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BACKGROUND: Although Huntington's disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression. OBJECTIVES: We sought to investigate whether new inflammation-related genetic variants may contribute to the onset and progression of HD. METHODS: We first used postmortem brain material from patients at different stages of HD to look at the protein expression of toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2). We then genotyped the TREM2 R47H gene variant and 3 TLR4 single nucleotide polymorphisms in a large cohort of HD patients from the European Huntington's Disease Network REGISTRY. RESULTS: We found an increase in the number of cells expressing TREM2 and TLR4 in postmortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas 2 of 3 TLR4 single nucleotide polymorphisms assessed were associated with changes in motor progression in this same group. CONCLUSIONS: These findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition. © 2019 International Parkinson and Movement Disorder Society.

Preconditioning (PC) is a cell adaptive response to oxidative stress and, with regard to neurons, can be considered as a neuroprotective strategy. The aim of the present study was to verify how neuronal-like differentiated SH-SY5Y cells adapt to a mild and transient H2 O2 -induced oxidative stress and, hence, whether may be considered as more sensitive cell model to study PC pathways. A first screening allowed to define H2 O2 concentrations for PC (10μM-50μM), applied before damage(100μM H2 O2 ). Cell viability measured 24 hours after 100μM H2 O2 -induced damage was ameliorated by 24-hour pre-exposure to low-concentration H2 O2 (10μM-30μM) with cell size as well restored. Markers for apoptosis (Bcl-2 and Bad), inflammation (iNOS), and redox system (MnSOD) were also determined, showing that, in cells pre-exposed to 10μM H2 O2 and then submitted to 100μM H2 O2 , Bcl-2 levels were higher, Bad and iNOS levels were lower than those observed in damaged cells, and MnSOD levels were unchanged. Such findings show that (1) neuronal-like differentiated SH-SY5Y cells are a suitable model to investigate PC response and more sensitive to the effect of a mild and transient H2 O2 -induced oxidative stress with respect to other neuronal cells; (2) 10μM H2 O2 -induced PC is mediated by apoptotic and inflammatory pathways, unlike antioxidant system; (3) such neuroprotective strategy and underlying signals proven in neuronal-like differentiated SH-SY5Y cells may contribute to understand in vivo PC mechanisms and to define a window for pharmacological intervention, namely, related to ischemic brain damage. Significance of the study Neuronal-like differentiated SH-SY5Y cells are a suitable model to investigate PC, an endogenous neuroprotective response to a mild and transient H2 O2 -induced oxidative stress, elicited by 24-hour exposure to very low H2 O2 concentrations and mediated by both apoptotic and inflammatory pathways. This model reflects in vivo PC mechanisms occurring after brain trauma and provides novel information about pathways and time of protection useful for an appropriate pharmacological intervention.

The sediment budget is a key concept and tool for characterizing the mobilisation, transfer and storage of fine sediment within a catchment. Caesium-137 measurements can provide valuable information on gross and net erosion rates associated with sheet and rill erosion that can be used to establish the slope component of a catchment sediment budget. However, there is a need to validate the use of 137Cs measurements for this purpose, since their reliability has sometimes been questioned. The study reported focuses on a small (3.04 ha) steepland (mean slope 37%) catchment in Southern Italy. It exploits the availability of information on the medium-term sediment output from the catchment provided by the construction of a reservoir at its outlet in 1978 and the existence of estimates of soil redistribution rates derived from 137Cs measurements made on 68 replicate soil cores collected from the slopes of a substantial proportion of the catchment, to validate the use of 137Cs measurements to construct the slope component of the catchment sediment budget. An additional 50 replicate soil cores were collected from the catchment slopes for 137Cs analysis, to complement the data already available for constructing the slope component of the sediment budget. Nine cores collected from the area occupied by the reservoir were used to estimate the mean annual sediment input to the reservoir. In the absence of evidence that the poorly developed channel system in the catchment was either a significant sediment source or sink, it was possible to directly compare the estimate of net soil loss from the catchment slopes (7.33 Mg ha-1 yr-1) with the estimate of sediment output from the catchment provided by the reservoir deposits (7.52 Mg ha-1 yr-1). Taking account of the uncertainties involved, the close agreement of the two values is seen as providing a convincing validation of the use of 137Cs measurements to both estimate soil redistribution rates and as a basis for constructing the slope component of the sediment budget of a small catchment.

