long been a goal of research toxicologists to use the data from these models to refine hazard identification and characterization to better inform human health risk assessments. This review provides an overview on the applications of transgenic animal models in the assessment of mutagenicity and carcinogenicity, their use as reporter systems, and as tools for understanding the roles of xenobiotic-metabolizing enzymes and biological

receptors in the etiology

of chemical toxicity. Perspectives are also shared on the future outlook for these models in toxicology and risk assessment and how transgenic technologies are likely to be an integral tool for toxicity testing in the 21st century.”
“We report on the design, synthesis, and structural analysis of cyclic oligomers with an amyloidogenic peptide sequence as the repeating unit to obtain novel self-assembling bionanomaterials. The peptide was derived from the Alzheimer A beta(16-22) sequence since its strong tendency to form antiparallel beta-sheets ensured the formation of intermolecular hydrogen bridges on which the supramolecular assembly of the individual GDC-0973 ic50 cyclic oligomers was based. The synthesis of the cyclic oligomers was performed via a microwave-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of azido-Lys-Leu-Val-Phe-Phe-Ala-Glu-propargyl amide as the monomer. The formation of cyclic oligomers, up to pentamers (35 amino acid residues), was verified by MALDI-TOF analysis

and the individual cyclic monomer and dimer could be isolated by HPLC. Gelation behavior and the self-assembly of the linear monomer and the cyclic monomer and dimer were studied by TEM, FTIR and CD. Significant differences were observed in the morphology of the supramolecular aggregates of these three peptides that could be https://www.selleckchem.com/products/wh-4-023.html explained by alterations of the hydrogen bond network.”
“A mixed MEKC method for the analysis of budesonide and its related substances is presented. The micelles were formed from sodium cholate (CHOL) and 3-(N,N-dimethylmyristylammonio) propanesulfonate (MAPS). A multivariate optimisation was carried out with the aim of obtaining a baseline separation of all compounds. The influence of voltage, borate concentration, cholate concentration, MAPS concentration and pH was evaluated on the responses, corresponding to critical resolution values. Problems with the investigated experimental design were encountered due to the complexity of the separation process.

However, controversial results have been reported regarding the r

However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is learn more missing. We investigated the effects of the NMDAR antagonist

dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons; in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. We found that MK-801 induced distinct changes of NMDAR subunits in the parvalbumin-immunoreactive (PV-ir) interneurons vs. pyramidal neurons in the PFC circuitry. The messenger RNA (mRNA) expression of all NMDAR subtypes, including NR1 and NR2A to Torin 1 2D, exhibited inverted-U dose-dependent changes in response to MK-801 treatment

in the PFC. In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons

and GABAergic interneurons in the prefrontal cortical circuitry.”
“Background Thyrotropin-releasing hormones (TRH) added to prenatal corticosteroids has been suggested as a way to further reduce breathing problems and neonatal lung disease in infants born preterm.\n\nObjectives To assess the effects of giving prenatal TRH in addition to corticosteroids to women at risk of preterm birth for the prevention of neonatal respiratory disease.\n\nSearch methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 June 2013) and reference lists of retrieved studies. We also contacted trial authors.\n\nSelection criteria Randomised controlled trials in women at selleck chemicals llc sufficient risk of preterm birth to warrant the use of prenatal corticosteroids to promote lung maturity. TRH and corticosteroids were compared with corticosteroids, with or without placebo.\n\nData collection and analysis All assessments of trial eligibility, risk of bias and data extractions were independently carried out by at least two review authors.\n\nMain results Over 4600 women were recruited into the 15 trials included in the review, however two trials did not contribute any outcome data to the review. The trials had a moderate risk of bias.

Amnion-derived cellular cytokine solution (ACCS), a secreted prod

Amnion-derived cellular cytokine solution (ACCS), a secreted product of AMP cells, is a cocktail of cytokines existing at physiological

levels and has been used to accelerate epithelialization of experimental partial-thickness burns.\n\nMethods Using modifications of Zawacki’s guinea pig partial-thickness scald burn model, a total of 65 animals were treated with ACCS, ACCS + AMP cells, unconditioned medium (UCM) + AMP cells, or either UCM alone or saline as controls. Dosage times ranged from every other day to once a week. Percent epithelialization click here was serially determined from acetate wound tracings. Histology was performed on wound biopsies.\n\nResults ACCS, UCM + AMP cells, and ACCS + AMP cells improved epithelialization compared this website with the two control groups (P < 0.05). When ACCS was delivered more frequently, statistically significant more rapid epithelialization occurred (P < 0.05). By day 7, all groups treated with ACCS had reached at least 90% epithelialization, whereas control groups were only 20-40% epithelialized (P < 0.05). Histology showed excellent regeneration of the epidermis with rete ridge formation. Hair growth occurred in ACCS-treated animals but not in the control group.\n\nConclusions Amnion-derived

