Characterization of the MitoPark mouse model of Parkinson’s disease for neurotoxicity and neuroprotection studies

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting about one million people in the United States and an estimated 10 million people worldwide. Although the pathological features of the disease, including dopaminergic neuronal loss and protein aggregation in the nigrostriatal tract are well understood, no cure or therapy exists that can decelerate or halt the neurodegenerative process. The exact mechanisms leading to cell death are still unresolved and advances in drug discovery for PD have been hampered by the lack of animal models that faithfully recapitulate the chronic, progressive nature of the disease, the full range of symptomology, and the underlying pathophysiological pathways. A recent transgenic mouse model, referred to as “MitoPark”, was created by selective inactivation of mitochondrial transcription factor A (TFAM) in the nigrostriatal pathway through control of the dopamine transporter (DAT) promotor by utilizing Cre/LoxP recombination. MitoPark mice model human PD by exhibiting a progressive course of the phenotypic manifestations and neurodegeneration, protein inclusions in nigral tissues, L-DOPA responsiveness, and adult-onset of disease. Considering that nonmotor symptoms reduce the quality of life and increase the cost of healthcare for PD patients, we characterized the full range of symptomatology in the MitoPark model. Similar to human PD, our MitoPark data suggest that many nonmotor symptoms, including cognitive deficits in learning and memory, olfactory discrimination, and neuropsychiatric deficits, are present in the model prior to severe motor dysfunction. Moreover, we have identified changes in neurogenesis, oxidative stress markers, and neurochemistry in the brain that correlate with the nonmotor symptoms observed. Furthermore, we have established that neuroinflammation (as a result of reactive microgliosis) and altered neurogenesis (subsequent to dopamine depletion) are present in later stages of the disease in this mouse model, making it particularly valuable for translational neurotoxicity and drug discovery studies. We also demonstrate that manganese, an environmentally relevant toxin linked to increased PD risk, can exacerbate some of these effects and accelerate disease onset in MitoPark mice. Finally, we explore two promising therapeutic options for PD: a mitochondrially targeted antioxidant and a neuroprotective protein. Our data demonstrate that Mito-apocynin treatment effectively attenuates progressive motor deficits, neuroinflammation, oxidative stress, and neurodegeneration in a comprehensive PD model via NOX2 inhibition in microglia and antioxidant effects in neurons. By expanding on recent work in our laboratory showing that Prokineticin-2 (PK2) serves a compensatory neuroprotective role in PD models, we identified a new mechanism by which PK2 may exert its effect: promoting neural stem cell proliferation and differentiation. Taken together, we have identified salient features of PD disease progression in a mouse model and applied the model to elucidate gene-environment interactions and to evaluate novel therapeutic strategies

Allo-suckling occurrence and its effect on lactation and nursing duration in harbour seals (Phoca vitulina) in Orkney, Scotland

This study was funded by Scottish Government (grant number MMSS/002/15).Fostering and allo-suckling are widespread among pinnipeds, and several hypotheses have been formulated to explain their occurrence. Here, we describe the occurrence of allo-suckling in harbour seals from photo-identification data of females and pups in Orkney (Scotland) during the pupping seasons between 2016 and 2019. We used a generalised linear model framework to investigate the effect of allo-suckling on the duration of lactation (females) and of nursing period (pups). A generalised additive model framework was used to explore how the probability of allo-suckling varied throughout the pupping season, and with changes in mother-pup separation time. Allo-suckling was observed in 31 females, at higher rates (18–37% of lactating females and 18–47% of the pups every year) than those observed in other phocid populations, with 13 females allo-suckling in multiple years. The duration of the pups’ nursing period was not affected by allo-suckling occurrence. However, females in mother-pup pairs where both mother and pup allo-suckled had longer lactation duration than when only the pup allo-suckled, or than in pairs where no allo-suckling was observed. The probability of allo-suckling increased during the pupping season and with increased mother-pup separation time. However, the proximate causes and the consequences on future reproductive output and pup survival remain unknown.Publisher PDFPeer reviewe

Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson’s disease

Impaired mitochondrial function and biogenesis have strongly been implicated in the pathogenesis of Parkinson’s disease (PD). Thus, identifying the key signaling mechanisms regulating mitochondrial biogenesis is crucial to developing new treatment strategies for PD. We previously reported that protein kinase D1 (PKD1) activation protects against neuronal cell death in PD models by regulating mitochondrial biogenesis. To further harness the translational drug discovery potential of targeting PKD1-mediated neuroprotective signaling, we synthesized mito-metformin (Mito-Met), a mitochondria-targeted analog derived from conjugating the anti-diabetic drug metformin with a triphenylphosphonium functional group, and then evaluated the preclinical efficacy of Mito-Met in cell culture and MitoPark animal models of PD. Mito-Met (100–300 nM) significantly activated PKD1 phosphorylation, as well as downstream Akt and AMPKα phosphorylation, more potently than metformin, in N27 dopaminergic neuronal cells. Furthermore, treatment with Mito-Met upregulated the mRNA and protein expression of mitochondrial transcription factor A (TFAM) implying that Mito-Met can promote mitochondrial biogenesis. Interestingly, Mito-Met significantly increased mitochondrial bioenergetics capacity in N27 dopaminergic cells. Mito-Met also reduced mitochondrial fragmentation induced by the Parkinsonian neurotoxicant MPP+ in N27 cells and protected against MPP+-induced TH-positive neurite loss in primary neurons. More importantly, Mito-Met treatment (10 mg/kg, oral gavage for 8 week) significantly improved motor deficits and reduced striatal dopamine depletion in MitoPark mice. Taken together, our results demonstrate that Mito-Met possesses profound neuroprotective effects in both in vitro and in vivo models of PD, suggesting that pharmacological activation of PKD1 signaling could be a novel neuroprotective translational strategy in PD and other related neurocognitive diseases

