Search

Abstract Although primarily studied in relation to photorespiration, serine metabolism in chloroplasts may play a key role in plant CO2 fertilization responses by linking CO2 assimilation with growth. Here, we show that the phosphorylated serine pathway is part of a ‘photosynthetic C1 pathway’ and demonstrate its high activity in foliage of a C3 tree where it rapidly integrates photosynthesis and C1 metabolism contributing to new biomass via methyl transfer reactions, imparting a large natural 13C-depleted signature. Using 13CO2-labelling, we show that leaf serine, the S-methyl group of leaf methionine, pectin methyl esters, and the associated methanol released during cell wall expansion during growth, are directly produced from photosynthetically-linked C1 metabolism, within minutes of light exposure. We speculate that the photosynthetic C1 pathway is highly conserved across the photosynthetic tree of life, is responsible for synthesis of the greenhouse gas methane, and may have evolved with oxygenic photosynthesis by providing a mechanism of directly linking carbon and ammonia assimilation with growth. Although the rise in atmospheric CO2 inhibits major metabolic pathways like photorespiration, our results suggest that the photosynthetic C1 pathway may accelerate and represents a missing link between enhanced photosynthesis and plant growth rates during CO2 fertilization under a changing climate.

The past decade has seen a global transformation in how we communicate and connect with one another, making it easier to network and collaborate with colleagues worldwide. The COVID-19 pandemic led to a rapid and unplanned shift toward virtual platforms, resulting in several accessibility challenges that have excluded many people during virtual events. Virtual and hybrid conferences have the potential to present opportunities and collaborations to groups previously excluded from purely in-person conference formats. This can only be achieved through thoughtful and careful planning with inclusion and accessibility in mind, learning lessons from previous events' successes and failures. Without effective planning, virtual and hybrid events will replicate many biases and exclusions inherent to in-person events. This article provides guidance on best practices for making online/virtual and hybrid events more accessible based on the combined experiences of diverse groups and individuals who have planned and run such events. Our suggestions focus on the accessibility considerations of three event planning stages: (1) pre-event planning, (2) on the day/during the event, and (3) after the event. Ensuring accessibility and inclusivity in designing and running virtual events can help everyone engage more meaningfully, resulting in more impactful discussions that will more fully include contributions from the many groups with limited access to in-person events. However, while this article is intended to act as a starting place for inclusion and accessibility in online and hybrid event planning, it is not a fully comprehensive guide. As more events are run, it is expected that new insights and experiences will be gained, helping to continually update standards.

Abstract Introduction Arthrodesis of a (diseased) ankle joint is usually performed to achieve pain relief and stability. One basic principle of arthrodesis techniques includes rigid fixation of the surfaces until union. It seems plausible that stable anchoring and homogeneous pressure distribution should be advantageous, however, it has not been investigated yet. The aim is to achieve uniform compression, as this is expected to produce favorable results for the bony fusion of the intended arthrodesis. Numerous implants with different biomechanical concepts can be used for ankle fusion. In this study, headless compression screws (HCS, DePuy Synthes, Zuchwil, Switzerland) were compared biomechanically to an alternative fixation System, the IOFix device (Extremity Medical, Parsippany, NJ, USA) in regard to the distribution of the compression force (area of contact) and peak compression in a sawbone arthrodesis-model (Sawbones® Pacific Research Laboratories, Vashon, WA, USA). This study aims to quantify the area of contact between the bone interface that can be obtained using headless compression screws compared to the IOFix. In current literature, it is assumed, that a large contact surface with sufficient pressure between the bones brings good clinical results. However, there are no clinical or biomechanical studies, that describe the optimal compression pressure for an arthrodesis. Material and methods Two standardized sawbone blocks were placed above each other in a custom-made jig. IOFix and headless compression screws were inserted pairwise parallel to each other using a template for a uniform drilling pattern. All screws were inserted with a predefined torque of 0.5 Nm. Pressure transducers positioned between the two sawbone blocks were compressed for the measurement of peak compression force, compression distribution, and area of contact. Results With the IOFix, the compression force was distributed over significantly larger areas compared to the contact area of the HCS screws, resulting in a more homogenous contact area over the entire arthrodesis surface. Maximum compression force showed no significant difference. Conclusion The IOFix system distributes the compression pressure over a much larger area, resulting in more evenly spread compression at the surface. Clinical studies must show whether this leads to a lower pseudarthrosis rate.

Background: Amyloid beta (Aβ) accumulation in the brain is one of the earliest findings in Alzheimer's disease (AD). The dog is a natural animal model for amyloid processing and early brain amyloid pathology. The goal of this study is to examine which differences in metabolomic profiles in cerebrospinal fluid (CSF) could be detected in dogs with a difference in CSF Aβ concentrations before amyloid accumulation occurs. Method: Metabolic profiling was performed on CSF from 4 to 8 year old dogs with different CSF Aβ concentrations. Results: Metabolomic profiling of CSF showed differences in brain energy metabolism. More specifically, increases in N-acetylation of amino acids and amino sugars, creatine and pentose metabolism, and a decrease in tricarboxylic acid (TCA) cycle were seen in dogs with a high CSF Aβ concentration. In addition, signs of elevated oxidative stress, higher methionine, lipid and nucleotide metabolism and increased levels of cysteine, myo-inositol and trimethylamine N-oxide were noted in these animals. Conclusions: Differences in energy metabolism and stress mediated metabolic changes are seen in the brain of dogs with different CSF Aβ concentrations, before any amyloid deposition occurs. Similar metabolic changes, as in the high Aβ dogs, have been described in AD in humans and/or transgenic AD mice, some of them in very early phases. General significance: The differences observed in metabolomic profiles could help in identifying potential biomarkers for an increased risk of developing amyloid pathology in the brain and open the door to the evaluation of preventive treatments for amyloid pathology in humans.

Abstract Understanding the solid target dynamics resulting from the interaction with an ultrashort laser pulse is a challenging fundamental multi-physics problem involving atomic and solid-state physics, plasma physics, and laser physics. Knowledge of the initial interplay of the underlying processes is essential to many applications ranging from low-power laser regimes like laser-induced ablation to high-power laser regimes like laser-driven ion acceleration. Accessing the properties of the so-called pre-plasma formed as the laser pulse’s rising edge ionizes the target is complicated from the theoretical and experimental point of view, and many aspects of this laser-induced transition from solid to overdense plasma over picosecond timescales are still open questions. On the one hand, laser-driven ion acceleration requires precise control of the pre-plasma because the efficiency of the acceleration process crucially depends on the target properties at the arrival of the relativistic intensity peak of the pulse. On the other hand, efficient laser ablation requires, for example, preventing the so-called “plasma shielding”. By capturing the dynamics of the initial stage of the interaction, we report on a detailed visualization of the pre-plasma formation and evolution. Nanometer-thin diamond-like carbon foils are shown to transition from solid to plasma during the laser rising edge with intensities < 1016 W/cm². Single-shot near-infrared probe transmission measurements evidence sub-picosecond dynamics of an expanding plasma with densities above 1023 cm−3 (about 100 times the critical plasma density). The complementarity of a solid-state interaction model and kinetic plasma description provides deep insight into the interplay of initial ionization, collisions, and expansion.

