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Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

We demonstrate the capabilities of a novel frequency-domain terahertz spectrometer based on a comb-locked frequency synthesizer, which provides absolute frequency calibration. The inherent stability and repeatability of the scans allow for the combination of fast data acquisition with an average time-limited signal-to-noise ratio. We demonstrate kilohertz level frequency resolution in terahertz precision spectroscopy of ultra-high quality whispering-gallery-mode resonators. Spectra covering multiple free spectral ranges (>36 GHz) with sub-20 kHz resolution are acquired in 5 s. We analyze the coupling behavior and temperature tuning of single resonances and, for the first time, observe minute red and blue shifts of different mode families. The experimental results are supported with finite element simulations.

Background: Collaborative comparisons and combinations of epidemic models are used as policy-relevant evidence during epidemic outbreaks. In the process of collecting multiple model projections, such collaborations may gain or lose relevant information. Typically, modellers contribute a probabilistic summary at each time-step. We compared this to directly collecting simulated trajectories. We aimed to explore information on key epidemic quantities; ensemble uncertainty; and performance against data, investigating potential to continuously gain information from a single cross-sectional collection of model results. Methods: We compared projections from the European COVID-19 Scenario Modelling Hub. Five teams modelled incidence in Belgium, the Netherlands, and Spain. We compared July 2022 projections by incidence, peaks, and cumulative totals. We created a probabilistic ensemble drawn from all trajectories, and compared to ensembles from a median across each model’s quantiles, or a linear opinion pool. We measured the predictive accuracy of individual trajectories against observations, using this in a weighted ensemble. We repeated this sequentially against increasing weeks of observed data. We evaluated these ensembles to reflect performance with varying observed data. Results: By collecting modelled trajectories, we showed policy-relevant epidemic characteristics. Trajectories contained a right-skewed distribution well represented by an ensemble of trajectories or a linear opinion pool, but not models’ quantile intervals. Ensembles weighted by performance typically retained the range of plausible incidence over time, and in some cases narrowed this by excluding some epidemic shapes. Conclusions: We observed several information gains from collecting modelled trajectories rather than quantile distributions, including potential for continuously updated information from a single model collection. The value of information gains and losses may vary with each collaborative effort’s aims, depending on the needs of projection users. Understanding the differing information potential of methods to collect model projections can support the accuracy, sustainability, and communication of collaborative infectious disease modelling efforts.

Abstract Addressing recent calls by European regulatory and supervisory authorities, we develop a new bottom-up climate risk assessment method to examine the resilience of the European banking industry regarding transitory climate risks. We illustrate our approach by estimating the impact of a 50–100 EUR carbon tax per $$\textit{tCO}_{2}$$ tCO 2 equivalent on the valuation and default risk of STOXX Europe 600 firms. For about 5% of the sample firms, we find asset devaluation shocks larger than 30% and for about 16% of the firms probabilities of default (PDs) dropping below investment-grade level of 3%. At the sector level, our results yield asset devaluations shocks of 15–36% and new PDs of 5–34% for the six most affected sectors. Running a stress test on credit risk based on these results, we find a decrease in capital ratios between $$-1.2$$ - 1.2 and $$-1.6$$ - 1.6 percentage points for key regulatory capital ratios in the most adverse scenario while only addressing 36% of the bank’s total risk-weighted assets. Our analysis sheds light on the substantial transitory climate risk for asset portfolios of banks and contributes to the pressing question how to integrate climate risk into risk management and regulation of financial institutions.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Abstract Background Little is known about knee mechanics and muscle control after augmented ACL repair. Our aim was to compare knee biomechanics and leg muscle activity during walking between the legs of patients 2 years after InternalBraceTM-augmented anterior cruciate ligament repair (ACL-IB) and between patients after ACL-IB and ACL reconstruction (ACL-R), and controls. Methods Twenty-nine ACL-IB, 27 sex- and age-matched ACL-R (hamstring tendon autograft) and 29 matched controls completed an instrumented gait analysis. Knee joint angles, moments, power, and leg muscle activity were compared between the involved and uninvolved leg in ACL-IB (paired t-tests), and between the involved legs in ACL patients and the non-dominant leg in controls (analysis of variance and posthoc Bonferroni tests) using statistical parametric mapping (SPM, P uninvolved) and maximum knee flexion moment during stance (-0.07Nm/kg, CI [-0.13;-0.00]; involved ACL-R). Compared to controls, ACL-IB (SPM: 0–3%GC, P = 0.015; 98–100%, P = 0.016; DP: -6.3 mm, CI [-11.7;-0.8]) and ACL-R (DP: -6.0 mm, CI [-11.4;-0.2]) had lower (maximum) anterior tibia position around heel strike. ACL-R also had lower maximum knee extension moment (DP: -0.13Nm/kg, CI [-0.23;-0.02]) and internal knee rotation moment (SPM: 34–41%GC, P

