Effect of subthalamic coordinated reset deep brain stimulation on Parkinsonian gait.

Introduction: Coordinated Reset Deep Brain Stimulation (CR DBS) is a novel DBS approach for treating Parkinson's disease (PD) that uses lower levels of burst stimulation through multiple contacts of the DBS lead. Though CR DBS has been demonstrated to have sustained therapeutic effects on rigidity, tremor, bradykinesia, and akinesia following cessation of stimulation, i.e., carryover effect, its effect on Parkinsonian gait has not been well studied. Impaired gait is a disabling symptom of PD, often associated with a higher risk of falling and a reduced quality of life. The goal of this study was to explore the carryover effect of subthalamic CR DBS on Parkinsonian gait. Methods: Three non-human primates (NHPs) were rendered Parkinsonian and implanted with a DBS lead in the subthalamic nucleus (STN). For each animal, STN CR DBS was delivered for several hours per day across five consecutive days. A clinical rating scale modified for NHP use (mUPDRS) was administered every morning to monitor the carryover effect of CR DBS on rigidity, tremor, akinesia, and bradykinesia. Gait was assessed quantitatively before and after STN CR DBS. The stride length and swing speed were calculated and compared to the baseline, pre-stimulation condition. Results: In all three animals, carryover improvements in rigidity, bradykinesia, and akinesia were observed after CR DBS. Increased swing speed was observed in all the animals; however, improvement in stride length was only observed in NHP B2. In addition, STN CR DBS using two different burst frequencies was evaluated in NHP B2, and differential effects on the mUPDRS score and gait were observed. Discussion: Although preliminary, our results indicate that STN CR DBS can improve Parkinsonian gait together with other motor signs when stimulation parameters are properly selected. This study further supports the continued development of CR DBS as a novel therapy for PD and highlights the importance of parameter selection in its clinical application.

Investigating the functional role of SETD6 in lung adenocarcinoma.

BACKGROUND: SET domain containing 6 (SETD6) has been shown to be upregulated in multiple human cancers and can promote malignant cell survival. However, expression and function of SETD6 in lung adenocarcinoma (LUAD) remains unaddressed. This study aimed to demonstrate the expression pattern, biological roles and potential mechanisms by which SETD6 dysregulation is associated with LUAD. METHODS: The expression level of SETD6 was evaluated in LUAD clinical specimens and its correlation with clinical parameters were analyzed. In vitro, gain-of-function and loss-of-function experiments were performed to evaluate the effects of SETD6 on cell proliferation, apoptosis, migration, and colony formation of LUAD cell line A549. Western-blot was performed to investigate the involvement of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways as downstream signaling of SETD6 in LUAD cells. RESULTS: Compared with non-tumorous tissues, SETD6 was overexpressed in tumor tissues, and its overexpression significantly correlates with higher rates of regional lymph node metastasis and poor prognosis in patients with LUAD. In A549 cell line, SETD6 overexpression could promote cell proliferation, migration, colony formation and inhibit cell apoptosis, whereas SETD6 knockdown caused the opposite effects. Furthermore, we demonstrated that the mechanisms underlying the effect of SETD6 on LUAD biological behaviors may be through its interaction with NF-κB and Nrf2 signaling pathways. CONCLUSIONS: SETD6, which is highly expressed in LUAD tumor tissues, plays an important role in promoting the malignant behaviors of LUAD via likely the NF-κB and Nrf2 signaling pathways.

Spatiotemporal scaling changes in gait in a progressive model of Parkinson's disease.

Objective: Gait dysfunction is one of the most difficult motor signs to treat in patients with Parkinson's disease (PD). Understanding its pathophysiology and developing more effective therapies for parkinsonian gait dysfunction will require preclinical studies that can quantitatively and objectively assess the spatial and temporal features of gait. Design: We developed a novel system for measuring volitional, naturalistic gait patterns in non-human primates, and then applied the approach to characterize the progression of parkinsonian gait dysfunction across a sequence of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatments that allowed for intrasubject comparisons across mild, moderate, and severe stages. Results: Parkinsonian gait dysfunction was characterized across treatment levels by a slower stride speed, increased time in both the stance and swing phase of the stride cycle, and decreased cadence that progressively worsened with overall parkinsonian severity. In contrast, decreased stride length occurred most notably in the moderate to severe parkinsonian state. Conclusion: The results suggest that mild parkinsonism in the primate model of PD starts with temporal gait deficits, whereas spatial gait deficits manifest after reaching a more severe parkinsonian state overall. This study provides important context for preclinical studies in non-human primates studying the neurophysiology of and treatments for parkinsonian gait.

Media Bias and Factors Affecting the Impartiality of News Agencies during COVID-19.

When COVID-19 was raging around the world, people were more fearful and anxious. In this context, the media should uphold impartiality and shoulder the responsibility of eliminating misinformation. Therefore, our research adopted sentiment analysis technologies to analyze the impartiality of news agencies and analyzed the factors that affect the impartiality of COVID-19-related articles about various countries. The SentiWordNet3.0 and bidirectional encoder representations from transformers (BERT) models were employed to analyze the articles and visualize the data. The following conclusions were redrawn in our research. During the pandemic, articles of some news agencies were not objective; the impartiality of news agencies was related to the reliability of news agencies instead of the bias of news agencies; there were obvious differences in the coverage and positivity of international news agencies to report the performance of COVID-19 prevention and control in different countries.

Variable-Metric Localization of Occupied and Virtual Orbitals.

