The clinical pregnancy rate was higher in patients with EFI greater

than or equal to 6 score than with EFI lower than or equal to 5 score.”
“Background: CREBZF is a member of the mammalian ATF/CREB family of the basic region-leucine zipper (bZIP) transcription factors. Two isoforms of CREBZF have been identified from the alternative usage of initiation codons, SMILE (long isoform of CREBZF) and Zhangfei (short isoform of CREBZF). Until recently, the physiological function of CREBZF in mammalian reproductions has not been reported.

Methods: Multiple techniques were performed to investigate the spatiotemporal expression and hormonal regulation of the CREBZF gene in the mouse uterus and its role in embryo implantation.

Results: Blasticidin S datasheet Zhangfei was not detected in the mouse uterus. SMILE immunostaining was mainly expressed in the uterine luminal and glandular epithelium, and the expression levels of both SMILE mRNA and protein selleck chemical gradually decreased from days 1-3 of pregnancy, peaked on day 4, and then declined again on day 6. On day 5 of pregnancy, SMILE protein expression was detected only in the luminal epithelium at implantation sites compared with the expression at inter-implantation sites. SMILE protein was not detected in decidual cells from days 6-8 of pregnancy or artificial decidualisation.

Furthermore, SMILE protein was not detected in the mouse uterus on days 3-6 of pseudopregnancy, and SMILE expression was also induced in the delayed-implantation uterus, indicating that the presence of an active blastocyst was required for SMILE expression at the implantation site. Oestrogen significantly stimulated SMILE expression in the ovariectomised mouse uterus. In addition, in cycling mice, high levels of SMILE protein and mRNA expression were also observed in proestrus and oestrus uteri.

Conclusions: Taken together, these results suggested that SMILE expression was closely related to mouse implantation and up-regulated by oestrogen.”
“In individual cells, transcription is a random process obeying single-molecule kinetics. Often, it occurs in a bursty, intermittent manner. The frequency and size of these bursts affect the magnitude of temporal fluctuations

in messenger RNA and protein content within a cell, creating CB-839 purchase variation or “”noise”" in gene expression. It is still unclear to what degree transcriptional kinetics are specific to each gene and determined by its promoter sequence. Alternative scenarios have been proposed, in which the kinetics of transcription are governed by cellular constraints and follow universal rules across the genome. Evidence from genome-wide noise studies and from systematic perturbations of promoter sequences suggest that both scenarios-namely gene-specific versus genome-wide regulation of transcription kinetics-may be present to different degrees in bacteria, yeast, and animal cells.”
“A fundamental problem in biology is to understand how genetic circuits implement core cellular functions.

18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P=0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P=0.003).

Conclusions: The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.).”
“Epstein-Barr virus (EBV) SM protein is an essential nuclear shuttling protein expressed by EBV early during the lytic

phase of MRT67307 replication. SM acts to increase EBV lytic gene expression by binding EBV mRNAs and enhancing accumulation of the majority of EBV lytic cycle

mRNAs. SM increases target mRNA stability and nuclear export, in addition to modulating RNA splicing. SM and its homologs in other herpesvirus have been hypothesized to function in part by binding viral RNAs and recruiting cellular export factors. Although activation of gene expression by SM is gene specific, it is unknown whether SM binds to mRNA in a specific manner or whether its RNA binding is target independent. SM-mRNA complexes were isolated from EBVinfected B-lymphocyte cell lines induced to permit lytic EBV replication, and a quantitative measurement of mRNAs corresponding LY2874455 clinical trial to all known EBV open reading frames

was performed by real-time quantitative reverse transcription-PCR. The results showed that although SM has broad RNA binding properties, there is a clear hierarchy of affinities among EBV mRNAs with respect to SM complex formation. In vitro binding assays with two of the most highly SM-associated transcripts suggested that SM binds preferentially to specific sequences or structures present in noncoding regions of some EBV mRNAs. Furthermore, the presence of these sequences conferred responsiveness to SM. These data are consistent with a mechanism of action similar to that of hnRNPs, which exert sequence-specific effects on gene expression despite having multiple degenerate consensus binding sites Smad inhibitor common to a large number of RNAs.”
“Attenuated live vaccines of measles virus (MV) have been developed from clinical isolates by serial propagation in heterologous cells, mainly chicken embryonic cells. The safety and effectiveness of these vaccines have been well established. However, the molecular mechanism of their attenuation remains a subject of investigation. The CAM-70 MV vaccine strain was developed from the Tanabe strain by serial propagation in chicken embryonic cells. In the present study, we assessed the contribution of each gene in the CAM-70 strain to efficient growth in chicken embryonic fibroblasts (CEF).

