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BACKGROUND: Sulfur (S) is a mineral nutrient essential for plant growth and development, which is incorporated into diverse molecules fundamental for primary and secondary metabolism, plant defense, signaling, and maintaining cellular homeostasis. Although, S starvation response is well documented in the dicot model Arabidopsis thaliana, it is not clear if the same transcriptional networks control the response also in the monocots. RESULTS: We performed series of physiological, expression, and metabolite analyses in two model monocot species, one representing the C3 plants, Oryza sativa cv. kitaake, and second representing the C4 plants, Setaria viridis. Our comprehensive transcriptomic analysis revealed twice as many differentially expressed genes (DEGs) in S. viridis than in O. sativa under S-deficiency, consistent with a greater loss of sulfur and S-containing metabolites under these conditions. Surprisingly, most of the DEGs and enriched gene ontology terms were species-specific, with an intersect of only 58 common DEGs. The transcriptional networks were different in roots and shoots of both species, in particular no genes were down-regulated by S-deficiency in the roots of both species. CONCLUSIONS: Our analysis shows that S-deficiency seems to have different physiological consequences in the two monocot species and their nutrient homeostasis might be under distinct control mechanisms.

This study aims to understand the general web accessibility of digital information networks which may serve as barriers for access to the global discipline of Communication through institutional and departmental websites, specifically for persons with disabilities and those with limited English proficiency (LEP). Our exploratory content analysis relies on computer-aided software to systematically analyze the departmental home pages of websites of institutional members of the International Communication Association (ICA), N = 77, representing 26 countries, globally. Findings from this study help us to: (1) better understand the general web, language, and mobile accessibility of discipline-related online information; (2) identify strengths and opportunities for improvement; and, (3) to reflect upon the anticipated barriers impacting persons with disabilities when accessing higher education information online.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Abstract Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals, and often, the use of cannabis precedes the onset of schizophrenic psychosis. Therefore, we investigated if different types of cannabinoids impact methylation patterns and expression of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function in a SH-SY5Y cell culture model. For this purpose, SH-SY5Y cells were differentiated into a neuron-like cell type as previously described. Effects of the cannabinoids delta-9-THC, HU-210, and Anandamide were investigated by analysis of cell morphology and measurement of neurite/dendrite lengths as well as determination of methylation pattern, expression (real time-qPCR, western blot) and localization (immunocytochemistry) of different target molecules concerned with the formation of synapses. Regarding the global impression of morphology, cells, and neurites appeared to be a bit more blunted/roundish and to have more structures that could be described a bit boldly as resembling transport vesicles under the application of the three cannabinoids in comparison to a sole application of retinoic acid (RA). However, there were no obvious differences between the three cannabinoids. Concerning dendrites or branch lengths, there was a significant difference with longer dendrites and branches in RA-treated cells than in undifferentiated control cells (as shown previously), but there were no differences between cannabinoid treatment and exclusive RA application. Methylation rates in the promoter regions of synapse candidate genes in cannabinoid-treated cells were in between those of differentiated cells and untreated controls, even though findings were significant only in some of the investigated genes. In other targets, the methylation rates of cannabinoid-treated cells did not only approach those of undifferentiated cells but were also valued even beyond. mRNA levels also showed the same tendency of values approaching those of undifferentiated controls under the application of the three cannabinoids for most investigated targets except for the structural molecules (NEFH, MAPT). Likewise, the quantification of expression via western blot analysis revealed a higher expression of targets in RA-treated cells compared to undifferentiated controls and, again, lower expression under the additional application of THC in trend. In line with our earlier findings, the application of RA led to higher fluorescence intensity and/or a differential signal distribution in the cell in most of the investigated targets in ICC. Under treatment with THC, fluorescence intensity decreased, or the signal distribution became similar to the dispersion in the undifferentiated control condition. Our findings point to a decline of neuronal differentiation markers in our in vitro cell-culture system under the application of cannabinoids.

