Enhancer in cancer pathogenesis and treatment.

Enhancers are essential cis-acting regulatory elements that determine cell identity and tumor progression. Enhancer function is dependent on the physical interaction between the enhancer and its target promoter inside its local chromatin environment. Enhancer reprogramming is an important mechanism in cancer pathogenesis and can be driven by both cis and trans factors. Super enhancers are acquired at oncogenes in numerous cancer types and represent potential targets for cancer treatment. BET and CDK inhibitors act through mechanisms of enhancer function and have shown promising results in therapy for various types of cancer. Genome editing is another way to reprogram enhancers in cancer treatment. The relationship between enhancers and cancer has been revised by several authors in the past few years, which mainly focuses on the mechanisms by which enhancers can impact cancer. Here, we emphasize SE's role in cancer pathogenesis and the new therapies involving epigenetic regulators (BETi and CDKi). We suggest that understanding mechanisms of activity would aid clinical success for these anti-cancer agents.

Fluid-structure interaction analysis of airflow, structural mechanics and aerosol dynamics in a four-generation acinar model.

Elucidating the aerosol dynamics in the pulmonary acinar region is imperative for both health risk assessment and inhalation therapy, especially nowadays with the occurrence of the global COVID-19 pandemic. During respiration, the chest's outward elastic recoil and the lungs' inward elastic recoil lead to a change of transmural pressure, which drives the lungs to expand and contract to inhale and expel airflow and aerosol. In contrast to research using predefined wall motion, we developed a four-generation acinar model and applied an oscillatory pressure on the model outface to generate structure deformation and airflow. With such tools at hand, we performed a computational simulation that addressed both the airflow characteristic, structural mechanics, and aerosol dynamics in the human pulmonary acinar region. Our results showed that there is no recirculating flow in the sac. The structural displacement and stress were found to be positively related to the change of model volume and peaked at the end of inspiration. It was noteworthy that the stress distribution on the acinar wall was significantly heterogeneous, and obvious concentrations of stress were found at the junction of the alveoli and the ducts or the junction of the alveoli and alveoli in the sac. Our result demonstrated the effect of breathing cycles and aerosol diameter on deposition fraction and location of aerosols in the size range of 0.1-5 µm. Multiple respiratory cycles were found necessary for adequate deposition or escape of submicron particles while having a negligible influence on the transport of large particles, which were dominated by gravity. Our study can provide new insights into the further investigation of airflow, structural mechanics, and aerosol dynamics in the acinar depth.

Postbiotics Derived from L. paracasei ET-22 Inhibit the Formation of S. mutans Biofilms and Bioactive Substances: An Analysis.

Globally, dental caries is one of the most common non-communicable diseases for patients of all ages; Streptococcus mutans (S. mutans) is its principal pathogen. Lactobacillus paracasei (L. paracasei) shows excellent anti-pathogens and immune-regulation functions in the host. The aim of this study is to evaluate the effects of L. paracasei ET-22 on the formation of S. mutans biofilms. The living bacteria, heat-killed bacteria, and secretions of L. paracasei ET-22 were prepared using the same number of bacteria. In vitro, they were added into artificial-saliva medium, and used to coculture with the S. mutans. Results showed that the living bacteria and secretions of L. paracasei ET-22 inhibited biofilm-growth, the synthesis of water-soluble polysaccharide and water-insoluble polysaccharide, and virulence-gene-expression levels related to the formation of S. mutans biofilms. Surprisingly, the heat-killed L. paracasei ET-22, which is a postbiotic, also showed a similar regulation function. Non-targeted metabonomics technology was used to identify multiple potential active-substances in the postbiotics of L. paracasei ET-22 that inhibit the formation of S. mutans biofilms, including phenyllactic acid, zidovudine monophosphate, and citrulline. In conclusion, live bacteria and its postbiotics of L. paracasei ET-22 all have inhibitory effects on the formation of S. mutans biofilm. The postbiotics of L. paracasei ET-22 may be a promising biological anticariogenic-agent.

Doping-induced magnetism and magnetoelectric coupling in one-dimensional NbOCl3 and NbOBr3.