Furthermore, these unexpected and newly identified transcripts lead to the synthesis

of viral proteins termed HBZ (HTLV-1 basic leucine zipper) and APH-2 (antisense protein of HTLV-2), respectively. As potential open reading frames are present on the antisense strand of HTLV-3 and HTLV-4, we tested whether in vitro antisense transcription occurred in these viruses and whether these transcripts had a coding potential. Using HTLV-3 and HTLV-4 proviral DNA constructs, antisense transcripts were detected by reverse transcriptase PCR. These transcripts are spliced and polyadenylated and initiate at multiple sites from the 3′ long terminal repeat (LTR). The resulting proteins, termed APH-3 and APH-4, are devoid of a typical basic leucine zipper domain but contain basic amino acid-rich regions. Confocal microscopy and Western blotting experiments demonstrated a nucleus-restricted pattern for APH-4, FRAX597 ic50 while APH-3 was localized both in the cytoplasm and in the nucleus. Both proteins showed partial colocalization with nucleoli and HBZ-associated structures. Finally, click here both proteins inhibited Tax1-

and Tax3-mediated HTLV-1 and HTLV-3 LTR activation. These results further demonstrate that retroviral antisense transcription is not exclusive to HTLV-1 and HTLV-2 and that APH-3 and APH-4 could impact HTLV-3 and HTLV-4 replication.”
“Mutations of the voltage gated sodium channel gene (SCN4A) are responsible for non-dystrophic myotonia including hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia, as well as congenital myasthenic syndrome. In vitro functional analyses have demonstrated the nondystrophic mutants to show a gain-of-function defect of the channel; a disruption of fast inactivation, an enhancement of activation, or both, while the myasthenic mutation presents a loss-of function defect. This report

Wnt inhibitor presents a case of non-dystrophic myotonia that is incidentally accompanied with acquired myasthenia. The patient presented a marked warm-up phenomenon of myotonia but the repeated short exercise test suggested mutations of the sodium channel. The genetic analysis identified a novel mutation, G1292D, of SCN4A. A functional study of the mutant channel revealed marked enhancement of activation and slight impairment of fast inactivation, which should induce muscle hyperexcitability. The effects of the alteration of channel function to the myasthenic symptoms were explored by using stimulation of repetitive depolarization pulses. A use-dependent channel inactivation was reduced in the mutant in comparison to normal channel, thus suggesting an opposing effect to myasthenia. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“High levels of homocysteine (Hcy) were suggested to contribute to the pathogenesis of schizophrenia.

“
“Many viruses encode proteins that inhibit the induction of programmed cell death at the mitochondrial checkpoint. Murine cytomegalovirus (MCMV) encodes the m38.5 protein, which localizes to mitochondria and protects human HeLa cells and fibroblasts from apoptosis triggered by proteasome inhibitors https://www.selleckchem.com/products/cobimetinib-gdc-0973-rg7420.html but not from Fas-induced

apoptosis. However, the ability of this protein to suppress the apoptosis of murine cells and its role during MCMV infection have not been investigated previously. Here we show that m38.5 is expressed at early time points during MCMV infection. Cells infected with MCMVs lacking m38.5 showed increased sensitivity to cell death induced by staurosporine, MG132, or the viral infection itself compared to the sensitivity of cells

infected with wild-type MCMV. This defect was eliminated when an m38.5 or Bcl-X-L gene was inserted into the genome of a deletion mutant. Using fibroblasts deficient in the www.selleckchem.com/products/lxh254.html proapoptotic Bcl-2 family proteins Bak and/or Bax, we further demonstrated that m38.5 protected from Bax- but not Bak-mediated apoptosis and interacted with Bax in infected cells. These results consolidate the role of m38.5 as a viral mitochondrion-localized inhibitor of apoptosis and its functional similarity to the human cytomegalovirus UL37x1 gene product. Although the m38.5 gene is not homologous to the UL37x1 gene at the sequence level, m38.5 is conserved among rodent cytomegaloviruses. Moreover, the fact that MCMV-infected cells are protected from both Bak- and Bax-mediated cell death suggests that MCMV possesses

an additional, as-yet-unidentified mechanism to block Bak-mediated apoptosis.”
“A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased Levetiracetam responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by alpha 1b-adrenergic and 5-HT2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783.

