Aim
The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with ...a simulated day shift schedule.
Methods
Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively.
Results
Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L−1; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II‐V) or insulin‐stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2).
Conclusion
Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.
The aim of this research was to examine the impact of the xanthine oxidase (XO) inhibitor allopurinol on the skeletal muscle activation of cell signaling kinases' and adaptations to mitochondrial ...proteins and antioxidant enzymes following acute endurance exercise and endurance training. Male Sprague-Dawley rats performed either acute exercise (60 min of treadmill running, 27 m/min, 5% incline) or 6 wk of endurance training (5 days/wk) while receiving allopurinol or vehicle. Allopurinol treatment reduced XO activity to 5% of the basal levels (P < 0.05), with skeletal muscle uric acid levels being almost undetectable. Following acute exercise, skeletal muscle oxidized glutathione (GSSG) significantly increased in allopurinol- and vehicle-treated groups despite XO activity and uric acid levels being unaltered by acute exercise (P < 0.05). This suggests that the source of ROS was not from XO. Surprisingly, muscle GSSG levels were significantly increased following allopurinol treatment. Following acute exercise, allopurinol treatment prevented the increase in p38 MAPK and ERK phosphorylation and attenuated the increase in mitochondrial transcription factor A (mtTFA) mRNA (P < 0.05) but had no effect on the increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor-2, GLUT4, or superoxide dismutase mRNA. Allopurinol also had no impact on the endurance training-induced increases in PGC-1α, mtTFA, and mitochondrial proteins including cytochrome c, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase. In conclusion, although allopurinol inhibits cell signaling pathways in response to acute exercise, the inhibitory effects of allopurinol appear unrelated to exercise-induced ROS production by XO. Allopurinol also has little effect on increases in mitochondrial proteins following endurance training.
Abstract This study was aimed at the effects of different Creep-feeding protocols on piglet performance and its residual effects during the nursery phase. Experimental design used was five groups: WC ...(without creep); DCF (dry creep feeding); WCF (wet creep feeding); LD (additional liquid creep with automatic feed dispenser plus DCF); and LLF (additional liquid creep with linear feeder plus DCF). Ten litters per treatment were selected a total 50 sows and 645 piglets. During the first two weeks of lactation, the LD treatment (2.61 and 4.20 kg) promoted greater body weight (P <0.001) than the DCF (2.55 and 3.93 kg), (WFS) (2.43 and 3.69 kg) and LLF (2.50 and 4.00 kg) treatments, but did not differ from the WC treatment (2.68 and 4.09 kg). At weaning, the WC (5.22 kg), LD (5.32 kg) and LLF (5.27 kg) treatments gave higher body weights (P <0.001) when compared to the DCF (4.97 kg) and WCF (4.69 kg) treatments. We concluded that there was no change in the behavior of the piglets, and the use of dry feed with liquid supplements did not improve weight gain. The different creep feeding systems did not influence the weight and performance of the piglets in the nursery phase.
This study aimed to determine whether the addition of a microencapsulated herbal blend (MHB) based on thymol, carvacrol, and cinnamaldehyde in dairy sheep feed would improve production efficiency, ...milk quality, and animal health. Thirty lactating Lacaune ewes were divided into three groups: Control (T0), 150 mg blend/kg of feed (T150), and 250 mg blend/kg of feed (T250). Milk was measured before the beginning of the experiment (d 0), at the end of the adaptation period (d 15), and during the experiment (d 20). In milk samples, was measured the composition, somatic cell count (SCC), reactive oxygen species (ROS), lipoperoxidation (LPO), and total antioxidant capacity. The MHB improved the milk production (only T150 vs. T0 sheep on d 20), productive efficiency and feed efficiency, and reduced the milk SCC (only T250 vs. T0 sheep, on d 20), ROS and tended to reduce the milk levels of LPO (only T250 vs. T0 sheep on d 20). Also, MHB reduced the blood levels of neutrophils and ROS (only T250 vs. T0 sheep on d 20) and increased total protein and globulin levels. Thus, a microencapsulated blend of thymol, carvacrol, and cinnamaldehyde improved the productive performance and milk quality of sheep.
