doi:10 2215/CJN 01970310″
“Ag2Co3(HPO4)(PO4)(2) contains CoO

“Ag2Co3(HPO4)(PO4)(2) contains CoO6 octahedra and phosphate groups linked to form a three-dimensional network defining tunnels parallel to the a axis that are occupied selleck screening library by Ag+ ions.”
“In order to investigate poly(N-vinyl pyrrolidone) as an alternative to poly(ethylene glycol) in preparing a biomedical polymer, we synthesized a series of reverse thermogelling

poly(N-vinyl pyrrolidone-b-alanine) (PVP-PA). The amphiphilic polymers consisting of the hydrophilic PVP block and the hydrophobic PA block formed micelles in water and the micelles aggregated as the temperature increased. FTIR spectroscopy, circular dichrosim spectroscopy, and (13)C NMR spectroscopy showed that the aggregation behavior accompanied a change in PA conformation as well as a decrease

in the molecular motion of beta-catenin signaling PVPPA. The sol-to-gel transition temperature decreased as the PA block length increased, PVP block length decreased, and L-alanine/DL-alanine ratio of PA increased. This paper suggests that PVP can be a promising alternative to poly(ethylene glycol) in designing a reverse thermogelling biomaterial.”
“Fungi have been recently recognized as organisms able to grow in presence of high salt concentration with halophilic and halotolerance properties and their ligninolytic enzyme complex have an unspecific action enabling their use to degradation of a number of xenobiotic compounds. In this work, both the effect of salt and polyols on growth of the basidiomycetes strains, on their ability to produce ligninolytic enzyme and diuron degradation were evaluated. Results showed that the presence of NaCl in the culture medium affected fungal specimens in

different ways. Seven out of ten tested strains had growth inhibited by salt while Dacryopinax elegans SXS323, Polyporus sp MCA128 and Datronia stereoides MCA167 fungi exhibited higher biomass production in medium containing Nutlin-3 nmr 0.5 and 0.6 mol.L-1 of NaCl, suggesting to be halotolerant. Polyols such as glycerol and mannitol added into the culture media improved the biomass and ligninases production by D. elegans but the fungus did not reveal consumption of these polyols from media. This fungus degraded diuron in medium control, in presence of NaCl as well as polyols, produced MnP, LiP and laccase.”
“The perception and processing of pain is disturbed in many psychiatric diseases. Some diseases are known to show decreased perception of pain (e.g. borderline personality disorder), while others are associated with augmented pain perception (e.g. alcohol and drug dependence). The close relationship between psychiatric diseases and pain is most probably caused by aberrant processing of pain in brain structures, known to be involved in psychiatric disorders as well. Aberrant perception and processing of pain in patients with anorexia nervosa (AN) will be used to demonstrate this close relationship.

Visually significant, potentially life-threatening, and even trea

Visually significant, potentially life-threatening, and even treatable conditions were detected serendipitously during routine ROP screening

that may be missed or detected late otherwise. This pilot data may be used to advocate for a possible universal infant eye screening program using digital imaging.”
“The ability to control the differentiation of stem cells into specific neuronal types has a tremendous potential for the treatment of neurodegenerative diseases. DMXAA solubility dmso In vitro neuronal differentiation can be guided by the interplay of biochemical and biophysical cues. Different strategies to increase the differentiation yield have been proposed, focusing everything on substrate topography, or, alternatively on substrate stiffness. Both strategies demonstrated an improvement of the cellular response. However it was often impossible to separate the topographical and the mechanical contributions. Here we investigate the role of the mechanical properties

of nanostructured substrates, aiming at understanding the ultimate parameters which govern the stem cell differentiation. To this purpose a set of different substrates with controlled stiffness and with or without nanopatterning are used for stem cell differentiation. Our results show that the neuronal differentiation yield depends mainly on the substrate Wnt activity mechanical properties while the learn more geometry plays a minor role. In particular nanostructured and flat polydimethylsiloxane (PDMS) substrates with comparable stiffness show the same neuronal yield. The improvement in the differentiation yield obtained through surface nanopatterning in the submicrometer scale could be explained as a consequence of a substrate softening effect. Finally we investigate by single cell force spectroscopy the neuronal precursor adhesion on the substrate immediately after seeding, as a possible critical

