Circadian rest-activity rhythms predict cognitive function in early Parkinson's disease independently of sleep

BACKGROUND: Cognitive impairment is a common and debilitating symptom of Parkinson's disease (PD), and its etiology is likely multifactorial. One candidate mechanism is circadian disruption. Although there is evidence of circadian abnormalities in PD, no studies have directly assessed their association with cognitive impairment. OBJECTIVES: Investigate whether circadian rest-activity rhythm is associated with cognitive function in PD independently of sleep. METHODS: Thirty-five participants with PD wore wrist actigraph monitors and completed sleep diaries for 7 to 10 days, then underwent neuropsychological testing. Rest-activity rhythm was characterized using nonparametric circadian rhythm analysis of actigraphy data. Objective sleep parameters were also estimated using actigraphy data. Hierarchical regression models assessed the independent contributions of sleep and rest-activity rhythm to cognitive performance. RESULTS: Less stable day-to-day rest-activity rhythm was associated with poorer executive, visuospatial, and psychomotor functioning, but not with memory. Hierarchical regressions showed that interdaily stability's contribution to cognitive performance was independent of sleep's contributions. Whereas sleep contributed to executive function, but not psychomotor or visuospatial performance, rest-activity rhythm stability significantly contributed to variance in all three of these domains, uniquely accounting for 14.4% to 17.6% of their performance variance. CONCLUSIONS: Our findings indicate that circadian rest-activity rhythm is associated with cognitive impairment independently of sleep. This suggests the possible utility of rest-activity rhythm as a biomarker for circadian function in PD. Future research should explore interventions to stabilize behavioral rhythms in order to strengthen circadian function, which, in turn, may reduce cognitive impairment in PD.R00 HL102241 - NHLBI NIH HHS; R01 AG048108 - NIA NIH HHSAccepted manuscrip

The effect of Parkinson’s disease subgroups on verbal and nonverbal fluency

BACKGROUND: Parkinson’s disease (PD) leads to deficits in executive function, including verbal and nonverbal fluency, as a result of compromised frontostriatal circuits. It is unknown whether deficits in verbal and nonverbal fluency in PD are driven by certain subgroups of patients, or how strategy use may facilitate performance. PARTICIPANTS: Sixty-five nondemented individuals with PD, including 36 with right-body onset (RPD; 20 with tremor as their initial symptom, 16 nontremor) and 29 with left-body onset (LPD; 14 with tremor as their initial symptom, 15 nontremor), and 52 normal control participants (NC) took part in the study. MEASUREMENTS: Verbal fluency was assessed using the FAS and Animals tests. Nonverbal fluency was assessed using the Ruff Figural Fluency Test. RESULTS: Both RPD and LPD were impaired in generating words and in using clustering and switching strategies on phonemic verbal fluency, whereas different patterns of impairment were found on nonverbal fluency depending on the interaction of side of onset and initial motor symptom (tremor vs. nontremor). Strategy use correlated with number of correct responses on verbal fluency in LPD, RPD, and NC. By contrast, on nonverbal fluency, strategy use correlated with correct responses for RPD and LPD, but not for NC. CONCLUSION: Our findings demonstrate the importance of considering subgroups in PD and analyzing subcomponents of verbal and nonverbal fluency (correct responses, errors, and strategies), which may depend differently on the integrity of dorsolateral prefrontal cortex, inferior frontal cortex, and anterior cingulate cortex.Published versio

Real-time analysis of endogenous Wnt signalling in 3D mesenchymal stromal cells

Wnt signalling has been implicated in the regulation of stem cell self-renewal and differentiation; however, the majority of in vitro studies are carried out using monolayer 2D culture techniques. Here, we used mesenchymal stromal cell (MSC) EGFP reporter lines responsive to Wnt pathway activation in a 3D spheroid culture system to mimic better the in vivo environment. Endogenous Wnt signalling was then investigated under basal conditions and when MSCs were induced to undergo osteogenic and adipogenic differentiation. Interestingly, endogenous Wnt signalling was only active during 3D differentiation whereas 2D cultures showed no EGFP expression throughout an extended differentiation time-course. Furthermore, exogenous Wnt signalling in 3D adipogenic conditions inhibited differentiation compared to unstimulated controls. In addition, suppressing Wnt signalling by Dkk-1 restored and facilitated adipogenic differentiation in MSC spheroids. Our findings indicate that endogenous Wnt signalling is active and can be tracked in 3D MSC cultures where it may act as a molecular switch in adipogenesis. The identification of the signalling pathways that regulate MSCs in a 3D in vivo-like environment will advance our understanding of the molecular mechanisms that control MSC fate

