Electron Glass Phase with Resilient Zhang-Rice Singlets in LiCu_{3}O_{3}.

LiCu_{3}O_{3} is an antiferromagnetic mixed valence cuprate where trilayers of edge-sharing Cu(II)O (3d^{9}) are sandwiched in between planes of Cu(I) (3d^{10}) ions, with Li stochastically substituting Cu(II). Angle-resolved photoemission spectroscopy (ARPES) and density functional theory reveal two insulating electronic subsystems that are segregated in spite of sharing common oxygen atoms: a Cu d_{z^{2}}/O p_{z} derived valence band (VB) dispersing on the Cu(I) plane, and a Cu 3d_{x^{2}-y^{2}}/O 2p_{x,y} derived Zhang-Rice singlet (ZRS) band dispersing on the Cu(II)O planes. First-principle analysis shows the Li substitution to stabilize the insulating ground state, but only if antiferromagnetic correlations are present. Li further induces substitutional disorder and a 2D electron glass behavior in charge transport, reflected in a large 530 meV Coulomb gap and a linear suppression of VB spectral weight at E_{F} that is observed by ARPES. Surprisingly, the disorder leaves the Cu(II)-derived ZRS largely unaffected. This indicates a local segregation of Li and Cu atoms onto the two separate corner-sharing Cu(II)O_{2} sub-lattices of the edge-sharing Cu(II)O planes, and highlights the ubiquitous resilience of the entangled two hole ZRS entity against impurity scattering.

Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection.

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.

Microwave graph analogs for the voltage drop in three-terminal devices with orthogonal, unitary, and symplectic symmetry.

Transmission measurements through three-port microwave graphs are performed, in analogy to three-terminal voltage drop devices with orthogonal, unitary, and symplectic symmetry. The terminal used as a probe is symmetrically located between two chaotic subgraphs, and each graph is connected to one port, the input and the output, respectively. The analysis of the experimental data clearly exhibits the weak localization and antilocalization phenomena. We find a good agreement with theoretical predictions, provided that the effects of dissipation and imperfect coupling to the ports are taken into account.

A novel electrochemical anodization cell for the synthesis of mesoporous silicon.

A novel design of an electrochemical anodization cell dedicated to the synthesis of mesoporous, single-crystalline silicon is presented. First and foremost, the design principle follows user safety since electrochemical etching of silicon requires highly hazardous electrolytes based on hydrofluoric (HF) acid. The novel cell design allows for safe electrolyte handling prior, during, and post-etching. A peristaltic pump with HF-resistant fluoroelastomer tubing transfers electrolytes between dedicated reservoirs and the anodization cell. Due to the flexibility of the cell operation, different processing conditions can be realized providing a large parameter range for the attainable sample thickness, its porosity, and the mean pore size. Rapid etching on the order of several minutes to synthesize micrometer-thick porous silicon epilayers on bulk silicon is possible as well as long-time etching with continuous, controlled electrolyte flow for several days to prepare up to 1000 µm thick self-supporting porous silicon membranes. A highly adaptable, LabVIEW™-based control software allows for user-defined etching profiles.

Lactifluus (Russulaceae) diversity in Central America and the Caribbean: melting pot between realms.

Species of the ectomycorrhizal genus Lactifluus, and often entire sections, are typically unique to a single continent. Given these biogeographic patterns, an interesting region to study their diversity is Central America and the Caribbean, since the region is closely connected to and often considered a part of the North American continent, but biogeographically belong to the Neotropical realm, and comprises several regions with different geologic histories. Based on a multi-gene phylogeny and morphological study, this study shows that Central America, Mexico and the Caribbean harbour at least 35 Lactifluus species, of which 33 were never reported outside of this region. It was found that species from the Caribbean generally show affinities to South American taxa, while species from the Central American mainland generally show affinities to Northern hemispheric taxa. We hypothesise that host specificity and/or climate play a crucial role in these different origins of diversity. Because of these different affinities, Caribbean islands harbour a completely different Lactifluus diversity than the Central American mainland. The majority of species occurring on the islands can be considered endemic to certain islands or island groups. In this paper, detailed morphological descriptions are given, with a focus on the unique diversity of the islands, and identification keys to all hitherto described Lactifluus species occurring in Central America and the Caribbean are provided. One new section, Lactifluus sect. Nebulosi, and three new species, Lactifluus guadeloupensis, Lactifluus lepus and Lactifluus marmoratus are described.

Terahertz-frequency dielectric anisotropy in three-dimensional polymethacrylates fabricated by stereolithography.

