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Abstract Steranes preserved in sedimentary rocks serve as molecular fossils, which are thought to record the expansion of eukaryote life through the Neoproterozoic Era ( ~ 1000-541 Ma). Scientists hypothesize that ancient C27 steranes originated from cholesterol, the major sterol produced by living red algae and animals. Similarly, C28 and C29 steranes are thought to be derived from the sterols of prehistoric fungi, green algae, and other microbial eukaryotes. However, recent work on annelid worms–an advanced group of eumetazoan animals–shows that they are also capable of producing C28 and C29 sterols. In this paper, we explore the evolutionary history of the 24-C sterol methyltransferase (smt) gene in animals, which is required to make C28+ sterols. We find evidence that the smt gene was vertically inherited through animals, suggesting early eumetazoans were capable of C28+ sterol synthesis. Our molecular clock of the animal smt gene demonstrates that its diversification coincides with the rise of C28 and C29 steranes in the Neoproterozoic. This study supports the hypothesis that early eumetazoans were capable of making C28+ sterols and that many animal lineages independently abandoned its biosynthesis around the end-Neoproterozoic, coinciding with the rise of abundant eukaryotic prey.

Abstract In this work we present a keV-scale sterile-neutrino search with a low-tritium-activity data set of the KATRIN experiment, acquired in a commissioning run in 2018. KATRIN performs a spectroscopic measurement of the tritium $$\upbeta $$ β -decay spectrum with the main goal of directly determining the effective electron anti-neutrino mass. During this commissioning phase a lower tritium activity facilitated the measurement of a wider part of the tritium spectrum and thus the search for sterile neutrinos with a mass of up to $$1.6\, \textrm{keV}$$ 1.6 keV . We do not find a signal and set an exclusion limit on the sterile-to-active mixing amplitude of $$\sin ^2\theta < 5\times 10^{-4}$$ sin 2 θ < 5 × 10 - 4 ( $$95\%$$ 95 % C.L.) at a mass of 0.3 keV. This result improves current laboratory-based bounds in the sterile-neutrino mass range between 0.1 and 1.0 keV.

Purpose: ARID1B is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with ARID1B-related disorder have been described, which limits our understanding of the disease’s natural history and our ability to counsel patients and their families. Methods: Data on patients aged 18+ years with ARID1B-related disorder were collected through an online questionnaire completed by clinicians and parents. Results: Eighty-seven adult patients with ARID1B were included. Cognitive functioning ranged from borderline to severe intellectual disability. Patients identified through the genetic workup of their child were either mosaic or had a variant in exon 1. New clinical features identified in this population are loss of skill (16/64, 25%) and recurrent patella luxation (12/45, 32%). Self-sustainability data showed that 88% (45/51) could eat independently, and 16% (7/45) could travel alone by public transport. Facial photo analysis showed that patients’ photographs taken at different ages clustered consistently, separate from matched controls. Conclusion: The ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

Abstract Liquid xenon time projection chambers are promising detectors to search for neutrinoless double beta decay (0 $$\nu \beta \beta $$ ν β β ), due to their response uniformity, monolithic sensitive volume, scalability to large target masses, and suitability for extremely low background operations. The nEXO collaboration has designed a tonne-scale time projection chamber that aims to search for 0 $$\nu \beta \beta $$ ν β β of $$^{136}$$ 136 Xe with projected half-life sensitivity of $$1.35\times 10^{28}$$ 1.35 × 10 28 yr. To reach this sensitivity, the design goal for nEXO is $$\le $$ ≤ 1% energy resolution at the decay Q-value ( $$2458.07\pm 0.31$$ 2458.07 ± 0.31 keV). Reaching this resolution requires the efficient collection of both the ionization and scintillation produced in the detector. The nEXO design employs Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm scintillation light of liquid xenon. This paper reports on the characterization of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3 SiPMs specifically designed for nEXO, as well as new measurements on new test samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters (MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct crosstalk, correlated avalanches and photon detection efficiency were measured as a function of the applied over voltage and wavelength at liquid xenon temperature (163 K). The results from this study are used to provide updated estimates of the achievable energy resolution at the decay Q-value for the nEXO design.

Not available.

