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Three species of the Rutaceae family, including Acronychia pedunculata, Euodia lepta, and Severinia monophylla have been used in traditional medicine. However, the comparison of the chemical composition, anti-cancer, and anti-inflammatory effects of the leaf essential oils of these species have not been investigated yet. A total of 38 compounds were identified via gas chromatography-mass spectrometry, comprising 96.5-99.8% of the total composition.  Both A. pedunculata and E. lepta essential oils exhibited strong inhibitory effects against cancer cells (IC50: 59.04-97.52 µg/mL) while that of S. monophylla showed a lower anti-cancer effect (IC50>100 µg/mL). Among three essential oils, only the E. lepta leaf oil demonstrated a high anti-inflammatory effect on LPS-stimulated macrophages (IC50=6.47 ± 0.65 µg/mL), while the other showed a moderate anti-inflammatory effect (IC50>50 µg/mL). Molecular docking studies also suggested the binding potential of the key compounds from three essential oils against inducible nitric oxide synthase and cyclooxygenase-2, two proteins associated with inflammatory response, with the negative energies ranging from -41.0 to -71.9 kcal/mol. The present findings suggest the leaf essential oils from these species as potential medicines for treatment of cancer or inflammation associated diseases, especially the ones from A. pedunculata and E. lepta oils., (© 2024 Wiley‐VCH GmbH.)

The molecular machines of life, proteins, are made up of twenty kinds of amino acids, each with distinctive side chains. We present a geometrical analysis of the protrusion statistics of side chains in more than 4000 high-resolution protein structures. We employ a coarse-grained representation of the protein backbone viewed as a linear chain of C α atoms and consider just the heavy atoms of the side chains. We study the large variety of behaviors of the amino acids based on both rudimentary structural chemistry as well as geometry. Our geometrical analysis uses a backbone Frenet coordinate system for the common study of all amino acids. Our analysis underscores the richness of the repertoire of amino acids that is available to nature to design protein sequences that fit within the putative native state folds.

This study investigates the role of all-trans retinoic acid (ATRA) in modulating the expression of heat shock protein 90 (Hsp90) and its influence on the uptake and degradation of tau proteins in immortalized human microglia cells. We demonstrate that ATRA significantly upregulates Hsp90 expression in a concentration-dependent manner, enhancing both extracellular and intracellular Hsp90 levels. Our results show that ATRA-treated cells exhibit increased tau protein uptake via caveolae/raft-dependent endocytosis pathways. This uptake is mediated by surface Hsp90, as evidenced by the inhibition of tau internalization using an extracellular Hsp90-selective inhibitor. Further, we establish that the exogenously added full-sized monomeric tau proteins bind to Hsp90. The study also reveals that ATRA-enhanced tau uptake is followed by effective degradation through both lysosomal and proteasomal pathways. We observed a significant reduction in intracellular tau levels in ATRA-treated cells, which was reversed by lysosome or proteasome inhibitors, suggesting the involvement of both degradation pathways. Our findings highlight the potential therapeutic role of ATRA in Alzheimer's disease and related tauopathies. By enhancing Hsp90 expression and facilitating tau degradation, ATRA could contribute to the clearance of pathological tau proteins, offering a promising strategy for mitigating neurodegeneration. This research underscores the need for further exploration into the molecular mechanisms of tau protein internalization and degradation, which could provide valuable insights into the treatment of neurodegenerative diseases., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma 1-4 , but the efficacy of CAR T cell therapy in solid tumours has been limited 5 . This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass 6-8 . We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours., (© 2024. The Author(s).)

Linear chain molecules play a central role in polymer physics with innumerable industrial applications. They are also ubiquitous constituents of living cells. Here, we highlight the similarities and differences between two distinct ways of viewing a linear chain. We do this, on the one hand, through the lens of simulations for a standard polymer chain of tethered spheres at low and high temperatures and, on the other hand, through published experimental data on an important class of biopolymers, proteins. We present detailed analyses of their local and non-local structures as well as the maps of their closest contacts. We seek to reconcile the startlingly different behaviors of the two types of chains based on symmetry considerations.

We have shown recently that the notion of poking pairwise interactions along a chain provides a unifying framework for understanding the formation of both secondary and the tertiary protein structure based on symmetry and geometry. α-helices and β-sheets are found to be special geometries that have systematic poking contacts in a repetitive manner with the contacts being local along the α-helix and non-local along a pair of adjacent strands within a β-sheet. Pairwise poking interactions also govern tertiary structure formation, but they are weaker and there are no special geometrical constraints as in secondary structure formation. Here we demonstrate that protein turns, the most prevalent non-repetitive structural element in proteins, are instances of local (as in α-helices) and isolated (non-repetitive) poking pairwise contacts for which the geometrical constraints are partially relaxed. This simple and purely geometrical definition of protein turns (also sometimes known as reverse turns, β-turns, β-bends, hairpin bends, 3 10 bends, kinks, widgets, etc.) provides a simple framework for unifying them. We present the results of a systematic analysis and identify their structural classes as well as their respective amino acid preferences., (© 2024 Wiley Periodicals LLC.)

We introduce the concept of photonic flatband resonances and demonstrate it for an array of high-index dielectric particles. We employ the multiple Mie scattering theory and demonstrate that both short- and long-range interactions between the resonators are crucial for the emerging collective resonances and their associated photonic flatbands. By examining both near- and far-field characteristics, we uncover how the flatbands emerge due to a fine tuning of resonators' radiation fields, and predict that hybridization of a flatband resonance with an electric hot spot can lead to giant values of the Purcell factor for the electric dipolar emitters.

Launaea sarmentosa, also known as Sa Sam Nam, is a widely used remedy in Vietnamese traditional medicine and cuisine. However, the chemical composition and bioactivity of its essential oil have not been elucidated yet. In this study, we identified 40 compounds (98.6% of total peak area) in the essential oil via GC-MS analysis at the first time. Among them, five main compounds including Thymohydroquinone dimethyl ether (52.4%), (E)-α-Atlantone (9.0%), Neryl isovalerate (6.6%), Davanol D2 (isomer 2) (3.9%), and trans-Sesquisabinene hydrate (3.9%) have accounted for 75.8% of total peak area. The anti-bacterial activity of the essential oil against 4 microorganisms including Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa has also investigated via agar well diffusion assay. The results showed that the essential oil exhibited a strong antibacterial activity against Bacillus subtilis with the inhibition zones ranging from 8.2 to 18.7 mm. To elucidate the anti-bacterial effect mechanism of the essential oil, docking study of five main compounds of the essential oil (Thymohydroquinone dimethyl ether, (E)-α-Atlantone, Neryl isovalerate, Davanol D2 (isomer 2), and trans-Sesquisabinene hydrate) against some key proteins for bacterial growth such as DNA gyrase B, penicillin binding protein 2A, tyrosyl-tRNA synthetase, and dihydrofolate reductase were performed. The results showed that the main constituents of essential oil were highly bound with penicillin binding protein 2A with the free energies ranging -27.7 to -44.8 kcal/mol, which suggests the relationship between the antibacterial effect of essential oil and the affinity of main compounds with penicillin binding protein. In addition, the free energies of main compounds of the essential oil with human cyclooxygenase 1, cyclooxygenase 2, and phospholipase A2, the crucial proteins related with inflammatory response were less than diclofenac, a non-steroidal antiinflammatory drug. These findings propose the essential oil as a novel and promising anti-bacterial and anti-inflammatory medicine or cosmetic products.