Respiratory Virus Surveillance Among Children with Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN inpatient (i.e., hospital) surveillance began in 2015, expanded to emergency departments (EDs) in 2016, and to outpatient clinics in 2018. This report describes demographic characteristics of enrolled children who received care in these settings, and yearly circulation of influenza, RSV, HMPV, HPIV1-3, adenovirus, human rhinovirus and enterovirus (RV/EV),* and SARS-CoV-2 during December 2016-August 2021. Among 90,085 eligible infants, children, and adolescents (children) aged \u3c18 \u3eyear

Clinical Impact of the Line Probe Assay and Xpert® MTB/RIF Assay in the Presumptive Diagnosis of Drug-Resistant Tuberculosis in Brazil: A Pragmatic Clinical Trial

Background: Rapid molecular methods such as the line probe assay (LPA) and Xpert® MTB/RIF assay (Xpert) have been recommended by the World Health Organization for drug-resistant tuberculosis (DR-TB) diagnosis. We conducted an interventional trial in DR-TB reference centers in Brazil to evaluate the impact of the use of LPA and Xpert. Methods: Patients with DR-TB were eligible if their drug susceptibility testing results were available to the treating physician at the time of consultation. The standard reference MGITTM 960 was compared with Xpert (arm 1) and LPA (arm 2). Effectiveness was considered as the start of the appropriate TB regimen that matched drug susceptibility testing (DST) and the proportions of culture conversion and favorable treatment outcomes after 6 months. Results: A higher rate of empirical treatment was observed with MGIT alone than with the Xpert assay (97.0% vs. 45.0%) and LPA (98.2% vs. 67.5%). Patients started appropriate TB treatment more quickly than those in the MGIT group (median 15.0 vs. 40.5 days; p<0.01) in arm 1. Compared to the MGIT group, culture conversion after 6 months was higher for Xpert in arm 1 (90.9% vs. 79.3%, p=0.39) and LPA in arm 2 (80.0% vs. 83.0%, p=0.81). Conclusions: In the Xpert arm, there was a significant reduction in days to the start of appropriate anti-TB treatment and a trend towards greater culture conversion in the sixth month

Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice

Aims: Parkinson\u27s disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction. Results: Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation. Innovation: The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches. Conclusion: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048–1066

The walnut (Juglans regia) genome sequence reveals diversity in genes coding for the biosynthesis of non-structural polyphenols

The Persian walnut (Juglans regia L.), a diploid species native to the mountainous regions of Central Asia, is the major walnut species cultivated for nut production and is one of the most widespread tree nut species in the world. The high nutritional value of J. regia nuts is associated with a rich array of polyphenolic compounds, whose complete biosynthetic pathways are still unknown. A J. regia genome sequence was obtained from the cultivar ‘Chandler’ to discover target genes and additional unknown genes. The 667-Mbp genome was assembled using two different methods (SOAPdenovo2 and MaSuRCA), with an N50 scaffold size of 464 955 bp (based on a genome size of 606 Mbp), 221 640 contigs and a GC content of 37%. Annotation with MAKER-P and other genomic resources yielded 32 498 gene models. Previous studies in walnut relying on tissue-specific methods have only identified a single polyphenol oxidase (PPO) gene (JrPPO1). Enabled by the J. regia genome sequence, a second homolog of PPO (JrPPO2) was discovered. In addition, about 130 genes in the large gallate 1-β-glucosyltransferase (GGT) superfamily were detected. Specifically, two genes, JrGGT1 and JrGGT2, were significantly homologous to the GGT from Quercus robur (QrGGT), which is involved in the synthesis of 1-O-galloyl-β-d-glucose, a precursor for the synthesis of hydrolysable tannins. The reference genome for J. regia provides meaningful insight into the complex pathways required for the synthesis of polyphenols. The walnut genome sequence provides important tools and methods to accelerate breeding and to facilitate the genetic dissection of complex traitsWe would especially like to thank Gale McGranahan, Emeritus Professor of the Department of Plant Sciences at UC Davis, for providing tissue culture materials for the transcriptome sequencing and assembly and the California Walnut Board for supporting this study. We gratefully acknowledge the editor and two anonymous referees for their constructive criticism and helpful comments that improved the manuscriptPeer reviewe

Entry and Exit Strategies in Migration Dynamics

This work is devoted to study the role of combined entry and exit strategies in the migration process. We develop a real option model in which the community of immigrants in the host country is described as a club and the immigrants benefits is a U-shaped function, depending on the dimension of the district. There exist two threshold levels: the first one triggers the migration choice, while the second triggers the return to the country of origin. The theoretical results show that the phenomenon of hysteresis is amplified by the existence of a community both in the entry case and in the exit case. Furthermore, the community can reduce the minimum wage level required to trigger both exit and entry: this fact could explain why in some cases we observe migration inflows with a low wage differential and also with underunemployment. We show also some possible further extensions of the model: in one case we introduce a possible way to select the entrants skills and in another case we show some theoretical implementations to include possible policy shocks in the migrants choice