cellular cytolcine solution accelerates the healing of experimental partial-thickness burns. Based on these findings, a multicenter clinical trial is underway.”
“How do we recognize people that are familiar to us? There is overwhelming evidence that our brains process voice and face in a combined fashion to optimally

recognize both who Selleck Torin 2 is speaking and what is said. Surprisingly, this combined processing of voice and face seems to occur even if one stream of information is missing. For example, if subjects only hear someone who is familiar to them talking, without seeing their face, visual face-processing areas are active. One reason for this crossmodal activation might be that it is instrumental for early sensory processing of voices a hypothesis that is contrary to current models of unisensory perception. Here, we test this hypothesis by harnessing a temporally highly resolved method, i.e., magnetoencephalography (MEG), to identify the temporal response profile of the fusiform face area in response to auditory-only voice recognition. Participants briefly learned a set of voices audio-visually, i.e., together with a talking face. After learning, we measured subjects’ MEG signals in response to the auditory-only, now familiar, voices. The results revealed three key mechanisms that characterize the sensory processing of familiar speakers’ voices: (i) activation in the face-sensitive fusiform gyms at very early auditory processing stages, i.e., only 100 ms after auditory onset, (ii) a temporal facilitation of auditory processing (M200), and (iii) a correlation of this temporal facilitation with recognition performance.

Here we tested whether this effect can be observed in the absence

Here we tested whether this effect can be observed in the absence of some of the visual areas showing a preferential response to faces as typically identified in neuroimaging. Event-related potentials were recorded in response to faces, cars, and their phase-scrambled versions in a well-known brain damaged case of prosopagnosia

(PS). Despite the patient’s right inferior occipital gyrus lesion encompassing the most posterior cortical area showing preferential response to faces (“occipital face area”), we identified an early face-sensitive component over the right occipito temporal hemisphere of the patient that was identified as the N170. A second experiment supported this conclusion, showing the typical N170 increase of latency and amplitude in response to inverted faces. In contrast, MS-275 supplier there was no N170 in the left hemisphere, where PS has a lesion to the middle fusi form gyrus and shows no evidence of face preferential response in neuroimaging( no left “fusiform face area”). These results were replicated by a magnetoencephalographic investigation of the patient, disclosing a ON-01910 M170 component only in the right

hemisphere. These observations indicate that face preferential activation in the inferior occipital cortex is not necessary to elicit early visual responses associated with face perception (N170/M170) on the human scalp. These results further suggest that when the right inferior occipital cortex is damaged, the integrity of the middle fusiform gyrus and/or the superior temporal sulcus – two areas showing face-preferential responses in the patient’s right hemisphere – might be necessary to generate the N170 effect.”
“Mitochondrial reactive oxygen species regulate many important biological GSK2118436 inhibitor processes. We studied H2O2 formation by nonsynaptic brain mitochondria in response to the addition of low concentrations of glutamate, an excitatory neurotransmitter. We demonstrated that glutamate at concentrations from 10 to 50 mu M stimulated the H2O2 generation in mitochondria up to 4-fold, in a dose-dependent manner. The effect of glutamate was observed

only in the presence of Ca2+ (20 mu M) in the incubation medium, and the rate of calcium uptake by the brain mitochondria was increased by up to 50% by glutamate. Glutamate-dependent effects were sensitive to the NMDA receptor inhibitors MK-801 (10 mu M) and D-AP5 (20 mu M) and the inhibitory neurotransmitter glycine (5 mM). We have shown that the H2O2 formation caused by glutamate is associated with complex II and is dependent on the mitochondrial potential. We have found that nonsynaptic brain mitochondria are a target of direct glutamate signaling, which can specifically activate H2O2 formation through mitochondrial respiratory chain complex II. The H2O2 formation induced by glutamate can be blocked by glycine, an inhibitory neurotransmitter that prevents the deleterious effects of glutamate in brain mitochondria. (C) 2013 Elsevier Inc. All rights reserved.