Abstract Objective Most patients with alcohol use disorder (AUD) regularly take medication. Alcohol interacts negatively with many commonly prescribed medications. Little is known about whether the risk of potential alcohol-medication and drug-drug interactions increases or decreases in patients with AUD during inpatient withdrawal treatment. The aim of our study was to determine the prevalence and characteristics of potential alcohol-medication and drug-drug interactions in patients with AUD before and after withdrawal treatment in an addiction unit. Design Prospective monocentric quasi-experimental pre-post study. Methods Medication records before and after withdrawal treatment were analyzed and screened for potential alcohol-medication (pAMI) and drug-drug interactions (pDDI) using the drugs.com classification and the AiDKlinik ® electronic interaction program, respectively. Results We enrolled 153 patients with AUD who were treated in an addiction unit of a university hospital in Germany. Of these, 67.3% experienced at least one pAMI before and 91.5% after withdrawal treatment. In total, there were 278 pAMIs classified as “mild,” “moderate,” or “severe” before and 370 pAMIs after withdrawal treatment. Additionally, there were 76 pDDIs classified as “moderate,” “severe,” or “contraindicated combinations” both before and after withdrawal treatment. Conclusion The risk of exposure to pAMIs and pDDIs increases during inpatient withdrawal treatment in patients with AUD. Improvements in the quality of prescribing should particularly focus on the use of antihypertensives and opioids.

Abstract Background Patients presenting to Emergency Departments (ED) with opioid use disorder may be candidates for buprenorphine treatment, making EDs an appropriate setting to initiate this underused, but clinically proven therapy. Hospitals are devoting increased efforts to routinizing buprenorphine initiation in the ED where clinically appropriate, with the greatest successes occurring in academic medical centers. Overall, however, clinician participation in these efforts is suboptimal. Hospitals need more information to inform the standardized implementation of these programs nationally. Using an implementation science framework, we investigated ED providers’ concerns about ED buprenorphine programs and their willingness to prescribe buprenorphine in the ED. Methods We conducted Consolidated Framework for Implementation Research (CFIR)-informed interviews with 11 ED staff in Nevada and analyzed the transcripts using a six-step thematic approach. Results were organized within the CFIR 1.0 domains of inner setting, outer setting, intervention characteristics, and individual characteristics; potential implementation strategies were recommended. Results Physicians expressed that the ED is a suitable location for prescribing buprenorphine. However, they expressed concerns about: information gaps in the prescribing protocols (inner setting), patient outcomes beyond the ED, buprenorphine effectiveness and appropriate timing of treatment initiation (intervention characteristics), and their own competence in managing opioid withdrawal (individual characteristics). Some were anxious about patients’ outcomes and continuity of care in the community (outer setting), others desired access to prospective data that demonstrate buprenorphine effectiveness. Additional concerns included a lack of availability of the required support to prescribe buprenorphine, a lack of physicians’ experience and competence, and concerns about opioid withdrawal. Recommended implementation strategies to address these concerns include: designating personnel at the ED to bridge the information gap, engaging emergency physicians through educational meetings, creating a community of practice, facilitating mentorship opportunities, and leveraging existing collaborative learning platforms. Conclusion Overall, physicians in our study believed that implementing a buprenorphine program in the ED is appropriate, but had concerns. Implementation strategies could be deployed to address concerns at multiple levels to increase physician willingness and program uptake.

We investigate the lock-in zone (LIZ) of the East Greenland Ice Core Project (EastGRIP) region, northeastern Greenland, in detail. We present results from the firn air-pumping campaign of the S6 borehole, forward modeling, and a novel technique for finding the lock-in depth (LID, the top of the LIZ) based on the visual stratigraphy of the EastGRIP ice core. The findings in this work help to deepen our knowledge of how atmospheric gases are trapped in ice cores. CO2, δ15N, and CH4 data suggest that the LID lies around 58 to 61 m depth. With the pixel value intensity and bright-spot analysis based on visual stratigraphy, we can pinpoint a change in ice properties to exactly 58.3 m depth, which we define as the optical lock-in depth (OLID). This visual change in ice properties is caused by the formation of rounded and enclosed air bubbles that alter the measured refraction of the light pathways. The results for the LID and OLID agree accurately on the depth. We furthermore use the visual stratigraphy images to obtain information on the sharpness of the open- to closed-porosity transition. Combining traditional methods with the independent optical method presented here, we can now better constrain the bubble closure processes in polar firn.