step governing the neuronal differentiation efficiency. We observed that neuronal precursor adhesion depends on substrate stiffness but not on surface structure, and in particular it is higher on softer substrates. Our results suggest that cell-substrate adhesion forces and mechanical response are the key parameters to be considered for substrate design in neuronal regenerative medicine. Biotechnol. Bioeng. 2013; 110: 2301-2310. (c) 2013 Wiley Periodicals, Inc.”
“A pleiotropic hormone, leptin, secreted into saliva by the acinar cells of salivary glands is an important mediator of the processes of oral mucosal defense. Here, we report on the role of epidermal growth factor receptor (EGFR) transactivation in the signaling events that mediate leptin protection of sublingual salivary gland acinar cells against ethanol cytotoxicity.

We find that activation of ERK1/2 also occurs in response to inju

We find that activation of ERK1/2 also occurs in response to injury in

retinal explants. However, this is a transient response and appears to be overcome by Jun N-terminal kinase activation resulting in induction of Bim(EL) mRNA and photoreceptor apoptosis. Our findings provide new insights into the intracellular pathways responsible for regulating apoptosis during neuronal development and degeneration.”
“OBJECTIVE\n\nTo investigate the detailed mechanism of prostate-specific antigen (PSA) decline in metabolic syndrome (MS) and insulin resistance (IR), which lowers the predictive JQ-EZ-05 price value of the PSA test, we examined the effect of haemodilution and

Anti-infection Compound Library research buy the possibility of an intrinsic metabolic effect. PATIENTS AND\n\nMETHODS\n\nWe analysed 28 315 men who underwent routine check-ups. We compared the age-adjusted mean PSA levels in subjects with and without MS before and after adjusting or stratifying the plasma volume. We analysed changes in PSA level, plasma volume and PSA mass according to obesity grade, number of MS components, IR severity and diagnosis of MS, IR or both using an analysis of covariance.\n\nRESULTS\n\nThe PSA levels were lower in the group with MS than in the group without MS (P = 0.001), but this difference disappeared after adjusting or stratifying the plasma volume (P > 0.05 for all). The PSA levels decreased, plasma volume increased, and PSA mass did not change as the number of MS components increased (P = 0.002, P < 0.001, P = 0.55, respectively) or the IR severity increased (P = 0.001, P < 0.001, P = 0.34, Doramapimod datasheet respectively).\n\nSimilarly, PSA levels were lower, plasma volumes were higher and PSA masses were the same in subjects with MS (P = 0.002, P < 0.001, P = 0.10,

respectively), IR (P = 0.018, P < 0.001, P = 0.94, respectively), or both (P = 0.003, P < 0.001, P = 0.86, respectively) than in subjects without those conditions.\n\nCONCLUSION\n\nThe PSA decline in MS and IR may result simply from a haemodilution effect and be unrelated to intrinsic metabolic disturbances. For this reason, PSA levels could be underestimated in patients with MS or IR because of haemodilution.”
“External morphological characters were used to reconstruct a phylogeny of the mite family Syringophilidae (Acariformes: Cheyletoidea), which are permanent parasites inhabiting the quills of bird feathers. A total of 53 syringophilid genera and 79 characters were included in the data matrix; maximum parsimony (MP) and Bayesian analyses (BA) were performed to determine their phylogenetic relationships. The consensus of unweighted MP trees was weakly resolved.

Broth microdilution method was employed to determine minimum inhi

Broth microdilution method was employed to determine minimum inhibitory

concentration (MIC) of the extract and fractions against MRSA. Evaluation of synergistic activity of the active fraction with ampicillin was determined using checkerboard methodand kinetic growth experiments. Effect of combination treatments on expression of PBP2a, a protein that confers resistance to beta-lactam antibiotics, was elucidated with the Western blot assay. Results: MIC of F-10 against MRSA was 750 mg/L which showed an improved activity by 4-fold compared to its crude extract (MIC = 3000 mg/L). Phytochemical analysis revealed occurrence of tannins, saponin, flavonoids, sterols, and glycosides in F10 fraction. In FIC index interpretation, the most synergistic activity was achieved for combinations of 1/64 x MIC ampicillin + 1/4 x MIC F-10. The combination also evidently inhibited MRSA growth in kinetic growth curve assay. As a result of this synergistic interaction, MIC of ampicillin against MRSA was reduced to 0.78 mg/L (64-fold) from initial value of 50 mg/L. Western blot analysis suggested

