Rhythmic gene expression is found throughout the central nervous system. This harmonized regulation can be dependent on- and independent of- the master regulator of biological clocks, the suprachiasmatic nucleus (SCN). Substantial oscillatory activity in the brain's reward system is regulated by dopamine. While light serves as a primary time-giver (zeitgeber) of physiological clocks and synchronizes biological rhythms in 24-h cycles, nonphotic stimuli have a profound influence over circadian biology. Indeed, reward-related activities (e.g., feeding, exercise, sex, substance use, and social interactions), which lead to an elevated level of dopamine, alters rhythms in the SCN and the brain's reward system. In this chapter, we will discuss the influence of the dopaminergic reward pathways on circadian system and the implication of this interplay on human health.

Background

Liver cancer incidence has increased for several decades in the United States. Recently, reports have suggested that rates of hepatocellular carcinoma (HCC), the dominant form of liver cancer, had declined in certain groups. However, to the authors' knowledge, the most recent histology-specific liver cancer rates have not been reported to date.

Methods

The authors examined the incidence of HCC and intrahepatic cholangiocarcinoma (ICC) from 1992 through 2016 using data from the Surveillance, Epidemiology, and End Results registries. Age-standardized incidence rates were calculated by histology, sex, race and/or ethnicity, and age. Trends were analyzed using the National Cancer Institute's Joinpoint Regression Program to estimate the annual percent change.

Results

Between 2011 and 2016, HCC rates significantly declined (annual percent change, -1.9%), with more prominent declines noted among males, Asian/Pacific Islanders, and individuals aged <50 years. Conversely, ICC rates increased from 2002 through 2016.

Conclusions

Declining HCC rates may persist due to improved treatment of the hepatitis C virus and/or competing causes of mortality among individuals with fatty liver disease.

Dense urban morphologies further amplify extreme climate events due to the urban heat island phenomenon, rendering cities more vulnerable to extreme climate events. Here we develop a modelling framework using multi-scale climate and energy system models to assess the compound impact of future climate variations and urban densification on renewable energy integration for 18 European cities. We observe a marked change in wind speed and temperature due to the aforementioned compound impact, resulting in a notable increase in both peak and annual energy demand. Therefore, an additional cost of 20‒60% will be needed during the energy transition (without technology innovation in building) to guarantee climate resilience. Failure to consider extreme climate events will lower power supply reliability by up to 30%. Energy infrastructure in dense urban areas of southern Europe is more vulnerable to the compound impact, necessitating flexibility improvements at the design phase when improving renewable penetration levels.

Background

Bezafibrate (BZF) is effective in the treatment of hypertriglyceridemia in human patients, but there are no data on its use in dogs.

Objective

To assess the safety of BZF in hyperlipidemic dogs and its efficacy in decreasing serum triglyceride (TG) and cholesterol (CHO) concentrations.

Animals

Forty-six dogs, 26 females and 20 males, mean (±SD) age of 9 (±3) years, with TG ≥150 mg/dL (33 dogs also were hypercholesterolemic [>300 mg/dL]).

Methods

Prospective, uncontrolled clinical trial. Dogs were treated with bezafibrate once daily, using 200 mg tablets at a dosage of 4-10 mg/kg (depending on body weight). Serum TG and CHO concentrations and alanine aminotransferase (ALT) and creatine kinase (CK) activity before and after 30 days of treatment were compared.

Results

Sixteen dogs (34.8%) had primary hyperlipidemia, and 30 dogs (65.2%) had secondary hyperlipidemia (including spontaneous hyperadrenocorticism [41.3%, n = 19/46], chronic treatment with glucocorticoids [10.8%, n = 5/46], and hypothyroidism [15.2%, n = 7/46]). After 30 days, serum TG concentration normalized (<150 mg/dL) in 42 dogs (91.3%) and CHO concentration normalized (<270 mg/dL) in 22 of 33 dogs (66.7%). There was no difference in baseline TG concentration between the primary and secondary hyperlipidemia subgroups, but the decrease in TG concentration after treatment was greater in the primary hyperlipidemia subgroup. No adverse effects were observed, but ALT activity decreased significantly after 30 days of treatment.

Conclusions and clinical importance

Over 30 days, BZF was safe and effective in treatment of primary and secondary hyperlipidemia in dogs.

Degeneration of dopaminergic neurons leads to Parkinson's disease (PD), characterized by reduced levels of striatal dopamine (DA) and impaired voluntary movements. DA replacement is achieved by levodopa treatment which in long-term causes involuntary movements or dyskinesia. Dyskinesia is linked to the pulsatile activation of D1 receptors of the striatal medium spiny neurons (MSNs) forming the direct output pathway (dMSNs). The contribution of DA stimulation of D2R in MSNs of the indirect pathway (iMSNs) is less clear. Using the 6-hydroxydopamine model of PD, here we show that loss of DA-mediated inhibition of these neurons intensifies levodopa-induced dyskinesia (LID) leading to reprogramming of striatal gene expression. We propose that the motor impairments characteristic of PD and of its therapy are critically dependent on D2R-mediated iMSNs activity. D2R signaling not only filters inputs to the striatum but also indirectly regulates dMSNs mediated responses.

Proteins implicated in neurodegenerative conditions such as Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have been identified in bodily fluids encased in extracellular vesicles called exosomes. Whether exosomes found in DLB patients can transmit pathology is not clear. In this study, exosomes were successfully harvested through ultracentrifugation from brain tissue from DLB and AD patients as well as non-diseased brain tissue. Exosomes extracted from brains diagnosed with either AD or DLB contained aggregate-prone proteins. Furthermore, injection of brain-derived exosomes from DLB patients into the brains of wild type mice induced α-synuclein (α-syn) aggregation. As assessed through immunofluorescent double labeling, α-syn aggregation was observed in MAP2⁺, Rab5⁺ neurons. Using a neuronal cell line, we also identified intracellular α-syn aggregation mediated by exosomes is dependent on recipient cell endocytosis. Together, these data suggest that exosomes from DLB patients are sufficient for seeding and propagating α-syn aggregation in vivo.

An amendment to this paper has been published and can be accessed via the original article.

Background

Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) Tau. While 3R tau is found in Pick's disease and Alzheimer's disease (AD), 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and AD. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the pathology in amyloid precursor protein transgenic (tg) mouse model of AD and 4R tau, however it is unclear if CBL ameliorates the deficits and neuropathology in the mouse model of Pick's disease over expressing 3R tau.

Results

Mice expressing 3R tau (L266V and G272V mutations) under the mThy-1 promoter were treated with CBL in two separate groups, the first was 3 months old (treated for 3 months, IP) and the second was 6 months old (treated for 3 months, IP) at the start of the treatment. We found that although the levels of total 3R tau were unchanged, CBL reduced the levels of hyper-phosphorylated tau in both groups of mice. This was accompanied by reduced neurodegenerative pathology in the neocortex and hippocampus in both groups and by improvements in the behavioral deficits in the nest-building test and water maze in the 3-6 month group.

Conclusion

Taken together these results support the notion that CBL may be beneficial in other taupathy models by reducing the levels of aberrantly phosphorylated tau.

Background

HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity.

Methods

GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy.

Results

We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field.

Conclusions

Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.