Dark ocean microbial communities are actively involved in chemoautotrophic and anaplerotic fixation of bicarbonate. Thus, aphotic pelagic realm of the ocean might represent a significant sink of CO2 and source of primary production. However, the estimated metabolic activities in the dark ocean are fraught with uncertainties. Typically, deep-sea samples are recovered to the sea surface for downstream processing on deck. Shifts in ambient settings, associated with such treatments, can likely change the metabolic activity and community structure of deep-sea adapted autochthonous microbial populations. To estimate influence of recovery and short-term handling of deep-sea samples, we monitored the succession of bathypelagic microbial community during its 3 days long on deck incubation. We demonstrated that at the end of exposition, the deep-sea archaeal population decreased threefold, whereas the bacterial fraction doubled in size. As revealed by phylogenetic analyses of amoA gene transcripts, dominance of the active ammonium-oxidizing bathypelagic Thaumarchaeota groups shifted over time very fast. These findings demonstrated the simultaneous existence of various 'deep-sea ecotypes', differentially reacting to the sampling and downstream handling. Our study supports the hypothesis that metabolically active members of meso- and bathypelagic Thaumarchaeota possess the habitat-specific distribution, metabolic complexity and genetic divergence at subpopulation level.

Summary Within the complex of deep, hypersaline anoxic lakes (DHALs) of the Mediterranean Ridge, we identified a new, unexplored DHAL and named it 'Lake Kryos' after a nearby depression. This lake is filled with mag- nesium chloride (MgCl2)-rich, athalassohaline brine (salinity > 470 practical salinity units), presumably formed by the dissolution of Messinian bischofite. Compared with the DHAL Discovery, it contains elevated concentrations of kosmotropic sodium and sulfate ions, which are capable of reducing the net chaotropicily of MgCl2-rich solutions. The brine of Lake Kryos may therefore be biologically permissive at MgCl2 concentrations previously considered incompatible with life. We characterized the microbi- ology of the seawater-Kryos brine interface and managed to recover mRNA from the 2.27-3.03 M MgCl2 layer (equivalent to 0.747-0.631 water activity), thereby expanding the established chaotropicity window-for-life. The primary bacterial taxa present there were Kebrit Deep Bacteria 1 candidate division and DHAL-specific group of organisms, distantly related to Desulfohalobium. Two euryarchaeal candi- date divisions, Mediterranean Sea Brine Lakes group 1 and halophilic cluster 1, accounted for > 85% of the rRNA-containing archaeal clones derived from the 2.27-3.03 M MgCl2 layer, but were minority community-members in the overlying interface- layers. These findings shed light on the plausibility of life in highly chaotropic environments, geochemical windows for microbial extremophiles, and have impli- cations for habitability elsewhere in the Solar System.

Objective Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1α in mitochondria, no studies have addressed whether PGC-1α directly influences oligomerization of α-syn or whether α-syn oligomers impact PGC-1α expression. Materials and Methods We tested whether pharmacological or genetic activation of PGC-1α or PGC-11α knockdown could modulate the oligomerization of α-syn in vitro by using an α-syn -fragment complementation assay. Results In this study, we found that both PGC-1α reference gene (RG-PGC-1α) and the central nervous system (CNS)-specific PGC-1α (CNS-PGC-1α) are downregulated in human PD brain, in A30P α-syn transgenic animals, and in a cell culture model for α-syn oligomerization. Importantly, downregulation of both RG-PGC-1α and CNS-PGC-1α in cell culture or neurons from RG-PGC-1α–deficient mice leads to a strong induction of α-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1α reduced α-syn oligomerization and rescued α-syn–mediated toxicity. Interpretation Based on our results, we propose that PGC-1α downregulation and α-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1α is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies. ANN NEUROL 2015;77:15–32