inhibition of PBP2a in MRSA cultures grown in synergistic combination treatment in which no PBP2a band was expressed. Conclusions: The results demonstrated synergism between fraction F-10 of D. grandiflora with ampicillin in suppressing MRSA growth via PBP2a inhibition.”
“Orthopoxvirus (OPV) has been associated with worldwide exanthematic outbreaks, which have resulted in serious economic losses as well as impact on public health. Although NSC23766 mouse the current classical and molecular methods are useful for the diagnosis of OPV, they are largely inaccessible to unsophisticated clinical laboratories. The major reason for the inaccessibility SCH727965 is that they require both virus isolation and DNA manipulation. In this report, a rapid, sensitive and low-cost semi-nested

PCR method is described for the detection of OPV DNA directly from clinical specimens. A set of primers was designed to amplify the conserved OPV vgf gene. The most useful thermal and chemical conditions were selected and minimum non-inhibitory dilutions were determined. More than 100 Brazilian Vaccinia virus (VACV) field clinical specimens were tested using this semi-nested PCR in order to confirm its applicability. Cowpox virus was also detected by PCR from the ear scabs of scarified Balb/c mice. In addition, the method was highly sensitive for the detection of VACV DNA in murine blood and excreta, which are among the suggested reservoirs of OPV. Together, these data suggest that semi-nested PCR can be used for initial screening for OPV and as a routine diagnostic laboratory method. J. Med. Virol. 82:692-699, 2010. (C) 2010 Wiley-Liss, Inc.”
“Obese white adipose tissue is hypoxic but is incapable of inducing compensatory angiogenesis. Brown adipose tissue is highly vascularized, facilitating delivery of nutrients to brown adipocytes for heat production.

Our results suggest that the retinal consequences of albinism cau

Our results suggest that the retinal consequences of albinism caused by changes in melanin synthetic machinery may be treated by L-DOPA supplementation.”
“Monoclonal ONO-7706 gammopathy of undetermined significance (MGUS) and monoclonal

B lymphocytosis (MBL) are asymptomatic premalignant conditions which can progress to a symptomatic disease state requiring therapy. Considering the high prevalence rate of these disorders, precursor patients are often diagnosed during routine clinical examinations. Only a minor portion of cases progress to overt malignancies, which raises the question of how to identify patients with the probability of progression. In recent years improvements in the understanding of the pathogenesis of both disorders led to the development of risk models and the estimation of the individual risk of progression. The definition of high-risk and low-risk patients allows

a tailored clinical management. This report provides information on the biology, risk stratification, diagnosis, and follow-up of patients with MGUS and MBL.”
“Background: Epidemiologic studies have been inconclusive regarding the impact of coexposure to long chain polyunsaturated fatty acids LBH589 molecular weight (LCPUFA) and methylmercury (MeHg) from fish consumption during pregnancy on measures of fetal development.\n\nObjectives: We evaluated the association between birth weight and prenatal maternal LCPUFA status and MeHg exposure in the Republic of Seychelles.\n\nMethods: We measured LCPUFA in maternal whole blood collected at 28 weeks of gestation and following delivery and MeHg in maternal hair obtained at delivery. There were 230 births with complete data on birth weight and covariates. Multiple linear regression models controlled for infant sex, gestational age, maternal age, smoking during pregnancy, intrapartum weight gain, prepregnancy body mass index, maternal socioeconomic status, parity, gestational diabetes, and alcohol use during pregnancy.\n\nResults: The average AZD1208 manufacturer birth weight was 3252 g (range 1654-4450) and the average gestational

age was 39 weeks (range 34-41). Prenatal MeHg exposure and maternal LCPUFA status were not associated with birth weight. Infant sex and length of gestation were the only predictors, with male sex and increased gestational age consistently associated with greater birth weight.\n\nConclusions: These findings do not support a relationship between prenatal exposure to LCPUFA and/or MeHg from fish consumption and birth weight. (C) 2014 Elsevier Inc. All rights reserved.”
“Objective To expose causes leading to the delayed arrival of phenylketonuria (PKU) patients at a governmental reference centre (RC), and to describe their clinical characteristics.\n\nMaterial and methods PKU files registered during the past 18 years at the National Institute of Pediatrics in Mexico City were evaluated.

