Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic ...transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.
Mass filter operation in higher stability zones is known to provide better resolution. Unfortunately, for sine driven instruments, higher stability zone operation reduces the accessible mass range ...and increases the degenerative effects of fringe fields. Conversely, digitally driven mass filters do not suffer from loss of mass range, and the fringe field effects do not increase significantly by switching stability zones because the AC voltage is always constant and the DC voltage is always zero. This work catalogues 12 stability zones that are accessible with the new digital waveform generation technology. These zones have theoretical baseline resolving powers that range from 22 to 1 300 000 with pseudopotential well depths that range from 3.5 to 43 V. Operation in higher stability zones also has the advantage of aligned axial stability wells. That alignment maximizes the pseudopotential well depth for each higher stability zone, making them more than an order of magnitude greater than the standard ∼0.2 V well of a sine filter operating in the first stability zone at unit resolution. Increased pseudopotential well depth correlates with better ion transmission and sensitivity. Our theoretical examination suggests that the digital mass filter can obtain both high resolution and high sensitivity with essentially unlimited mass range.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Depletion of macrophages is thought to be a therapeutic option for obesity-induced inflammation and metabolic dysfunction. However, whether the therapeutic effect is a direct result of reduced ...macrophage-derived inflammation or secondary to decreases in fat mass is controversial, as macrophage depletion has been shown to disrupt energy homeostasis. This study was designed to determine if macrophage depletion via clodronate-liposome (CLD) treatment could serve as an effective intervention to reduce obesity-driven inflammatory and metabolic impairments independent of changes in energy intake. After 16 wk on a high-fat diet (HFD) or the AIN-76A control (low-fat) diet (LFD) ( n = 30/diet treatment), male C57BL/6J mice were assigned to a CLD- or PBS-liposome treatment ( n = 15/group) for 4 wk. Liposomes were administered biweekly via intraperitoneal injections (8 administrations in total). PBS-liposome-treated groups were pair-fed to their CLD-treated dietary counterparts. Metabolic function was assessed before and after liposome treatment. Adipose tissue, as well as the liver, was investigated for macrophage infiltration and the presence of inflammatory mediators. Additionally, a complete blood count was performed. CLD treatment reduced energy intake. When controlling for energy intake, CLD treatment was unable to regress metabolic dysfunction or nonalcoholic fatty liver disease and impaired adipose tissue insulin action. Moreover, repeated CLD treatment induced neutrophilia and anemia, increased adipose tissue mRNA expression of the proinflammatory cytokines IL-6 and IL-1β, and augmented circulating IL-6 and monocyte chemoattractant protein-1 concentrations ( P < 0.05). This study suggests that repeated intraperitoneal administration of CLD to deplete macrophages attenuates obesity by limiting energy intake. Moreover, after controlling for the benefits of weight loss, the accompanying detrimental side effects limit regular CLD treatment as an effective therapeutic strategy.
Proposed indicators for the Marine Strategy Framework Directive (MSFD) food webs Descriptor focus on structural elements of food webs, and in particular on the abundance and productivity of top ...predators. However, the inferences that can be drawn from such indicators depend on whether or not the predators are "bottom-up limited" by the availability of their prey. Many seabird populations appear to be "bottom-up limited" so that variation in their reproductive success and/or abundance reflects changes in lower trophic levels. Here we find that gadoid fish predators off the Firth of Forth, southeast Scotland, do not appear to be "bottom-up limited" by the biomass of their main prey, 0-group sandeels; gadoid biomass and feeding performance was independent of sandeel biomass. Variability in food web indicators based on these gadoid predators seems to impart little insight into underlying processes occurring at lower trophic levels in the local food web. The implications of this in terms of how the currently proposed MSFD food web indicators should be used and interpreted are considered, and the ramifications in terms of setting targets representing good environmental status for both fish and seabird communities are discussed.
The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic ...energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-κB (Nuclear factor-κB) signaling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Predicting intentions from observing another agent's behaviours is often thought to depend on motor resonance - i.e., the motor system's response to a perceived movement by the activation of its ...stored motor counterpart, but observers might also rely on prior expectations, especially when actions take place in perceptually uncertain situations. Here we assessed motor resonance during an action prediction task using transcranial magnetic stimulation to probe corticospinal excitability (CSE) and report that experimentally-induced updates in observers' prior expectations modulate CSE when predictions are made under situations of perceptual uncertainty. We show that prior expectations are updated on the basis of both biomechanical and probabilistic prior information and that the magnitude of the CSE modulation observed across participants is explained by the magnitude of change in their prior expectations. These findings provide the first evidence that when observers predict others' intentions, motor resonance mechanisms adapt to changes in their prior expectations. We propose that this adaptive adjustment might reflect a regulatory control mechanism that shares some similarities with that observed during action selection. Such a mechanism could help arbitrate the competition between biomechanical and probabilistic prior information when appropriate for prediction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
There is increasing evidence that oxidative stress (OS) and neuroinflammation play a role in the neuroprogression of schizophrenia (SCZ). Promising novel candidates which have been proposed in the ...search for biomarkers of psychotic illness include NADPH oxidase 1,2 (NOX1,2) and raftlin. NOX1 from the NOX family is the main source of physiological reactive oxygen species (ROS) and raftlin, the main lipid raft protein, is associated with inflammatory processes. The aim of the present study was to evaluate serum NOX1 and raftlin levels in chronic stable patients with SCZ.
