Here and throughout this article, X^ denote an estimate of X   W

Here and throughout this article, X^ denote an estimate of X  . Wang and Swail, 2006 and Wang et al., 2010 applied this model to simulate seasonal mean or 12-hourly HsHs in the global oceans and in the North Atlantic, respectively, with spatial resolution of 2°°. Recently, Wang et al. (2012) extended the set of predictors in model (1), adding the principle components (PCs) of P(t,m)P(t,m)

and of G(t,m)G(t,m) over a domain that is larger than the wave field in question to represent the swell component of waves, as well as p  -lagged dependent variables, Hs(t-p,m)Hs(t-p,m), to account for serial correlation in the predictand (dependent variable) HsHs. They also proposed a data adaptive Box–Cox Seliciclib solubility dmso transformation procedure to diminish the departure of HsHs and SLP gradients from a normal distribution. They have shown that their new model is more skillful, resulting in less biased simulations of 6-hourly HsHs, than model (1). The methodological developments we propose below include physical and statistical aspects. On the physical aspects, we modify the way to account for swell waves by using the term ΔswΔsw as defined later in Section 4.2, and the way to account

for serial correlation in HsHs using the term ΔtΔt defined later in Section 4.3. Thus, our new model is of the form: equation(2) H^s(t,m)=aˆ(m)+aˆP(m)P(t,m)+aˆG(m)G(t,m)+Δsw(t,m)+Δt(t,m). The last term makes the statistical model more coherent with ocean wave physics, because it can be interpreted selleck chemicals llc as a discrete approximation of the first order derivative that appears in the spectral energy balance governing equation (e.g. Holthuijsen, 2007). Such temporal dependence is especially important for high temporal resolution data as in the present study. In fact, it is closely related to the large autocorrelation found in the 3-hourly HsHs time series. More

details about the inclusion of this term are given in Section 4.3. On the statistical aspects, we take into account the data scale and explore the effects of deviation from the Gaussian distribution below assumption in the multiple linear regression analysis by transforming the data in different ways, as detailed below in Section 4.4. Since different regimes dominate in different seasons (see Section 2.1), waves in different seasons should be modeled, separately. In this study, we focus on the winter (most energetic) season, which is defined here as December–January–February. Swell waves are waves propagating across the ocean, after being generated remotely during a storm. As explained in Section 2.2, the Catalan coast is often affected by an important swell component coming from E. Ignoring swell waves would lead to a significant underestimation of HsHs.

Phytoplankton cells draw the energy to drive photosynthesis from

Phytoplankton cells draw the energy to drive photosynthesis from the sunlight entering the sea water. The quanta of this light are selectively absorbed by the various pigments contained in these cells. selleck kinase inhibitor However, only part of the energy activating the pigment molecules as a result of light absorption is expended during photosynthesis; the remainder is deactivated in two other processes, namely, fluorescence, and radiationless nonphotochemical quenching, which generates heat (Butler and Kitajima, 1975, Weis and Berry, 1987, Kolber and Falkowski,

1993 and Ostrowska, 2001). The objective of the present work is to investigate and model the distribution of the activation energy of phytoplankton pigment molecules among these three processes under the many and various conditions prevailing in the

marine environment. Photosynthesis itself is, of course, the most important of the three processes, its yield being governed by environmental factors determining their utilization of this energy. Our models describe the distribution of this energy by comparing the quantum yields and energy efficiencies of the three processes. These yields/efficiencies are complex functions of environmental state parameters. Our models take these relationships into account and enable the distribution of the pigment excitation energy to be calculated for the various selleck chemicals llc typical conditions obtaining in the waters of the World Ocean. The light-absorbing pigments in phytoplankton cells can be classified into two groups. One comprises the photosynthetic pigments, PSPs (the main abbreviations and symbols used in the text are listed in Annex 1), contains chlorophyll a and a set of pigments accessory to chlorophyll a. These accessory pigments absorb light from different spectral bands, and the energy thereby acquired drives the processes contributing to the photosynthesis

of organic matter. Plant cells form PSPs in order to make optimal use of the light spectrum available in their particular living environment. The other group consists of mafosfamide photoprotecting pigments (PPPs), which protect chlorophyll a at the photosynthetic reaction centres from an undesirable excess of light energy (e.g. Bartley and Scolnik, 1995, Majchrowski, 2001, Pascal et al., 2005 and Woźniak and Dera, 2007). Figure 1 shows in a simplified way how these pigments absorb this energy and how it is distributed among the various processes. Excited PPP molecules are mainly deactivated as a result of radiationless transitions, during which they release their excitation energy EAPPP to the surroundings in the form of heat EH1.