Conversely, Notch pathway genes continue to oscillate in the pres

Conversely, Notch pathway genes continue to oscillate in the presence of stabilized beta-catenin but boundary formation is delayed and anteriorized. Together, these results suggest that the Wnt3a/beta-catenin pathway is permissive but not instructive for oscillating clock genes and that it controls the anterior-posterior positioning of boundary formation VX-770 inhibitor in the presomitic mesoderm (PSM). The Wnt3a/beta-catenin pathway does so by regulating the activation of the segment boundary determination genes Mesp2 and Ripply2 in the PSM through the activation of the Notch ligand Dll1 and the mesodermal transcription factors T and Tbx6. Spatial restriction

of Ripply2 to the anterior PSM is ensured by the Wnt3a/beta-catenin-mediated repression of Ripply2 in posterior PSM. Thus, Wnt3a regulates somitogenesis by activating a network of interacting target genes that promote mesodermal fates, activate the segmentation clock, and position boundary determination genes in the anterior PSM.”
“The aim of the present study was to investigate whether locomotor stimulation training

could have beneficial effects on the morphometric alterations of spinal cord and sciatic nerve consequent to sensorimotor restriction (SR). Male Wistar AZD5582 rats were exposed to SR from postnatal day 2 (P2) to P28. Control and experimental rats underwent locomotor stimulation training in a treadmill for three weeks (from P31 to P52). The cross-sectional area (CSA) of spinal motoneurons innervating hind limb muscles was determined. Both fiber and axonal CSA of myelinated fibers were also assessed. The growth-related increase in CSA of motoneurons in the SR group was less than controls. After SR, the mean motoneuron soma size was reduced with an increase in the proportion of

motoneurons with a soma size of between 0 and 800 mu m(2). The changes in soma size of motoneurons were accompanied by a reduction in the mean fiber and axon CSA of sciatic nerve. The soma size of motoneurons was reestablished at the end of the training period reaching controls level. Our results suggest that SR during early postnatal life retards the growth-related increase in the cell body size of motoneurons in spinal cord and the development of sciatic nerve. Additionally, three weeks of locomotor stimulation Small molecule library screening using a treadmill seems to have a beneficial effect on motoneurons’ soma size. (C) 2011 ISDN. Published by Elsevier Ltd. All rights reserved.”
“The in vitro infectivity and genotype of three IPNV strains (V70, V112 and V98) was linked to the level of transcript synthesis for the Mx3 protein in RTG-2 (Rainbow trout gonad) cells and in Salmo salar. The V70 and V98 strains corresponded to the Sp genotype, whilst the V112 corresponded to VR-299: the presence of Pro-217 and Ala-221 in VP2 identified V70 as a strain of medium virulence level whilst V112 (Ala-217 and Thr-221) and V98 (Pro-217 and Thr-221) were of low virulence.

Conclusion:

Conclusion: SIS3 inhibitor Assessing the significance of compound similarity computed with PhAST allows for a statistically motivated identification of candidate screening compounds. Inhibitors of Aurora A kinase were retrieved from a large compound library.”
“Introduction: Sacral nerve modulation (SNM) is an established and successful treatment for fecal incontinence. We present the first successful case in Greece, performed in our department.\n\nPatients and Methods: A 60-year-old female patient presented with a 5-year-old history of fecal incontinence. The Cleveland Clinic

Florida (CCF) Incontinence Score was 15. Endoanal ultrasound did not show defects of the internal or external anal sphincter. Conservative and pharmacological therapy was unsuccessful. The patient subsequently underwent a total pelvic floor repair, which was also unsuccessful. After discussing further options, the patient gave consent for percutaneous nerve evaluation (PNE), for possible permanent stimulator implantation.\n\nResults: A quadripolar lead was placed percutaneously through the dorsal S3 foramen under local anesthesia. This was connected to a test stimulator (Medtronic Interstim Model 3625, selleckchem Minneapolis, MN). The stimulator was activated

for a period of 4 weeks. At the end of the test period, the CCF Incontinence score was 5. This was considered successful. A permanent stimulator (Medtronic Interstim Implantable Pulse Generator Model 3058, Minneapolis, MN) was then implanted under local anesthesia. Two months after permanent implantation, the Wexner Epigenetic inhibitor cost Score has not increased.\n\nConclusion: SNM is a relatively simple, safe and minimally invasive

