Kinome and phosphoproteome reprogramming underlies the aberrant immune responses in critically ill COVID-19 patients.

SARS-CoV-2 infection triggers extensive host immune reactions, leading to severe diseases in certain individuals. However, the molecular basis underlying the excessive yet non-productive immune responses in severe COVID-19 remains incompletely understood. In this study, we conducted a comprehensive analysis of the peripheral blood mononuclear cell (PBMC) proteome and phosphoproteome in sepsis patients positive or negative for SARS-CoV-2 infection, as well as healthy subjects, using quantitative mass spectrometry. Our findings demonstrate dynamic changes in the COVID-19 PBMC proteome and phosphoproteome during disease progression, with distinctive protein or phosphoprotein signatures capable of distinguishing longitudinal disease states. Furthermore, SARS-CoV-2 infection induces a global reprogramming of the kinome and phosphoproteome, resulting in defective adaptive immune response mediated by the B and T lymphocytes, compromised innate immune responses involving the SIGLEC and SLAM family of immunoreceptors, and excessive cytokine-JAK-STAT signaling. In addition to uncovering host proteome and phosphoproteome aberrations caused by SARS-CoV-2, our work recapitulates several reported therapeutic targets for COVID-19 and identified numerous new candidates, including the kinases PKG1, CK2, ROCK1/2, GRK2, SYK, JAK2/3, TYK2, DNA-PK, PKCδ, and the cytokine IL-12.

Pleosmaranes A-R, Isopimarane and 20-nor Isopimarane Diterpenoids with Anti-inflammatory Activities from the Mangrove Endophytic Fungus Pleosporales sp. HNQQJ-1.

Pleosmaranes A-R (1-18), 18 new isopimarane-type diterpenoids, together with four known analogs (19-22), were isolated from the mangrove endophytic fungus Pleosporales sp. HNQQJ-1. Their structures and absolute configurations were established by analysis of their spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1-9 possess an unusual aromatic B ring and a 20-nor-isopimarane skeleton. Compounds 15-17 contain a unique 2-oxabicyclo[2.2.2]octane moiety. Compound 18 features an unexpected 2-oxabicyclo[3.2.1]octane moiety. Compounds 8 and 12 exhibited a moderate inhibitory effect against LPS-induced NO production, with IC50 values of 19 and 25 µM, respectively.

CHI3L1 promotes myocardial fibrosis via regulating lncRNA TUG1/miR-495-3p/ETS1 axis.

Abnormal levels of CHI3L1 and lnc TUG1 are often associated with myocardial fibrosis, and their specific expressions may be closely related to the process of myocardial fibrosis. In addition, CHI3L1 was found to significantly up-regulate the expression of lncTUG1. Therefore, this study further explored the major role of CHI3L1 in regulating the progression of myocardial fibrosis. Myocardial fibrosis in mice was established using an angiotensin (Ang II) model, and the degree of myocardial fibrosis was assessed by qPCR, western blot and pathological techniques. HL-1 cells with overexpression and silencing of CHI3L1 were constructed, and the cell migration ability was detected using the Transwell method. Biological information was used to predict the potential target miRNA of lnc TUG1, and the interaction between them was verified by dual luciferase reporter assay. Using functional rescue assay and the rAAV9 technique, CHI3L1 was verified to affect the fibrotic process of myocardial cells by regulating the lnc TUG1/miR-495-3p/ETS1 axis in vitro and in vivo. The myocardial fibrosis index in the model group was significantly upregulated, and expression of both CHI3L1 and lnc TUG1 was upregulated. Pathological results revealed fibrosis and collagen deposition in the myocardium. Overexpression of lnc TUG1 reversed the inhibitory effect of CHI3L1 silencing on myocardial fibrosis. Mechanistically, CH3L1 upregulates the expression of lnc TUG1, and lnc TUG1 weakens the inhibition of ETS1 through sponge absorption of miR-495-3p, promoting the process of myocardial fibrosis.

Embedding TiO2microspheres into the active layer as light scatterers in a perovskite photodetector to boost light harvesting.

