Research onto the pathogenesis of amyotrophic lateral sclerosis (ALS) has obtained notable gene discoveries, although, to date, only progress with regard to treatment has been very modest. Currently ...ALS is considered a multifactorial disease that presents diverse clinical presentations, ranging from a monogenic inherited disease to an autoimmune pathology, and develops with misfolded protein aggregation and neuroinflammation. An important factor related to ALS pathogenesis is the microglial activation associated with degenerative motor neurons. This activation leads to changes in the expression of a wide range of genes related to phagocytosis and inflammation, and to profound modifications in the dynamic interactions between neurons and glial cells. Overactivation and deregulation of microglial activity causes deleterious effects and leads to neuronal death. However, the involvement of microglia in non-inflammatory functions challenges our concept of neuroinflammation and opens up new possibilities for the study of the pathophysiological mechanisms of ALS. In this review we summarize the current knowledge on the adaptive interactions between neurons and microglia in ALS. We also discuss the hypothesis that controlling the extent of microglial activation and neuroinflammation may have clinical and therapeutic benefits for the condition.
The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the ...survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic sALS and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27 ± 4.90) than patients with 249V/V genotype (67.65 ± 7.42; diff -25.49 months 95%CI -42.79,-8.18; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff = -29.78 months; 95%CI -49.42,-10.14; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff = -27.02 months; 95%CI -49.57, -4.48; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% 1.32, 5.07; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.
•Plants use MVA and MEP pathways to produce the common precursors of all isoprenoids.•The two pathways are physically separated but coordinated at several levels.•The subcelular distribution of plant ...MVA pathway enzymes remains controversial.•Post-translational control is central to regulate MVA and MEP pathway activities.•Mechanisms for coordination with related metabolic pathways are little known.
The common metabolic precursors used for the production of all isoprenoid compounds are synthesized by two unrelated pathways in plants. The methylerythritol 4-phosphate (MEP) pathway produces these precursors in the plastid, whereas the biosynthesis of non-plastidial isoprenoids relies on the operation of the mevalonic acid (MVA) pathway. Despite the physical separation of the two pathways, some interaction exists at molecular and metabolic levels. Recent results have provided strong evidence that a high degree of control over each individual pathway takes place at the post-translational level. In particular, new mechanisms regulating the levels and activity of rate-determining enzymes have been unveiled. Current challenges include the study of the subcellular operation of the MEP and MVA pathways and their coordination with upstream and downstream pathways that supply their substrates and consume their products.
The formation and maintenance of the epidermis depend on epidermal stem cell differentiation and must be tightly regulated. Epigenetic mechanisms such as DNA methylation allow the precise gene ...expression cascade needed during cellular differentiation. However, these mechanisms become deregulated during aging and tumorigenesis, where cellular function and identity become compromised. Here we provide a review of this rapidly developing field. We discuss recent discoveries related to epidermal homeostasis, aging, and cancer, including the functional role of DNA methyltransferases, the methylation clock, and the determination of tumor cells-of-origin. Finally, we focus on future advances, greatly influenced by single-cell sequencing technologies.
Well-being in children with a complex medical condition (CMC) impacts the way they view and communicate with their immediate environment as well as their development, and it is thus necessary to ...inquire about the contextual issues and different needs that a CMC carries. This pilot study aimed to identify factors of pediatric well-being from the experience of hospitalization and convalescence of youth with CMC and their caregivers, in a cross-sectional analysis using a selective methodology complemented by an indirect observational methodology. We analyzed the quality of life and well-being of youth with CMC using a validated KINDLR questionnaire. We collected 35 surveys: 11 from youth with CMC and 24 from caregivers from Spain. We focused the analysis on sociodemographics, well-being perceptions, and coping strategies variables. The results show that children aged between 3 and 6 years and their caregivers scored physical well-being the lowest out of all dimensions of well-being, and they scored family well-being the highest. Moreover, youth between the ages of 7 and 17 years and their caregivers scored school-related well-being the lowest. Coping strategies to deal with stressful situations differ between children and caregivers. While children mainly engage in social withdrawal, caregivers engage in cognitive restructuring and expressing emotions. However, we did not find a relationship between coping strategies and well-being perceptions. These results highlight the need to facilitate communication spaces with both families and health professionals where the voice of children is considered.
There is a significant number of funerary contexts for the Early Neolithic in the Iberian Peninsula, and the body of information is much larger for the Late Neolithic. In contrast, the archaeological ...information available for the period in between (ca. 4800-4400/4200 cal BC) is scarce. This period, generally called Middle Neolithic, is the least well-known of the peninsular Neolithic sequence, and at present there is no specific synthesis on this topic at the peninsular scale. In 2017, an exceptional funerary context was discovered at Dehesilla Cave (Sierra de C#225;diz, Southern Iberian Peninsula), providing radiocarbon dates which place it at the beginning of this little-known Middle Neolithic period, specifically between ca. 4800-4550 cal BC. Locus 2 is a deposition constituted by two adult human skulls and the skeleton of a very young sheep/goat, associated with stone structures and a hearth, and a number of pots, stone and bone tools and charred plant remains. The objectives of this paper are, firstly, to present the new archaeological context documented at Dehesilla Cave, supported by a wide range of data provided by interdisciplinary methods. The dataset is diverse in nature: stratigraphic, osteological, isotopic, zoological, artifactual, botanical and radiocarbon results are presented together. Secondly, to place this finding within the general context of the contemporaneous sites known in the Iberian Peninsula through a systematic review of the available evidence. This enables not only the formulation of explanations of the singular new context, but also to infer the possible ritual funerary behaviours and practices in the 5.sup.th millennium cal BC in the Iberian Peninsula.
Extraordinarily simple, convenient, and efficient: A general and operationally simple one‐pot synthesis of unsymmetrical diaryl sulfides by coupling two different bromoarenes and ...triisopropylsilanethiol (TIPS‐SH) is reported. This protocol overcomes the narrow availability of arene thiols and their instability to oxidation. These reactions catalyzed by palladium complexes generated from the alkylbisphosphine CyPF‐tBu occur in good to excellent yields with wide scope and high tolerance of functional groups.
Recent preclinical studies have shown that regulatory T cells (Treg) play a key role in the immune response after ischemic stroke (IS). However, the role of Treg in human acute IS has been poorly ...investigated. Our aim was to study the relationship between circulating Treg and outcome in human IS patients.
A total of 204 IS patients and 22 control subjects were recruited. The main study variable was good functional outcome at 3 months (modified Rankin scale ≤2) considering infarct volume, Early Neurological Deterioration (END) and risk of infections as secondary variables. The percentage of circulating Treg was measured at admission, 48, 72 h and at day 7 after stroke onset.
Circulating Treg levels were higher in IS patients compared to control subjects. Treg at 48 h were independently associated with good functional outcome (OR, 3.5; CI: 1.9-7.8) after adjusting by confounding factors. Patients with lower Treg at 48 h showed higher frequency of END and risk of infections. In addition, a negative correlation was found between circulating Treg at 48 h (r = - 0.414) and 72 h (r = - 0.418) and infarct volume.
These findings suggest that Treg may participate in the recovery of IS patients. Therefore, Treg may be considered a potential therapeutic target in acute ischemic stroke.
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