Concept: Necessary and sufficient condition
Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle.
Short Vacation Improves Stress-Level and Well-Being in German-Speaking Middle-Managers-A Randomized Controlled Trial
- International journal of environmental research and public health
- Published over 2 years ago
Stress in the work place has a detrimental effect on people’s health. Sufficient recovery is necessary to counteract severe chronic negative load reactions. Previous research has shown that vacationing for at least seven consecutive days provided an efficient recovery strategy. Yet, thus far, the effects of short vacations and the mode of vacation (whether at home or in a new environment) have rarely been studied. We investigated the immediate and long-term effects of a short vacation (four nights) on well-being and perceived stress and whether the mode of vacation impacted on these results. Data was obtained from 40 middle managers (67.5% men and 32.5% women). The intervention group (n = 20) spent a short vacation in a hotel outside their usual environment. The control group (n = 20) spent their vacation at home. Results indicated that one single short-term vacation, independent of the mode, has large, positive and immediate effects on perceived stress, recovery, strain, and well-being. Strain levels decreased to a greater extent in the intervention group compared to the control group. The effects can still be detected at 30 days (recovery) and 45 days (well-being and strain) post-vacation. Encouraging middle management employees to take short vacations seems to be an efficient health promotion strategy; environmental effects seem to play a minor role.
Mechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury in mice. Mice in which TrkB-Cre-expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB-positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.
Recognizing the intention of others is important in all social interactions, especially in the service domain. Enabling a bartending robot to serve customers is particularly challenging as the system has to recognize the social signals produced by customers and respond appropriately. Detecting whether a customer would like to order is essential for the service encounter to succeed. This detection is particularly challenging in a noisy environment with multiple customers. Thus, a bartending robot has to be able to distinguish between customers intending to order, chatting with friends or just passing by. In order to study which signals customers use to initiate a service interaction in a bar, we recorded real-life customer-staff interactions in several German bars. These recordings were used to generate initial hypotheses about the signals customers produce when bidding for the attention of bar staff. Two experiments using snapshots and short video sequences then tested the validity of these hypothesized candidate signals. The results revealed that bar staff responded to a set of two non-verbal signals: first, customers position themselves directly at the bar counter and, secondly, they look at a member of staff. Both signals were necessary and, when occurring together, sufficient. The participants also showed a strong agreement about when these cues occurred in the videos. Finally, a signal detection analysis revealed that ignoring a potential order is deemed worse than erroneously inviting customers to order. We conclude that (a) these two easily recognizable actions are sufficient for recognizing the intention of customers to initiate a service interaction, but other actions such as gestures and speech were not necessary, and (b) the use of reaction time experiments using natural materials is feasible and provides ecologically valid results.
Clostridium difficile disease has recently increased to become a dominant nosocomial pathogen in North America and Europe, although little is known about what has driven this emergence. Here we show that two epidemic ribotypes (RT027 and RT078) have acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose. RT027 strains contain a single point mutation in the trehalose repressor that increases the sensitivity of this ribotype to trehalose by more than 500-fold. Furthermore, dietary trehalose increases the virulence of a RT027 strain in a mouse model of infection. RT078 strains acquired a cluster of four genes involved in trehalose metabolism, including a PTS permease that is both necessary and sufficient for growth on low concentrations of trehalose. We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence.
The brain regulates food intake by processing sensory cues and peripheral physiological signals, but the neural basis of this integration remains unclear. Hypothalamic, agouti-related protein (AgRP)-expressing neurons are critical regulators of food intake. AgRP neuron activity is high during hunger and is rapidly reduced by the sight and smell of food. Here, we reveal two distinct components of AgRP neuron activity regulation: a rapid but transient sensory-driven signal and a slower, sustained calorie-dependent signal. We discovered that nutrients are necessary and sufficient for sustained reductions in AgRP neuron activity and that activity reductions are proportional to the calories obtained. This change in activity is recapitulated by exogenous administration of gut-derived satiation signals. Furthermore, we showed that the nutritive value of food trains sensory systems-in a single trial-to drive rapid, anticipatory AgRP neuron activity inhibition. Together, these data demonstrate that nutrients are the primary regulators of AgRP neuron activity.
A central question in Alzheimer’s Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.
Clathrin-mediated endocytosis (CME) is the major route of receptor internalization at the plasma membrane. Analysis of constitutive CME is difficult because the initiation of endocytic events is unpredictable. When and where a clathrin-coated pit will form and what cargo it will contain are difficult to foresee. Here we describe a series of genetically encoded reporters that allow the initiation of CME on demand. A clathrin-binding protein fragment (“hook”) is inducibly attached to an “anchor” protein at the plasma membrane, which triggers the formation of new clathrin-coated vesicles. Our design incorporates temporal and spatial control by the use of chemical and optogenetic methods for inducing hook-anchor attachment. Moreover, the cargo is defined. Because several steps in vesicle creation are bypassed, we term it “hot-wiring.” We use hot-wired endocytosis to describe the functional interactions between clathrin and AP2. Two distinct sites on the β2 subunit, one on the hinge and the other on the appendage, are necessary and sufficient for functional clathrin engagement.
AMPK exerts prolongevity effects in diverse species; however, the tissue-specific mechanisms involved are poorly understood. Here, we show that upregulation of AMPK in the adult Drosophila nervous system induces autophagy both in the brain and also in the intestinal epithelium. Induction of autophagy is linked to improved intestinal homeostasis during aging and extended lifespan. Neuronal upregulation of the autophagy-specific protein kinase Atg1 is both necessary and sufficient to induce these intertissue effects during aging and to prolong the lifespan. Furthermore, upregulation of AMPK in the adult intestine induces autophagy both cell autonomously and non-cell-autonomously in the brain, slows systemic aging, and prolongs the lifespan. We show that the organism-wide response to tissue-specific AMPK/Atg1 activation is linked to reduced insulin-like peptide levels in the brain and a systemic increase in 4E-BP expression. Together, these results reveal that localized activation of AMPK and/or Atg1 in key tissues can slow aging in a non-cell-autonomous manner.
Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin’s behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans.