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The properties of modified conventional wrought aluminum alloys cannot be significantly enhanced by normal post-heat treatment in that the fine-grained strengthening, arising from high cooling rate in SLM, is underutilized. In this work, compared with the normal T6 heat treatment, a novel simple direct aging regime was proposed to maintain the grain-boundary strengthening and to utilize the precipitation strengthening of secondary Al3Zr. It was found that a heterogeneous grain structure, which consisted of ultrafine equiaxed (∼0.82 μm) and columnar (∼1.80 μm) grains at the bottom and top of molten pool, respectively, was formed in the SLM processed sample. After direct aging (DA), the ultrafine grains were maintained and a mass of spherical coherent L12-Al3Zr particles with a mean radius of approximately 1.15 nm was precipitated. In contrast, after solution treatment and aging (STA), a significant grain coarsening occurred in the equiaxed grain region. Meanwhile, the coarsening L12-Al3Zr particles, nano-sized S′ phases and GPB zones were detected in the STA sample. This subsequently induced that the yield strength of the DA sample (∼435 MPa) was higher than that of the STA sample (∼402 MPa) owing to the grain boundary strengthening and precipitation strengthening. Both the STA and DA samples exhibited a higher strength than that of the other SLMed Al-Cu-Mg series alloys; this was comparable to that of the wrought AA2024-T6 alloy (∼393 MPa). Both the STA and DA samples exhibited a higher strength than that of the other SLMed Al-Cu-Mg series alloys; this was comparable to that of the wrought AA2024-T6 alloy (∼393 MPa).

At present, polymer PM6 is most widely used donor, many researches focus on the improvement of PM6 performance. Most commonly used strategy of modifying polymer PM6 is to achieve ternary random copolymer by incorporating a third component. However, mostly reported modified PM6 terpolymers are with strictly equal D unit and A unit, while the third component has the disadvantage of high cost and complex synthesis. Herein, we develop four novel D-A-D-D1-type copolymer donors (PM6-T5, PM6-T10, PM6-T15 and PM6-T20 with D1 unit molar ratios of 5%, 10%, 15% and 20%, respectively) by introducing a component (BDT-T) with low synthetic complexity into the backbone of PM6 with unequal D and A unit (D/A unit ratio>1). Compared with alternate D-A copolymer PM6, four D-A-D-D1-type copolymers show the up-shifted lowest unoccupied molecular orbital (LUMO), down-shifted highest occupied molecular orbital (HOMO), higher degree of self-assembly. As a result, owing to the suitable level energy, crystallinity, better absorption, higher hole mobility and prolonger the exciton life, the PM6-T15:Y6-based OSCs achieved high power conversion efficiency (PCE) of 16.61% with a remarkably enhanced short-circuit current density (JSC) of 27.02 mA/cm2 and higher fill factor (FF) simultaneously, which performed better than the reference PM6:Y6-based OSCs (PCE:14.51%).

The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na+, K+-ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss.

The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.

p-Benzoquinone (BQ) is a promising candidate for next-generation sodium-ion batteries (SIBs) because of its high theoretical specific capacity, good reaction reversibility, and high resource availability. However, practical application of BQ faces many challenges, such as a low discharge plateau (∼2.7 V) as cathode material or a high discharge plateau as anode material compared with inorganic materials for SIBs and high solubility in organic electrolytes, resulting in low power and energy densities. Here, tetrahydroxybenzoquinone tetrasodium salt (Na4C6O6) is synthesized through a simple neutralization reaction at low temperatures. The four −ONa electron-donating groups introduced on the structure of BQ greatly lower the discharge plateau by over 1.4 V from ∼2.70 V to ∼1.26 V, which can change BQ from cathode to anode material for SIBs. At the same time, the addition of four −ONa hydrophilic groups inhibits the dissolution of BQ in the organic electrolyte to a certain extent. As a result, Na4C6O6 as the anode displays a moderate discharge capacity and cycling performance at an average work voltage of ∼1.26 V versus Na/Na+. When evaluated as a Na-ion full cell (NIFC), a Na3V2(PO4)3 ‖ Na4C6O6 NIFC reveals a moderate discharge capacity and an average discharge plateau of ∼1.4 V. This research offers a new molecular structure design strategy for reducing the discharge plateau and simultaneously restraining the dissolution of organic electrode materials.

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential. H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia.