Saprotrophic fungi, key players in global carbon cycling, have been identified as methane (CH4) sources not yet accounted for in the global CH4 budget. This study, for the first time, explores the influence of oxygen (O2) and temperature on CH4 production by two fungi, Laetiporus sulphureus and Pleurotus sapidus. To explore the relationship between these parameters and fungal CH4 formation, we examined CH4 formation under varying O2 levels (0 to 98%) and temperatures (17, 27, and 40 °C) during fungal growth on pine wood, beech wood, and grass under sterile conditions. Our findings show that fungal CH4 formation strongly depends on O2 levels. Methane formation was highest when O2 levels exceeded 5%, whilst no CH4 formation was observed after complete O2 consumption. Reintroducing O2 immediately resumed fungal CH4 production. Methane formation normalized to O2 consumption (CH4_norm) showed a different pattern. L. sulphureus showed higher CH4_norm rates with higher O2 levels, whereas P. sapidus showed elevated rates between 0 and 5%. Temperature also significantly influenced CH4 and CH4_norm rates, with the highest production at 27 °C, and comparatively lower rates at 17 and 40 °C. These findings demonstrate the importance of O2 levels and temperature in fungal CH4 emissions, which are essential for refining CH4 source predictions.

Abstract The SARS-CoV-2 pandemic has highlighted the need to better define in-hospital transmissions, a need that extends to all other common infectious diseases encountered in clinical settings. To evaluate how whole viral genome sequencing can contribute to deciphering nosocomial SARS-CoV-2 transmission 926 SARS-CoV-2 viral genomes from 622 staff members and patients were collected between February 2020 and January 2021 at a university hospital in Munich, Germany, and analysed along with the place of work, duration of hospital stay, and ward transfers. Bioinformatically defined transmission clusters inferred from viral genome sequencing were compared to those inferred from interview-based contact tracing. An additional dataset collected at the same time at another university hospital in the same city was used to account for multiple independent introductions. Clustering analysis of 619 viral genomes generated 19 clusters ranging from 3 to 31 individuals. Sequencing-based transmission clusters showed little overlap with those based on contact tracing data. The viral genomes were significantly more closely related to each other than comparable genomes collected simultaneously at other hospitals in the same city (n = 829), suggesting nosocomial transmission. Longitudinal sampling from individual patients suggested possible cross-infection events during the hospital stay in 19.2% of individuals (14 of 73 individuals). Clustering analysis of SARS-CoV-2 whole genome sequences can reveal cryptic transmission events missed by classical, interview-based contact tracing, helping to decipher in-hospital transmissions. These results, in line with other studies, advocate for viral genome sequencing as a pathogen transmission surveillance tool in hospitals.

A social memory pathway connecting the ventral hippocampus, the lateral septum and the ventral tegmental area helps to regulate how mice react to unknown individuals.

Abstract The pandemic caused by SARS-CoV-2 impacted health systems globally, creating increased workload and mental stress upon health care workers (HCW). During the first pandemic wave (March to May 2020) in southern Germany, we investigated the impact of stress and the resilience to stress in HCW by measuring changes in hair concentrations of endocannabinoids, endocannabinoid-like compounds and cortisone. HCW (n = 178) recruited from multiple occupation and worksites in the LMU-University-Hospital in Munich were interviewed at four interval visits to evaluate mental stress associated with the COVID-19 pandemic. A strand of hair of up to 6 cm in length was sampled once in May 2020, which enabled retrospective individual stress hormone quantifications during that aforementioned time period. Perceived anxiety and impact on mental health were demonstrated to be higher at the beginning of the COVID-19 pandemic and decreased significantly thereafter. Resilience was stable over time, but noted to be lower in women than in men. The concentrations of the endocannabinoid anandamide (AEA) and the structural congeners N-palmitoylethanolamide (PEA), N-oleoylethanolamide (OEA) and N-stearoylethanolamide (SEA) were noted to have decreased significantly over the course of the pandemic. In contrast, the endocannabinoid 2-arachidonoylglycerol (2-AG) levels increased significantly and were found to be higher in nurses, laboratory staff and hospital administration than in physicians. PEA was significantly higher in subjects with a higher resilience but lower in subjects with anxiety. SEA was also noted to be reduced in subjects with anxiety. Nurses had significantly higher cortisone levels than physicians, while female subjects had significant lower cortisone levels than males. Hair samples provided temporal and measurable objective psychophysiological-hormonal information. The hair endocannabinoids/endocannabinoid-like compounds and cortisone correlated to each other and to professions, age and sex quite differentially, relative to specific periods of the COVID-19 pandemic.

Empirical evidence indicates that conscious states, distinguished by the presence of phenomenal qualities, are closely linked to synchronized neural activity patterns whose dynamical characteristics can be attributed to self-organized criticality and phase transitions. These findings imply that insight into the mechanism by which the brain controls phase transitions will provide a deeper understanding of the fundamental mechanism by which the brain manages to transcend the threshold of consciousness. This article aims to show that the initiation of phase transitions and the formation of synchronized activity patterns is due to the coupling of the brain to the zero-point field (ZPF), which plays a central role in quantum electrodynamics (QED). The ZPF stands for the presence of ubiquitous vacuum fluctuations of the electromagnetic field, represented by a spectrum of normal modes. With reference to QED-based model calculations, the details of the coupling mechanism are revealed, suggesting that critical brain dynamics is governed by the resonant interaction of the ZPF with the most abundant neurotransmitter glutamate. The pyramidal neurons in the cortical microcolumns turn out to be ideally suited to control this interaction. A direct consequence of resonant glutamate-ZPF coupling is the amplification of specific ZPF modes, which leads us to conclude that the ZPF is the key to the understanding of consciousness and that the distinctive feature of neurophysiological processes associated with conscious experience consists in modulating the ZPF. Postulating that the ZPF is an inherently sentient field and assuming that the spectrum of phenomenal qualities is represented by the normal modes of the ZPF, the significance of resonant glutamate-ZPF interaction for the formation of conscious states becomes apparent in that the amplification of specific ZPF modes is inextricably linked with the excitation of specific phenomenal qualities. This theory of consciousness, according to which phenomenal states arise through resonant amplification of zero-point modes, is given the acronym TRAZE. An experimental setup is specified that can be used to test a corollary of the theory, namely, the prediction that normally occurring conscious perceptions are absent under experimental conditions in which resonant glutamate-ZPF coupling is disrupted.

Summary: Resting CD4 T cells resist productive HIV-1 infection. The HIV-2/simian immunodeficiency virus protein viral accessory protein X (Vpx) renders these cells permissive to infection, presumably by alleviating blocks at cytoplasmic reverse transcription and subsequent nuclear import of reverse-transcription/pre-integration complexes (RTC/PICs). Here, spatial analyses using quantitative virus imaging techniques reveal that HIV-1 capsids containing RTC/PICs are readily imported into the nucleus, recruit the host dependency factor CPSF6, and translocate to nuclear speckles in resting CD4 T cells. Reverse transcription, however, remains incomplete, impeding proviral integration and viral gene expression. Vpx or pharmacological inhibition of the deoxynucleotide triphosphohydrolase (dNTPase) activity of the restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) increases levels of nuclear reverse-transcribed cDNA and facilitates HIV-1 integration. Nuclear import and intranuclear transport of viral complexes therefore do not pose important blocks to HIV-1 in resting CD4 T cells, and the limitation to reverse transcription by SAMHD1’s dNTPase activity constitutes the main pre-integration block to infection.