Due to a critical organ shortage, pig organs are being explored for use in transplantation. Differences between species, particularly in cell surface glycans, can trigger elevated immune responses in xenotransplantation. To mitigate the risk of hyperacute rejection, genetically modified pigs have been developed that lack certain glycans and express human complement inhibitors. Nevertheless, organs from these pigs may still provoke stronger inflammatory and innate immune reactions than allotransplants. Dysregulation of coagulation and persistent inflammation remain obstacles in the transplantation of pig organs into primates. Regulatory macrophages (Mregs), known for their anti-inflammatory properties, could offer a potential solution. Mregs secrete interleukin 10 and transforming growth factor beta, thereby suppressing immune responses and promoting the development of regulatory T cells. These Mregs are typically induced via the stimulation of monocytes or macrophages with macrophage colony-stimulating factor and interferon gamma, and they conspicuously express the stable marker dehydrogenase/reductase 9. Consequently, understanding the precise mechanisms governing Mreg generation, stability, and immunomodulation could pave the way for the therapeutic use of Mregs generated in vitro . This approach has the potential to reduce the required dosages and durations of anti-inflammatory and immunosuppressive medications in preclinical and clinical settings.

Epaltes australis Less. has been traditionally used to treat fever and snake bites, whereas Lindera myrrha (Lour.) Merr. is well-known for addressing colds, chest pain, indigestion, and worm infestations. This study marks the first report on the chemical compositions and biological potentials of essential oils extracted from the leaves of Epaltes australis and Lindera myrrha. Essential oils obtained by hydro-distillation were analysed using the GC/MS (gas chromatography-mass spectrometry). E. australis exhibited a predominant presence of non-terpenic compounds (46.3 %), with thymohydroquinone dimethyl ether as the major compound, constituting 44.2 % of the oil. L. myrrha leaf oil contained a good proportion of sesquiterpene hydrocarbons (56.8 %), with principal compounds including (E)-caryophyllene (22.2 %), ledene (9.7 %), selina-1,3,7(11)-trien-8-one (9.6 %), and α-pinene (7.0 %). Both essential oils exhibited antimicrobial activity against the bacteria Bacillus subtilis and Clostridium sporogenes, and Escherichia coli, and the fungus Aspergillus brasiliensis. L. myrrha leaf essential oil exhibited potent control over the yeast Saccharomyces cerevisiae with a MIC of 32 μg/mL. Additionally, L. myrrha leaf oil showed strong anti-inflammatory activity with an IC 50 value of 15.20 μg/mL by inhibiting NO (nitric oxide) production in LPS (lipopolysaccharide)-stimulated RAW2647 murine macrophage cells. Regarding anti-tyrosinase activity, E. australis leaf oil showed the best monophenolase inhibition with the IC 50 of 245.59 μg/mL, while L. myrrha leaf oil successfully inhibited diphenolase with the IC 50 of 152.88 μg/mL. From molecular docking study, selina-1,3,7(11)-trien-8-one showed the highest affinity for both COX-2 (cyclooxygenase-2) and TNF-α (tumor necrosis factor-α) receptors. Hydrophobic interactions play a great role in the bindings of ligand-receptor complexes., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A 2A R receptor. Understanding of the mechanism by which A 2A R is regulated has been hindered by difficulty in identifying the cell types that express A 2A R due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A 2A R eGFP reporter mouse is developed, enabling the expression of A 2A R during ongoing anti-tumor immune responses to be assessed. This reveals that A 2A R is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4 + and CD8 + T lymphocytes and on a MHCII hi CD86 hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1 + A 2A R - cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A 2A R and synergizes with A 2A R deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A 2A R in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches., (© 2023. The Author(s).)

Recently, we presented a framework for understanding protein structure based on the idea that simple constructs of holding hands or touching of objects can be used to rationalize the common characteristics of globular proteins. We developed a consistent approach for understanding the formation of the two key common building blocks of helices and sheets as well as the compatible assembly of secondary structures into the tertiary structure through the notion of poking pairwise interactions. Here we benchmark our predictions with a detailed analysis of structural data of over 4000 proteins from the Protein Data Bank. We also present the results of detailed computer simulations of a simplified model demonstrating a pre-sculpted free energy landscape, determined by geometry and symmetry, comprising numerous minima corresponding to putative native state structures. We explore the consequences of our model. Our results suggest that symmetry and geometry are a powerful guide to capture the simplicity underlying protein complexity., (© 2023 Wiley Periodicals LLC.)

We present a model, based on symmetry and geometry, for proteins. Using elementary ideas from mathematics and physics, we derive the geometries of discrete helices and sheets. We postulate a compatible solvent-mediated emergent pairwise attraction that assembles these building blocks, while respecting their individual symmetries. Instead of seeking to mimic the complexity of proteins, we look for a simple abstraction of reality that yet captures the essence of proteins. We employ analytic calculations and detailed Monte Carlo simulations to explore some consequences of our theory. The predictions of our approach are in accord with experimental data. Our framework provides a rationalization for understanding the common characteristics of proteins. Our results show that the free energy landscape of a globular protein is pre-sculpted at the backbone level, sequences and functionalities evolve in the fixed backdrop of the folds determined by geometry and symmetry, and that protein structures are unique in being simultaneously characterized by stability, diversity, and sensitivity., (© 2023 Wiley Periodicals LLC.)

