This book studies the connections between the political reform of the Holy Roman Empire and the German lands around 1500 and the sixteenth-century religious reformations, both Protestant and ...Catholic. It argues that the character of the political changes (dispersed sovereignty, local autonomy) prevented both a general reformation of the Church before 1520 and a national reformation thereafter. The resulting settlement maintained the public peace through politically structured religious communities (confessions), thereby avoiding further religious strife and fixing the confessions into the Empire's constitution. The Germans' emergence into the modern era as a people having two national religions was the reformation's principal legacy to modern Germany.
To reestablish homeostasis and mitigate stress, cells must activate a series of adaptive intracellular signaling pathways. The participation of the transcription factors TFEB and TFE3 in cellular ...adaptation to starvation is well established. Here, we show that TFEB and TFE3 also play an important role in the cellular response to ER stress. Treatment with ER stressors causes translocation of TFEB and TFE3 to the nucleus in a process that is dependent on PERK and calcineurin but not on mTORC1. Activated TFEB and TFE3 enhance cellular response to stress by inducing direct transcriptional upregulation of ATF4 and other UPR genes. Under conditions of prolonged ER stress, TFEB and TFE3 contribute to cell death, thus revealing an unexpected role for these proteins in controlling cell fate. This work evidences a broader role of TFEB and TFE3 in the cellular response to stress than previously anticipated and reveals an integrated cooperation between different cellular stress pathways.
Synopsis
The transcription factors TFEB and TFE3 are activated upon starvation‐induced mTORC1 inhibition, but also respond to ER stress in a PERK‐dependent manner. This finding reveals a hitherto unknown level of crosstalk between cellular stress pathways.
ER stress activates TFEB and TFE3 through a process that requires PERK but not mTORC1.
TFEB and TFE3 modulate the Integrative Stress Response by regulating ATF4 expression both under ER stress and starvation conditions.
In response to stress TFE3 regulates not only autophagic and lysosomal genes, but also genes implicated in cellular homeostasis, stress response, signaling, and regulation of apoptosis.
TFEB and TFE3 play a dual role in cell fate by promoting either survival or cell death depending on the duration and strength of the stress.
The transcription factors TFEB and TFE3 are activated upon starvation‐induced mTORC1 inhibition, but also respond to ER stress in a PERK‐dependent manner. This finding reveals a hitherto unknown level of crosstalk between cellular stress pathways.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional ...activation mutants. Microarray analysis reveals that one mutant, p53
25,26, is severely compromised for transactivation of most p53 target genes, and, moreover, p53
25,26 cannot induce G
1-arrest or apoptosis in response to acute DNA damage. Surprisingly, p53
25,26 retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p53
25,26,53,54 mutant cannot induce senescence or inhibit tumorigenesis, like
p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression—a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.
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► Full p53 transactivation potential is required for acute DNA-damage responses ► Robust transactivation of most known p53 targets is dispensable for tumor suppression ► p53 transactivation function is critical for tumor suppression ► This tumor suppression is associated with activation of a set of new target genes
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Scattering using resonant soft X-rays probes nano- to meso-scale structures.•Tunable contrast provides chemical sensitivity for complex structural information.•Resonant polarized ...X-rays elucidate molecular orientation.•In-Situ RSoXS probes morphology, chemistry and dynamics of broad range of materials.
Resonant Soft X-ray Scattering (RSoXS) was developed over the last a few years, and the first dedicated resonant soft X-ray scattering beamline for soft materials was constructed at the Advanced Light Source, LBNL. RSoXS combines soft X-ray spectroscopy with X-ray scattering and thus offers statistical information for 3D chemical morphology over a large length scale range from nanometers to micrometers. Using RSoXS to characterize multi-length scale soft materials with heterogeneous chemical structures, we have demonstrated that soft X-ray scattering is a unique complementary technique to conventional hard X-ray and neutron scattering. Its unique chemical sensitivity, large accessible size scale, molecular bond orientation sensitivity with polarized X-rays, and high coherence have shown great potential for chemically specific structural characterization for many classes of materials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
A key limitation in assessing the therapeutic impact of non-pharmacological approaches to treating hypertension is the method of reporting outcomes. Reducing the medications required to ...achieve the same blood pressure may be reported separately to a reduction in the blood pressure without change in medication, and thus lessen the reported beneficial impact of treatment. This study aims to derive a novel scoring system to gauge the therapeutic impact of non-drug treatment of hypertension by utilising a combination of excessive blood pressure and the number of anti-hypertensives into a combined score—the hypertensive index (HTi). The hypertensive index was empirically derived based on the systolic blood pressure and number of antihypertensive drugs, and applied retrospectively to a cohort undergoing intervention for renovascular hypertension. Subgroup and receiver operating characteristic analyses were used to compare the HTi to traditional methods of reporting outcomes. Following intervention (99 patients), 46% had improvement in both medication load and blood pressure, 29% had benefit in blood pressure without reduction in medication load, 15% had reduction in medication load without significant change in blood pressure and 9% showed no benefit in either parameter. The HTi was superior in detecting benefit from intervention compared with measuring blood pressure or medication load alone (AUC
0.94
vs
0.85;0.84
). The hypertensive index may be a more sensitive marker of treatment effect than assessing blood pressure measurements alone. The use of such scoring systems in future trial design may allow more accurate reporting of the effects of interventions for hypertension.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Previous work showed that two types of slow waves are temporally dissociated during the transition to sleep: widespread, large and steep slow waves predominate early in the falling asleep period (
), ...while smaller, more circumscribed slow waves become more prevalent later (
). Here, we studied the possible occurrence of these two types of slow waves in stable non-REM (NREM) sleep and explored potential differences in their regulation. A heuristic approach based on slow wave synchronization efficiency was developed and applied to high-density electroencephalographic (EEG) recordings collected during consolidated NREM sleep to identify the potential
and
slow waves. Slow waves with characteristics compatible with those previously described for
and
were identified in stable NREM sleep. Importantly, these slow waves underwent opposite changes across the night, with only
slow waves displaying a clear homeostatic regulation. In addition, we showed that the occurrence of
slow waves was often followed by larger
, whereas the occurrence of
slow waves was usually followed by smaller
waves. Finally,
slow waves were associated with a relative increase in spindle activity, while
slow waves triggered periods of high-frequency activity. Our results provide evidence for the existence of two distinct slow wave synchronization processes that underlie two different types of slow waves. These slow waves may have different functional roles and mark partially distinct "micro-states" of the sleeping brain.