Objectiveto analyze oncological, obstetrical, and surgical results of young early-stage cervical cancer patients who underwent radical trachelectomy (RT) surgery and wished to maintain their fertility.Methodologya retrospective cohort study was carried out concerning cases attended at the Brazilian National Cancer Institute Gynecology Oncology Service. Patients who underwent RT between January 2005 and January 2021 were included.ResultsA total of 32 patients with median age of 32 years old, 62.5% of whom were nulliparous, were assessed. Concerning cancer type, 65.6% squamous cell carcinoma (SCC) cases, 31.2% adenocarcinoma cases and 3.1% adenosquamous carcinoma cases were verified. Stage IA2 was evidenced in 12.5% of the patients and stage IB < 4 cm in 87.5%. Regarding surgical approaches, 68.25% of the patients underwent vaginal RT (VRT), 18.75%, abdominal RT (ART), 9.3%, the robotic radical trachelectomy (RORT) and 3.1%, video laparoscopy radical trachelectomy (VLRT). The median number of removed lymph nodes was 14, with only two detected as positive. Two cases of positive surgical margins were noted. A total of 3.1% intraoperative and 31.25% postoperative complications were observed, with cervical stenosis being the most common. The recurrence rate of the study was 3.1%, with a median follow-up time of 87 months, where 3.1% deaths occurred. The pregnancy rate of the study was 17.85% (5/28), with 54.5% evolving to live births and 45.5% evolving to abortion.ConclusionRadical trachelectomy is a feasible procedure presenting good oncological results and acceptable pregnancy rates.

In this study we demonstrated for the first time synthetic procedures for composites of salinomycin (SalH) and two-line ferrihydrite. The products were characterized by various methods such as elemental analysis, attenuated total reflectance–Fourier-transform spectroscopy (ATR-FTIR), electron paramagnetic resonance spectroscopy (EPR), powder X-ray diffraction analysis (XRD), electrospray-ionization mass spectrometry (ESI-MS), thermogravimetric analysis with differential thermal analysis (DTA) and mass spectrometry (TG-DTA/MS). The EPR spectra of the isolated compounds consisted of signals associated with both isolated Fe3+ ions and magnetically coupled Fe3+ ions. Powder XRD analyses of the isolated products showed two intense and broad peaks at 9° and 15° 2Θ, corresponding to salinomycinic acid. Broad peaks with very low intensity around 35°, assigned to two-line ferrihydrite, were also registered. Based on the experimental results, we concluded that salinomycin sodium reacted with Fe(III) chloride to form composites consisting of two-line ferrihydrite and salinomycinic acid. One of the composites exerted pronounced antitumor activity in the sub-micromolar concentration range against human cervical cancer (HeLa), non-small-cell lung cancer (A549), colon cancer (SW480), and ovarian teratocarcinoma (CH1/PA1) cells.

In Section 2 [...]

Abstract Methane is a potent greenhouse gas, which likely enabled the evolution of life by keeping the early Earth warm. Here, we demonstrate routes towards abiotic methane and ethane formation under early-earth conditions from methylated sulfur and nitrogen compounds with prebiotic origin. These compounds are demethylated in Fenton reactions governed by ferrous iron and reactive oxygen species (ROS) produced by light and heat in aqueous environments. After the emergence of life, this phenomenon would have greatly intensified in the anoxic Archean by providing methylated sulfur and nitrogen substrates. This ROS-driven Fenton chemistry can occur delocalized from serpentinization across Earth’s humid realm and thereby substantially differs from previously suggested methane formation routes that are spatially restricted. Here, we report that Fenton reactions driven by light and heat release methane and ethane and might have shaped the chemical evolution of the atmosphere prior to the origin of life and beyond.

Abstract Hells Bells are underwater secondary carbonates discovered in sinkholes (cenotes) southeast of Cancun on the north-eastern Yucatán peninsula, Mexico. These authigenic calcite precipitates, reaching a length of up to 4 m, most likely grow in the pelagic redoxcline. Here we report on detailed 230Th/U-dating and in-depth geochemical and stable isotope analyses of specimens from cenotes El Zapote, Maravilla and Tortugas. Hells Bells developed since at least ~ 8000 years ago, with active growth until present day. Initial (234U/238U) activity ratios (δ234U0) in Hells Bells calcite decreas from 55 to 15‰ as sea level converges toward its present state. The temporal evolution of the geochemistry and isotope composition of Hells Bells calcites thus appears to be closely linked to sea-level rise and reflects changing hydrological conditions (desalinization) of the aquifer. We suggest that decelerated leaching of excess 234U from the previously unsaturated bedrock traces Holocene relative sea-level rise. Considering this proxy, the resulting mean sea-level reconstruction contains half as much scatter, i.e. improves by a factor of two, when compared to previously published work for the period between 8 and 4 ky BP.

Abstract Isotopic and elemental signatures in arc magmas bear similarities to marine sediments from the forearc. Partial melts of subducted sediments were previously invoked as the predominant carrier of material between the slab and mantle wedge, whereas aqueous fluids were deemed too inefficient at mobilizing trace elements to account for arc magma compositions. However, trace element solubility in aqueous fluids may be significantly affected by the formation of chloride complexes. We introduced NaCl into the sediment‐H2O system, and re‐investigated trace element partitioning between aqueous fluids and metasediments in a series of piston cylinder experiments at 2.5–4.5 GPa and 600–700°C. The diamond trap method was employed to separate the fluids, which were analyzed in the frozen state. Trace element compositions of fluids and all solid phases were obtained by LA‐ICP‐MS. We combined our data with published literature to demonstrate that saline fluids and sediment melts have a comparable efficiency in extracting incompatible elements from subducted sediments, producing similar element fractionation during mobile phase expulsion. Accessory phases such as allanite may only be stable in particularly Rare Earth Elements‐enriched lithologies. The Sr, Pb and Nd isotopic signatures of arc magma suggest that the mantle wedge is infiltrated by mobile phases derived from both the sediment and basalt sections of the subducted oceanic crust. Up to several percent of either sediment‐derived saline fluid or melt can account for the isotopic and elemental compositions of most arc magma. Geochemical similarities between arc magma and forearc sediments are not necessarily evidence of slab melting.

The mucosal immunity is crucial for restricting SARS-CoV-2 at its entry site. Intramuscularly applied vaccines against SARS-CoV-2 stimulate high levels of neutralizing Abs in serum, but the impact of these intramuscular vaccinations on features of mucosal immunity is less clear. Here, we analyzed kinetic and functional properties of anti-SARS-CoV-2 Abs in the saliva after vaccination with BNT162b2. We analyzed a total of 24 healthy donors longitudinally for up to 16 months. We found that specific IgG appeared in the saliva after the second vaccination, declined thereafter and reappeared after the third vaccination. Adjusting serum and saliva for the same IgG concentration revealed a strong correlation between the reactivity in these two compartments. Reactivity to VoCs correlated strongly as seen by ELISAs against RBD variants and by live-virus neutralizing assays against replication-competent viruses. For further functional analysis, we purified IgG and IgA from serum and saliva. In vaccinated donors we found neutralizing activity towards authentic virus in the IgG, but not in the IgA fraction of the saliva. In contrast, IgA with neutralizing activity appeared in the saliva only after breakthrough infection. In serum, we found neutralizing activity in both the IgA and IgG fractions. Together, we show that intramuscular mRNA vaccination transiently induces a mucosal immunity that is mediated by IgG and thus differs from the mucosal immunity after infection. Waning of specific mucosal IgG might be linked to susceptibility for breakthrough infection.

