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Plant phenology, i. e. the timing of life cycle events, is related to individual fitness and species distribution ranges. Temperature is one of the most important drivers of plant phenology together with day length. The adaptation of their phenology may be important for the success of invasive plant species. The present study aims at understanding how the performance and the phenology of the invasive legume Lupinus polyphyllus vary with latitude. We sampled data across a >2000 km latitudinal gradient from Central to Northern Europe. We quantified variation in phenology of flowering and fruiting of L. polyphyllus using >1600 digital photos of inflorescences from 220 individual plants observed weekly at 22 sites. The day of the year at which different phenological phases were reached, increased 1.3–1.8 days per degree latitude, whereas the growing degree days (gdd) required for these phenological phases decreased 5–16 gdd per degree latitude. However, this difference disappeared, when the day length of each day included in the calculation of gdd was considered. The day of the year of the earliest and the latest climatic zone to reach any of the three studied phenological phases differed by 23–30 days and temperature requirements to reach these stages differed between 62 and 236 gdd. Probably, the invasion of this species will further increase in the northern part of Europe over the next decades due to climate warming. For invasive species control, our results suggest that in countries with a large latitudinal extent, the mowing date should shift by ca. one week per 500 km at sites with similar elevations.

Abstract We revisit the generation of a matter-antimatter asymmetry in the minimal extension of the Standard Model with two singlet heavy neutral leptons (HNL) that can explain neutrino masses. We derive an accurate analytical approximation to the solution of the complete linearized set of kinetic equations, which exposes the non-trivial parameter dependencies in the form of parameterization-independent CP invariants. The identification of various washout regimes relevant in different regions of parameter space sheds light on the relevance of the mass corrections in the interaction rates and clarifies the correlations of baryogenesis with other observables. In particular, by requiring that the measured baryon asymmetry is reproduced, we derive robust upper or lower bounds on the HNL mixings depending on their masses, and constraints on their flavour structure, as well as on the CP-violating phases of the PMNS mixing matrix, and the amplitude of neutrinoless double-beta decay. We also find certain correlations between low and high scale CP phases. Especially emphasizing the testable part of the parameter space we demonstrate that our findings are in very good agreement with numerical results. The methods developed in this work can help in exploring more complex scenarios.

Abstract Background Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential. Methods We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592). Results Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model. Conclusion Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Diabetes mellitus (DM) is an independent risk factor for micro- and macrovascular complications such as nephropathy and atherosclerosis respectively, which are the major causes of premature morbidity and mortality in Type 1 and Type 2 diabetic patients. Endothelial dysfunction is the critical first step of vascular disease and is characterized by reduced bioavailability of the essential endothelial vasodilator, nitric oxide (NO), coupled with an elevation in inflammation and oxidative stress. A novel pathway to bolster NO activity is to upregulate soluble guanylate cyclase (sGC), an enzyme responsible for mediating the protective actions of NO. Two classes of sGC modulators exist, activators and stimulators, with differing sensitivity to oxidative stress. In this study, we investigated the therapeutic effects of the sGC stimulator BAY 41-2272 (Bay 41) and the sGC activator BAY 60-2770 (Bay 60) on endpoints of atherosclerosis and renal disease as well as inflammation and oxidative stress in diabetic Apolipoprotein E knockout (ApoE-/-) mice. We hypothesized that under oxidative conditions known to accompany diabetes, sGC activation might be more efficacious than sGC stimulation in limiting diabetic vascular complications. We demonstrate that Bay 60 not only significantly decreased nitrotyrosine staining (P

ObjectiveAcyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far.Design/methodsSerum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate.ResultsMedian [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p

Experiments in a tunable graphene superlattice show that the unusual 1/B periodic resistance oscillations at high temperatures in the energy spectrum of electrons in a 2D periodic potential, known as the Hofstadter butterfly, coexist with oscillations due to commensurability between the electron cyclotron radius and the superlattice’s period.

Abstract Successful therapy of heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical need. Device-based treatment approaches include the interatrial shunt device (IASD), conventional assist devices pumping blood from the left ventricle (LV-VAD) or the left atrium (LA-VAD) towards the aorta, and a valveless pulsatile assist device with a single cannula operating in co-pulsation with the native heart (CoPulse). Hemodynamics of two HFpEF subgroups during rest and exercise condition were translated into a lumped parameter model of the cardiovascular system. The numerical model was applied to assess the hemodynamic effect of each of the four device-based therapies. All four therapy options show a reduction in left atrial pressure during rest and exercise and in both subgroups (> 20%). IASDs concomitantly reduce cardiac output (CO) and shift the hemodynamic overload towards the pulmonary circulation. All three mechanical assist devices increase CO while reducing sympathetic activity. LV-VADs reduce end-systolic volume, indicating a high risk for suction events. The heterogeneity of the HFpEF population requires an individualized therapy approach based on the underlying hemodynamics. Whereas phenotypes with preserved CO may benefit most from an IASD device, HFpEF patients with reduced CO may be candidates for mechanical assist devices.