The anisotropic optical dielectric functions of slanted columnar layers fabricated using polymethacrylate based stereolithography are reported for the terahertz-frequency domain using generalized spectroscopic ellipsometry. The slanted columnar layers are composed of spatially coherent columnar structures with a diameter of 100 µm and a length of 700 µm that are tilted by 45° with respect to the surface normal of the substrates. A simple biaxial (orthorhombic) layer homogenization approach is used to analyze the terahertz ellipsometric data obtained at three different sample azimuthal orientations. The permittivity along the major polarizability directions varies by almost 25%. Our results demonstrate that stereolithography allows tailoring of the polarizability and anisotropy of the host material, and provides a flexible alternative metamaterials fabrication method for the terahertz spectral range.

[Laparoscopic versus open gastrectomy for advanced gastric cancer : Operative and postoperative results]. / Laparoskopische vs. offene Gastrektomie bei fortgeschrittenem Magenkarzinom : Operative und postoperative Ergebnisse.

BACKGROUND: Minimally invasive gastrectomy is increasingly becoming established worldwide as an alternative to open gastrectomy (OG); however, the majority of available articles in the literature refer to Asian populations and early stages of gastric cancer. This makes an international comparison difficult due to a discrepancy in patient populations and tumor biology as well as Asian and western treatment approaches. Little is known, therefore, whether laparoscopic gastrectomy (LG) can be performed in advanced cancer, in particular with respect to laparoscopic D2 lymphadenectomy, with sufficient radicality and safety in this country. MATERIAL AND METHODS: All gastrectomies performed for the treatment of advanced gastric cancer with clinical UICC stages 2 and 3 between 2005 and 2017 were analyzed. A case match by age, gender and UICC stage was performed to compare the operative and early postoperative results of LG and OG. RESULTS: A total of 243 patients with advanced gastric cancer were analyzed. Of these 81 patients (33.3%) underwent LG. The operative time for LG was around 74 min longer (279.2 min vs. 353.4 min, OG vs. LG; p < 0.001), the hospital stay after LG was around 4 days shorter (22.9 days vs. 18.4 days, OG vs. LG; p < 0.001). Significantly more lymph nodes were resected by LG (24.1 lymph nodes vs. 28.8 lymph nodes, OG vs. LG; p < 0.001). In terms of morbidity and mortality there were no differences between the groups. CONCLUSION: The present study showed that minimally invasive gastrectomy can be performed safely and with comparable histopathological results to open surgery, even in advanced gastric cancer in western populations; however, larger case series and evidence from high-quality studies are urgently needed especially to compare short-term and long-term survival.

Identification of responders to immune checkpoint therapy: which biomarkers have the highest value?

Evasion of immune recognition by the innate and acquired immune system is a major principle of tumour cells and belongs to the hallmarks of cancer. Immune checkpoint inhibitor-based cancer therapies targeting the co-inhibitory receptors CTLA-4 or PD-1 have received enormous scientific and clinical attention during the last few years, because of promising clinical results observed in the treatment of different cancer entities including melanoma and cutaneous squamous cell carcinoma. However, the enthusiasm about the effects of the immune checkpoint inhibitors is muted as only a subfraction of patients shows a stable clinical response. To predefine the patient cohorts that may benefit from immune checkpoint therapy, rigorous biomarker analyses, which predict the response to these novel therapies, need to be performed. In addition, combination of immune checkpoint therapy with classical DNA-damaging chemotherapy or radiotherapy, which positively affects tumour neo-antigen presentation, appears to be a promising approach in optimizing patients' response. In this review, we briefly summarize important biomarkers for patient stratification and discuss the current limitations of these biomarkers in defining responders vs. non-responders to immune checkpoint therapy.

Prediction of positron emitter distributions for range monitoring in carbon ion therapy: an analytical approach.

Range verification is one of the most relevant tasks in ion beam therapy. In the case of carbon ion therapy, positron emission tomography (PET) is the most widely used method for this purpose, which images the [Formula: see text]-activation following nuclear interactions of the ions with the tissue nuclei. Since the positron emitter activity profile is not directly proportional to the dose distribution, until today only its comparison to a prediction of the PET profile allows for treatment verification. Usually, this prediction is obtained from time-consuming Monte Carlo simulations of high computational effort, which impacts the clinical workflow. To solve this issue in proton therapy, a convolution approach was suggested to predict positron emitter activity profiles from depth dose distributions analytically. In this work, we introduce an approach to predict positron emitter distributions from depth dose profiles in carbon ion therapy. While the distal fall-off position of the positron emitter profile is predicted from a convolution approach similar to the one suggested for protons, additional analytical functions are introduced to describe the characteristics of the positron emitter distribution in tissue. The feasibility of this approach is demonstrated with monoenergetic depth dose profiles and spread out Bragg peaks in homogeneous and heterogeneous phantoms. In all cases, the positron emitter profile is predicted with high precision and the distal fall-off position is reproduced with millimeter accuracy.