Abstract Background While clinical and patient-reported outcomes have been investigated in patients after InternalBrace™-augmented anterior cruciate ligament repair (ACL-IB), less is known regarding restoration of functional performance. We aimed to determine differences in functional performance within and between patients 2 years after ACL-IB, patients 2 years after ACL reconstruction (ACL-R), and healthy controls. Materials and Methods A total of 29 ACL-IB, 27 ACL-R (hamstring autograft), and 29 controls performed single-leg hop (maximum forward distance hop, SLH; side hop > 40 cm in 30 s, SH), proprioception (knee joint position sense at 30° and 60° flexion), and dynamic postural balance (Y Balance) tests. Differences were calculated within groups (side-to-side difference) and between the involved leg of patients and the non-dominant leg of controls, and were evaluated to predefined statistical (P

Abstract Medical artificial intelligence (AI) is considered to be one of the most important assets for the future of innovative individual and public health care. To develop innovative medical AI, it is necessary to repurpose data that are primarily generated in and for the health care context. Usually, health data can only be put to a secondary use if data subjects provide their informed consent (IC). This regulation, however, is believed to slow down or even prevent vital medical research, including AI development. For this reason, a number of scholars advocate a moral civic duty to share electronic health records (EHRs) that overrides IC requirements in certain contexts. In the medical AI context, the common arguments for such a duty have not been subjected to a comprehensive challenge. This article sheds light on the correlation between two normative discourses concerning informed consent for secondary health record use and the development and use of medical AI. There are three main arguments in favour of a civic duty to support certain developments in medical AI by sharing EHRs: the ‘rule to rescue argument’, the ‘low risks, high benefits argument’, and the ‘property rights argument’. This article critiques all three arguments because they either derive a civic duty from premises that do not apply to the medical AI context, or they rely on inappropriate analogies, or they ignore significant risks entailed by the EHR sharing process and the use of medical AI. Given this result, the article proposes an alternative civic responsibility approach that can attribute different responsibilities to different social groups and individuals and that can contextualise those responsibilities for the purpose of medical AI development.

Since the 19th century, the interest of scholars and lovers of antiquity has been focused on the prehistoric hillfort settlements, also known as gradine, castellieri or kastelliere, on the Istrian peninsula. Several hundred of these fortified settlements, located on the tops of the countless hills of the Karst, are registered today. However, only a few of them have been explored through systematic archaeological research. The site that is currently best investigated and excavated with modern methods is the Gradina of Monkodonja near the small port town of Rovinj on the west coast of Istria, which is dated to the developed Early and to the beginning of the Middle Bronze Age. The research has led to numerous new findings, for example regarding chronology, settlement organisation and long-distance contacts. But they have also raised new questions. Given the size of Gradina Monkodonja, with an outer fortification wall almost 1 km long, and its prominent location, it was considered by the excavators to be the centre within a settlement system consisting of a large central settlement and various smaller satellite settlements. However, not much is known about these smaller, presumed satellite settlements to date - especially with regard to their chronology. Therefore, it is especially unclear whether they actually lived at the same time as the presumed central settlement of Monkodonja and whether a hierarchical system of hillforts existed in the Bronze Age. New research, funded by the National Research Foundation of Korea and supported by the Archaeological Museum of Istria in Pula and the Rovinj Heritage Museum, has been aiming to explore the system of hillforts around Rovinj since 2016. One step in the investigation is aimed at obtaining new data on the chronological classification of the smaller hillforts. Significant new results come from Gradina Monbrodo, which shed new light on the above-mentioned questions about the settlement system around Rovinj. With a view to the pottery spectrum of Monkodonja, we will discuss some previously unpublished ceramic finds in this paper.