Abstract Epidemiology of bacteria isolated from pyogenic liver abscesses change, and an increase in enterococci has been reported in European hospitals. The aim of this study was to investigate the clinical characteristics and outcome of enterococcal PLA. We performed a retrospective analysis of patients with microbiologically confirmed PLA at three German university centers. Indicators of enterococcal PLA were determined using binary logistic regression, and survival analysis was performed using Kaplan–Meier statistics and Cox regression analysis. Enterococci were isolated in 51/133 (38%) patients with PLA. Patients with enterococcal PLA had smaller abscess diameter (4.8 vs. 6.7 cm, p = 0.03) than patients with non-enterococcal PLA, but had more frequent polymicrobial culture results. In univariate logistic regression analysis, alcohol abuse (OR 3.94, 95% CI 1.24–12.49, p = 0.02), hepatobiliary malignancies (OR 3.90, 95% CI 1.86–8.18, p

Mass measurements continue to provide invaluable information for elucidating nuclear structure and scenarios of astrophysical interest. The transition region between the Z=20 and 28 proton shell closures is particularly interesting due to the onset and evolution of nuclear deformation as nuclei become more neutron-rich. This provides a critical testing ground for emerging ab-initio nuclear structure models. Here, we present high-precision mass measurements of neutron-rich chromium isotopes using the sensitive electrostatic Multiple-Reflection Time-Of-Flight Mass Spectrometer (MR-TOF-MS) at TRIUMF's Ion Trap for Atomic and Nuclear Science (TITAN) facility. Our high-precision mass measurements of 59,61−63Cr confirm previous results, and the improved precision in measurements of 64−65Cr refine the mass surface beyond N=40. With the ab initio in-medium similarity renormalization group, we examine the trends in collectivity in chromium isotopes and give a complete picture of the N=40 island of inversion from calcium to nickel.

Abstract The KATRIN experiment is designed for a direct and model-independent determination of the effective electron anti-neutrino mass via a high-precision measurement of the tritium $$\upbeta $$ β -decay endpoint region with a sensitivity on $$m_\nu $$ m ν of 0.2 $$\hbox {eV}/\hbox {c}^2$$ eV / c 2 (90% CL). For this purpose, the $$\upbeta $$ β -electrons from a high-luminosity windowless gaseous tritium source traversing an electrostatic retarding spectrometer are counted to obtain an integral spectrum around the endpoint energy of 18.6 keV. A dominant systematic effect of the response of the experimental setup is the energy loss of $$\upbeta $$ β -electrons from elastic and inelastic scattering off tritium molecules within the source. We determined the energy-loss function in-situ with a pulsed angular-selective and monoenergetic photoelectron source at various tritium-source densities. The data was recorded in integral and differential modes; the latter was achieved by using a novel time-of-flight technique. We developed a semi-empirical parametrization for the energy-loss function for the scattering of 18.6-keV electrons from hydrogen isotopologs. This model was fit to measurement data with a 95% $$\hbox {T}_2$$ T 2 gas mixture at 30 K, as used in the first KATRIN neutrino-mass analyses, as well as a $$\hbox {D}_2$$ D 2 gas mixture of 96% purity used in KATRIN commissioning runs. The achieved precision on the energy-loss function has abated the corresponding uncertainty of $$\sigma (m_\nu ^2)< {{10}^{-2}}{\hbox {eV}^{2}}$$ σ ( m ν 2 ) < 10 - 2 eV 2 [1] in the KATRIN neutrino-mass measurement to a subdominant level.

Abstract The KArlsruhe TRItium Neutrino experiment (KATRIN) aims to determine the effective electron (anti)-neutrino mass with a sensitivity of 0.2eV/c $$^2$$ 2 by precisely measuring the endpoint region of the tritium $$\beta $$ β -decay spectrum. It uses a tandem of electrostatic spectrometers working as magnetic adiabatic collimation combined with an electrostatic (MAC-E) filters. In the space between the pre-spectrometer and the main spectrometer, creating a Penning trap is unavoidable when the superconducting magnet between the two spectrometers, biased at their respective nominal potentials, is energized. The electrons accumulated in this trap can lead to discharges, which create additional background electrons and endanger the spectrometer and detector section downstream. To counteract this problem, “electron catchers” were installed in the beamline inside the magnet bore between the two spectrometers. These catchers can be moved across the magnetic-flux tube and intercept on a sub-ms time scale the stored electrons along their magnetron motion paths. In this paper, we report on the design and the successful commissioning of the electron catchers and present results on their efficiency in reducing the experimental background.

