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"Lee, J. C."
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Order of same-day concurrent training influences some indices of power development, but not strength, lean mass, or aerobic fitness in healthy, moderately-active men after 9 weeks of training
The importance of concurrent exercise order for improving endurance and resistance adaptations remains unclear, particularly when sessions are performed a few hours apart. We investigated the effects of concurrent training (in alternate orders, separated by ~3 hours) on endurance and resistance training adaptations, compared to resistance-only training.
Twenty-nine healthy, moderately-active men (mean ± SD; age 24.5 ± 4.7 y; body mass 74.9 ± 10.8 kg; height 179.7 ± 6.5 cm) performed either resistance-only training (RT, n = 9), or same-day concurrent training whereby high-intensity interval training was performed either 3 hours before (HIIT+RT, n = 10) or after resistance training (RT+HIIT, n = 10), for 3 d.wk-1 over 9 weeks. Training-induced changes in leg press 1-repetition maximal (1-RM) strength, countermovement jump (CMJ) performance, body composition, peak oxygen uptake ([Formula: see text]), aerobic power ([Formula: see text]), and lactate threshold ([Formula: see text]) were assessed before, and after both 5 and 9 weeks of training.
After 9 weeks, all training groups increased leg press 1-RM (~24-28%) and total lean mass (~3-4%), with no clear differences between groups. Both concurrent groups elicited similar small-to-moderate improvements in all markers of aerobic fitness ([Formula: see text] ~8-9%; [Formula: see text] ~16-20%; [Formula: see text] ~14-15%). RT improved CMJ displacement (mean ± SD, 5.3 ± 6.3%), velocity (2.2 ± 2.7%), force (absolute: 10.1 ± 10.1%), and power (absolute: 9.8 ± 7.6%; relative: 6.0 ± 6.6%). HIIT+RT elicited comparable improvements in CMJ velocity only (2.2 ± 2.7%). Compared to RT, RT+HIIT attenuated CMJ displacement (mean difference ± 90%CI, -5.1 ± 4.3%), force (absolute: -8.2 ± 7.1%) and power (absolute: -6.0 ± 4.7%). Only RT+HIIT reduced absolute fat mass (mean ± SD, -11.0 ± 11.7%).
In moderately-active males, concurrent training, regardless of the exercise order, presents a viable strategy to improve lower-body maximal strength and total lean mass comparably to resistance-only training, whilst also improving indices of aerobic fitness. However, improvements in CMJ displacement, force, and power were attenuated when RT was performed before HIIT, and as such, exercise order may be an important consideration when designing training programs in which the goal is to improve lower-body power.
Journal Article
Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice
Aims/hypothesis
The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.
Methods
Rat insulin promoter (RIP)-
Cre
+
;autophagy-related 7 (
Atg7
)
F/W
mice were bred with
ob/w
mice to derive RIP-
Cre
+
;
Atg7
F/F
-
ob/ob
mice and to induce ER stress in vivo.
GFP-LC3
+
-
ob/ob
mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.
Results
Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with
ob/ob
mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.
Conclusions/interpretation
These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.
Journal Article
Analysis of the B cell receptor repertoire in six immune-mediated diseases
B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)
1
, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the ‘BCR repertoire’. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn’s disease, Behçet’s disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and—in particular—isotype use. An increase in clonality in systemic lupus erythematosus and Crohn’s disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.
An analysis of the B cell receptor repertoire in six immune-mediated diseases reveals that there are substantial differences in clonality, isotype use, class switching and use of the IGHV genes between diseases.
Journal Article
Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells
The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial–mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity
in vitro
and tumorigenicity
in vivo
. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance
in vitro
and exhibited stronger tumorigenic potential
in vivo
than CXCR4− cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.
Journal Article
Laguerre–Gauss and Hermite–Gauss soft X-ray states generated using diffractive optics
Light’s capacity to carry angular momentum is integral to our knowledge of physics and ability to probe matter. In addition to spin, photons can occupy free-space orbital angular momentum eigenstates1,2. Visible light orbital angular momentum is used in quantum information experiments, super-resolution microscopy, optical tweezers and angular momentum transfer to atoms in optical lattices3,4. Soft X-ray orbital angular momentum applications, slowed by the lack of suitable optics and the rarity of coherent X-ray sources, could enable the direct alteration of atomic states through orbital angular momentum exchange, and methods to study the electronic properties of quantum materials. We have made soft X-ray diffractive optics that generate single Laguerre–Gauss modes, observed carrying up to 30ħ angular momentum per photon, or their superpositions. We also present Hermite–Gauss diffractive optics and a soft X-ray orbital angular momentum analyser. These tools could enable both the manipulation and finer characterization of topologically complex electronic matter, such as magnetic skyrmions.Robust methods for creating and analysing soft X-ray modes, with as much as 30ħ angular momentum per photon, are demonstrated.
Journal Article