(C) 2009 Elsevier Ltd. All rights reserved.”
“Orientation CP is the faster or more accurate discrimination RAD001 purchase of two orientations from different categories (e.g., oblique1 and vertical1) compared to two orientations from the same category (e.g., oblique1 and oblique2), even when the degree of difference is equated across conditions. Here, we assess whether there are hemispheric asymmetries in this effect for adults and 5-month-old infants. Experiment I identified the location of the vertical-oblique category boundary. Experiment

2, using a visual search task with oriented lines found that adult search was more accurate when the target and distractors were from different orientation categories, compared to targets and distractors of an equivalent physical difference taken from the same category. This effect was stronger for targets lateralized to the left visual field (LVF) than the right visual field (RVF), indicating a right hemisphere (RH) bias in adult orientation CP. Experiment 3, replicated the RH bias using different stimuli and also investigated the impact of visual

and verbal interference on the category effect. Experiment 4, using the same visual search task, found that infant search was also faster when the target and distractors were from different orientation categories than PF299804 in vivo the same, yet this category effect was stronger for RVF than LVF lateralized targets, indicating a LH bias in orientation CP at 5 months. These findings are contrasted to equivalent studies on the lateralization of color CP (e.g., Gilbert, Regier, Kay, & Ivry, 2005). The implications for theories on the contribution of the left and

right hemispheres of the infant and adult brain to categorical computations are discussed. (C) 2010 Elsevier Ltd. All rights reserved.”
“1. The effect of temperature oil the activity of the freshwater snail Pomacea canaliculata was investigated through field Surveys and laboratory trials.

2. Ruboxistaurin concentration During winter most snails in the field were inactive but not in a deep lethargic state; the temperature at which half of the snails were active was 13-15 degrees C.

3. The time spent active and feeding increased with temperature between 10 and 30 degrees C, exposure time being unimportant except in foul water at 35 degrees C, while tirne spent crawling remained constant above 10 degrees C.

4. Activity decreased above 30 degrees C but no heat coma was observed with temperatures raised to 36.2 degrees C.

5. Under fluctuating temperatures, the rate of change in the percentage of active snails during cooling was higher than during warming, whereas the temperature at which half of the snails were active was lower. (C) 2009 Elsevier Ltd. All rights reserved.

Urban environmental quality, including air and water pollution, contributes to disease both in urban and in rural areas, and traffic-related accidents pose a major public health threat as the country becomes increasingly motorised. To address the health challenges and maximise the benefits that accompany this rapid urbanisation, innovative health policies focused on the needs of migrants and research that could close knowledge gaps on urban population exposures are needed.”
“Recent research suggests an involvement

of pro-opiomelanocortin (POMC) gene products in modulating cocaine reward and addiction-like behaviors in rodents. In this study, we investigated whether cocaine-induced conditioned place preference (CPP) alters POMC gene expression in the brain or pituitary of rats. Sprague-Dawley rats were conditioned see more with 4 injections of 0, 10 or 30 mg/kg cocaine (i.p.) over 8 days and tested 4 days after the last conditioning session. Another group received the same pattern of cocaine injections without conditioning. POMC mRNA levels in the hypothalamus (including

arcuate nucleus), amygdala and anterior pituitary, as well as plasma ACTH and corticosterone levels were measured. Cocaine place conditioning at 10 and 30 mg/kg doses increased POMC mRNA levels in a dose-dependent manner in the hypothalamus, with no effect in the amygdala. Cocaine CPP had no effect on POMC mRNA levels in the anterior pituitary or on plasma ACTH or corticosterone levels. In rats that received cocaine at 30 GSK2118436 datasheet mg/kg without click here conditioning, there was no such effect on hypothalamic POMC

mRNA levels. Alteration of POMC gene expression in the hypothalamus is region-specific after cocaine place conditioning, and dose-dependent. The increased POMC gene expression in the hypothalamus suggests that it is involved in the reward/learning process of cocaine-induced conditioning. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Autonoetic awareness associated with the projection of the self into the future was assessed in patients with schizophrenia using an experiential approach. Patients anticipated fewer specific future events than controls, and their ability to pre-experience future events was impaired. indicating that autonoetic awareness for the future is impaired in schizophrenia. (C) 2008 Published by Elsevier Ireland Ltd.”
“Major earthquakes often result in incalculable environmental damage, loss of life, and threats to health. Tremendous progress has been made in response to many medical challenges resulting from earthquakes. However, emergency medical rescue is complicated, and great emphasis should be placed on its organisation to achieve the best results.