Abstract Background A two-fold risk increase to develop basal cell carcinoma was seen in outdoor workers exposed to high solar UV radiation compared to controls. However, there is an ongoing discussion whether histopathological subtype, tumor localization and Fitzpatrick phototype may influence the risk estimates. Objectives To evaluate the influence of histological subtype, tumor localization and Fitzpatrick phototype on the risk to develop basal cell carcinoma in highly UV-exposed cases and controls compared to those with moderate or low solar UV exposure. Methods Six hundred forty-three participants suffering from incident basal cell carcinoma in commonly sun-exposed anatomic sites (capillitium, face, lip, neck, dorsum of the hands, forearms outside, décolleté) of a population-based, case-control, multicenter study performed from 2013 to 2015 in Germany were matched to controls without skin cancer. Multivariate logistic regression analysis was conducted stratified for histological subtype, phototype 1/2 and 3/4. Dose-response curves adjusted for age, age2, sex, phototype and non-occupational UV exposure were calculated. Results Participants with high versus no (OR 2.08; 95% CI 1.24–3.50; p = 0.006) or versus moderate (OR 2.05; 95% CI 1.15–3.65; p = 0.015) occupational UV exposure showed a more than two-fold significantly increased risk to develop BCC in commonly UV-exposed body sites. Multivariate regression analysis did not show an influence of phototype or histological subtype on risk estimates. The restriction of the analysis to BCC cases in commonly sun-exposed body sites did not influence the risk estimates. The occupational UV dosage leading to a 2-fold increased basal cell carcinoma risk was 6126 standard erythema doses. Conclusion The risk to develop basal cell carcinoma in highly occupationally UV-exposed skin was doubled consistently, independent of histological subtype, tumor localization and Fitzpatrick phototype.

Integrated Voltage Regulators (IVRs) are attractive substitutes for conventional voltage regulators located on the motherboards, due to outstanding dynamic performances and superior power densities. IVRs operate with switching frequencies in the range of 100 MHz and are assembled in highly compact packages close to the microprocessor load. This paper presents a comprehensive characterization of a PCB and inductor-based four-phase ANPC-type IVR that uses a Power Management IC (PMIC) implemented in a 14 nm CMOS technology node. The characterization is based on the results of electrical measurements, thermal inspections of the chip surface, and simulations, which enables the separation of the total losses into on-chip and off-chip loss components and the allocation of important loss components inside the chip. The investigated IVR achieves a maximum efficiency of 84.1% at an output power of Pout = 640 mW and a switching frequency of fs = 50 MHz. The thermal measurements reveal that the maximum efficiency of the PMIC itself is between 88 % and 90 % at fs = 50 MHz and Pout ∈ [500 mW, 600 mW]; at Pout = 890 mW, a chip current density of 24.7 A/mm2 is achieved. The findings in particular point out that the losses in the chip-internal interconnections, i.e., the conductors of the Power Distribution Network (PDN) and the twelve stacked metal layers below the PDN, have a substantial contribution to the total losses. Furthermore, the combination of Cadence post-layout simulations with impedance networks obtained from an appropriate software tool, e.g., FastHenry, is found to establish a suitable toolbox for estimating losses in IVRs.

Abstract The KATRIN experiment aims to measure the effective electron antineutrino mass $$m_{\overline{\nu }_e}$$ mν¯e with a sensitivity of $${0.2}\,{\hbox {eV}/\hbox {c}^2}$$ 0.2eV/c2 using a gaseous tritium source combined with the MAC-E filter technique. A low background rate is crucial to achieving the proposed sensitivity, and dedicated measurements have been performed to study possible sources of background electrons. In this work, we test the hypothesis that gamma radiation from external radioactive sources significantly increases the rate of background events created in the main spectrometer (MS) and observed in the focal-plane detector. Using detailed simulations of the gamma flux in the experimental hall, combined with a series of experimental tests that artificially increased or decreased the local gamma flux to the MS, we set an upper limit of $${0.006}\,{\hbox {count}/\hbox {s}}$$ 0.006count/s (90% C.L.) from this mechanism. Our results indicate the effectiveness of the electrostatic and magnetic shielding used to block secondary electrons emitted from the inner surface of the MS.