Sea-level rise, like the change of many other climate variables,

Sea-level rise, like the change of many other climate variables, will be experienced mainly as an increase in the frequency or likelihood (probability) of extreme events, rather than simply as a steady increase in an otherwise constant state. One of the most obvious adaptations Selleck ALK inhibitor to sea-level rise is to raise an asset (or its protection) by an amount that is sufficient to achieve a required level of precaution. The selection of such an allowance has often, unfortunately, been quite subjective and qualitative, involving

concepts such as ‘plausible’ or ‘high-end’ projections. Hunter (2012) described a simple technique for estimating an allowance for sea-level rise using extreme-value theory. This allowance ensures that the expected, or average, number of extreme (flooding) events in a given period is preserved. In other words, any asset raised by this allowance would experience the same frequency of flooding events under sea-level rise as it would without the allowance and without

sea-level rise. It is important to note that this allowance only relates to the effect of sea-level rise on inundation and not on the recession of soft (e.g. sandy) shorelines or on other impacts. Under conditions of uncertain sea-level rise, the ‘expected number of flooding events in a given period’ is here defined in the following way. It is supposed that there are n GSI-IX molecular weight   possible futures, each with a probability, P  i, of being realised. For each of these futures, the expected number Cell press of flooding events in a given period is given by N  i. The effective, or overall, expected number of flooding events (considering all possible futures) is then considered to be ∑i=1nPiNi, where ∑i=1nPi=1. In the terminology of risk assessment (e.g. ISO, 2009), the expected number of flooding events in a given period is known as the likelihood. If a specific cost may be attributed to one flooding event, then this cost is termed the consequence, and the combined effect (generally the product) of the likelihood and the consequence is the risk (i.e. the total effective cost of damage from flooding over the given period). The allowance is the height

that an asset needs to be raised under sea-level rise in order to keep the flooding likelihood the same. If the cost, or consequence, of a single flooding event is constant than this also preserves the flooding risk. An important property of the allowance is that it is independent of the required level of precaution (when measured in terms of likelihood of flooding). In the case of coastal infrastructure, an appropriate height should first be selected, based on present conditions and an acceptable degree of precaution (e.g. an average of one flooding event in 100 years). If this height is then raised by the allowance calculated for a specific period, the required level of precaution will be sustained until the end of this period.

The resting MP was recorded at times 5, 15, 30, 60 and 90 min and

The resting MP was recorded at times 5, 15, 30, 60 and 90 min and MEPPs at 5, 30, 60 and 90 min after MjTX-II administration. Recording sites were rejected if the membrane potential was less than – 65 mV on the initial impalement. Institutional Animal Care and Use Committee (Institute of Biosciences –

Sao Paulo State University – UNESP) approved this study under the number 033/05. Animal procedures were in accordance with the guidelines for animal care prepared by the Committee on Care and Use of Laboratory Animal Resources, National Research Council, USA. Results are expressed as mean ± S.E. Data were analyzed by ANOVA complemented by the Tukey–Kramer test. Values Pirfenidone chemical structure of P < 0.05 were considered significant. The crystal structure of MjTX-II was solved at 1.92 Å resolution reveling an asymmetric unit containing two monomers. As shown in Table 1, the refinement of the model converged to a final Rcryst

of 22.8% and an Rfree of 25.7%. The final model is constituted by 1916 non-hydrogen protein atoms, 186 water, four polyethylene glycol 4000 (PEG4K) and six isopropanol molecules. The overall stereochemical quality of the final MjTX-II structure was judged as satisfactory since 96.7% and 100% of the total number of amino acid residues are located in the favored and allowed regions of the Ramachandran plot respectively, according to their φ/ψ angle combinations. MjTX-II structure is stabilized by seven disulfide bridges and preserves the classical secondary structure elements found in this group of proteins, i.e., an N-terminal α-helix, a “short” helix, a non-functional Ca2+-binding loop, two anti-parallel α-helices (2 and 3), two short strands of Enzalutamide manufacturer anti-parallel β-sheet (known as β-wing), and a C-terminal loop (Fig. 1A). MjTX-II structure presents four PEG4K molecules interacting with it (Fig. 2): (i) two PEG4K (PEG 1 and 2) molecules are found Loperamide inside of the hydrophobic channels (one molecule in each protein protomer), displaying hydrogen bond with Gly30 and also other interactions with “active site” residues; (ii) one PEG4K (PEG 3) molecule interacts

