Altered dynamic functional network connectivity in drug-naïve Parkinson's disease patients with excessive daytime sleepiness.

Background: Excessive daytime sleepiness (EDS) is a frequent nonmotor symptoms of Parkinson's disease (PD), which seriously affects the quality of life of PD patients and exacerbates other nonmotor symptoms. Previous studies have used static analyses of these resting-state functional magnetic resonance imaging (rs-fMRI) data were measured under the assumption that the intrinsic fluctuations during MRI scans are stationary. However, dynamic functional network connectivity (dFNC) analysis captures time-varying connectivity over short time scales and may reveal complex functional tissues in the brain. Purpose: To identify dynamic functional connectivity characteristics in PD-EDS patients in order to explain the underlying neuropathological mechanisms. Methods: Based on rs-fMRI data from 16 PD patients with EDS and 41 PD patients without EDS, we applied the sliding window approach, k-means clustering and independent component analysis to estimate the inherent dynamic connectivity states associated with EDS in PD patients and investigated the differences between groups. Furthermore, to assess the correlations between the altered temporal properties and the Epworth sleepiness scale (ESS) scores. Results: We found four distinct functional connectivity states in PD patients. The patients in the PD-EDS group showed increased fractional time and mean dwell time in state IV, which was characterized by strong connectivity in the sensorimotor (SMN) and visual (VIS) networks, and reduced fractional time in state I, which was characterized by strong positive connectivity intranetwork of the default mode network (DMN) and VIS, while negative connectivity internetwork between the DMN and VIS. Moreover, the ESS scores were positively correlated with fraction time in state IV. Conclusion: Our results indicated that the strong connectivity within and between the SMN and VIS was characteristic of EDS in PD patients, which may be a potential marker of pathophysiological features related to EDS in PD patients.

Fabrication of an Injectable Star-polylactide/Thiolated Hyaluronate Hydrogel as a Double Drug-Delivery System for Cancer Treatment.

Unsatisfactory solid-tumor penetration or rapid metabolism of nanomaterials limits their therapeutic efficacy. Here, we designed an injectable thiolated hyaluronate (HA-SH) hydrogel as a stable drug-releasing platform for in situ tumor treatment. Biodegradable star-shaped polylactide (S-PLLA) was first synthesized and fabricated to porous microspheres to encapsulate hydrophobic curcumin (Cur@S-PLLA), which was then blended with hydrophilic doxorubicin (Dox) and the HA-SH precursor to form composite in situ formable hydrogels [Cur@S-PLLA/(Dox)HA-SH]. The results showed that adding the microspheres improved the performance of the hydrogel, such as decreasing the gelation time from 1080 s to 960 s and also the swelling ratio. The mechanical strength increased from 27 to 45 kPa. In addition, the double drug system guaranteed a sustained release of drugs, releasing Dox at the early stage, with the continuous later release of Cur after gel swelling or S-PLLA degradation to achieve long-lasting tumor suppression, which inhibits the survival of cancer cells. The inhibitory effects of the hydrogels on MCF-7 were studied. The cell activity in the double-loaded hydrogel was significantly lower than that of the control groups, and apparent dead cells appeared in 2 days and fewer living cells with time. Flow cytometry revealed that the Cur@S-PLLA/(Dox)HA-SH group had the highest apoptosis ratio of 86.60% at 12 h, and the drugs caused the cell cycle to be blocked in phase M to reduce cell division. In summary, the innovative release platform is expected to be used in long-lasting tumor suppression and provides more ideas for the design of drug carriers.

Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition.

Systemic exposure of metronidazole is increased in patients with inflammatory bowel diseases (IBDs), while the underlying mechanism remains unknown. Here, we aim to decipher the mechanisms by which experimental colitis regulates metronidazole disposition in mice. We first confirmed that the systemic exposure of metronidazole was elevated in dextran sulfate sodium (DSS)-induced experimental colitis. Hepatic microsomal incubation with metronidazole revealed that the production rate of 2-hydroxymetronidazole was inhibited, suggestive of a diminished hydroxylation reaction upon colitis. Remarkably, the hydroxylation reaction of metronidazole was selectively catalyzed by CYP2A5, which was downregulated in the liver of colitis mice. In addition, hepatic nuclear factor (NF)-κB (a prototypical and critical signaling pathway in inflammation) was activated in colitis mice. Luciferase reporter and chromatin immunoprecipitation assay indicated that NF-κB downregulated Cyp2a5 transcription through binding to an NF-κB binding site (-1711 to -1720 bp) in the promoter. We further verified that the regulatory effects of colitis on CYP2A5 depended on the disease itself rather than the DSS compound. First, one-day administration of DSS did not alter mRNA and protein levels of CYP2A5. Moreover, CYP2A5 was suppressed in the Il-10-/- spontaneously developing colitis model. Furthermore, Cyp2a5 expression was downregulated in both groups of mice with modest or severe colitis, whereas the expression change was much more significant in severe colitis as compared to modest colitis. Altogether, activated hepatic NF-κB in experimental colitis regulates CYP2A5 and metronidazole disposition, revealing the mechanism of pharmacokinetic instability under IBDs, and providing a theoretical foundation for rational drug use in the future.

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes.

Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1-3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body's response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body's local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.

Tight upper bounds for semi-online scheduling on two uniform machines with known optimum.

We consider a semi-online version of the problem of scheduling a sequence of jobs of different lengths on two uniform machines with given speeds 1 and s. Jobs are revealed one by one (the assignment of a job has to be done before the next job is revealed), and the objective is to minimize the makespan. In the considered variant the optimal offline makespan is known in advance. The most studied question for this online-type problem is to determine the optimal competitive ratio, that is, the worst-case ratio of the solution given by an algorithm in comparison to the optimal offline solution. In this paper, we make a further step towards completing the answer to this question by determining the optimal competitive ratio for s between [Formula: see text] and [Formula: see text], one of the intervals that were still open. Namely, we present and analyze a compound algorithm achieving the previously known lower bounds.