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Sleep is a universal phenomenon necessary for maintaining homeostasis and function across a range of organs. Lack of sleep has severe health-related consequences affecting whole-body functioning, yet no other organ is as severely affected as the brain. The neurophysiological mechanisms underlying these deficits are poorly understood. Here, we characterize the dynamic changes in brain connectivity profiles inflicted by sleep deprivation and how they deviate from regular daily variability. To this end, we obtained functional magnetic resonance imaging data from 60 young, adult male participants, scanned in the morning and evening of the same day and again the following morning. 41 participants underwent total sleep deprivation before the third scan, whereas the remainder had another night of regular sleep. Sleep deprivation strongly altered the connectivity of several resting-state networks, including dorsal attention, default mode, and hippocampal networks. Multivariate classification based on connectivity profiles predicted deprivation state with high accuracy, corroborating the robustness of the findings on an individual level. Finally, correlation analysis suggested that morning-to-evening connectivity changes were reverted by sleep (control group)—a pattern which did not occur after deprivation. We conclude that both, a day of waking and a night of sleep deprivation dynamically alter the brain functional connectome. •We scanned 60 participants in the morning, evening and next morning.•N=41 were sleep deprived before the third scan, N=19 had a night of regular sleep.•Sleep deprivation strongly altered functional brain connectivity.•Diurnal connectivity changes reversed after sleep, but not after deprivation.•Diurnal and deprivation-induced connectivity alterations were reliably classified.

Elucidating the neurobiological effects of sleep and wake is an important goal of the neurosciences. Whether and how human cerebral blood flow (CBF) changes during the sleep-wake cycle remain to be clarified. Based on the synaptic homeostasis hypothesis of sleep and wake, we hypothesized that a day of wake and a night of sleep deprivation would be associated with gray matter resting CBF (rCBF) increases and that sleep would be associated with rCBF decreases. Thirty-eight healthy adult males (age 22.1 ± 2.5 years) underwent arterial spin labeling perfusion magnetic resonance imaging at three time points: in the morning after a regular night's sleep, the evening of the same day, and the next morning, either after total sleep deprivation (n = 19) or a night of sleep (n = 19). All analyses were adjusted for hematocrit and head motion. rCBF increased from morning to evening and decreased after a night of sleep. These effects were most prominent in bilateral hippocampus, amygdala, thalamus, and in the occipital and sensorimotor cortices. Group × time interaction analyses for evening versus next morning revealed significant interaction in bilateral lateral and medial occipital cortices and in bilateral insula, driven by rCBF increases in the sleep deprived individuals and decreases in the sleepers, respectively. Furthermore, group × time interaction analyses for first morning versus next morning showed significant effects in medial and lateral occipital cortices, in anterior cingulate gyrus, and in the insula, in both hemispheres. These effects were mainly driven by CBF increases from TP1 to TP3 in the sleep deprived individuals. There were no associations between the rCBF changes and sleep characteristics, vigilant attention, or subjective sleepiness that remained significant after adjustments for multiple analyses. Altogether, these results encourage future studies to clarify mechanisms underlying sleep-related rCBF changes. •How cerebral blood flow changes during the sleep-wake cycle remains to be clarified.•We examined cerebral blood flow after wake, sleep, and sleep deprivation.•There were morning-to-evening increases in cerebral blood flow.•These changes were reversed by a night of sleep.•A night of sleep deprivation was associated with further cerebral blood flow increases.

Elucidating the neurobiological effects of sleep and waking remains an important goal of the neurosciences. Recently, animal studies indicated that sleep is important for cell membrane and myelin maintenance in the brain and that these structures are particularly susceptible to insufficient sleep. Here, we tested the hypothesis that a day of waking and sleep deprivation would be associated with changes in diffusion tensor imaging (DTI) indices of white matter microstructure sensitive to axonal membrane and myelin alterations. Twenty-one healthy adult males underwent DTI in the morning [7:30AM; time point (TP)1], after 14 hours of waking (TP2), and then after another 9 hours of waking (TP3). Whole brain voxel-wise analysis was performed with tract based spatial statistics. A day of waking was associated with widespread increases in white matter fractional anisotropy, which were mainly driven by radial diffusivity reductions, and sleep deprivation was associated with widespread fractional anisotropy decreases, which were mainly explained by reductions in axial diffusivity. In addition, larger decreases in axial diffusivity after sleep deprivation were associated with greater sleepiness. All DTI changes remained significant after adjusting for hydration measures. This is the first DTI study of sleep deprivation in humans. Although previous studies have observed localized changes in DTI indices of cerebral microstructure over the course of a few hours, further studies are needed to confirm widespread DTI changes within hours of waking and to clarify whether such changes in white matter microstructure serve as neurobiological substrates of sleepiness.