at the same time with the residues Lys49 and Tyr52 from both monomers and (iii) one PEG4K (PEG 4) molecule interacts with Lys7, Trp77 and several other residues of monomer A (Fig. 3). Dynamic light scattering experiments indicates a mean hydrodynamic radius (RH) of 2.3 nm with a polydispersity of 12.0%. This RH value corresponds to a molecular weight of approximately 23 kDa and is, thus, equivalent to a dimer. These results are in agreement with other literature data for Lys49-PLA2s since electrophoresis, spectroscopic ( Arni et al., 1999 and da Silva Giotto et al., 1998), crystallographic ( Arni and Ward, 1996, dos Santos et al., 2009, Magro et al., 2003 and Murakami et al., 2005), small angle X-ray scattering ( Murakami et al., 2007) and dynamic light scattering ( Fernandes et al., 2010) experiments demonstrates that bothropic Lys49-PLA2s are dimeric in solution.

, 2008) Of those visiting their GP with a new episode of CANS, 3

, 2008). Of those visiting their GP with a new episode of CANS, 33% are diagnosed with SIS (Feleus

et al., 2008). Work-related factors associated with the occurrence of SIS are highly repetitive work, forceful exertion in work, awkward postures, and high psychosocial job demand (van Rijn et al., 2010). The consequences of SIS are functional loss and disability. Pathology of SIS is considered to be the principal cause of pain Inhibitor Library concentration and symptoms arising from the shoulder. In general, the diagnosis SIS relates more to a clinical hypothesis as to the underlying cause of the symptoms than to definitive evidence of the histological basis for the diagnosis or the correlation between structural failure and symptoms (Lewis, 2009). Some patients with SIS have calcific tendinosis, a reactive calcification that affects one of the rotator cuff tendons, which leads to the characteristic impingement symptoms (Sabeti-Aschraf et al., 2005). In the last 20 years extracorporeal shock-wave therapy (ESWT) has been used to treat soft tissue pain in the vicinity of bone structures (Chow and Cheing, 2007). The non-invasive ESWT is achieved through acoustic waves associated with a sudden rise in pressure generated by electrohydraulic, piezoelectric and electromagnetic devices resulting in release of low-, medium- Pirfenidone manufacturer or high-energy extracorporeal shockwaves (Uhthoff and Sarkar, 1989 and Ogden et al., 2001). ESWT

is currently applied to treat chronic enthesiopathies tuclazepam such as epicondylitis, plantar heel spur, and calcifying

rotator cuff tendinosis (RC-tendinosis) (Gerdesmeyer et al., 2002). The exact mechanism by which ESWT relieves tendon-associated pain is still unclear. The theoretical benefits are the stimulation of tissue healing (Schmitz and DePace, 2009). and the breakdown of calcification (Loew et al., 1995). Of those with a calcific RC-tendinosis, the supraspinatus tendon is most affected (80%) followed by the infraspinatus tendon (15%) and subscapularis tendon (5%) (Bosworth, 1941, Molé et al., 1997 and Bianchi and Martinoli, 2007). For these patients, ESWT is supposed to be successful. Moreover, ESWT is suggested to play a role in the management of non-calcific RC-tendinosis, especially in those who have had repeated non-surgical treatment failures (Chung and Wiley, 2002). The purpose of this study is to present an evidence-based overview of the effectiveness of ESWT for the management of calcific and non-calcific RC-tendinosis. This information can be helpful to further optimize the quality of care for patients with these disorders. Further, it can support developing and updating evidence-based protocols and clinical guidelines and it will identify gaps in our scientific knowledge and therefore can give direction to future research on calcific and non-calcific RC-tendinosis. This study was part of a literature study concentrating on evidence for effectiveness of non-surgical and surgical interventions for SIS.

