Where is my sink? Reconstruction of landscape development in 1 southwestern Africa since the Late Jurassic

Quantifying the rates and timing of landscape denudation provides a means to constrain sediment flux through time to offshore sedimentary basins. The Late Mesozoic evolution of drainage basins in southern Africa is poorly constrained despite the presence of several onshore and offshore sedimentary basins. A novel approach has been developed to calculate the volume of material eroded since the Late Jurassic at different time steps by constructing structural cross-sections and extrapolating thicknesses of eroded material. Using different assumptions, the calculated volumes of material eroded from southwestern Africa range from 2.52x10⁶ km³ (11.3 km of vertical thickness removed) to 8.87 x10⁵ km³ (4.0 km of vertical thickness removed). For the southward draining systems alone, the calculated removal of 7.81 x10⁵ – 2.60 x10⁵ km³ of material is far greater than the volumes of sediment recorded in offshore sedimentary basins (268 500 km³). Reconstruction of the drainage systems using geomorphic indicators and clast provenance of the Uitenhage Group, as well as extrapolated surface exposure ages, indicate the southern draining systems were active from the Late Jurassic with coeval activity in axial and transverse drainage systems. The calculated volumes are tied to published apatite fission track (AFT) dates to constrain the changes in exhumation rate through time (using multiple scenarios), which indicate a significant amount of Early Cretaceous exhumation (up to 1.26 x10⁶ km³, equivalent to 5.70km of vertical thickness). For the first time, this has permitted long-term landscape evolution to be used to support the interpretation that some of the ‘missing’ sediment was deposited in sedimentary basins on the Falkland Plateau as it moved past southern Africa during the Early Cretaceous. This implies that in this instance, the sinks are separated from their source areas by ~6000 km

Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction

Aims: Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short‐term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH). Methods and results: Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta‐analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post‐IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta‐analysis Global Group in Chronic Heart Failure score‐predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD‐treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan–Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload‐corrected exercise pulmonary capillary wedge pressure at the 6 months post‐IASD study were associated with HFH. Conclusions: The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large‐scale ongoing randomized studies are required to confirm the potential benefit of this therapy

Sensory Electrical Stimulation Improves Foot Placement during Targeted Stepping Post-Stroke

Proper foot placement is vital for maintaining balance during walking, requiring the integration of multiple sensory signals with motor commands. Disruption of brain structures post-stroke likely alters the processing of sensory information by motor centers, interfering with precision control of foot placement and walking function for stroke survivors. In this study, we examined whether somatosensory stimulation, which improves functional movements of the paretic hand, could be used to improve foot placement of the paretic limb. Foot placement was evaluated before, during, and after application of somatosensory electrical stimulation to the paretic foot during a targeted stepping task. Starting from standing, twelve chronic stroke participants initiated movement with the non-paretic limb and stepped to one of five target locations projected onto the floor with distances normalized to the paretic stride length. Targeting error and lower extremity kinematics were used to assess changes in foot placement and limb control due to somatosensory stimulation. Significant reductions in placement error in the medial–lateral direction (p = 0.008) were observed during the stimulation and post-stimulation blocks. Seven participants, presenting with a hip circumduction walking pattern, had reductions (p = 0.008) in the magnitude and duration of hip abduction during swing with somatosensory stimulation. Reductions in circumduction correlated with both functional and clinical measures, with larger improvements observed in participants with greater impairment. The results of this study suggest that somatosensory stimulation of the paretic foot applied during movement can improve the precision control of foot placement

The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor-driven inflammation.</p

Design principles for riboswitch function

Scientific and technological advances that enable the tuning of integrated regulatory components to match network and system requirements are critical to reliably control the function of biological systems. RNA provides a promising building block for the construction of tunable regulatory components based on its rich regulatory capacity and our current understanding of the sequence–function relationship. One prominent example of RNA-based regulatory components is riboswitches, genetic elements that mediate ligand control of gene expression through diverse regulatory mechanisms. While characterization of natural and synthetic riboswitches has revealed that riboswitch function can be modulated through sequence alteration, no quantitative frameworks exist to investigate or guide riboswitch tuning. Here, we combined mathematical modeling and experimental approaches to investigate the relationship between riboswitch function and performance. Model results demonstrated that the competition between reversible and irreversible rate constants dictates performance for different regulatory mechanisms. We also found that practical system restrictions, such as an upper limit on ligand concentration, can significantly alter the requirements for riboswitch performance, necessitating alternative tuning strategies. Previous experimental data for natural and synthetic riboswitches as well as experiments conducted in this work support model predictions. From our results, we developed a set of general design principles for synthetic riboswitches. Our results also provide a foundation from which to investigate how natural riboswitches are tuned to meet systems-level regulatory demands

Therapeutic suggestion helps to cut back on drug intake for mechanically ventilated patients in intensive care unit

Research was conducted on ventilated patients treated in an intensive care unit (ICU) under identical circumstances; patients were divided into two groups (subsequently proved statistically identical as to age and Simplified Acute Physiology Score II [SAPS II]). One group was treated with positive suggestions for 15-20 min a day based on a predetermined scheme, but tailored to the individual patient, while the control group received no auxiliary psychological treatment. Our goal was to test the effects of positive communication in this special clinical situation. In this section of the research, the subsequent data collection was aimed to reveal whether any change in drug need could be demonstrated upon the influence of suggestions as compared to the control group. Owing to the strict recruitment criteria, a relatively small sample (suggestion group n = 15, control group n = 10) was available during the approximately nine-month period of research. As an outcome of suggestions, there was a significant drop in benzodiazepine (p < 0.005), opioid (p < 0.001), and the α2-agonist (p < 0.05) intake. All this justifies the presence of therapeutic suggestions among the therapies used in ICUs. However, repeating the trial on a larger sample of patients would be recommended. © 2013 Akadémiai Kiadó, Budapest

Entrepreneurs’ age, institutions, and social value creation goals: a multi-country study

This study explores the relationship between an entrepreneur's age and his/her social value creation goals. Building on the lifespan developmental psychology literature and institutional theory, we hypothesize a U-shaped relationship between entrepreneurs’ age and their choice to create social value through their ventures, such that younger and older entrepreneurs create more social value with their businesses while middle age entrepreneurs are relatively more economically and less socially oriented with their ventures. We further hypothesize that the quality of a country’s formal institutions in terms of economic, social, and political freedom steepen the U-shaped relationship between entrepreneurs’ age and their choice to pursue social value creation as supportive institutional environments allow entrepreneurs to follow their age-based preferences. We confirm our predictions using multilevel mixed-effects linear regressions on a sample of over 15,000 entrepreneurs (aged between 18 and 64 years) in 45 countries from Global Entrepreneurship Monitor data. The findings are robust to several alternative specifications. Based on our findings, we discuss implications for theory and practice, and we propose future research directions

Ulk4 regulates GABAergic signaling and anxiety-related behavior

Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4(+/tm1a) mice, demonstrating that Ulk4(+/tm1a) mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4(+/tm1a) mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67⁺ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4(+/tm1a) mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3&gt;2.1×10-12¿¿s/eV at 90% C.L

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT