Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms ...remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.
The Transiting Exoplanet Survey Satellite (TESS) recently observed 18 transits of the hot Jupiter WASP-4b. The sequence of transits occurred 81.6 11.7 s earlier than had been predicted, based on data ...stretching back to 2007. This is unlikely to be the result of a clock error, because TESS observations of other hot Jupiters (WASP-6b, 18b, and 46b) are compatible with a constant period, ruling out an 81.6 s offset at the 6.4 level. The 1.3 day orbital period of WASP-4b appears to be decreasing at a rate of ms per year. The apparent period change might be caused by tidal orbital decay or apsidal precession, although both interpretations have shortcomings. The gravitational influence of a third body is another possibility, though at present there is minimal evidence for such a body. Further observations are needed to confirm and understand the timing variation.
Individuals who regularly shift their sleep timing, like night and/or shift‐workers suffer from circadian desynchrony and are at risk of developing cardiometabolic diseases and cancer. Also, ...shift‐work is are suggested to be a risk factor for the development of mood disorders such as the burn out syndrome, anxiety, and depression. Experimental and clinical studies provide evidence that food intake restricted to the normal activity phase is a potent synchronizer for the circadian system and can prevent the detrimental health effects associated with circadian disruption. Here, we explored whether adult male Wistar rats exposed to an experimental model of shift‐work (W‐AL) developed depressive and/or anxiety‐like behaviors and whether this was associated with neuroinflammation in brain areas involved with mood regulation. We also tested whether time‐restricted feeding (TRF) to the active phase could ameliorate circadian disruption and therefore would prevent depressive and anxiety‐like behaviors as well as neuroinflammation. In male Wistar rats, W‐AL induced depressive‐like behavior characterized by hypoactivity and anhedonia and induced increased anxiety‐like behavior in the open field test. This was associated with increased number of glial fibrillary acidic protein and IBA‐1‐positive cells in the prefrontal cortex and basolateral amygdala. Moreover W‐AL caused morphological changes in the microglia in the CA3 area of the hippocampus indicating microglial activation. Importantly, TRF prevented behavioral changes and decreased neuroinflammation markers in the brain. Present results add up evidence about the importance that TRF in synchrony with the light–dark cycle can prevent neuroinflammation leading to healthy mood states in spite of circadian disruptive conditions.
In male rats exposed to an experimental model of shift‐work, we reported circadian disruption, depressive and anxiety‐like behaviors as well as neuroinflammation in brain areas associated with mood regulation. Time‐restricted feeding associated with the normal activity phase prevents depressive and anxiety‐like behaviors as well as neuroinflammation.
Night-workers, transcontinental travelers and individuals that regularly shift their sleep timing, suffer from circadian desynchrony and are at risk to develop metabolic disease, cancer, and mood ...disorders, among others. Experimental and clinical studies provide evidence that food intake restricted to the normal activity phase is a potent synchronizer for the circadian system and can prevent the detrimental metabolic effects associated with circadian disruption. As an alternative, we hypothesized that a timed piece of chocolate scheduled to the onset of the activity phase may be sufficient stimulus to synchronize circadian rhythms under conditions of shift-work or jet-lag. In Wistar rats, a daily piece of chocolate coupled to the onset of the active phase (breakfast) accelerated re-entrainment in a jet-lag model by setting the activity of the suprachiasmatic nucleus (SCN) to the new cycle. Furthermore, in a rat model of shift-work, a piece of chocolate for breakfast prevented circadian desynchrony, by increasing the amplitude of the day-night c-Fos activation in the SCN. Contrasting, chocolate for dinner prevented re-entrainment in the jet-lag condition and favored circadian desynchrony in the shift-work models. Moreover, chocolate for breakfast resulted in low body weight gain while chocolate for dinner boosted up body weight. Present data evidence the relevance of the timing of a highly caloric and palatable meal for circadian synchrony and metabolic function.
