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Combination of flexible bpba and benzenetetracarboxylate ligands showing various coordination modes is important in forming interesting structures, and the porosity of the CPs may govern the structural transformation.

TRIM28/KAP1/TIF1β is a crucial epigenetic modifier. Genetic ablation of trim28 is embryonic lethal, although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, several lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. Here, we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs). The TRIM28-K304Q knock-in cells were created in K562 erythroleukemia cells by CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein nuclease 9) gene editing method. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from wild-type K562 cells. The expression levels of embryonic-related globin gene and a platelet cell marker integrin-beta 3 were increased in TRIM28-K304Q mutant cells, indicating the induction of differentiation. In addition to the differentiation-related genes, many zinc-finger-proteins genes and imprinting genes were activated in TRIM28-K304Q cells; they were inhibited by wild-type TRIM28 via binding with KRAB-ZNFs. These results suggest that acetylation/deacetylation of K304 in TRIM28 constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation as demonstrated by the acetylation mimic TRIM28-K304Q.

MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic “oncomiR” and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)–dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer. Cancer Res; 70(21); 8822–31. ©2010 AACR.

Supplementary Methods, Figures 1-6, Tables 1-3 from EGFR Promotes Lung Tumorigenesis by Activating miR-7 through a Ras/ERK/Myc Pathway That Targets the Ets2 Transcriptional Repressor ERF

Supplementary Table 4 from EGFR Promotes Lung Tumorigenesis by Activating miR-7 through a Ras/ERK/Myc Pathway That Targets the Ets2 Transcriptional Repressor ERF

The World Animal Health Information System (WAHIS) from the World Organization for Animal Health (WOAH) is an online reporting system, essential for ensuring the transparency and accuracy of global animal health. One of the WOAH’s objectives is to disseminate timely notifications to support countries’ efforts to prevent and control the spread of animal diseases. This paper describes the 3,263 exceptional events notified through immediate notifications sent to WOAH from 2005 to February 2021 and their distribution in time and space and by disease. To evaluate the timeliness of reporting, we defined and analysed two periods: the confirmation period (CT), which is the time interval between the disease onset date and the confirmation date, and the notification period (NT), defined as the interval between the disease confirmation and the date of reporting to WOAH. The results showed that (1) the number of events increased over the analysis period; (2) the events were mainly reported for domestic animals and the data provided for wildlife were limited; (3) the official source of disease introduction was often unknown when the event was reported; and (4) the global median CT value was 5 days while the global median NT value was 4 days, with a decreasing trend in both cases over the study period. Divergences were found across world regions and country income categories. This analysis provides interesting insights into the early detection capabilities and transparency of countries, globally and over time.

The observation that the

Subcellular localization of the deubiquitinating enzyme BAP1 is deterministic for its tumor suppressor activity. While the monoubiquitination of BAP1 by an atypical E2/E3-conjugated enzyme UBE2O and BAP1 auto-deubiquitination are known to regulate its nuclear localization, the molecular mechanism by which BAP1 is imported into the nucleus has remained elusive. Here, we demonstrated that transportin-1 (TNPO1, also known as Karyopherin β2 or Kapβ2) targets an atypical C-terminal proline-tyrosine nuclear localization signal (PY-NLS) motif of BAP1 and serves as the primary nuclear transporter of BAP1 to achieve its nuclear import. TNPO1 binding dissociates dimeric BAP1 and sequesters the monoubiquitination sites flanking the PY-NLS of BAP1 to counteract the function of UBE2O that retains BAP1 in the cytosol. Our findings shed light on how TNPO1 regulates the nuclear import, self-association, and monoubiquitination of BAP1 pertinent to oncogenesis.