Abstract Background The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. Methods The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. Results Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. Conclusion In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

Abstract The KATRIN experiment aims to determine the effective electron neutrino mass with a sensitivity of $${0.2}{\hbox { eV/c}^{2}}$$ 0.2eV/c2 (%90 CL) by precision measurement of the shape of the tritium $$\upbeta $$ β -spectrum in the endpoint region. The energy analysis of the decay electrons is achieved by a MAC-E filter spectrometer. A common background source in this setup is the decay of short-lived isotopes, such as $${}^{\text {219}}\text {Rn}$$ 219Rn and $${}^{\text {220}}\text {Rn}$$ 220Rn , in the spectrometer volume. Active and passive countermeasures have been implemented and tested at the KATRIN main spectrometer. One of these is the magnetic pulse method, which employs the existing air coil system to reduce the magnetic guiding field in the spectrometer on a short timescale in order to remove low- and high-energy stored electrons. Here we describe the working principle of this method and present results from commissioning measurements at the main spectrometer. Simulations with the particle-tracking software Kassiopeia were carried out to gain a detailed understanding of the electron storage conditions and removal processes.

Abstract The neutrino mass experiment KATRIN requires a stability of 3 ppm for the retarding potential at − 18.6 kV of the main spectrometer. To monitor the stability, two custom-made ultra-precise high-voltage dividers were developed and built in cooperation with the German national metrology institute Physikalisch-Technische Bundesanstalt (PTB). Until now, regular absolute calibration of the voltage dividers required bringing the equipment to the specialised metrology laboratory. Here we present a new method based on measuring the energy difference of two $$^{83{\mathrm{m}}}$$ 83m Kr conversion electron lines with the KATRIN setup, which was demonstrated during KATRIN’s commissioning measurements in July 2017. The measured scale factor $$M=1972.449(10)$$ M=1972.449(10) of the high-voltage divider K35 is in agreement with the last PTB calibration 4 years ago. This result demonstrates the utility of the calibration method, as well as the long-term stability of the voltage divider.

Abstract Background The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. Methods From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. Results In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1–4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1–13) and dose per fraction (median: 18.5 Gy; range 3–37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control. Conclusion After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.

The worldwide plasticizer markets are facing constant substitution processes. Many classic ortho-phthalate plasticizers like di(2-ethylhexyl) phthalate (DEHP) are phased out, due to their proven toxicity to reproduction. Assumedly less critical, less regulated plasticizers such as di(2-ethylhexyl) terephthalate (DEHTP) are increasingly applied in consumer near products like toys, food contact materials, and medical devices. With the increasing use of DEHTP, increasing exposures of the general population have to be expected likewise. Human biomonitoring is a well-established tool to determine population exposures. In the present study we investigate the time trend of exposure to DEHTP using 24-hour urine samples of the German Environmental Specimen Bank (ESB) collected from 1999 to 2017. In these samples (60 per odd-numbered year, 600 samples in total) collected from young German adults (20–29 years, equal gender distribution) we determined four specific urinary metabolites as biomarkers of DEHTP exposure. From 1999 to 2009, the main specific urinary metabolite 5cx-MEPTP was quantifiable in

Remote sensing Synthetic Aperture Radar (SAR) data from TerraSAR-X and Tandem-X (TS-X and TD-X) satellites have been used for validation and verification of newly developed coastal forecast models in the German Bight of the North Sea. The empirical XWAVE algorithm for estimation of significant wave height has been adopted for coastal application and implemented for NRT services. All available TS-X images in the German Bight collocated with buoy measurements (6 buoys) since 2013 were processed and analysed (total of 46 scenes/passages with 184 StripMap images). Sea state estimated from series of TS-X images cover strips with length of ~200km and width of 30km over the German Bight from East-Frisian Islands to the Danish coast. The comparisons with results of wave prediction model show a number of local variations due to variety in bathymetry and wind fronts

Interfacial instabilities can be damaging as they may lead to fabrication defects. Here the authors harness a fluid instability to their advantage to produce thin polymeric films with drop-shaped structures which have tailored geometrical properties.

