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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.

Purpose: This study aimed to investigate the effect of chronic tinnitus on measures of listening effort and cognitive performance, as well as the relation between cognitive performance and the amount of listening effort obtained by those measures. Method: Thirteen normal-hearing young adults with chronic tinnitus were matched with a control group. First, behavioral listening effort was measured using a dual-task paradigm in various favorable and unfavorable listening conditions. Furthermore, verbal working memory, processing speed, selective attention, and cognitive flexibility and inhibition were evaluated. Results: A significant and nonsignificant trend toward more listening effort in the tinnitus group was, respectively, found for the quiet listening condition and the condition with a signal-to-noise ratio of +2 dB. No significant differences in cognitive performances were found between the groups, nor were there significant relationships between the cognitive factors and listening effort scores for either the control or tinnitus group. Conclusions: Listening effort was increased in the tinnitus group. Although no clear differences in cognitive performance could be found between the tinnitus group and their controls, a trend could be seen whereby selective attention deficits in the subjects with tinnitus may be an important factor that affects the amount of listening effort.

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.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

Purpose: Speech-in-noise tests and suprathreshold auditory evoked potentials are promising biomarkers to diagnose cochlear synaptopathy (CS) in humans. This study investigated whether these biomarkers changed after recreational noise exposure. Method: The baseline auditory status of 19 normal-hearing young adults was analyzed using questionnaires, pure-tone audiometry, speech audiometry, and auditory evoked potentials. Nineteen subjects attended a music festival and completed the same tests again at Day 1, Day 3, and Day 5 after the music festival. Results: No significant relations were found between lifetime noise-exposure history and the hearing tests. Changes in biomarkers from the first session to the follow-up sessions were nonsignificant, except for speech audiometry, which showed a significant learning effect (performance improvement). Conclusions: Despite the individual variability in prefestival biomarkers, we did not observe changes related to the noise-exposure dose caused by the attended event. This can indicate the absence of noise exposure-driven CS in the study cohort, or reflect that biomarkers were not sensitive enough to detect mild CS. Future research should include a more diverse study cohort, dosimetry, and results from test-retest reliability studies to provide more insight into the relationship between recreational noise exposure and CS.

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.