Here, TiO2microspheres with particle sizes of 200-400 nm are embedded in p-i-n perovskite photodetectors, which are used as light scatterers. This approach was implemented to change the light transfer path in the perovskite layer, which gives the device higher photon-capture ability in a specific incident wavelength range. Compared with a pristine device, the photocurrent and responsivity of the device based on such a structure are obviously enhanced in the ranges of 560-610 nm and 730-790 nm. The photocurrent under 590 nm incident light wavelength illumination (light intensityP= 31.42µW·cm-2) increases from 1.45µA to 1.71µA, with an increase of 17.93%, and the responsivity reaches 0.305 A·W-1. In addition, the introduction of TiO2has no additional negative impact on the carrier extraction and the dark current. Also, the response time of the device did not deteriorate. Finally, the role of TiO2as light scatterers is further verified by embedding microspheres into mixed-halide perovskite devices.

A theoretical study on the line defects in ß12-borophene: enhanced direct-current and alternating-current conductances.

Using density functional theory and the non-equilibrium Green's function method, we theoretically investigated the structures, stabilities, electronic properties, and the direct-current (DC) and alternating-current (AC) transport properties of the line defects in two-dimensional material ß12-borophene. Our results suggest that there exist six line defects that can enhance the stability of ß12-borophene and the line defects have profound influences on the electronic structure of ß12-borophene. Along the zigzag direction, the line defects can change the atomic orbital components of the Dirac cones in perfect ß12-borophene, but the line defects along the armchair direction have complicated influences on the Dirac cones. In the case of DC transport, some of the line defects lead to the constant DC phenomenon and the negative differential resistance effect, and enhance the DC conductances since the line defects exhibit typical one-dimensional characteristics. In the case of AC transport, some of the line defects enhance the AC conductances in the medium-frequency and high-frequency ranges through the photon-assisted tunneling effect. The microscopic mechanisms of the enhanced DC and AC conductances are different. In addition, for a low-frequency range, the equivalent circuits of ß12-borophene and the line defects were also suggested, which will be beneficial for designing borophene-based functional nanodevices.

Effect of SH2B1 on glucose metabolism during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

This study mainly explored the effect and mechanism of Src homology 2 (SH2) B adaptor protein 1 (SH2B1) on cardiac glucose metabolism during pressure overload-induced cardiac hypertrophy and dysfunction. A pressure-overloaded cardiac hypertrophy model was constructed, and SH2B1-siRNA was injected through the tail vein. Haematoxylin and eosin (H&E) staining was used to detect myocardial morphology. ANP, BNP, ß-MHC and the diameter of myocardial fibres were quantitatively measured to evaluate the degree of cardiac hypertrophy, respectively. GLUT1, GLUT4, and IR were detected to assess cardiac glucose metabolism. Cardiac function was determined by echocardiography. Then, glucose oxidation and uptake, glycolysis and fatty acid metabolism were assessed in Langendorff perfusion of hearts. Finally, PI3K/AKT activator was used to further explore the relevant mechanism. The results showed that during cardiac pressure overload, with the aggravation of cardiac hypertrophy and dysfunction, cardiac glucose metabolism and glycolysis increased, and fatty acid metabolism decreased. After SH2B1-siRNA transfection, cardiac SH2B1 expression was knocked down, and the degree of cardiac hypertrophy and dysfunction was alleviated compared with the Control-siRNA transfected group. Simultaneously, cardiac glucose metabolism and glycolysis were reduced, and fatty acid metabolism was enhanced. The SH2B1 expression knockdown mitigated the cardiac hypertrophy and dysfunction by reducing cardiac glucose metabolism. After using PI3K/AKT activator, the effect of SH2B1 expression knockdown on cardiac glucose metabolism was reversed during cardiac hypertrophy and dysfunction. Collectively, SH2B1 regulated cardiac glucose metabolism by activating the PI3K/AKT pathway during pressure overload-induced cardiac hypertrophy and cardiac dysfunction.