Regulatory macrophages (Mregs) are unique in that they have anti-inflammatory and immunosuppressive properties. Thus, treating inflammatory diseases using Mregs is an area of active research. Human Mregs are usually generated by culturing peripheral blood monocytes stimulated using a macrophage colony-stimulating factor with interferon (IFN)-γ. Herein, we generated Mregs with an elongated cell morphology from THP-1 cells that were stimulated with phorbol 12-myristate 13-acetate and cultured with both arginylglycylaspartic acid and vitamin D3. These Mregs regulated macrophage function, and respectively downregulated and upregulated the expression of pro-inflammatory and immunosuppressive mediators. They also expressed Mregs-specific markers, such as dehydrogenase/reductase 9, even when exposed to such inflammatory stimulants as IFN-γ, lipopolysaccharide, purified xenogeneic antigen, and xenogeneic cells. The Mregs also exerted anti-inflammatory and anticoagulatory actions in response to xenogeneic cells, as well as exerting immunosuppressive effects on mitogen-induced Jurkat T-cell proliferation. Our method of generating functional Mregs in vitro without cytokines is simple and cost-effective.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia as the primary clinical symptom. The production and accumulation of aggregated β -amyloid (A β ) in patient brain tissues is one of the hallmarks of AD pathogenesis. Microglia, brain-resident macrophages, produce inflammatory cytokines in response to A β oligomers or fibrils exacerbating A β pathology in AD. HMO6 cells were treated with A β 42 in the presence or absence of 1,25-dihydroxy vitamin D 3 (1,25(OH) 2 D 3 ) to determine its potential immunomodulatory effects, and the expression of pro-/anti-inflammatory cytokines, M1/M2-associated markers, Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 2 (TREM2) was examined. 1,25(OH) 2 D 3 was found to suppress A β -induced expression of proinflammatory cytokines (TNF- α , IL-1 β , and IL-6), M1 markers (CD86 and iNOS), and TLR2/4, whilst increasing the expression of anti-inflammatory cytokines (IL-4, IL-10, and CCL17) and M2 markers (CD206 and Arg-1). Furthermore, 1,25(OH) 2 D 3 promoted TREM2 expression and A β uptake by HMO6 cells, and the enhancement of A β uptake and M2 polarization was revealed to be TREM2-dependent. The findings of this study suggest that 1,25(OH) 2 D 3 facilitates M2 polarization and A β uptake in a TREM2-dependent manner., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Vo Thuy Anh Thu et al.)

DNA toroids are compact torus-shaped bundles formed by one or multiple DNA molecules being condensed from the solution due to various condensing agents. It has been shown that the DNA toroidal bundles are twisted. However, the global conformations of DNA inside these bundles are still not well understood. In this study, we investigate this issue by solving different models for the toroidal bundles and performing replica-exchange molecular dynamics (REMD) simulations for self-attractive stiff polymers of various chain lengths. We find that a moderate degree of twisting is energetically favorable for toroidal bundles, yielding optimal configurations of lower energies than for other bundles corresponding to spool-like and constant radius of curvature arrangements. The REMD simulations show that the ground states of the stiff polymers are twisted toroidal bundles with the average twist degrees close to those predicted by the theoretical model. Constant-temperature simulations show that twisted toroidal bundles can be formed through successive processes of nucleation, growth, quick tightening, and slow tightening of the toroid, with the two last processes facilitating the polymer threading through the toroid's hole. A relatively long chain of 512 beads has an increased dynamical difficulty to access the twisted bundle states due to the polymer's topological constraint. Interestingly, we also observed significantly twisted toroidal bundles with a sharp U-shaped region in the polymer conformation. It is suggested that this U-shaped region makes the formation of twisted bundles easier by effectively reducing the polymer length. This effect can be equivalent to having multiple chains in the toroid.

Regulatory macrophages (Mreg) are a special cell type that present a potential therapeutic strategy for various inflammatory diseases. In vitro, Mreg generation mainly takes 7-10 days of treatment with chemicals, including cytokines. In the present study, we established a new approach for Mreg generation using a three-dimensional (3D) micropatterned polydimethylsiloxane (PDMS) surface coated with a natural biopolymer adhesive polydopamine (PDA) and the common cell adhesion peptide motif arginylglycylaspartic acid (RGD). The 3D PDMS surfaces were fabricated by photolithography and soft lithography techniques and were subsequently coated with an RGD+PDA mixture to form a surface that facilitates cell adhesion. Human monocytes (THP-1 cells) were cultured on different types of 2D or 3D micropatterns for four days, and the cell morphology, elongation, and Mreg marker expression were assessed using microscopic and flow cytometric analyses. The cells grown on the PDA+RGD-coated 3D micropatterns (20-µm width/20-µm space) exhibited the most elongated morphology and strongest expression levels of Mreg markers, such as CD163, CD206, CD209, CD274, MER-TK, TREM2, and DHRS9. The present study demonstrated that PDA+RGD-coated 3D PDMS micropatterns successfully induced Mreg-like cells from THP-1 cells within four days without the use of cytokines, suggesting a time- and cost-effective method to generate Mreg-like cells in vitro.

The ribosomal exit tunnel is the primary structure affecting the release of nascent proteins at the ribosome. The ribosomal exit tunnels from different species have elements of conservation and differentiation in structural and physico-chemical properties. In this study, by simulating the elongation and escape processes of nascent proteins at the ribosomal exit tunnels of four different organisms, we show that the escape process has conserved mechanisms across the domains of life. Specifically, it is found that the escape process of proteins follows the diffusion mechanism given by a simple diffusion model, and the median escape time positively correlates with the number of hydrophobic residues and the net charge of a protein for all the exit tunnels considered. These properties hold for 12 distinct proteins considered in two slightly different and improved Gō-like models. It is also found that the differences in physico-chemical properties of the tunnels lead to quantitative differences in the protein escape times. In particular, the relatively strong hydrophobicity of E. coli's tunnel and the unusually high number of negatively charged amino acids on the tunnel's surface of H. marismortui lead to substantially slower escapes of proteins at these tunnels than at those of S. cerevisiae and H. sapiens.

All-trans retinoic acid (ATRA) is an active metabolite of vitamin A, which plays an important role in the immune function. Here, we demonstrated that ATRA induces the heat shock protein (Hsp) 90 complex on the surface of THP-1 macrophages, which facilitates the internalization of exogenous bacterial flagellins to activate the inflammasome response. Mass spectrometric protein identification and co-immunoprecipitation revealed that the Hsp90 homodimer interacts with both Hsp70 and αMβ2 integrin. ATRA-induced complex formation was dependent on the retinoic acid receptor (RAR)/retinoid X receptor (RXR) pathway and intracellular calcium level and was essential for triggering the internalization of bacterial flagellin, which was clathrin dependent. Notably, in this process, αMβ2 integrin was found to act as a carrier to deliver flagellin to the cytosol to activate the inflammasome, leading to caspase-1 activity and secretion of interleukin (IL)-1β. Our study provides new insights into the underlying molecular mechanism by which exogenous bacterial flagellins are delivered into host cells without a bacterial transport system, as well as the mechanism by which vitamin A contributes to enhancing the human macrophage function to detect and respond to bacterial infection.