Polypropylene (PP) rapidly gains scientific attention as fatigue-resistant and lightweight tissue repair and implant material, while emerging laser-sintering based methods for PP processing further allow unlimited versatility of PP specimens and often reduced numbers of process steps, substituting traditional manufacturing approaches. Generally, PP is considered biocompatible for a variety of medical applications while showing superior long-term stability, however, thermoplastic processing of polypropylene may induce the formation of cytotoxic degradation products, necessitating its cytotoxicological assessment. In the present study, PP specimens have been fabricated using warm, quasi-isothermal and complementary cold, non-isothermal powder bed fusion (PBF), allowing processing PP at ambient powder bed temperature of 25 °C for minimizing thermal exposure and the formation of decomposition products. The surface of manufactured specimens has been modified with hybrid coatings consisting of mesoporous inorganic microcrystals of vaterite laden with model biomacromolecules, i.e., fluorescently labelled dextran, demonstrating the stable coating and attachment of dextran-loaded vaterite crystals independent of the applied PBF processing regime. Vaterite coating is degradable and enables the opportunity to endow the surface of PP with sustained release functionalities. Both coated and uncoated specimens demonstrated excellent biocompatibility independent of the applied processing regime, as evaluated in an ex ovo shell-less hen's egg model.

Abstract Background European wildcats (Felis silvestris) are widely distributed in Europe and a strictly protected species in Germany. Lately, anthropogenic protective efforts lead to increasing numbers of wildcats in southwestern Germany. Moreover, in recent years the numbers of domestic cats are increasing. Thus, the contact between domestic and wildcats may lead to the spread of zoonotic pathogens in both animal species. As data on vector-borne pathogens (VBPs) in wildcats from Germany are limited to date, the objective of this study was to investigate the presence and current distribution of VBPs in wildcats from southwestern Germany. Methods Skin and spleen samples from 117 European wildcats, originating from a regional carcass-monitoring program in southwestern Germany, were examined by real-time and conventional polymerase chain reaction (PCR) for the presence of Anaplasma phagocytophilum, Neoehrlichia mikurensis, Rickettsia spp., Bartonella spp., and Piroplasmida. Results In total, 6.8% (n = 8) of the wildcats were Rickettsia-positive, specified as R. helvetica. Three wildcats were positive for A. phagocytophilum (2.6%), one for Bartonella spp., namely B. taylorii (0.8%), and 84 for Cytauxzoon spp. (71.8%). Out of these 84 samples, 23 were further sequenced revealing very high identity levels (99.84–100%) to C. europaeus, which is considered to be pathogenic for domestic cats. All wildcats were negative for the presence of N. mikurensis DNA. Conclusions European wildcats in southwestern Germany are hosting several VBPs. With the exception of Cytauxzoon spp., low prevalence rates of most examined pathogens suggest that wildcats are primarily incidental hosts for sylvatic pathogens associated with rodents, in contrast to domestic cats. However, the high prevalence of the cat-associated pathogen C. europaeus suggests that wildcats in southwestern Germany may serve as reservoirs for this pathogen. Graphical Abstract

Abstract Here, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6α, and IRE1α. Notably, dual EZH2/CDK4/6 blockade also reduced 3D-spheroid invasion, partially inhibited tumor growth in ovo, and led to impaired viability of patient-derived organoids. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), EMT-counterregulation (PCDH1) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation.

Introduction: The aim of the presented prospective observational study was to evaluate the effect of fistula flow on peripheral wave morphology and pulse wave velocity by means of the oscillometric Vicorder®-device with the purpose of fistula surveillance. Methods: Digitized and normalized curves of 53 haemodialysis patients at the fistula and non-fistula arm were analysed. Slope parameters and the areas under the curve of characteristic sections of pulse waves as well as the power spectrum of the pulse waves and their first and second derivatives were computed. Furthermore, the amplitude of volumetric change (AMP) was assessed. Duplex sonography served as a reference method. Results: In the comprehensive set of novel pulse wave parameters significant inter-arm differences were demonstrated and a significant delay of the systolic maximum at the fistula arm in comparison to the non-fistula arm (204 ± 3.4 vs. 162 ± 5.3 ms, p < 0.001) was proven. Unexpectedly, pulse wave velocity apparently did not differ between both arms (7.85 vs. 8.05 m/s at the fistula/non-fistula side, p = 0.942). The inter-arm differences of the slope parameters were more pronounced in forearm than in upper arm fistulas. Finally, we showed that the inter-arm difference of AMP correlated with volume flow (r = 0.326 with p = 0.017). Conclusion: Pulse waves as assessed by oscillometric pulse wave analysis have distinct features at fistula and non-fistula arms. This is due to enhanced arteriovenous flow, i.e. in both the brachial artery and the fistula vein. The analysis of those alterations has the potential to assess fistula function.