Dose reconstruction from PET images in carbon ion therapy: a deconvolution approach.

Dose and range verification have become important tools to bring carbon ion therapy to a higher level of confidence in clinical applications. Positron emission tomography is among the most commonly used approaches for this purpose and relies on the creation of positron emitting nuclei in nuclear interactions of the primary ions with tissue. Predictions of these positron emitter distributions are usually obtained from time-consuming Monte Carlo simulations or measurements from previous treatment fractions, and their comparison to the current, measured image allows for treatment verification. Still, a direct comparison of planned and delivered dose would be highly desirable, since the dose is the quantity of interest in radiation therapy and its confirmation improves quality assurance in carbon ion therapy. In this work, we present a deconvolution approach to predict dose distributions from PET images in carbon ion therapy. Under the assumption that the one-dimensional PET distribution is described by a convolution of the depth dose distribution and a filter kernel, an evolutionary algorithm is introduced to perform the reverse step and predict the depth dose distribution from a measured PET distribution. Filter kernels are obtained from either a library or are created for any given situation on-the-fly, using predictions of the [Formula: see text]-decay and depth dose distributions, and the very same evolutionary algorithm. The applicability of this approach is demonstrated for monoenergetic and polyenergetic carbon ion irradiation of homogeneous and heterogeneous solid phantoms as well as a patient computed tomography image, using Monte Carlo simulated distributions and measured in-beam PET data. Carbon ion ranges are predicted within less than 0.5 mm and 1 mm deviation for simulated and measured distributions, respectively.

Comparison of adjustable male slings and artificial urinary sphincter in the treatment of male urinary incontinence: a retrospective analysis of patient selection and postoperative continence status.

PURPOSE: To analyze and compare preoperative patient characteristics and postoperative results in men with stress urinary incontinence (SUI) selected for an adjustable male sling system or an artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. METHODS: 658 male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in this study (n = 176 adjustable male sling; n = 482 AUS). Preoperative patient characteristics and postoperative outcomes were analyzed. For statistical analysis, the independent T test and Mann-Whitney U test were used. RESULTS: Patients undergoing adjustable male sling implantation were less likely to have a neurological disease (4.5% vs. 8.9%, p = 0.021), a history of urethral stricture (21.6% vs. 33.8%, p = 0.024) or a radiation therapy (22.7% vs. 29.9%, p = 0.020) compared to patients that underwent AUS implantation. Mean pad usage per day (6.87 vs. 5.82; p < 0.00) and the ratio of patients with a prior incontinence surgery were higher in patients selected for an AUS implantation (36.7% vs. 22.7%; p < 0.001). At maximum follow-up, patients that underwent an AUS implantation had a significantly lower mean pad usage during daytime (p < 0.001) and nighttime (p = 0.018). Furthermore, the patients' perception of their continence status was better with a subjective complete dry rate of 57.3% vs. 22.0% (p < 0.001). CONCLUSIONS: Patients selected for an AUS implantation showed a more complex prior history and pathogenesis of urinary incontinence as well as a more severe grade of SUI. Postoperative results reflect a better continence status after AUS implantation, favoring the AUS despite the more complicated patient cohort.

High-contrast infrared polymer photonic crystals fabricated by direct laser writing.

One-dimensional (1D) photonic crystals (PCs) were fabricated by three-dimensional (3D) direct laser writing using a single polymer to obtain reflectance values approaching that of a gold reference in the near-infrared (near-IR) spectral range. The PCs are composed of alternating compact and low-density polymer layers that provide the necessary periodic variation of the refractive index. The low-density polymer layers are composed of subwavelength-sized pillars which simultaneously serve as a scaffold while also providing refractive index contrast to the adjacent compact polymer layers. The Bruggemann effective medium theory and stratified-layer optical-model calculated reflectivity profiles were employed to optimize the PC's design to operate at a desired wavelength of 1.55 µm. After the fabrication, the PC's structure was compared to the nominal geometry using complementary scanning electron microscopy and optical microscopy micrographs identifying a true-to-form fabrication. The performance of the PCs was investigated experimentally using FTIR reflection and transmission measurements. A good agreement between stratified-layer optical-model calculated and measured data is observed. Therefore, we demonstrate the ease of predictive design and fabrication of highly efficient 1D PCs for the IR spectral range using 3D direct laser writing of a single polymer.

Broadband near-infrared antireflection coatings fabricated by three-dimensional direct laser writing.