Dry fractionation is low in energy and water use and thus a sustainable option to obtain protein-rich ingredients. Air-classification is used to remove starch from legumes, and electrostatic separation can be used to remove fibres from other starting materials like oilseeds. Flour from oil-rich crops needs to be de-oiled to facilitate dry fractionation, which involves the use of organic solvents or mechanical pressing and might affect the ingredient functionality. This research evaluated if the functionality of soy and lupin is affected by solvent de-oiling and electrostatic separation. Industrially toasted soy and lupin flour contained native protein, which was preserved upon electrostatic separation, de-oiling with hexane and de-oiling with acetone, but ethanol de-oiling resulted in protein denaturation. De-oiling with ethanol or hexane is preferred over de-oiling with acetone based on the flavour profile after de-oiling. The use of different solvents affected the solubility to a different extent and electrostatic separation resulted in a similar or higher solubility of the ingredients (22–49 %), dependent on the solvent, crop and pH condition used. Overall, electrostatic separation resulted in protein-enriched ingredients (43 %DM - 67 %DM Nfactor=5.7) that show potential for application as stabilizers in emulsion-based systems like dressings or frozen foam-based systems like ice-cream.

Subglacial meltwater of land-terminating glaciers in Greenland and Iceland are sources of methane (CH4) to the atmosphere, but sparse empirical data exist about the spatial distribution of subglacial CH4 production and emission from glaciers in other regions of the world. This study presents the first measurements of CH4 emissions from the subglacial meltwater of three outlet glaciers of the St. Elias Mountains in Yukon, Canada. Dissolved CH4 concentrations were highly elevated at 45, 135, and 250 times compared to the atmospheric equilibrium concentration in the meltwater of Dusty, Kluane, and Donjek glaciers, respectively. Dissolved CO2 concentrations were depleted relative to the atmospheric equilibrium. This points to the meltwater being a source of CH4 and a sink of CO2. Stable carbon (13C) and hydrogen (2H) isotopic signatures of the subglacial CH4 were depleted compared to atmospheric CH4 at all sites, indicating both biotic and abiotic sources and possible alteration from bacterial CH4 oxidation in the meltwater. No relation was found between CH4 concentrations in the meltwater and the meltwater chemistry or the size of the glaciers in this study. These findings suggest that CH4 emissions from subglacial environments under alpine glaciers may be a more common phenomenon than previously thought.

Abstract Background and objectives The treatment of elderly patients is an increasing challenge and the long-term sequelae often affect activities of daily living and quality of life in those patients. Handgrip strength (HGS) appears as a promising value to predict the outcome after trauma in elderly patients and to assess the overall muscle strength. Besides the possible role of psychological and hormonal factors, vitamin D may have a positive influence. Furthermore, some data suggest that Vitamin D is beneficial regarding muscle strength and possibly prevents further falls and injuries in orthogeriatric patients. The purpose of this study was to identify if Vitamin D is an influencing factor for HGSin elderly trauma patients. Materials and methods 94 elderly patients in a Level I Trauma Center aged 60 years or older were prospectively enrolled and HGS as well as serum 25-OH Vitamin D concentration (VDC) were measured. In addition, the standardized questionnaires Barthel Index (BI), Parker Mobility Score (PMS), Short Physical Performance Battery (SPPB), Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls (SARC-F) and European Quality of Life 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L), were used to record mental health status and demographic data. Results HGS is mainly related to age and sex in elderly trauma patients. HGS was higher in men (meanmale = 27.31 kg (± 8.11), meanfemale = 15.62 kg (± 5.63), p

In many fields of spinal health care, efforts have been made to offer individualized products and therapy tailored to the patient. Therefore, the prevailing alignment of the spine must be considered, which varies from person to person and depends on the movement and loading situation. With the help of patient-specific simulation models of the spine, the geometrical parameters in a specific body position can be analyzed, and the load situation of the spinal structures during dynamic processes can be assessed. However, to enable the future usability of such simulation models in medical reality, as many patient-specific conditions as possible need to be considered. Another critical requirement is that simulation models must be quickly and easily created for use in clinical routine. Building new or adapting existing spine multibody simulation (MBS) models is time-consuming due to their complex structure. To overcome this limitation, we developed a simple, efficient method by which to automatically adjust the lumbar curvature orientation of the spine model. The method extracts a new 3D lordosis curve from patient-specific data in the preprocessing step. Then the vertebrae and all linked spinal structures of an existing spinal simulation model are transformed so that the lumbar lordosis follows the curve obtained in the first part of the method. To validate the proposed approach, three independent experts measured the Cobb angle in the source and the generated spine alignments. We calculated a mean absolute error of 1.29° between the generated samples and the corresponded ground truth. Furthermore, the minor deviation in the root mean square error (RMSE) of 0.0012 m2 between the areas under the alignment curves in the original and target lordosis curvatures indicated the accuracy of the proposed method. The proposed method demonstrated that a new patient-specific simulation model can be generated in a short time from any suitable data source.

Abstract Anthropogenic carbon emissions and associated climate change are driving rapid warming, acidification, and deoxygenation in the ocean, which increasingly stress marine ecosystems. On top of long‐term trends, short term variability of marine stressors can have major implications for marine ecosystems and their management. As such, there is a growing need for predictions of marine ecosystem stressors on monthly, seasonal, and multi‐month timescales. Previous studies have demonstrated the ability to make reliable predictions of the surface ocean physical and biogeochemical state months to years in advance, but few studies have investigated forecast skill of multiple stressors simultaneously or assessed the forecast skill below the surface. Here, we use the Community Earth System Model (CESM) Seasonal to Multiyear Large Ensemble (SMYLE) along with novel observation‐based biogeochemical and physical products to quantify the predictive skill of dissolved inorganic carbon (DIC), dissolved oxygen, and temperature in the surface and subsurface ocean. CESM SMYLE demonstrates high physical and biogeochemical predictive skill multiple months in advance in key oceanic regions and frequently outperforms persistence forecasts. We find up to 10 months of skillful forecasts, with particularly high skill in the Northeast Pacific (Gulf of Alaska and California Current Large Marine Ecosystems) for temperature, surface DIC, and subsurface oxygen. Our findings suggest that dynamical marine ecosystem prediction could support actionable advice for decision making.

Abstract The leading first‐in‐class ruthenium‐complex BOLD‐100 currently undergoes clinical phase‐II anticancer evaluation. Recently, BOLD‐100 is identified as anti‐Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD‐100‐resistant colon and pancreatic carcinoma cells. Acute BOLD‐100 treatment reduces lipid droplet contents of BOLD‐100‐sensitive but not ‐resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD‐100‐resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame‐shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl‐coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell‐free BOLD‐100‐CoA adduct formation suggesting acetyl‐CoA depletion as mechanism bridging BOLD‐100‐induced lipid metabolism alterations and histone acetylation‐mediated gene expression deregulation. Indeed, BOLD‐100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de‐acetylation as central mode‐of‐action of BOLD‐100 and metabolic programs stabilizing histone acetylation as relevant Achilles’ heel of acquired BOLD‐100‐resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD‐100 responsiveness. Summarizing, BOLD‐100 is identified as epigenetically active substance acting via targeting several onco‐metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD‐100 resistance opens novel strategies to tackle therapy failure.

