Abstract
Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that has been linked to defective DNA repair. Many familial ALS patients harbor autosomal dominant mutations in the ...gene encoding the RNA/DNA binding protein ‘fused in sarcoma’ (FUS) commonly inducing its cytoplasmic mislocalization. Recent reports from our group and others demonstrate a role of FUS in maintaining genome integrity and the DNA damage response (DDR). FUS interacts with many DDR proteins and may regulate their recruitment at damage sites. Given the role of FUS in RNA transactions, here we explore whether FUS also regulates the expression of DDR factors. We performed RT
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PCR arrays for DNA repair and DDR signaling pathways in CRISPR/Cas9 FUS knockout (KO) and shRNA mediated FUS knockdown (KD) cells, which revealed significant (> 2-fold) downregulation of BRCA1, DNA ligase 4, MSH complex and RAD23B. Importantly, similar perturbations in these factors were also consistent in motor neurons differentiated from an ALS patient-derived induced pluripotent stem cell (iPSC) line with a FUS-P525L mutation, as well as in postmortem spinal cord tissue of sporadic ALS patients with FUS pathology. BRCA1 depletion has been linked to neuronal DNA double-strand breaks (DSBs) accumulation and cognitive defects. The ubiquitin receptor RAD23 functions both in nucleotide excision repair and proteasomal protein clearance pathway and is thus linked to neurodegeneration. Together, our study suggests that the FUS pathology perturbs DDR signaling via both its direct role and the effect on the expression of DDR genes. This underscors an intricate connections between FUS, genome instability, and neurodegeneration.
Highlights • Computer-aided cephalometric systems tend not to be practical and intuitive. • A new haptic-enabled landmarking approach for 3D cephalometry is proposed. • Several experimental tests ...were conducted to evaluate the proposed approach. • Haptic technologies facilities the landmark selection process in 3D cephalometry. • The haptic user interface allows the user to feel and touch the virtual patient's skull.
Although current research has contributed to the promotion of whole-food plant-based diets, few studies have examined healthy vegan dietary and lifestyle factors, especially in South America. ...Therefore, we aimed at investigating the adherence to healthy vegan lifestyle habits among Argentinian vegetarians and omnivorous, using a recently developed vegetarian lifestyle index adapted to the vegan dietary pattern. Also, accessibility of vegetarian foods, and the proportion of household income spent on food were assessed in a cross-sectional approach with 1454 participants. The population was comprised of females (84.9%), singles (55.0%), young-adults (mean age 32.1, standard deviation (SD) = 13.6), employed (50.8%), with high educational levels (50.4%), and low prevalence of both tobacco smoking (7.0%) and frequent alcohol consumption (7.6%). The mean score of adherence to healthy vegan lifestyle habits was 6.64 (SD = 1.72), with higher scores indicating better adherence. Non-vegetarians (5.75; 95% confidence interval (CI), 5.61⁻5.89) had a significantly lower adjusted mean score compared to semi-(6.32; 95% CI, 6.17⁻6.47), pesco-(6.99; 95% CI, 6.59⁻7.39), lacto-ovo-vegetarians (7.10; 95% CI, 6.96⁻7.24), as well as vegans (8.59; 95% CI, 8.35⁻8.83). The mean proportion of household income spent on food was significantly lower among vegans compared with other dietary patterns. The whole studied population showed a low consumption of whole grains, legumes, vegetables, nuts, and seeds. Although vegans showed a better diet and lifestyle pattern there is a need to improve eating and lifestyle habits to address risk factors for non-communicable diseases in Argentina.
•Control of the modular multilevel converter (MMC).•Reduction of the effect of grid harmonics.•Proportional resonant (PR) controllers and a harmonic compensator (HC) scheme.•Compliance with the low ...voltage ride through (LVRT) regulation.