SERS immunoassay analysis of Escherichia coli and Staphylococcus aureus based on sandwich-structured complex probe and target-induced strand displacement.

A direct and ultra-sensitive surface-enhanced Raman scattering (SERS) immunoassay method is introduced for the detection of Escherichia coli and Staphylococcus aureus. This methodology is based on a sandwich-structured complex probe (SCP) mechanism, combined with target-induced strand displacement. Moreover, by leveraging the amplified SERS signal from gold nanoparticles (AuNPs) corresponding to an increase in bacterial count, we achieve quantitative determination. The SCP demonstrates remarkable specificity, sensitivity, and anti-interference capability in bacterial detection. The detection limits for both bacterial strains are as low as 10 CFU/mL. In our selectivity tests, all peak intensities had standard deviations (n = 3) below 6%. Recoveries in normal human serum were 101-110% for E. coli and 96-101% for S. aureus. In milk, the recoveries were 102-105% for E. coli and 100-105% for S. aureus, respectively, demonstrating a high level of accuracy and resistance to interference. In addition, the SCP offers a dual-detection capability, enabling simultaneous diagnosis of multiple targets, which greatly simplifies the testing procedure. The findings underscore that this immunoassay platform fulfills the demand for rapid and precise pathogenic bacterial diagnosis, holding substantial potential for practical applications.

Dynamic interplay of two molecular switches enabled by the MEK1/2-ERK1/2 and IL-6-STAT3 signaling axes controls epithelial cell migration in response to growth factors.

Cell migration is an essential physiological process, and aberrant migration of epithelial cells underlies many pathological conditions. However, the molecular mechanisms governing cell migration are not fully understood. We report here that growth factor-induced epithelial cell migration is critically dependent on the crosstalk of two molecular switches, namely phosphorylation switch (P-switch) and transcriptional switch (T-switch). P-switch refers to dynamic interactions of deleted in liver cancer 1 (DLC1) and PI3K with tensin-3 (TNS3), phosphatase and tensin homolog (PTEN), C-terminal tension, and vav guanine nucleotide exchange factor 2 (VAV2) that are dictated by mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated protein kinase 1/2-dependent phosphorylation of TNS3, PTEN, and VAV2. Phosphorylation of TNS3 and PTEN on specific Thr residues led to the switch of DLC1-TNS3 and PI3K-PTEN complexes to DLC1-PTEN and PI3K-TNS3 complexes, whereas Ser phosphorylation of VAV2 promotes the transition of the PI3K-TNS3/PTEN complexes to PI3K-VAV2 complex. T-switch denotes an increase in C-terminal tension transcription/expression regulated by both extracellular signal-regulated protein kinase 1/2 and signal transducer and activator of transcription 3 (STAT3) via interleukin-6-Janus kinase-STAT3 signaling pathway. We have found that, the P-switch is indispensable for both the initiation and continuation of cell migration induced by growth factors, whereas the T-switch is only required to sustain cell migration. The interplay of the two switches facilitated by the interleukin-6-Janus kinase-STAT3 pathway governs a sequence of dynamic protein-protein interactions for sustained cell migration. That a similar mechanism is employed by both normal and tumorigenic epithelial cells to drive their respective migration suggests that the P-switch and T-switch are general regulators of epithelial cell migration and potential therapeutic targets.

Light-Assisted Ullmann Coupling of Phenols and Aryl Halides: The Synergetic Effect Between Plasmonic Copper Nanoparticles and Carbon Nanotubes from Various Sources.

Utilizing light and plastic wastes as resources to turn the wasted phenols and hazardous aryl halides into value added chemicals seems to be an attractive idea for alleviating the energy crisis and environmental problems. In this work, plasmonic copper nanoparticles (Cu NPs) were loaded onto carbon nanotubes (CNTs) from various sources including commercial CNTs and those derived from plastic wastes. Under visible-light irradiation, the catalyst could efficiently convert phenols and aryl halides to diaryl ethers. Similar with commercial CNTs, excellent activity is also achieved when utilizing CNTs derived from different kinds of plastic wastes as support for the system. Further investigation shows that the visible-light irradiation and light-excited plasmonic Cu NPs are necessary to inhibit the phenol degradation on CNTs and in turn promote the cross-coupling of phenol and aryl halides. Compared with metal oxides and other carbon materials, the excellent capability of CNTs to absorb light, to convert light to heat, and to adsorb both two reactants simultaneously are critical to enhance the activity of Cu NPs, achieving high yields of diaryl ethers. This study could provide a novel strategy for catalyst design and generate a more economically sustainable process.