Abstract
Background
Mitochondria have an essential role in regulating metabolism and integrate environmental and physiological signals to affect processes such as cellular bioenergetics and response ...to stress. In the metabolically active skeletal muscle, mitochondrial biogenesis is one important component contributing to a broad set of mitochondrial adaptations occurring in response to signals, which converge on the biogenesis transcriptional regulator peroxisome proliferator-activated receptor coactivator 1-alpha (PGC-1α), and is central to the beneficial effects of exercise in skeletal muscle. We investigated the role of long non-coding RNA (lncRNA) taurine-upregulated gene 1 (
TUG1
), which interacts with PGC-1α in regulating transcriptional responses to exercise in skeletal muscle.
Results
In human skeletal muscle,
TUG1
gene expression was upregulated post-exercise and was also positively correlated with the increase in PGC-1α gene expression (
PPARGC1A
).
Tug1
knockdown (KD) in differentiating mouse myotubes led to decreased
Ppargc1a
gene expression, impaired mitochondrial respiration and morphology, and enhanced myosin heavy chain slow isoform protein expression. In response to a Ca
2+
-mediated stimulus,
Tug1
KD prevented an increase in
Ppargc1a
expression. RNA sequencing revealed that
Tug1
KD impacted mitochondrial Ca
2+
transport genes and several downstream PGC-1α targets. Finally,
Tug1
KD modulated the expression of ~300 genes that were upregulated in response to an in vitro model of exercise in myotubes, including genes involved in regulating myogenesis.
Conclusions
We found that
TUG1
is upregulated in human skeletal muscle after a single session of exercise, and mechanistically,
Tug1
regulates transcriptional networks associated with mitochondrial calcium handling, muscle differentiation and myogenesis. These data demonstrate that lncRNA
Tug1
exerts regulation over fundamental aspects of skeletal muscle biology and response to exercise stimuli.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Soon after activation, CD4+ T cells are segregated into BCL6+ follicular helper (Tfh) and BCL6– effector (Teff) T cells. Here, we explored how these subsets are maintained during chronic antigen ...stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1+ TCF-1+ CD4+ T cells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4+ T cell responses to chronic infection. An analogous CD4+ T cell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4+ T cells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.
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•Activated memory-like PD-1+ CD4+ T cells develop in the presence of chronic Ag•They contain progenitor CD4+ T (Tprog) cells that give rise to Tfh and Teff cells•The CD4+ Tprog cells express TCF-1 and require BCL6 for their development•Tprog cells are critical for sustained CD4+ T cell responses to chronic antigen
Understanding T cell responses in the presence of chronic antigen has largely focused on CD8+ T cells, while the persistence of CD4+ T cells during continued antigen exposure is underexplored. Xia, Sandor, and Pai et al. identify a self-renewing progenitor CD4+ T cell population required for sustaining both follicular helper and effector CD4+ T cells.
Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common ...tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.
One of the first steps towards elucidating the biological function of a putative transcriptional regulator is to ascertain its preferred DNA-binding sequences. This may be rapidly and effectively ...achieved through the application of a combinatorial approach, one involving very large numbers of randomized oligonucleotides and reiterative selection and amplification steps to enrich for high-affinity nucleic acid-binding sequences. Previously, we had developed the novel combinatorial approach Restriction Endonuclease Protection, Selection and Amplification (REPSA), which relies not on the physical separation of ligand-nucleic acid complexes but instead selects on the basis of ligand-dependent inhibition of enzymatic template inactivation, specifically cleavage by type IIS restriction endonucleases. Thus, no prior knowledge of the ligand is required for REPSA, making it more amenable for discovery purposes. Here we describe using REPSA, massively parallel sequencing, and bioinformatics to identify the preferred DNA-binding sites for the transcriptional regulator SbtR, encoded by the TTHA0167 gene from the model extreme thermophile Thermus thermophilus HB8. From the resulting position weight matrix, we can identify multiple operons potentially regulated by SbtR and postulate a biological role for this protein in regulating extracellular transport processes. Our study provides a proof-of-concept for the application of REPSA for the identification of preferred DNA-binding sites for orphan transcriptional regulators and a first step towards determining their possible biological roles.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Severe disease was recorded in 10% of persons with breakthrough infections•In comparison, 26% of unvaccinated controls with infection had severe disease•Older age was a risk factor for severe ...disease in those with breakthrough infection•Vaccination status was associated with a significantly lower risk of severe disease
Breakthrough infections after SARS-CoV-2 vaccination have been reported. Clinical outcomes in these persons are not widely known.
