The RAPTOR/KOG1 proteins are binding partners of the target of rapamycin (TOR) kinase that is present in all eucaryotes and plays a central role in the stimulation of cell growth and metabolism in response to nutrients. We show in this report that two genes are coding for RAPTOR/KOG1 homologs in the Arabidopsis and rice genomes. Disruption of the Arabidopsis AtRaptor1 gene leads to a very early arrest of embryo development whereas disruption of the AtRaptor2 gene, which is expressed at a lower level than AtRaptor1, has no visible effects on embryo and plant development. We also observed that mutations in the AtRaptor1 gene result in an earlier halt of embryo development than disruption of the AtTor gene.

In type 2 diabetes mellitus (T2DM), little is known about hormonal responses to hypoglycemia. In particular, beta-cell responses to hypoglycemia have not been carefully investigated and potentially because of confounding factors or insufficient power, conflicting data have been obtained regarding growth hormone responses. We therefore compared hormonal responses including rates of insulin secretion during a 2-hour hyperinsulinemic hypoglycemic clamp in a relatively large number of nondiabetic (n=21) and moderately insulin-deficient subjects with T2DM (homeostasis model assessment of beta-cell function [HOMA-%B], 751+/-160 vs 1144+/-83 [pmol/L]/[mmol/L], P<.04) (n=14) matched for age, sex, and body mass index. Subjects with T2DM were excluded for antecedent hypoglycemia, and baseline glycemia was controlled by a variable infusion of insulin overnight. Although both groups of subjects had indistinguishable plasma glucose levels at baseline and virtually identical levels of plasma insulin and glucose throughout the hypoglycemic clamp, insulin secretion decreased more slowly in the subjects with T2DM. The time required for insulin secretion to decline to half its baseline level was markedly increased (38.9+/-4.9 vs 22.3+/-1.3 minutes [SD], P<.01), and insulin secretion decreased to a lesser extent (-0.79+/-0.17 vs -1.51+/-0.09 [pmol/L]/kg per minute, P<.002). Moreover, responses of glucagon (28.3+/-7.3 vs 52.8+/-7.0 ng/L, P<.05) and growth hormone (2.9+/-0.8 vs 6.3+/-0.9 ng/mL, P<.04) were reduced in the subjects with T2DM, whereas responses of epinephrine, norepinephrine, and cortisol were similar to those in nondiabetic subjects (all P>0.6). We conclude that multiple defects exist in hormonal responses to hypoglycemia in T2DM with moderate beta-cell failure. These include delayed and reduced decreases in insulin secretion, and impaired increases of plasma glucagon and growth hormone.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.

Arabidopsis thaliana cytosolic ribosomes are large complexes containing eighty-one distinct ribosomal proteins (r-proteins), four ribosomal RNAs (rRNA) and a plethora of associated (non-ribosomal) proteins. In plants, r-proteins of cytosolic ribosomes are each encoded by two to seven different expressed and similar genes, forming an r-protein family. Distinctions in the r-protein coding sequences of gene family members are a source of variation between ribosomes. We performed proteomic investigation of actively translating cytosolic ribosomes purified using both immunopurification and a classic sucrose cushion centrifugation-based protocol from plants of different developmental stages. Both 1D and 2D LC-MS(E) with data-independent acquisition as well as conventional data-dependent MS/MS procedures were applied. This approach provided detailed identification of 165 r-protein paralogs with high coverage based on proteotypic peptides. The detected r-proteins were the products of the majority (68%) of the 242 cytosolic r-protein genes encoded by the genome. A total of 70 distinct r-proteins were identified. Based on these results and information from DNA microarray and ribosome footprint profiling studies a re-annotation of Arabidopsis r-proteins and genes is proposed. This compendium of the cytosolic r-protein proteome will serve as a template for future investigations on the dynamic structure and function of plant ribosomes.

Background and Objectives: Selective pulmonary vein (PV) angiography has been established as the gold standard for PV visualization in cryoballoon (CB)-based pulmonary vein isolation (PVI). We sought to simplify this approach to reduce procedural complexity and radiation exposure. Materials and Methods: Patients with paroxysmal and recently diagnosed persistent AF undergoing CB-based PVI from January 2015 to December 2017 were retrospectively analyzed. Patients underwent either selective PV angiography or conventional left atrial (LA) angiography for PV visualization. Results: A total of 336 patients were analyzed. A total of 87 patients (26%) received PV angiography and 249 (74%) LA angiography. LA angiography required fewer cine-sequences for PV visualization, translating into a significant reduction in procedure duration, fluoroscopy time and dose area product. Additionally, less contrast medium was utilized. PV occlusion by the CB, CB temperature and time to isolation showed no significant differences. The number of CB applications and total application time (LA angiography: 1.4 ± 0.02 vs. PV Angiography: 1.6 ± 0.05; p < 0.0001; LA angiography: 297.9 ± 4.62 vs. PV-Angiography: 348.9 ± 11.03; p < 0.001, respectively) per vein were slightly but significantly higher in the PV angiography group. We observed no difference in late AF recurrence (24.7% LA angiography vs. 21.3% PV angiography; p = 0.2657). Conclusions: A simplified protocol, using LA angiography for PV visualization, entails a reduction in procedure time and radiation exposure while equally maintaining procedural efficiency and safety in both groups.