Precise measurement of the surface energy of nanoscale metal thin films is crucial for the fabrication of reliable miniaturized electronic devices consisting of multi-stacked thin film strips. However, the conventional method utilizing sessile drops to measure the surface energy is not suitable for nanoscale samples owing to the much larger size of the liquid droplets than those of the samples being measured. Herein, nCA-AFM (nano contact angle-atomic force microscopy) based on PF-QNM (PeakForce quantitative nanomechanical mapping) imaging mode is explored as a novel tool to measure the surface energy of nanoscale Au strips. Au strips with thicknesses of 50 and 100 nm were patterned to have widths in a range from 200 to 500 nm. The surface energy of the nano-patterned Au strips measured with PF-QNM methods revealed that grain size is the most important factor determining the surface energy. The sample having different widths with the same grain size showed similar surface energy values, regardless of the sample dimensions. Our results highlight that grain size control is required to achieve the target surface energy of metal strips for applications in nanoscale electronic devices.

The authors show that the N-acetyltransferase PamZ acts as a self-resistance factor disabling the antibacterial paenilamicin that is produced by the honey bee larvae pathogen Paenibacillus larvae.

Abstract Background The workplace has been identified as a priority setting for health promotion. There are potential advantages of systematically integrating Occupational Health Management (OHM) and Corporate Social Responsibility (CSR). However, OHM and CSR are usually overseen by different management branches with different sets of values, and there is a lack of empirical research regarding interfaces between OHM and CSR. Germany offers a particularly useful setting due to legislation requiring health to be promoted in the workplace. This study aims to examine key stakeholders’ views and experiences regarding interfaces between OHM and CSR in German companies. Methods Individual semi-structured qualitative interviews were conducted with a sample of 77 German stakeholders from three different groups: experts in occupational health and corporate social responsibility from various companies (n = 35), business partners (n = 19), and various non-business partners (n = 23). Transcripts were analysed using qualitative content analysis. Results Participants identified several areas in which OHM and CSR are already interacting at strategic, structural and cultural levels, but also highlighted several barriers that undermine a more meaningful interaction. Participants reported difficulties in articulating the underlying ethical values relevant to both OHM and CSR at the strategic level. Several structural barriers were also highlighted, including a lack of resources (both financial and knowledge), and OHM and CSR departments not being fully developed or undertaken at entirely different operational levels. Finally, the missing practical implementation of corporate philosophy was identified as a critical cultural barrier to interfaces between OHM and CSR, with existing guidelines and companies’ philosophies that already connect OHM and CSR not being embraced by employees and managers. Conclusions There is already significant overlap in the focus of OHM and CSR, at the structural, strategic and cultural levels in many German companies. The potential is there, both in theory and practice, for the systematic combination of OHM and CSR. The insights from this study will be useful to ensure that closer integration between both management branches is set up in a socially sustainable and ethical manner.

The present article discusses the mounded tombs of the Maripkan peri-od (356-514) located in the city of Kyŏngju in the southeastern part of the Korean Peninsula regarding their impact on the collective memory of the early Silla polity. The theoretical framework for the following considera-tions draws from the seminal research of the cultural scientist Jan Ass-mann, who distinguishes between a communicative and cultural memory. It is being argued that one of the motivations for constructing the monu-mental and lavishly equipped graves was the manipulation of communica-tive memory by creating memorable events in the course of the funerary process. The construction of the graves as mounds created spatial refer-ence points in the landscape which affected subsequently the collective long-term or cultural memory. Consequently, it is assumed that the mounds became mnemonic devices for cultural memory and, therefore, crucial factors for the formation and stabilization of the kingdom.