Macroautophagy/autophagy is an evolutionarily conserved intracellular pathway for the degradation of cytoplasmic materials. Under stress conditions, autophagy is upregulated and double-membrane autophagosomes are formed by the expansion of phagophores. The ATG16L1 precursor fusion contributes to development of phagophore structures and is critical for the biogenesis of autophagosomes. Here, we discovered a novel role of the protein tyrosine phosphatase PTPN9 in the regulation of homotypic ATG16L1 vesicle fusion and early autophagosome formation. Depletion of PTPN9 and its Drosophila homolog Ptpmeg2 impaired autophagosome formation and autophagic flux. PTPN9 colocalized with ATG16L1 and was essential for homotypic fusion of ATG16L1(+) vesicles during starvation-induced autophagy. We further identified the Q-SNARE VTI1B as a substrate target of PTPN9 phosphatase. Like PTPN9, the VTI1B nonphosphorylatable mutant but not the phosphomimetic mutant enhanced SNARE complex assembly and autophagic flux. Our findings highlight the important role of PTPN9 in the regulation of ATG16L1(+) autophagosome precursor fusion and autophagosome biogenesis through modulation of VTI1B phosphorylation status. Abbreviations: csw: corkscrew; EBSS: Earle’s balanced salt solution; ERGIC: ER-Golgi intermediate compartment; ESCRT: endosomal sorting complexes required for transport; mop: myopic; NSF: N-ethylmaleimide-sensitive factor; PAS: phagophore assembly site; PolyQ: polyglutamine; PtdIns3P: phosphatidylinositol-3-phosphate; PTK: protein tyrosine kinase; PTM: posttranslational modification; PTP: protein tyrosine phosphatase; PTPN23/HD-PTP: protein tyrosine phosphatase non-receptor type 23; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; STX7: syntaxin 7; STX8: syntaxin 8; STX17: syntaxin 17; VAMP3: vesicle associated membrane protein 3; VAMP7: vesicle associated membrane protein 7; VTI1B: vesicle transport through interaction with t-SNAREs 1B; YKT6: YKT6 v-SNARE homolog; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

Alternative reality (XR) tools are becoming more commonplace in the realm of architecture, engineering, and construction (AEC); however, these digitally immersive technologies vary greatly in their degree of virtuality and individual capabilities. While many studies detail the performance of one specific XR technology for a particular use case, little work exists comparing numerous modern XR technologies in a side-by-side manner for a single use case. In this work, we construct four equal-fidelity, alternative reality environments for the application of spacecraft habitat design evaluation, starting with a baseline habitat mockup constructed in physical reality (PR). Three digital environments—augmented reality, hybrid reality (HR), and virtual reality—were modeled after the PR environment and developed in parallel. The implementation of each environment was carefully documented, along with relative strengths and weaknesses associated with both development and use. Additionally, we have developed a novel HR implementation that includes realistic and intuitive haptics, hand tracking, a fully virtual audiovisual scene, and responsive habitat elements, all wirelessly synched with a game engine and spatially synched with the PR environment. In sum, this work serves as a resource for those considering XR technologies for any variety of applications, particularly in AEC disciplines.

Guava extracts purified from leaf and bark have many bio-active molecules with anti-cancer activities. In addition, lycopene-rich extracts obtained from red guava fruit can induce apoptosis in estrogen receptor-positive breast cancers. Triple-negative breast cancer (TNBC) lacks estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) and, therefore, hormone therapy and targeted therapy are not used in the clinic. The purpose of this study was to determine whether red guava fruit extracts can affect the proliferation of TNBC cells. In this study, cell viability was determined by using the MTT assay. Apoptosis and necrosis were analyzed using flow cytometry. Cleaved caspase-3 and PARP were analyzed by western blotting. We found that red guava extracts can, through caspase-3 activation and PARP cleavage signaling, induce apoptotic and necrotic death in TNBC cells. Our results thus show the therapeutic benefit of red guava extracts as a potential cancer treatment for TNBC in combination with doxorubicin or targeted therapy.

G9a (also known as EHMT2 - Euchromatin histone methyltransferase 2) is a protein lysine methyltransferase which introduces methylation modification in variety of proteins including histones. G9a catalyzes the dimethylation of lysine 9 on histone 3 (H3K9me2) which is a repressive epigenetic modification. H3K9me2 is associated with the silencing of several genes including tumor suppressor genes in many cancers and hence G9a is a well characterized drug target for cancer therapy. Here, we report the discovery of CSV0C018875 as a novel quinoline based G9a inhibitor through virtual screening strategy from a HTS database. Sub-structure querying based on the known G9a inhibitors, followed by docking based virtual screening, led to the identification of CSV0C018875 as G9a inhibitor. We found that CSV0C018875 inhibits the activity of G9a in both enzyme and cell based assays. Importantly, the toxicity of CSV0C018875 is much lesser than that of the well-studied G9a inhibitor, BIX-01294. Molecular dynamics simulations shows that CSV0C018875 binds deeper inside the active site cavity of G9a, which facilitates the tight binding and also increases the compounds residence time, which in turn reflects better G9a inhibition. The novel quinoline CSV0C018875 could be further optimized to improve the ADME as well pharmacodynamic property.

