Character varieties on a four-holed sphere

For each $k\in\mathbb{A}^4(\mathbb{C})$, consider the character variety $X_k$ on a four-holed sphere. We prove that it is decidable whether or not any two integral solutions of $X_k$ are in the same mapping class group orbit. For this, using a delta map and Vieta maps, we will introduce graphs corresponding to the orbits and observe the properties of vertices on the graph.Comment: 12 page

Role of Serotonin Neurons in L-DOPA- and Graft-Induced Dyskinesia in a Rat Model of Parkinson's Disease

L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID). In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID), a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1A receptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons

α-Synuclein induced toxicity in brain stem serotonin neurons mediated by an AAV vector driven by the tryptophan hydroxylase promoter

We studied the impact of α-synuclein overexpression in brainstem serotonin neurons using a novel vector construct where the expression of human wildtype α-synuclein is driven by the tryptophan hydroxylase promoter, allowing expression of α-synuclein at elevated levels, and with high selectivity, in serotonergic neurons. α-Synuclein induced degenerative changes in axons and dendrites, displaying a distorted appearance, suggesting accumulation and aggregation of α-synuclein as a result of impaired axonal transport, accompanied by a 40% loss of terminals, as assessed in the hippocampus. Tissue levels of serotonin and its major metabolite 5-HIAA remained largely unaltered, and the performance of the α-synuclein overexpressing rats in tests of spatial learning (water maze), anxiety related behavior (elevated plus maze) and depressive-like behavior (forced swim test) was not different from control, suggesting that the impact of the developing axonal pathology on serotonin neurotransmission was relatively mild. Overexpression of α-synuclein in the raphe nuclei, combined with overexpression in basal forebrain cholinergic neurons, resulted in more pronounced axonal pathology and significant impairment in the elevated plus maze. We conclude that α-synuclein pathology in serotonergic or cholinergic neurons alone is not sufficient to impair non-motor behaviors, but that it is their simultaneous involvement that determines severity of such symptoms

A HISTORICAL APPROACH TO SYPHILIS INFECTION IN KOREA

From the end of the 15th century, syphilis spread worldwide, posing a serious threat to public health. Venereal syphilis has been a major research topic, not only in clinical medicine but also in paleopathology, especially because it is a disease of questionable origin and of high prevalence until the discovery of antibiotics. Syphilis in history has been studied extensively in Europe and the Americas, though less so in Asia. In this review, based on extant historical documents and available paleopathological data, we pinpoint the introduction and trace the spread of venereal syphilis in Korea to the end of the 19th century. This review provides fundamental information that will be of great help to future research on pre-20th century syphilis in Korea

Transient ultrasound stimulation has lasting effects on neuronal excitability

Background Transcranial ultrasound stimulation can acutely modulate brain activity, but the lasting effects on neurons are unknown. Objective To assess the excitability profile of neurons in the hours following transient ultrasound stimulation. Methods Primary rat cortical neurons were stimulated with a 40 s, 200 kHz pulsed ultrasound stimulation or sham-stimulation. Intrinsic firing properties were investigated through whole-cell patch-clamp recording by evoking action potentials in response to somatic current injection. Recordings were taken at set timepoints following ultrasound stimulation: 0–2 h, 6–8 h, 12–14 h and 24–26 h. Transmission electron microscopy was used to assess synaptic ultrastructure at the same timepoints. Results In the 0–2 h window, neurons stimulated with ultrasound displayed an increase in the mean frequency of evoked action potentials of 32% above control cell levels (p = 0.023). After 4–6 h this increase was measured as 44% (p = 0.0043). By 12–14 h this effect was eliminated and remained absent 24–26 h post-stimulation. These changes to action potential firing occurred in conjunction with statistically significant differences between control and ultrasound-stimulated neurons in action potential half-width, depolarisation rate, and repolarisation rate, that were similarly eliminated by 24 h following stimulation. These effects occurred in the absence of alterations to intrinsic membrane properties or synaptic ultrastructure. Conclusion We report that stimulating neurons with 40 s of ultrasound enhances their excitability for up to 8 h in conjunction with modifications to action potential kinetics. This occurs in the absence of major ultrastructural change or modification of intrinsic membrane properties. These results can inform the application of transcranial ultrasound in experimental and therapeutic settings