Heart rate variability (HRV) has become an increasingly popular index of cardiac autonomic control in the biobehavioral sciences due to its relationship with mental illness and cognitive traits. However, the intraindividual stability of HRV in response to sleep and diurnal disturbances, which are commonly reported in mental illness, and its relationship with executive function are not well understood. Here, in 40 healthy adult males we calculated high frequency HRV-an index of parasympathetic nervous system (PNS) activity-using pulse oximetry during brain imaging, and assessed attentional and executive function performance in a subsequent behavioral test session at three time points: morning, evening, and the following morning. Twenty participants were randomly selected for total sleep deprivation whereas the other 20 participants slept as normal. Sleep deprivation and morning-to-night variation did not influence high frequency HRV at either a group or individual level; however, sleep deprivation abolished the relationship between orienting attention performance and HRV. We conclude that a day of wake and a night of laboratory-induced sleep deprivation do not alter supine high frequency HRV in young healthy male adults.

Sleep is an evolutionarily conserved process required for human health and functioning. Insufficient sleep causes impairments across cognitive domains, and sleep deprivation can have rapid antidepressive effects in mood disorders. However, the neurobiological effects of waking and sleep are not well understood. Recently, animal studies indicated that waking and sleep are associated with substantial cortical structural plasticity. Here, we hypothesized that structural plasticity can be observed after a day of waking and sleep deprivation in the human cerebral cortex. To test this hypothesis, 61 healthy adult males underwent structural magnetic resonance imaging (MRI) at three time points: in the morning after a regular night's sleep, the evening of the same day, and the next morning, either after total sleep deprivation (N=41) or a night of sleep (N=20). We found significantly increased right prefrontal cortical thickness from morning to evening across all participants. In addition, pairwise comparisons in the deprived group between the two morning scans showed significant thinning of mainly bilateral medial parietal cortices after 23h of sleep deprivation, including the precuneus and posterior cingulate cortex. However, there were no significant group (sleep vs. sleep deprived group) by time interactions and we can therefore not rule out that other mechanisms than sleep deprivation per se underlie the bilateral medial parietal cortical thinning observed in the deprived group. Nonetheless, these cortices are thought to subserve wakefulness, are among the brain regions with highest metabolic rate during wake, and are considered some of the most sensitive cortical regions to a variety of insults. Furthermore, greater thinning within the left medial parietal cluster was associated with increased sleepiness after sleep deprivation. Together, these findings add to a growing body of data showing rapid structural plasticity within the human cerebral cortex detectable with MRI. Further studies are needed to clarify whether cortical thinning is one neural substrate of sleepiness after sleep deprivation. •We examined the effects of a day of wake and sleep deprivation on the human cortex.•There was morning-to-evening increase in right prefrontal cortex thickness.•Non-sleepers had bilateral parietal thinning; no group*time interaction was found.•These findings suggest rapid structural plasticity within the human cerebral cortex.•Whether sleep deprivation causes cerebral cortical thinning remains to be clarified.

Copper transporting P-type (P 1B-1 -) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P 1B-1 -ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P 1B-1 -ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD −1 , serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD −1 , MBD −2 , likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P 1B-1 -ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P 1B-1 -disorders and ongoing clinical trials. Controlling copper levels is essential for life, causing disease when impaired. Here, structures of a copper transporter sheds light on the function of its metal binding domains and unifies previous theories on the details of copper transport.