We evaluated all vaccinated persons with breakthrough infection ≥14 days after the second vaccine dose and unvaccinated controls matched on age, sex, nationality, and reason for testing between December 23, 2020 and March 28, 2021 in Qatar. Our primary outcome was severe disease defined as hospitalization, mechanical ventilation, or death.
Among 456 persons cases of breakthrough infection and 456 unvaccinated matched controls with confirmed infection, median age was 45 years, 60.7% were males, and ≥1 comorbid condition was present in 61.2% of the vaccinated and 47.8% of the unvaccinated persons (P=0.009). Severe disease was recorded in 48 (10.5%) of the vaccinated and 121 (26.5%) of the unvaccinated group (P<0.001). Factors associated with severe disease included increasing age (HR vs. <40 years old: >40–60 years, HR 2.32; >60–70 years, HR 4.34; >70 years, HR 5.43); presence of symptoms at baseline (HR 2.42, 95%CI 1.44-4.07); and being unvaccinated (HR 2.84, 95%CI 1.80-4.47).
In persons with breakthrough SARS-CoV-2 infection, increasing age is associated with a higher risk of severe disease or death, while vaccination is associated with a lower risk. Presence of comorbidities was not associated with severe disease or death among persons with breakthrough infection.
Acute exercise increases osteocalcin (OC), a marker of bone turnover, and in particular the undercarboxylated form (ucOC). Males and females differ in baseline levels of total OC and it is thought ...the hormonal milieu may be driving these differences. Males and females adapt differently to the same exercise intervention, however it is unclear whether the exercise effects on OC are also sex-specific. We tested whether the responses of OC and its forms to acute High Intensity Interval Exercise (HIIE) and High Intensity Interval Training (HIIT) differed between males and females. Secondly, we examined whether sex hormones vary with OC forms within sexes to understand if these are driving factor in any potential sex differences.
Total OC (tOC), undercarboxylated OC (ucOC), and carboxylated OC (cOC) were measured in serum of 96 healthy participants from the Gene SMART cohort (74 males and 22 females) at rest, immediately after, and 3 h after a single bout of HIIE, and at rest, 48 h after completing a four week HIIT intervention. Baseline testosterone and estradiol were also measured for a subset of the cohort (Males = 38, Females = 20). Linear mixed models were used to a) uncover the sex-specific effects of acute exercise and short-term training on OC forms and b) to examine whether the sex hormones were associated with OC levels.
At baseline, males had higher levels of tOC, cOC, and ucOC than females (q < 0.01). In both sexes tOC, and ucOC increased to the same extent after acute HIIE. At baseline, in males only, higher testosterone was associated with higher ucOC (β = 3.37; q < 0.046). Finally, tOC and ucOC did not change following 4 weeks of HIIT.
While there were no long-term changes in OC and its forms. tOC and ucOC were transiently enhanced after a bout of HIIE similarly in both sexes. This may be important in metabolic signalling in skeletal muscle and bone suggesting that regular exercise is needed to maintain these benefits. Overall, these data suggest that the sex differences in exercise adaptations do not extend to the bone turnover marker, OC.
•No long-term changes in Osteocalcin after 4 week low-impact exercise intervention.•Osteocalcin is transiently enhanced after an acute bout of exercise in both sexes.•Sex differences in exercise adaptations are not evident in bone turnover marker, OC
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