The perivascular adipose tissue (PVAT) surrounding vessels constitutes a distinct functional integral layer of the vasculature required to preserve vascular tone under physiological conditions. ...However, there is little information on the relationship between PVAT and blood pressure regulation, including its potential contributions to circadian blood pressure variation.
Using unique brown adipocyte-specific aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and angiotensinogen knockout mice, we determined the vasoactivity of homogenized PVAT in aortic rings and how brown adipocyte peripheral expression of Bmal1 and angiotensinogen in PVAT regulates the amplitude of diurnal change in blood pressure in mice.
We uncovered a peripheral clock in PVAT and demonstrated that loss of Bmal1 in PVAT reduces blood pressure in mice during the resting phase, leading to a superdipper phenotype. PVAT extracts from wild-type mice significantly induced contractility of isolated aortic rings in vitro in an endothelium-independent manner. This property was impaired in PVAT from brown adipocyte-selective Bmal1-deficient (BA-Bmal1-KO) mice. The PVAT contractile properties were mediated by local angiotensin II, operating through angiotensin II type 1 receptor-dependent signaling in the isolated vessels and linked to PVAT circadian regulation of angiotensinogen. Indeed, angiotensinogen mRNA and angiotensin II levels in PVAT of BA-Bmal1-KO mice were significantly reduced. Systemic infusion of angiotensin II, in turn, reduced Bmal1 expression in PVAT while eliminating the hypotensive phenotype during the resting phase in BA-Bmal1-KO mice. Angiotensinogen, highly expressed in PVAT, shows circadian expression in PVAT, and selective deletion of angiotensinogen in brown adipocytes recapitulates the phenotype of selective deletion of Bmal1 in brown adipocytes. Furthermore, angiotensinogen is a transcriptional target of Bmal1 in PVAT.
These data indicate that local Bmal1 in PVAT regulates angiotensinogen expression and the ensuing increase in angiotensin II, which acts on smooth muscle cells in the vessel walls to regulate vasoactivity and blood pressure in a circadian fashion during the resting phase. These findings will contribute to a better understanding of the cardiovascular complications of circadian disorders, alterations in the circadian dipping phenotype, and cross-talk between systemic and peripheral regulation of blood pressure.
A high-resolution stalagmite oxygen isotope record from Tianmen Cave, located in the south central Tibetan Plateau, characterizes detailed climatic variations between 8.7 and 4.3ka BP on centennial ...and decadal time scales, with a temporal resolution of 3 to 7 years. The Tianmen record is in good agreement with speleothem records from Asian monsoon regions (i.e., Dongge Cave, Dykoski et al., 2005; Wang et al., 2005; Qunf Cave, Fleitmann et al., 2003), upwelling records from the Arabian Sea (Gupta et al., 2003, 2005) and peat bog records from southeast Tibetan Plateau (Hong et al., 2003), indicating that the Indian summer monsoon (ISM) gradually weakened as Northern Hemisphere summer insolation declined during the early-mid Holocene and that ISM intensity, rather than temperature, dominates the precipitation δ18O on centennial to decadal time scales in the southern TP. On centennial to decadal time scales, the detrended Tianmen record correlates well with the Greenland ice core record, further confirming the mechanistic connection between the ISM and high northern latitude temperature changes. Meanwhile, the Tianmen record bears significant solar activity cycles, suggesting that the solar output changes may affect the variability of the ISM and likely the position of the Intertropical Convergence Zone (ITCZ) as well. Moreover, due to joint effects of changes in monsoon precipitation, moisture source and temperature, the Tianmen δ18O record shows much larger amplitude changes than speleothem δ18O records from low-elevation Asian Monsoon regions, which is similar to the previously reported Marine Isotope Stage (MIS) 5 record (Cai et al., 2010), suggesting heightened sensitivity of precipitation isotope composition to climate changes over the high-elevation regions and further demonstrating that the stable isotope lapse rate may change under different climatic conditions.