Crown ethers are common building blocks in supramolecular chemistry and are frequently applied as cation sensors or as subunits in synthetic molecular machines. Developing switchable and specifically designed crown ethers enables the implementation of function into molecular assemblies. Seven tailor-made redox-active crown ethers incorporating tetrathiafulvalene (TTF) or naphthalene diimide (NDI) as redox-switchable building blocks are described with regard to their potential to form redox-switchable rotaxanes. A combination of isothermal titration calorimetry and voltammetric techniques reveals correlations between the binding energies and redox-switching properties of the corresponding pseudorotaxanes with secondary ammonium ions. For two different weakly coordinating anions, a surprising relation between the enthalpic and entropic binding contributions of the pseudorotaxanes was discovered. These findings were applied to the synthesis of an NDI-[2]rotaxane, which retains similar spectroelectrochemical properties compared to the corresponding free macrocycle. The detailed understanding of the thermodynamic and electrochemical properties of the tailor-made crown ethers lays the foundation for the construction of new types of molecular redox switches with emergent properties.

Abstract Background Balanced Steady State Free Precession (b-SSFP) sequences and the newly developed Fast-Spin-Echo (FSE)-sequences enable an optimized visualization of neurovascular compression (NVC) in patients with trigeminal neuralgia (TN). Arterial conflicts are mostly associated with a favorable outcome of microvascular decompression (MVD) compared to venous conflicts. An additional Time-of-Flight (TOF) angiography provides the differentiation between offending arteries and veins and a precise counselling of the patient concerning postoperative pain relief. The goal of this study was to analyze the reliability and impact of the combination of highly-resoluted MRI techniques on the correct prediction of the vessel type and the estimation of postoperative outcome of microvascular decompression (MVD). Methods In total, 48 patients (m/f: 32/16) underwent MVD for TN. All the preoperative imaging data (T2: b-SFFP and FSE, MRA: TOF) were compared to the intraoperative microsurgical findings during MVD. b-SFFP was available in 14 patients, FSE in 34 patients and an additional TOF sequence was available in 38 patients (9 times in combination with b-SSFP, 29 times in combination with FSE). The patients were categorized into four subgroups: 1) NVC negative, 2) venous NVC, 3) arterial NVC, 4) combined arterial and venous NVC. The preoperative MRI findings were compared to the intraoperative morphological findings. Postoperative pain relief was quantified by the Barrow Neurological Institute pain score. Results Twenty-five purely arterial NVC, 9 purely venous NVC and 5 combined arterial and venous NVC were detected by MRI. In 9 cases NVC was absent on MRI. Overall, the MRI findings correctly predicted the intraoperative findings in 91.7% of the 48 patients. The percentage of correct prediction increased from 80 to 94.7%, when TOF angiography was adjoined. Conclusion The visualization of the trigeminal nerve using sequences such as b-SSFP or FSE in combination with TOF angiography enables an optimized delineation of arterial and venous neurovascular conflicts and may allow a more reliable differentiation between veins and arteries, resulting in superior prediction of postoperative pain relief compared to T2 imaging data alone.

