Summary Parkinson's disease is a common progressive neurodegenerative disease, of which the main neuropathological hallmark is dopaminergic neuronal loss. Increased attention has been directed ...towards non-motor symptoms in Parkinson's disease, such as cognitive impairment and behavioural disorders. Clinical and experimental findings support the view that the hippocampus, a temporal lobe structure involved in physiological learning and memory, is also implicated in the cognitive dysfunction seen in some patients with Parkinson's disease. Moreover, emerging data suggest interactions between the dopaminergic systems and the hippocampus in synaptic plasticity, adaptive memory, and motivated behaviour. This structure is also implicated in the pathophysiology of other non-motor symptoms, such as impulse control disorders, anosmia, and fatigue. Evidence from clinical observations and experimental studies suggest a complex hippocampal cross-talk among the dopaminergic and other transmitter systems. Furthermore, neurotrophic factors might interact with the hippocampal dopaminergic system having possible implications on the non-motor symptoms seen in patients with Parkinson's disease.
ARPE-19 retinal pigment epithelial cells cultured in a medium containing 35 mM D-glucose led to an augmented ROS formation and release of vascular endothelial factor (VEGF)-containing exosomes ...compared to ARPE-19 cells cultured in a medium containing 5 mM D-glucose (standard medium). Exposing these cells to the melanocortin 5 receptor agonist (MCR
5
) PG-901 (10
−10
M), for 9 d reduced ROS generation, the number of exosomes released and their VEGF content. In contrast, incubating the cells with the melanocortin receptor MCR
1
agonist BMS-470539 (10
−5
M) or with the mixed MCR
3/4
agonist MTII (0.30 nmol) did not produce any significant decrease in ROS levels. ARPE-19-derived VEGF-containing exosomes promoted neovascularization in human umbilical vein endothelial cells (HUVEC), an effect that was markedly reduced by PG-901 (10
−10
M) but not by the MCR
3/4
agonist MTII (0.30 nmol) or the MCR
1
agonist BMS-470539 (10
−5
M). The MCR
5
-related action in the ARPE-19 cells was accompanied by the increased expression of two coupled factors, cytochrome p4502E1 (CYP2E1) and nuclear factor kappa b (Nf-κB). These are both involved in high glucose signalling, in ROS generation and, interestingly, were reduced by the MCR
5
agonist in the ARPE-19 cells. Altogether, these data suggest that MCR
5
is a modulator of the responses stimulated by glucose in ARPE-19 cells, which might possibly be translated into a modulation of the retinal pigment epithelium response to diabetes in vivo.
Summary Levodopa is the most effective drug for the treatment of Parkinson's disease. However, the long-term use of this dopamine precursor is complicated by highly disabling fluctuations and ...dyskinesias. Although preclinical and clinical findings suggest pulsatile stimulation of striatal postsynaptic receptors as a key mechanism underlying levodopa-induced dyskinesias, their pathogenesis is still unclear. In recent years, evidence from animal models of Parkinson's disease has provided important information to understand the effect of specific receptor and post-receptor molecular mechanisms underlying the development of dyskinetic movements. Recent preclinical and clinical data from promising lines of research focus on the differential role of presynaptic versus postsynaptic mechanisms, dopamine receptor subtypes, ionotropic and metabotropic glutamate receptors, and non-dopaminergic neurotransmitter systems in the pathophysiology of levodopa-induced dyskinesias.
The response of forest growth to climate variability varies along environmental gradients. A growth increase and decrease with warming is usually observed in cold‐humid and warm‐dry regions, ...respectively. However, it remains poorly known where the sign of these temperature effects switches. Here we introduce a newly developed European tree ring network that has been specifically collected to reconstruct forest aboveground biomass increment (ABI). We quantify, how the long‐term (1910–2009) interannual variability of ABI depends on local mean May–August temperature and test, if a dynamic global vegetation model ensemble reflects the resulting patterns. We find that sites at 8 °C mean May–August temperature increase ABI on average by 5.7 ± 1.3%, whereas sites at 20 °C decrease ABI by 3.0 ± 1.8% m−2 year−1 Δ°C−1. A threshold temperature between beneficial and detrimental effects of warming and the associated increase in water demand on tree growth emerged at 15.9 ± 1.4 °C mean May–August temperature. Because interannual variability increases proportionally with mean growth rate—that is, the coefficient of variation stays constant—we were able to validate these findings with a much larger tree ring data set that had been established following classic dendrochronological sampling schemes. While the observed climate sensitivity pattern is well reflected in the dynamic global vegetation model ensemble, there is a large spread of threshold temperatures between the individual models. Also, individual models disagree strongly on the magnitude of climate impact at the coldest and warmest locations, suggesting where model improvement is most needed to more accurately predict forest growth and effectively guide silvicultural practices.