This research studied the immersive projection technology based on the dining experience of a set meal to show the dining atmosphere, reshape the cultural memory of culinary arts, and highlight the connotation of image and taste. The immersive installations are planned in a dining space with a square table to accommodate eight people. In addition, it is matched with a wall projection to present a sense of a fully immersive environment. The use of infrared cameras and visual recognition results allows the participants to see the presentations. The immersive experiences are in three areas: tabletop, tablewares, and walls. The tabletop shows the abstract images related to the meal; the tablewares interact with dining actions; the surrounding walls of the dining space present the consequence animation from the tabletop. The findings of setting up the projection and detection devices related to the three essential areas to support the immersive experiences in a square-shaped structure space are stated in this paper. The research result describes creating the image related to the food taste, traceability, and surrounding environment.

Extended red emission (ERE) is a broad feature in the spectral region of 500–900 nm commonly observed in a wide range of circumstellar and interstellar environments. Although the observational constraints for ERE are well established, definitive identifications of the carriers and associated processes complying with these constraints remain unanswered. We report a plausible two-step model involving far-ultraviolet (UV)-irradiated single-layer graphene (SLG), considered as large polycyclic aromatic hydrocarbons, to meet these constraints and supported by laboratory experiments. The far-UV-treated SLG, producing structural defects and graphene quantum dots, showed photoluminescence excitation spectrum extending from the far-UV to UV–visible region, hence meeting the requirements of far-UV light and high photon conversion efficiency. Furthermore, a photoluminescence band shifted from ∼585 to ∼750 nm for high-dose-exposed SLG agrees with the observed redshift of the ERE band in regions under a greater far-UV radiation density.

We identified, via high-throughput screening using a FLIPR® calcium assay, compound 1, which incorporated a dihydroquinolinyl-2-oxoethylsulfanyl-(1H,5H)-pyrimidinedione core and activated the μ-opioid receptor (MOR) in the presence of naloxone or naltrexone. A structure-activity relationship study of the analogs of 1 led to the design of compound 21, which activated MOR in the presence of naloxone with an EC

Nowadays, there are numerous social platforms for people to discuss and share information. However, certain users may post contents that discriminate against specific groups or spread inappropriate behaviors. Therefore, it is desired to have a detection mechanism that is able to accurately identify these offensive comments and inappropriate messages before appearing on social platforms. To address this need, we propose a novel model called Attention-based Multi-filter Convolutional Neural Network (AMCNN) for inappropriate speech detection. Our model combines CNN and BiLSTM to acquire the advantages of the two. AM CNN leverages CNN filters of various kernel sizes for convolution operations to capture the relation between words of different lengths. The convolutional features are then used as the inputs of BiLSTM, which is able to obtain the bidirectional semantics via the forward and backward directions. AMCNN further incorporates the attention mechanism to highlight the important parts of the hidden layer output for better classification. Our model can be applied to various types and lengths of text, and it is also able to support different languages. To evaluate the model performance, we conduct extensive experiments on various real-world datasets. According to the experimental results, our model achieves the best performance, which is on average 12.63% higher than the state-of-the-art approach on the F1-score indicator. We also conduct ablation analysis, and the results show that the attention mechanism and the usage of BiLSTM can considerably improve the classification performance and effectively detect inappropriate speech in sentences.

Integrative medicine comprising a tumor-associated antigen vaccine and chemotherapeutic regimens has provided new insights into cancer therapy. In this study, the AB-type diblock copolymers poly(ethylene glycol)–polylactide (PEG–PLA) were subjected to the dispersion of poorly water-soluble molecules in aqueous solutions. The physicochemical behavior of the chemotherapeutic agent DBPR114 in the PEG–PLA-polymeric aqueous solution was investigated by dynamic light scattering (DLS) technology. In vitro cell culture indicated that replacing the organic solvent DMSO with PEG–PLA polymeric micelles could maintain the anti-proliferative effect of DBPR114 on leukemia cell lines. A murine tumor-associated antigen vaccine model was established in tumor-bearing mice to determine the effectiveness of these formulas in inducing tumor regression. The results demonstrated that the therapeutic treatments effectively reinforced each other via co-delivery of antitumor drug/antigen agents to synergistically integrate the efficacy of cancer therapy. Our findings support the potential use of polymeric micellar systems for aqueous solubilization and expansion of antitumor activity intrinsic to DBPR114 and tumor-associated antigen therapy.