Understanding the fate of terrestrial organic carbon (OC) in a cascade impoundment system is critical for recognizing the role of carbon sink for reservoirs. Surface sediments collected from eight cascade reservoirs across the Wujiang River, southwestern China, were analyzed for elemental and stable carbon isotopic (δ13C) composition, and lignin phenols (Σ8 and Λ8) to investigate the spatial distribution, contribution, origin and degradation of sedimentary terrestrial OC. The values of total organic carbon (TOC) and Σ8 exhibited a remarkable reduction along the upstream–downstream transect suggesting the trapping effect of cascade-damming. A relatively broad range of δ13C (−26.61 to −25.54‰, 95% CI) and C/N (6.80–18.20) indicated mixed allochthonous/autochthonous OC sources in surface sediments. The quantitative simulation indicates that the OC of the sediments mainly was derived from terrestrial organic matter. Soil-derived OC rather than C3 vascular plant-derived OC makes a major contribution to sedimentary terrestrial OC in reservoirs on karst terrain. As evidenced by lignin compositions and δ13C, the predominant vascular plant origins of terrestrial OC along the Wujiang River are non-woody angiosperm C3 plants. The aged reservoirs showed a trend of increasing contribution of autochthonous OC, which potentially weaken the role of carbon sink for reservoirs. The relationship between runoff inputs, watershed area/water surface area ratios, and water residence time and Λ8 were explored, indicating the natural and anthropogenic influences on terrestrial OC remains very complex in a cascade-damming river.

Electrochemical CO2 reduction provides a promising strategy to product value-added fuels and chemical feedstocks. However, it remains a grand challenge to further reduce the overpotentials and increase current density for large-scale applications. Here, spontaneously Sn doped Bi/BiOx nanowires (denoted as Bi/Bi(Sn)Ox NWs) with a core-shell structure were synthesized by an electrochemical dealloying strategy. The Bi/Bi(Sn)Ox NWs exhibit impressive formate selectivity over 92% from -0.5 to -0.9 V versus reversible hydrogen electrode (RHE) and achieve a current density of 301.4 mA cm-2 at -1.0 V vs RHE. In-situ Raman spectroscopy and theoretical calculations reveal that the introduction of Sn atoms into BiOx species can promote the stabilization of the *OCHO intermediate on the Bi(Sn)Ox surface and suppress the competitive H2/CO production. This work provides effective in situ construction of the metal/metal oxide hybrid composites with heteroatom doping and new insights in promoting electrochemical CO2 conversion into formate for practical applications.

Photocatalytic selective organic transformation represents an emerging avenue for artificial photosynthesis toward renewable solar energy conversion. However, solar-to-chemical conversion efficiency in photocatalysis is largely hampered by the sluggish charge transfer kinetic and difficulty in precise control over the charge migration pathway. Herein, we demonstrate conceptually new metal–insulator–semiconductor (MIS) electron tunneling photosystems to finely modulate the directional charge flow for photoredox selective organic transformation. The ultrathin insulating organic ligands layers capped on the surfaces of metal nanocrystals (NYs) and transition metal chalcogenides quantum dots (TMCs QDs) mutually function as precise directing-mediums to stimulate spontaneous electrostatic self-assembly between the tailor-made oppositely charged metal NYs and TMCs QDs for constructing metal (Au, Pd) NYs/TMCs (CdSe, CdS) QDs heterostructured electron tunneling photosystems. The electrons photoexcited from TMCs QDs can be efficaciously extracted and tunneled to metal NYs across the intermediate insulating hierarchical ligands layers to participate in the photoredox catalysis. The metal NYs-insulating ligands-TMCs QDs photosystems can efficiently mediate the minority carrier transport across the intermediate insulating ligand layers with minimal recombination, thereby resulting in the significantly enhanced net efficiency of multifarious photoactivities toward selective organic transformation including anaerobic photoreduction of nitroaromatics to amino derivatives and selective photo-oxidation of aromatic alcohols to aldehydes under visible light irradiation. The ligand-triggered electron tunneling effect has been evidence to be universal. Our work would inspire ongoing interest in exploring diverse organic ligands-based charge tunneling photosystems and provide a valuable roadmap for substantial solar energy conversion.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by genetic defects in leukocyte NADPH oxidase, which has both microbicidal and immunomodulatory roles. Hence, CGD is characterized by recurrent bacterial and fungal infections as well as aberrant inflammation. Fungal cell walls induce neutrophilic inflammation in CGD; yet, underlying mechanisms are incompletely understood. This study investigated the receptors and signaling pathways driving aberrant proinflammatory cytokine production in CGD neutrophils activated by fungal cell walls. Although cytokine responses to β-glucan particles were similar in NADPH oxidase–competent and NADPH oxidase–deficient mouse and human neutrophils, stimulation with zymosan, a more complex fungal particle, induced elevated cytokine production in NADPH oxidase–deficient neutrophils. The dectin-1 C-type lectin receptor, which recognizes β-glucans (1–3), and TLRs mediated cytokine responses by wild-type murine neutrophils. In the absence of NADPH oxidase, fungal pathogen-associated molecular patterns engaged additional collaborative signaling with Mac-1 and TLRs to markedly increase cytokine production. Mechanistically, this cytokine overproduction is mediated by enhanced proximal activation of tyrosine phosphatase SHP2–Syk and downstream Card9-dependent NF-κB and Card9-independent JNK–c-Jun. This activation and amplified cytokine production were significantly decreased by exogenous H2O2 treatment, enzymatic generation of exogenous H2O2, or Mac-1 blockade. Similar to zymosan, Aspergillus fumigatus conidia induced increased signaling in CGD mouse neutrophils for activation of proinflammatory cytokine production, which also used Mac-1 and was Card9 dependent. This study, to our knowledge, provides new insights into how NADPH oxidase deficiency deregulates neutrophil cytokine production in response to fungal cell walls.

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of the TNF-α–induced cell death program. The function of RIPK1 is tightly controlled by posttranslational modifications, including linear ubiquitin chain assembly complex–mediated linear ubiquitination. However, the physiological function and molecular mechanism by which linear ubiquitination of RIPK1 regulates TNF-α–induced intracellular signaling remain unclear. In this article, we identified Lys627 residue as a major linear ubiquitination site in human RIPK1 (or Lys612 in murine RIPK1) and generated Ripk1K612R/K612R mice, which spontaneously develop systemic inflammation triggered by sustained emergency hematopoiesis. Mechanistically, without affecting NF-κB activation, Ripk1K612R/K612R mutation enhances apoptosis and necroptosis activation and promotes TNF-α–induced cell death. The systemic inflammation and hematopoietic disorders in Ripk1K612R/K612R mice are completely abolished by deleting TNF receptor 1 or both RIPK3 and Caspase-8. These data suggest the critical role of TNF-α–induced cell death in the resulting phenotype in Ripk1K612R/K612R mice. Together, our results demonstrate that linear ubiquitination of RIPK1 on K612 is essential for limiting TNF-α–induced cell death to further prevent systemic inflammation.

Background Thermotolerant yeast has outstanding potential in industrial applications. Komagataella phaffii (Pichia pastoris) is a common cell factory for industrial production of heterologous proteins. Results Herein, we obtained a thermotolerant K. phaffii mutant G14 by mutagenesis and adaptive evolution. G14 exhibited oxidative and thermal stress cross-tolerance and high heterologous protein production efficiency. The reactive oxygen species (ROS) level and lipid peroxidation in G14 were reduced compared to the parent. Oxidative stress response (OSR) and heat shock response (HSR) are two major responses to thermal stress, but the activation of them was different in G14 and its parent. Compared with the parent, G14 acquired the better performance owing to its stronger OSR. Peroxisomes, as the main cellular site for cellular ROS generation and detoxification, had larger volume in G14 than the parent. And, the peroxisomal catalase activity and expression level in G14 was also higher than that of the parent. Excitingly, the gene knockdown of CAT encoding peroxisomal catalase by dCas9 severely reduced the oxidative and thermal stress cross-tolerance of G14. These results suggested that the augmented OSR was responsible for the oxidative and thermal stress cross-tolerance of G14. Nevertheless, OSR was not strong enough to protect the parent from thermal stress, even when HSR was initiated. Therefore, the parent cannot recover, thereby inducing the autophagy pathway and resulting in severe cell death. Conclusions Our findings indicate the importance of peroxisome and the significance of redox balance in thermotolerance of yeasts.

Transition metal chalcogenide quantum dots (TMCs QDs) constitute a crucial sector of semiconductors on account of large absorption coefficient for light harvesting, peculiar quantum confinement effect, and abundant active sites stemming from ultra-small size. However, elaborate and tunable modulation of anisotropic photoinduced charge carriers over TMCs QDs represents an enduring challenge in terms of sluggish charge transfer kinetic and ultra-short charge lifetime compared with nanoparticulate counterparts, thereby rendering maneuvering charge transfer of TMCs QDs a tough issue. We herein conceptually unlock the unanticipated charge transport capability of solid-state non-conductive poly(diallyl dimethylammonium chloride) (PDDA) for constructing cascade charge transfer pathway over self-assembled wide bandgap semiconductors (WBS)/PDDA/TMCs QDs multilayered heterostructures, by which unidirectional and accelerated electron transfer from TMCs QDs to WBS support mediums was spontaneously activated, markedly boosting the charge separation/migration efficiency. The integrated roles of such ultrathin insulating PDDA intermediate layer as simultaneous surface charge modifying agent and interfacial charge transfer mediator have been evidenced to be universal. The unexpected electron-withdrawing capability of ultrathin PDDA layer endows WBS (SnO 2, TiO2)@PDDA@TMCs (CdSe, CdS) QDs heterostructures with significantly enhanced net efficiency of photoactivities toward selective anaerobic reduction of nitroaromatics to amino derivatives under visible light irradiation. Our work would feature a promising scope for rational design of multifarious novel insulating polymers-based photosystems for solar energy conversion.