Electron microscopy revealed that the VBNC cells changed from rod to coccoid and decreased in size. Resuscitation of VBNC cells was achieved by temperature

upshift in nutrition of yeast extract and peptone by addition of catalase or compound vitamin B. The VBNC and resuscitative cells were intraperitoneally injected into zebra fish separately. No death was observed in the group inoculated with the VBNC cells.

Vibrio cincinnatiensis VIB287 could enter VBNC state in adverse environments. Resuscitation of VBNC cells occurred by addition of compound vitamin B or catalase to VBNC cells Erastin supplier containing nutrient. The resuscitative cells might retain their pathogenicity.

The study confirmed that V. cincinnatiensis could enter into VBNC state in seawater at low temperature and resuscitated. The resuscitative cells retained

their pathogenicity, which may be important in future studies of ecology of V. cincinnatiensis.”
“The identification of a new compound active against Agrobacterium tumefaciens.

The culture conditions of a newly isolated Bacillus subtilis strain, designed 14B, were optimized, as a first step, to produce its bacteriocin (termed Bac 14B) for the biocontrol of Agrobacterium spp., the causal agents of the crown gall disease. Bac 14B was then partially purified and biochemically characterized. Bacillus subtilis 14B was observed to produce Hydroxylase inhibitor an antibacterial compound having a protinaceous nature. As estimated by sodium dodecyl sulfate-polyacrilamide gel electrophoresis (SDS-PAGE), the semi-purified bacteriocin substance was found to be a monomeric protein with a molecular weight of 21 kDa. While the latter’s antimicrobial activity was completely stable during exposure to a temperature range of up to 100 degrees C for 2 h, its initial activity was totally lost at 121 degrees C

for Bromosporine 20 min. The maximum bacteriocin production (4096 AU ml(-1)) was recorded after 96 h-incubation in an optimized Luria Bertani medium supplemented with 10 g l(-1) glucose, 15 g l(-1) K(2)HPO(4) and 5 g l(-1) MgSO(4) 7H(2)O at 30 degrees C in a shaking flask culture. Interestingly, the B. subtilis 14B culture supernatant that contained the bacteriocin under study was proved efficient in reducing both the percentage of galled plants and the number of galls in tomato.

The findings revealed that B. subtilis 14B and its bacteriocin are efficient in reducing the percentage of infections in plants caused by Ag. tumefaciens.

The results could be useful for the nurserymen who are particularly interested in the biocontrol of the crown gall disease.”
“This study was aimed to investigate the effects of a high-pressure homogenization (HPH) treatment on some micro-organisms, involved in the spoilage of fruit juices.

Lactobacillus plantarum, Lactobacillus brevis, Bacillus coagulans cells, Saccharomyces bayanus, Pichia membranaefaciens and Rhodotorula bacarum were separately inoculated in a saline solution (0.9% NaCl); the initial inoculum was ca.

The present investigation used anterograde tract tracing in the rat to study the projections of the ventromedial PFC, including the IL, to the ICNs and surrounding amygdalar

regions. Immunohistochemistry for the mu-opioid receptor (MOR) was used to identify the ICNs. At rostral levels of the amygdala there was a very dense projection to a far SHP099 solubility dmso lateral portion of the capsular subdivision of the central nucleus (CLC) located between the main and medial ICNs, but only very light projections to these ICNs and the lateral ICNs. This distinct portion of the CLC receiving strong IL inputs was termed the capsular infralimbic target zone (CITZ), and was MOR-negative. Likewise, at more caudal levels of the amygdala, IL projections to the medial, lateral, and dorsal ICNs were light to moderate compared with projections to adjacent portions of the basolateral amygdala and amygdalostriatal transitional area. These findings suggest that the putative role of the IL-to-ICN https://www.selleckchem.com/products/citarinostat-acy-241.html connection in fear inhibition may be mediated by light to moderate

projections from the IL to the medial ICN, and that the CITZ may be an equally important amygdalar target for this function. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Avian influenza A H5N1 remains unusual in its virulence for humans. Although infection of humans remains inefficient, many of those with H5N1 disease have a rapidly progressing viral pneumonia that leads to acute respiratory distress syndrome and death, but its pathogenesis remains an enigma. Comparison of the virology and pathogenesis of human seasonal influenza viruses selleck kinase inhibitor (H3N2 and H1N1) and H5N1 in patients, animal models and relevant primary human cell cultures is instructive. Although the direct effects of viral replication and differences in the tropism of the virus for cells in the lower respiratory tract clearly contribute to pathogenesis, we focus here on the possible contribution of the host innate immune response in the pathogenesis of this disease.”
“Although bats are important reservoirs

