Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism.

Eukaryotic chromosomes contain compartments of various functions, which are marked by and enriched with specific histone modifications. However, the molecular mechanisms by which these histone marks function in chromosome compartmentalization are poorly understood. Constitutive heterochromatin is a largely silent chromosome compartment characterized in part by H3K9me2 and 3. Here, we show that heterochromatin protein 1 (HP1), an H3K9me2 and 3 "reader," interacts with SUV39H1, an H3K9me2 and 3 "writer," and with TRIM28, an abundant HP1 scaffolding protein, to form complexes with increased multivalent engagement of H3K9me2 and 3-modified chromatin. H3K9me2 and 3-marked nucleosomal arrays and associated complexes undergo phase separation to form macromolecule-enriched liquid droplets. The droplets are reminiscent of heterochromatin as they are highly dense chromatin-containing structures that are resistant to DNase and exclude the general transcription factor TFIIB. Our data suggest a general mechanism by which histone marks regulate chromosome compartmentalization by promoting phase separation.

Mirror-image trypsin digestion and sequencing of D-proteins.

The development of mirror-image biology systems and related applications is hindered by the lack of effective methods to sequence mirror-image (D-) proteins. Although natural-chirality (L-) proteins can be sequenced by bottom-up liquid chromatography-tandem mass spectrometry (LC-MS/MS), the sequencing of long D-peptides and D-proteins with the same strategy requires digestion by a site-specific D-protease before mass analysis. Here we apply solid-phase peptide synthesis and native chemical ligation to chemically synthesize a mirror-image version of trypsin, a widely used protease for site-specific protein digestion. Using mirror-image trypsin digestion and LC-MS/MS, we sequence a mirror-image large subunit ribosomal protein (L25) and a mirror-image Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), and distinguish between different mutants of D-Dpo4. We also perform writing and reading of digital information in a long D-peptide of 50 amino acids. Thus, mirror-image trypsin digestion in conjunction with LC-MS/MS may facilitate practical applications of D-peptides and D-proteins as potential therapeutic and informational tools.

Association between extremely high-density lipoprotein cholesterol and adverse cardiovascular outcomes: a systematic review and meta-analysis.

Background: The association between high-density lipoprotein cholesterol (HDL-C) and adverse cardiovascular outcomes is understudied. Based on cohort studies, the current study aimed to investigate the association of extremely high HDL-C with all-cause, atherosclerotic cardiovascular disease (CVD) mortality, and stroke risk. Methods: A systematic literature search in Embase, PubMed, Cochrane Library, and Web of Science was performed to collect relevant cohort studies published before August 20, 2022. A random-effects model was used to pool relative risks (RRs) and 95% confidence intervals (CIs). Results: A total of 17 cohort studies involving 19,630,829 participants were included, encompassing 18,547,132 total deaths (1,328,036 CVD deaths). All-cause mortality, CVD mortality, and stroke risk in the extremely high HDL-C group were increased by 15% (RR = 1.15, 95% CI:1.05-1.25), 14% (RR = 1.14, 95% CI:0.96-1.35) and 14% (RR = 1.14, 95% CI:0.82-1.58), compared to the normal HDL-C group. In subgroup analyses, extremely high HDL-C was associated with a reduced risk of CVD mortality in women and a lower risk of stroke in men compared to normal HDL-C levels. Conclusions: The extremely high levels of HDL-C were associated with elevated risks of all-cause mortality, CVD mortality, and stroke. More well-designed studies are needed to confirm our findings. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370201, identifier: CRD42022370201.

Efficacy and safety of cutting therapy in the treatment of migraine: A protocol for systematic review and meta-analysis.

BACKGROUND: Migraine is a chronic paroxysmal neurovascular disease in which pain on one or both sides of the head is the main manifestation and is accompanied by other neurological manifestations. Clinical practice has shown that cutting therapy as a complementary alternative medicine can play a role in relieving migraine attacks. However, there is no consensus on the efficacy of cutting treatment in the treatment of migraine. The aim of this study was to conduct a meta-analysis to systematically evaluate the efficacy and safety of cutting therapy in the treatment of migraine. METHODS: First, databases were searched for relevant literature. The main databases we searched were PubMed, the Web of Science, MEDLINE, Embase, Cochrane Library, the Chinese National Knowledge Infrastructure, the Chinese Science Journal Database, Wanfang Data, and the Chinese Biomedical Literature Database. The keywords searched were "cutting treatment," " traditional Chinese medicine cutting treatment," and "migraine." The search was conducted from inception to November 2021. Second, 2 reviewers independently completed the process of study selection, data extraction, risk of bias assessment and data synthesis in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols statement guidelines. Finally, we will use Review Manager Version 5.3 software for meta-analysis. RESULTS: This study will provide the most recent evidence related to the treatment of migraine by cutting therapy. CONCLUSION: The results of this systematic evaluation will provide an objective evidence-based framework for judging the effectiveness and safety of cutting therapy in the treatment of migraine.

Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription.

Abnormally formed FUS/EWS/TAF15 (FET) fusion oncoproteins are essential oncogenic drivers in many human cancers. Interestingly, at the molecular level, they also form biomolecular condensates at specific loci. However, how these condensates lead to gene transcription and how features encoded in the DNA element regulate condensate formation remain unclear. Here, we develop an in vitro single-molecule assay to visualize phase separation on DNA. Using this technique, we observe that FET fusion proteins undergo phase separation at target binding loci and the phase separated condensates recruit RNA polymerase II and enhance gene transcription. Furthermore, we determine a threshold number of fusion-binding DNA elements that can enhance the formation of FET fusion protein condensates. These findings suggest that FET fusion oncoprotein promotes aberrant gene transcription through loci-specific phase separation, which may contribute to their oncogenic transformation ability in relevant cancers, such as sarcomas and leukemia.

Clinical efficacy of Xinkeshu Pian on coronary heart disease and mood disorder complications after PCI.

AIM: To assess the efficacy and safety of combining Xinkeshu tablet treatment with routine Western medicine treatment for patients with coronary heart disease (CHD) and mood disorders after PCI postoperative period. METHOD: 100 patients were randomly divided into treatment group of 50 cases, and control group of 50 cases. The control group was given routine Western medical treatment, whereas the treatment group was given routine Western medical treatment in combination with Xinkeshu tablets. Eight weeks after treatment, the patients underwent SF-36 life quality evaluation, self-rating depression scale (SDS) evaluation, and self-rating anxiety scale (SAS) evaluation. RESULT: After the eight-week treatment, the SF-36 life quality scores, SAS scores, SDS score, as well as the reduction in heart creatinine levels of the two groups were compared. The results show statistical significance (P<0.05). CONCLUSION: Xinkeshu can effectively address the PCI postoperative mood disorders in patients with coronary heart disease and improve the quality of life.