Dysregulated Lipid Metabolism and Its Role in α-Synucleinopathy in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease, the main pathological hallmark of which is the accumulation of α-synuclein (α-syn) and the formation of filamentous aggregates called Lewy bodies in the brainstem, limbic system, and cortical areas. Lipidomics is a newly emerging field which can provide fresh insights and new answers that will enhance our capacity for early diagnosis, tracking disease progression, predicting critical endpoints, and identifying risk in pre-symptomatic persons. In recent years, lipids have been implicated in many aspects of PD pathology. Biophysical and lipidomic studies have demonstrated that α-syn binds preferentially not only to specific lipid families but also to specific molecular species and that these lipid-protein complexes enhance its interaction with synaptic membranes, influence its oligomerization and aggregation, and interfere with the catalytic activity of cytoplasmic lipid enzymes and lysosomal lipases, thereby affecting lipid metabolism. The genetic link between aberrant lipid metabolism and PD is even more direct, with mutations in GBA and SMPD1 enhancing PD risk in humans and loss of GALC function increasing α-syn aggregation and accumulation in experimental murine models. Moreover, a number of lipidomic studies have reported PD-specific lipid alterations in both patient brains and plasma, including alterations in the lipid composition of lipid rafts in the frontal cortex. A further aspect of lipid dysregulation promoting PD pathogenesis is oxidative stress and inflammation, with proinflammatory lipid mediators such as platelet activating factors (PAFs) playing key roles in arbitrating the progressive neurodegeneration seen in PD linked to α-syn intracellular trafficking. Lastly, there are a number of genetic risk factors of PD which are involved in normal lipid metabolism and function. Genes such as PLA2G6 and SCARB2, which are involved in glycerophospholipid and sphingolipid metabolism either directly or indirectly are associated with risk of PD. This review seeks to describe these facets of metabolic lipid dysregulation as they relate to PD pathology and potential pathomechanisms involved in disease progression, while highlighting incongruous findings and gaps in knowledge that necessitate further research

Phenology and temperature‐dependent development of Ceutorhynchus assimilis, a potential biological control agent for Lepidium draba

Lepidium draba (Brassicaceae) is a major concern for agriculture and biodiversity in the western United States. As current control methods do not provide long-term, sustainable solutions, research has been conducted to find biological control agents. Ceutorhynchus assimilis is one of the currently investigated candidates. Known as oligophagous in the literature, a specialist clade of this root-galling weevil exists in southern Europe. This raised the question of its ability to survive in colder climates in the target range. We investigated the phenology of C. assimilis in the field in southern France (specialist clade) and Romania (generalist clade) and measured various temperature-dependent parameters in the laboratory. In both ranges, weevils were univoltine. Oviposition in autumn started later in France compared to Romania, while mature larvae exited galls (to pupate in the soil) earlier the following year. On average, 25% and 32% of galls from France and Romania were completely below the soil surface, respectively, and this appeared to depend on soil substrate. Weevils transported from France to Romania were able to develop, but at a much lower rate than Romanian weevils. Mortality of overwintering larvae of both clades increased with decreasing temperature and exposure time. At −5°C, lethal times Lt50 and Lt95 were 15 and 42 days for the specialist clade and 26 and 72 days for the generalist clade. A higher proportion of third instar larvae compared to first and second instar larvae survived. Pupation time at different temperatures did not differ between weevils from France or Romania. A climate match model (comparing winter temperatures) indicated that the specialist clade of C. assimilis from France has the potential to establish in some parts of the target range (e.g. Washington, Oregon, California). However, temperature extremes and winters without snow cover will likely limit its establishment unless rapid adaptive evolution takes place

Plasma Sphingoid Base Profiles of Patients Diagnosed with Intrinsic or Idiosyncratic Drug-induced Liver Injury

Sphingolipids are exceptionally diverse, comprising hundreds of unique species. The bulk of circulating sphingolipids are synthesized in the liver, thereby plasma sphingolipid profiles represent reliable surrogates of hepatic sphingolipid metabolism and content. As changes in plasma sphingolipid content have been associated to exposure to drugs inducing hepatotoxicity both in vitro and in rodents, in the present study the translatability of the preclinical data was assessed by analyzing the plasma of patients with suspected drug-induced liver injury (DILI) and control subjects. DILI patients, whether intrinsic or idiosyncratic cases, had no alterations in total sphingoid base levels and profile composition compared to controls, whereby cardiovascular disease (CVD) was a confounding factor. Upon exclusion of CVD individuals, elevation of 1-deoxysphingosine (1-deoxySO) in the DILI group emerged. Notably, 1-deoxySO values did not correlate with ALT values. While 1-deoxySO was elevated in all DILI cases, only intrinsic DILI cases concomitantly displayed reduction of select shorter chain sphingoid bases. Significant perturbation of the sphingolipid metabolism observed in this small exploratory clinical study is discussed and put into context, in the consideration that sphingolipids might contribute to the onset and progression of DILI, and that circulating sphingoid bases may function as mechanistic markers to study DILI pathophysiology