Three-dimensional direct laser writing via two-photon polymerization is used to fabricate anti-reflective structured surfaces (ARSSs) composed of subwavelength conicoid features optimized to operate over a wide bandwidth in the near-infrared range from 3700 cm-1 to 6600 cm-1 (2.7-1.52 µm). Analytic Bruggemann effective medium calculations are used to predict nominal geometric parameters such as the fill factor of the constitutive conicoid features of the anti-reflective structured surfaces (ARSSs) presented here. The performance of the ARSSs was investigated experimentally using infrared reflection and transmission measurements. An enhancement of the transmittance by 1.35%-2.14% over a broadband spectral range from 3700 cm-1 to 6600 cm-1 (2.7-1.52 µm) was achieved. We further report on finite-element-based reflection and transmission data using three-dimensional (3D) model geometries for comparison. A good agreement between experimental results and the finite-element-based numerical analysis is observed once as-fabricated deviations from the nominal conicoid forms are included in the model. 3D direct laser writing is demonstrated here as an efficient method for the fabrication and optimization of ARSSs designed for the infrared spectral range.

Effects of the Mammalian Target of Rapamycin Inhibitor Everolimus on Hepatitis C Virus Replication In Vitro and In Vivo.

BACKGROUND: The influence of immunosuppressants on hepatitis C virus (HCV) re-infection after liver transplantation, particularly mammalian target of rapamycin inhibitors, remains unclear. The aim of our study was to analyze the influence of everolimus (EVR) on HCV replication activity in the context of underlying molecular mechanisms, with focus on the pro-myelocytic leukemia protein (PML). METHODS: HCV viral load was recorded in 40 patients with post-transplant HCV re-infection before and 8 weeks after introduction of EVR. An HCV cell culture replicon system for genotype (GT) 1b, GT2b, and GT3a was used to compare the influence of EVR on HCV replication for the respective genotypes in vitro. Fluorescence-activated cell-sorting analysis was used to test for effects on cell proliferation. PML expression was silenced with the use of small hairpin RNA constructs, and PML expression was quantified by means of quantitative real-time polymerase chain reaction. RESULTS: In patients with HCV, the viral load of GT1a and GT1b was hardly affected by EVR, whereas the viral load was reduced in patients with GT2a (P ≤ .0001) or GT3 infection (P ≤ .05). In vitro EVR impairs HCV replication activity of GT2a and GT3a up to 60% (P ≤ .0005), whereas in GT1b cells, HCV replication activity is increased by 50% (P ≤ .005). Replicon cell viability was not impaired. HCV replication activity is impaired in the absence of PML, which can be reversed by overexpression of PML isoforms. Furthermore, in the absence of PML, the effect of EVR on HCV replication activity is nearly abrogated. CONCLUSIONS: The mammalian target of rapamycin inhibitor EVR influences HCV replication via PML. The herein presented results suggest a genotype-dependent benefit for an EVR-based immunosuppressive regimen in patients with GT2a or GT3 re-infection after liver transplantation.

Anisotropic contrast optical microscope.

An optical microscope is described that reveals contrast in the Mueller matrix images of a thin, transparent, or semi-transparent specimen located within an anisotropic object plane (anisotropic filter). The specimen changes the anisotropy of the filter and thereby produces contrast within the Mueller matrix images. Here we use an anisotropic filter composed of a semi-transparent, nanostructured thin film with sub-wavelength thickness placed within the object plane. The sample is illuminated as in common optical microscopy but the light is modulated in its polarization using combinations of linear polarizers and phase plate (compensator) to control and analyze the state of polarization. Direct generalized ellipsometry data analysis approaches permit extraction of fundamental Mueller matrix object plane images dispensing with the need of Fourier expansion methods. Generalized ellipsometry model approaches are used for quantitative image analyses. These images are obtained from sets of multiple images obtained under various polarizer, analyzer, and compensator settings. Up to 16 independent Mueller matrix images can be obtained, while our current setup is limited to 11 images normalized by the unpolarized intensity. We demonstrate the anisotropic contrast optical microscope by measuring lithographically defined micro-patterned anisotropic filters, and we quantify the adsorption of an organic self-assembled monolayer film onto the anisotropic filter. Comparison with an isotropic glass slide demonstrates the image enhancement obtained by our method over microscopy without the use of an anisotropic filter. In our current instrument, we estimate the limit of detection for organic volumetric mass within the object plane of ≈49 fg within ≈7 × 7 µm2 object surface area. Compared to a quartz crystal microbalance with dissipation instrumentation, where contemporary limits require a total load of ≈500 pg for detection, the instrumentation demonstrated here improves sensitivity to a total mass required for detection by 4 orders of magnitude. We detail the design and operation principles of the anisotropic contrast optical microscope, and we present further applications to the detection of nanoparticles, to novel approaches for imaging chromatography and to new contrast modalities for observations on living cells.