Concise Synthesis of BN-Dibenzo[f,k]tetraphenes with Different BN Substitution Positions and Direct Comparison with Their Carbonaceous Analogue.

Two types of "parental" BN-dibenzo[f,k]tetraphenes (BNDBT-1 and BNDBT-2) have been synthesized via a transition-metal-catalyzed tandem cross-coupling reaction as key steps. Both BNDBT-1 and BNDBT-2 are fully characterized; one of them is unambiguously confirmed by a single X-ray crystal structure. Compared to its all-carbon analogue DBT, BNDBT-1 and BNDBT-2 exhibit a higher highest occupied molecular orbital (HOMO) and lower lowest unoccupied molecular orbital (LUMO) energy, while the BN doping position slightly influences the HOMO and LUMO energies of BNDBT-1 and BNDBT-2. Both BNDBT-1 and BNDBT-2 exhibit red-shifted absorption and emission spectra and higher emission efficiencies, as compared to their carbonaceous analogue DBT. Moreover, organic light emitting diodes were fabricated using BNDBT-1 and BNDBT-2 as emitters, demonstrating their potential applications.

Synthetic Doping of Acenaphthylene through BN/CC Isosterism and a Direct Comparison with BN-Acenaphthene.

Boron/nitrogen-doped acenaphthylenes, a new class of BN-doped cyclopenta-fused polycyclic aromatic hydrocarbons, were synthesized via indole-directed C-H borylation. The reference molecule BN-acenaphthene was also synthesized in a similar manner. Both BN-acenaphthylene and BN-acenaphthene were unequivocally characterized by single-crystal X-ray analysis. The aromaticities of each ring in BN-acenaphthylenes were quantified by experimental and theoretical methods. Moreover, doping the BN unit into acenaphthylene can increase the LUMO level and decrease the HOMO level, resulting in wider HOMO-LUMO energy gaps. Furthermore, regioselective bromination of BN-acenaphthylene (B-Mes) afforded monobrominated BN-acenaphthylene in good yield. Subsequently, cross-coupling of brominated BN-acenaphthylene gave a series of BN-acenaphthylene derivatives. In addition, the photophysical properties of these BN-acenaphthylene derivatives can be fine-tuned by the substituents on the BN-acenaphthylene scaffold.

Recent research progress in CDs@MOFs composites: fabrication, property modulation, and application.

Carbon dots (CDs) have exhibited a promising application prospect in many fields because of their good fluorescence properties, biocompatibility, low toxicity, and easy functionalization. In order to improve their photoelectricity and stability, metal-organic frameworks (MOFs) can be used as host materials to provide ideal carriers for CDs to realize the multifunctional composites of CDs and MOFs (CDs@MOFs). At present, CDs@MOFs composites have shown tremendous application potential because they have various advantages of both CDs and MOFs. In this review, the synthesis methods of CDs@MOFs composites are firstly introduced. Then, the influence of the synergy between CDs and MOFs on the regulation of their structures and optical properties is highlighted. Furthermore, the recent application researches of CDs@MOFs composites in fluorescent probes, solid-state lighting, and photoelectrocatalysis are generalized. Finally, the critical issues, challenges, and solutions on their structure and property regulation and application are put forward, and their commercialization direction is also prospected.

Pyrrolic Type N Directed Borylation Route to BN-PAHs: Tuning the Photophysical Properties by Varying the Conjugation Shape and Size.