Recently, irreversible inhibitors have attracted great interest in antitumors due to their advantages of forming covalent bonds to target proteins. Herein, some benzothiazepinone compounds (BTZs) have been designed and synthesized as novel covalent GSK-3β inhibitors with high selectivity for the kinase panel. The irreversible covalent binding mode was identified by kinetics and mass spectrometry, and the main labeled residue was confirmed to be the unique Cys14 that exists only in GSK-3β. The candidate 4-3 (IC50 = 6.6 μM) showed good proliferation inhibition and apoptosis-inducing ability to leukemia cell lines, low cytotoxicity on normal cell lines, and no hERG inhibition, which hinted the potential efficacy and safety. Furthermore, 4-3 exhibited decent pharmacokinetic properties in vivo and remarkably inhibited tumor growth in the acute promyelocytic leukemia (APL) mouse model. All the results suggest that these newly irreversible BTZ compounds might be useful in the treatment of cancer such as APL.

The new design strategy will provide the possibility for preparing a dynamic sensor by employing the inhibition of C = N isomerization. In this work, the functional probe 4-(1 H-imidazo [4,5-f] [1,10]-phenanthrolin-2-yl) benzaldehyde oxime (compound 4) has been synthesized and such molecule gives rise to blue emission. Due to the incorporation of hypochlorite, the oxime group can be oxidized to the structure of aldehyde. As a result, the molecular motif exhibits sharp emission change from blue to green due to the addition of hypochlorite with enough sensitivity and selectivity (detection limit = 53 nM, linear range 0.5-8.0 µM). It has also been used for monitoring ClO− by employing solution color change and the absorption signal difference could effectively rule out the effects of interference species. To our knowledge, it will be the first case of a highly selective hypochlorite sensor derived from oxime isomerization reaction based on phenanthroline backbone.

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases., Graphical abstract The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. A potent and orally active VHL-recruiting PROTAC was developed, displaying robust HMGCR degradation and potent hypolipidemic activity in diet-induced mice.Image 1

Electronic doping of organic semiconductors is essential for their usage in highly efficient optoelectronic devices. Although molecular and metal complex-based dopants have already enabled significant progress of devices based on organic semiconductors, there remains a need for clean, efficient and low-cost dopants if a widespread transition towards larger-area organic electronic devices is to occur. Here we report dimethyl sulfoxide adducts as p-dopants that fulfil these conditions for a range of organic semiconductors. These adduct-based dopants are compatible with both solution and vapour-phase processing. We explore the doping mechanism and use the knowledge we gain to 'decouple' the dopants from the choice of counterion. We demonstrate that asymmetric p-doping is possible using solution processing routes, and demonstrate its use in metal halide perovskite solar cells, organic thin-film transistors and organic light-emitting diodes, which showcases the versatility of this doping approach.

Circulating microRNAs (miRNA) can serve as key biomarkers for early diagnose of cholangiocarcinoma. Herein, an assay that uses circulating miRNA to trigger strand displacement amplification (SDA) and a CRISPR-Cas14a system to report the SDA process has been developed. In the proposed method, SDA directly amplifies miRNAs without reverse transcription. The reporter, CRISPR-Cas14a, can reduce the risks of non-specific amplification and offers a sequential amplification that improves the sensitivity for miRNA detection. The assay, termed Cas14SDA, can discriminate miRNAs with similar sequences and can detect as low as 680 fM miR-21 (miRNAs overexpressed in cholangiocarcinoma) within 1 h. In particular, Cas14a was efficiently activated by a single-stranded SDA amplicon which improved the sensitivity by 2.86 times compared to that using Cas12a. This research has demonstrated that the Cas14SDA assay can discriminate cholangiocarcinoma patients from healthy donors by testing miR-21 in their blood samples. The Cas14SDA assay developed broadens the toolbox for miRNA biomarker analysis.

The establishment of highly permanent porosity in hydrogen-bonded organic frameworks (HOFs) is a long-standing challenge due to the fragile nature of hydrogen bonds, which delimits their broad appl...

In this study, injectable peptide hydrogels were designed and fabricated based on the crosslinking of peptides and hyaluronic acid (HA) by 1,4-butanediol diglycidyl ether (BDDE). An anticancer bioa...