IntroductionTo explore whether the reported lower pathogenicity in infected individuals of variant of concern (VoC) Omicron and its current subvariants compared to VoC Delta may be related to fundamental differences in the initial virus-tissue interaction, we assessed their ability to penetrate, replicate and cause damage in a human 3D respiratory model.MethodsFor this, we used TEER measurements, real-time PCR, LDH, cytokine and complex confocal imaging analyses.Results and discussionWe observed that Delta readily penetrated deep into the respiratory epithelium and this was associated with major tissue destruction, high LDH activity, high viral loads and pronounced innate immune activation as observed by intrinsic C3 activation and IL-6 release at infection sites. In contrast, Omicron subvariants BA.5, BQ.1.1 and BF7 remained superficially in the mucosal layer resulting merely in outward-directed destruction of cells, maintenance of epithelial integrity, minimal LDH activity and low basolateral release of virus at infection sites, as well as significantly smaller areas of complement activation and lower IL-6 secretion. Interestingly, also within Omicron subvariants differences were observed with newer Omicron subvariants BQ.1.1 and BF.7 illustrating significantly reduced viral loads, IL-6 release and LDH activity compared to BA.5. Our data indicate that earliest interaction events after SARS-CoV-2 transmission may have a role in shaping disease severity.

ABSTRACT Currently, SARS-CoV-2 Omicron BA.5 subvariants BF.7 and BQ.1.1 are rapidly emerging worldwide. To evaluate the SARS-CoV-2-neutralizing capacity of sera and saliva from triple vaccinated individuals, either boosted with an adapted bivalent COVID-19 vaccine or recovered from BA.4/BA.5 infection, we analyzed the sensitivity of replication-competent SARS-CoV-2 Omicron subvariants BA.4/5, BQ.1.1 and BF.7 to neutralization. Analysis of SARS-CoV-2-specific IgGs and IgAs showed increased serum IgG titers in the vaccinated group, while the serum and salivary IgA levels were comparable. Similar and efficient serum neutralization against the ancestral strain of SARS-CoV-2 and Omicron BA.4/BA.5 was detected in both cohorts, but critically reduced for BQ.1.1 and BF.7. In contrast, salivary neutralization against BA.4/BA.5 was increased in the convalescent compared to the vaccinated group, while salivary neutralizing capacity against BQ.1.1 and BF.7 was comparable in these groups. Further, personalized protective effects studied in a human 3D respiratory model revealed the importance of salivary protection against different Omicron subvariants. IMPORTANCE In BA.4/BA.5-convalescent versus vaccinated groups, salivary neutralization capacity increased against SARS-CoV-2 Omicron BA.4/BA.5. In contrast, it neutralized novel Omicron subvariants BQ.1.1 and BF.7 similarly. Salivary protection against various Omicron subvariants was even more evident when tested in a personalized approach using highly differentiated respiratory human 3D models.

Abstract Background Tibial plateau fractures and tibial implant- loosening are severe complications in cementless unicompartmental knee replacement (UKR). The tibial keel preparation is particularly demanding and different saw blades can be used. It was hypothesized that different blade designs and thickness have an influence on the frequency of tibial plateau fractures and implant-loosening in cementless medial UKR. Methods 1258 patients with cementless medial UKR were included in this retrospective study between 2013 and 2020. The tibial keel cut was performed either with a double keel saw blade (DKS; 2.8 mm) and added hand guided pick or a mono reciprocating saw blade (RKB) of different thickness (2.5 mm; 2.65 mm; 2.75 mm). Tibial plateau fracture and loosening were demonstrated by standard two-plane radiographs. Tibial implant-loosening was defined as complete radiolucency and implant migration. Fracture and loosening were combined with pain and loss of function. Results In 126 patients (10%) the tibial keel was prepared with DKS, in 407 patients (32.4%) with RKB 2.5 mm, in 330 patients (26.2%) with RKB 2.65 mm and in 395 patients (31.4%) with 2.75 mm. In 4 patients (3.17%) with DKS tibial plateau fracture occurred, in 4 patients (0.99%) with 2.5 mm RKB, in 3 patients (0.92%) with 2.65 mm RKB and in 1 patient (0.25%) with 2.75 mm RKB. Significantly fewer fractures occurred with a RKB design (p = 0.007). A negative correlation between fracture incidence and RKB saw blade thickness was found (Spearman-r = − 0.93). No difference for tibial implant-loosening was shown (p = 0.51). Conclusion Different blade designs and thickness have a significant influence on the incidence of tibial plateau fractures and aseptic tibial implant-loosening. The incidence of tibial plateau fractures in cementless medial UKR can be reduced by changing the design and thickness of the tibial keel saw blade. Greater thickness of RKB leads to significantly fewer tibial plateau fractures while the incidence of implant-loosening is not increasing. Trial registration: This study was retrospectively registered and ethical approval was waived by the local ethical committee (No. 2020–1174).

Abstract Single-cell analysis, or cytometry, is a ubiquitous tool in the biomedical sciences. Whereas most cytometers use fluorescent probes to ascertain the presence or absence of targeted molecules, biophysical parameters such as the cell density, refractive index, and viscosity are difficult to obtain. In this work, we combine two complementary techniques—quantitative phase imaging and Brillouin spectroscopy—into a label-free image cytometry platform capable of measuring more than a dozen biophysical properties of individual cells simultaneously. Using a geometric simplification linked to freshly plated cells, we can acquire the cellular diameter, volume, refractive index, mass density, non-aqueous mass, fluid volume, dry volume, the fractional water content of cells, both by mass and by volume, the Brillouin shift, Brillouin linewidth, longitudinal modulus, longitudinal viscosity, the loss modulus, and the loss tangent, all from a single acquisition, and with no assumptions of underlying parameters. Our methods are validated across three cell populations, including a control population of CHO-K1 cells, cells exposed to tubulin-disrupting nocodazole, and cells under hypoosmotic shock. Our system will unlock new avenues of research in biophysics, cell biology, and medicine.

SARS-CoV-2 mutations associated with the escape from antibody-mediated neutralization have been widely reported. Here, in a patient with defective antibody responses, the authors find a potential association between SARS-CoV-2 mutations and CD8 T alterations to implicate possible contributions of CD8 T cells in evasion of SARS-CoV-2 from host immunity.