To predict depressive symptom severity and presence of major depression along the full alcohol use continuum.

To estimate mortality on grounds of the severity of alcohol dependence which has been assessed by two approaches: the frequency of alcohol dependence symptoms (FADS) and the number of alcohol dependence criteria (NADC).

Several studies point towards a role for dopaminergic circuits in the pathophysiology of problematic gambling behavior. The aim of the present study was to investigate alterations of DNA methylation in the dopamine D2 receptor (DRD2)-gene in participants with pathologic gambling behavior.

Particularly in groups of adolescents with lower educational level the smoking prevalence is still high and constitutes a serious public health problem. There is limited evidence of effective smoking cessation interventions in this group. Individualised text messaging (SMS) based interventions are promising to support smoking cessation and could be provided to adolescents irrespective of their motivation to quit. The aim of the current paper is to outline the study protocol of a trial testing the efficacy of an SMS based intervention for smoking cessation in apprentices.

Plants, unlike animals, have plastic organ growth that is largely dependent on environmental information. However, so far, little is known about how this information is perceived and transduced into coherent growth and developmental decisions. Here, we report that the growth of Arabidopsis is positively correlated with the level of expression of the TARGET OF RAPAMYCIN (TOR) kinase. Diminished or augmented expression of the AtTOR gene results in a dose-dependent decrease or increase, respectively, in organ and cell size, seed production and resistance to osmotic stress. Strong downregulation of AtTOR expression by inducible RNA interference also leads to a post-germinative halt in growth and development, which phenocopies the action of the plant hormone abscisic acid, to an early senescence and to a reduction in the amount of translated messenger RNA. Thus, we propose that the AtTOR kinase is one of the contributors to the link between environmental cues and growth processes in plants.

Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs).

Phrenic nerve injury (PNI) remains one of the most frequent complications during cryoballoon-based pulmonary vein isolation (CB-PVI). Since its introduction in 2013, the use of compound motor action potential (CMAP) for the prevention of PNI during CB-PVI is increasing; however, systematic outcome data are sparse.

General population data on associations between mental disorders and total mortality are rare. The aim was to analyze whether the number of mental disorders, single substance use, mood, anxiety, somatoform or eating disorders during the lifetime and whether treatment utilization may predict time to death 20 years later in the general adult population.

Atrial fibrillation (AF) is characterized by the repetitive regeneration of unstable rotational events, the pivot of which are known as phase singularities (PSs). The spatial concentration and distribution of PSs have not been systematically investigated using quantitative statistical approaches.

Right ventricular pacing (RVP) may cause electrical and mechanical desynchrony leading to impaired left ventricular ejection fraction (LVEF). We investigated the outcomes of RVP with His bundle pacing (HBP) and left bundle branch pacing (LBBP) for patients requiring a de novo permanent pacemaker (PPM) for bradyarrhythmia.

Deficient ankle control after incomplete spinal cord injury (iSCI) often accentuates walking impairments. Transcutaneous electrical spinal cord stimulation (tSCS) has been shown to augment locomotor activity after iSCI, presumably due to modulation of spinal excitability. However, the effects of possible excitability modulations induced by tSCS on ankle control have not yet been assessed. This study investigated the immediate (i.e., without training) effects during single-sessions of tonic tSCS on ankle control, spinal excitability, and locomotion in ten individuals with chronic, sensorimotor iSCI (American Spinal Injury Association Impairment Scale D). Participants performed rhythmic ankle movements (dorsi- and plantar flexion) at a given rate, and irregular ankle movements following a predetermined trajectory with and without tonic tSCS at 15 Hz, 30 Hz, and 50 Hz. In a subgroup of eight participants, the effects of tSCS on assisted over-ground walking were studied. Furthermore, the activity of a polysynaptic spinal reflex, associated with spinal locomotor networks, was investigated to study the effect of the stimulation on the dedicated spinal circuitry associated with locomotor function. Tonic tSCS at 30 Hz immediately improved maximum dorsiflexion by +4.6° ± 0.9° in the more affected lower limb during the rhythmic ankle movement task, resulting in an increase of +2.9° ± 0.9° in active range of motion. Coordination of ankle movements, assessed by the ability to perform rhythmic ankle movements at a given target rate and to perform irregular movements according to a trajectory, was unchanged during stimulation. tSCS at 30 Hz modulated spinal reflex activity, reflected by a significant suppression of pathological activity specific to SCI in the assessed polysynaptic spinal reflex. During walking, there was no statistical group effect of tSCS. In the subgroup of eight assessed participants, the three with the lowest as well as the one with the highest walking function scores showed positive stimulation effects, including increased maximum walking speed, or more continuous and faster stepping at a self-selected speed. Future studies need to investigate if multiple applications and individual optimization of the stimulation parameters can increase the effects of tSCS, and if the technique can improve the outcome of locomotor rehabilitation after iSCI.