Inflammation response is a regulated cellular process and excessive inflammation has been recognized in numerous diseases, such as cardiovascular disease, neurodegenerative disease, inflammatory bowel disease, and cancer. Tribulus terrestris L. (TT), also known as Bai Jili in Chinese, has been applied in traditional Chinese medicine for thousands of years while its anti-inflammatory activity and underlying mechanism are not fully elucidated. Here, we hypothesize Tribulus terrestris L. extract (BJL) which presents anti-inflammatory effect, and the action mechanism was also investigated. We employed the transgenic zebrafish line Tg(MPO:GFP), which expresses green fluorescence protein (GFP) in neutrophils, and mice macrophage RAW 264.7 cells as the in vivo and in vitro model to evaluate the anti-inflammatory effect of BJL, respectively. The production of nitric oxide (NO) was measured by Griess reagent. The mRNA expression levels of inflammatory cytokines and inducible nitric oxide synthase (iNOS) were measured by real-time PCR, and the intracellular total or phosphorylated protein levels of NF-κB, Akt, and MAPKs including MEK, ERK, p38, and JNK were detected by western blot. We found that BJL significantly inhibited fin transection or lipopolysaccharide- (LPS-) induced neutrophil migration and aggregation in zebrafish in vivo. In mice macrophage RAW 264.7 cells, BJL ameliorated LPS-triggered excessive release of NO and transcription of inflammatory cytokine genes including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). BJL also reduced the LPS-induced elevations of intracellular iNOS and nuclear factor kappa B (NF-κB) which mediate the cellular NO and inflammatory cytokine productions, respectively. Moreover, LPS dramatically increased the phosphorylation of Akt and MAPKs including MEK, ERK, p38, and JNK in RAW 264.7 cells, while cotreatment BJL with LPS suppressed their phosphorylation. Taken together, our data suggested that BJL presented potent anti-inflammatory effect and the underlying mechanism was closely related to the inhibition of Akt/MAPKs and NF-κB/iNOS-NO signaling pathways.

New drugs aimed at novel targets are urgently needed to combat the increasing rate of drug resistant tuberculosis (TB). Here, the National Cancer Institute Developmental Therapeutic Program (NCI-DTP) chemical library was screened against a promising new target, ketol-acid reductoisomerase (KARI), the second enzyme in the branched chain amino acid (BCAA) biosynthesis pathway. From this library, 6-hydroxy-2-methylthiazolo[4,5- d ]pyrimidine-5,7(4 H ,6 H )-dione (NSC116565) was identified as a potent time-dependent inhibitor of Mycobacterium tuberculosis ( Mt ) KARI with a K i of 95.4 nM. Isothermal Titration Calorimetry (ITC) studies showed that this inhibitor binds to Mt KARI in the presence and absence of the co-factor, NADPH, which was confirmed by crystal structures of the compound in complex with the closely related Staphylococcus aureus ( Sa ) KARI. We have also shown that NSC116565 inhibits the growth of H37Ra and H37Rv strains of Mt with MIC 50 values of 2.93 µM and 6.06 µM, respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti-TB drug development.

Laser-induced breakdown spectroscopy (LIBS) experiments were carried out with an ammonium dinitramide (ADN)-based propellant to measure its distribution, that is the mixture ratio, in an inert atmosphere. A heating sampler was developed to produce a premixed sample with a known mixture ratio and this was connected to a chamber that had been designed to simulate the space propulsion environment. Determining the time window for the acquisition and saturation threshold of LIBS were the main motivations to investigate the effective lifetimes of atomic spectral lines and the effect of laser energy on the emission ratio. From the spectroscopic analysis, it was found that the ratio of the intensities of H (656.3 nm), O (777 nm) and N (746.8 nm) over Ar (738.4 nm) increased monotonically with the mixture ratio in the range of 0–0.06. A series of propellant/Ar mixtures with a pressure in the region of 40–100 kPa were used to obtain a linear correlation between the intensity ratio of LIBS spectra and the local mixture ratio. It was observed that the logarithm of the slope of the lines also showed a linear correlation with the pressure. Considering that the current method was applied by necessity with the given pressure, the local pressure was studied based on its dependence on the full width at half maximum (FWHM) of H and Ar spectral lines. Consequently, the emission ratios of H/Ar, O/Ar and N/Ar were utilized as a diagnostic tool to obtain the distribution of the propellant in the inert atmosphere. The LIBS-based results not only provide fundamental data for the on-line measurements of ADN-based thrusters, but also hold promise for promoting the application of LIBS in the field of energetic ionic liquids.

Unlike silicon carbide ceramic, the alumina ceramic and zirconia ceramic are by its very nature weakly absorbing in visible and near infrared wavebands. Therefore, open-cell foams made of such ceramics are rarely used in applications requiring strong absorption of radiation energy, such as solar absorbers. In order to improve the potential of such foams, open-cell foams with dual-scale pores were digitally designed in the limit of geometric optics. The first-order pores are obtained by Voronoi tessellation technique and then the second-order pores are realized by the design of 'porous strut'. A Monte Carlo Ray-tracing method is applied in the dual-scale foam structure for radiative transfer calculation. The parameterized study is conducted on the radiation absorption of alumina foam sheets and zirconia foam sheets. The results show that for the present cases, the designed dual-scale alumina foams with strut porosity p s = 0.3 can increase the normal absorptance within the wavebands from 0.4 μm to 7.0 μm by 62.7% than the foams with single-scale pores. For the zirconia foams, this increase is 115.9% within the wavebands from 1.2 μm to 7.6 μm. The findings can provide strong confidence on dual-scale foams to enhance the absorption of radiation energy in potential applications.

We herein successfully realized the first example of using a stable HOF (ZJU-HOF-1) for highly efficient removal of both trace (1%) and bulk (50%) CO2 from CO2/CO mixtures under dry and humid conditions.