The overall effectiveness of nonlinear optical processes along extended nonlinear media highly depends on the fulfillment of the phase-matching condition for pump and generated fields. This is traditionally accomplished by exploiting the birefringence of nonlinear crystals requiring long interaction lengths (cm-scale). For nonbirefringent media and integrated photonic devices, modal phase matching can compensate the index mismatch. Here, the various interacting waves propagate in transverse modes with appropriate phase velocities, but they suffer from a low refractive index contrast and cm-scale interaction lengths. This work harnesses modal phase matching for third-harmonic generation (THG) in plasmonic waveguides using an organic polymer (poly[3-hexylthiophene-2,5-diyl]) as the nonlinear medium. One demonstrates experimentally an effective interaction area as small as ≈ 0.11 µm 2 and the phase-matched modal dispersion results in THG efficiency as high as ≈ 10 -3 W -2 within an effective length scale of ≈ 4.3 µm. THG also shows a strong correlation with the polarization of the incident laser beam, corresponding to the excitation of the antisymmetric plasmonic modes, corroborating that plasmonic modal phase matching is achieved. This large reduction in device area of orders of magnitude is interesting for various applications where space is critical (e.g., device integration or on-chip applications)., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Although iron is an essential constituent for almost all living organisms, iron dyshomeostasis at a cellular level may trigger oxidative stress and neuronal damage. Hence, there are numerous reported carbon dots (CDs) that have been synthesized and applied to determine intracellular iron ions. However, among reported CDs focused to detect Fe 3+ ions, only a few CDs have been designed to specifically determine Fe 2+ ions over Fe 3+ ions for monitoring of intracellular Fe 2+ ions. We have developed the nitrogen-doped CDs (NCDs) for fluorescence turn-off detection of Fe 2+ at cellular level. The as-synthesized NCDs exhibit a strong blue fluorescence and low cytotoxicity, acting as fluorescence probes to detect Fe 2+ as low as 0.702 µM in aqueous solution within 2 min and visualize intracellular Fe 2+ in the concentration range from 0 to 500 µM within 20 min. The as-prepared NCDs possess some advantages such as high biocompatibility, strong fluorescence properties, selectivity, and rapidity for intracellular Fe 2+ monitoring, making NCDs an excellent nanoprobe for biosensing of intracellular ferrous ions.

To develop methods to generate, manipulate, and detect plasmonic signals by electrical means with complementary metal-oxide-semiconductor (CMOS)-compatible materials is essential to realize on-chip electronic-plasmonic transduction. Here, electrically driven, CMOS-compatible electronic-plasmonic transducers with Al-AlO X -Cu tunnel junctions as the excitation source of surface plasmon polaritons (SPPs) and Si-Cu Schottky diodes as the detector of SPPs, connected via plasmonic strip waveguides of Cu, are demonstrated. Remarkably, the electronic-plasmonic transducers exhibit overall transduction efficiency of 1.85 ± 0.03%, five times higher than previously reported transducers with two tunnel junctions (metal-insulator-metal (MIM)-MIM transducers) where SPPs are detected based on optical rectification. The result establishes a new platform to convert electronic signals to plasmonic signals via electrical means, paving the way toward CMOS-compatible plasmonic components., (© 2021 The Authors. Small published by Wiley-VCH GmbH.)

Inelastic quantum mechanical tunneling of electrons across plasmonic tunnel junctions can lead to surface plasmon polariton (SPP) and photon emission. So far, the optical properties of such junctions have been controlled by changing the shape, or the type of the material, of the electrodes, primarily with the aim to improve SPP or photon emission efficiencies. Here we show that by tuning the tunneling barrier itself, the efficiency of the inelastic tunneling rates can be improved by a factor of 3. We exploit the anisotropic nature of hexagonal boron nitride (hBN) as the tunneling barrier material in Au//hBN//graphene tunnel junctions where the Au electrode also serves as a plasmonic strip waveguide. As this junction constitutes an optically transparent hBN-graphene heterostructure on a glass substrate, it forms an open plasmonic system where the SPPs are directly coupled to the dedicated strip waveguide and photons outcouple to the far field. We experimentally and analytically show that the photon emission rate per tunneling electron is significantly improved (~ ×3) in Au//hBN//graphene tunnel junction due to the enhancement in the local density of optical states (LDOS) arising from the hBN anisotropy. With the dedicated strip waveguide, SPP outcoupling efficiency is quantified and is found to be ∼ 80% stronger than the radiative outcoupling in Au//hBN//graphene due to the high LDOS of the SPP decay channel associated with the inelastic tunneling. The new insights elucidated here deepen our understanding of plasmonic tunnel junctions beyond the isotropic models with enhanced LDOS., (© 2021. The Author(s).)

After translation, nascent proteins must escape the ribosomal exit tunnel to attain complete folding to their native states. This escape process also frees up the ribosome tunnel for a new translation job. In this study, we investigate the impacts of energetic interactions between the ribosomal exit tunnel and nascent proteins on the protein escape process by molecular dynamics simulations using partially coarse-grained models that incorporate hydrophobic and electrostatic interactions of the ribosome tunnel of Haloarcula marismortui with nascent proteins. We find that, in general, attractive interactions slow down the protein escape process, whereas repulsive interactions speed it up. For the small globular proteins considered, the median escape time correlates with both the number of hydrophobic residues, N h , and the net charge, Q, of a nascent protein. A correlation coefficient exceeding 0.96 is found for the relation between the median escape time and a combined quantity of N h  + 5.9Q, suggesting that it is ∼6 times more efficient to modulate the escape time by changing the total charge than the number of hydrophobic residues. The estimated median escape times are found in the submillisecond-to-millisecond range, indicating that the escape does not delay the ribosome recycling. For various types of the tunnel model, with and without hydrophobic and electrostatic interactions, the escape time distribution always follows a simple diffusion model that describes the escape process as a downhill drift of a Brownian particle, suggesting that nascent proteins escape along barrier-less pathways at the ribosome tunnel., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by uncontrollable epithelial cell growth, cyst formation, and kidney malfunction. In the present study, we investigated the antiproliferative effects of the treatment with the combination of paclitaxel (PAC) and all-trans retinoic acid (ATRA) on ADPKD epithelial cells. Our results show that the combined treatment with 1 nM PAC and 10 nM ATRA significantly suppressed ADPKD cell proliferation (20%), while the treatment with ATRA or PAC alone had no such effect. Treatment with PAC and ATRA induced cell cycle arrest at the G2/M phase and apoptosis by upregulating p53 and caspase-8 expression and increased the intracellular calcium (Ca 2+ ) level possibly by enhancing Ca 2+ uptake via plasma membrane channels. In addition, this treatment suppressed extracellular signal-regulated kinase signaling possibly through mitogen-activated protein kinase phosphatase-1 activation. Thus, the combination of PAC and ATRA can be explored as a potential treatment regimen for ADPKD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Que Thanh Thanh Nguyen et al.)