Low-dimensional multiferroic systems with magnetoelectric coupling have attracted considerable attention due to their important applications in high-density low-power storage. Based on the first-principles calculations, we demonstrated that the recently proposed one-dimensional (1D) ferroelectric materials NbOCl3 and NbOBr3 have good stabilities, and found that they can be easily separated from the bulk phase. Due to the flat band near the Fermi level, the itinerant ferromagnetism can be induced over a wide range of electron-doping concentrations, and it leads to the coexistence of ferroelectricity and ferromagnetism in 1D NbOX3 (X = Cl, Br) and finite-length nanochains. More interestingly, there is strong magnetoelectric coupling on finite-length nanochains, which is caused by the spontaneous electrical polarization and redistribution of magnetic carriers. In addition, magnetism also can be introduced by oxygen vacancies. We also analyzed the effects of doping concentration, strain, and length on ferroelectric polarization and magnetism. Our findings provide a way to design and search low-dimensional multiferroics.

Virus-like Particles as Antiviral Vaccine: Mechanism, Design, and Application.

Virus-like particles (VLPs) are viral structural protein that are noninfectious as they do not contain viral genetic materials. They are safe and effective immune stimulators and play important roles in vaccine development because of their intrinsic immunogenicity to induce cellular and humoral immune responses. In the design of antiviral vaccine, VLPs based vaccines are appealing multifunctional candidates with the advantages such as self-assembling nanoscaled structures, repetitive surface epitopes, ease of genetic and chemical modifications, versatility as antigen presenting platforms, intrinsic immunogenicity, higher safety profile in comparison with live-attenuated vaccines and inactivated vaccines. In this review, we discuss the mechanism of VLPs vaccine inducing cellular and humoral immune responses. We outline the impact of size, shape, surface charge, antigen presentation, genetic and chemical modification, and expression systems when constructing effective VLPs based vaccines. Recent applications of antiviral VLPs vaccines and their clinical trials are summarized.

Experimental Investigation on the Low-Velocity Impact Response of Tandem Nomex Honeycomb Sandwich Panels.

Sandwich panels are often subjected to unpredictable impacts and crashes in applications. The core type and impactor shape affect their impact response. This paper investigates the responses of five tandem Nomex honeycomb sandwich panels with different core-types under low-velocity-impact conditions with flat and hemispherical impactors. From the force response and impact displacement, gradient-tandem and foam-filled structures can improve the impact resistance of sandwich panels. Compared with the single-layer sandwich panel, the first peak of contact force of the foam-gradient-filled tandem honeycomb sandwich panels increased by 34.84%, and maximum impact displacement reduced by 50.98%. The resistance of gradient-tandem Nomex honeycomb sandwich panels under low-velocity impact outperformed uniform-tandem structures. Foam-filled structures change the impact responses of the tandem sandwich panels. Impact damage with a flat impactor was more severe than the hemispherical impactor. The experimental results are helpful in the design of tandem Nomex honeycomb sandwich panels.

Production of Coenzyme Q10 by microbes: an update.

Coenzyme Q10 (CoQ10) is the main CoQ species in human and is used extensively in food, cosmetic and medicine industries because of its antioxidant properties and its benefit in prophylactic medicine and therapy for a variety of diseases. Among various approaches to increase the production of CoQ10, microbial fermentation is the most effective. As knowledge of the biosynthetic enzymes and regulatory mechanisms modulating CoQ10 production increases, opportunities arise for metabolic engineering of CoQ10 in microbial hosts. In this review, we present various strategies used up to date to improve CoQ10 production and focus on metabolic engineering of CoQ10 overproduction in microbes. General strategies of metabolic engineering include providing sufficient precursors for CoQ10, increasing metabolic fluxes, and expanding storage capacity for CoQ10. Based on these strategies, CoQ10 production has been significantly improved in natural CoQ10 producers, as well as in heterologous hosts.

X-Chromosome Inactivation and Related Diseases.

X-chromosome inactivation (XCI) is the form of dosage compensation in mammalian female cells to balance X-linked gene expression levels of the two sexes. Many diseases are related to XCI due to inactivation escape and skewing, and the symptoms and severity of these diseases also largely depend on the status of XCI. They can be divided into 3 types: X-linked diseases, diseases that are affected by XCI escape, and X-chromosome aneuploidy. Here, we review representative diseases in terms of their definition, symptoms, and XCI's role in the pathogenesis of these diseases.

Visualization of the infection risk assessment of SARS-CoV-2 through aerosol and surface transmission in a negative-pressure ward.