technique for the treatment of fecal incontinence. Hippokratia 2011; 15 (4): 366-369″
“The presence of reticuloendotheliosis virus (REV) was examined in flocks affected with Marek’s disease (MD). Sera were positive to REV antibodies by agar gel precipitation. However, these findings were not conclusive since fowlpox vaccines can have REV fragments or the whole genome inserted. Frozen sections from tumors were positive for MD virus (MDV) but negative for REV. Chicken embryo fibroblast (CEF) and chicken kidney cell (CKC) culture inoculated with buffy coat cells or blood from the affected birds were examined. Positive cells were shown for REV and MDV by fluorescent antibodies tests in CEF and CKC, respectively, indicating the presence of REV in Argentinean layer flocks. This is the first report of REV in Argentina and also in South America.”
“Head injury has been recognized as an increasingly important determinant of late-life cognitive function Despite a large number of research and clinical studies, no direct link has been established between minor head trauma with or without loss of consciousness and the development of dementia of the Alzheimer type.

Provision of healthy snacks and improved perceived behavioral con

Provision of healthy snacks and improved perceived behavioral control regarding sugar avoidance might restrict snacking during school hours.”
“Length-frequency data of eight commercial fish species in the Beibu Gulf (Golf of Tonkin), northern South China Sea, were collected during 2006-2007. Length-weight relationships and growth and mortality parameters were analyzed using FiSAT II software. Five species had isometric growth, two species had negative allometric growth,

and one species had positive allometric growth. Overall, the exploitation rates of the eight species BVD-523 were lower in 2006-2007 than in 1997-1999: for four species (Saurida tumbil, Saurida undosquamis, Argyrosomus macrocephalus, and Nemipterus virgatus) it was lower in 2006-2007 than in 1997-1999, for two species (Parargyrops edita and Trichiurus haumela) it remained the same, and for the other two species (Trachurus japonicus and Decapterus maruadsi) it was higher in 2006-2007 than in 1997-1999. The exploitation rates might have declined because of the decline in fishing intensity caused by high crude oil prices. The optimum exploitation rate, estimated using Beverton-Holt dynamic pool models, indicated that although fishes in the Beibu Gulf could sustain high exploitation rates,

the under-size fishes at first capture resulted in low yields. To increase the yield per recruitment, selleck inhibitor it is more effective to increase the size at first capture than to control fishing effort.”
“Cross sectional serological surveys were conducted between March and December 2009 to determine the distribution of foot-and-mouth disease and also to validate the current passive surveillance system in Bhutan. A total of 1909 YM155 clinical trial sera collected from cattle, goats, sheep, and pigs, from 485 herds in 106 villages, were tested using a foot-and-mouth disease non-structural protein 3ABC ELISA. The true prevalence at the animal-level for all species was 15% (95% CI: 13.5,

16.7) using the sensitivity (97.2%) and specificity (99.5%) for cattle. The true prevalence for cattle, goats, sheep and pigs were 17.6 (95% CI: 15.6, 19.5), 11.9% (95% CI: 5.6, 18.3). 11.9% (95% CI: 1.3, 25.1), and 1.9% (95% CI: 0.0, 3.8), respectively.\n\nThe sub-districts that shared border with India had significantly (p = 0.03) higher seroprevalence than the interior sub-districts. Villages located in the sub-tropical zone had significantly (p < 0.0001) higher seroprevalence than those located at high altitude zones. Herds with known outbreaks of FMD were 3.6 times more likely (p < 0.001) to be seropositive than those with no history of outbreaks of FMD. The study showed the usefulness of population-based serological surveys in detecting circulation of active infection in populations which were, until now, considered to be free of disease based on a passive surveillance system.

This is the first attempt

to knock out multiple, nearly i

This is the first attempt

to knock out multiple, nearly identical, genes in a cellular genome using ZFN. The attempt failed, and other strategies should be used to prevent PERV transmission.”
“Clinical trials typically examine associations between an intervention and the occurrence of a clinical event. The association is often reported as a relative risk, more rarely as an odds ratio. Unfortunately, when the scientific interest lies with the ratio of incidence rates, both these statistics are inaccurate: the odds ratio is too extreme, and the relative risk too conservative. These biases are particularly strong when the outcomes are common. This paper describes an alternative statistic, the P5091 Ubiquitin inhibitor selleck compound ratio of logarithms of event-free proportions (or relative log survival), which is simple to compute yet unbiased vis-a-vis the relative hazard. A formula to compute the sampling error of this statistic is also provided. Multivariate analysis can be conducted using complementary log-log regression. Precise knowledge of event occurrence times is not required for these analyses. Relative log survival may be particularly useful for