of diverse viruses that can cause human epidemics, little is known about the presence of picornaviruses in these flying mammals. Among 1,108 bats of 18 species studied, three novel picornaviruses (groups 1, 2, and 3) were identified from alimentary specimens of 12 bats from five species and four genera. Two complete genomes, each from the three picornaviruses, were sequenced. Phylogenetic analysis showed that they fell into three distinct clusters in the Picornaviridae family, with low homologies to known picornaviruses, especially in leader and 2A proteins. Moreover, group 1 and 2 viruses are more closely related to each other than to group 3 viruses, which exhibit genome features distinct from those of the former two virus groups.

As aging leads to reduced water content in the brain, age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level were compared. There were significant differences in L-arginine, L-citrulline, L-ornithine, agmatine, putrescine, spermidine, spermine, and glutamate, but not GABA, in find more the CA1, CA2/3, and dentate gyrus sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, and postrhinal cortices in 24 (aged)

and 4 (young) months old rats in a region-specific manner. The overall pattern of age-related changes in amino acids (L-arginine, L-citrulline, L-ornithine, glutamate, and GABA) was largely similar between homogenates and synaptoneurosomes, whereas the pattern for the amines (agmatine, putrescine, spermidine, and spermine) was quite different. Furthermore, the pattern of age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level was very similar for all 9 neurochemicals measured. These findings suggest that there are differential effects of aging on L-arginine metabolism at the tissue and synaptoneurosome levels and that the way of data normalization (tissue

weight vs. protein level) has no or very minor effects on 9 neurochemicals measured. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Translation initiation dependent on the foot-and-mouth Flavopiridol manufacturer disease virus (FMDV) internal ribosome entry site (IRES) 8-Bromo-cAMP cell line occurs at two sites (Lab and Lb), 84 nucleotides (nt) apart. In vitro translation of an mRNA comprising the IRES and Lab-Lb intervening segment fused to a chloramphenicol acetyltransferase (CAT) reporter has been used to study the parameters influencing the ratio of the two products and the combined product yield as measures of relative initiation site usage and productive ribosome recruitment, respectively. With wild-type mRNA, similar to 40%

of initiation occurred at the Lab site, which was increased to 90% by optimization of its context, but decreased to 20% by mutations that reduced downstream secondary structure, with no change in recruitment in either case. Inserting 5 nt into the pyrimidine-rich tract located just upstream of the Lab site increased initiation at this site by 75% and ribosome recruitment by 50%. Mutating the Lab site to RCG or RUN codons decreased recruitment by 20 to 30% but stimulated Lb initiation by 20 to 40%. An antisense oligodeoxynucleotide annealing across the Lab site inhibited initiation at both sites. These and related results lead to the following conclusions. Recruitment by the wild-type IRES is limited by its short oligopyrimidine tract. At least 90% of internal ribosome entry occurs at the Lab AUG, but initiation at this site is restricted by its poor context, despite a counteracting effect of downstream secondary structure.

Thus, a genetic background for autonomic dysfunction is rather unlikely. (C) 2011 Elsevier Inc. All rights reserved.”
“Donor T cells directed at hematopoietic system-specific minor histoconnpatibility antigens (mHags) are considered important cellular tools to induce

PD173074 price therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using HSP990 genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling.

UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus,

with the capacity to induce relevant immunotherapeutic CTLs, it’s HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based innnnunotherapy. Leukemia (2013) 27, 642-649; doi:10.1038/leu.2012.277″
“Bipolar II depression is a serious and disabling illness associated with significant impairment and high rates of suicide attempts. However, mechanisms underlying emotional dysregulation Wortmannin in this condition are poorly characterized. The goal of this work was to investigate one component of emotional processing in this disorder, brain activation associated with exposure to emotional faces. Functional MRI was used to study 16 unmedicated male subjects with bipolar II depression and 19 healthy male controls. The activation paradigm exposed subjects to happy, fearful and neutral faces. The two key findings of this study were as follows. First, bipolar subjects demonstrated significantly decreased activation in response to happy facial expression in the left posterior cortical midline structures (CMS) and frontal cortex. Second, depression severity was positively correlated with activation of the posterior CMS and other regions. Our results suggest that mechanisms involving CMS dysfunction may play a role in the neurobiology of bipolar II depression as has been demonstrated for unipolar illness. Further investigations of CMS function in bipolar spectrum disorders are warranted.