The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional ...networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.
Even modest sleep restriction, especially the loss of sleep slow wave activity (SWA), is invariably associated with slower electroencephalogram (EEG) activity during wake, the occurrence of local ...sleep in an otherwise awake brain, and impaired performance due to cognitive and memory deficits. Recent studies not only confirm the beneficial role of sleep in memory consolidation, but also point to a specific role for sleep slow waves. Thus, the implementation of methods to enhance sleep slow waves without unwanted arousals or lightening of sleep could have significant practical implications. Here we first review the evidence that it is possible to enhance sleep slow waves in humans using transcranial direct-current stimulation (tDCS) and transcranial magnetic stimulation. Since these methods are currently impractical and their safety is questionable, especially for chronic long-term exposure, we then discuss novel data suggesting that it is possible to enhance slow waves using sensory stimuli. We consider the physiology of the K-complex (KC), a peripheral evoked slow wave, and show that, among different sensory modalities, acoustic stimulation is the most effective in increasing the magnitude of slow waves, likely through the activation of non-lemniscal ascending pathways to the thalamo-cortical system. In addition, we discuss how intensity and frequency of the acoustic stimuli, as well as exact timing and pattern of stimulation, affect sleep enhancement. Finally, we discuss automated algorithms that read the EEG and, in real-time, adjust the stimulation parameters in a closed-loop manner to obtain an increase in sleep slow waves and avoid undesirable arousals. In conclusion, while discussing the mechanisms that underlie the generation of sleep slow waves, we review the converging evidence showing that acoustic stimulation is safe and represents an ideal tool for slow wave sleep (SWS) enhancement.
The activation of transcription factors is critical to ensure an effective defense against pathogens. In this study we identify a critical and complementary role of the transcription factors TFEB and ...TFE3 in innate immune response. By using a combination of chromatin immunoprecipitation, CRISPR-Cas9-mediated genome-editing technology, and in vivo models, we determined that TFEB and TFE3 collaborate with each other in activated macrophages and microglia to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of numerous proinflammatory cytokines. Furthermore, secretion of key mediators of the inflammatory response (CSF2, IL1B, IL2, and IL27), macrophage differentiation (CSF1), and macrophage infiltration and migration to sites of inflammation (CCL2) was significantly reduced in TFEB and TFE3 deficient cells. These new insights provide us with a deeper understanding of the transcriptional regulation of the innate immune response.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
To assess how the characteristics of slow waves and spindles change in the falling-asleep process.
Participants undergoing overnight high-density electroencephalographic recordings were awakened at ...15- to 30-min intervals. One hundred forty-one falling-asleep periods were analyzed at the scalp and source level.
Sleep laboratory.
Six healthy participants.
Serial awakenings.
The number and amplitude of slow waves followed two dissociated, intersecting courses during the transition to sleep: slow wave number increased slowly at the beginning and rapidly at the end of the falling-asleep period, whereas amplitude at first increased rapidly and then decreased linearly. Most slow waves occurring early in the transition to sleep had a large amplitude, a steep slope, involved broad regions of the cortex, predominated over frontomedial regions, and preferentially originated from the sensorimotor and the posteromedial parietal cortex. Most slow waves occurring later had a smaller amplitude and slope, involved more circumscribed parts of the cortex, and had more evenly distributed origins. Spindles were initially sparse, fast, and involved few cortical regions, then became more numerous and slower, and involved more areas.
Our results provide evidence for two types of slow waves, which follow dissociated temporal courses in the transition to sleep and have distinct cortical origins and distributions. We hypothesize that these two types of slow waves result from two distinct synchronization processes: (1) a "bottom-up," subcorticocortical, arousal system-dependent process that predominates in the early phase and leads to type I slow waves, and (2) a "horizontal," corticocortical synchronization process that predominates in the late phase and leads to type II slow waves. The dissociation between these two synchronization processes in time and space suggests that they may be differentially affected by experimental manipulations and sleep disorders.
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