Since December 2019, coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a great challenge to the world's public health system. Nosocomial infections have occurred frequently in medical institutions worldwide during this pandemic. Thus, there is an urgent need to construct an effective surveillance and early warning system for pathogen exposure and infection to prevent nosocomial infections in negative-pressure wards. In this study, visualization and construction of an infection risk assessment of SARS-CoV-2 through aerosol and surface transmission in a negative-pressure ward were performed to describe the distribution regularity and infection risk of SARS-CoV-2, the critical factors of infection, the air changes per hour (ACHs) and the viral variation that affect infection risk. The SARS-CoV-2 distribution data from this model were verified by field test data from the Wuhan Huoshenshan Hospital ICU ward. ACHs have a great impact on the infection risk from airborne exposure, while they have little effect on the infection risk from surface exposure. The variant strains demonstrated significantly increased viral loads and risks of infection. The level of protection for nurses and surgeons should be increased when treating patients infected with variant strains, and new disinfection methods, electrostatic adsorption and other air purification methods should be used in all human environments. The results of this study may provide a theoretical reference and technical support for reducing the occurrence of nosocomial infections.

Mesonephric-like Endometrial Carcinoma: Results From Immunohistochemical Screening of 300 Endometrial Carcinomas and Carcinosarcomas for This Often Overlooked and Potentially Aggressive Entity.

Mesonephric-like endometrial carcinoma is a rare but frequently misclassified and aggressive malignancy. KRAS mutations, limited estrogen receptor (ER) expression, and TTF-1, GATA3, and luminal CD10 expression are described in these tumors, but an immunohistochemistry-based screening approach has not been studied. We assessed 300 endometrial carcinomas/carcinosarcomas to ascertain the specificity of TTF-1/GATA3/luminal CD10 expression with or without ER staining for this diagnosis. Next-generation sequencing and morphologic review were performed on screen-positive cases. In all, 3% (9/300) were TTF-1+; 2 coexpressed GATA3. No cases expressed luminal CD10 or GATA3 in isolation. Two TTF-1+/ER- cases, one of which was also GATA3+, were reclassified as mesonephric-like based on morphology and molecular results (KRAS mutations without mismatch repair deficiency, TP53 mutations, or PTEN mutations): these represented 0.7% of all cases (2/300). The reclassified cases were originally diagnosed as grade 1 and 2 endometrioid carcinoma, and the latter had pulmonary metastases and pelvic recurrences. Six TTF-1+ cases retained their original serous (3) and endometrioid (3) diagnoses; 1 was reclassified as dedifferentiated. All had negative or low ER. KRAS mutations were identified in 4 TTF-1+ non-mesonephric-like cases, including 1 serous and 1 grade 3 endometrioid with p53 abnormalities, 1 mismatch repair-deficient endometrioid with a complex molecular profile, and 1 endometrioid with mucinous differentiation. These findings suggest that TTF-1 and ER are good first-line screens for mesonephric-like carcinoma, but caution that a TTF-1+/ER- immunoprofile is not specific, even in the setting of KRAS mutations. A final diagnosis of mesonephric-like carcinoma requires integration of morphologic and immunohistochemical features, with molecular support when relevant.

Improving squalene production by blocking the competitive branched pathways and expressing rate-limiting enzymes in Rhodopseudomonas palustris.

Squalene is a medically valuable bioactive compound that can be used as a raw material for fuels. Microbial fermentation is the preferred method for the squalene production. In this study, we employed several metabolic engineering strategies to increase squalene yield in Rhodopseudomonas palustris. A 57% increase in squalene titer was achieved by blocking the carotenoid pathway, thus directing more FPP into the squalene biosynthetic pathway. In order to cut down the conversion of squalene to haponoids, a recombinant strain R. palustris [Δshc, ΔcrtB] in which both carotenoid and haponoid pathways were blocked was then constructed, resulting in a 50-fold increase in squalene titer. Based on the expression of rate-limiting enzymes involved in the squalene pathway, the final squalene content reached 23.3 mg/g DCW, which was 178-times higher than that of the wild-type strain. In this study, several methods effective in improving squalene yield have been described and the potential of R. palustris for producing squalene has been demonstrated.

The assembly of a noncanonical LINC complex in Saccharomyces cerevisiae.

The linker of nucleoskeleton and cytoskeleton (LINC) complex is a protein complex across the nuclear envelope and has maintained its general assembly mode throughout evolution. SUN and KASH proteins, which are the major components of LINC complex, interact with each other in the nuclear lumen to transmit forces across the nuclear envelope and have diverse functions. However, research of LINC complex in budding yeast has been limited due to the lack of identification of a canonical KASH protein and a cytoskeleton factor. Here, we review recent findings that addressed these puzzles in budding yeast. We highlight the distinct assembly model of the telomere-associated LINC complex in budding yeast, which could be beneficial for identifying LINC variants in other eukaryotes.

trans-Acting Factors and cis Elements Involved in the Human Inactive X Chromosome Organization and Compaction.