Foods industry calls for effective methods to prepare thin shell structures, such as hollow chocolate eggs, which are also relevant to many industrial applications. Here, Lee et al. show how to fabricate hemispherical shells with nearly uniform yet tunable thickness to produce elastic structures.

While treatment of localized cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) is based on surgery, brachytherapy, which delivers a high dose of radiation to tumor tissue while sparing healthy tissue, is an alternative. Since the withdrawal of iridium wires from the market, brachytherapy has mainly been performed with high-dose-rate iridium-192 (HDR). This study evaluated the efficacy of HDR brachytherapy in terms of local control, survival, toxicity, and quality of life in patients with facial periorificial cutaneous SCC or BCC treated in our center between 2015 and 2021. Sixty-seven patients were treated for SCC ( n = 49) or BCC ( n = 18), on the nose ( n = 29), lip ( n = 28), eyelid ( n = 7), or ear ( n = 3). The majority had Tis or T1 tumors (73.1%). After a median follow-up of 28 months, 8 patients had a local recurrence. The local control rate at 3 years was 87.05% (95% CI 74.6-93.7). All patients developed grade 1-2 acute radio-mucositis or radiodermatitis and one experienced reversible grade 3 acute radio-mucositis. Of the 27 patients who completed the quality-of-life questionnaire, 77.8% recommended the treatment. This study confirms that HDR brachytherapy for facial cutaneous carcinomas provides good local control, good tolerance, and satisfactory functional outcome.

Provision of amino acids to the liver is instrumental for gluconeogenesis while it requires safe disposal of the amino group. The mitochondrial enzyme glutamate dehydrogenase (GDH) is central for hepatic ammonia detoxification by deaminating excessive amino acids toward ureagenesis and preventing hyperammonemia. The present study investigated the early adaptive responses to changes in dietary protein intake in control mice and liver-specific GDH KO mice (Hep-Glud1 -/- ). Mice were fed chow diets with a wide coverage of protein contents; i.e., suboptimal 10%, standard 20%, over optimal 30%, and high 45% protein diets; switched every 4 days. Metabolic adaptations of the mice were assessed in calorimetric chambers before tissue collection and analyses. Hep-Glud1 -/- mice exhibited impaired alanine induced gluconeogenesis and constitutive hyperammonemia. The expression and activity of GDH in liver lysates were not significantly changed by the different diets. However, applying an in situ redox-sensitive assay on cryopreserved tissue sections revealed higher hepatic GDH activity in mice fed the high-protein diets. On the same section series, immunohistochemistry provided corresponding mapping of the GDH expression. Cosinor analysis from calorimetric chambers showed that the circadian rhythm of food intake and energy expenditure was altered in Hep-Glud1 -/- mice. In control mice, energy expenditure shifted from carbohydrate to amino acid oxidation when diet was switched to high protein content. This shift was impaired in Hep-Glud1 -/- mice and consequently the spontaneous physical activity was markedly reduced in GDH KO mice. These data highlight the central role of liver GDH in the energy balance adaptation to dietary proteins., Competing Interests: Conflict of interest The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Microbial lipids are a valuable source of potential biofuels and essential polyunsaturated fatty acids. The optimization of the fermentation conditions is a strategy that affects the total lipid concentration. The genus Nigrospora sp. has been the target of investigations based on its potential bioherbicidal action. Therefore, this study developed a strategy to maximize the biomass concentration and lipid accumulation by Nigrospora sp. in submerged fermentation. Different media compositions and process variables were investigated in shaken flasks and bioreactor in batch and fed-batch modes. Maximum biomass concentration and lipid accumulations were 40.17 g/L and 21.32 wt% in the bioreactor, which was 2.1 and 5.4 times higher than the same condition in shaken flasks, respectively. This study presents relevant information to the production of fungal lipids since few investigations are exploring the fed-batch strategy to increase the yield of fungi lipids, as well as few studies investigating Nigrospora sp. to produce lipids.