$5,566) This study shows that DVA management provided in a FOC h

$5,566). This study shows that DVA management provided in a FOC has multiple advantages over that provided in a HOPD.”
“Background: Unexplained infertility

is still a challenging issue as to its causes, appropriate management and treatment. Evidence implicates early embryopathy or implantation failure as likely causes.\n\nObjective: This study aims Selleckchem GDC 0068 to investigate the effect of local endometrial injury on pregnancy rate in selected unexplained infertile patients.\n\nMaterials and Methods: This was a randomized clinical trial conducted in Shiraz University Infertility Clinic of Ghadir Hospital. A total of 217 women with unexplained infertility aged 23-35 years old were randomly divided into two study groups through block randomization. After superovulation by clomiphene-citrate and gonadotropins and when the dominant follicles reached 18-20 mm, patients were randomly assigned to undergo endometrial local injury at posterior uterine wall by piplle endometrial sampling (n=114) or mock pipette biopsy (n=103) during preovulatory days (when spontaneous urinary LH surge was detected). Then all the patients were instructed to follow a regularly timed intercourse.\n\nResults: Y-27632 purchase The pregnancy rate was significantly higher in the endometrial injury group compared to the control

group [17/114 (14.9%) vs. 6/103 (5.8%) (OR: 2.83 95% CI: 1.07-7.49, p=0.03]. The abortion rate was comparable between two groups Bafilomycin A1 (17.64% vs. 14.28%; p=0.701).\n\nConclusion: Local mechanical injury of the endometrium can enhance the uterine receptivity and facilitates the embryo implantation. This simple, easy, and cost effective procedure is worth considering in selective unexplained infertility patients who implantation failure is the likely causes of infertility before complex treatments. This procedure may help reduce psychological tensions and high expenses imposed through such interventions.”

GaN/Si nanoheterostructure is prepared by growing wurtzite GaN on a silicon nanoporous pillar array (Si-NPA) with a chemical vapor deposition method. The temperature evolution of the photoluminescence (PL) of GaN/Si-NPA is measured and the PL mechanism is analyzed. It is found that the PL spectrum is basically composed of two narrow ultraviolet peaks and a broad blue peak, corresponding to the near band edge emission of GaN and its phonon replicas, and the emission from Si-NPA. No GaN defect-related PL is observed in the as-prepared GaN/Si-NPA. Our experiments prove that Si-NPA might be an ideal substrate for preparing high-quality Si-based GaN nanomaterials or nanodevices.”
“In both humans and mice there are numerous reports of Y chromosome abnormalities that interfere with sex determination. Recent studies in the mouse of one such mutation have identified Y chromosome nondisjunction during preimplantation development as the cause of abnormal testis determination that results in a high frequency of true hermaphroditism.

Design: Cohort study Setting: Urban tertiary care hospita

\n\nDesign: Cohort study.\n\nSetting: Urban tertiary care hospital serving southern Alberta.\n\nParticipants: Three hundred fifty patients 60 years or older (73.7% male) undergoing nonemergent catheterization (October 27, 2003, through February 28, 2007) without prior revascularization. We compared a baseline measure of depressive symptoms (Geriatric Depression Scale score