Abstract Background Ankle fractures are common fractures in trauma surgery. Several studies have compared gait patterns between affected patients and control groups. However, no one used the Heidelberg Foot Measurement Method in combination with statistical parametric mapping of the entire gait cycle in this patient cohort. We sought to identify possible mobility deficits in the tibio‐talar joint and medial arch in patients after ankle fractures as a sign of stiffness and pain that could result in a pathological gait pattern. We focused on the tibio‐talar flexion as it is the main movement in the tibio‐talar joint. Moreover, we examined the healing progress over time. Methods Fourteen patients with isolated ankle fractures were included prospectively. A gait analysis using the Heidelberg Foot Measurement Method was performed 9 and 26 weeks after surgery to analyse the tibio‐talar dorsal flexion, the foot tibia dorsal flexion, the subtalar inversion and the medial arch as well as the cadence, the walking speed and the ground reaction force. The American Orthopedic Foot & Ankle Society ankle hindfoot score was used to obtain clinical data. Results were compared to those from 20 healthy participants. Furthermore, correlations between the American Orthopedic Foot & Ankle Society hindfoot score and the results of the gait analysis were evaluated. Results Statistical parametric mapping showed significant differences for the Foot Tibia Dorsal Flexion for patients after 9 weeks (53–75%: p = 0.001) and patients after 26 weeks (58–70%: p = 0.011) compared to healthy participants, respectively. Furthermore, significant differences regarding the tibio‐talar dorsal flexion for patients 9 weeks after surgery (15–40%: p

Background: Patella instability with recurrent dislocations is a result of various pathologies, for example, patella alta, trochlea dysplasia or medial patellofemoral ligament (MPFL) rupture. The recurrent dislocation rate of conservatively treated chronic patellar instability is high; therefore, it is recommended to manage it surgically. This video presents a new operative approach to stabilize the patella in a dynamic MPFL reconstruction, which addresses the most common complications occurring in static reconstructions: malpositioning and overtensioning the graft. Indications: Surgical indications for the new dynamic procedure mirror the indications for static MPFL reconstruction. This is MPFL insufficiency (patella instability in the first 30° of knee flexion), which is most frequently seen in recurrent lateral patella dislocations. Moreover in very rare cases of first patella dislocation with a patellar instability severity score equal or higher than 4. Technique Description: The dynamic MPFL reconstruction consists of 3 steps: First, detaching and mobilizing the gracilis muscle at its anatomical insertion. Second, redirecting the freed gracilis muscle to its new patellar insertion. Third, reinserting the gracilis muscle at the patella. Results: The dynamic MPFL reconstruction has the advantage of lesser risk of overtensioning and malpositioning the graft. The insertion point of the MPFL surrogate is easier to locate, and the patella is dynamically stabilized through reflectory gracilis muscle contraction. Compared with the static reconstruction, only one instead of 3 holes have to be drilled and only 1 interference screw has to be placed, thus shortening the surgery time. From a theoretical biomechanical perspective, the dynamic tensioning is superior to the static procedure. The few accomplished studies published so far by Becher et al and Ostermeier et al show good or better functional results (Kujala, Lysholm, Tegner scores) with the dynamic MPFL reconstruction, yet higher evidence studies need to be performed. Conclusion: Dynamic MPFL reconstruction appears to be a simpler and more effective surgical technique for MPFL reconstruction. Because of its novelty, high evidence studies assessing long-term therapeutical outcomes are still lacking and need to be conducted in order to compare it conclusively with the static procedure.

The recognition of the importance of HCHO in methanol to olefins (MTO) makes it imperative to quantify its concentration in the reaction and distribution over the catalyst bed. Here the authors quantify the concentration level of HCHO and its distribution along the catalyst bed in MTO, and explores its role in methanol conversion.

This paper investigates several voting consensus protocols with low computational complexity in noisy Byzantine infrastructures. Using computer simulations, we show that explicit randomization of the consensus protocol can significantly increase the robustness towards faulty and malicious nodes. We identify the optimal amount of randomness for various Byzantine attack strategies on different kinds of network topologies.

When exposed to cold temperatures, mice increase their thermogenic capacity by an expansion of brown adipose tissue mass and the formation of brite/beige adipocytes in white adipose tissue depots. However, the process of the transcriptional changes underlying the conversion of a phenotypic white to brite/beige adipocytes is only poorly understood. By analyzing transcriptome profiles of inguinal adipocytes during cold exposure and in mouse models with a different propensity to form brite/beige adipocytes, we identified ESRRG and PERM1 as modulators of this process. The production of heat by mitochondrial uncoupled respiration is a key feature of brite/beige compared to white adipocytes and we show here that both candidates are involved in PGC1α transcriptional network to positively regulate mitochondrial capacity. Moreover, we show that an increased expression of ESRRG or PERM1 supports the formation of brown or brite/beige adipocytes in vitro and in vivo. These results reveal that ESRRG and PERM1 are early induced in and important regulators of brite/beige adipocyte formation.