Objectives: The trial aimed to compare the pain perceived by women during intrauterine device (IUD) insertion, with or without virtual reality (VR) therapy. Furthermore, anxiety during the insertions, pain after the insertions, and satisfaction with the insertions were compared., Methods: The trial was designed as a prospective, bi-centric, randomized, open-label interventional trial. All adult women that chose an IUD during a contraceptive consultation, and who provided informed consent were eligible. Women under legal guardianship, not affiliated to a national social security system, and with pre-existing dizziness, severe facial wounds, or epilepsy were not eligible. Eligible women were randomly allocated either standard care without VR therapy (Control group) or with VR therapy (Experimental group). Pain, anxiety, and satisfaction were measured using a 10-cm numerical scale., Results: Between September 2020 and April 2022, 100 women were randomized: 50 to each group. The mean pain scores during IUD insertion were 5.4 cm in the Control group versus 5.1 cm in the Experimental group (p = 0.54). Mean anxiety during insertion were 4.8 cm in the Control group versus 4.2 cm in the Experimental group (p = 0.13). While mean pain perceived after insertions were 2.4 cm in the Control Group and 2.4 cm in the Experimental group (p = 0.98). Mean satisfaction with the insertions was 9.6 cm in both groups (p = 0.87). Anxiety before IUD insertion, as well as anticipated pain, were significantly correlated with pain perceived during insertions., Conclusions: VR therapy performed during the procedure did not alleviate perceived pain in women undergoing IUD insertions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

The anti-Müllerian hormone (AMH) is a heterodimeric glycoprotein belonging to the TGFb superfamily implicated in human embryonic development. This hormone was first described as allowing regression of the epithelial embryonic Müllerian structures in males, which would otherwise differentiate into the uterus and fallopian tubes. It activates a signaling pathway mediated by two transmembrane receptors. Binding of AMH to its receptor induces morphological changes leading to the degeneration of Müllerian ducts. Recently, new data has shown the role played by this hormone on structures other than the genital tract. If testicular AMH expression decreases in humans over the course of a lifetime, synthesis may persist in other tissues in adulthood. The mechanisms underlying its production have been unveiled. The aim of this review is to describe the different pathways in which AMH has been identified and plays a pivotal role., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

This study describes the use of spray drying technology to obtain a powder containing biomolecules with herbicidal activity produced by submerged fermentation using Diaporthe schini . The efficiency of the bioherbicide was tested for the post-emergence control of Bidens pilosa L., Amaranthus viridis L., Echinochloa crusgalli (L.) Beauv., and Lolium multiflorum Lam. In the first step, different additives were used and lactose was the most suitable one because it resulted in high herbicidal activity and weed suppression. In the second step, process variables were investigated, including inlet air temperature, drying air flow rate, and feed flow rate. The highest herbicidal activity was obtained with an inlet air temperature of 100°C, and air and feed flow rates of 1.4 m 3 /min and 0.22 L/h, respectively. Maximum herbicidal activities were 38, 45, 21 and 18%, while weed heights reduction were 69.0, 74.3, 20.4 and 24.8% for B. pilosa , A. viridis, E. crusgalli and L. multiflorum , respectively. The bioherbicide was effective to suppress weed growth and spray drying is a promising technology for the production of solid formulations of bioherbicides.