The COVID-19 pandemic has continued to spread rapidly, and patients with diabetes are at risk of experiencing rapid progression and poor prognosis for appropriate treatment. Continuous glucose monitoring (CGM), which includes accurately tracking fluctuations in glucose levels without raising the risk of coronavirus exposure, becomes an important strategy for the self-management of diabetes during this pandemic, efficiently contributing to the diabetes care and the fight against COVID-19. Despite being less accurate than direct blood glucose monitoring, wearable noninvasive systems can encourage patient adherence by guaranteeing reliable results through high correlation between blood glucose levels and glucose concentrations in various other biofluids. This review highlights the trending technologies of glucose sensors during the ongoing COVID-19 pandemic (2019-2020) that have been developed to make a significant contribution to effective management of diabetes and prevention of coronavirus spread, from off-body systems to wearable on-body CGM devices, including nanostructure and sensor performance in various biofluids. The advantages and disadvantages of various human biofluids for use in glucose sensors are also discussed. Furthermore, the challenges faced by wearable CGM sensors with respect to personalized healthcare during and after the pandemic are deliberated to emphasize the potential future directions of CGM devices for diabetes management., Competing Interests: The authors declare no conflict of interest., (© 2021 Wiley‐VCH GmbH.)

We present the results of a quantitative study of the phase behavior of a model polymer chain with side spheres using two independent computer simulation techniques. We find that the mere addition of side spheres results in key modifications of standard polymer behavior. One obtains a marginally compact phase at low temperatures; the structures in this phase are reduced in dimensionality and are ordered, they include strands assembled into sheets and a variety of helices, and at least one of the transitions on lowering the temperature to access these ordered states is found to be first order. Our model serves to partially bridge conventional polymer phases with biomolecular phases.

Chain molecules play a key role in the polymer field and in living cells. Our focus is on a new homopolymer model of a linear chain molecule subject to an attractive self-interaction promoting compactness. We analyze the model using simple analytic arguments complemented by extensive computer simulations. We find several striking results: there is a first-order transition from a high-temperature random coil phase to a highly unusual low-temperature phase; the modular ground states exhibit significant degeneracy; the ground state structures exhibit spontaneous dimensional reduction and have a two-layer structure; and the ground states are assembled from secondary motifs of helices and strands connected by tight loops. We discuss the similarities and notable differences between the ground state structures [we call these PoSSuM (Planar Structures with Secondary Motifs)] in the phase and protein native state structures.

The potential applications of metal-enhanced fluorescence (MEF) devices include biosensors for the detection of trace amounts in biosciences, biotechnology, and pathogens that are relevant to medical diagnostics and food control. In the present study, the silver (Ag) film thickness (56 nm) of an MEF system was calibrated to maximize the depth-to-width ratio (Γ) of the surface plasmon resonance (SPR) active metal from reflectance dip curves. Upon plasmon coupling with thermally evaporated Ag, we demonstrated a 2.21-fold enhancement compared to the pristine flat substrate with the coefficient of variation (CV) ≈0.22% and the limit of detection (LOD) 0.001 mg L -1 of the concentration of an Alexa Fluor 488-labeled anti-C-reactive protein antibody (CRP@Alexa fluor 488). The structure was developed to simplify the in situ generation of biosensors for the surface-enhanced Raman spectroscopy (SERS) to determine Rhodamine B (RhB) with a highly robust performance. The procedure presented a simple and rapid sample pretreatment for the determination of RhB with a limit of quantification of 10 -10 M and a satisfactory linear response (0.98). The results showed the excellent performance of the surface plasmon coupled emission (SPCE), which opens up possibilities for the accurate detection of small-volume and low-concentration target analytes due to the improved sensitivity and signal-to-noise ratio (SNR).

Paper-based analytical devices (PADs) have emerged as a promising approach to point-of-care (POC) detection applications in biomedical and clinical diagnosis owing to their advantages, including cost-effectiveness, ease of use, and rapid responses as well as for being equipment-free, disposable, and user-friendly. However, the overall sensitivity of PADs still remains weak, posing a challenge for biosensing scientists exploiting them in clinical applications. This review comprehensively summarizes the current applicable potential of PADs, focusing on total signal-amplification strategies that have been applied widely in PADs involving colorimetry, luminescence, surface-enhanced Raman scattering, photoacoustic, photothermal, and photoelectrochemical methods as well as nucleic acid-mediated PAD modifications. The advances in signal-amplification strategies in terms of signal-enhancing principles, sensitivity, and time reactions are discussed in detail to provide an overview of these approaches to using PADs in biosensing applications. Furthermore, a comparison of these methods summarizes the potential for scientists to develop superior PADs. This review serves as a useful inside look at the current progress and prospective directions in using PADs for clinical diagnostics and provides a better source of reference for further investigations, as well as innovations, in the POC diagnostics field.

Metal-insulator-metal tunnel junctions (MIM-TJs) can electrically excite surface plasmon polaritons (SPPs) well below the diffraction limit. When inelastically tunneling electrons traverse the tunnel barrier under applied external voltage, a highly confined cavity mode (MIM-SPP) is excited, which further out-couples from the MIM-TJ to photons and single-interface SPPs via multiple pathways. In this work we control the out-coupling pathways of the MIM-SPP mode by engineering the geometry of the MIM-TJ. We fabricated MIM-TJs with tunneling directions oriented vertical or lateral with respect to the directly integrated plasmonic strip waveguides. With control over the tunneling direction, preferential out-coupling of the MIM-SPP mode to SPPs or photons is achieved. Based on the wavevector distribution of the single-interface SPPs or photons in the far-field emission intensity obtained from back focal plane (BFP) imaging, we estimate the out-coupling efficiency of the MIM-SPP mode to multiple out-coupling pathways. We show that in the vertical-MIM-TJs the MIM-SPP mode preferentially out-couples to single-interface SPPs along the strip waveguides while in the lateral-MIM-TJs photon out-coupling to the far-field is more efficient.

