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Inhibitors of bromodomain and extraterminal domain (BET) proteins are possible anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here we show that BET proteins should not be inactivated therapeutically because they are critical antiviral factors at the post-entry level. Depletion of BRD3 or BRD4 in cells overexpressing ACE2 exacerbates SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the envelope (E) protein previously identified as a possible "histone mimetic." E protein, in an acetylated form, directly binds the second bromodomain of BRD4. Our data support a model where SARS-CoV-2 E protein evolved to antagonize interferon responses via BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment.

Chemical probes for chromatin reader proteins are valuable tools for investigating epigenetic regulatory mechanisms and evaluating whether the target of interest holds therapeutic potential. Developing potent inhibitors for the plant homeodomain (PHD) family of methylation readers remains a difficult task due to the charged, shallow and extended nature of the histone binding site that precludes effective engagement of conventional small molecules. Herein, we describe the development of novel proximity-reactive cyclopeptide inhibitors for PHD3-a trimethyllysine reader domain of histone demethylase KDM5A. Guided by the PHD3-histone co-crystal structure, we designed a sidechain-to-sidechain linking strategy to improve peptide proteolytic stability whilst maintaining binding affinity. We have developed an operationally simple solid-phase macrocyclization pathway, capitalizing on the inherent reactivity of the dimethyllysine ε-amino group to generate scaffolds bearing charged tetraalkylammonium functionalities that effectively engage the shallow aromatic 'groove' of PHD3. Leveraging a surface-exposed lysine residue on PHD3 adjacent to the ligand binding site, cyclic peptides were rendered covalent through installation of an arylsulfonyl fluoride warhead. The resulting lysine-reactive cyclic peptides demonstrated rapid and efficient labeling of the PHD3 domain in HEK293T lysates, showcasing the feasibility of employing proximity-induced reactivity for covalent labeling of this challenging family of reader domains.

Separation of hydrogen isotopes (D2/H2) attracts wide interest due to its important applications, such as nuclear fusion. Kinetic quantum sieving‐induced separation over tailored nanoporous solids is a promising method; however, the dynamic separation often shows a transient feature, thus a low D2/H2 selectivity even at temperature below 50 K. Herein, we selectively enriched the accessible quantum sieving (AQS) sites in two‐dimensional carbons by chemically growing a pore‐narrowing layer. The spatial density of such AQS sites is 8.5 times higher than that of commercial carbon molecular sieves. The kinetic selectivity of D2/H2 reached 4.6 at 77 K. Column breakthrough experiments revealed that the dynamic D2/H2 separation was enhanced by such a nanopore design. Aspen simulation indicated that D2 was enriched to 93.1% within 11 pressure swing adsorption cycles with a 1% D2/99% H2 mixture as feed. [ABSTRACT FROM AUTHOR]

As of March 30, 2020, approximately 750,000 cases of coronavirus disease (COVID-19) had been reported globally since December 2019 (1), severely burdening the healthcare system (2). The extremely fast transmission [...]

In recent years, algae bloom phenomenon outbreaks frequently in large-scale water bodies during summer. At present, mechanical method is used to collect cyanobacteria and reduce volume. However, the characteristics of algae, namely high viscosity, small particle size and high moisture content, lead to poor efficiency of dehydration. In order to improve the dehydration efficiency of algae and achieve the purpose of volume reduction and dehydration, the dehydration performance of Microcystis aeruginosa was studied in this paper. Three filter aid agent, including Poly Aluminium Chloride (PAC), Montmorillonite and Diatomite were added to the algae solution to improve filterability of Microcystis aeruginosa. The results showed that all of three filter aid agent have positive effect on the algae filtration rate, specific resistance, compression index and dehydration efficiency. Compared with the other two filter aid agents, the filtration rate of Diatomite is relatively faster. Meanwhile dehydration performance is better as well. When the dosage of Diatomite was 10.0g/L, the filtration rate increased from 0.108 L/h to 0.504 L/h. In addition, the compression index was reduced from 0.710 to 0.594. The specific resistance was reduced from 7.62 × 1010 s2/g to 2.35 × 108 s2 /g while the water content was decreased from 86.5% to 66.4%.