Depression and increased risk of nonalcoholic fatty liver disease in individuals with obesity

Aims: the longitudinal relationship between depression and the risk of nonalcoholic fatty liver disease (NAFLD) is uncertain. We examined: a) the association between depressive symptoms and incident hepatic steatosis (HS), both with and without liver fibrosis; and b) the influence of obesity on this association. Methods: cohort of 142,005 Korean adults with neither HS nor excessive alcohol consumption at baseline were followed for up to 8.9 years. The validated Center for Epidemiologic Studies-Depression score (CES-D) was assessed at baseline, and subjects were categorized as non-depressed (a CES-D <8, reference) or depression (CES-D ≥16). HS was diagnosed by ultrasonography. Liver fibrosis was assessed by the fibrosis-4 index (FIB-4). Parametric proportional hazards models were used to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: during a median follow-up of 4.0 years, 27,810 people with incident HS and 134 with incident HS plus high FIB-4 were identified. Compared with the non-depressed category, the aHR (95% CIs) for incident HS was 1.24 (1.15-1.34) for CES-D ≥16 among obese individuals, and 1.00 (0.95-1.05) for CES-D ≥16 among non-obese individuals (P for interaction with obesity <0.001). The aHR (95% CIs) for developing HS plus high FIB-4 was 3.41 (1.33-8.74) for CES-D≥16 among obese individuals, and 1.22 (0.60-2.47) for CES-D≥16 among non-obese individuals (P for interaction =0.201). Conclusions: depression was associated with an increased risk of incident HS and HS plus high probability of advanced fibrosis, especially among obese individuals

Glycemic status, insulin resistance, and mortality from lung cancer among individuals with and without diabetes

Background: The effects of glycemic status and insulin resistance on lung cancer remain unclear. We investigated the associations between both glycemic status and insulin resistance, and lung cancer mortality, in a young and middle-aged population with and without diabetes. Methods: This cohort study involved individuals who participated in routine health examinations. Lung cancer mortality was identified using national death records. Cox-proportional hazards models were used to calculate hazard ratios (HRs) with 95% CIs for lung cancer mortality risk. Results: Among 666,888 individuals (mean age 39.9±10.9 years) followed for 8.3 years (interquartile range, 4.6–12.7), 602 lung cancer deaths occurred. Among individuals without diabetes, the multivariable-adjusted HRs (95% CI) for lung cancer mortality comparing hemoglobin A1c categories (5.7–5.9, 6.0–6.4, and ≥ 6.5% or 36–38, 39–46, and ≥ 48 mmol/mol, respectively) with the reference (&lt; 5.7% or &lt; 36 mmol/mol) were 1.39 (1.13–1.71), 1.72 (1.33–2.20), and 2.22 (1.56–3.17), respectively. Lung cancer mortality was associated with fasting blood glucose categories in a dose-response manner (P for trend = 0.001) and with previously diagnosed diabetes. Insulin resistance (HOMA-IR ≥ 2.5) in individuals without diabetes was also associated with lung cancer mortality (multivariable-adjusted HR, 1.41; 95% CI, 1.13–1.75). These associations remained after adjusting for changing status in glucose, hemoglobin A1c, insulin resistance, smoking status, and other confounders during follow-up as time-varying covariates. Conclusions: Glycemic status within both diabetes and prediabetes ranges and insulin resistance were independently associated with an increased risk of lung cancer mortality. Keywords Diabetes mellitus, Glycated hemoglobin A1c, Hyperglycemia, Insulin resistance, Lung cancer<br/