Increasing the service life of die casting dies is an important goal of the foundry industry. Approaches are either material- or process-related. Despite new material concepts, hot work steels such as H11 are still predominantly used in the uncoated condition for die casting dies. In order to withstand the stresses that occur, this steel is used exclusively in the quenched and tempered condition. Required properties such as high high-temperature strength and high hardness combined with high toughness are, in principle, contradictory and can only be adjusted consistently over the entire die by furnace-based heat treatment. However, the results of various investigations have shown that improvements in the thermal shock resistance and wear resistance of hot work tool steels can be achieved by thermally influencing the microstructure near the surface. Based on these studies and related findings, an approach to surface heat treatment using the electron beam was developed. Due to the particle character of the radiation and the associated possibility of high-frequency beam deflection, the electron beam offers significantly greater flexibility in energy input into the workpiece surface compared with lasers or induction. The overall technological concept envisages replacing furnace-based heat treatment in the production of casting dies by localized and demand-oriented boundary layer heat treatment with the electron beam. The experiments include, on the one hand, the experimental determination of a suitable temperature–time interval with a focus on short-term austenitization. On the other hand, a simulation-based approach of boundary layer heat treatment with validation of a suitable heat source is investigated. Regarding short-term austenitization, the corresponding temperature and time range could be narrowed down more precisely. Some of these parameter combinations seem to be very suitable for practical use. The test specimens show a hard surface layer with a depth of at least up to 6 mm and a very tough buffer layer. Numerical simulation is used to estimate the resulting metallurgical microstructure and the achievable hardness as a function of the temperature–time interval. In addition, the results provided show the possibility of determining and optimizing the material properties by means of a simulation-based approach within the framework of a purely digital process planning and subsequently transferring them into a process planning. In the technical implementation, a temperature control was first established by means of a two-color pyrometer. In the further course of research, the pyrometer will be supplemented by an internally installed infrared camera, which will allow the reproducible setting of specified temperature profiles even for complex, large-area contours in the future.

Objective: Adipose tissue shows a high degree of plasticity, and adipocyte hyperplasia is an important mechanism for adipose tissue expansion. Different adipose depots respond differently to an increased demand for lipid storage. Orchestrating cellular expansion in vivo requires extracellular matrix (ECM) remodeling and a high degree of interaction between cells and ECM. Methods: We studied decellularized primary adipose stromal cell derived ECM of different adipose depots and reseeded them with primary adipose precursors. We tested ECM effect on adipocyte differentiation and analyzed ECM composition using proteomic and immunohistochemical approaches to identify factors in the ECM influencing adipogenesis. Results: We show that the ECM of an adipose depot is the major determinant for the differentiation capacity of primary preadipocytes. Visceral adipose tissue stromal cells differentiate less than subcutaneous cells, which, in turn, are less adipogenic than BAT-derived cells. This effect is based on the ECM composition of the respective depot and not dependent on the precursor origin. Addition of vitamin C pronounces the pro-adipogenic effects of the ECM, indicating the importance of collagenous ECM in mediating the effect. Using a proteomic global and a targeted downstream analysis, we identify Flotillin 2 as a protein enriched in pro-adipogenic ECM, which is involved in orchestrating ECM to preadipocyte signaling. Conclusions: We show that adipose tissue SVF secretes collagenous ECM, which directly modulates terminal differentiation of adipocyte precursors in a depot specific manner. These data demonstrate the importance of the tissue microenvironment in preadipocyte differentiation. Keywords: Adipocyte precursors, Extracellular matrix, Collagen, Stem cell niche, Flotillin 2

Sediments record variations of the Earth’s magnetic field via the alignment of magnetic grains during and after deposition, yet the role of post-depositional processes remains unclear. Here, the authors present experiments showing how microbially-induced bioturbation controls the alignment process.