In order to study multiple problems concerning quickly tunneling in long distance tunnel, we design and develop a shield machine based on drilling, tunneling, protecting and transporting. By study the shield technique method, working sequences, guiding system composition and working principle, direction fixation, forehand detection and new support and protection of coal mining and tunneling in detail, we analyze the difference regarding the usage effectiveness between traditional tunnel tunneling and shield tunneling. Shield tunneling shows the advantage of quickly tunneling, effectiveness and efficiency, safety and cost saving points of view.

Background cumulative evidence from cohort studies suggested that there were inconsistent conclusions as to whether there was a bidirectional association between depression and frailty. Therefore, this study used a bidirectional two-sample Mendelian randomisation (MR) study to investigate the causal relationship between depression and frailty. Methods we performed univariate and multivariate bidirectional MR analyses to assess the causal association between depression and frailty. Independent genetic variants associated with depression and frailty were selected as instrumental variables. Inverse variance weighted (IVW), MR-Egger, weighted median and weighted mode were mainly used in univariate MR analysis. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for three potential confounders, body mass index (BMI), age at menarche (AAM) and waist-to-hip ratio (WHR, adjusted for BMI). Results univariate MR analysis showed a positive causal relationship between depression and risk of frailty (IVW, odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.23–1.37, P  = 6.54E−22). Causal relationship between frailty and risk of depression (IVW, OR = 1.69, 95% CI = 1.33–2.16, P  = 2.09E−05). MVMR analysis revealed that the bidirectional causal association between depression and frailty remained after adjusting for three potential confounders, BMI, AAM and WHR (adjusted for BMI), individually and in combination. Conclusions our findings supported a causal relationship between genetically predicted depression and frailty in both directions. [ABSTRACT FROM AUTHOR]

In this study, a dysprosium-based metal–organic framework (MOF) sensor (Dy-MOF) was developed for the ratiometric detection of I− in aqueous medium. Upon excitation at 230 nm, Dy-MOF shows two dominant emission bands at 464 nm and 574 nm assigned to (4F, 4D)5/2 → 6H9/2 + 6F11/2 and 4F9/2 → 6H13/2 transition of Dy3+, respectively, which have different sensitivities toward iodide ions. The introduction of I− slightly weakened the blue emission at 464 nm and significantly quenched the yellow emission at 574 nm. Thus, ratiometric sensing for iodide was realized using the yellow-to-blue intensity ratio of Dy3+. Dy-MOF exhibits superior sensing behavior towards I− with high selectivity, sensitivity and low detection limit (24 nM). This study also provides a strategy for the construction of a ratiometric sensor with dual-emission bands originating from only one emission center. [ABSTRACT FROM AUTHOR]

Detection of Fe(III) and Cu(II) in water is highly desirable because their abnormal levels can cause serious harm to human health and environmental safety. In this work, a ratiometric luminescence sensing platform based on lanthanide-based silica nanoparticles was constructed for the detection of Fe3+ and Cu2+ ions. The terbium-silica nanoparticles (named SiO2@Tb) with dual-emission signals were successfully prepared by grafting Tb3+ ions onto trimellitic anhydride (TMA) functionalized silica nanospheres. It can serve as a ratiometric fluorescent probe for the detection of Fe3+ and Cu2+ ions in water with the green emission of Tb3+ ions as a response signal and the blue emission of silica nanospheres as the reference signal. Significantly, an easy-to-differentiate color change for visual detection was also realized. SiO2@Tb shows high sensitivity even in very low concentration regions towards the sensing of Fe3+ and Cu2+ with low detection limits of 0.75 μM and 0.91 μM, respectively. Moreover, the mechanism for the luminescence quenching of SiO2@Tb was systematically investigated, and was attributed to the synergetic effect of the absorption competition quenching (ACQ) mechanism and cation exchange. This study demonstrates that SiO2@Tb can be employed as a promising fluorescent probe for the detection of Fe3+ and Cu2+ ions, and the combination of lanthanide ions with silica nanoparticles is an effective strategy to construct a ratiometric fluorescent sensing platform for the determination of analytes in environmental detection. [ABSTRACT FROM AUTHOR]