In this paper, the design of large-size rectangular ultrasonic plastic soldering system is studied by using the band gap theory of phononic crystal and coupled vibration theory of large-size rectangular tool. In practical engineering applications, lateral vibration of the large-size rectangular tool will seriously cause the displacement of the tool's radiation surface uneven. So the lateral vibration of the tool should be suppressed. As we all know, phononic crystal materials can suppress the vibration and they are composed of two or more different materials periodically (including matrix material and scattering material). This paper uses periodic slotted structure to suppress the lateral vibration of the large-size rectangular tool. The lateral vibration band gap of the large-size rectangular tool which has periodic slotted structure in this paper is simulated. In addition, the influence of the scatterer's size on the lateral vibration band gap is also obtained. At the same time, the magnitude and uniformity of the tool's radiation surface displacement before and after slotting is compared in experiments. The research shows that by reasonably designing the periodic structure and size of the phononic crystal, the lateral vibration of the large-size rectangular tool can be effectively suppressed, and the displacement of the tool's radiation surface can be more even.

Autotrophic plants have evolved distinctive mechanisms for maintaining a range of homeostatic states for sugars. The on/off switch of reversible gene expression by sugar starvation/provision represents one of the major mechanisms by which sugar levels are maintained, but the details remain unclear. α-Amylase (αAmy) is the key enzyme for hydrolyzing starch into sugars for plant growth, and it is induced by sugar starvation and repressed by sugar provision. αAmy can also be induced by various other stresses, but the physiological significance is unclear. Here, we reveal that the on/off switch of αAmy expression is regulated by 2 MYB transcription factors competing for the same promoter element. MYBS1 promotes αAmy expression under sugar starvation, whereas MYBS2 represses it. Sugar starvation promotes nuclear import of MYBS1 and nuclear export of MYBS2, whereas sugar provision has the opposite effects. Phosphorylation of MYBS2 at distinct serine residues plays important roles in regulating its sugar-dependent nucleocytoplasmic shuttling and maintenance in cytoplasm by 14-3-3 proteins. Moreover, dehydration, heat, and osmotic stress repress MYBS2 expression, thereby inducing αAmy3. Importantly, activation of αAmy3 and suppression of MYBS2 enhances plant growth, stress tolerance, and total grain weight per plant in rice. Our findings reveal insights into a unique regulatory mechanism for an on/off switch of reversible gene expression in maintaining sugar homeostatic states, which tightly regulates plant growth and development, and also highlight MYBS2 and αAmy3 as potential targets for crop improvement.

Among the plant constituents of Clerodendrum colebrookianum Walp., acteoside, martinoside, and osmanthuside β6 interact with ROCK, a drug target for cancer. In this study, aglycone fragments of these plant constituents (caffeic acid, ferulic acid, and p-coumaric acid) along with the homopiperazine ring of fasudil (standard ROCK inhibitor) were used to design hybrid molecules. The designed molecules interact with the key hinge region residue Met156/Met157 of ROCK I/II in a stable manner according to our docking and molecular dynamics simulations. These compounds were synthesized and tested in vitro in SW480, MDA-MB-231, and A-549 cancer cell lines. The most promising compound was chemically optimized to obtain a thiourea analog, 6a (IC50 = 25 µM), which has >3-fold higher antiproliferative activity than fasudil (IC50 = 87 µM) in SW480 cells. Treatment with this molecule also inhibits the migration of colon cancer cells and induces cell apoptosis. Further, SPR experiments suggests that the binding affinity of 6a with ROCK I protein is better than that of fasudil. Hence, the drug-like natural product analog 6a constitutes a highly promising new anticancer lead. Communicated by Ramaswamy H. Sarma

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin–proteasome system. Chen et al. identify ASB11 as an E3 ligase for BIK ubiquitination and degradation and uncover different mechanisms that regulate ASB11 activity, and thus cell survival versus death, during ER stress and DNA damage responses. Blocking this degradative pathway may increase the efficacy of active BIK gene therapy as an anti-cancer therapy., The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin–proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α–XBP1s–ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.

Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics.