Abstract Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness.

Abstract In the present work, the influence of increasing brick scrap additions on the setting behavior and material properties of fly ash‐based geopolymers is investigated. The geopolymers produced are tested for their compressive strengths, bulk densities, and thermal conductivities, among other properties. Both the starting materials and the produced geopolymers are also investigated by infrared spectroscopy, X‐ray diffraction analysis, and scanning electron microscopy to show the relationship between the solidification behavior and the resulting material properties. The investigations show that brick scrap is very suitable as a matrix material for geopolymer production. Increasing brick scrap additions lead, among other things, to a reduction in bulk density, thermal conductivity and compressive strength.

Abstract Background Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. Objective To analyze systematically the CSF profile in COVID-19. Methods Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers Results The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72–50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3–240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF l-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2–4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. Conclusions The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and ‘long COVID’. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.

Coronary artery bypass grafting (CABG) is the most frequently performed cardiac surgery worldwide. The reported incidence of graft failure ranges between 10% and 50%, depending upon the type of conduit used. Thrombosis is the predominant mechanism of early graft failure, occurring in both arterial and vein grafts. Significant advances have been made in the field of antithrombotic therapy since the introduction of aspirin, which is regarded as the cornerstone of antithrombotic therapy for prevention of graft thrombosis. Convincing evidence now exists that dual antiplatelet therapy (DAPT), consisting of aspirin and a potent oral P2Y12 inhibitor, effectively reduces the incidence of graft failure. However, this is achieved at the expense of an increase in clinically important bleeding, underscoring the importance of balancing thrombotic risk and bleeding risk when considering antithrombotic therapy after CABG. In contrast, anticoagulant therapy has proved ineffective at reducing the occurrence of graft thrombosis, pointing to platelet aggregation as the key driver of graft thrombosis. We provide a comprehensive review of current practice for prevention of graft thrombosis and discuss potential future concepts for antithrombotic therapy including P2Y12 inhibitor monotherapy and short-term DAPT.

The complex mechanism by which stress can affect sensory processes such as hearing is still poorly understood. In a previous study, the mineralocorticoid (MR) and/or glucocorticoid receptor (GR) were deleted in frontal brain regions but not cochlear regions using a CaMKIIα-based tamoxifen-inducible CreERT2/loxP approach. These mice exhibit either a diminished (MRTMXcKO) or disinhibited (GRTMXcKO) auditory nerve activity. In the present study, we observed that mice differentially were (MRTMXcKO) or were not (GRTMXcKO) able to compensate for altered auditory nerve activity in the central auditory pathway. As previous findings demonstrated a link between central auditory compensation and memory-dependent adaptation processes, we analyzed hippocampal paired-pulse facilitation (PPF) and long-term potentiation (LTP). To determine which molecular mechanisms may impact differences in synaptic plasticity, we analyzed Arc/Arg3.1, known to control AMPA receptor trafficking, as well as regulators of tissue perfusion and energy consumption (NO-GC and GC-A). We observed that the changes in PPF of MRTMXcKOs mirrored the changes in their auditory nerve activity, whereas changes in the LTP of MRTMXcKOs and GRTMXcKOs mirrored instead the changes in their central compensation capacity. Enhanced GR expression levels in MRTMXcKOs suggest that MRs typically suppress GR expression. We observed that hippocampal LTP, GC-A mRNA expression levels, and ABR wave IV/I ratio were all enhanced in animals with elevated GR (MRTMXcKOs) but were all lower or not mobilized in animals with impaired GR expression levels (GRTMXcKOs and MRGRTMXcKOs). This suggests that GC-A may link LTP and auditory neural gain through GR-dependent processes. In addition, enhanced NO-GC expression levels in MR, GR, and MRGRTMXcKOs suggest that both receptors suppress NO-GC; on the other hand, elevated Arc/Arg3.1 levels in MRTMXcKOs and MRGRTMXcKOs but not GRTMXcKOs suggest that MR suppresses Arc/Arg3.1 expression levels. Conclusively, MR through GR inhibition may define the threshold for hemodynamic responses for LTP and auditory neural gain associated with GC-A.

Sixteen months after the January 30, 2020 declaration by the World Health Organization of a Public Health Emergency of International Concern regarding the spread of COVID-19, SARS-CoV-2 had infected ~ 170 million humans worldwide of which > 3.5 million had died. We critically examine information on the virus origin, when and where the first human cases occurred, and point to differences between Chinese and later clinical presentations. The official patient Zero was hospitalized in Wuhan, Hubei province, China, on December 8, 2019, but retrospective analyses demonstrate prior viral circulation. Coronaviruses are present in mammals and birds, but whether a wild animal (e.g. bat, pangolin) was the source of the human pandemic remains disputed. We present two contamination models, the spillover versus the circulation model; the latter brings some interesting hypotheses about previous SARS-CoV-2 virus circulation in the human population. The age distribution of hospitalized COVID-19 patients at the start of the epidemic differed between China and the USA–EU; Chinese hospitalized patients were notably younger. The first Chinese publications did not describe anosmia-dysgeusia, a cardinal symptom of COVID-19 in Europe and USA. The prominent endothelial involvement linked with thrombotic complications was discovered later. These clinical discrepancies might suggest an evolution of the virus.