The key idea of the variable-metric approach to orbital localization is to allow nonorthogonality between orbitals while, at the same time, preventing them from becoming linearly dependent. The variable-metric localization has been shown to improve the locality of occupied nonorthogonal orbitals relative to their orthogonal counterparts. In this work, numerous localization algorithms are designed and tested to exploit the conceptual simplicity of the variable-metric approach with the goal of creating a straightforward and reliable localization procedure for virtual orbitals. The implemented algorithms include the steepest descent, conjugate gradient (CG), limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS), and hybrid procedures as well as trust-region (TR) methods based on the CG and Cauchy-point subproblem solvers. Comparative analysis shows that the CG-based TR algorithm is the best overall method to obtain nonorthogonal localized molecular orbitals (NLMOs), occupied or virtual. The L-BFGS and CG algorithms can also be used to obtain NLMOs reliably but often at higher computational cost. Extensive tests demonstrate that the implemented methods allow us to obtain well-localized Boys-Foster (i.e., maximally localized Wannier functions) and Pipek-Mezey, orthogonal and nonorthogonal, and occupied and virtual orbitals for a variety of gas-phase molecules and periodic materials. The tests also show that virtual NLMOs, which have not been described before, are, on average, 13% (Boys-Foster) and 18% (Pipek-Mezey) more localized than their orthogonal counterparts.

Direct Unconstrained Variable-Metric Localization of One-Electron Orbitals.

Spatially localized one-electron orbitals, orthogonal and non-orthogonal, are widely used in electronic structure theory to describe chemical bonding and speed up calculations. In order to avoid linear dependencies of localized orbitals, the existing localization methods either constrain orbital transformations to be unitary, that is, metric preserving, or, in the case of variable-metric methods, fix the centers of non-orthogonal localized orbitals. Here, we developed a different approach to orbital localization, in which these constraints are replaced with a single restriction that specifies the maximum allowed deviation from the orthogonality for the final set of localized orbitals. This reformulation, which can be viewed as a generalization of existing localization methods, enables one to choose the desired balance between the orthogonality and locality of the orbitals. Furthermore, the approach is conceptually and practically simple as it obviates the necessity in unitary transformations and allows one to determine optimal positions of the centers of non-orthogonal orbitals in an unconstrained and straightforward minimization procedure. It is demonstrated to produce well-localized orthogonal and non-orthogonal orbitals with the Berghold and Pipek--Mezey localization functions for a variety of molecules and periodic materials including large systems with nontrivial bonding.

Visualization of Long Noncoding RNA MEG3 in Living Cells by a Triple-Helix-Powered 3D Catcher.

Visual imaging of long noncoding RNA (lncRNA) MEG3, a newfound regulator of transactivation and tumor growth suppression, is conducive to unlock the secrets of MEG3 in some important biological processes. Here, for the first time, we designed a DNA tetrahedron-based three-dimensional (3D) catcher for imaging cytoplasmic lncRNA MEG3 in living cells. The 3D catcher is composed of a triple-helix-forming dsDNA with capacity to bind the 5'-end GA-rich domain of the lncRNA MEG3 and four hairpin-shaped antisense sequences toward contiguous domain on MEG3. Once ingested by the cell, the 3D catcher quickly captures lncRNA MEG3 via forming a DNA-RNA triple-helix structure and triggering the hybridization-based string disassembly of the catcher. Concomitantly, the quenched hairpin is opened and the fluorescent signal undergoes lighting on conversion. Ascribed to the triple-helix-induced "domino effect," the disassembly reaction time is greatly shorter than the reaction with the inability to form a triple helix. The 3D catcher allows detection of long-chain targets as long as 129 nucleotide (129 nt) with a detection limit of 0.36 nM and distinguishes endogenous lncRNA MEG3 fragments in living cells between hepatoma cells and normal hepatocytes, which provides a reliable strategy for monitoring endogenous long fragment nucleic acid biomarkers in early clinical lesion diagnoses.

Why pregnenolone and progesterone, two structurally similar steroids, exhibit remarkably different cocrystallization with aromatic molecules.

Selective binding of steroid molecules is of paramount importance for designing drugs that can target the biological pathways of only individual steroids. From this perspective, it is remarkable that progesterone (PRO) and pregnenolone (PRE), two structurally similar steroids, demonstrate a dramatically different propensity to interact with aromatic molecules. It has been recently reported that, in solid-state cocrystallization, PRO forms cocrystals with a wide variety of aromatic systems whereas PRE cocrystallizes only with a few. In this work, a simple yet effective computational procedure was developed to explain the fundamental origins of this surprising phenomenon. This procedure enables a direct comparison of the strength of intermolecular binding in the structurally similar cocrystals of PRO and PRE by generating experimentally inaccessible meta-stable cocrystals of PRE that closely resemble those observed for PRO. Direct comparative analysis shows that interactions between the α-face of the steroid and the π-electrons of aromatic molecules, the focus of previous studies, are not sufficiently different to explain the cocrystallization behavior of PRO and PRE. Instead, the observed difference is attributed to the different stabilities of the cocrystals relative to their pure components: organic and steroid crystals. It is calculated that the cocrystallization process is thermodynamically favorable in the case of PRO and unfavorable in the case of PRE. Furthermore, strong hydrogen bonds in the pure PRE crystal appear to be the major factor that makes the cocrystallization of PRE energetically unfavorable for a wide range of aromatic molecules. The fundamental analysis performed in this work has important practical implications for designing new steroid-containing crystals, selective biomolecular steroid receptors, and steroid-specific drugs. It suggests that a strategy for the selective binding of steroids should focus primarily on tuning the strength of hydrogen bonding.