Our capability to visualize protein complexes such as RNA polymerase II (pol II) by single-molecule imaging techniques has largely been hampered by the absence of a simple bio-orthogonal approach for selective labeling with a fluorescent probe. Here, we modify the existing calmodulin-binding peptide (CBP) in the widely used Tandem Affinity Purification (TAP) tag to endow it with a high affinity for calmodulin (CaM) and use dye-CaM to conduct site-specific labeling of pol II. To demonstrate the single molecule applicability of this approach, we labeled the C-terminus of the Rpb9 subunit of pol II with donor-CaM and a site in TFIIF with an acceptor to generate a FRET (fluorescence resonance energy transfer) pair in the pol II-TFIIF complex. We then used total internal reflection fluorescence microscopy (TIRF) with alternating excitation to measure the single molecule FRET (smFRET) efficiency between these two sites in pol II-TFIIF. We found they exhibited a proximity consistent with that observed in the transcription pre-initiation complex by cryo-electron microscopy (cryo-EM). We further compared our non-covalent labeling approach with an enzyme-enabled covalent labeling method. The virtually indistinguishable results validate our smFRET approach and show that the observed proximity between the two sites represents a hallmark of the pol II-TFIIF complex. Taken together, we present a simple and versatile bio-orthogonal method derived from TAP to enable selective labeling of a protein complex. This method is suitable for analyzing dynamic relationships among proteins involved in transcription and it can be readily extended to many other biological processes.

Since its discovery in Tanganyika, Africa in 1952, chikungunya virus (CHIKV) outbreaks have occurred in Africa, Asia, Europe, and America. Till now chikungunya fever has spread in nearly 40 countries. Because of lack of effective vaccines and antiviral drugs to intervene this disease, 21 new conjugated compounds were designed and synthesized by coupling of 6,8-dithioguanosine at its C-6 position with 3-(chloromethyl)coumarins bearing an F, Cl, Br, Me, or –OMe substituent through the –SCH2– joint. Meanwhile, an organic “dummy” ligand (e.g., methyl, benzyl, and naphthylmethyl) or a coumarinyl moiety was attached at the C-8 position. By high through-put screening, three of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC50 = 9.9–13.9 μM) and showed low toxicity (CC50 = 96.5–212 μM). The selectivity index values were 9.37–21.7. Their structure–activity relationship was deduced, which indicates that the coumarin moiety is essential and the presence of a –OMe group enhances the antiviral activity.

Electron bombardment of aniline (PhNH

We propose a density-near-zero piezoelectric metamaterial for realizing tunable sound transmission in real-time. The proposed mechanism is that the static voltage exerted on piezoelectric patches breaks the tension balance of the middle membrane, making the resonance frequency of the hybrid membrane structure dependence of static voltage. The numerical results verify the theoretical predictions and the effectiveness of the resulting device is demonstrated via multi-extraordinary phenomena at two predesigned frequencies. We anticipate our methodology to offer new possibilities for metamaterial-based piezoelectric devices and may promote applications in various fields such as acoustic communication.

This study presents a noncontact electrocardiogram (ECG) measurement system to replace conventional ECG electrode pads during ECG measurement. The proposed noncontact electrode design comprises a surface guard ring, the optimal input resistance, a ground guard ring, and an optimal voltage divider feedback. The surface and ground guard rings are used to reduce environmental noise. The optimal input resistor mitigates distortion caused by the input bias current, and the optimal voltage divider feedback increases the gain. Simulated gain analysis was subsequently performed to determine the most suitable parameters for the design, and the system was combined with a capacitive driven right leg circuit to reduce common-mode interference. The present study simulated actual environments in which interference is present in capacitive ECG signal measurement. Both in the case of environmental interference and motion artifact interference, relative to capacitive ECG electrodes, the proposed electrodes measured ECG signals with greater stability. In terms of R–R intervals, the measured ECG signals exhibited a 98.6% similarity to ECGs measured using contact ECG systems. The proposed noncontact ECG measurement system based on capacitive sensing is applicable for use in everyday life.

Developing a cost-effective and reliable sensing platform for the routine screening of microalbuminuria and early diagnosis of chronic kidney disease is of great importance. Herein, we report on the high specificity and electrocatalytic activity of CNT/ABTS

BackgroundTRIM28/KAP1/TIF1β is a key epigenetic modifier. Genetic ablation of trim28 is embryonic lethal although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, the methylation of DNA, RNA and histones and acetylation of histones are key epigenetic modifications that regulate gene expression. A number of lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. ResultsHere we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs), with consequent effects on the phenotype of the erythroleukemic cell line K562. TRIM28-K304Q was comparable with its wild-type counterpart with respect to intracellular level, homodimerization, phosphorylation at S473 and S824, and interactions with heterochromatin-binding protein HP1. The expression of embryonic-related and fetal globin genes was activated in TRIM28-K304Q mutant cells. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from that of wild-type K562 cells. The gene expression ensemble of mutant K562 cells indicated a general induction of differentiation-promoting genes and attenuation of proliferation-promoting genes. ConclusionsThese results suggest that acetylation/deacetylation of K304 in TRIM28 or TRIM28-K304Q constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation of this key epigenetic modifier as demonstrated by the acetylation mimic TRIM28-K304Q.