Conjugated polymers are deemed as conductive carrier mediators for engendering the π electrons along the molecular framework, while the role of nonconjugated insulated polymers has been generally overlooked without the capability to participate in the solar-powered oxidation-reduction kinetics and charge-transfer process. Alternatively, considering the ultrashort charge lifetime and significant deficiency of metal nanocluster (NC)-based photosystems, the fine tuning of charge migration over atomically precise ultrasmall metal NCs as novel light-harvesting antennas has so far not yet been unleashed. Here, we unlock the charge-transfer capability of a nonconjugated polymer to modulate the charge flow over metal NCs (Au

Two-dimensional (2D) transition metal carbide, known as MXene, has recently received enduring attention for solar energy conversion by virtue of its pivotal role as efficient interfacial charge transfer mediator for photocatalysis. However, controllable design of MXene-based heterostructured photosystems is still in the infant stage and MXene-dominated photoredox mechanism in photoredox selective organic catalysis has so far not yet been unleashed. Herein, we conceptually report the rational construction of 2D/2D heterostructures by a facile electrostatic self-assembly approach utilizing oppositely charged transition metal chalcogenides (TMCs: CdIn2S4, CdS, Zn0.5Cd0.5S, ZnIn2S4) nanosheets (NSs) and Ti3C2Tx (MXene) as the building blocks for photocatalytic selective organic transformation. The peculiar face-to-face stacking mode between the building blocks and suitable energy level alignment synergistically endow the MXene-TMCs NSs heterostructures with markedly enhanced photoactivities toward multifarious photoredox catalysis including anaerobic selective photoreduction of nitroaromatics to amino derivatives and photoxidation of aromatic alcohols to aldehydes under the irradiation of visible light. The considerably enhanced photoactivities of MXene-TMCs NSs heterostructures are caused by the integrated merits of Ti3C2Tx (MXene) including: (i) abundant hydrophilic groups on the Ti3C2Tx (MXene) surface for affording substantial interaction with TMCs NSs, which benefits the charge migration; (ii) strong redox activities of surface Ti sites which promotes multiple electron reduction; (iii) electrons-withdrawing capability of Ti3C2Tx (MXene) to boost the electron transfer from TMCs NS to Ti3C2Tx (MXene), thereby enhancing the charge separation. This work would open a new frontier for constructing a host of MXene-based heterostructured photosystems and unveiling the charge transfer mechanism of MXene for solar energy conversion.

Transition metal chalcogenide quantum dots (TMC QDs) represent promising light-harvesting antennas because of their fascinating physicochemical properties including quantum confinement effect and suitable energy band structures. However, TMC QDs generally suffer from poor photoactivities and photostability due to deficiency of active sites and ultrafast recombination rate of photoinduced charge carriers. Here, we demonstrate how to rationally arouse the charge transfer kinetic of TMC QDs by close monolayered graphene (GR) encapsulation via a ligand-dominated layer-by-layer (LbL) assembly utilizing oppositely charged TMC QDs and GR nanosheets as the building blocks. The assembly units were spontaneously and intimately integrated in an alternate integration mode, thereby resulting in the multilayered three-dimensional (3D) TMC QDs/GR ensembles. It was unveiled that multifarious photoactivities of TMC QDs/GR nanocomposites toward versatile photoredox organic catalysis including photocatalytic aromatic alcohols oxidation to aldehydes and nitroaromatics reduction to amino derivatives under visible light irradiation are conspicuously boosted because of spatially multilayered monolayered GR encapsulation which are superior to those of TMC QDs counterparts. The substantially enhanced photoactivities of TMC QDs/GR nanocomposites arise from reasons including improved light absorption and enhanced charge separation efficacy because of GR encapsulation together with unique stacking mode between TMC QDs and GR endowed by LbL assembly. Our work would provide a promising and efficacious route to smartly accelerate the charge transfer kinetic of TMC QDs for solar energy conversion.

Background Chinese horsebean-chili-paste (CHCP) is a traditional fermented condiment in China, known as 'the soul of Sichuan cuisine'. The horsebean-to-meju phase in its preparation is important for CHCP production and contributes significantly to its taste and odor. In this study, a comprehensive flavor compound profiling analysis of the naturally brewed horsebean meju (NBHM) and the temperature-controlled brewed horsebean meju (TCBHM) was performed with two-dimensional gas chromatography time-of-flight mass spectrometry (GC × GC-TOFMS), and the analysis of physicochemical characteristics and free amino acids. Their aroma-active components and characteristic flavor compounds were evaluated. The flavor compounds responsible for differentiating NBHM and TCBHM were also determined based on the Fisher ratio and principal component analysis. Results The pH and the reducing sugar and amino-acid nitrogen content of NBHM were 5.38, 64.43, and 5.76 g kg-1 , respectively, whereas those of TCBHM were 5.13, 29.20, and 7.43 g kg-1 . A total of 356 volatiles were identified from 2571 compounds, and 257 volatile compounds were identified in NBHM compared to 322 volatiles in TCBHM. These two horsebean mejus (HMs) exhibited a similar proportion profile for 30 aroma-active compounds. Benzoic acid ethyl ester, 4-ethyl-2-methoxy-phenol and argnine were determined to be characteristic flavor components for NBHM, while 1-(2-furanyl)-ethanone, 2,6-dimethyl-pyrazine, threonine, valine and tyrosine were specific to TCBHM. Conclusion Temperature-controlled brewed horsebean meju possessed better physicochemical and flavor characteristics than NBHM. The temperature-controlled brewing technique in CHCP production can be used as a promising alternative to the traditional natural brewing method. © 2020 Society of Chemical Industry.

