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"Cheng, Tan"
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Nucleosome allostery in pioneer transcription factor binding
While recent experiments revealed that some pioneer transcription factors (TFs) can bind to their target DNA sequences inside a nucleosome, the binding dynamics of their target recognitions are poorly understood. Here we used the latest coarse-grained models and molecular dynamics simulations to study the nucleosome-binding procedure of the two pioneer TFs, Sox2 and Oct4. In the simulations for a strongly positioning nucleosome, Sox2 selected its target DNA sequence only when the target was exposed. Otherwise, Sox2 entropically bound to the dyad region nonspecifically. In contrast, Oct4 plastically bound on the nucleosome mainly in two ways. First, the two POU domains of Oct4 separately bound to the two parallel gyres of the nucleosomal DNA, supporting the previous experimental results of the partial motif recognition. Second, the POUS domain of Oct4 favored binding on the acidic patch of histones. Then, simulating the TFs binding to a genomic nucleosome, the LIN28B nucleosome, we found that the recognition of a pseudo motif by Sox2 induced the local DNA bending and shifted the population of the rotational position of the nucleosomal DNA. The redistributed DNA phase, in turn, changed the accessibility of a distant TF binding site, which consequently affected the binding probability of a second Sox2 or Oct4. These results revealed a nucleosomal DNA-mediated allosteric mechanism, through which one TF binding event can change the global conformation, and effectively regulate the binding of another TF at distant sites. Our simulations provide insights into the binding mechanism of single and multiple TFs on the nucleosome.
Journal Article
التعليم والتواصل : مقدمة نقدية في الثقافة واللسان
لم يعد التعليم قائما على التلقين والحفظ، كما كان الأمر في كلاسيكيات المجال التربوي، بل صار مرتبطا بقوة بمجالات معرفية بينية شديدة الأهمية والتخصص، منها مجالات : الثقافة المعرفية، والذكاء الاصطناعي AI، والتطور الهائل في علوم اللسان، وتعلقها التوثيق بالعلوم العرفانية Cognitive Sciences، وتكنولوحيا علوم المستقبل، والتحليل النقدي للخطاب CDA، وتداوليات الصف... إلخ، وفي هذا الكتاب حاول المؤلف أن ينقل مجموعة من هذه الرؤى المعرفية البينية، وبيان كيفية استثمارها في مجال التعليم عموما.
BOOK
Influence of torsion charge on shadow and observation signature of black hole surrounded by various profiles of accretions
In this paper, we carefully study the shadow and observational signature of the black hole with torsion charge for a distant observer, and further compare the results with that gotten in Schwarzschild spacetime. For thin disk accretion cases, the result shows that there are not only dark areas in the observed image of black hole, but also photon rings and lensing rings, which are closely associated with the torsion charge. The change of torsion charge will directly affect the range of photon ring and lens ring, and the contribution proportion of these rings to the observed intensity. In addition, the total flux of observed intensity is mainly provided by direct emission, and the lensing ring and photon ring contribute only a small part. By further considering the static and infalling cases of spherically symmetric accretion, one can find that the observed image is much darker for the falling accretion matters, but the shadow radius does not change. However, both the observed intensity and shadow size are significantly different when the torsion charge changes. That is, the size of the observed shadow is related to the spacetime geometry. In addition, based on the shadow of M87, we also constraint the torsion charge of black hole by using the diameter of shadow approximately. Finally, by comparing our results and that in Schwarzschild spacetime, it shows that black hole shadow can provide a feasible method for distinguishing those two spacetime.
Journal Article
The relationships between family socioeconomic status, gender inequality, and higher education selection from 1962 to 2018
This study contributes to the substantial body of studies on the relationships between family socioeconomic status (SES), gender inequality, and higher education selection. It does so by 1) examining the association between SES and gender inequality in higher education, and 2) comparing changes in socioeconomic and gender inequality before and after the 1999 higher education expansion using eight waves of China General Social Survey (CGSS) data (2008-2018), which comprised a total sample of 57,067. The results of this study revealed that gender inequality in higher education selection in China is driven by SES, and that higher education expansion in China has not reduced socioeconomic and gender inequality in terms of higher education selection. The established inequality persists for low SES students, especially low SES females. This study not only underscores the importance of SES and gender but also expands the conceptual validity of SES (effects of SES on gender inequality) in higher education selection. (HRK / Abstract übernommen).
Journal Article
GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems
Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large simulation system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop a hierarchical domain decomposition scheme with dynamic load balancing for heterogeneous biomolecular systems to keep computational efficiency even after drastic changes in particle distribution. These schemes are applied to the dynamics of intrinsically disordered protein (IDP) droplets. During the fusion of two droplets, we find that the changes in droplet shape correlate with the mixing of IDP chains. Additionally, we simulate large systems with multiple IDP droplets, achieving simulation sizes comparable to those observed in microscopy. In our MD simulations, we directly observe Ostwald ripening, a phenomenon where small droplets dissolve and their molecules redeposit into larger droplets. These methods have been implemented in CGDYN of the GENESIS software, offering a tool for investigating mesoscopic biological processes using the residue-level CG models.
Here, the authors report the development of heterogeneous domain decomposition with load balancing for large biological molecular dynamics simulations using residue-level coarse-grained models.
Journal Article
Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study
Abstract
Context
Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC).
Objective
We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients.
Design and Patients
In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed.
Results
TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression.
Conclusions
Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future.
Journal Article
Involvement Practices, Socioeconomic Status, and Student Science Achievement: Insights From a Typology of Home and School Involvement Patterns
The present study examines if higher socioeconomic statics (SES) parents are more involved in their children's education, and if greater involvement is associated with better student science achievement in Hong Kong (N = 5,353). Results showed that (a) there were three latent classes characterized by different patterns of parental involvement; (b) there was no simple relationship between SES and parental involvement patterns among the three latent classes; and (c) patterns of parental involvement were not significantly associated with levels of student science achievement. These findings support the contention that higher SES parents are not necessarily more involved than lower SES parents in all aspects, and that higher levels of parental involvement may not eventuate in higher levels of student achievement.
Journal Article
Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease
Amyloid-β (Aβ) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer’s disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aβ produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aβ clearance remain largely unknown. The kidney is thought to be responsible for Aβ clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aβ in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aβ clearance via the kidney were assessed. We detected Aβ in the kidneys and urine of both humans and animals and found that the Aβ level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aβ deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aβ levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aβ from the blood, suggesting that facilitation of Aβ clearance via the kidney represents a novel potential therapeutic approach for AD.
Journal Article