Abstract Background Fluticasone furoate/vilanterol trifenatate (FF/VI) is an inhaled therapy for the treatment of asthma, with a prolonged duration of anti-inflammatory and bronchodilatory action. This study investigated the global metabolomic and lipidomic profile following treatment with FF/VI or placebo and assessed whether changes correlated with exhaled nitric oxide levels as a measure of airway inflammation. Methods This was a single-center, randomized, double-blind, placebo-controlled, two-period, crossover, repeat-dose study. Adults with asthma (forced expiratory volume in 1 s ≥ 60% predicted; fraction of exhaled nitric oxide [FeNO] > 40 parts per billion) received once-daily FF/VI 100 µg/25 µg or placebo for 14 days, followed by a 21-day washout period. Serum samples were taken at pre-dose (T1), and 15 and 21 days (T2 and T3, respectively) post dose in each period. The metabolomic and lipidomic profiles were analyzed by liquid chromatography with tandem mass spectrometry and polar liquid chromatography platforms, and ions were matched to a library of standards for metabolite identification and quantification. FeNO values at each timepoint were evaluated for correlations with the biochemical data. Results Of 27 randomized participants (mean age 24.5 years, 63% male), 26 provided serum samples for metabolomic analysis. A total of 1969 metabolites were identified, 1634 of which corresponded to a named structure in a reference library. Treatment-related changes in the metabolome were generally subtle, with a modest increase in metabolite perturbations across timepoints. The percentage of metabolites with significant changes (p

Polyphosphate kinases (PPKs) have become popular biocatalysts for nucleotide 5'-triphosphate (NTP) synthesis and regeneration. Two unrelated families are described: PPK1 and PPK2. They are structurally unrelated and use different catalytic mechanisms. PPK1 enzymes prefer the usage of adenosine 5'-triphosphate (ATP) for polyphosphate (polyP) synthesis while PPK2 enzymes favour the reverse reaction. With the emerging use of PPK enzymes in biosynthesis, a deeper understanding of the enzymes and their thermodynamic reaction course is of need, especially in comparison to other kinases. Here, we tested four PPKs from different organisms under the same conditions without any coupling reactions. In comparison to other kinases using phosphate donors with comparably higher phosphate transfer potentials that are characterised by reaction yields close to full conversion, the PPK-catalysed reaction reaches an equilibrium in which about 30% ADP is left. These results were obtained for PPK1 and PPK2 enzymes, and are supported by theoretical data on the basic reaction. At high concentrations of substrate, the different kinetic preferences of PPK1 and PPK2 can be observed. The implications of these results for the application of PPKs in chemical synthesis and as enzymes for ATP regeneration systems are discussed.

Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, occurring in approximately 1% of affected individuals, are unknown. An autonomously signaling B-cell receptor (BCR) is essential for the pathogenesis of CLL. The objectives of this study were functional characterization of the BCR of MBL in siblings of CLL patients and a comparison of genetic variants in MBL-CLL sibling pairs. Screening of peripheral blood by flow cytometry detected 0.2-480 clonal CLL-phenotype cells per microliter (median: 37/μL) in 34 of 191 (17.8%) siblings of CLL patients. Clonal BCR isolated from highly purified CLL-phenotype cells induced robust calcium mobilization in BCR-deficient murine pre-B cells in the absence of external antigen and without experimental crosslinking. This autonomous BCR signal was less intense than the signal originating from the CLL BCR of their CLL siblings. According to genotyping by single nucleotide polymorphism array, whole exome, and targeted panel sequencing, CLL risk alleles were found with high and similar prevalence in CLL patients and MBL siblings, respectively. Likewise, the prevalence of recurrent CLL-associated genetic variants was similar between CLL and matched MBL samples. However, copy number variations and small variants were frequently subclonal in MBL cells, suggesting their acquisition during subclinical clonal expansion. These findings support a stepwise model of CLL pathogenesis, in which autonomous BCR signaling leads to a non-malignant (oligo)clonal expansion of CD5+ B cells, followed by malignant progression to CLL after acquisition of pathogenic genetic variants.

Abstract Aquatic ecosystems play an important role in global methane cycling and many field studies have reported methane supersaturation in the oxic surface mixed layer (SML) of the ocean and in the epilimnion of lakes. The origin of methane formed under oxic condition is hotly debated and several pathways have recently been offered to explain the “methane paradox.” In this context, stable isotope measurements have been applied to constrain methane sources in supersaturated oxygenated waters. Here we present stable carbon isotope signatures for six widespread marine phytoplankton species, three haptophyte algae and three cyanobacteria, incubated under laboratory conditions. The observed isotopic patterns implicate that methane formed by phytoplankton might be clearly distinguished from methane produced by methanogenic archaea. Comparing results from phytoplankton experiments with isotopic data from field measurements, suggests that algal and cyanobacterial populations may contribute substantially to methane formation observed in the SML of oceans and lakes.

TLR Agonists have promising activity in preclinical models of viral infection and cancer. However, clinical use is only in topical application. Systemic uses of TLR-ligands such as Resiquimod, have failed due to adverse effects that limited dose and thus, efficacy. This issue could be related to pharmacokinetic properties that include fast elimination leading to low AUC with simultaneously high cmax at relevant doses. The high cmax is associated with a sharp, poorly tolerated cytokine pulse, suggesting that a compound with a higher AUC/cmax-ratio could provide a more sustained and tolerable immune activation. Our approach was to design TLR7/8-agonist Imidazoquinolines intended to partition to endosomes via acid trapping using a macrolide-carrier. This can potentially extend pharmacokinetics and simultaneously direct the compounds to the target compartment. The compounds have hTLR7/8-agonist activity (EC50 of the most active compound in cellular assays: 75-120 nM hTLR7, 2.8-3.1 µM hTLR8) and maximal hTLR7 activation between 40 and 80% of Resiquimod. The lead candidates induce secretion of IFNα from human Leukocytes in the same range as Resiquimod but induce at least 10-fold less TNFα in this system, consistent with a higher specificity for human TLR7. This pattern was reproduced in vivo in a murine system, where small molecules are thought not to activate TLR8. We found that Imidazoquinolines conjugated to a macrolide or, substances carrying an unlinked terminal secondary amine, had longer exposure compared with Resiquimod. The kinetics of pro-inflammatory cytokine release for these substances in vivo were slower and more extended (for comparable AUCs, approximately half-maximal plasma concentrations). Maximal IFNα plasma levels were reached 4 h post application. Resiquimod-treated groups had by then returned to baseline from a peak at 1 h. We propose that the characteristic cytokine profile is likely a consequence of altered pharmacokinetics and, potentially, enhanced endosomal tropism of the novel substances. In particular, our substances are designed to partition to cellular compartments where the target receptor and a distinct combination of signaling molecules relevant to IFNα-release are located. These properties could address the tolerability issues of TLR7/8 ligands and provide insight into approaches to fine-tune the outcomes of TLR7/8 activation by small molecules.

Objective(s):. PIK3CA-related overgrowth spectrum (PROS) is a group of disorders caused by somatic variants in the PIK3CA gene. We aimed to update recommendations on the severity classification, testing, and medical management of patients with PROS. Methods:. Using validated consensus methodology, we convened a 13-member panel in 2020 and reviewed current evidence on how to diagnose and treat PROS. The panel was asked to rate the level of disease severity, and the appropriateness of whether to test for a mutation and medical therapy in 217 patient scenarios before a virtual meeting. Panelists discussed areas of disagreement and completed ratings following the meeting. Results:. The panel developed clinical presentations and endorsed the disease severity framework defined by functional impairment, a reduction in quality of life, and risk of death. Panelists agreed it is appropriate to test for a PIK3CA gene variant in every moderately/severely affected patient. Panelists agreed it may be appropriate to consider an mammalian (mechanistic) target of rapamycin inhibitor in some severely affected patients and some moderately affected patients with progressive disease. Although clinical trials have only recently begun and the evidence remains limited, panelists also agreed it may be appropriate to consider treatment with phosphoinositide 3-kinase/serine/threonine protein kinase inhibitors in severely affected patients with a confirmed PIK3CA variant or without a confirmed variant but with progressive disease. Conclusion:. These recommendations represent the consensus of experts informed by published literature and experience. Future research should validate this guidance using clinical data. Once validated, we hope these recommendations will improve outcomes for patients with PROS.