Aims/hypothesis: Chronic exposure of pancreatic beta cells to high glucose and fatty acids has been proposed to induce glucolipotoxicity. However, contradictory results suggest adaptations of the beta cells, which might be instrumental for partial preservation of the secretory response. In this context, we delineated the expression pattern of genes related to lipid pathways along with fat storage/mobilisation during glucose-stimulated insulin secretion., Methods: Insulin-secreting cells were cultured for 3 days at different glucose concentrations (5.5, 11.1, 25 mmol/l) without or with BSA-complexed 0.4 mmol/l palmitate and oleate. Then, transcriptomic analyses of lipid pathways were performed in human islets by RNA-Seq and in INS-1E cells and rat islets by quantitative RT-PCR. Storage of fat was assessed in INS-1E cells by electron microscopy and Bodipy staining, which was also used for measuring lipid mobilisation rate. The secretory response was monitored during acute 15 mmol/l glucose stimulation using online luminescence assay for INS-1E cells and by radioimmunoassay for rat islets., Results: In human islets, chronic exposure to palmitate and oleate modified expression of a panel of genes involved in lipid handling. Culture at 25 mmol/l glucose upregulated genes encoding for enzymes of the glycerolipid/NEFA cycle and downregulated receptors implicated in fatty acid signalling. Similar results were obtained in INS-1E cells, indicating enhanced capacity of the glycerolipid/NEFA cycle under glucotoxic conditions. Exposure to unsaturated C18:1 fatty acid favoured intracellular lipid accumulation in a glucose-dependent way, an effect also observed with saturated C16:0 fatty acid when combined with the panlipase inhibitor Orlistat. After the glucolipotoxic culture, intracellular fat mobilisation was required for acute glucose-stimulated secretion, particularly in oleate-treated cells under glucotoxic culture conditions. The lipid mobilisation rate was governed chiefly by the levels of stored fat as a direct consequence of the culture conditions rather than energetic demands, except in palmitate-loaded cells., Conclusions/interpretation: Glucolipotoxic conditions promote the capacity of the glycerolipid/NEFA cycle thereby preserving part of the secretory response. The cycle of fat storage/mobilisation emerges as a mechanism helping the beta cell to cope with glucotoxic conditions., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aims to assess the outcomes of adjuvant interstitial brachytherapy (BT) to the tumor bed for oral cavity squamous cell carcinoma (SCC), and to compare the oncological outcomes and toxicity profile of low-dose-rate (LDR) and pulsed-dose-rate (PDR) BT., Design: This retrospective single-center study included all patients who underwent postoperative LDR- or PDR-BT to the tumor bed as the sole adjuvant treatment for an oral tongue or floor of the mouth SCC between January 2000 and December 2020., Results: A total of 79 patients were eligible for this study. The cohort was divided into an LDR group (n = 38) and a PDR group (n = 41). The median time interval between surgery and brachytherapy was 55 days. Median delivered total dose was 55 Gy and median hospital stay was 5 days. Five patients (8.3%) experienced grade 3-4 early toxicity, 2 in the LDR group and 3 in the PDR group. Late toxicities were present in 28 patients (44.4%) and were dominated by grade 1-2 residual pain and dysesthesia, without a statistical difference between the groups. After a median follow-up of 65.1 months, 5‑year local control (LC), disease-free survival (DFS), and overall survival (OS) for the whole cohort were 76.3% (95% CI = 63.4-85.1), 61.6% (95% CI = 49.0-72.0), and 71.4% (95% CI = 58.6-80.8), respectively., Conclusion: Adjuvant BT after excision of oral cavity SCC provides satisfactory oncological outcomes along with good tolerance. In our study, PDR-BT showed similar oncological and functional results to LDR-BT in this indication., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Weed control is a critical factor to ensure productivity and quality for food production. Chemical control is the main method used worldwide, but the demand for healthier food and the farmers' health and environment concerns have led to an increase in the search for alternative control methods. In this way, the use of biomolecules produced by microorganisms that present phytotoxic activity against weeds, such as exopolysaccharides, is attracting attention. For this purpose, this work compared two techniques (solid-state and submerged fermentation) for bioherbicide production by Diaporthe schini . Physicochemical characterization of both fermented broth and evaluation of bioherbicidal effect in post-emergence of Amaranthus viridis , Bidens pilosa , Echinocloa crusgalli , and Lollium multiflorum were performed. Fungal broth obtained by submerged fermentation presented better physicochemical characteristics in terms of viscosity, density, and surface tension. Overall, it was more effective than the broth obtained by solid-state fermentation for weed control because it presented an average inhibition of 40% of weed growth and 45% lower surface tension if compared to the control test. Also, reductions of 1.4-4.2 times of root dry mass, 2.9-5.8 times of shoot dry mass and 1.2-3.9 times of weeds heights, if compared to the control test, were achieved.