Objective Growing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. Better comprehension of this issue might provide a new strategy for treatment of neurodegenerative diseases. We investigated possible roles of adiponectin (APN), the antidiabetes protein, in the pathogenesis of α-synucleinopathies. Methods Using biochemical and histological methods, we investigated autopsy brain of α-synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and analyzed the effects of APN in cellular and in mouse models of α-synucleinopathies. Results We observed that APN is localized in Lewy bodies derived from α-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing αS, both histopathology and movement disorder were significantly improved by intranasal treatment with globular APN when the treatment was initiated in the early stage of the disease. In a mouse model, reduced levels of guanosine and inosine monophosphates, both of which are potential stimulators of aggregation of αS, might partly contribute to suppression of aggregation of αS by APN. Interpretation Taken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a therapeutic potential against α-synucleinopathies.

We used a combination of molecular and microbiological approaches to determine the activity, abundance and diversity of archaeal populations inhabiting meromictic saline Lake Faro (Messina, Italy). Analysis of archaeal 16S rRNA, amoA, accA and hbd genes and transcripts revealed that sub- and anoxic layers of Lake Faro are primarily inhabited by the organisms related to the clusters of Marine Group I.1a of Thaumarchaeota frequently recovered from oxygen-depleted marine ecosystems. These organisms dominated the metabolically active archaea down to the bottom of the lake, indicating their adaptation to recurrent changes in the levels of water column hypoxia. The upper microaerobic layer of Lake Faro redoxcline has the maximal rates of dark primary production much lower than those of other previously studied pelagic redoxclines, but comparable to the values of meso- and bathypelagic areas of Mediterranean Sea. Application of bacterial inhibitors, especially azide, significantly declined the CO2 fixation rates in the low interface and monimolimnion, whereas archaea-specific inhibitor had effect only in upper part of the redoxcline. Based on these findings, we hypothesize that dark bicarbonate fixation in suboxic zone of Lake Faro results mainly from archaeal activity which is affected by the predicted lack in oxygen in lower layers.

Critical lower limb ischaemia is a diffuse pathology that could cause claudication, severe ischaemic pain and tissue loss. The common treatment includes modification of risk factors, pharmacological therapy and endovascular or surgical revascularisation of the lower limb to restore a pulsatile flow distally. Spinal cord stimulator is seen as a valid alternative in patients unsuitable for revascularisation after endovascular or surgical revascularisation failure and as adjuvant therapy in the presence of a functioning bypass in patients with extensive tissue loss and gangrene presenting a slow and difficult wound healing. We report our experience on spinal cord stimulation (SCS) indication and implantation in patients with critical lower limb ischaemia, at a high‐volume centre for the treatment of peripheral arterial disease.

In this study, we examined whether melatonin treatment would increase new cell formation in the hippocampus in ovariectomized (OVX) mice. Chronic exogenous melatonin administration increased bromodeoxyuridine (BrdU) (OVX-sham 72 ± 3.2 versus OVX-mel 122 ± 12.0; P < 0.05) and doublecortin (DCX) (OVX-sham 88 ± 3.1 versus OVX-mel 176 ± 9.9; P < 0.05) immunoreactive cells in the hippocampus of ovariectomized mice. This neuronal development was correlated with synaptic plasticity, identified using the Golgi impregnation method to quantify dendritic spines in mouse dentate gyrus (DG). Finally, the antidepressant-like state of the animals was evaluated by the tail suspension test. The results indicate that melatonin acts on birth, survival, and differentiation of new neurons in the hippocampus, stimulates maturation of spines, and exerts an antidepressant-like action under estrogen-deprived conditions, in both a strain- and gender-independent manner, suggesting that this indoleamine may be useful in improving brain functions.