This paper is about the control of Modular multilevel converters, an innovative technology in the design of converters, which is beginning to be included in real installations. Papers about this topic include simulation models, circulating current reduction, voltage modulators, capacitor voltage balancing and control issues. The scheme for current source regulation used in this article includes all control loops, which are, from the outermost to innermost, DC bus voltage regulator, current regulator, voltage modulator, capacitor voltage balancing, and a PLL for the synchronization to the grid. Disposition-sinusoidal pulse width modulation is used as the voltage modulator, and an enhanced control strategy in the stationary reference frame for 3-phase MMCs is used for the inner current control loops. Very detailed simulations of the complete control system have been performed for both the enhanced control strategy in the stationary reference frame, and the well-known control in the synchronous reference frame, as well as some experiments using the hardware-in-the-loop simulation technique. The validation of these control strategies is made by a comparison of the capability of each one to compensate the harmonic distortions of the utility grid according to the grid code. The correct operation has been tested in the case of a strong/weak grid, unbalances and grid failures.
To compare different volumes of injectate using electrostimulator (ES)-guided and blind brachial plexus blockade (BPB) techniques in dogs. Prospective, randomised, blinded study. Fifty-eight healthy ...adult purpose-bred beagle dogs. Animals were randomised into 4 groups based on the volume of methylene blue 0.1 per cent administered for BPB, three using ES technique: E1 (0.2 ml/kg, n=22), E2 (0.6 ml/kg, n=22), and E3 (1.0 ml/kg, n=14), and one using blinded technique B4 (1.0 ml/kg, n=14). After euthanasia, the axillary region was dissected and nerves identified by a blinded evaluator. Success was defined as 3/4 nerves stained, or presence of dye in the tissue immediately surrounding the plexus. There were no significant differences between groups when total nerve count, adjacent staining, success rate (92.8-100 per cent), or rate of haematoma were evaluated. The musculocutaneous nerve was significantly more targeted in B4 than E1 and E2, but not E3. Electrostimulator-guided BPB using lower volumes of injectate had similar success rate as the blinded technique using higher volume, thus, lower volumes can be used without compromising success. When an ES is not available, the blind technique with 1 ml/kg is also acceptable. However, when performing an ES-guided BPB, volumes as low as 0.2 ml/kg can be used. As volume is increased, the musculocutaneous nerve becomes more likely to be targeted.
Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical ...application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.
Restricted intermittent food access to palatable food (PF) induces addiction-like behaviors and plastic changes in corticolimbic brain areas. Intermittent access protocols normally schedule PF to a ...fixed time, enabling animals to predict the arrival of PF. Because outside the laboratory the presence of PF may occur in a random unpredictable manner, the present study explored whether random access to PF would stimulate similar addiction-like responses as observed under a fixed scheduled. Rats were randomly assigned to a control group without chocolate access, to ad libitum access to chocolate, to fixed intermittent access (CH-F), or to random unpredictable access (CH-R) to chocolate. Only the CH-F group developed behavioral and core temperature anticipation to PF access. Both groups exposed to intermittent access to PF showed binge eating, increased effort behaviors to obtain chocolate, as well as high FosB/ΔFosB in corticolimbic areas. Moreover, FosB/ΔFosB in all areas correlated with the intensity of binge eating and effort behaviors. We conclude that both conditions of intermittent access to PF stimulate addiction-like behaviors and FosB/ΔFosB accumulation in brain reward areas; while only a fixed schedule, which provides a time clue, elicited anticipatory activation, which is strongly associated with craving behaviors and may favor relapse during withdrawal.