There is a growing demand for nutritional, functional, and eco-friendly dairy products, which has increased the need for research regarding alternative and sustainable protein sources. Plant-based, single-cell (SCP), and recombinant proteins are being explored as alternatives to dairy proteins. Plant-Based Proteins (PBPs) are commonly used to replace total dairy protein. However, PBPs are generally mixed with dairy proteins to improve their functional properties, which makes them dependent on animal protein sources. In contrast, single-Cell Proteins (SCPs) and recombinant dairy proteins are promising alternatives for dairy protein replacement since they provide nutritional components, essential amino acids, and high protein yield and can use industrial and agricultural waste as carbon sources. Although alternative protein sources offer numerous advantages over conventional dairy proteins, several technical and sensory challenges must be addressed to fully incorporate them into cheese and yogurt products. Future research can focus on improving the functional and sensory properties of alternative protein sources and developing new processing technologies to optimize their use in dairy products. This review highlights the current status of alternative dairy proteins in cheese and yogurt, their functional properties, and the challenges of their use in these products.

The neural activity patterns associated with advanced cognitive processes are characterized by a high degree of collective organization, which raises the question of whether macroscopic quantum phenomena play a significant role in cortical dynamics. In order to pursue this question and scrutinize the feasibility of macroscopic quantum coherence in the brain, a model is developed regarding the functioning of microcolumns, which are the basic functional units of the cortex. This model assumes that the operating principle of a microcolumn relies on the interaction of a pool of neurotransmitter (glutamate) molecules with the vacuum fluctuations of the electromagnetic field, termed zero-point field (ZPF). Quantitative calculations reveal that the coupling strength of the glutamate pool to the resonant ZPF modes lies in the critical regime in which the criterion for the initiation of a phase transition is fulfilled, driving the ensemble of initially independent molecules toward a coherent state and resulting in the formation of a coherence domain that extends across the full width of a microcolumn. The formation of a coherence domain turns out to be an energetically favored state shielded by a considerable energy gap that protects the collective state against thermal perturbations and entails decoherence being greatly slowed down. These findings suggest that under the special conditions encountered in cortical microcolumns the emergence of macroscopic quantum phenomena is feasible. This conclusion is further corroborated by the insight that the presence of a coherence domain gives rise to downstream effects which may be crucial for the cortical communication and the formation of large-scale activity patterns. Taken together, the presented model sheds new light on the fundamental mechanism underlying cortical dynamics and suggests that long-range synchronization in the brain results from a bottom-up orchestration process involving the ZPF.

Cover crops are planted to reduce soil erosion, increase soil fertility, and improve watershed management. In the Delmarva Peninsula of the eastern United States, winter cover crops are essential for reducing nutrient and sediment losses from farmland. Cost-share programs have been created to incentivize cover crops to achieve conservation objectives. This program required that cover crops be planted and terminated within a specified time window. Usually, farmers report cover crop termination dates for each enrolled field (∼28,000 per year), and conservation district staff confirm the report with field visits within two weeks of termination. This verification process is labor-intensive and time-consuming and became restricted in 2020–2021 due to the COVID-19 pandemic. This study used Harmonized Landsat and Sentinel-2 (HLS, version 2.0) time-series data and the within-season termination (WIST) algorithm to detect cover crop termination dates over Maryland and the Delmarva Peninsula. The estimated remote sensing termination dates were compared to roadside surveys and to farmer-reported termination dates from the Maryland Department of Agriculture database for the 2020–2021 cover crop season. The results show that the WIST algorithm using HLS detected 94% of terminations (statuses) for the enrolled fields (n = 28,190). Among the detected terminations, about 49%, 72%, 84%, and 90% of remote sensing detected termination dates were within one, two, three, and four weeks of agreement to farmer-reported dates, respectively. A real-time simulation showed that the termination dates could be detected one week after termination operation using routinely available HLS data, and termination dates detected after mid-May are more reliable than those from early spring when the Normalized Difference Vegetation Index (NDVI) was low. We conclude that HLS imagery and the WIST algorithm provide a fast and consistent approach for generating near-real-time cover crop termination maps over large areas, which can be used to support cost-share program verification.

The UN sustainable development goals (SDGs) and the Paris climate target require a holistic transformation towards human well-being within planetary boundaries. However, there are growing debates on how to best pursue these targets. Proposed transformation strategies include market- and technology-driven green-growth, shifting towards a sufficiency-oriented post-growth economy, and a transformation driven primarily by strong government action. Here we quantify three alternative sustainable development pathways (SDPs), Economy-driven Innovation, Resilient Communities, and Managing the Global Commons, that reflect these different societal strategies. We compare the quantifications from two integrated assessment models and two sectoral models of the buildings and materials sectors across a broad set of indicators for sustainable development and climate action. Our global multi-scenario and multi-model analysis shows that all three SDPs enable substantial progress towards the human development goals of the SDGs. They simultaneously limit global warming and prevent further environmental degradation, with the sufficiency-oriented Resilient Communities scenario showing the lowest peak warming and lowest reliance on carbon dioxide removal as well as the largest improvements in biodiversity intactness. The SDPs also alleviate the concerns about the biogeophysical and technological feasibility of narrowly-focused climate change mitigation scenarios. However, the shifts in energy and food consumption patterns assumed in the SDPs, ranging from moderate in Economy-driven Innovation to very ambitious in Resilient Communities, also lead to increased challenges regarding socio-cultural feasibility.

2MASS J16075796-2040087 is an ∼5 Myr young star in Upper Sco with evidence for accretion bursts on a timescale of about 15 days and, uncommonly for its age, outflows traced by multicomponent forbidden emission lines (FELs). The accretion bursts may be triggered by a companion at ∼4.6 au. We analyze HIRES spectra optimised for spectro-astrometry to better understand the origin of the several FEL velocity components and determine whether a magnetohydrodynamic (MHD) disk wind is present. The FEL high-velocity component (HVC) traces an asymmetric, bipolar jet ∼700 au long. The jet’s position angle ∼ 277° is not perpendicular to the disk. The lower-velocity emission, classified previously as a disk wind low-velocity component, is found to have more in common with the HVC and overall it is not possible to identify an MHD disk wind component. The spectro-astrometric signal of the low-velocity emission resembles those of jets and its density and ionisation fraction fall into the range of HVCs. We suggest a scenario where the accretion bursts due to the close companion power the jets past the age where such activity ends around most stars. The low-velocity emission here could come from a slow jet launched near the close companion and this emission would be blended with emission from the MHD wind.