Recently, photothermal therapy (PTT) has emerged as one of the most promising biomedical strategies for different areas in the biomedical field owing to its superior advantages, such as being noninvasive, target-specific and having fewer side effects. Graphene-based hydrogels (GGels), which have excellent mechanical and optical properties, high light-to-heat conversion efficiency and good biocompatibility, have been intensively exploited as potential photothermal conversion materials. This comprehensive review summarizes the current development of graphene-integrated hydrogel composites and their application in photothermal biomedicine. The latest advances in the synthesis strategies, unique properties and potential applications of photothermal-responsive GGel nanocomposites in biomedical fields are introduced in detail. This review aims to provide a better understanding of the current progress in GGel material fabrication, photothermal properties and potential PTT-based biomedical applications, thereby aiding in more research efforts to facilitate the further advancement of photothermal biomedicine.

Introduction: Alzheimer's disease (AD), a heterogeneous pathological process representing the most common causes of dementia worldwide, has required early and accurate diagnostic tools. Neuropathological hallmarks of AD involve the aberrant accumulation of Amyloid beta (Aβ) into Amyloid plaques and hyperphosphorylated Tau into neurofibrillary tangles, occurring long before the onset of brain dysfunction. Areas covered: Considering the significance of Aβ and Tau in AD pathogenesis, these proteins have been adopted as core biomarkers of AD, and their quantification has provided precise diagnostic information to develop next-generation AD therapeutic approaches. However, conventional diagnostic methods may not suffice to achieve clinical criteria that are acceptable for proper diagnosis and treatment. The advantages of nanomaterial-based biosensors including facile miniaturization, mass fabrication, ultra-sensitivity, make them useful to be promising tools to measure Aβ and Tau simultaneously for accurate validation of low-abundance yet potentially informative biomarkers of AD.., Expert Opinion: The study has identified the potential application of advanced biosensors as standardized clinical diagnostic tools for AD, evolving the way for new and efficient AD control with minimum economic and social burden. After clinical trial, nanobiosensors for measuring Aβ and Tau simultaneously possess innovative diagnosis of AD to provide significant contributions to primary Alzheimer's care intervention.

Emerging nanomaterials providing benefits in sensitivity, specificity and cost-effectiveness are being widely investigated for biosensors in the application of Alzheimer's disease (AD) diagnosis. Core biomarkers amyloid-beta (Aβ) and Tau have been considered as key neuropathological hallmarks of AD. However, they did not sufficiently reflect clinical severity and therapeutic response, proving the difficulty of the Aβ- and Tau-targeting therapies in clinical trials. In recent years, there has still been a shortage of sensors for non-Aβ-Tau pathophysiological biomarkers that serve as advanced reporters for the early diagnosis of AD, predict AD progression, and monitor the treatment response. Nanomaterial-based sensors measuring multiple non-Aβ-Tau biomarkers could improve the capacity of AD progression characterization and supervised treatment, facilitating the comprehensive management of AD. This is the first review to principally represent current nanobiosensors for non-Aβ-Tau biomarker and that strategically deliberates future perspectives on the merit of non-Aβ-Tau biomarkers, in combination with Aβ and Tau, for the accurate diagnosis and prognosis of AD.

An active metabolite of vitamin A, all-trans retinoic acid (ATRA), is known to exert immunomodulatory functions. This study investigates the possible immune potentiating effect of ATRA on NF-κB activity in human monocytic THP-1 cells after exposure to unmethylated CpG DNA ODN2006. We observed that challenge with ODN2006 significantly enhanced the NF-κB activity of PMA-differentiated THP-1 cells. ATRA synergistically enhanced NF-κB activity of cells, in a concentration- and time-dependent manner. The enhanced NF-κB activity of PMA-differentiated THP-1 cells after ODN2006 challenge was dependent on the RAR/RXR pathway. To determine the mechanism involved in increasing in the NF-κB activity of stimulated THP-1 cells, we examined the effects of PMA and ATRA on the expression of TLR9 (a receptor of ODN2006) in THP-1 cells. PMA treatment significantly enhanced both the intracellular and cell surface expression of TLR9, while ATRA alone showed no effect. However, ATRA synergistically enhanced the cell surface TLR9 expression of PMA-differentiated cells. To determine whether the ATRA-enhanced NF-κB activity is due to the enhanced cell surface TLR9 expression, we examined NF-κB activity after treatment with anti-TLR9 blocking antibody. Results revealed that the anti-TLR9 antibody treatment almost completely reverses the ATRA-enhanced NF-κB activity, suggesting that ATRA enhances NF-κB activity through upregulation of the cell surface TLR9 expression in PMA-differentiated and unmethylated CpG challenged THP-1 cells.

A highly efficient nanocavity formed by optically coupled nanostructures is achieved by optimization of the collective Mie resonances in a one-dimensional array of semiconductor nanoparticles. Analysis of quasi-normal multipole modes enables us to reveal the close relation between the collective Mie resonances and Van Hove singularities. On the basis of these concepts, we experimentally demonstrate a directional GaAs nanolaser at cryogenic temperatures with well-defined, in-plane emission, which, moreover, can be controlled by selective excitation. The lasing threshold is shown to be significantly reduced by optimizing the interparticle gap such that the optimal near-field confinement is achieved at a resonant wavelength corresponding to the highest gain of GaAs. We show that the lasing performance of this nanolaser is orders of magnitude better than a nanowire-based laser of the same dimensions. The present work provides design guidelines for high performance in-plane emission nanolasers, which may find applications in future photonic integrated circuits.

We study the post-translational escape of nascent proteins at the ribosomal exit tunnel with the consideration of a real shape atomistic tunnel based on the Protein Data Bank structure of the large ribosome subunit of archeon Haloarcula marismortui. Molecular dynamics simulations employing the Go-like model for the proteins show that at intermediate and high temperatures, including a presumable physiological temperature, the protein escape process at the atomistic tunnel is quantitatively similar to that at a cylinder tunnel of length L = 72 Å and diameter d = 16 Å. At low temperatures, the atomistic tunnel, however, yields an increased probability of protein trapping inside the tunnel, while the cylinder tunnel does not cause the trapping. All-β proteins tend to escape faster than all-α proteins, but this difference is blurred on increasing the protein's chain length. A 29-residue zinc-finger domain is shown to be severely trapped inside the tunnel. Most of the single-domain proteins considered, however, can escape efficiently at the physiological temperature with the escape time distribution following the diffusion model proposed in our previous works. An extrapolation of the simulation data to a realistic value of the friction coefficient for amino acids indicates that the escape times of globular proteins are at the sub-millisecond scale. It is argued that this time scale is short enough for the smooth functioning of the ribosome by not allowing nascent proteins to jam the ribosome tunnel.

