Effects of angular shift transformations between movements and their visual feedback on coordination in unimanual circling

Tool actions are characterized by a transformation between movements and their resulting consequences in the environment. This transformation has to be taken into account when tool actions are planned and executed. We investigated how angular shift transformations between circling movements and their visual feedback affect the coordination of this feedback with visual events in the environment. We used a task that required participants to coordinate the visual feedback of a circular hand movement (presented on the right side of a screen) with a circling stimulus (presented on the left side of a screen). Four stimulus-visual feedback relations were instructed: same or different rotations of stimulus and visual feedback, either in same or different y-directions. Visual speed was varied in three levels (0.8, 1, and 1.2 Hz). The movement-visual feedback relation was manipulated using eight angular shifts: (-180, -135, -90, -45, 0, 45, 90, and 135°). Participants were not able to perform the different rotation/different y-direction pattern, but instead fell into the different rotation/same y-direction pattern. The different rotation/same y-direction pattern and the same rotation/same y-direction pattern were performed equally well, performance was worse in the same rotation/different y-direction pattern. Best performance was observed with angular shifts 0 and -45° and performance declined with larger angular shifts. Further, performance was better with negative angular shifts than with positive angular shifts. Participants did not fully take the angular shift transformation into account: when the angular shifts were negative the visual feedback was more in advance, and when angular shifts were positive the visual feedback was less in advance of the stimulus than in 0° angular shift. In conclusion, the presence and the magnitude of angular shift transformations affect performance. Internal models do not fully take the shift transformation into account

The zebrafish cerebellar rhombic lip is spatially patterned in producing granule cell populations of different functional compartments

AbstractThe upper rhombic lip, a prominent germinal zone of the cerebellum, was recently demonstrated to generate different neuronal cell types over time from spatial subdomains. We have characterized the differentiation of the upper rhombic lip derived granule cell population in stable GFP-transgenic zebrafish in the context of zebrafish cerebellar morphogenesis. Time-lapse analysis followed by individual granule cell tracing demonstrates that the zebrafish upper rhombic lip is spatially patterned along its mediolateral axis producing different granule cell populations simultaneously. Time-lapse recordings of parallel fiber projections and retrograde labeling reveal that spatial patterning within the rhombic lip corresponds to granule cells of two different functional compartments of the mature cerebellum: the eminentia granularis and the corpus cerebelli. These cerebellar compartments in teleosts correspond to the mammalian vestibulocerebellar and non-vestibulocerebellar system serving balance and locomotion control, respectively. Given the high conservation of cerebellar development in vertebrates, spatial partitioning of the mammalian granule cell population and their corresponding earlier-produced deep nuclei by patterning within the rhombic lip may also delineate distinct functional compartments of the cerebellum. Thus, our findings offer an explanation for how specific functional cerebellar circuitries are laid down by spatio-temporal patterning of cerebellar germinal zones during early brain development

The impact of vitamin D on cancer: A mini review.

In this review, we summarize the most recent advances in vitamin D cancer research to provide molecular clarity, as well as its translational trajectory across the cancer landscape. Vitamin D is well known for its role in regulating mineral homeostasis; however, vitamin D deficiency has also been linked to the development and progression of a number of cancer types. Recent epigenomic, transcriptomic, and proteomic studies have revealed novel vitamin D-mediated biological mechanisms that regulate cancer cell self-renewal, differentiation, proliferation, transformation, and death. Tumor microenvironmental studies have also revealed dynamic relationships between the immune system and vitamin D\u27s anti-neoplastic properties. These findings help to explain the large number of population-based studies that show clinicopathological correlations between circulating vitamin D levels and risk of cancer development and death. The majority of evidence suggests that low circulating vitamin D levels are associated with an increased risk of cancers, whereas supplementation alone or in combination with other chemo/immunotherapeutic drugs may improve clinical outcomes even further. These promising results still necessitate further research and development into novel approaches that target vitamin D signaling and metabolic systems to improve cancer outcomes

IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251

Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1–mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion–dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1–induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface

Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.

The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition.