In the case of casting processes with permanent molds, there is still a relatively pronounced lack of knowledge regarding the locally prevailing heat transfer between casts and mold. This in turn results in an insufficient knowledge of the microstructure and the associated material properties in the areas of the casting component close to the surface. Therefore, this work deals with the design and evaluation of a test tool with an integrated sensor system for temperature measurements, which was applied to obtain a time-dependent heat transfer coefficient (HTC) during casting solidification. For this purpose, the setup, design and computational approach are described first. Special attention is paid to the qualification of the multi-depth sensor and the calculation method. For the calculations, an inverse estimation method (nonlinear sequential function) was used to obtain the HTC profiles from the collected data. The developed sensor technology was used in a test mold to verify the usability of the sensor technology and the plausibility of the obtained calculation results under real casting conditions and associated temperature loads. Both the experimental temperature profiles and the HTC profiles showed that, in the evaluated casting series, the peak values determined were close to each other and reached values between 6000 W/(m2·K) and 8000 W/(m2·K) during solidification.

Summary: Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans. : By combining mouse and human transcriptome data, Perdikari et al. identify a gene signature that can classify brown and white adipocytes. Using a machine-learning-based cell deconvolution approach, they develop an algorithm proficient in calculating the brown adipocyte content in complex biopsies. This web tool allows in-depth characterization of adipose tissue samples. Keywords: pure adipocyte populations, gene signature, deconvolution, BAT content

The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than metformin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunction and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting.

[This corrects the article DOI: 10.1371/journal.pone.0206764.].

Objective: Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. Methods: We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. Results: Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted. Conclusions: Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans.

Although our understanding of centromere maintenance, marked by the histone H3 variant CenH3CENP-A in most eukaryotes, has progressed, the mechanism underlying the de novo formation of centromeres remains unclear. We used a synthetic system to dissect how CenH3CENP-A contributes to the accumulation of CENP-C and CENP-T, two key components that are necessary for the formation of functional kinetochores. We find that de novo CENP-T accumulation depends on CENP-C and that recruitment of these factors requires two domains in CenH3CENP-A: the HJURP-binding region (CATD) and the CENP-C-binding region (CAC). Notably, HJURP interacts directly with CENP-C and is critical for de novo accumulation of CENP-C at synthetic centromeres. On the basis of our findings, we propose that HJURP serves a dual chaperone function in coordinating CenH3CENP-A and CENP-C recruitment.

Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3CENP-A deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3CENP-A at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3CENP-A deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3CENP-A loading.

While the Internet increasingly permeates everyday life of individuals around the world, it becomes crucial to prevent unauthorized collection and abuse of personalized information. Internet anonymization software such as Tor is an important instrument to protect online privacy. However, due to the performance overhead caused by Tor, many Internet users refrain from using it. This causes a negative impact on the overall privacy provided by Tor, since it depends on the size of the user community and availability of shared resources. Detailed measurements about the performance of Tor are crucial for solving this issue. This paper presents comparative experiments on Tor latency and throughput for surfing to 500 popular websites from several locations around the world during the period of 28 days. Furthermore, we compare these measurements to critical latency thresholds gathered from web usability research, including our own user studies. Our results indicate that without massive future optimizations of Tor performance, it is unlikely that a larger part of Internet users would adopt it for everyday usage. This leads to fewer resources available to the Tor community than theoretically possible, and increases the exposure of privacy-concerned individuals. Furthermore, this could lead to an adoption barrier of similar privacy-enhancing technologies for a Future Internet.