ABSTRACT: Colostrum is a rich source of nutritional and non-nutritional components and is recognized as essential to transfer passive immunity to newborn calves. Because of the individual and seasonal variability in colostrum yield and composition, maintaining an adequate supply of high-quality colostrum year-round remains a challenge for commercial dairy producers. In this narrative review, we described the individual, seasonal, and herd-level variability of colostrum production and summarized the association between individual animal factors such as parity, sex of the calf, calf birth weight, as well as indicators of the cow's metabolic status and the yield and composition of colostrum. Further, we reviewed the current knowledge on the influence of prepartum nutrition and management strategies on colostrum production. Research on the metabolizable energy and protein supplied in the prepartum diet as well as on the inclusion and source of vitamins, minerals, and feed additives suggests prepartum nutrition influences the yield, quality, and composition of colostrum. Furthermore, the prepartum environment and dry period length remain influential factors in the production of colostrum. However, additional research is needed to understand the mechanisms by which prepartum nutrition and management affect colostrum production. Finally, time from calving to colostrum harvest and oxytocin administration as well as the current knowledge on the effect of heat treatment and colostrum storage strategies on colostral components were discussed. To conclude, we identify critical gaps in knowledge for future focus of investigation in colostrum research.

Abstract There is a controversial debate regarding whether unattended blood pressure (BP) measurement should be regarded as the new gold standard of office BP measurement. Unattended BP measurement eliminates the white‐coat effect and reduces external influences on the patient. On the other hand, it might underestimate real‐life BP. The present study compares the prevalence of masked hypertension using attended versus unattended office BP measurements. We performed a cross‐sectional study on 213 patients in a general practitioner's outpatient clinic and compared attended and unattended office BP with 24h‐ambulatory BP monitoring (24h‐ABPM). Masked hypertension was defined as pressure ≥135/85 mmHg in daytime ABPM with office systolic BP

Abstract Objectives We described age, gender, race, and ethnicity associations with filling buprenorphine prescriptions post‐emergency department (post‐ED) visits. Methods We analyzed 1.5 years (July 1, 2020–December 31, 2021) of encounter‐level Medicaid ED and retail pharmacy claims data obtained from the Nevada Department of Health and Human Services. We studied ED patients with an opioid use disorder (OUD) diagnosis who did not fill a prescription for OUD medications within 6 months before the ED encounter. Using logistic regression, we modeled the associations between the patient's demographic characteristics and the outcome, filling a buprenorphine prescription at a community pharmacy within 14 or 30 days of the ED encounter. Results Among 2781 ED visits, representing 2094 patients, the median age was 39 years, 54% were male, 18.5% were Black, 11.7% were Hispanic, and 62.3% were White. Only 4% of the ED visits were followed by a filled buprenorphine prescription. Increasing age (14‐day window: adjusted odds ratio (aOR) = 0.965, 95% confidence interval [CI]: 0.948–0.983) and being a Black patient (14‐day window: aOR: 0.114, 95% CI 0.036–0.361) were both associated with lower odds of filled buprenorphine prescriptions. These results were similar within 30 days of an ED visit. Conclusions Initiation of buprenorphine following an ED visit remains low among Nevadan Medicaid patients and is less likely with increasing age and among Black patients, despite strong evidence supporting its use. Overburdened EDs, lack of attention from managers, and substance use stigma are among possible explanations. When ED clinicians do write buprenorphine prescriptions, peer recovery support could increase the fill rates.

BackgroundLCP-Tacro [LCPT], a novel once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ∼30% dose reduction in contrast to immediate-release tacrolimus (IR-Tac). Once-daily LCPT in de novo kidney transplantation has a comparable efficacy and safety profile to that of IR-Tac with advantages in bioavailability and absorption. The present investigation intends to analyze the effects of conversion from IR-Tac to LCPT on phenotype and function of T-cells and B-cells.Methods16 kidney transplant patients treated by triple standard immunosuppression with a stable graft function undergoing a switch from IR-Tac to LCPT were included in this observational prospective study. We measured the main immune cell types and performed an in-depth characterization of B cell, dendritic cells and T cells including regulatory T cells of the patients before, 4 and 8 weeks after IR-Tac to LCPT conversion using multi-parameter fl ow cytometry. Additionally, we analyzed T cells by assessing third-party antigens (Tetanus Diphtheria, TD)-reactive T cells, which could be analyzed by restimulation with tetanus vaccine.ResultsOverall, we found no significant alterations following LCPT conversion for the most immune cell populations with a few cell populations showing transient quantitative increase. Thus, 4 weeks after conversion, more regulatory T cells could be measured in the patients with a significant shift from memory to naïve Tregs. Furthermore, we found a transient B cell expansion 4 weeks after conversion from IR-Tac to LCPT. There were no changes in the percentage of other basic immune cell types and the antigen-reactive T cells were also not altered after changing the medication to LCP-tacrolimus.ConclusionHere, we demonstrate first insights into the immune system changes occurred under IR-Tac to LCPT conversion therapy in kidney transplant patients. While phenotypic and functional characteristics of the most immune cell populations did not change, we could observe an a transient expansion of regulatory T cells in peripheral blood following IR-Tac to LCTP conversion, which might additionally contribute to the overall immunosuppressive effect.