► We present the Holocene Indian monsoon history and variability over South Tibet. ► Monsoon intensity, but not temperature, dominates the precipitation δ18O in South Tibet. ► The sensitivity of precipitation δ18O to climatic changes is heightened over the Tibet. ► The stable isotope lapse rate may change under different climatic conditions.
•C37/C38 and long chain alkenone (LCK) distribution in the lake showed changes in producers during the Holocene.•Species effect could cause inconsistency between the UK37 and UK′37 records.•New UKs37 ...proxy formulated to represent different exponential response of LCK unsaturation to temperature.•UKs37-derived temperature resembled general temperature trend of N Hemisphere on millennial scale.
The extent of unsaturation in long chain alkenones (LCKs) in lakes has potential for quantitatively indicating paleotemperature in terrigenous environments. However, the traditional temperature proxies derived from marine LCKs may not be able to address the problem related to the prevalent species effect, which restricts the application of LCKs in lacustrine studies. In our LCK record from the northeastern Tibetan Plateau, C37/C38 differences revealed that the LCK producer species in Lake Qinghai may have changed during the Holocene. This possible species effect may have caused inconsistency between the UK′37 and UK37 records. Therefore, we formulated a new proxy, UKs37, with a parameter “s” to indicate the different exponential response in LCK unsaturation to temperature change in multiple species. Our UKs37-derived temperature time series resembles the general temperature trends of the Northern Hemisphere on a millennial scale, while exhibiting several apparent cold events, especially at ca. 9ka. The result shows that the Holocene optimum in Lake Qinghai was interrupted by cold events in the early Holocene. This could be a result of a weak Asia summer monsoon and cold air transmission in the North Atlantic.
Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence ...set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.
Loss of physical and emotional health due to spinal cord injury (SCI) has been rapidly increasing worldwide. Effective evaluation of the severity of SCI is crucial to its prognosis. Herein, we ...constructed rat models of SCI with four different degrees of injury (sham group, light injury group, moderate injury group, and heavy injury group), using the surgical approach. Cerebrospinal fluid (CSF), plasma, and spinal cord were sampled at the sub-acute spinal cord (72 h post-injury) from each rat. The LC–MS-based metabolic profiling of these samples was performed according to a universal metabolome standard (UMS). The results demonstrated that 130, 104, and 128 metabolites were significantly altered within the CSF, plasma, and spinal cord samples, respectively. Among them, there were four differential metabolites, including uric acid, phosphorycholine, pyridoxine, and guanidoacetic acid, which were commonly identified within the CSF, plasma, and spinal cord samples. Further pathway analysis of these differential metabolites demonstrated a disturbance in the metabolism of glyoxylate and dicarboxylate and glycine, serine, and threonine which were associated with pathophysiologic consequence of spinal cord injury. In particular, phosphorycholine, pyridoxine, and guanidoacetic acid demonstrated a relationship with SCI severity. Thus, they could be utilized as potential metabolite biomarkers for SCI severity assessment.
Earth's climate system has experienced substantial millennial‐scale oscillations characterized by abrupt changes superimposed on orbital‐scale changes. However, the dynamic connection between ...millennial and orbital timescales remains elusive. Here, we provide a summer monsoon precipitation δ18O record spanning from ∼8 to ∼60.5 ka based on the oxygen isotopic composition of microcodium from loess deposits on the Chinese Loess Plateau. This record shows distinct precessional variations (23 ka) punctuated by prominent millennial‐scale oscillations. It is generally consistent with speleothem δ18O and other loess‐based records, reflecting the East Asian summer monsoon changes. More importantly, our result also shows that large increases in the magnitude of millennial‐scale variability correspond to the Northern Hemisphere summer insolation minimum. We propose that precession‐induced low‐latitude summer insolation modulates the amplitudes of millennial‐scale summer monsoon variability by changing the mean monsoon state during the last glaciation.