Using environmental DNA for detection of Batrachochytrium salamandrivorans in natural water

Rapid, early, and reliable detection of invasive pathogenic microorganisms is essential in order to either predict or delineate an outbreak, and monitor appropriate mitigation measures. The chytrid fungus Batrachochytrium salamandrivorans is expanding in Europe, and infection with this fungus may cause massive mortality in urodelans (salamanders and newts). In this study, we designed and validated species‐specific primers and a probe for detection of B. salamandrivorans in water. In a garden pond in close proximity to the B. salamandrivorans index site in the Netherlands, B. salamandrivorans‐infected newts had been detected in 2015 and have been monitored since. In 2016 and 2017, no B. salamandrivorans was detected at this site, but in 2018 B. salamandrivorans flared up in this isolated pond which allowed validation of the technique in situ. We here present the development of an environmental DNA technique that successfully detects B. salamandrivorans DNA in natural waterbodies even at low concentrations. This technique may be further validated to play a role in B. salamandrivorans range delineation and surveillance in both natural waterbodies and in captive collections

Photodissociation dynamics of the iodide-uracil (I-U) complex

Photofragment action spectroscopy and femtosecond time-resolved photoelectron imaging are utilized to probe the dissociation channels in iodide-uracil (I− ⋅ U) binary clusters upon photoexcitation. The photofragment action spectra show strong I− and weak [U- H]− ion signal upon photoexcitation. The action spectra show two bands for I− and [U- H]− production peaking around 4.0 and 4.8 eV. Time-resolved experiments measured the rate of I− production resulting from excitation of the two bands. At 4.03 eV and 4.72 eV, the photoelectron signal from I− exhibits rise times of 86 ± 7 ps and 36 ± 3 ps, respectively. Electronic structure calculations indicate that the lower energy band, which encompasses the vertical detachment energy (4.11 eV) of I−U, corresponds to excitation of a dipole-bound state of the complex, while the higher energy band is primarily a π-π∗ excitation on the uracil moiety. Although the nature of the two excited states is very different, the long lifetimes for I− production suggest that this channel results from internal conversion to the I− ⋅ U ground state followed by evaporation of I−. This hypothesis was tested by comparing the dissociation rates to Rice-Ramsperger-Kassel-Marcus calculations

Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan.

The topoisomerase I (TOP1) inhibitor irinotecan triggers cell death by trapping TOP1 on DNA, generating cytotoxic protein-linked DNA breaks (PDBs). Despite its wide application in a variety of solid tumors, the mechanisms of cancer cell resistance to irinotecan remains poorly understood. Here, we generated colorectal cancer (CRC) cell models for irinotecan resistance and report that resistance is neither due to downregulation of the main cellular target of irinotecan TOP1 nor upregulation of the key TOP1 PDB repair factor TDP1. Instead, the faster repair of PDBs underlies resistance, which is associated with perturbed histone H4K16 acetylation. Subsequent treatment of irinotecan-resistant, but not parental, CRC cells with histone deacetylase (HDAC) inhibitors can effectively overcome resistance. Immunohistochemical analyses of CRC tissues further corroborate the importance of histone H4K16 acetylation in CRC. Finally, the resistant clones exhibit cross-resistance with oxaliplatin but not with ionising radiation or 5-fluoruracil, suggesting that the latter two could be employed following loss of irinotecan response. These findings identify perturbed chromatin acetylation in irinotecan resistance and establish HDAC inhibitors as potential therapeutic means to overcome resistance

Technologies for the high seas: meeting the climate challenge

Progress toward decarbonizing shipping has been slow compared with other sectors. To explore the scope for an urgent step-change cut in CO2, this paper presents results from a participatory technology roadmapping exercise. Results: Combining existing incremental and novel technologies with slow-steaming can deliver reductions in CO2 of over 50% even in the short term for existing ships. However, roadmaps for three vessel types illustrate barriers to change including the sector's complexity, infrastructure lock-in and a need for tailored market and vessel-specific roadmaps to support decision-making. Conclusions: Through technology and engineering, the outlook for the shipping sector to significantly cut its CO2 emissions, even in the short term, is promising. Nevertheless, the scale of change requires support to demonstrate how the long-term low-carbon vision offers enough benefit to overcome necessary short-term investment