The circadian rhythmicity of endogenous metabolic and hormonal processes is controlled by a complex system of central and peripheral pacemakers, influenced by exogenous factors like ...light/dark-cycles, nutrition and exercise timing. There is evidence that alterations in this system may be involved in the pathogenesis of metabolic diseases. It has been shown that disruptions to normal diurnal rhythms lead to drastic changes in circadian processes, as often seen in modern society due to excessive exposure to unnatural light sources. Out of that, research has focused on time-restricted feeding and exercise, as both seem to be able to reset disruptions in circadian pacemakers. Based on these results and personal physical goals, optimal time periods for food intake and exercise have been identified. This review shows that appropriate nutrition and exercise timing are powerful tools to support, rather than not disturb, the circadian rhythm and potentially contribute to the prevention of metabolic diseases. Nevertheless, both lifestyle interventions are unable to address the real issue: the misalignment of our biological with our social time.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We wanted to determine the influence of total blood volume (BV) and blood lactate quantity on lactate concentrations during incremental exercise. Twenty-six healthy, nonsmoking, heterogeneously ...trained females (27.5 ± 5.9 ys) performed an incremental cardiopulmonary exercise test on a cycle ergometer during which maximum oxygen uptake (V·O
), lactate concentrations (La
) and hemoglobin concentrations (Hb) were determined. Hemoglobin mass and blood volume (BV) were determined using an optimised carbon monoxide-rebreathing method. V·O
and maximum power (P
) ranged between 32 and 62 mL·min
·kg
and 2.3 and 5.5 W·kg
, respectively. BV ranged between 81 and 121 mL·kg
of lean body mass and decreased by 280 ± 115 mL (5.7%,
= 0.001) until P
. At P
, the La
was significantly correlated to the systemic lactate quantity (La
, r = 0.84,
< 0.0001) but also significantly negatively correlated to the BV (r = -0.44,
< 0.05). We calculated that the exercise-induced BV shifts significantly reduced the lactate transport capacity by 10.8% (
< 0.0001). Our results demonstrate that both the total BV and La
have a major influence on the resulting La
during dynamic exercise. Moreover, the blood La
transport capacity might be significantly reduced by the shift in plasma volume. We conclude, that the total BV might be another relevant factor in the interpretation of La
during a cardio-pulmonary exercise test.
Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic ...skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in Dystrophin, one of the largest proteins in the mammalian body, are causative for a severe form of muscle disease, Duchenne Muscular Dystrophy (DMD), affecting not only skeletal muscle, ...but also the heart. In particular, exons 45-52 constitute a hotspot for DMD mutations. A variety of molecular therapies have been developed, comprising vectors encoding micro- and minidystrophins as well as utrophin, a protein with partially overlapping functions. With the advent of the CRISPR-Cas9-nuclease, genome editing offers a novel option of correction of the disease-cuasing mutations. Full restoration of the healthy gene by homology directed repair is a rare event. However, non-homologous end-joining (NHEJ) may restore the reading frame by causing exon excision. This approach has first been demonstrated in mice and then translated to large animals (dogs, pigs). This review discusses the potential opportunities and limitations of genome editing in DMD, including the generation of appropriate animal models as well as new developments in genome editing tools.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Adoptive cellular immunotherapy (ACI) is a promising treatment for a number of cancers. Cytokine-induced killer cells (CIKs) are considered to be major cytotoxic immunologic effector cells. Usually ...cancer cells are able to suppress antitumor responses by secreting immunosuppressive factors. CIKs have significant antitumor activity and are capable of eradicating tumors with few side effects. They are a very encouraging cell population used against hematological and solid tumors, with an inexpensive expansion protocol which could yield to superior clinical outcome in clinical trials employing adoptive cellular therapy combination. In the last decade, clinical protocols have been modified by enriching lymphocytes with CIK cells. They are a subpopulation of lymphocytes characterized by the expression of CD3+ and CD56+ wich are surface markers common to T lymphocytes and natural killer NK cells. CIK cells are mainly used in two diseases: in hematological patients who suffer relapse after allogeneic transplantation and in patients with hepatic carcinoma after surgical ablation to eliminate residual tumor cells. Dendritic cells DCs could play a pivotal role in enhancing the antitumor efficacy of CIKs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Catatonia is a central aspect of schizophrenia spectrum disorders (SSD) and most likely associated with abnormalities in affective, motor, and sensorimotor brain regions. However, contributions of ...different cortical features to the pathophysiology of catatonia in SSD are poorly understood. Here, T1-weighted structural magnetic resonance imaging data at 3 T were obtained from 56 right-handed patients with SSD. Using FreeSurfer version 6.0, we calculated cortical thickness, area, and local gyrification index (LGI). Catatonic symptoms were examined on the Northoff catatonia rating scale (NCRS). Patients with catatonia (NCRS total score ≥3; n = 25) showed reduced surface area in the parietal and medial orbitofrontal gyrus and LGI in the temporal gyrus (P < .05, corrected for cluster-wise probability CWP) as well as hypergyrification in rostral cingulate and medial orbitofrontal gyrus when compared with patients without catatonia (n = 22; P < .05, corrected for CWP). Following a dimensional approach, a negative association between NCRS motor and behavior scores and cortical thickness in superior frontal, insular, and precentral cortex was found (34 patients with at least 1 motor and at least 1 other affective or behavioral symptom; P < .05, corrected for CWP). Positive associations were found between NCRS motor and behavior scores and surface area and LGI in superior frontal, posterior cingulate, precentral, and pericalcarine gyrus (P < .05, corrected for CWP). The data support the notion that cortical features of distinct evolutionary and genetic origin differently contribute to catatonia in SSD. Catatonia in SSD may be essentially driven by cortex variations in frontoparietal regions including regions implicated in the coordination and goal-orientation of behavior.
A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify ...reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in
infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS). We identified the inhibitor of κB (IκB) kinase (IKK) complex regulatory subunit NEMO nuclear factor κB (NF-κB) essential modulator as a target for mtROS. Specifically, mtROS induced intermolecular covalent linkage of NEMO through disulfide bonds formed by Cys
and Cys
, which was essential for activation of the IKK complex and subsequent signaling through the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and NF-κB pathways that eventually led to the secretion of proinflammatory cytokines. We thus identify mtROS-dependent disulfide linkage of NEMO as an essential regulatory step of the proinflammatory response of macrophages to bacterial infection.
Parallel multisite recordings in the visual cortex of trained monkeys revealed that the responses of spatially distributed neurons to natural scenes are ordered in sequences. The rank order of these ...sequences is stimulus-specific and maintained even if the absolute timing of the responses is modified by manipulating stimulus parameters. The stimulus specificity of these sequences was highest when they were evoked by natural stimuli and deteriorated for stimulus versions in which certain statistical regularities were removed. This suggests that the response sequences result from a matching operation between sensory evidence and priors stored in the cortical network. Decoders trained on sequence order performed as well as decoders trained on rate vectors but the former could decode stimulus identity from considerably shorter response intervals than the latter. A simulated recurrent network reproduced similarly structured stimulus-specific response sequences, particularly once it was familiarized with the stimuli through non-supervised Hebbian learning. We propose that recurrent processing transforms signals from stationary visual scenes into sequential responses whose rank order is the result of a Bayesian matching operation. If this temporal code were used by the visual system it would allow for ultrafast processing of visual scenes.
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