On the quest for solving structures of membrane proteins by X-ray crystallography or cryo-EM, large quantities of ultra-pure protein are a paramount prerequisite. Obtaining enough protein of such high standard is not a trivial task, especially for difficult-to-express membrane proteins. Producing membrane protein for structural studies is often performed in Escherichia coli or Saccharomyces cerevisiae and is frequently complemented with functional studies. Ion channels and electrogenic receptors are traditionally studied in terms of their electrophysiological behavior, which cannot be performed in neither E . coli nor yeast. Therefore, they are frequently characterized in mammalian cells or in Xenopus laevis oocytes. To avoid generating two different plasmids, we here describe the construction of a dual-function plasmid, pXOOY, for membrane protein production in yeast and for electrophysiology in oocytes. pXOOY was constructed such that all elements required for oocyte expression were copied from the dual Xenopus -mammalian vector pXOOM and meticulously introduced into the high-yield yeast expression vector pEMBLyex4. pXOOY is thus designed to preserve the high yield of protein from pEMBLyex4 while simultaneously permitting in vitro transcription for expression in oocytes. We evaluated the performance of pXOOY by comparing expression of two yeast codon o ptimized h uman potassium channels, oh ERG and oh Slick (Slo2.1) from pXOOY to expression of these channels obtained from the reference vectors pEMBLyex4 and pXOOM. Our proof-of-concept study indicates that accumulation in PAP1500 yeast cells was higher when the channels were expressed from pXOOY, which was verified both qualitatively and quantitatively. Two-electrode voltage clamp measurements in oocytes showed that the pXOOY constructs encoding ohERG and ohSlick gave currents with full preservation of electrophysiological characteristics. Our results show that it is possible to design a dual-function Xenopus -yeast vector without compromising expression in yeast and simultaneously maintaining channel activity in oocytes.

Brand experience has been conceptualized as a multidimensional construct that explains customer loyalty. The authors present a study with the purpose of testing a recently published brand experience scale in a service brand context. In addition to validating the established dimensions of the measurement scale, the study tests an additional dimension, relational experience, which is proposed as particularly relevant for service brands. The study also reports results of a test of the relationship between each of the experience dimensions and other brand-related constructs. The results reveal significant influences of dimensions of brand experience on brand personality, brand satisfaction and brand loyalty

ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia congenita, a disease impairing muscle relaxation. Here, we present the cryo-electron microscopy (cryo-EM) structure of human ClC-1, uncovering an architecture reminiscent of that of bovine ClC-K and CLC transporters. The chloride conducting pathway exhibits distinct features, including a central glutamate residue (\"fast gate\") known to confer voltage-dependence (a mechanistic feature not present in ClC-K), linked to a somewhat rearranged central tyrosine and a narrower aperture of the pore toward the extracellular vestibule. These characteristics agree with the lower chloride flux of ClC-1 compared with ClC-K and enable us to propose a model for chloride passage in voltage-dependent CLC channels. Comparison of structures derived from protein studied in different experimental conditions supports the notion that pH and adenine nucleotides regulate ClC-1 through interactions between the so-called cystathionine-β-synthase (CBS) domains and the intracellular vestibule (\"slow gating\"). The structure also provides a framework for analysis of mutations causing myotonia congenita and reveals a striking correlation between mutated residues and the phenotypic effect on voltage gating, opening avenues for rational design of therapies against ClC-1-related diseases.

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005-2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin. Using multivariable Cox regression we found that high age, high ISS score, high LDH and IgA MM were associated to both shorter overall survival and progression free survival. Furthermore, bone marrow plasma cell % was associated to short progression free survival. Immunoparesis had no independent significant effect on OS (HR 0.9 (95%CI: 0.7;1.0; p = 0.12)). Likewise, the number of suppressed immunoglobulins or the relative degree of suppressed uninvolved immunoglobulins from lower normal level (quantitative immunoparesis) was not associated to OS in the multivariable analysis. However, quantitative immunoparesis with at least 25% reduction (from lower normal level) of uninvolved immunoglobulins was associated to shorter PFS for the entire population. The impact of quantitative immunoparesis on PFS was present irrespective of calendar periods 2005-2008 and 2009-2013. Our population-based study does not confirm that immunoparesis at diagnosis is an independent prognostic factor regarding OS. However, quantitative immunoparesis is associated to a shorter PFS.