Key Points
Central and Northern European forest growth is expected to benefit (suffer) from additional warming in regions with a mean growing season temperature below (above) 15.9 plus‐minus 1.4 degrees Celsius
A vegetation model ensemble mean agrees with this threshold but is too sensitive to temperature changes at coldest and warmest locations
Model improvements are needed to predict forest growth more accurately and guide silvicultural practices
Abstract Background Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given ...that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3 , a potent inducer of IFNs, were proposed to underlie AVM. Objectives This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. Methods We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. Results We found that TLR3- and STAT1 -deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes ( BAG3 , DSP , PKP2 , RYR2 , SCN5A , or TNNI3 ). Conclusions Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children.
Vermamoeba vermiformis
represents one of the most common free-living amoebae identified in worldwide environmental surveys. We analyzed 56 water samples with varying characteristics, including ...temperature and the particular settings in which humans may be exposed to water, plus one corneal scraping from a keratitis patient, with the following aims: (i) to investigate the presence of
V. vermiformis
; (ii) to identify the isolate subtypes; (iii) to place the Italian isolates in the broader picture of the genetic diversity within
V. vermiformis.
Twenty-two isolates were identified upon culturing and sequencing of > 600 bp in the 18S ribosomal RNA (rRNA) gene sequence, bringing to 27 the number of sequences recovered from Italian sources. By adding deposited sequences, we assembled a dataset of 74 isolates. Three of our isolates were characterized by allelic code 7-5-1-1, never reported before, and two showed 100% identity with an uncultured eukaryote and carried the 719T>C variant. We show that the variable segments E5, E3, F, and G convey most of the information on diversity, enabling the clustering of the isolates in a replicable fashion. The presence of different strains in natural thermal waters and in distribution systems indicated heterogeneity of the amoebic populations. Also, ours and the only other sequence from human infection were mapped in different clades. Overall, we enlarged the repertoire of single nucleotide and indel variants and the list of allelic codes, proceeding one step further in the description of the diversity within the genus.
Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the ...progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving “chronic” worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion‐independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1–20
Productivity of old-growth beech forests in the Mediterranean Basin was measured by average stem basal area increment (BAI) of dominant trees at two mountain sites in the Italian Apennines. Both ...forests could be ascribed to the old-growth stage, but they differed markedly with regard to elevation (1000 vs. 1725 m a.s.l.), soil parent material (volcanic vs. calcareous), mean tree age (less than 200 years vs. 300 years), and stand structure (secondary old-growth vs. primary old-growth forest). Drought at the two sites was quantified by the self-calibrated Palmer Moisture Anomaly Index (Z-index), and by the self-calibrating Palmer Drought Severity Index (PDSI) for summer (June through August) and the growing season (May through September). Dendroclimatological analyses revealed a moisture limitation of beech BAI at interannual (water availability measured by Z-index) and decadal scales (water availability measured by PDSI). Both BAI and water availability increased from 1950 to 1970, and decreased afterwards. Trees were grouped according to their BAI trends in auxological groups (growth-type chronologies), which confirmed that growth of most trees at both sites declined in recent decades, in agreement with increased drought. Because BAI is not expected to decrease without an external forcing, the patterns we uncovered suggest that long-term drought stress has reduced the productivity of beech forests in the central Apennines, in agreement with similar trends identified in other Mediterranean mountains, but opposite to growth trends reported for many forests in central Europe.
PDF