Epstein-Barr virus (EBV) is a γ-herpesvirus associated with the occurrence of several human malignancies. BBRF2 and BSRF1 are two EBV tegument proteins that have been suggested to form a hetero-complex and mediate viral envelopment, but the molecular basis of their interaction and the functional mechanism of this complex remains unknown. Here, we present crystal structures of BBRF2 alone and in complex with BSRF1. BBRF2 has a compact globular architecture featuring a central β-sheet that is surrounded by 10 helices, it represents a novel fold distinct from other known protein structures. The central portion of BSRF1 folds into two tightly associated antiparallel α-helices, forming a composite four-helix bundle with two α-helices from BBRF2 via a massive hydrophobic network. In vitro, a BSRF1-derived peptide binds to BBRF2 and reduces the number of viral genome copies in EBV-positive cells. Exogenous BBRF2 and BSRF1 co-localize at the Golgi apparatus. Furthermore, BBRF2 binds capsid and capsid-associated proteins, whereas BSRF1 associates with glycoproteins. These findings indicate that the BBRF2-BSRF1 complex tethers EBV nucleocapsids to the glycoprotein-enriched Golgi membrane, facilitating secondary envelopment., Epstein-Barr virus (EBV) tegument proteins BBRF2 and BSRF1 have been suggested to form a hetero-complex. Here, He et al. provide the crystal structures of BBRF2 alone and in complex with BSRF1 and suggest that the complex tethers EBV nucleocapsids to the Golgi membrane, facilitating secondary envelopment.

Phytoplankton have evolved a capability to acquire phosphorus (P) from dissolved organic phosphorus (DOP) since the preferred form, dissolved inorganic phosphate (DIP, or Pi), is often limited in parts of the ocean. Phytic acid (PA) is abundantly synthesized in plants and rich in excreta of animals, potentially enriching the DOP pool in coastal oceans. However, whether and how PA may be used by phytoplankton are poorly understood. Here, we investigated PA utilization and underlying metabolic pathways in the diatom model Phaeodactylum tricornutum. The physiological results showed that P. tricornutum could utilize PA as a sole source of P nutrient to support growth. Meanwhile, the replacement of PA for DIP also caused changes in multiple cellular processes such as inositol phosphate metabolism, photosynthesis, and signal transduction. These results suggest that PA is bioavailable to P. tricornutum and can directly participate the metabolic pathways of PA-grown cells. However, our data showed that the utilization of PA was markedly less efficient than that of DIP, and PA-grown cells exhibited P and iron (Fe) nutrient stress signals. Implicated in these findings is the potential of complicated responses of phytoplankton to an ambient DOP species, which calls for more systematic investigation. IMPORTANCE PA is abundant in plants, and cannot be digested by non-ruminant animals. Hence, it is potentially a significant component of the DOP pool in the coastal waters. Despite the potential importance, there is little information about its bioavailability to phytoplankton as a source of P nutrient and if so what molecular mechanisms are involved. In this study, we found that part of PA could be utilized by the diatom P. tricornutum to support growth, and another portion of PA can act as a substrate directly participating in various metabolism pathways and cellular processes. However, our physiological and transcriptomic data show that PA-grown cells still exhibited signs of P stress and potential Fe stress. These results have significant implications in phytoplankton P nutrient ecology and provide a novel insight into multi-faceted impacts of DOP utilization on phytoplankton nutrition and metabolism.