Melatonin (N-acetyl-5-methoxytryptamine) is an efficient free radical scavenger and antioxidant, both in vitro and in vivo. The role of melatonin as an immunomodulator is, in some cases, contradictory. In this study we have investigated the therapeutic efficacy of melatonin in rats subjected to Pelagia noctiluca crude venom (of the familia Pelaguiidae; and genus Pelagia) induced acute paw inflammation. In particular, injection of the venom into the paw of rats elicited an acute inflammatory response characterized by accumulation of fluid containing a large number of polymorphonuclear neutrophils in the paw and subsequent lipid peroxidation. Furthermore, the venom promoted an expression of iNOS, nitrotyrosine and the activation of the nuclear enzyme poly (ADP-ribose) polymerase as determined by immunohistochemical analysis of paw tissues. Administration of melatonin 30 min, 1 and 6 hr after the challenge with the venom, caused a significant reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that melatonin may be useful a treatment of local acute inflammation induced by P. noctiluca crude venom.

Spinocerebellar ataxia type 7 (SCA7) represents a rare and severe autosomal dominantly inherited ataxic disorder and is among the known CAG-repeat, or polyglutamine, diseases. In contrast to other currently known autosomal dominantly inherited ataxic disorders, SCA7 may manifest itself with different clinical courses. Because the degenerative changes evolving during these different clinical courses are not well known, many neurological disease symptoms still are unexplained. We performed an initial pathoanatomical study on unconventional thick tissue sections of the brain of a clinically diagnosed and genetically confirmed adult-onset SCA7 patient with progressive visual impairments. In this patient we observed loss of myelinated fibres in distinct central nervous fibre tracts, and widespread degeneration of the cerebellum, telencephalon, diencephalon and lower brainstem. These degenerative changes offer appropriate explanations for a variety of less-understood neurological symptoms in adult-onset SCA7 patients with visual impairments: gait, stance and limb ataxia, falls, dysarthria, dysphagia, pyramidal signs, Parkinsonian features, writing problems, impairments of saccades and smooth pursuits, altered pupillary functions, somatosensory deficits, auditory deficits and mental impairments.

At the beginning of this decade, the American Association of Neurology decided that the 1990's should be labelled “the decade of the brain” for expected advances in our understanding of neurological disorders and neuroscience. By the end of this decade, clinicians and researchers who work in the field of inherited neurological disorders might well remember the 1990's as “the decade of the trinucleotide repeat”. At the time of writing this introduction, eleven inherited neurological disorders have been found to be caused by expansions of trinucleotide repeats, and a twelfth trinucleotide repeat expansion mutation has been identified (6), although the gene containing this mutant triplet repeat has not been cloned to our knowledge (Table 1).

Melatonin, involved in circadian cycle, provides protective effects on neuronal cells and acts as antidepressant by restoration of corticosterone levels. A mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone treatment, has been used to evaluate behavior and adult hippocampal neurogenesis in mice and their possible modulation under melatonin. With this aim, CD1 mice were subjected to 7 wk of corticosterone administration, and then behavioral tests as novelty-suppressed feeding, open field and a forced swim test were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by 5-bromo-2'-deoxyuridine and doublecortin immunohistochemistry techniques, and stereological procedure was used to quantify labeled cells. Golgi-impregnated method was used to evaluate the changes of dendritic spines in DG neurons. A new therapeutic approach with antidepressant-like substances (3 wk) such as melatonin (8 mg/kg) was employed to possibly modulate neural development in the adult hippocampus and the behavioral changes. The depressive-like state caused by chronic corticosterone treatment was reversed by exogenous administration of melatonin; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment (cort- 83.7 +/- 20.3 versus cort+ 60.5 +/- 18.2; P < 0.05), whereas long-term treatment with melatonin prevented the corticosterone-induced reduction in hippocampal cell proliferation (cort- 60.5 +/- 18.2 versus mel 133.4 +/- 26.9; P < 0.05). Corticosterone-treated mice exhibited a reduced spine density, which was ameliorated by melatonin administration. These findings suggest a strong correspondence between behavior and neurogenesis, strengthening the hypothesis that neurogenesis contributes to the effects of melatonin as an antidepressant.