The circadian system organizes circadian rhythms (biological cycles that occur around 24 h) that couple environmental cues (zeitgebers) with internal functions of the organism. The misalignment ...between circadian rhythms and external cues is known as chronodisruption and contributes to the development of mental, metabolic and other disorders, including cancer, cardiovascular diseases and addictive disorders. Drug addiction represents a global public health concern and affects the health and well-being of individuals, families and communities. In this manuscript, we reviewed evidence indicating a bidirectional relationship between the circadian system and the development of addictive disorders. We provide information on the interaction between the circadian system and drug addiction for each drug or drug class (alcohol, cannabis, hallucinogens, psychostimulants and opioids). We also describe evidence showing that drug use follows a circadian pattern, which changes with the progression of addiction. Furthermore, clock gene expression is also altered during the development of drug addiction in many brain areas related to drug reward, drug seeking and relapse. The regulation of the glutamatergic and dopaminergic neurocircuitry by clock genes is postulated to be the main circadian mechanism underlying the escalation of drug addiction. The bidirectional interaction between the circadian system and drug addiction seems to be mediated by the effects caused by each drug or class of drugs of abuse. These studies provide new insights on the development of successful strategies aimed at restoring/stabilizing circadian rhythms to reduce the risk for addiction development and relapse.
•Chronodisruption is a risk factor for the development of addictive disorders.•Frequent use of drugs of abuse promotes circadian disruption.•Chronodisruption contributes to withdrawal signs leading to relapse.•Circadian rhythms restoration could help to successfully treat addictive disorders.
Light at night is an emergent problem for modern society. Rodents exposed to light at night develop a loss of circadian rhythms, which leads to increased adiposity, altered immune response, and ...increased growth of tumors. In female rats, constant light (LL) eliminates the estrous cycle leading to a state of persistent estrus. The suprachiasmatic nucleus (SCN) drives circadian rhythms, and it interacts with the neuroendocrine network necessary for reproductive function. Timed restricted feeding (RF) exerts a powerful entraining influence on the circadian system, and it can influence the SCN activity and can restore rhythmicity or accelerate re-entrainment in experimental conditions of shift work or jet lag. The present study explored RF in female rats exposed to LL, with the hypothesis that this cyclic condition can rescue or prevent the loss of daily rhythms and benefit the expression of the estrous cycle. Two different feeding schedules were explored: 1. A 12-h food/12-h fasting schedule applied to arrhythmic rats after 3 weeks in LL, visualized as a rescue strategy (LL + RFR, 3 weeks), or applied simultaneously with the first day of LL as a preventive strategy (LL + RFP, 6 weeks). 2. A 12-h window of food intake with food given in four distributed pulses (every 3 h), applied after 3 weeks in LL, as a rescue strategy (LL + PR, 3 weeks) or applied simultaneously with the first day of LL as a preventive strategy (LL + PP, 6 weeks). Here, we present evidence that scheduled feeding can drive daily rhythms of activity and temperature in rats exposed to LL. However, the protocol of distributed feeding pulses was more efficient to restore the day–night activity and core temperature as well as the c-Fos day–night change in the SCN. Likewise, the distributed feeding partially restored the estrous cycle and the ovary morphology under LL condition. Data here provided indicate that the 12-h feeding/12-h fasting window determines the rest-activity cycle and can benefit directly the circadian and reproductive function. Moreover, this effect is stronger when food is distributed along the 12 h of subjective night.
More than thirty years have passed since the discovery of the prion protein (PrP) and its causative role in transmissible spongiform encephalopathy. Since a combination of both gain- and ...loss-of-function mechanisms may underlay prion pathogenesis, understanding the physiological role of PrP may give important clues about disease mechanisms. Historically, the primary strategy for prion research has involved the use of human tissue, cell cultures and mammalian animal models. Nevertheless, experimental difficulties of in vivo studies and controversial observations obtained in these systems have stimulated the search for alternative animal models. PrPC is highly conserved in mammals, and PrPC-related orthologs are expressed in zebrafish, a vertebrate model organism suitable to study the mechanisms associated with human diseases. Invertebrate models, as they do not express PrPC have served to investigate the neurotoxic mechanisms of mammalian PrP. Here we overview most recent advances in the study of PrP function in normal and pathogenic conditions based on non-mammalian studies, highlighting the contribution of zebrafish, fly and worms to our current understanding of PrP biology.
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