Thiolutin has complex effects in vivo but is a direct inhibitor of RNA polymerase II in vitro.

Thiolutin is a natural product transcription inhibitor with an unresolved mode of action. Thiolutin and the related dithiolopyrrolone holomycin chelate Zn2+ and previous studies have concluded that RNA Polymerase II (Pol II) inhibition in vivo is indirect. Here, we present chemicogenetic and biochemical approaches to investigate thiolutin's mode of action in Saccharomyces cerevisiae. We identify mutants that alter sensitivity to thiolutin. We provide genetic evidence that thiolutin causes oxidation of thioredoxins in vivo and that thiolutin both induces oxidative stress and interacts functionally with multiple metals including Mn2+ and Cu2+, and not just Zn2+. Finally, we show direct inhibition of RNA polymerase II (Pol II) transcription initiation by thiolutin in vitro in support of classical studies that thiolutin can directly inhibit transcription in vitro. Inhibition requires both Mn2+ and appropriate reduction of thiolutin as excess DTT abrogates its effects. Pause prone, defective elongation can be observed in vitro if inhibition is bypassed. Thiolutin effects on Pol II occupancy in vivo are widespread but major effects are consistent with prior observations for Tor pathway inhibition and stress induction, suggesting that thiolutin use in vivo should be restricted to studies on its modes of action and not as an experimental tool.

AdaCS: Adaptive Compressive Sensing With Restricted Isometry Property-Based Error-Clamping.

Scene-dependent adaptive compressive sensing (CS) has been a long pursuing goal that has huge potential to significantly improve the performance of CS. However, with no access to the ground truth, how to design the scene-dependent adaptive strategy is still an open problem. In this paper, a restricted isometry property (RIP) condition-based error-clamping is proposed, which could directly predict the reconstruction error, i.e., the difference between the current-stage reconstructed image and the ground truth image, and adaptively allocate more samples to regions with larger reconstruction error at the next sampling stage. Furthermore, we propose a CS reconstruction network composed of Progressively inverse transform and Alternating Bi-directional Multi-grid Network, named PiABM-Net, that could efficiently utilize the multi-scale information for reconstructing the target image. The effectiveness of the proposed adaptive and cascaded CS method is demonstrated with extensive quantitative and qualitative experiments, compared with the state-of-the-art CS algorithms.

Higher-order epistasis within Pol II trigger loop haplotypes.

RNA polymerase II (Pol II) has a highly conserved domain, the trigger loop (TL), that controls transcription fidelity and speed. We previously probed pairwise genetic interactions between residues within and surrounding the TL and identified widespread incompatibility between TLs of different species when placed in the Saccharomyces cerevisiae Pol II context, indicating epistasis between the TL and its surrounding context. We sought to understand the nature of this incompatibility and probe higher order epistasis internal to the TL. We have employed deep mutational scanning with selected natural TL variants ("haplotypes"), and all possible intermediate substitution combinations between them and the yeast Pol II TL. We identified both positive and negative higher-order residue interactions within example TL haplotypes. Intricate higher-order epistasis formed by TL residues was sometimes only apparent from analysis of intermediate genotypes, emphasizing complexity of epistatic interactions. Furthermore, we distinguished TL substitutions with distinct classes of epistatic patterns, suggesting specific TL residues that potentially influence TL evolution. Our examples of complex residue interactions suggest possible pathways for epistasis to facilitate Pol II evolution.

Research progress on the functions and biosynthesis of theaflavins.

Theaflavins are beneficial to human health due to various bioactivities. Biosynthesis of theaflavins using polyphenol oxidase (PPO) is advantageous due to cost effectiveness and environmental friendliness. In this review, studies on the mechanism of theaflavins formation, the procedures to screen and prepare PPOs, optimization of reaction systems and immobilization of PPOs were described. The challenges associated with the mass biosynthesis of theaflavins, such as poor enzyme activity, undesirable subproducts and inclusion bodies of recombinant PPOs were presented. Further strategies to solve these challenges and improve theaflavins production, including enzyme engineering, immobilization enzyme technology, water-immiscible solvent-water biphasic systems and recombinant enzyme technology, were proposed.

The role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Tauopathies are neurodegenerative diseases characterized by deposits of abnormal Tau protein in the brain. Conventional tauopathies are often defined by a limited number of Tau epitopes, notably neurofibrillary tangles, but emerging evidence suggests structural heterogeneity among tauopathies. The prolyl isomerase Pin1 isomerizes cis P-tau to inhibit the development of oligomers, tangles and neurodegeneration in multiple neurodegenerative diseases such as Alzheimer's disease, traumatic brain injury, vascular contribution to cognitive impairment and dementia (VCID) and preeclampsia (PE). Thus, cis P-tau has emerged as an early etiological driver, blood marker and therapeutic target for multiple neurodegenerative diseases, with clinical trials ongoing. The discovery of cis P-tau and other tau pathologies in VCID and PE calls attention for simplistic classification of tauopathy in neurodegenerative diseases. These recent advances have revealed the exciting novel role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Five-week music therapy improves overall symptoms in schizophrenia by modulating theta and gamma oscillations.

Introduction: Some clinical studies have shown that music therapy as an adjunctive therapy can improve overall symptoms in patients with schizophrenia. However, the neural mechanisms of this improvement remain unclear due to insufficient neuroimaging evidence. Methods: In this work, 17 patients with schizophrenia accepted a five-week music therapy (music group) that integrated listening, singing, and composing, and required patients to cooperate in a group to complete music therapy tasks. Meanwhile, 15 patients with schizophrenia received a five-week visual art intervention as the control group including handicraft and painting activities. We collected the Manchester Scale (MS) and Positive and Negative Symptom Scale (PANSS) scores and electroencephalography (EEG) data before and after intervention in two groups. Results: Behavioral results showed that both interventions mentioned above can effectively help patients with schizophrenia relieve their overall symptoms, while a trend-level effect was observed in favor of music therapy. The EEG results indicated that music therapy can improve abnormal neural oscillations in schizophrenia which is reflected by a decrease in theta oscillation in the parietal lobe and an increase in gamma oscillation in the prefrontal lobe. In addition, correlation analysis showed that in the music group, both reductions in theta oscillations in the parietal lobe and increases in gamma oscillations in the prefrontal lobe were positively correlated with the improvement of overall symptoms. Discussion: These findings help us to better understand the neural mechanisms by which music therapy improves overall symptoms in schizophrenia and provide more evidence for the application of music therapy in other psychiatric disorders.

Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry.

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.