Two series of BN-cyclopenta[a]phenalenes have been synthesized through an indole/pyrrole oriented borylation reaction. A total of five compounds are obtained and fully characterized; one of them is unambiguously confirmed by single X-ray crystal structure. Their photophysical properties could be finely tuned through varying the conjugation size and shape of the bottom PAHs applied. Moreover, their response toward fluoride anions was also investigated.

BN/BO-Ullazines and Bis-BO-Ullazines: Effect of BO Doping on Aromaticity and Optoelectronic Properties.

We have achieved substitutional doping of ullazine with either two BO units or with one BO unit and one BN unit. The synthesis of these B-doped ullazines is straightforward, using demethylation and borylative cyclization as the key steps. Ullazine cores of both BN/BO-ullazines (2) and bis-BO-ullazines (3) are very close to being planar. Their electronic and photophysical properties were investigated by ultraviolet-visible, fluorescence spectroscopy, cyclic voltammetry, and density functional theory calculations.

A method for systematic mapping of protein lysine methylation identifies functions for HP1ß in DNA damage response.

Lysine methylation occurs on both histone and nonhistone proteins. However, our knowledge on the prevalence and function of nonhistone protein methylation is poor. We describe an approach that combines peptide array, bioinformatics, and mass spectrometry to systematically identify lysine methylation sites and map methyllysine-driven protein-protein interactions. Using this approach, we identified a high-confidence and high-resolution interactome of the heterochromatin protein 1ß (HP1ß) and uncovered, simultaneously, numerous methyllysine sites on nonhistone proteins. We found that HP1ß binds to DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and regulates its localization to double-strand breaks (DSBs) during DNA damage response (DDR). Mutation of the methylation sites in DNA-PKcs or depletion of HP1ß in cells caused defects in DDR. Furthermore, we showed that the methylation of DNA-PKcs and many other proteins in the HP1ß interactome undergoes large changes in response to DNA damage, indicating that Lys methylation is a highly dynamic posttranslational modification.

Total Structure of Bimetallic Core-Shell [Au42 Cd40 (SR)52 ]2- Nanocluster and Its Implications.

Bimetallic core-shell nanostructures hold great promise in elucidating the bimetallic synergism. However, it remains a challenge to construct atomically precise core-shell with high-valence active metals on the gold surface. In this work, we report the total structure of a [Au42 Cd40 (SR)52 ]2- core-shell nanocluster and multiple implications. Single crystal X-ray diffraction (SCXRD) reveals that the structure possesses a two-shelled Au6 @Au36 core and a closed cadmium shell of Cd40 , and the core-shell structure is then protected by 52 thiolate (-SR) ligands. The composition of the nanocluster is further confirmed by electrospray ionization mass spectrometry (ESI-MS). A catalytic test for styrene oxidation and a comparison with relevant nanoclusters reveal the surface effect on the catalytic activity and selectivity.

Parasitic Ferromagnetism in Few-Layered Transition-Metal Chalcogenophosphate.

Since the rise of two-dimensional (2D) semiconductors, it seems that electronic devices will soon be upgraded with spintronics, in which the manipulation of spin degree of freedom endows it obvious advantages over conventional charge-based electronics. However, as the most crucial prerequisite for the above-mentioned expectation, 2D semiconductors with adjustable magnetic interaction are still rare, which has greatly hampered the promotion of spintronics. Recently, transition metal phosphates have attracted tremendous interest due to their intrinsic antiferromagnetism and potential applications in spintronics. In the work described herein, parasitic ferromagnetism is achieved for the first time by exfoliating an antiferromagnetic chalcogenophosphate to a few layers. Taking the transition metal chalcogenophosphate Mn2P2S6 as an example, the antiferromagnetic transition at the Néel temperature is completely suppressed, and the magnetic behaviors of the as-obtained few-layered Mn2P2S6 are dominated by parasitic ferromagnetism. We experimentally verify an electron redistribution by which part of the Mn 3d electrons migrate and redistribute on P atoms in few-layered Mn2P2S6 due to the introduced Mn vacancies. The results demonstrated here broaden the tunability of the material's magnetic properties and open up a new strategy to rationally design the magnetic behaviors of 2D semiconductors, which could accelerate the applications of spintronics.