Young, low-mass brown dwarfs orbiting early-type stars, with low mass ratios ( q ≲ 0.01), appear to be intrinsically rare and present a formation dilemma: could a handful of these objects be the highest-mass outcomes of “planetary” formation channels (bottom up within a protoplanetary disk), or are they more representative of the lowest-mass “failed binaries” (formed via disk fragmentation or core fragmentation)? Additionally, their orbits can yield model-independent dynamical masses, and when paired with wide wavelength coverage and accurate system age estimates, can constrain evolutionary models in a regime where the models have a wide dispersion depending on the initial conditions. We present new interferometric observations of the 16 Myr substellar companion HD 136164 Ab (HIP 75056 Ab) made with the Very Large Telescope Interferometer (VLTI)/GRAVITY and an updated orbit fit including proper motion measurements from the Hipparcos–Gaia Catalog of Accelerations. We estimate a dynamical mass of 35 ± 10 M _J ( q ∼ 0.02), making HD 136164 Ab the youngest substellar companion with a dynamical mass estimate. The new mass and newly constrained orbital eccentricity ( e = 0.44 ± 0.03) and separation (22.5 ± 1 au) could indicate that the companion formed via the low-mass tail of the initial mass function. Our atmospheric fit to a SPHINX M-dwarf model grid suggests a subsolar C/O ratio of 0.45 and 3 × solar metallicity, which could indicate formation in a circumstellar disk via disk fragmentation. Either way, the revised mass estimate likely excludes bottom-up formation via core accretion in a circumstellar disk. HD 136164 Ab joins a select group of young substellar objects with dynamical mass estimates; epoch astrometry from future Gaia data releases will constrain the dynamical mass of this crucial object further.

Stable hydrogen and carbon isotope ratios of wood lignin methoxy groups (δ13CLM and δ2HLM values) have been shown to be reliable proxies of past temperature variations. Previous studies showed that δ2HLM values even work in temperate environments where classical tree-ring width and maximum latewood density measurements are less successful for climate reconstructions. Here, we analyse the annually resolved δ13CLM values from 1916–2015 of four beech trees (Fagus sylvatica) from a temperate site near Hohenpeißenberg in southern Germany and compare these data with regional- to continental-scale climate observations. Initial δ13CLM values were corrected for the Suess effect (a decrease of δ13C in atmospheric CO2) and physiological tree responses to increasing atmospheric CO2 concentrations considering a range of published discrimination factors. The calibration of δ13CLM chronologies against instrumental data reveals the highest correlations with regional summer (r=0.68) and mean annual temperatures (r=0.66), as well as previous-year September to current-year August temperatures (r=0.61), all calculated from 1916–2015 and reaching p. Additional calibration trials using detrended δ13CLM values and climate data (to constrain effects of autocorrelation on significance levels) returned rsummer=0.46 (p), rannual=0.25 (p) and rprev.September-August=0.18 (p>0.05). The new δ13CLM chronologies were finally compared with the previously produced δ2HLM values of the same trees in order to evaluate the additional gain of assessing past climate variability using a dual-isotope approach. Compared to δ13CLM, δ2HLM values correlate substantially more strongly with large-scale temperatures averaged over western Europe (rprev.September-August=0.69), whereas only weak and mainly insignificant correlations are obtained between precipitation and both isotope chronologies (δ13CLM and δ2HLM values). Our results indicate the great potential of using δ13CLM values from temperate environments as a proxy for local temperatures and, in combination with δ2HLM values, to assess regional- to sub-continental scale temperature patterns.

Abstract Methane (CH4) formation by vegetation has been studied intensively over the last 15 years. However, reported CH4 emissions vary by several orders of magnitude, thus making global estimates difficult. Moreover, the mechanism(s) for CH4 formation by plants is (are) largely unknown. Here, we introduce a new approach for making CH4 formation by plants clearly visible. By application of 13C‐labeled dimethyl sulfoxide (DMSO) onto the leaves of tobacco plants (Nicotiana tabacum) and Chinese silver grass (Miscanthus sinensis) the effect of light and dark conditions on CH4 formation of this pathway was examined by monitoring stable carbon isotope ratios of headspace CH4 (δ13C‐CH4 values). Both plant species showed increasing headspace δ13C‐CH4 values while exposed to light. Higher light intensities increased CH4 formation rates in N. tabacum but decreased rates for M. sinensis. In the dark no formation of CH4 could be detected for N. tabacum, while M. sinensis still produced ~50% of CH4 compared to that during light exposure. Our findings suggest that CH4 formation is clearly dependent on light conditions and plant species and thus indicate that DMSO is a potential precursor of vegetative CH4. The novel isotope approach has great potential to investigate, at high temporal resolution, physiological, and environmental factors that control pathway‐specific CH4 emissions from plants.

Platinum(IV) complexes have the potential to overcome several limitations and reduce adverse effects of platinum-based cancer therapy. Resistance to clinically approved platinum(II) drugs is, at least in part, associated with elevated levels of glutathione. Here, the authors report on an oxaliplatin-based platinum(IV) prodrug, which releases L-buthionine-S,R-sulfoximine, an inhibitor of the rate-limiting enzyme in glutathione biosynthesis, to circumvent glutathione-based resistance mechanisms.

Progressive respiratory failure is the primary cause of death in patients with COVID-19, but pathologies in other tissues may also occur. Here the authors report that adrenal tropism of SARS-CoV-2 is associated with adrenalitis, reduced adrenal cortisol levels and severe adrenal damage in a post-mortem case series of patients with severe fatal COVID-19.

Graphene oxide (GOX) has become attractive due to its unique physicochemical properties. This nanomaterial can associate with other dendrimers, making them more soluble and allowing better interaction with biomacromolecules. The present study aimed to investigate, by real-time microscopy, the behavior of human breast cancer cells exposed to particles of materials based on graphene oxide. The MCF-7 cell line was exposed to GOX, GOX associated with Polypropylenimine hexadecaamine Dendrimer, Generation 3.0—DAB-AM-16 (GOXD) and GOX associated with polypropyleneimine—PAMAM (GOXP) in the presence or absence of fetal bovine serum (FBS). GOX, GOXD and GOXP were taken up by the cells in clusters and then the clusters were fragmented into smaller ones inside the cells. Real-time microscopy showed that the presence of FBS in the culture medium could allow a more efficient internalization of graphene materials. After internalizing the materials, cells can redistribute the clumps to their daughter cells. In conclusion, the present study showed that the particles can adhere to the cell surface, favoring their internalization. The presence of FBS contributed to the formation of smaller aggregates of particles, avoiding the formation of large ones, and thus transmitted a more efficient internalization of the materials through the interaction of the particles with the cell membrane.

The first-in-class ruthenium-based chemotherapeutic agent BOLD-100 (formerly IT-139, NKP-1339, KP1339) is currently the subject of clinical evaluation for the treatment of gastric, pancreatic, colorectal and bile duct cancer. A radiolabeled version of the compound could present a helpful diagnostic tool. Thus, this study investigated the pharmacokinetics of BOLD-100 in more detail to facilitate the stratification of patients for the therapy. The synthesis of [103Ru]BOLD-100, radiolabeled with carrier added (c.a.) ruthenium-103, was established and the product was characterized by HPLC and UV/Vis spectroscopy. In order to compare the radiolabeled and non-radioactive versions of BOLD-100, both complexes were fully evaluated in vitro and in vivo. The cytotoxicity of the compounds was determined in two colon carcinoma cell lines (HCT116 and CT26) and biodistribution studies were performed in Balb/c mice bearing CT26 allografts over a time period of 72 h post injection (p.i.). We report herein preclinical cytotoxicity and pharmacokinetic data for BOLD-100, which were found to be identical to those of its radiolabeled analog [103Ru]BOLD-100.