e , median memory z-score) Instead, we used a function to empiri

e., median memory z-score). Instead, we used a function to empirically search for any potential breakpoints where the slopes of the two segments are significantly different, according to memory score. Thus, we fitted a two-segment model parameterized so as to estimate the difference in linear slope between the segments. The model was fitted using 120 breakpoints in order to locate the memory

scores at which there was a significant (p < .05) difference between segment slopes. The significant breakpoint that divided group size most evenly (in order to distribute power between segments as equally as possible) was then identified, and the model was then re-parameterized to estimate ABT-199 manufacturer and test the slopes of the two segments joined at this breakpoint. This was conducted for right frontal volumes (DLPFC and IFG) with Immediate and Delayed recall score. We then created a general measure of memory network integrity for each participant. We created standardised scores (mean = 100, SD = 15) for each MRI variable significantly associated with memory at the Akt inhibitor group level, and then compared the means between the participants on either side of the breakpoint. The compensatory hypothesis would predict that poorer performers would have a significantly lower mean score than their counterparts. Our

sample included 8 left-handed participants. It has been proposed that the role of handedness may be Glutathione peroxidase particularly relevant to performance

on some verbal memory tasks, such as paired associate recall (e.g., Lyle, McCabe, & Roediger, 2008). As such, we conclude by conducting sensitivity analysis, to check for any confounding of handedness on the reported results. Participant characteristics are described in Table 1 and the correlations among brain imaging variables can be found in Supplementary Table II. Compared to normed data for 70–74 year olds (Wechsler, 1998), participants’ mean scores on subtests were within the normal range, but slightly above the average scaled score of 10 on LM (scaled score = 13 for both I and II) and VPA (part I scaled score = 12, part II scaled score = 13). Within this, scaled scores ranged from very high to very low scores on LM (scaled score of 3–18 for part 1 and 4–19 for part II) and VPA (5–18 for part 1, 5–15 to II). Frontal volumes were generally well-correlated (r > .26, p < .05) apart from a non-significant correlation between right IFG and left DLPFC. Frontal volumes did not correlate significantly with callosal measures, nor were splenium and genu measures significantly related. We conducted correlations between the two verbal memory indices (Immediate and Delayed) against the 10 MRI-derived measures (bilateral region volumes of the IFG, DLPFC, and hippocampus, and FA and MD of the callosal splenium and genu) ( Fig. 1).

, 2004 and Rushworth et al , 2002), as volition or self-generated

, 2004 and Rushworth et al., 2002), as volition or self-generated actions (not externally cued) appear to be a common factor across experimental findings. For example, the Bereitschaftspotential – a negative premotor potential recorded over central frontal electrodes in humans – has larger peak amplitudes with self-initiated actions ( Deecke & Kornhuber, 1978); while in monkeys, lesions of the pre-SMA impair the ability to initiate arbitrary movements to obtain a reward, but the effect is ameliorated if the animals

GSI-IX clinical trial are cued with an external tone ( Thaler, Chen, Nixon, Stern, & Passingham, 1995). Unilateral inactivation of monkey pre-SMA with muscimol has been found to induce deficits in sequence learning, but performance of previously well-learnt sequences was left intact (Nakamura, Sakai, & Hikosaka, 1999). This has

led to the suggestion that this might reflect an impairment of the mechanism responsible for updating the association between the correct action given current conditions. Therefore, it is possible that deficits in self-initiated action observed after SMA/pre-SMA disruption might arise from a failure to make the appropriate connection between the action to be initiated in a novel situation ( Nachev et al., 2008). Trans-cranial magnetic stimulation (TMS) has also been employed to measure physiological interactions between pre-SMA Selleck Dapagliflozin and other brain regions associated with response selection. This has demonstrated that in the presence

of response conflict, pre-SMA facilitates motor-evoked potentials in M1 during action reprogramming (Mars et al., 2009), and suppresses unselected response options (Duque, Olivier, & Rushworth, 2013). TMS over pre-SMA has been associated with an increased delay in the ability to inhibit responses (Cai, George, Verbruggen, Chambers, & Aron, 2012), but there is also evidence that activity in pre-SMA can occur before stopping is initiated, which would be indicative of a role in selecting rather than implementing responses (Swann et al., 2012). However, a caveat of this approach is that TMS stimulation which induces a transient ‘lesion’ may also propagate MRIP to other brain networks. Similar effects on network function have also been observed following anatomical focal lesions, dependent on the position of the brain area within the network architecture and degree of white matter involvement (Gratton, Nomura, Pérez, & D’Esposito, 2012). Although cognitive control, self-initiated action and sequence learning may not be mutually exclusive functions, providing an overarching framework which can account for the range of such complex behaviour has proven difficult. Due to the extremely rare incidence of focal damage to this brain area in humans, only a very small number of lesion studies of pre-SMA have been reported.