Natural killer (NK) cells have been involved in the pathology of different inflammatory and autoimmune disorders. Inflammation is an important regulator of osteoarthritis (OA), but the molecular and ...cellular mechanisms regulating this process are not well defined.
To understand the role of NK cells in OA, we have compared the phenotype (CD56 subsets and perforin and granzyme expression) and cytotoxic function of NK cells in peripheral blood and synovial fluid from patients with OA undergoing total knee arthroplasty.
In contrast to peripheral blood lymphocytes (PBLs), the majority of NK cells from the synovial fluid were CD56brightCD16(−) cells. As expected the expression of the cytolytic mediators perforin and granzyme B in CD56brightCD16(−) cells was low and correlated with a poor cytotoxic potential against K562 sensitive target cells. Surprisingly, this low cytotoxic NK cell subset expressed high levels of granzyme A (a protease recently characterized as a key modulator of inflammation in mouse models) in synovial fluid but not in peripheral blood. The presence of the CD56(+)brightCD16(−) cells expressing granzyme A correlated with increased levels of pro-inflammatory cytokines in synovial fluid from OA patients.
Our results indicate that NK cells from the synovium of patients with OA, which present an immunoregulatory non-cytotoxic phenotype, show different phenotype comparing with NK cells from peripheral blood, especially expressing granzyme A, a pro-inflammatory molecule which may contribute to the establishment of chronic articular inflammation in this type of patients.
Microglia is considered the central nervous system (CNS) resident macrophages that establish an innate immune response against pathogens and toxins. However, the recent studies have shown that ...microglial gene and protein expression follows a circadian pattern; several immune activation markers and clock genes are expressed rhythmically without the need for an immune stimulus. Furthermore, microglia responds to an immune challenge with different magnitudes depending on the time of the day. This review examines the circadian control of microglia function and the possible physiological implications. For example, we discuss that synaptic prune is performed in the cortex at a certain moment of the day. We also consider the implications of daily microglial function for maintaining biological rhythms like general activity, body temperature, and food intake. We conclude that the developmental stage, brain region, and pathological state are not the only factors to consider for the evaluation of microglial functions; instead, emerging evidence indicates that circadian time as an essential aspect for a better understanding of the role of microglia in CNS physiology.
Main Points
Microglia are rhythmic cells with an oscillatory expression in clock genes, cytokines, and other microglial markers.
Microglial circadian rhythms determine their physiological function and immune responses.
Dominant mutations in the RNA/DNA-binding protein TDP-43 have been linked to amyotrophic lateral sclerosis (ALS). Here, we screened genomic DNA extracted from spinal cord specimens of sporadic ALS ...patients for mutations in the TARDBP gene and identified a patient specimen with previously reported Q331K mutation. The patient spinal cord tissue with Q331K mutation showed accumulation of higher levels of DNA strand breaks and the DNA double-strand break (DSB) marker γH2AX, compared to age-matched controls, suggesting a role of the Q331K mutation in genome-damage accumulation. Using conditional SH-SY5Y lines ectopically expressing wild-type (WT) or Q331K-mutant TDP-43, we confirmed the increased cytosolic sequestration of the poly-ubiquitinated and aggregated form of mutant TDP-43, which correlated with increased genomic DNA strand breaks, activation of the DNA damage response factors phospho-ataxia-telangiectasia mutated (ATM), phospho-53BP1, γH2AX and neuronal apoptosis. We recently reported the involvement of WT TDP-43 in non-homologous end joining (NHEJ)-mediated DSB repair, where it acts as a scaffold for the recruitment of XRCC4-DNA ligase 4 complex. Here, the mutant TDP-43, due to its reduced interaction and enhanced cytosolic mislocalization, prevented the nuclear translocation of XRCC4-DNA ligase 4. Consistently, the mutant cells showed significantly reduced DNA strand break sealing activity and were sensitized to DNA-damaging drugs. In addition, the mutant cells showed elevated levels of reactive oxygen species, suggesting both dominant negative and loss-of-function effects of the mutation. Together, our study uncovered an association of sporadic Q331K mutation with persistent genome damage accumulation due to both damage induction and repair defects.