Ubiquitination and SUMOylation of protein are crucial for various biological responses. The recent unraveling of cross-talk between SUMO and ubiquitin (Ub) has shown the pressing needs to develop the platform for the synthesis of Ub tagged SUMO2 dimers to decipher its biological functions. Still, the platforms for facile synthesis of dimers under native condition are less explored and remain major challenges. Here, we have developed the platform that can expeditiously synthesize all eight Ub tagged SUMO2 and SUMOylated proteins under native condition. Expanding genetic code (EGC) method was employed to incorporate Se-alkylselenocysteine at lysine positions. Oxidative selenoxide elimination generates the electrophilic center, dehydroalanine, which upon Michael addition with C-terminal modified ubiquitin, a nucleophile, yield Ub tagged SUMO2. The dimers were further interrogated with USP7, a SUMO2 deubiquitinase, which is involved in DNA repair, to understand specificity toward the Ub tagged SUMO2 dimer. Our results have shown that the C-terminal domain of USP7 is crucial for USP7 efficiency and selectivity for the Ub tagged SUMO2 dimer.

A shift in dengue cases toward the adult population, accompanied by an increased risk of severe cases of dengue in the elderly, has created an important emerging issue in the past decade. To understand the level of past DENV infection among older adults after a large dengue outbreak occurred in southern Taiwan in 2015, we screened 1498 and 2603 serum samples from healthy residents aged ≥ 40 years in Kaohsiung City and Tainan City, respectively, to assess the seroprevalence of anti-DENV IgG in 2016. Seropositive samples were verified to exclude cross-reaction from Japanese encephalitis virus (JEV), using DENV/JEV-NS1 indirect IgG ELISA. We further identified viral serotypes and secondary DENV infections among positive samples in the two cities. The overall age-standardized seroprevalence of DENV-IgG among participants was 25.77% in Kaohsiung and 11.40% in Tainan, and the seroprevalence was significantly higher in older age groups of both cities. Although the percentages of secondary DENV infection in Kaohsiung and Tainan were very similar (43.09% and 44.76%, respectively), DENV-1 and DENV-2 spanned a wider age range in Kaohsiung, whereas DENV-2 was dominant in Tainan. As very few studies have obtained the serostatus of DENV infection in older adults and the elderly, this study highlights the need for further investigation into antibody status, as well as the safety and efficacy of dengue vaccination in these older populations., Author summary The dengue virus (DENV) has rapidly spread out in tropical and sub-tropical regions. To measure the level of past DENV infections in the older population, we conducted a post-outbreak serosurvey in 2016 among a total of 4,101 older and elderly adults in Kaohsiung and Tainan cities in southern Taiwan. Our results showed district- and city-level differences in the overall seroprevalence of anti-DENV IgG antibody, increased seroprevalence with age, heterogeneous distributions of DENV serotypes, and similar percentages of secondary DENV infection in both metropolises, closely matching past histories of dengue outbreaks. This study demonstrates the importance of monitoring individual’s antibody status among the older and elderly population and highlights the need to investigate the safety and efficacy of dengue vaccination in these populations in the future.

The radial vibration of a radial composite tubular transducer with a large radiation range and power capacity is studied. The transducer is composed of a longitudinally polarized piezoelectric ceramic tube and a coaxial outer metal tube. Assuming that the longitudinal length is much larger than the radius, the electromechanical equivalent circuits of the radial vibration of a piezoelectric ceramic long tube and a metal long tube are derived and obtained for the first time following the plane strain theory. As per the condition of the continuous forces and displacements of two contact surfaces, the electromechanical equivalent circuit of the tubular transducer is obtained. The radial resonance/anti-resonance frequency equation and the expression of the effective electromechanical coupling coefficient are obtained. Then, the effects of the radial geometry dimension of the transducer on the vibration characteristics are analyzed. The theoretical resonance frequencies, anti-resonance frequencies, and the effective electromechanical coupling coefficients at the fundamental mode and the second mode are in good agreement with the finite element analysis (FEA) results. The study shows that when the overall size of the transducer is unchanged, as the proportion of piezoelectric ceramic increases, the radial resonance/anti-resonance frequency and the effective electromechanical coupling coefficient of the transducer at the fundamental mode and the second mode have certain characteristics. The radial composite tubular transducer is expected to be used in high-power ultrasonic wastewater treatment, ultrasonic degradation, and underwater acoustics, as well as other high-power ultrasonic fields.