In a previous study, we showed an anti-inflammatory effect of propionic acid supplementation in dialysis patients. The present study intends to analyze the effect of propionic acid on the chronic inflammatory state and T-cell composition in kidney transplant patients compared to dialysis patients. A total of 10 dialysis patients and 16 kidney transplant patients under immunosuppressive standard triple immunosuppressive therapy received 2 × 500 mg propionic acid per day for 30 days. The cellular immune system was analyzed before and after the propionic acid supplementation and 30–90 days thereafter as a follow-up. We measured the main immune cell types and performed an in-depth characterization of T cells including regulatory T cells (Tregs), B cells, and dendritic cells. In addition, we assessed the functional activity and antigenic responsiveness by analysis of third-party antigen-specific T cells after their stimulation by recall (tetanus diphtheria vaccine) antigen. In dialysis patients, we observed an expansion of CD25highCD127− Tregs after propionic acid intake. In contrast, the same supplementation did not result in any expansion of Tregs in transplant patients under immunosuppressive therapy. We also did not observe any changes in the frequencies of the main immune cell subsets except for CD4+/CD8+ distribution with an increase of CD4+ T cells and decrease of CD8+ T cells in the transplant population. Our data suggest that dietary supplements containing propionate might have a beneficial effect decreasing systemic inflammation in dialysis patients through Treg expansion. However, this effect was not observed in transplant patients, which could be explained by counteracting effect of immunosuppressive drugs preventing Treg expansion.

XK disease is a very rare, multi-system disease, which can present with a wide spectrum of symptoms. This disorder can also be identified pre-symptomatically with the incidental detection of serological abnormalities when typing erythrocytes in peripheral blood, or on other routine laboratory testing. Increasing awareness of this disorder and improved access to genetic testing are resulting in increasing identification of affected patients and families. Here we provide updates to some previously-reported families and patients and provide additional clinical details. We also report four new cases with a variety of presentations, one of whom had a novel mutation.

Background: The prevalence of vitamin D deficiency and secondary hyperparathyroidism (sHPT) in adult Fontan patients remains unstudied, and the role of vitamin D and parathyroid hormone (PTH) levels in assessing heart and circulatory failure in these patients is unclear. Methods: We compared vitamin D deficiency and sHPT prevalence in adult Fontan patients (n = 35; mean age 33 ± 7.5 years) to adults with mild congenital heart disease (ACHD, n = 14). We analyzed associations between laboratory measurements, patient characteristics, and clinical events. Findings: Vitamin D deficiency was highly prevalent in both Fontan patients and ACHD controls (76.5 % vs. 71.4 %, p = 0.726). sHPT was exclusively present in Fontan patients (31.4 %). PTH levels correlated with NYHA class (r = 0.412), O2 saturation (r = −0.39), systemic ventricular function (r = 0.465), and NT-proBNP levels (r = 0.742). 25-hydroxyvitamin D showed an inverse correlation with NYHA class and systemic ventricular function (both r ≤ −0.38). Fontan patients with sHPT had a higher incidence of prior hospitalization for worsening heart failure and atrial arrhythmias compared to Fontan patients without HPT or ACHD controls. (Hospitalization: Fontan with HPT vs. Fontan without HPT: OR 5.46 [95 % CI 1.25–23.86], p = 0.021; arrhythmia: Fontan with HPT vs. Fontan without HPT: OR 1.96 [95 % CI 1.13–3.4], p = 0.035; ACHD: OR 11.45 [95 % CI 1.7–77.28], p=