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti- cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand- bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR’s integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients

Vitamin D Modulation of Mitochondrial Oxidative Metabolism and mTOR Enforces Stress Adaptations and Anticancer Responses

The relationship between the active form of vitamin D(3) (1,25‐dihydroxyvitamin D, 1,25(OH)(2)D) and reactive oxygen species (ROS), two integral signaling molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)(2)D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)‐sensitive MG‐63 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)(2)D decreased mt ROS levels, membrane potential (ΔΨ(mt)), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress adaptive responses. Using a mitochondria‐focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)(2)D lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)(2)D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non‐oxidative energy metabolism. ATACseq revealed putative oxi‐sensitive and tumor‐suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG‐63 cells yet sequestered in the cytoplasm after 1,25(OH)(2)D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)(2)D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

Two-photon axotomy and time-lapse confocal imaging in live zebrafish embryos

Zebrafish have long been utilized to study the cellular and molecular mechanisms of development by time-lapse imaging of the living transparent embryo. Here we describe a method to mount zebrafish embryos for long-term imaging and demonstrate how to automate the capture of time-lapse images using a confocal microscope. We also describe a method to create controlled, precise damage to individual branches of peripheral sensory axons in zebrafish using the focused power of a femtosecond laser mounted on a two-photon microscope. The parameters for successful two-photon axotomy must be optimized for each microscope. We will demonstrate two-photon axotomy on both a custom built two-photon microscope and a Zeiss 510 confocal/two-photon to provide two examples

A comparative study between olive oil and corn oil on oxidative metabolism

Fats are an important part of diet, but not all lipids have the same structure and chemical properties. Unsaturated fatty acids have one or more double bonds in their structure and can be monounsaturated or polyunsaturated, respectively. Most vegetable oils, such as olive oil and corn oil, contain significant amounts of these fatty acids. The presence of double bonds in the molecule of a fatty acid constitutes vulnerable sites for oxidation reactions generating lipid peroxides, potentially toxic compounds that can cause cellular damage. In response to this oxidative damage, aerobic organisms have intracellular enzymatic antioxidant defense mechanisms. The aim of the present investigation was to study comparatively the effects of control liquid diets, of a defined composition, containing olive oil or corn oil as a lipid source respectively of monounsaturated and polyunsaturated fatty acids, on the oxidative metabolism of rats. Rats were divided into three groups which received a control animal feed diet (A.F.), olive oil liquid diet (O.O) and corn oil liquid diet (C.O) for 30 days. It was observed that the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), increased in the liver and white fat tissue of rats fed with olive oil when compared to the corn oil group. However, in brown fat tissue and blood cells, the enzyme activities showed a tendency to decrease in the olive oil group. In addition, the effect of olive oil and corn oil on several glucose metabolism parameters (pyruvate, lactate, LDH, acetoacetate and beta-hydroxybutyrate) showed that corn oil impairs to a greater extent the cellular metabolism. All these results helped in concluding that some body tissues are more adversely affected than others by the administration of corn oil or olive oil, and their antioxidant defenses and cellular metabolism respond differently too.This work was supported by the Universidad Católica de Valencia “San Vicente Mártir” (grant number: UCV257-001)Nutrición humana y dietétic

Nutrition planning and hydration control during a six-stage Pirineos FIT Endurance trail-running race. A case report

Ultra-endurance competitions are highly demanding sport events for athletes and require a carefully controlled nutrition, hydration and supplementation before, during and after the physical effort. Scientific research has shown a positive relationship between dietetic (caloric and macronutrient ingestion) recommendations and sport performance. This study describes the nutritional and hydration planning applied to an athlete competing at the Pirineos FIT (a semi-self-sufficient trail-running multi-stage event). Diary caloric ingestion was around 4000 Kcal, 550 Kcal were consumed during the race. In general, the athlete maintained the minimal recommendable levels of hydration (2.5% Body Weight Loss) and Borg's Scale of Exertion (RPE) was used to report subjective perception of fatigue after each stage. Hematological and biochemical parameters showed a normal response to endurance physical exercise. Therefore, the nutrition and hydration planning were successfully applied.Nutrición humana y dietétic