The infrared (IR) spectrum of monobridged Si

COVID-19 is currently a pandemic in the world, can invade multiple systems, and has a high morbidity and mortality. So far, no cases of acute cerebrovascular disease have been reported. This article reports the clinical features of a COVID-19 patient whose first symptom was cerebral hemorrhage. More importantly, after the craniotomy, the patient had high fever and it was difficult to retreat. After cerebrospinal fluid testing, it was determined that an intracranial infection had occurred. After anti-infection and plasma infusion of the recovered person, the patient's symptoms gradually improved. This case suggests that COVID-19 may infringe on cerebral blood vessels and cause cerebral hemorrhage. Transfusion of plasma from rehabilitation patients is effective for critically ill patients.

The ubiquitin–proteasome system (UPS) and autophagy are two major quality control processes whose impairment is linked to a wide variety of diseases. The coordination between UPS and autophagy remains incompletely understood. Here, we show that ubiquitin ligase UBE3C and deubiquitinating enzyme TRABID reciprocally regulate K29/K48-branched ubiquitination of VPS34. We find that this ubiquitination enhances the binding of VPS34 to proteasomes for degradation, thereby suppressing autophagosome formation and maturation. Under ER and proteotoxic stresses, UBE3C recruitment to phagophores is compromised with a concomitant increase of its association with proteasomes. This switch attenuates the action of UBE3C on VPS34, thereby elevating autophagy activity to facilitate proteostasis, ER quality control and cell survival. Specifically in the liver, we show that TRABID-mediated VPS34 stabilization is critical for lipid metabolism and is downregulated during the pathogenesis of steatosis. This study identifies a ubiquitination type on VPS34 and elucidates its cellular fate and physiological functions in proteostasis and liver metabolism., Autophagy and the ubiquitin–proteasome system (UPS) are cellular quality control processes, but their coordination remains unclear. Here, the authors show that branched ubiquitination of VPS34 functions as a switch between UPS and autophagy and has an important role in lipid metabolism in the liver.

COVID-19 is currently a pandemic in the world, can invade multiple systems, and has a high morbidity and mortality. So far, no cases of acute cerebrovascular disease have been reported. This article reports the clinical features of a COVID-19 patient whose first symptom was cerebral hemorrhage. More importantly, after the craniotomy, the patient had high fever and it was difficult to retreat. After cerebrospinal fluid testing, it was determined that an intracranial infection had occurred. After anti-infection and plasma infusion of the recovered person, the patient's symptoms gradually improved. This case suggests that COVID-19 may infringe on cerebral blood vessels and cause cerebral hemorrhage. Transfusion of plasma from rehabilitation patients is effective for critically ill patients.

Protein deubiquitination contributes to cortical development, and its dysregulation is linked to intellectual disability., The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the USP11 gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse Usp11 is expressed highly in embryonic cerebral cortex, and Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. Mechanistically, these functions are mediated by a previously unidentified Usp11 substrate, Sox11. Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of Sox11 mRNA. The disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration. Our findings define a critical function of Usp11 in cortical development and highlight the importance of orchestrating protein stabilization mechanisms into transcription regulatory programs for a robust induction of cell fate determinants during early brain development.

P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB ChR 8-5, SW480-VCR, and HCT-15). Both the analogs significantly increased the vincristine efficacy in MDR cancer cell lines at low micromole concentrations. Specifically, 3 caused complete reversal of vincristine resistance in KB ChR 8-5 cells and found to act as competitive inhibitor of P-gp as well as potentiated the vincristine-induced NF-KB-mediated apoptosis. Therefore, 3 ((2E,4E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dien-1-one) can serve as a potential P-gp inhibitor for in vivo investigations, to reverse multidrug resistance in cancer.

In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.

Excessive generation and accumulation of highly reactive oxidizing molecules causes oxidative stress and oxidative damage to cellular components. Accumulating evidence indicates that autophagy diminishes oxidative damage in cells and maintains redox homeostasis by degrading and recycling intracellular damaged components. Here, we show that TRAF6 E3 ubiquitin ligase and A20 deubiquitinase coordinate to regulate ATG9A ubiquitination and autophagy activation in cells responding to oxidative stress. The ROS-dependent TRAF6-mediated non-proteolytic, K48/63-linked ubiquitination of ATG9A enhances its association with Beclin 1 and the assembly of VPS34-UVRAG complex, thereby stimulating autophagy. Notably, expression of the ATG9A ubiquitination mutants impairs ROS-induced VPS34 activation and autophagy. We further find that lipopolysaccharide (LPS)-induced ROS production also stimulates TRAF6-mediated ATG9A ubiquitination. Ablation of ATG9A causes aberrant TLR4 endosomal trafficking and decreases IRF-3 phosphorylation in LPS-stimulated macrophages. Our findings provide important insights into how K48/K63-linked ubiquitination of ATG9A contributes to the regulation of oxidative stress-induced autophagy.