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

Abstract Pyuria in dipstick examination serves as the most widespread screening tool for urinary tract infections (UTI). The absence of pyuria, however, does not exclude UTI. We investigated the diagnostic value of urinary calprotectin, a mediator protein of the innate immune system, which is released by leukocytes, for the detection of UTI and compared it with dipstick pyuria. Since even low numbers of leukocytes in the urine significantly increase urinary calprotectin concentrations, calprotectin might be a more sensitive marker than pyuria detected by dipstick. All 162 patients were prospectively included and underwent a urine dipstick, urine culture, quantification of proteinuria and determination of calprotectin in the urine. Urinary calprotectin was determined using an enzyme-linked immunosorbent assay (ELISA). UTI was defined as urine cultures with detection of one or a maximum of two uropathogenic bacteria with ≥ 105 colony-forming units per millilitre (CFU/ml). Exclusion criteria were acute kidney injury, chronic renal insufficiency and tumors of the urinary tract. 71 (43.8%) patients had a UTI. Of the 91 patients without UTI, 23 had a contamination and 19 had evidence of ≥ 105 CFU/ml considered to be asymptomatic bacteriuria. The median calprotectin concentration in patients with UTI and pyuria was significantly higher than in patients with UTI and without pyuria (5510.4 vs. 544.7 ng/ml). In ROC analyses, calprotectin revealed an area under the curve (AUC) of 0.70 for the detection of significant bacteriuria. Pyuria in dipstick examinations provided an AUC of 0.71. There was no significant difference between these AUCs in the DeLong test (p = 0.9). In patients with evidence of significant bacteriuria but without pyuria, a significantly higher calprotectin concentration was measured in the urine than in patients with neither pyuria nor UTI (544.7 ng/ml vs 95.6 ng/ml, p = 0.029). Urinary calprotectin is non-inferior to dipstick pyuria in the detection of UTI.

Abstract We present an in-depth analysis of axions and axion-like particles in top-pair production at the LHC. Our main goal is to probe the axion coupling to top quarks at high energies. To this end, we calculate the top-antitop cross section and differential distributions including ALP effects up to one-loop level. By comparing these predictions with LHC precision measurements, we constrain the top coupling of axion-like particles with masses below the top-antitop threshold. Our results apply to all UV completions of the ALP effective theory with dominant couplings to top quarks, in particular to DFSZ-like axion models.

Abstract Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Abstract Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.

Abstract Background Sulfur (S) is a mineral nutrient essential for plant growth and development, which is incorporated into diverse molecules fundamental for primary and secondary metabolism, plant defense, signaling, and maintaining cellular homeostasis. Although, S starvation response is well documented in the dicot model Arabidopsis thaliana, it is not clear if the same transcriptional networks control the response also in the monocots. Results We performed series of physiological, expression, and metabolite analyses in two model monocot species, one representing the C3 plants, Oryza sativa cv. kitaake, and second representing the C4 plants, Setaria viridis. Our comprehensive transcriptomic analysis revealed twice as many differentially expressed genes (DEGs) in S. viridis than in O. sativa under S-deficiency, consistent with a greater loss of sulfur and S-containing metabolites under these conditions. Surprisingly, most of the DEGs and enriched gene ontology terms were species-specific, with an intersect of only 58 common DEGs. The transcriptional networks were different in roots and shoots of both species, in particular no genes were down-regulated by S-deficiency in the roots of both species. Conclusions Our analysis shows that S-deficiency seems to have different physiological consequences in the two monocot species and their nutrient homeostasis might be under distinct control mechanisms.

Abstract Psychological flexibility plays a crucial role in how young adults adapt to their evolving cognitive and emotional landscapes. Our study investigated a core aspect of psychological flexibility in young adults: adaptive variability and maladaptive rigidity in the capacity for behavior change. We examined the interplay of these elements with cognitive-affective processes within a dynamic network, uncovering their manifestation in everyday life. Through an Ecological Momentary Assessment design, we collected intensive longitudinal data over 3 weeks from 114 young adults ages 19 to 32. Using a dynamic network approach, we assessed the temporal dynamics and individual variability in flexibility in relation to cognitive-affective processes in this sample. Rigidity exhibited the strongest directed association with other variables in the temporal network as well as highest strength centrality, demonstrating particularly strong associations to other variables in the contemporaneous network. In conclusion, the results of this study suggest that rigidity in young adults is associated with negative affect and cognitions at the same time point and the immediate future.