Context. Large sub-Neptunes are uncommon around the coolest stars in the Galaxy and are rarer still around those that are metal-poor. However, owing to the large planet-to-star radius ratio, these ...planets are highly suitable for atmospheric study via transmission spectroscopy in the infrared, such as with JWST. Aims. Here we report the discovery and validation of a sub-Neptune orbiting the thick-disk, mid-M dwarf star TOI-2406. The star’s low metallicity and the relatively large size and short period of the planet make TOI-2406 b an unusual outcome of planet formation, and its characterisation provides an important observational constraint for formation models. Methods. We first infer properties of the host star by analysing the star’s near-infrared spectrum, spectral energy distribution, and Gaia parallax. We use multi-band photometry to confirm that the transit event is on-target and achromatic, and we statistically validate the TESS signal as a transiting exoplanet. We then determine physical properties of the planet through global transit modelling of the TESS and ground-based time-series data. Results. We determine the host to be a metal-poor M4 V star, located at a distance of 56 pc, with properties T eff = 3100 ± 75 K, M * = 0.162 ± 0.008 M ⊙ , R * = 0.202 ± 0.011 R ⊙ , and Fe∕H = −0.38 ± 0.07, and a member of the thick disk. The planet is a relatively large sub-Neptune for the M-dwarf planet population, with R p = 2.94 ± 0.17 R ⊕ and P = 3.077 d, producing transits of 2% depth. We note the orbit has a non-zero eccentricity to 3 σ , prompting questions about the dynamical history of the system. Conclusions. This system is an interesting outcome of planet formation and presents a benchmark for large-planet formation around metal-poor, low-mass stars. The system warrants further study, in particular radial velocity follow-up to determine the planet mass and constrain possible bound companions. Furthermore, TOI-2406 b is a good target for future atmospheric study through transmission spectroscopy. Although the planet’s mass remains to be constrained, we estimate the S/N using amass-radius relationship, ranking the system fifth in the population of large sub-Neptunes, with TOI-2406 b having a much lower equilibrium temperature than other spectroscopically accessible members of this population.
The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a ...novel class of small molecules (1,2,3triazolo4,5-dpyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
Interaction between the hypothalamus and the immune system Soto‐Tinoco, Eva; Guerrero‐Vargas, Natalí N.; Buijs, Ruud M.
Experimental physiology,
1 December 2016, 2016-Dec-01, 2016-12-00, 20161201, Letnik:
101, Številka:
12
Journal Article
Recenzirano
Odprti dostop
New Findings
What is the topic of this review?
Both branches of the autonomic nervous system are involved in the regulation of the inflammatory response. We explore how the hypothalamus may influence ...this process.
What advances does it highlight?
We analyse how a lipopolysaccharide signal is transmitted to the brain and which areas participate in the response of the brain to lipopolysaccharide. Recent studies show that the hypothalamus can influence the inflammatory response by modifying the autonomic output. The biological clock, the suprachiasmatic nucleus, is integrated into this circuit, putting a time stamp on the intensity of the inflammatory response.
The brain is responsible for maintaining homeostasis of the organism, constantly adjusting its output via hormones and the autonomic nervous system to reach an optimal setting in every compartment of the body. Also, the immune system is under strong control of the brain. Apart from the conventional systemic responses evoked by the brain during inflammation, such as hypothalamic–pituitary–adrenal axis activation and the induction of sickness behaviour, the autonomic nervous system is now recognized to exert regulatory effects on the inflammatory response. Both branches of the autonomic nervous system are proposed to influence the inflammatory process. Here, we focus on those areas of the brain that might be involved in sensing inflammatory stimuli, followed by how that sensing could change the output of the autonomic nervous system in order to regulate the inflammatory response. Finally, we will discuss how the defenses of the body against a lipopolysaccharide challenge are organized by the hypothalamus.
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