Surface plasmon polaritons (SPPs) are viable candidates for integration into on-chip nano-circuitry that allow access to high data bandwidths and low energy consumption. Metal-insulator-metal tunneling junctions (MIM-TJs) have recently been shown to excite and detect SPPs electrically; however, experimentally measured efficiencies and outcoupling mechanisms are not fully understood. It is shown that the MIM-TJ cavity SPP mode (MIM-SPP) can outcouple via three pathways to i) photons via scattering of MIM-SPP at the MIM-TJ interfaces, ii) SPPs at the metal-dielectric interfaces (bound-SPPs) by mode coupling through the electrodes, and iii) photons and bound-SPP modes by mode coupling at the MIM-TJ edges. It is also shown that, for Al-AlO x -Cr-Au MIM-TJs on glass, the MIM-SPP mode outcouples efficiently to bound-SPPs through either electrode (pathway 2); this outcoupling pathway can be selectively turned on and off by changing the respective electrode thickness. Outcoupling at the MIM-TJ edges (pathway 3) is efficient and sensitive to the edge topography, whereas most light emission originates from roughness-induced scattering of the MIM-SPP mode (pathway 1). Using an arbitrary roughness profile, it is demonstrated that various roughness facets can raise MIM-SPP outcoupling efficiencies to 0.62%. These results pave the way for understanding the topographical parameters needed to develop CMOS-compatible plasmonic circuitry elements., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

All-trans retinoic acid (ATRA), an active form of vitamin A, exerts immunomodulatory functions. In this study, we examined the immune potentiating effect of ATRA on bacterial flagellin-induced NF- κ B activation and proinflammatory cytokine production in human monocytic cell line THP-1. ATRA treatment significantly enhanced the flagellin-induced NF- κ B/AP-1 activity in THP-1 via the RAR/RXR pathway. Similarly, ATRA enhanced the expression and production of TNF- α and IL-1 β in THP-1 cells upon flagellin challenge. The cell surface expression of toll-like receptor 5 (TLR5), which is the receptor for bacterial flagellin, was significantly reduced by ATRA in a concentration- and time-dependent manner. To determine the mechanisms underlying the ATRA-enhanced immune response against bacterial flagellin despite the reduced cell surface expression of TLR5 in ATRA-treated THP-1, we examined the cell surface expression of CD14, which has been proposed to be a TLR co-receptor that enhances the response to microbial components. The cell surface expression of CD14 was significantly enhanced by ATRA treatment, especially in the presence of flagellin. Anti-CD14 antibody treatment prior to ATRA and flagellin treatments completely abolished ATRA-enhanced TNF- α and IL-1 β production. Our results suggest that ATRA enhances flagellin-stimulated proinflammatory responses in human monocyte THP-1 cells by upregulating CD14 in a RAR/RXR-dependent manner., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Thi Xoan Hoang et al.)

We discuss the relation between the emergence of new phases with broken symmetry within the framework of simple models of biopolymers. We start with a classic model for a chain molecule of spherical beads tethered together, with the steric constraint that non-consecutive beads cannot overlap, and with a pairwise attractive square well potential accounting for the hydrophobic effect and promoting compaction. We then discuss the consequences of the successive breaking of spurious symmetries. First, we allow the partial interpenetration of consecutive beads. In addition to the standard high temperature coil phase and the low temperature collapsed phase, this results in a new class of marginally compact ground states comprising conformations reminiscent of α-helices and β-sheets, the building blocks of the native states of globular proteins. We then discuss the effect of a further symmetry breaking of the cylindrical symmetry on attaching a side-sphere to the backbone beads along the negative normal of the chain, to mimic the presence of side chains in real proteins. This leads to the emergence of a novel phase within the previously obtained marginally compact phase, with the appearance of more complex secondary structure assemblies. The potential importance of this new phase in the de novo design of self-assembled peptides is highlighted.

We propose a simple approach to investigate the structural relaxation time and glass transition of amorphous drugs. Amorphous materials are modeled as a set of equal sized hard spheres. The structural relaxation time over many decades in hard-sphere fluids is theoretically calculated using the elastically collective nonlinear Langevin equation theory associated with Kramer's theory. Then, new thermal mapping from a real material to an effective hard-sphere fluid provides temperature-dependent relaxation time, which can be compared to experiments. Numerical results quantitatively agree with previous experiments for pharmaceutical binary mixtures having different weight ratios. We carry out experiments to test our calculations for an ezetimibe-simvastatin-Kollidon VA64 mixture. Our approach would provide a simple but comprehensive description of glassy dynamics in amorphous composites.

An extended model of the surface energetic attachment (SEA) model is introduced to study the fouling of marine organisms on microtopographic surfaces, taking into account the excluded volume interaction and the attraction between the organisms. It is shown that the excluded volume interaction leads to changes in the site-typed attachment probabilities which increase with the average spore density on the surface. As a result of these changes, the spore density map is flattened under very high density fouling. The attractive interaction on the other hand leads to aggregation of spores and the average aggregate size increased with the strength of attraction. The model can be mapped to a specific experiment to determine the attachment energy parameters. In contrast to various prior empirical approaches, the extended SEA model is rigorous from the statistical mechanics viewpoint, thus it provides a reliable tool for studying complex attachment behaviors of microorganisms on topographic surfaces.

A phase of matter is a familiar notion for inanimate physical matter. The nature of a phase of matter transcends the microscopic material properties. For example, materials in the liquid phase have certain common properties independent of the chemistry of the constituents: liquids take the shape of the container; they flow; and they can be poured-alcohol, oil, and water as well as a Lennard-Jones computer model exhibit similar behavior when poised in the liquid phase. Here, we identify a hitherto unstudied "phase" of matter, the elixir phase, in a simple model of a polymeric chain whose backbone has the correct local cylindrical symmetry induced by the tangent to the chain. The elixir phase appears on breaking the cylindrical symmetry by adding side spheres along the negative normal direction, as in proteins. This phase, nestled between other phases, has multiple ground states made up of building blocks of helices and almost planar sheets akin to protein native folds. We discuss the similarities of this "phase" of a finite size system to the liquid crystal and spin glass phases. Our findings are relevant for understanding proteins; the creation of novel bioinspired nanomachines; and also may have implications for life elsewhere in the cosmos., (© 2018 Wiley Periodicals, Inc.)