Another feeding approach that can be used is based on the direct

Another feeding approach that can be used is based on the direct or indirect feedback control systems for the controlled addition of nutrients. Indirect control is based on online monitoring of parameters such as pH, dissolved oxygen, CO2 evolution rate and cell concentration. Direct feedback is based on monitoring the concentration of the major carbon substrate [14] and [22].

In this work, a fed-batch bioprocess was developed, via an up-scaling of hSCOMT production. Initially, several batch fermentations were carried out, in order to establish the ideal culture conditions, Everolimus cost for instance batch phase and bioreactor operation for the fed-batch fermentations. After this stage, several fed-batch fermentations with different feeding profiles were tested in order to maximize biomass production and to improve protein activity levels, without compromising cell viability. Ultrapure reagent-grade water was obtained from a Mili-Q system (Millipore/Waters). Carbenicillin disodium

salt, calcium chloride dihydrate, magnesium sulfate heptahydrate, lysozyme, cobalt(II) chloride hexahydrate, dithiothreitol (DTT), SAM chloride salt, DNase, epinephrine (bitartrate salt), disodium ethylenediamine tetraacetic learn more acid (EDTA), sodium octyl sulfate (OSA), bovine serum albumin (BSA), LB-Agar, IPTG, tryptone, glycerol and propidium iodide (PI) were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Potassium chloride, sodium chloride, boric acid were supplied by Fluka (Buchs, Switzerland). Sodium phosphate dibasic and potassium dihydrogen phosphate monobasic were obtained from Panreac (Barcelona, Spain). Bis-(1,3-dibutylbarbituric acid)trimethine oxonol (BOX) was obtained from Molecular Probes®, Invitrogen, part of Life Technologies (Carlsbad, CA, USA). All other chemicals were of analytical grade and used without further purification. The Champion pET101 Directional TOPO expression kit

(Invitrogen Corporation, Carlsbad, CA, USA) was used for the expression of hSCOMT on E. coli BL21(DE3) strain kindly provided by Bial (Departamento de Investigação e Desenvolvimento, São TCL Mamede do Coronado, Portugal). In this study, except for tryptone and glycerol concentrations, all media components for the semi-defined medium were kept constant (5.5 g/L Na2HPO4, 0.5 g/L NaCl, 1.64 g/L citric acid monohydrate, 2 g/L potassium citrate, 1.21 g/L MgSO2·7H2O, 50 μg/mL carbenicillin and 1.5 mL/L trace elements solution) for the pre-cultivations, batch, and batch phase of fed-batch experiments. The trace elements solution consisted of 27 g/L FeCl3·6H2O, 2 g/L ZnCl2, 2 g/L CoCl2·6H2O, 2 g/L Na2MoO4·2H2O, 1 g/L CaCl2·2H2O, 1.2 g/L CuSO4 and 0.5 g/L H3BO4, prepared in 1.2 M HCl. LB agar plates supplemented with 50 μg/mL carbenicillin were inoculated from a cell bank aliquot and grown overnight at 37 °C.

Quality control samples were prepared and analyzed along with eac

Quality control samples were prepared and analyzed along with each batch of cigarettes extracted. These see more quality control samples consisted of continuing calibration verification standards, an extraction solvent blank, an aliquot of extraction solvent spiked with known amounts of menthol and nicotine, and matrix blanks and spikes prepared using “nicotine-free” (Quest 3®) nonmenthol cigarettes. To generate the matrix spikes, approximately 7 mg/g and 25 mg/g of menthol

and nicotine, respectively, were added to the denicotinized cigarettes, with roughly 60% and 40% of the menthol applied to the tobacco rod and filter, respectively, and approximately 95% and 5% of the nicotine added to the rod and filter, respectively. Extraction efficiencies were determined by comparison of measured amounts to nominal spiked amounts. To qualify the extraction and analysis technique, the menthol and nicotine content of three brands of popular, commercially-available menthol cigarettes (Salem FF