Thanks to the rapid development of Wearable Fitness Trackers (WFTs) and Smartphone Pedometer Apps (SPAs), people are keeping an eye on their health through fitness and heart rate tracking; therefore, home weight training exercises have received a lot of attention lately. A multi-procedure intelligent algorithm for weight training using two inertial measurement units (IMUs) is proposed in this paper. The first procedure is for motion tracking that estimates the arm orientation and calculates the positions of the wrist and elbow. The second procedure is for posture recognition based on deep learning, which identifies the type of exercise posture. The final procedure is for exercise prescription variables, which first infers the user’s exercise state based on the results of the previous two procedures, triggers the corresponding event, and calculates the key indicators of the weight training exercise (exercise prescription variables), including exercise items, repetitions, sets, training capacity, workout capacity, training period, explosive power, etc.). This study integrates the hardware and software as a complete system. The developed smartphone App is able to receive heart rate data, to analyze the user’s exercise state, and to calculate the exercise prescription variables automatically in real-time. The dashboard in the user interface of the smartphone App can display exercise information through Unity’s Animation System (avatar) and graphics, and records are stored by the SQLite database. The designed system was proven by two types of experimental verification tests. The first type is to control a stepper motor to rotate the designed IMU and to compare the rotation angle obtained from the IMU with the rotation angle of the controlled stepper motor. The average mean absolute error of estimation for 31 repeated experiments is 1.485 degrees. The second type is to use Mediapipe Pose to calculate the position of the wrist and the angles of upper arm and forearm between the Z-axis, and these calculated data are compared with the designed system. The root-mean-square (RMS) error of positions of the wrist is 2.43 cm, and the RMS errors of two angles are 5.654 and 4.385 degrees for upper arm and forearm, respectively. For posture recognition, 12 participants were divided into training group and test group. Eighty percent and 20% of 24,963 samples of 10 participants were used for the training and validation of the LSTM model, respectively. Three-thousand-three-hundred-and-fifty-nine samples of two participants were used to evaluate the performance of the trained LSTM model. The accuracy reached 99%, and F1 score was 0.99. When compared with the other LSTM-based variants, the accuracy of one-layer LSTM presented in this paper is still promising. The exercise prescription variables provided by the presented system are helpful for weight trainers/trainees to closely keep an eye on their fitness progress and for improving their health.

Made available in DSpace on 2021-06-25T11:07:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-13 Acetohydroxyacid synthase (AHAS, EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides, and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Thirteen AHAS inhibiting herbicides have Ki values of 100 μM and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections. School of Chemistry and Molecular Biosciences University of Queensland School of Biomedical Sciences University of Queensland Institute for Molecular Bioscience University of Queensland School of Dentistry São Paulo State University (UNESP) Araraquara, Rua Humaita, 1680 School of Dentistry São Paulo State University (UNESP) Araraquara, Rua Humaita, 1680

Miltiradiene is a key intermediate in the biosynthesis of many important natural diterpene compounds with significant pharmacological activity, including triptolide, tanshinones, carnosic acid and carnosol. Sufficient accumulation of miltiradiene is vital for the production of these medicinal compounds. In this study, comprehensive engineering strategies were applied to construct a high-yielding miltiradiene producing yeast strain. First, a chassis strain that can accumulate 2.1 g L-1 geranylgeraniol was constructed. Then, diterpene synthases from various species were evaluated for their ability to produce miltiradiene, and a chimeric miltiradiene synthase, consisting of class II diterpene synthase (di-TPS) CfTPS1 from Coleus forskohlii (Plectranthus barbatus) and class I di-TPS SmKSL1 from Salvia miltiorrhiza showed the highest efficiency in the conversion of GGPP to miltiradiene in yeast. Moreover, the miltiradiene yield was further improved by protein modification, which resulted in a final yield of 550.7 mg L-1 in shake flasks and 3.5 g L-1 in a 5-L bioreactor. This work offers an efficient and green process for the production of the important intermediate miltiradiene, and lays a foundation for further pathway reconstruction and the biotechnological production of valuable natural diterpenes.

In this work, one three-dimensional periodic composite structure consisting of alumina frame and inscribed nickel spheres is proposed for designing the micron composite porous structure. The finite...

AMP-activated protein kinase (AMPK) integrates the regulation of cell growth and metabolism. AMPK activation occurs in response to cellular energy decline and mitochondrial dysfunction triggered by reactive oxygen species (ROS). In aged Tg-mtTFB1 mice, a mitochondrial deafness mouse model, hearing loss is accompanied with cochlear pathology including reduced endocochlear potential (EP) and loss of spiral ganglion neurons (SGN), inner hair cell (IHC) synapses and outer hair cells (OHC). Accumulated ROS and increased apoptosis signaling were also detected in cochlear tissues, accompanied by activation of AMPK. To further explore the role of AMPK signaling in the auditory phenotype, we used genetically knocked out AMPKα1 as a rescue to Tg-mtTFB1 mice and observed: improved ABR wave I, EP and IHC function, normal SGNs, IHC synapses morphology and OHC survivals, with decreased ROS, reduced pro-apoptotic signaling (Bax) and increased anti-apoptotic signaling (Bcl-2) in the cochlear tissues, indicating that reduced AMPK attenuated apoptosis via ROS-AMPK-Bcl2 pathway in the cochlea. To conclude, AMPK hyperactivation causes accelerated presbycusis in Tg-mtTFB1 mice by redox imbalance and dysregulation of the apoptosis pathway. The effects of AMPK downregulation on pro-survival function and reduction of oxidative stress indicate AMPK serves as a target to rescue or relieve mitochondrial hearing loss.