The exercise-induced myokine irisin does not show an association with depressiveness, anxiety and perceived stress in obese women.

Irisin has recently been proposed to act as a myokine secreted from skeletal muscle following exercise and to exert several health-beneficial effects, although its role is far from being established. In contrast to the growing body of literature on the biological regulation and function of irisin, there is no evidence on potential associations with mental functions. Since physical activity has been reported to have favorable impact on mental functions, we investigated the association of irisin with depressiveness, perceived stress, and anxiety as well as eating disorder symptoms in obese women. We included 98 female obese inpatients (age: mean ± S.D. 43.9 ± 12.5 years; body mass index 49.2 ± 8.3 kg/m(2)) covering a broad spectrum of psychopathology. Depressiveness (PHQ-9), perceived stress (PSQ-20), anxiety (GAD-7), and eating disorder symptoms (EDI-2) were assessed psychometrically. Plasma irisin obtained at the same time was determined by ELISA. Irisin did not correlate with depressiveness (r = -0.03, P = 0.80), anxiety (r = 0.14, P = 0.17) and perceived stress (r = -0.14, P = 0.18) as well as eating disorder symptoms in general (r = -0.09, P = 0.39). No correlation of irisin was observed with any subscales of the PSQ-20 and EDI-2 (after Bonferroni correction). In conclusion, irisin is not associated with depressiveness, anxiety and perceived stress in female obese patients. These results do not support the assumption of irisin being involved in psychoendocrine pathways of the regulation of depression or other mental functions such as anxiety and perceived stress.

The type of loose seton for complex anal fistula is essential to improve perianal comfort and quality of life.

AIM: The use of a loose seton for complex anal fistulae can cause perianal discomfort and reduced quality of life. The aim of this study was to assess the impact of the novel knot-free Comfort Drain on quality of life, perianal comfort and faecal continence compared to conventional loose setons. METHOD: Forty-four patients treated for complex anal fistula at a single institution between July 2013 and September 2014 were included in the study. A matched-pair analysis was performed to compare patients with a knot-free Comfort Drain and controls who were managed by conventional knotted setons. The 12-item Short Form survey (SF-12) questionnaire was used to assess quality of life. Additionally, patients reported perianal comfort and faecal incontinence using a Visual Analog Scale (VAS) and the St Mark's Incontinence Score. RESULTS: The Comfort Drain was associated with improved quality of life with significant higher median physical (P = 0.001) and mental (P = 0.04) health scores compared with a conventional loose seton. According to the VAS, patients with a Comfort Drain in situ reported greater perianal comfort with significantly less burning sensation (P < 0.001) and pruritus (P < 0.001). Faecal continence was similar in each group. CONCLUSION: The Comfort Drain offers improved perianal comfort and better quality of life compared with a conventional loose seton and therefore facilitates long-term therapy in patients with complex fistula-in-ano.

HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism.

Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response.

Treatment with the ghrelin-O-acyltransferase (GOAT) inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats.

The ghrelin acylating enzyme ghrelin-O-acyltransferase (GOAT) was recently identified and implicated in several biological functions. However, the effects on food intake warrant further investigation. While several genetic GOAT mouse models showed normal food intake, acute blockade using a GOAT inhibitor resulted in reduced food intake. The underlying food intake microstructure remains to be established. In the present study we used an automated feeding monitoring system to assess food intake and the food intake microstructure. First, we validated the basal food intake and feeding behavior in rats using the automated monitoring system. Afterwards, we assessed the food intake microstructure following intraperitoneal injection of the GOAT inhibitor, GO-CoA-Tat (32, 96 and 288 µg/kg) in freely fed male Sprague-Dawley rats. Rats showed a rapid habituation to the automated food intake monitoring system and food intake levels were similar compared to manual monitoring (P = 0.43). Rats housed under these conditions showed a physiological behavioral satiety sequence. Injection of the GOAT inhibitor resulted in a dose-dependent reduction of food intake with a maximum effect observed after 96 mg/kg (-27%, P = 0.03) compared to vehicle. This effect was delayed in onset as the first meal was not altered and lasted for a period of 2 h. Analysis of the food intake microstructure showed that the anorexigenic effect was due to a reduction of meal frequency (-15%, P = 0.04), whereas meal size (P = 0.29) was not altered compared to vehicle. In summary, pharmacological blockade of GOAT reduces dark phase food intake by an increase of satiety while satiation is not affected.