meta-analyses of trials in which the proportion of events varies between studies. (C) 2008 Elsevier Inc. All rights reserved.”
“A new coumarin derivative (8-methylcoumaro-4a,10a-pyrone-3-carbaidehyde benzoyl hydrazone) ligand and its novel Cu(II) complex have been synthesized and characterized on the basis of elemental analyses, molar conductivities, (1)H-NMR, IR spectra, UV-visible spectroscopy and thermal analyses. In addition, the interactions of the Cu(II) complex and the ligand with calf-thymus DNA were investigated by spectrometric titrations, ethidium bromide displacement experiments and viscosity measurements. It

was found that both the two compounds, specially the Cu(II) complex, strongly bind with calf-thymus DNA, presumably via an intercalation mechanism.”
“Experiments were performed with the aim of determining the influence of vitamins A and E on the fluctuations in rectal temperature (RT) of Black Harco pullets during the hot-dry season. The RT of 29 experimental and 20 control pullets were measured every hour from 06:00 to 19:00 https://www.selleckchem.com/products/wzb117.html hours for three days. The experimental pullets were administered vitamins A and E orally at 1200IU/kg and 30mg/kg, respectively. The control pullets were given water only. The lowest hourly RT of 41.030.03C was obtained in experimental pullets at 06:00h, while the highest value of 41.230.04C was recorded at 18:00h (P0.001). In control pullets, the RT rose significantly from 41.000.04C at 06:00h to a maximum value of 41.610.04C at 15:00h (P0.001). It is concluded that vitamins A and E decreased the thermally stressful effect of the hot-dry season, and may enhance the productivity and health of pullets during the season.

Other proteins, such as psoriasin, galectin 1, cofilin, peroredox

Other proteins, such as psoriasin, galectin 1, cofilin, peroredoxins, SH3L1, and others, showed sporadic presence and high expression

level, which suggests their possible role for patient stratification.”
“The Golgi complex is essential for many aspects of cellular function, including trafficking and sorting of membrane and secretory proteins and posttranslational modification by glycosylation. We observed reversible fragmentation of the Golgi complex in cultured hippocampal neurons cultured this website in hyperexcitable conditions. In addition, Golgi fragmentation was found in cultured neurons with hyperactivity due to prolonged blockade of GABA(A)-mediated inhibition or withdrawal of NMDA receptor antagonism. The interplay between neuronal hyperactivity and Golgi structure established in this study thus reveals a previously uncharacterized impact of neuronal activity on organelle structure. This finding may have important roles in protein processing and trafficking in the Golgi as well as effects on neuronal signaling.”
“Objective: The objective of our study was to field test different chronic migraine (CM) criteria and compare CM epidemiological profiles, which include demographic, personal, and lifestyle characteristics, with high-frequency episodic migraine (HFEM) and low-frequency episodic migraine (LFEM).\n\nMethods:

Questionnaires were mailed to a random sample of 18,000 18-65-year-olds in demographically diverse regions of Germany. The epidemiological data for the three classifications of CM, LFEM and HFEM were assessed using descriptive statistics, 3-deazaneplanocin A molecular weight Pearson Chi-square, and analysis of variance tests.\n\nResults: Among 9350 respondents, CM_I was the most restrictive (N=37, 0.4%), followed by CM_II (N=45, 0.5%) and CM_III (N=185, 2.0%). CM groups did not differ in distribution by age, gender, body mass index, education or smoking and find more alcohol consumption. Compared to those with LFEM and HFEM, those with CM (CM_III) had significantly different epidemiological profiles.\n\nConclusions:

CM prevalence varies by case definition. The epidemiological profiles of the three CM groups are similar but differ significantly from those of HFEM and LFEM. Optimal definitions for clinical practice and epidemiological research require additional field testing.”
“Purpose of review\n\nBladder cancer development in organ transplant recipients remains a complex problem to manage as it has been demonstrated that the clinical course seems worse than in the general population. Most of the reports on bladder cancer after organ transplantation were done for kidney transplantation. Both virally and nonvirally are involved in bladder tumor development. The immunosuppressed status of the transplant recipients renders the screening, the therapeutic management, and the post-treatment surveillance very difficult.