During X chromosome inactivation, many chromatin changes occur on the future inactive X chromosome, including acquisition of a variety of repressive covalent histone modifications, heterochromatin protein associations, and DNA methylation of promoters. Here, we summarize trans-acting factors and cis elements that have been shown to be involved in the human inactive X chromosome organization and compaction.

Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast.

The linker of the nucleoskeleton and cytoskeleton (LINC) complex is composed of two transmembrane proteins: the KASH domain protein localized to the outer nuclear membrane and the SUN domain protein to the inner nuclear membrane. In budding yeast, the sole SUN domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here, we show that Mps2 mediates the interaction between Csm4 and Mps3 to form a heterotrimeric telomere-associated LINC (t-LINC) complex in budding yeast meiosis. Mps2 binds to Csm4 and Mps3, and all three are localized to the telomere. Telomeric localization of Csm4 depends on both Mps2 and Mps3; in contrast, Mps2's localization depends on Mps3 but not Csm4. Mps2-mediated t-LINC complex regulates telomere movement and meiotic recombination. By ectopically expressing CSM4 in vegetative yeast cells, we reconstitute the heterotrimeric t-LINC complex and demonstrate its ability to tether telomeres. Our findings therefore reveal the heterotrimeric composition of the t-LINC complex in budding yeast and have implications for understanding variant LINC complex formation.

Intraoperative cell salvage is associated with reduced allogeneic blood requirements and has no significant impairment on coagulation function in patients undergoing cesarean delivery: a retrospective study.

OBJECTIVE: The aim of the study is to examine the association between Intraoperative cell salvage (ICS), allogeneic blood transfusion (ABT) and coagulation function in obstetrics. METHODS: A total of 486 pregnant women undergoing cesarean delivery, of whom 157 were enrolled in this retrospective study. Patients were divided into ICS group (n = 101, ICS used during operation) and control group (n = 56, ICS not used during operation). Clinical data, including plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and thrombin time (TT) levels, were collected from all patients preoperatively (within 12-24 h) and postoperatively (within 6-12 h) and analyzed by t test, two-way repeated-measures ANOVA and Spearman's correlation. RESULTS: The use of ICS is associated with lower requirement rate for ABT (P < .001), while the blood loss was similar between the two groups (P = .990). Mean volume of ICS transfusion was 432.65 mL. Compared to preoperative values, the postoperative PT and APTT levels were significantly increased, while Fib was decreased in the two groups (all P < .01). No significant difference in coagulation function was observed between groups in preoperative and postoperative phase (P > .05). Furthermore, PT, APTT and TT after surgery were not correlated with the transfused volume of salvaged blood (P > .05) while the levels of Fib were negatively correlated with the volume (P < .01). In addition, there were no transfusion reactions in both two groups. CONCLUSIONS: Intraoperative cell salvage is correlated with reduced allogeneic blood requirements but did not impair blood coagulation significantly in patients undergoing cesarean delivery.

Micro-Structure Modelling and Electrical Properties Analysis of PZT Matrix Ferroelectric Composites.

PZT matrix ferroelectric composite is an important research topic in material science because of its many practical, industrial, and scientific applications. Materials with high dielectric permittivity are used to manufacture electronic devices, particularly capacitors and dynamic random access memory (DRAM). Therefore, the development of reliable and efficient micro models to be utilized in analyzing electrical properties can be of great value in accelerating research in this field. In this paper, a 3D microstructure model for PZT matrix ferroelectric composites has been developed and adopted the finite element method (FEM) to calculate the dielectric constant. The microscopy parameters of developed microstructure model are acquired based on the real composites from X-ray (micro-) diffraction and stereological method. The dielectric constant of different volume ratios of PZT matrix ferroelectric composites can be calculated by accurately controlling the volume of Ferrite particles. At the point of validation, the proposed approach makes visual and numeric comparisons between the morphology of the real microstructure and the model generated by the proposed technique. The simulation results by our method was essentially in agreement with experimental results in other literature. Simulation Experimental results also demonstrate that the dielectric constant of PZT matrix ferroelectric composites is significantly changed while the volume ratio of high dielectric phase particles was below 20%. PZT matrix ferroelectric composites Consequently, this method can be easily extended to composites preparation.

Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies.

OBJECTIVES: Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability. METHODS: We analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining. We submitted any results with MMR loss for microsatellite instability testing. RESULTS: We found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P < .0001). No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome. CONCLUSIONS: Solid, mucinous, or signet-ring appearance of a cholangiocarcinoma should prompt MMR testing for immunotherapy options but should not necessarily raise concern about Lynch syndrome.

Yeast R2TP Interacts with Extended Termini of Client Protein Nop58p.

The AAA + ATPase R2TP complex facilitates assembly of a number of ribonucleoprotein particles (RNPs). Although the architecture of R2TP is known, its molecular basis for acting upon multiple RNPs remains unknown. In yeast, the core subunit of the box C/D small nucleolar RNPs, Nop58p, is the target for R2TP function. In the recently observed U3 box C/D snoRNP as part of the 90 S small subunit processome, the unfolded regions of Nop58p are observed to form extensive interactions, suggesting a possible role of R2TP in stabilizing the unfolded region of Nop58p prior to its assembly. Here, we analyze the interaction between R2TP and a Maltose Binding Protein (MBP)-fused Nop58p by biophysical and yeast genetics methods. We present evidence that R2TP interacts largely with the unfolded termini of Nop58p. Our results suggest a general mechanism for R2TP to impart specificity by recognizing unfolded regions in its clients.

Atypical Lymphoid Proliferations and Clonality in Helicobacter-associated Inflammatory Infiltrates in Children.

Helicobacter infection is considered the major predisposing factor for gastric mucosa-associated lymphoid tissue (MALT) lymphoma with initial infection likely occurring in childhood. Primary gastric MALT lymphoma most commonly occurs in patients older than 50 years which is attributed to the lengthy chronic infection time required before the development of MALT lymphoma. Our study analyzes the histologic features and presence of immunoglobulin heavy chain (IGH) clonality in Helicobacter-associated chronic gastritis (62 cases) and Helicobacter-negative chronic gastritis (17 cases) biopsies within the pediatric population, diagnosed between 1996 and 2018. Helicobacter-associated gastritis was more likely to show active inflammation (P=0.01), with no significant difference in number of germinal centers or the strength, linear property, or depth of the inflammatory infiltrate. In total, 47% (29/62) of the Helicobacter-associated cases had at least 1 lymphoepithelial lesion, equivocal or definitive (a modified Wotherspoon score of 3 to 5), compared with 24% (4/17) of the Helicobacter-negative cases (P=0.5). All cases with lymphoepithelial lesions were assessed for IGH clonality, showing the presence of monoclonality in 27% (8/30) of evaluable cases. None of our patients were diagnosed with gastric lymphoma within available follow-up data. Although 4% of our cases could be considered MALT lymphoma in an adult patient based on prominent lymphoepithelial lesions and IGH monoclonality, caution is advised when diagnosing lymphoma in the pediatric population given the good prognosis of Helicobacter-associated gastritis in this age group. It is unclear if these monoclonal lymphoid proliferations require close follow-up.

Single-molecule catalytic hairpin assembly for rapid and direct quantification of circulating miRNA biomarkers.

The emergence of circulating miRNAs as potential biomarkers for cancer necessitates reliable approaches to detect miRNAs with high sensitivity and specificity. We disclose a highly sensitive method for rapid and direct quantification of circulating miRNA in serum by combining dynamic DNA circuit and single-molecule fluorescence detection. The product of DNA circuits based amplification is detected by total internal reflection fluorescence microscopy (TIRFM). The single-molecule counting allows the quantification of miRNA targets. Owing to the high sensitivity for fluorophore labeled nucleic acids of TIRFM, the products generated by 15 min amplification are sufficient for quantification. Meanwhile, the fast detection also addresses the problem of leakage because non-target triggered DNA circuits is relatively slow. There miRNA biomarkers miR-141, miR-21, miR-16 were detected with remarkable sensitivity as detection limits of 0.017, 0.012, 0.006 fM, respectively. This approach was applied for the direct quantification of the circulating miRNAs in human serum. The results of 29 health samples, 18 prostate cancer samples, 23 breast cancer samples imply that miR-141 and miR-21 are up-regulated in the prostate cancer samples and the breast cancer samples, respectively, and as reference miR-16 shows no difference in health and patient samples.