Plants respond to oxygen deprivation by activating the expression of a set of hypoxia-responsive genes (HRGs). The master regulator of this process is a small group of transcription factors belonging to group VII of the ethylene response factors (ERF-VIIs). ERF-VIIs are highly unstable under aerobic conditions due to the continuous oxidation of their characteristic Cys residue at the N terminus by plant cysteine oxidases (PCOs). Under hypoxia, PCOs are inactive and the ERF-VIIs activate transcription of the HRGs required for surviving hypoxia. However, if the plant exposed to hypoxia has limited sugar reserves, the activity of ERF-VIIs is severely dampened. This suggests that oxygen sensing by PCO/ERF-VII is fine-tuned by another sensing pathway, related to sugar or energy availability. Here, we show that oxygen sensing by PCO/ERF-VII is controlled by the energy sensor target of rapamycin (TOR). Inhibition of TOR by genetic or pharmacological approaches leads to a much lower induction of HRGs. We show that two serine residues at the C terminus of RAP2.12, a major ERF-VII, are phosphorylated by TOR and are needed for TOR-dependent activation of transcriptional activity of RAP2.12. Our results demonstrate that oxygen and energy sensing converge in plants to ensure an appropriate transcription of genes, which is essential for surviving hypoxia. When carbohydrate metabolism is inefficient in producing ATP because of hypoxia, the lower ATP content reduces TOR activity, thus attenuating the efficiency of induction of HRGs by the ERF-VIIs. This homeostatic control of the hypoxia-response is required for the plant to survive submergence.

A quantitative framework to summarize and explain the quasi-stationary population dynamics of unstable phase singularities (PS) and wavelets in human atrial fibrillation (AF) is at present lacking. Building on recent evidence showing that the formation and destruction of PS and wavelets in AF can be represented as renewal processes, we sought to establish such a quantitative framework, which could also potentially provide insight into the mechanisms of spontaneous AF termination.

Dynamic contacts are formed between endoplasmic reticulum (ER) and mitochondria that enable the exchange of calcium and phospholipids. Disturbed contacts between ER and mitochondria impair mitochondrial dynamics and are a molecular hallmark of Parkinson's disease, which is also characterized by impaired complex I activity and dopaminergic neuron degeneration. Here, we analyzed the role of cysteine-rich with EGF-like domain (Creld), a poorly characterized risk gene for Parkinson's disease, in the regulation of mitochondrial dynamics and function. We found that loss of Creld leads to mitochondrial hyperfusion and reduced ROS signaling in Drosophila melanogaster, Xenopus tropicalis, and human cells. Creld fly mutants show differences in ER-mitochondria contacts and reduced respiratory complex I activity. The resulting low-hydrogen peroxide levels are linked to disturbed neuronal activity and lead to impaired locomotion, but not neurodegeneration, in Creld mutants. We conclude that Creld regulates ER-mitochondria communication and thereby hydrogen peroxide formation, which is required for normal neuron function.

Mortality is predicted by the sum of behavior-related health risk factors (BRFs: tobacco smoking, alcohol drinking, body overweight, and physical inactivity). We analyzed degrees and combinations of BRFs in their relation to mortality and adjusted for mental disorders. In a random sample of the general population in northern Germany aged 18-64, BRFs and mental disorders had been assessed in 1996-1997 by the Munich Composite International Diagnostic Interview. A sum score including eight ranks of the behavior-related health risk factors was built. Death and its causes were ascertained 2017-2018 using residents' registration files and death certificates. Relations of the sum score and combinations of the BRFs at baseline with all-cause, cancer, and cardiovascular mortality 20 years later were analyzed. The sum score and combinations predicted all-cause, cardiovascular and cancer mortality. The odds ratio of the sum score was 1.38 (95% confidence interval 1.31-1.46) after adjustment for age, gender, and mental disorder. In addition to the BRFs, mood, anxiety or somatoform disorders were not related to mortality. We concluded that the sum score and combinations of behavior-related health risk factors predicted mortality, even after adjustment for mental disorders.