In liquids, bubbles usually exist in the form of bubble groups. Due to their interaction with other bubbles, the resonance frequency of bubbles decreases. In this paper, the resonance frequency of bubbles in a columnar bubble group is obtained by linear simplification of the bubbles&rsquo, dynamic equation. The correction coefficient between the resonance frequency of the bubbles in the columnar bubble group and the Minnaert frequency of a single bubble is given. The results show that the resonance frequency of bubbles in the bubble group is affected by many parameters such as the initial radius of bubbles, the number of bubbles in the bubble group, and the distance between bubbles. The initial radius of the bubbles and the distance between bubbles are found to have more significant influence on the resonance frequency of the bubbles. When the distance between bubbles increases to 20 times the bubbles&rsquo, initial radius, the coupling effect between bubbles can be ignored, and after that the bubbles&rsquo, resonance frequency in the bubble group tends to the resonance frequency of a single bubble&rsquo, s resonance frequency. Fluent software is used to simulate the bubble growth, shrinkage, and collapse of five and seven bubbles under an ultrasonic field. The simulation results show that when the bubble breaks, the two bubbles at the outer field first begin to break and form a micro-jet along the axis line of the bubbles. Our methods and conclusions will provide a reference for further simulations and indicate the significance of the prevention or utilization of cavitation.

Cdc7-Dbf4 kinase plays a key role in the initiation of DNA replication and contributes to the replication stress in cancer. The activity of human Cdc7-Dbf4 kinase remains active and acts as an effector of checkpoint under replication stress. However, the downstream targets of Cdc7-Dbf4 contributed to checkpoint regulation and replication stress-support function in cancer are not fully identified. In this work, we showed that aberrant Cdc7-Dbf4 induces DNA lesions that activate ATM/ATR-mediated checkpoint and homologous recombination (HR) DNA repair. Using a phosphoproteome approach, we identified HSP90-S164 as a target of Cdc7-Dbf4 in vitro and in vivo. The phosphorylation of HSP90-S164 by Cdc7-Dbf4 is required for the stability of HSP90-HCLK2-MRN complex and the function of ATM/ATR signaling cascade and HR DNA repair. In clinically, the phosphorylation of HSP90-S164 indeed is increased in oral cancer patients. Our results indicate that aberrant Cdc7-Dbf4 enhances replication stress tolerance by rewiring ATR/ATM mediated HR repair through HSP90-S164 phosphorylation and by promoting recovery from replication stress. We provide a new solution to a subtyping of cancer patients with dominant ATR/HSP90 expression by combining inhibitors of ATR-Chk1, HSP90, or Cdc7 in cancer combination therapy.

In recent years, many researchers have examined dynamic optimization problems (DOPs). The key challenge lies in the fact that the optimal solution of a DOP typically changes over time. This paper focuses on using query-based learning dynamic particle swarm optimization (QBLDPSO) to solve DOPs. QBLDPSO is mainly used for improving multi-population-based PSO; our QBL mechanism includes two learning strategies that integrate the concepts of diversity and memory into PSO. The first learning strategy, QBL quantum parameter adaptation (QBLQPA), is used to apply the concept of diversity to the multi-population based algorithm. This is different from typical diversity-based PSO approaches, which passively maintain the diversity of particles in the solution space. We actively adapt the ratio of quantum particles and neutral particles to achieve diversity without analyzing the distribution of optima in the solution space. The second learning strategy is query-based learning optima prediction (QBLOP). Although QBLOP exploits the concept of memory, we do not need to analyze the history of all particles. We select the $k$ nearest particles to the current best solution and use a minimum encompassing circle as the possible prediction region. Our experimental results are based on the generalized dynamic benchmark generator (GDBG), which is adopted as a benchmark for the DOP. The proposed method outperforms two state-of-the-art multi-population-based PSO methods with the average improvements of 11.37% and 8% using QBLQPA. In particular, for the recurrent problems in GDBG, our method improves performance by 35.06%.