Synthesis, Structures, and Properties of BN-Dinaphthothiophenes: Influence of B and N Placement on Photophysical Properties and Aromaticity.

Substitution of the C═C functionality with the isosteric and isoelectronic B-N moiety has emerged as a powerful way to expand the family of polycyclic aromatic hydrocarbons. In this paper, two types of BN-dinaphthothiophene (BN-DNT) derivatives with different B and N substitution patterns were synthesized in short steps from commercially available materials. X-ray crystallographic analysis revealed that BN-DNT 1 and 2 had rigid and planar frameworks. Their photophysical properties and the aromaticity of the BN rings of the BN-DNTs were slightly dependent on the B and N substitution patterns. However, their response toward fluoride anions was greatly dependent on the B and N substitution patterns.

Interactome Mapping Uncovers a General Role for Numb in Protein Kinase Regulation.

Cellular functions are frequently regulated by protein-protein interactions involving the binding of a modular domain in one protein to a specific peptide sequence in another. This mechanism may be explored to identify binding partners for proteins harboring a peptide-recognition domain. Here we report a proteomic strategy combining peptide and protein microarray screening with biochemical and cellular assays to identify modular domain-mediated protein-protein interactions in a systematic manner. We applied this strategy to Numb, a multi-functional protein containing a phosphotyrosine-binding (PTB) domain. Through the screening of a protein microarray, we identified >100 protein kinases, including both Tyr and Ser/Thr kinases, that could potentially interact with the Numb PTB domain, suggesting a general role for Numb in regulating kinase function. The putative interactions between Numb and several tyrosine kinases were subsequently validated by GST pull-down and/or co-immunoprecipitation assays. Furthermore, using the Oriented Peptide Array Library approach, we defined the specificity of the Numb PTB domain which, in turn, allowed us to predict binding partners for Numb at the genome level. The combination of the protein microarray screening with computer-aided prediction produced the most expansive interactome for Numb to date, implicating Numb in regulating phosphorylation signaling through protein kinases and phosphatases. Not only does the data generated from this study provide an important resource for hypothesis-driven research to further define the function of Numb, the proteomic strategy described herein may be employed to uncover the interactome for other peptide-recognition domains whose consensus motifs are known or can be determined.

Genetic code expansion and live cell imaging reveal that Thr-308 phosphorylation is irreplaceable and sufficient for Akt1 activity.

The proto-oncogene Akt/protein kinase B (PKB) is a pivotal signal transducer for growth and survival. Growth factor stimulation leads to Akt phosphorylation at two regulatory sites (Thr-308 and Ser-473), acutely activating Akt signaling. Delineating the exact role of each regulatory site is, however, technically challenging and has remained elusive. Here, we used genetic code expansion to produce site-specifically phosphorylated Akt1 to dissect the contribution of each regulatory site to Akt1 activity. We achieved recombinant production of full-length Akt1 containing site-specific pThr and pSer residues for the first time. Our analysis of Akt1 site-specifically phosphorylated at either or both sites revealed that phosphorylation at both sites increases the apparent catalytic rate 1500-fold relative to unphosphorylated Akt1, an increase attributable primarily to phosphorylation at Thr-308. Live imaging of COS-7 cells confirmed that phosphorylation of Thr-308, but not Ser-473, is required for cellular activation of Akt. We found in vitro and in the cell that pThr-308 function cannot be mimicked with acidic residues, nor could unphosphorylated Thr-308 be mimicked by an Ala mutation. An Akt1 variant with pSer-308 achieved only partial enzymatic and cellular signaling activity, revealing a critical interaction between the γ-methyl group of pThr-308 and Cys-310 in the Akt1 active site. Thus, pThr-308 is necessary and sufficient to stimulate Akt signaling in cells, and the common use of phosphomimetics is not appropriate for studying the biology of Akt signaling. Our data also indicate that pThr-308 should be regarded as the primary diagnostic marker of Akt activity.