Aim:: Examine how innate bladder contractility and corresponding receptor expression was affected by chronic prostatitis (CP) and how treatment with the soluble guanylate cyclase (sGC) activator BAY 60-2770 influenced this. Methods:: To create a functional model for CP, 24 male Sprague-Dawley rats were intraprostatically injected with either zymosan or saline, serving as control. After a recovery period, the rats were treated with either BAY 60-2770 or dimethyl sulfoxide (DMSO; vehicle) on days 8–20. Urine samples were collected for measurement of ATP. On day 21, the bladder was excised and contractile responses to electrical field stimulation (EFS), methacholine, ATP and nitric oxide (NO) were examined in an in vitro organ bath. Subsequently, the expression of purinergic (P2X1 & P2X3) and muscarinic (M3) receptors as well as sGC was examined immunohistochemically. Results:: Induction of CP led to significantly attenuated purinergic bladder contractions, which were normalized by treatment with BAY 60-2770. Induction of CP did not alter the contractile bladder responses to EFS, methacholine or NO. However, treatment with BAY 60-2770 led to significantly increased contractile bladder responses to EFS and MeCh and significantly enhanced relaxatory nitrergic responses. There were no significant differences between the groups regarding purinergic or cholinergic receptor expression, however treatment with BAY 60-2770 led to attenuated expression of sGC in the urothelium. Conclusion:: Taken together, these findings indicate that drugs targeting the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway may be a promising option to restore alterations in bladder contractility that arise due to CP.

The emergence and global spread of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is critical to understanding how to prevent or control a future viral pandemic. We review the tools used for this retrospective search, their limits, and results obtained from China, France, Italy and the USA. We examine possible scenarios for the emergence of SARS-CoV-2 in the human population. We consider the Chinese city of Wuhan where the first cases of atypical pneumonia were attributed to SARS-CoV-2 and from where the disease spread worldwide. Possible superspreading events include the Wuhan-based 7th Military World Games on October 18–27, 2019 and the Chinese New Year holidays from January 25 to February 2, 2020. Several clues point to an early regional circulation of SARS-CoV-2 in northern Italy (Lombardi) as soon as September/October 2019 and in France in November/December 2019, if not before. With the goal of preventing future pandemics, we call for additional retrospective studies designed to trace the origin of SARS-CoV-2.

Summary: Background: Glycans play essential functional roles in the nervous system and their pathobiological relevance has become increasingly recognized in numerous brain disorders, but not fully explored in traumatic brain injury (TBI). We investigated longitudinal glycome patterns in patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) to characterize glyco-biomarker signatures and their relation to clinical features and long-term outcome. Methods: This prospective single-center observational study included 51 adult patients with TBI (GCS ≤12) admitted to the neurosurgical unit of the University Hospital of Pecs, Pecs, Hungary, between June 2018 and April 2019. We used a high-throughput liquid chromatography–tandem mass spectrometry platform to assess serum levels of N-glycans up to 3 days after injury. Outcome was assessed using the Glasgow Outcome Scale-Extended (GOS-E) at 12 months post-injury. Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, were used to analyze glycomics data and define highly influential structures driving class distinction. Receiver operating characteristic analyses were used to determine prognostic accuracy. Findings: We identified 94 N-glycans encompassing all typical structural types, including oligomannose, hybrid, and complex-type entities. Levels of high mannose, hybrid and sialylated structures were temporally altered (p

BackgroundThe advance of the COVID-19 pandemic and spread of SARS-CoV-2 around the world has generated the emergence of new genomic variants. Those variants with possible clinical and therapeutic implications have been classified as variants of concern (VOCs) and variants of interest (VOIs).ObjectiveThis study aims to describe the COVID-19 pandemic and build the evolutionary and demographic dynamics of SARS-CoV-2 populations in Mexico, with emphasis on VOCs.Methods30,645 complete genomes of SARS-CoV-2 from Mexico were obtained from GISAID databases up to January 25, 2022. A lineage assignment and phylogenetic analysis was completed, and demographic history for Alpha, Gamma, Delta and Omicron VOCs, and the Mexican variant (B.1.1.519) was performed.Results148 variants were detected among the 30,645 genomes analyzed with the Delta variant being the most prevalent in the country, representing 49.7% of all genomes.ConclusionThe COVID-19 pandemic in Mexico was caused by several introductions of SARS-CoV-2, mainly from the United States of America and Europe, followed by local transmission. Regional molecular epidemiological surveillance must implement to detect emergence, introductions and spread of new variants with biologically important mutations.