This study investigates the impact of women's employment in the manufacturing sector and in the services sector on the well-being of children aged 0 to 5 years in Vietnam. Our findings show that women's employment decreases the quantity of time that mothers spend with their children. At the same time, women's employment increases their income. The magnitude of the impact of women's employment in the services sector on child nutrition is greater than that of women's employment in manufacturing. This may be because of the higher income of mothers working in the service sector when compared to those working in manufacturing.

All-trans retinoic acid (ATRA) is an effective drug for the induction therapy of acute promyelocytic leukemia. However, the treatment is associated with adverse events such as retinoic acid syndrome (RAS) in some patients, whose histologic characteristics included organ infiltration by leukemic cells. Matrix metalloproteinase 2 (MMP-2) is often upregulated in tumor cells and plays a role in tumor cell migration and invasion by degrading the extracellular matrix. In this study, we examined the possible modulatory effects of ATRA on MMP-2 expression and secretion in human myeloid leukemia cell line THP-1. The cells were treated with various concentrations of ATRA, and MMP-2 expression and secretion were examined. MMP-2 expression and secretion started to increase with ATRA concentration as low as 0.1 nM and gradually increased thereafter. Agonists of retinoic acid receptor (RAR) or retinoid X receptor (RXR) alone could enhance MMP-2 secretion, and RAR or RXR antagonists alone could reverse ATRA-induced MMP-2 secretion. ATRA increased intracellular calcium ion levels, and a calcium-channel blocker inhibited ATRA-induced MMP-2 secretion. Dexamethasone suppressed ATRA-induced MMP-2 secretion. Our results suggest that ATRA enhances MMP-2 expression and secretion in human myeloid leukemia THP-1 cells in a calcium ion dependent manner through RAR/RXR signaling pathways, and this enhanced expression and secretion may be associated with the possible mechanisms of RAS.

How fast a post-translational nascent protein escapes from the ribosomal exit tunnel is relevant to its folding and protection against aggregation. Here, by using Langevin molecular dynamics, we show that non-local native interactions help decrease the escape time, and foldable proteins generally escape much faster than same-length, self-repulsive homopolymers at low temperatures. The escape process, however, is slowed down by the local interactions that stabilize the α-helices. The escape time is found to increase with both the tunnel length and the concentration of macromolecular crowders outside the tunnel. We show that a simple diffusion model described by the Smoluchowski equation with an effective linear potential can be used to map out the escape time distribution for various tunnel lengths and various crowder concentrations. The consistency between the simulation data and the diffusion model, however, is found only for the tunnel length smaller than a crossover length of 90 Å-110 Å, above which the escape time increases much faster with the tunnel length. It is suggested that the length of ribosomal exit tunnel has been selected by evolution to facilitate both the efficient folding and the efficient escape of single-domain proteins. We show that macromolecular crowders lead to an increase in the escape time, and attractive crowders are unfavorable for the folding of nascent polypeptide.

Tumors highly express active heat shock protein 90 (Hsp90), which is involved in tumor survival and progression. Enhanced Toll-like receptor (TLR) 5 expression and signaling were reported to be associated with acute myeloid leukemia. In the present study, we investigated the possible modulatory effects of Hsp90 inhibitors on TLR5 expression and signaling in the human myeloid leukemia cell line THP-1. Cells were pretreated with various concentrations of the Hsp90 inhibitor geldanamycin (GA) or the Hsp70 inhibitor VER155008, followed by stimulation with bacterial flagellin. Flagellin-induced nuclear factor- κ B (NF- κ B) activation was significantly reduced by treatment with GA or VER155008. To elucidate the underlying mechanism of this effect, mRNA and cell surface expression of TLR5 was examined. TLR5 mRNA expression was enhanced by both GA and VER155008, whereas cell surface expression of TLR5 was reduced by three different Hsp90 inhibitors, including GA, 17-(allylamino)-17-demethoxygeldanamycin, and radicicol, and an Hsp70 inhibitor. The inhibitory effect of Hsp90 inhibitors was much higher than that of Hsp70 inhibitor. Our results suggest that Hsp90 inhibitors suppress TLR5 surface expression and activation of NF- κ B in THP-1 cells in response to TLR5 ligand, and these inhibitory effects may be associated with the possible mechanisms by which Hsp90 inhibitors suppress myeloid leukemia.

Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study the aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientations for hydrophobic contacts. A significant heterogeneity is observed in the aggregate structures and in the thermodynamics of aggregation for systems of different HP sequences and different numbers of peptides. Fibril-like ordered aggregates are found for several sequences that contain the common HPH pattern, while other sequences may form helix bundles or disordered aggregates. A wide variation of the aggregation transition temperatures among sequences, even among those of the same hydrophobic fraction, indicates that not all sequences undergo aggregation at a presumable physiological temperature. The transition is found to be the most cooperative for sequences forming fibril-like structures. For a fibril-prone sequence, it is shown that fibril formation follows the nucleation and growth mechanism. Interestingly, a binary mixture of peptides of an aggregation-prone and a non-aggregation-prone sequence shows the association and conversion of the latter to the fibrillar structure. Our study highlights the role of a sequence in selecting fibril-like aggregates and also the impact of a structural template on fibril formation by peptides of unrelated sequences.

In the search for new antibacterial agents from natural sources, we revealed that a crude methanol extract of Sapium baccatum was highly active against Ralstonia solanacearum, a causal agent of a serious disease called bacterial wilt of tomato. The bioassay-guided fractionation of this extract resulted in the isolation of seven known active compounds, including gallic acid, methyl gallate, corilagin, tercatain, chebulagic acid, chebulinic acid, and quercetin 3-O-α-L-arabinopyranoside. Their chemical structures were determined by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. An in vitro antibacterial bioassay using a broth microdilution method revealed that, except for quercetin 3-O-α-L-arabinopyranoside (MIC = 250 μg/mL), the isolated compounds exhibited strong antibacterial activity against R. solanacearum (MIC = 26-52 μg/mL). Among the seven compounds, methyl gallate exhibited the strongest broad-spectrum activity against most of the plant pathogenic bacteria tested (MIC = 26-250 μg/mL). In the in vivo experiments, the crude extract of S. baccatum at 2000 and 1000 μg/mL reduced the development of tomato bacterial wilt by 83 and 63%, respectively, under greenhouse conditions after 14 days of infection. The results suggested that the extracts of S. baccatum or isolated tannins could be used as natural bactericides for the control of bacterial wilt of tomato.