We measured serum NOX1 and raftlin levels from 45 clinically stable patients with SCZ and 45 healthy controls (HCs) matched for age, sex, and body-mass index. The Positive and Negative Syndrome Scale was applied to the patient group to evaluate the severity of psychotic symptoms.
NOX1 and raftlin levels in the patients were statistically significantly higher than the HCs (NOX1 p<0.001, raftlin p<0.001). Both parameters showed very good diagnostic performance (NOX1 AUC = 0.931, raftlin AUC = 0.915). We obtained positive and significant correlations between serum levels of both biomarkers and symptom severity.
This preliminary study indicating elevations in serum NOX1 and raftlin levels in patients with SCZ supports the importance of OS and inflammatory processes in the etiopathogenesis of the illness.
This review paper describes the energy-upgraded Continuous Electron Beam Accelerator Facility (CEBAF) accelerator. This superconducting linac has achieved 12 GeV beam energy by adding 11 new ...high-performance cryomodules containing 88 superconducting cavities that have operated cw at an average accelerating gradient of
20
MV
/
m
. After reviewing the attributes and performance of the previous 6 GeV CEBAF accelerator, we discuss the upgraded CEBAF accelerator system in detail with particular attention paid to the new beam acceleration systems. In addition to doubling the acceleration in each linac, the upgrade included improving the beam recirculation magnets, adding more helium cooling capacity to allow the newly installed modules to run cold, adding a new experimental hall, and improving numerous other accelerator components. We review several of the techniques deployed to operate and analyze the accelerator performance and document system operating experience and performance. In the final portion of the document, we present much of the current planning regarding projects to improve accelerator performance and enhance operating margins, and our plans for ensuring CEBAF operates reliably into the future. For the benefit of potential users of CEBAF, the performance and quality measures for the beam delivered to each of the experimental halls are summarized in the Appendix.
<supplementary-material>
<copyright-statement>Published by the American Physical Society</copyright-statement>
2024
</supplementary-material>
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
OBJECTIVE: To assess the prevalence of combined fecal and urinary incontinence.
DESIGN: A cross‐sectional, community‐based study.
SETTING: Olmsted County, Minnesota.
PARTICIPANTS: Men (n = 778) and ...women (n = 762), aged 50 years or older, selected randomly from the population.
MEASUREMENTS: Participants completed a previously validated self‐administered questionnaire that assessed the occurrence of fecal and urinary incontinence in the previous year.
RESULTS: The age‐adjusted prevalence of incontinence was 11.1% (95% Confidence Interval (CI), 8.8–13.5) in men and 15.2% (95% CI, 12.5–17.9) in women for fecal incontinence; 25.6% (95% CI, 22.5–28.8) in men and 48.4% (95% CI, 44.7–52.2) in women for urinary incontinence; and 5.9% (95% CI, 4.1–7.6) in men and 9.4% (95% CI, 7.1–11.6) in women for combined urinary and fecal incontinence. The prevalence of fecal incontinence increased with age in men but not in women, from 8.4% among men in their fifties to 18.2% among men in their eighties (P for trend =. 001). For women, the prevalence increased from 13.1% among 50‐ year‐old women to 20.7% among women 80 years or older (P for trend =. 5). Among persons with fecal incontinence, the prevalence of concurrent urinary incontinence was 51.1% among men and 59.6% among women (P =. 001 and P =. 003, respectively). Cross‐sectionally, the age‐adjusted, relative odds of fecal incontinence among persons with urinary incontinence was greater in men than in women (Odds Ratio (OR) = 3.0; 95% CI, 1.9–4.8 in men and OR = 1.8; 95% CI, 1.2–2.7 in women, P =. 04).
CONCLUSIONS: These findings suggest that persons with one form of incontinence are likely to have the other form as well. Despite the higher prevalence of urinary and fecal incontinence among women, the association between fecal incontinence and urinary incontinence was stronger among men than women. This finding, and the significant association between fecal incontinence and age observed in men but not in women, suggest that the etiologies may be more closely linked in men than in women.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Ideopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder resulting in bone marrow fibrosis as a consequence of growth factor release from clonal haematopoiesis. Conventional ...cytogenetic analysis identifies abnormalities in approximately a third of cases at diagnosis, although rarely uncovers unique, primary genetic events. We have used comparative genomic hybridization (CGH) to study 25 IMF cases and have compared the results with conventional cytogenetics. Metaphase cells were available for analysis in 13 cases, of which seven showed an abnormal karyotype. CGH chromosomal profiles showed imbalances in 21 of 25 cases. The most frequent aberrations were gains of 9p (12 cases), 2q (seven cases), 3p (seven cases), chromosome 4 (seven cases), 12q (seven cases), 13q (eight cases). The main losses were at 17q and occurred in six cases. The results for CGH and cytogenetics were matched for one case only. Investigation of IMF by CGH suggests that genomic aberrations are much more common than has been previously indicated by conventional cytogenetic analysis and occur in the majority of cases. Gains of 9p were the most frequent finding, occurring in 50% of patients and suggests that genes on 9p may play a crucial role in the pathogenesis of IMF.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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