king, Kool FF king, and Marlboro Gold FF king) and one brand of a nonmenthol cigarette (Camel FF king) were determined, along with the distributions of menthol and nicotine between the tobacco rod and filter. To verify GC/FID peak identification and to ascertain whether there were interferences in the analysis that might require the use of a more sophisticated analytical technique, these analyses were also performed by GC with LY2835219 datasheet detection by mass spectrometry (MS) using the identical temperature program with a similar column (30 m x 0.32 mm, 0.50 μm film DB-WAX [Agilent]), similar constant

flow rate (2 mL/min helium), a 15:1 split 1 μL injection, and full scan over the mass range of 35 to 300 amu. A popular, commercially-available nonmenthol cigarette (Camel full flavor [FF], hard pack, king [85 mm mafosfamide length]), was selected for mentholation as it matched the tar, nicotine, and ventilation levels of a popular menthol brand. Cigarettes were purchased commercially and stored before use at approximately 4 °C in their sealed original packages. Prior to mentholation, 200 cigarettes (one carton) were conditioned for at least 48 hours at 22 ± 1 °C and 60 ± 3% relative humidity in clean glass baking dishes (ISO 3402:1999). Menthol crystals (L-menthol, Sigma Aldrich) were pulverized and manually sieved using #12- and #30-size sieves (U.S. Standard Test Sieves, Advantech Manufacturing, New Berlin, WI) to generate menthol crystals with the largest dimension nominally ranging between 0.6 and 1.7 mm. The sieved crystals (500 ± 5 g) were placed into a stainless steel pan with a wire rack (rack dimensions 41 cm x 22 cm) so that 100 of the conditioned cigarettes were in a single layer and elevated 4 cm above the bed of pulverized menthol.

The SNR for autofluorescence is the inverse of this definition as

The SNR for autofluorescence is the inverse of this definition as tumor autofluorescence is lower than normal tissue autofluorescence due to lower NADH levels [24] and [25]; thus this SNR is the MFI of the normal tissue divided by the MFI of the cancerous tissue. This SNR calculation provides the most robust measure of differential fluorescent values, since the samples were imaged together and no other manipulation of the raw values were made. Following imaging, each sample received a unique label to remove any trace of patient information

so that the pathological diagnosis was blinded and separated from the fluorescent staining results. Tissue samples were selleckchem then bisected so that a portion was fixed in formaldehyde and paraffin embedded, and another could be used for frozen section analysis for quick histological diagnosis. True pathological diagnosis consisted of a routine hematoxylin and eosin (H&E) stain performed and analyzed by a board certified pathologist. The pathological diagnosis was then classified into the following three categories: (1) normal, (2) dysplasia and (3) cancer with stage. All specimens were then returned to the Pathology Department of Selleckchem PARP inhibitor the Narayana Hrudayalaya Multispecialty Hospital and Mazumdar-Shaw Cancer Center. Data are presented as mean ± SD. Statistical

analysis of ex vivo fluorescence measurements was conducted using a 2-tailed, paired Student’s t test. All statistical analyses were performed using a 95% confidence interval, which relates to a P value < .05 being statistically significant. Both AF647 and AF350 conjugated WGA yielded similar binding results. This can be seen in Figure 2 which shows white light (Figure 2A and C), red light ( Figure 2B), and UV ( Figure 2D) excitation images of cancerous and normal tissues from the same patient stained with both

fluorophore conjugates. The excised tissue was stained Sclareol with AF647-WGA while the smaller tissue biopsies, from the same excised tissue specimen, were stained with AF350-WGA. The fluorescence seen on the periphery of the normal tissue specimen (B) is due to AF647-WGA staining of the stroma layer, instead of the epithelial layer; the stroma layer was exposed due to tissue resection. However, the clinical topical application of WGA will not concern the deeper tissue layers and will only analyze epithelial glycan expression profiles. Therefore, these recorded intensity measurements were omitted from ROIs of epithelial fluorescence. Histological evaluation of the tissue samples revealed normal epithelium ( Figure 3A) and stage I squamous cell carcinoma ( Figure 3B) for the normal and cancerous tissue samples, respectively.