>= 5) with a dynamic measure capturing change from baseline to 12 months.\n\nMain Outcome Measures: Mean change in domain (z scores for attention/executive function, learning/memory, and verbal fluency) and global (raw Mini-Mental State Volasertib cost Examination) cognitive scores from baseline to 6, 12, and 30 months and from 12 to 30 months.\n\nResults: In adjusted models,

participants with persistent depressive symptoms (at baseline and >= 1follow-up visit) showed significantly greater declines at 30 months in attention/ executive function (mean z score change, -0.22), learning/memory (-0.19), verbal fluency (-0.18), and global cognition (mean Mini-Mental State Examination [MMSE] score change, -0.99) compared with participants with no or baseline-only depressive symptoms. Persistent depressive symptoms were associated with significantly greater declines in all cognitive measures from 12 to 30 months after adjusting for sociodemographic RSL3 clinical trial and clinical selleck inhibitor factors. For global cognition, a significantly greater decline

was evident for patients with persistent depressive symptoms and the APOE e4 allele (mean MMSE score change, -2.93 [95% CI, -4.40 to -1.45]).\n\nConclusions: Depressive symptoms persist in some patients with coronary artery disease, placing them at a greater risk for cognitive decline. Whether this decline is additionally modified by the presence of APOE e4 requires further investigation.”
“By using Mawhin’s continuation theorem, some analysis techniques and Lyapunov functional, we establish the sufficient conditions ensuring the existence of exponential periodic attractor of an impulsive BAM neural network with both periodic coefficients and distributed delays. Our results generalize and improve the previously known results. Finally, an example is given to illustrate the effectiveness of the results. (C) 2010 Elsevier B.V. All rights reserved.”
“Attention bias modification (ABM) is a newly emerging therapy for anxiety disorders that is rooted in current cognitive models of anxiety and in established experimental data on threat-related attentional biases in anxiety. This review describes the evidence indicating that ABM has the potential to become an enhancing tool for current psychological and pharmacological treatments for anxiety or even a novel standalone treatment.

Here, we show that sensory functions can be restored in the adult

Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic

tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed Liproxstatin-1 datasheet robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale Bafilomycin A1 molecular weight for the development of novel stem cell-based strategies for functionally useful bridging of

the peripheral and central nervous system.”
“Naturally occurring CD4(+)CD25(high)FOXP3(+) regulatory T cells (Tregs) constitute a powerful mechanism of immune regulation and therefore, have important therapeutic potential for disorders such as autoimmune diseases, allograft rejection and graft-versus-host disease. Disruption of the IL-2R signalling pathway by genetic defects of the interleukin (IL)-2 gene or components of the IL-2 receptor (R) complex results in severe T cell-mediated autoimmunity rather than immunodeficiency, indicating a crucial role for IL-2R signalling

for Treg development and function. Signalling downstream of the IL-2R can act through the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway, the Janus kinase (JAK)/Signal transducers and Activators of Transcription (STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway. In this report we focus on the relevance of these pathways as well as the impact of immunosuppressive drugs that may affect or enhance Selleckchem C59 wnt Treg function by targeting IL-2R signalling.”
“Natural killer (NK) cells have killer cell immunoglobulin-like receptors (KIR) that recognize and interact with HLA class I antigen. The KIRs are a multigene family and its members are often highly polymorphic. Evidence is emerging from disease-association studies that KIR receptors can play beneficial roles in viral infections, such as HIV, HCV, but may also predispose to certain autoimmune diseases. Knowledge regarding expression and function of KIR on human NK cells is lagging behind the rapid expansion of sequencing and genetic data already generated. This review focuses on recent discoveries that have been made, which help bridge this gap.

All patients required re-interventions in adulthood Tricuspid va

All patients required re-interventions in adulthood. Tricuspid valve (TV) (n = 5), pulmonary valve (PV)/conduit (n = 6), and mitral valve (n = 2) replacements were the most frequent re-intervention in the biventricular repair subset. Atrial arrhythmias were present in 80% of the total cohort, the highest

rate among Fontan repairs (n = 7) and biventricular repairs (n = 7). Ventricular arrhythmias occurred in 15% of the cohort.\n\nConclusions: Although limited in number, the adult PA/IVS patients in this series continue to have high rates of morbidity and mortality, with arrhythmias and need for re-operations as the major causes. Patients with biventricular repairs had the highest re-intervention rate in adulthood. While this subset of patients might not be representative of all adult LBH589 PA/IVS survivors, continued follow-up at centers with expertise in adult congenital cardiology is recommended for all patients. MRT67307 datasheet (c) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Abnormal c-Src expression and activation has been observed in a number of tumors. To determine the therapeutic potential of Src inhibitors for ovarian cancer patients, this study aimed to explore the expression patterns of c-Src and phospho-Src in epithelial ovarian cancer. A total of 82 patients with epithelial ovarian cancer