Abstract Background Charcot‐Marie‐Tooth disease (CMT), one of the most common hereditary neurologic disorders, often results in debilitating cavovarus foot deformities. The deformities are still not fully understood, and the treatment recommendations are consequently heterogeneous, often including calf muscle or Achilles tendon lengthening. Methods We examined 40 patients (80 feet) with CMT and bilateral cavovarus deformities (19 men and 21 women, mean age 33.6 ± 14.6 years) and the feet of a healthy control population of 13 individuals (7 men and 6 women, mean age 43.9 ± 10.8 years). In all cases 3D instrumented gait analysis results with both conventional Plug‐in‐Gait analysis and the Heidelberg Foot Measurement Method (HFMM) were used to determine the sagittal plane kinematics, dorsi‐plantar flexion (DPF), tibio‐talar dorsiflexion (TTDF), and medial arch angle (MAA), and the results of patients and the control group were compared using the 2 methods. Decreased and increased dorsiflexion using TTDF was defined as 1 standard deviation below or above the mean of the control. Comparisons were done using descriptive statistics, the Pearson correlation coefficient and ANOVA. Results The TTDF was found to be decreased in 18 of the 80 feet examined (22.5 %), normal in 31 feet (38.75 %), and increased in 31 feet (38.75 %). The Pearson coefficient showed a positive correlation with R = 0.765, p

Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed.

The Gram-positive bacterium Paenibacillus larvae is the etiological agent of American Foulbrood. This bacterial infection of honey bee brood is a notifiable epizootic posing a serious threat to global honey bee health because not only individual larvae but also entire colonies succumb to the disease. In the recent past considerable progress has been made in elucidating molecular aspects of host pathogen interactions during pathogenesis of P. larvae infections. Especially the sequencing and annotation of the complete genome of P. larvae was a major step forward and revealed the existence of several giant gene clusters coding for non-ribosomal peptide synthetases which might act as putative virulence factors. We here present the detailed analysis of one of these clusters which we demonstrated to be responsible for the biosynthesis of bacillibactin, a P. larvae siderophore. We first established culture conditions allowing the growth of P. larvae under iron-limited conditions and triggering siderophore production by P. larvae. Using a gene disruption strategy we linked siderophore production to the expression of an uninterrupted bacillibactin gene cluster. In silico analysis predicted the structure of a trimeric trithreonyl lactone (DHB-Gly-Thr)3 similar to the structure of bacillibactin produced by several Bacillus species. Mass spectrometric analysis unambiguously confirmed that the siderophore produced by P. larvae is identical to bacillibactin. Exposure bioassays demonstrated that P. larvae bacillibactin is not required for full virulence of P. larvae in laboratory exposure bioassays. This observation is consistent with results obtained for bacillibactin in other pathogenic bacteria.

We study initial cuts of models of weak two-sorted Bounded Arithmetics with respect to the strength of their theories and show that these theories are stronger than the original one. More explicitly we will see that polylogarithmic cuts of models of $\mathbf{V}^0$ are models of $\mathbf{VNC}^1$ by formalizing a proof of Nepomnjascij's Theorem in such cuts. This is a strengthening of a result by Paris and Wilkie. We can then exploit our result in Proof Complexity to observe that Frege proof systems can be sub exponentially simulated by bounded depth Frege proof systems. This result has recently been obtained by Filmus, Pitassi and Santhanam in a direct proof. As an interesting observation we also obtain an average case separation of Resolution from AC0-Frege by applying a recent result with Tzameret.

We derive a trace formula that expresses the level density of chaotic many-body systems as a smooth term plus a sum over contributions associated to solutions of the nonlinear Schrödinger (or Gross–Pitaevski) equation. Our formula applies to bosonic systems with discretised positions, such as the Bose–Hubbard model, in the semiclassical limit as well as in the limit where the number of particles is taken to infinity. We use the trace formula to investigate the spectral statistics of these systems, by studying interference between solutions of the nonlinear Schrödinger equation. We show that in the limits taken the statistics of fully chaotic many-particle systems becomes universal and agrees with predictions from the Wigner–Dyson ensembles of random matrix theory. The conditions for Wigner–Dyson statistics involve a gap in the spectrum of the Frobenius–Perron operator, leaving the possibility of different statistics for systems with weaker chaotic properties.