Purpose: To compare the ovarian response to controlled ovarian hyperstimulation (COH) in patients with hematologic malignancies treated for fertility preservation (FP) and healthy subjects (oocyte donors (OD))., Patients and Methods: Retrospective cohort study comparing 41 women (18-37 years) who underwent COH for oocyte vitrification prior to gonadotoxic treatment for hematologic cancer (FP group) from January 2014 to February 2019 and with 117 women undergoing COH as part of an OD protocol (OD group) during the same period. The number of frozen mature oocytes, number of oocytes retrieved, total dose of rFSH, maximal estradiol levels, percentage of maturity, number of dominant follicles >14 mm, days of stimulation were evaluated. Results were adjusted for age, body mass index (BMI), anti-Mullerian hormone (AMH) and rFSH starting dose., Results: Patients in the FP group were younger and had a lower BMI than those in the OD group. rFSH starting dose was higher in the FP group (median 225UI (125;450) vs 150UI (87.5;337.5), p < 0.0001). After adjusting for age, BMI and starting rFSH dose according to ANCOVA, more frozen mature oocytes (median 10 (0;45) vs 8 (0;22] p = 0.0055) and retrieved oocytes (median 12 (0;49) vs 11 (0;29) p = 0.0468) were found in the FP group. Other outcome measures did not differ between the groups., Conclusion: Ovarian response after COH in women with a hematologic cancer is similar to that in the general population. A higher number of mature oocytes were collected in the FP group after strong COH., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest, (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Chronic exposure of β-cells to nutrient-rich metabolic stress impairs mitochondrial metabolism and its coupling to insulin secretion. We exposed isolated human islets to different metabolic stresses for 3 days: 0.4 mM oleate or 0.4 mM palmitate at physiological 5.5 mM glucose (lipotoxicity), high 25 mM glucose (glucotoxicity), and high 25 mM glucose combined with 0.4 mM oleate and/or palmitate (glucolipotoxicity). Then, we profiled the mitochondrial carriers and associated genes with RNA-Seq. Diabetogenic conditions, and in particular glucotoxicity, increased expression of several mitochondrial solute carriers in human islets, such as the malate carrier DIC, the α-ketoglutarate-malate exchanger OGC, and the glutamate carrier GC1. Glucotoxicity also induced a general upregulation of the electron transport chain machinery, while palmitate largely counteracted this effect. Expression of different components of the TOM/TIM mitochondrial protein import system was increased by glucotoxicity, whereas glucolipotoxicity strongly upregulated its receptor subunit TOM70. Expression of the mitochondrial calcium uniporter MCU was essentially preserved by metabolic stresses. However, glucotoxicity altered expression of regulatory elements of calcium influx as well as the Na + /Ca 2+ exchanger NCLX, which mediates calcium efflux. Overall, the expression profile of mitochondrial carriers and associated genes was modified by the different metabolic stresses exhibiting nutrient-specific signatures.

Chronic exposure of pancreatic β-cells to elevated nutrient levels impairs their function and potentially induces apoptosis. Like in other cell types, AMPK is activated in β-cells under conditions of nutrient deprivation, while little is known on AMPK responses to metabolic stresses. Here, we first reviewed recent studies on the role of AMPK activation in β-cells. Then, we investigated the expression profile of AMPK pathways in β-cells following metabolic stresses. INS-1E β-cells and human islets were exposed for 3 days to glucose (5.5-25 mM), palmitate or oleate (0.4 mM), and fructose (5.5 mM). Following these treatments, we analyzed transcript levels of INS-1E β-cells by qRT-PCR and of human islets by RNA-Seq; with a special focus on AMPK-associated genes, such as the AMPK catalytic subunits α1 ( Prkaa1 ) and α2 ( Prkaa2 ). AMPKα and pAMPKα were also evaluated at the protein level by immunoblotting. Chronic exposure to the different metabolic stresses, known to alter glucose-stimulated insulin secretion, did not change AMPK expression, either in insulinoma cells or in human islets. Expression profile of the six AMPK subunits was marginally modified by the different diabetogenic conditions. However, the expression of some upstream kinases and downstream AMPK targets, including K-ATP channel subunits, exhibited stress-specific signatures. Interestingly, at the protein level, chronic fructose treatment favored fasting-like phenotype in human islets, as witnessed by AMPK activation. Collectively, previously published and present data indicate that, in the β-cell, AMPK activation might be implicated in the pre-diabetic state, potentially as a protective mechanism.