AP-4-mediated axonal transport controls endocannabinoid production in neurons

Davies et al. identify a putative mechanism underlying the childhood neurological disorder AP-4 deficiency syndrome. In the absence of AP-4, an enzyme that makes 2-AG is not transported to the axon, leading to axonal growth defects, which can be rescued by inhibition of 2-AG breakdown. The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as a cargo of AP-4 vesicles. During normal development, DAGLB is targeted to the axon, where 2-AG signalling drives axonal growth. We show that DAGLB accumulates at the trans-Golgi network of AP-4-deficient cells, that axonal DAGLB levels are reduced in neurons from a patient with AP-4 deficiency, and that 2-AG levels are reduced in the brains of AP-4 knockout mice. Importantly, we demonstrate that neurite growth defects of AP-4-deficient neurons are rescued by inhibition of MGLL (monoacylglycerol lipase), the enzyme responsible for 2-AG hydrolysis. Our study supports a new model for AP-4 deficiency syndrome in which axon growth defects arise through spatial dysregulation of endocannabinoid signalling.Special thanks to the MPIB Imaging Facility for outstanding technical support, in particular to Giovanni Cardone for his advice and assistance with the implementation of image analysis pipelines, as well as feedback on the manuscript, and to Martin Spitaler for his expert technical advice for imaging experiments

Graph parameters, implicit representations and factorial properties

How to efficiently represent a graph in computer memory is a fundamental data structuring question. In the present paper, we address this question from a combinatorial point of view. A representation of an n-vertex graph G is called implicit if it assigns to each vertex of G a binary code of length 0(log n) so that the adjacency of two vertices is a function of their codes. A necessary condition for a hereditary class x of graphs to admit an implicit representation is that x has at most factorial speed of growth. This condition, however, is not sufficient, as was recently shown in [19]. Several sufficient conditions for the existence of implicit representations deal with boundedness of some parameters, such as degeneracy or clique-width. In the present paper, we analyze more graph parameters and prove a number of new results related to implicit representation and factorial properties

The treewidth and pathwidth of graph unions

For two graphs $G_1$ and $G_2$ on the same vertex set $[n]:=\{1,2, \ldots, n\}$, and a permutation $\varphi$ of $[n]$, the union of $G_1$ and $G_2$ along $\varphi$ is the graph which is the union of $G_2$ and the graph obtained from $G_1$ by renaming its vertices according to $\varphi$. We examine the behaviour of the treewidth and pathwidth of graphs under this "gluing" operation. We show that under certain conditions on $G_1$ and $G_2$, we may bound those parameters for such unions in terms of their values for the original graphs, regardless of what permutation $\varphi$ we choose. In some cases, however, this is only achievable if $\varphi$ is chosen carefully, while yet in others, it is always impossible to achieve boundedness. More specifically, among other results, we prove that if $G_1$ has treewidth $k$ and $G_2$ has pathwidth $\ell$, then they can be united into a graph of treewidth at most $k + 3 \ell + 1$. On the other hand, we show that for any natural number $c$ there exists a pair of trees $G_1$ and $G_2$ whose every union has treewidth more than $c$

Gamma-nail nail breakage in the osteosynthesis of trochanteric femoral fractures

Clinic of Orthopedics and Traumatology, Emergency County Hospital Constanța, Romania, Al VIII-lea Congres Naţional de Ortopedie și Traumatologie cu participare internaţională 12-14 octombrie 2016Objective Mechanical breakage of the implant is a rare complication attributed to delayed fracture union or nonunion. This study presents a series of cases of breakage and secondary lag screw dislocation after cephalomedullary nailing. Material. Methods. In a retrospective study between 02/2005 and 12/2013 we analyzed all patients with trochanteric and subtrochanteric fracture who had been treated by cephalomedullary nailing. Fractures were classified according to AO/OTA classification. 13 patients with third generation Gamma nail failure were included. 7 patients were women, and 6 men with a mean age of 72 years (range 35-94). Results Important breakage occurred 6 month postoperatively (range 1-19 month). In 10 cases breakage was secondary to delayed or nonunion, which was thought to be mainly due to insufficient reduction of the fracture, wrong handling, incorrect drilling in the critical “red zone” (weak point of the nail around the insertion hole for the lag screw due to forces more than 1800 Newton), and in two cases due to loss of the lag screw because of missing set screw. In 1 case, breakage was apparent during elective metal removal following complete fracture healing. Short-term outcome was evaluated six months after operative revision using Harris Hip Score in 11 out of 13 patients showing a mean score of 84%. Complete radiological fracture healing has been found in 11 patients available for follow-up within 6 month after revision surgery. Conclusions Even though breakage of cephalomedullary nail osteosynthesis of trochanteric and sub trochanteric fracture is a severe complication, the result of our study demonstrate that revision surgery is warranted and provides good clinical and radiological short-term results

The Treewidth and Pathwidth of Graph Unions

Given two n-vertex graphs G1 and G2 of bounded treewidth, is there an n-vertex graph G of bounded treewidth having subgraphs isomorphic to G1 and G2? Our main result is a negative answer to this question, in a strong sense: we show that the answer is no even if G1 is a binary tree and G2 is a ternary tree. We also provide an extensive study of cases where such "gluing" is possible. In particular, we prove that if G1 has treewidth k and G2 has pathwidth l, then there is an n-vertex graph of treewidth at most k + 3l + 1 containing both G1 and G2 as subgraphs