Plain Language Summary
Understanding the dynamic connections between different timescales is crucial to predicting future climate variability. Here, we provide a summer monsoon precipitation δ18O record based on the oxygen isotopic composition of microcodium from loess deposits on the Chinese Loess Plateau, showing that large increases in the magnitude of millennial‐scale variability correspond to Northern Hemisphere summer insolation minimum. We propose that low‐latitude summer insolation modulates the amplitudes of millennial monsoon variability during the last glaciation. Our work provides clues for deciphering the dynamic connections between orbital and millennial timescales.
Key Points
A summer precipitation δ18O record on the Chinese Loess Plateau during the last glaciation was reconstructed based on microcodium δ18O
The record shows distinct precessional variations punctuated by millennial‐scale oscillations, consistent with other monsoon records
The magnitude of millennial‐scale East Asian summer monsoon variability was found to be modulated by low‐latitude insolation during the last glaciation
•Service recovery awareness of frontline employees has the double-edged sword effect on post-recovery satisfaction of customers in service recovery.•SRA is appraised as a challenging demand that is ...positively associated with post-recovery satisfaction through work engagement.•SRA is considered a hindrance demand that leads to emotional exhaustion, which is negatively related to post-recovery satisfaction.•Perceived psychological empowerment (PPE) amplified the impact of SRA on work engagement.•PPE buffered the impact of SRA on emotional exhaustion.
Drawing on job demands-resources (JD-R) theory, this study examines the double-edged sword effect of service recovery awareness (SRA) on post-recovery satisfaction via frontline employees’ (FLEs) emotional responses (including emotional exhaustion and work engagement). The moderating effect of perceived psychological empowerment (PPE) was also assessed. Dyadic and matched responses from 267 five-star hotel FLEs and customers indicated that SRA is appraised as a challenging demand that is positively associated with post-recovery satisfaction through work engagement. However, SRA is also considered a hindrance demand that leads to emotional exhaustion, which is negatively related to post-recovery satisfaction. PPE amplified the impact of SRA on work engagement and buffered the impact of SRA on emotional exhaustion. The theoretical contribution, managerial implications, and suggestions for future research of this study are discussed in detail.
Sonodynamic therapy (SDT) is a noninvasive ultrasound-triggered therapeutic strategy for site-specific treatment of tumors with great depth penetration. The design of nano-sonosensitizers suitable ...for SDT treatment of bladder cancer (BCa) post-intravesical instillation has not yet been reported. Herein, a transmucosal oxygen-self-production SDT nanoplatform is developed to achieve highly efficient SDT against BCa. In this system, fluorinated chitosan (FCS) is synthesized as a highly effective nontoxic transmucosal delivery carrier to assemble with meso-tetra(4-carboxyphenyl)porphine-conjugated catalase (CAT-TCPP). The formed CAT-TCPP/FCS nanoparticles after intravesical instillation into the bladder cavity exhibit excellent transmucosal and intratumoral penetration capacities and could efficiently relieve hypoxia in tumor tissues by the catalase-catalyzed O2 generation from tumor endogenous H2O2 to further improve the therapeutic efficacy of SDT to ablate orthotopic bladder tumors under ultrasound. Our work presents a nano-sonosensitizer formulation with FCS to enhance transmucosal delivery and intratumoral diffusion and CAT to improve tumor oxygenation, promising for instillation-based SDT to treat bladder tumors without the concern of systemic toxicity.
In this paper, a parallel extended state observer (PESO) is proposed by merging a series of different order linear tracking differentiators and first-order nonlinear differentiators. Both measurement ...noises and system uncertainties are taken into account in design procedures. A distinct feature of the parallel structure is that the observed information of each part is independent of each other, which effectively avoids the accumulation of the observation error of each part. The PESO is utilized to estimate the total disturbance, which reflects the combined impacts of internal uncertainties and external disturbances. Based on the observation results generated by the PESO, a composite controller is developed for output feedback control of uncertain nonlinear systems. The convergence performance of the proposed PESO and PESO-based controller is rigorously verified. Finally, some numerical simulation results are provided to verify the effectiveness and superiority of the proposed method.
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