treated at Sun Yat-sen University Cancer Center from January 1999 to December 2005 were enrolled along with 25 patients with benign ovarian lesions; 20 normal ovarian tissues served as controls. Expression of c-Src and phospho-Src (Tyr416) was examined using immunohistochemistry. Survival analyses were performed using Kaplan-Meier curves. As compared to the control group, a significantly greater proportion of ovarian cancer

tissues were positive for c-Src and phospho-Src expression (P < 0.001). c-Src expression was associated with age, while phospho-Src expression was significantly associated with age, FIGO stage, histology grade, and residual tumor size after surgery (all P < 0.05). find more The mean survival time was associated with phospho-Src expression, but not with c-Src expression. The mean survival times of patients with phospho-Src-positive tumors were significantly greater than those with phospho-Src-negative tumors (87.4 months, 95 % CI = 74.3-100.5 months and 91.5 months, 95 % CI = 84.7-98.2 months, respectively; P = 0.013). The increased c-Src expression and activation in epithelial ovarian cancer suggests that ovarian cancer patients may benefit from tyrosine kinase inhibitors such as Dasatinib. Activation of c-Src through phosphorylation at Tyr416 may play a role in the early stages of ovarian cancer development, and evaluation of its expression may be a useful prognostic marker of epithelial ovarian cancer.

“Parkinson’s disease (PD) is one of the most common neurod

“Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Majority of PD are sporadic, for which genetic causes remain largely unknown. Alpha-synuclein, the main component of Lewy bodies, plays a central

role in the PD pathogenesis. Macroautophagy is a highly conserved cellular process that digests dysfunctional macromolecules and damaged organelles. Accumulating evidence indicates that macroautophagy (hereafter referred to as autophagy) is involved in alpha-synuclein degradation. Dysregulation of autophagy has been observed in the brain tissues from PD patients and animal models. We hypothesized that change expression levels of autophagy-related genes (ATG), including ATG5, may contribute to PD. In Dinaciclib this study, we genetically and functionally analyzed the ATG5 gene promoter in groups of sporadic PD patients and ethnic-matched healthy controls. A novel heterozygous variant, 106774459T>A, was identified in one female patient, but in none of controls, which significantly enhanced transcriptional activities of the ATG5 gene promoter. Furthermore, ATG5 gene expression level in the PD patient was significantly elevated than that in controls. Four novel heterozygous variants, 106774423C>A, 106774418C>A, 106774382C>A Selleck Pinometostat and 106774206G>A, were only found in controls. The variant, 106774464C>T, and SNP-106774030A>G (rs510432)

were found in PD patients and controls with similar frequencies. Vorinostat Collectively, the variant identified in PD patient may change ATG5 protein levels and alter autophagy activities, contributing to PD onset as a risk factor. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Copy number

expansions such as amplifications and duplications contribute to human phenotypic variation, promote molecular diversification during evolution, and drive the initiation and/or progression of various cancers. The mechanisms underlying these copy number changes are still incompletely understood, however. We recently demonstrated that transient, limited re-replication from a single origin in Saccharomyces cerevisiae efficiently induces segmental amplification of the re-replicated region. Structural analyses of such re-replication induced gene amplifications (RRIGA) suggested that RRIGA could provide a new mechanism for generating copy number variation by non-allelic homologous recombination (NAHR). Here we elucidate this new mechanism and provide insight into why it is so efficient. We establish that sequence homology is both necessary and sufficient for repetitive elements to participate in RRIGA and show that their recombination occurs by a single-strand annealing (SSA) mechanism. We also find that re-replication forks are prone to breakage, accounting for the widespread DNA damage associated with deregulation of replication proteins. These breaks appear to stimulate NAHR between re-replicated repeat sequences flanking a re-initiating replication origin.