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As the electronics industry is integrating more and more new molecules to utilize them in logic circuits and memories to achieve ultra-high efficiency and device density, many organic structures emerged as promising candidates either in conjunction with or as an alternative to conventional semiconducting materials such as but not limited to silicon. Owing to rotaxane's mechanically interlocked molecular structure consisting of a dumbbell-shaped molecule threaded through a macrocycle, they could be excellent nanomachines in molecular switches and memory applications. As a nanomachine, the macrocycle of rotaxane can move reversibly between two stations along its axis under external stimuli, resulting in two stable molecular configurations known as "ON" and "OFF" states of the controllable switch with distinct resistance. There are excellent reports on rotaxane's structure, properties, and function relationship and its application to molecular electronics (Ogino

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2–3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naive T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. Precis. The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

Funder: Lupus Foundation of America, Inc, Objective: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. Methods: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966���October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with

As VLSI technology is shifting from microelectronics to nanoelectronics era, bi-stable [2]rotaxane emerges as a promising candidate for molecular electronics. A typical voltage-driven [2]rotaxane consists of a cyclobis-(paraquat-p-phenylene) macrocycle encircling a dumbbell shape molecular chain and moving between two stations on the chain: tetrathiafulvalene (TTF) and 1,5-dioxynaphthalene (DNP). As a molecular switch, the macrocycle can move reversibly between two stations along its axis with appropriate driving voltage, resulting in two stable molecular conformational states with distinct high and low resistance. This makes it a well-suited candidate to represent binary states ("0" and "1") for digital electronics. In this work, we performed molecular simulation to investigate the switching mechanism of [2]rotaxane molecule. We used distance and angle variables to characterize the movement of the macrocycle along the chain, and compared the switching behavior of [2]rotaxane in water, ethanol, dimethyl ether and vacuum. The results show that the solvent environment plays an important role in the switching characteristics of [2]rotaxane molecule. The switching of [2]rotaxane is stable, controllable, reversible and repeatable. We also looked into potential failure mechanism of the [2]rotaxane, which could shed light on the fault model, testing and reliability enhancement of [2]rotaxane based molecular electronics. Our simulation results support that [2]rotaxane molecules possess potential to be used for molecular memory and logic applications.

MEMS devices are vulnerable to various defect sources, such as point stiction, broken-beams, etch variation. Point stiction is the defect in which the movable parts of the device is stuck to the substrate or fixed parts at one or multiple point locations. Point stictions may affect the yield as well as the reliability of MEMS devices. Fault simulation is an effective way to study how the point stiction defects will affect the device yield and reliability. For point stiction defects, the occurrence and the location are random and cannot be precisely predicted. Such stochastic behavior can be better predicted with the Monte Carlo simulation. Monte Carlo simulation is a stochastic technique used to approximate the probability of specific outcomes by running multiple trial simulations using random numbers and probability statistics. In this paper, the ANSYS Monte Carlo simulation is used to simulate point-stiction defects in surface-micromachined MEMS comb resonator devices. The yield of MEMS devices is estimated based on the simulation results. The fault simulation in MEMS devices is essential to optimize the device performance and to improve the yield and reliability of MEMS devices

This article reports a recent development of fabricating the flow channel of bipolar plates for direct methanol fuel cells (DMFC). Aluminum oxide film prepared by atomic layer deposition was used as a masking layer for the silicon etch in the deep reactive ion etching. The device design and fabrication of the bipolar plates are discussed. An aspect ratio of 20 was achieved for a 200-micron deep trench.

The graphene quantum dot (GQD) is a carbon allotrope with a planar surface amenable for functionalization and nanoscale dimensions that confer photoluminescent properties. Collectively, these properties render GQDs an advantageous platform for nanobiotechnology applications, including as optical biosensors and delivery platforms. In particular, noncovalent functionalization offers a route to reversible modification and preservation of the pristine GQD substrate. However, a clear paradigm for GQD noncovalent functionalization has yet to be realized. Herein, we demonstrate the feasibility of noncovalent polymer adsorption to the GQD surface, with a specific focus on single-stranded DNA (ssDNA). We study how GQD oxidation level affects the propensity for polymer adsorption by synthesizing and characterizing four types of GQD substrates and investigating noncovalent polymer association to these substrates. Distinct adsorption methods are developed for successful ssDNA attachment based upon the GQD’s initial level of oxidation. ssDNA adsorption to the GQD is confirmed by atomic force microscopy, by inducing ssDNA desorption, and with molecular dynamics simulations. ssDNA is determined to adsorb strongly to no-oxidation GQDs, weakly to low-oxidation GQDs, and not at all for heavily oxidized GQDs. We hypothesize that high GQD oxygen content disrupts the graphitic carbon domains responsible for stacking with the aromatic ssDNA bases, thus preventing the formation of stable polymer-GQD complexes. Finally, we develop a more generic adsorption platform and assess how the GQD system is tunable by modifying both the polymer sequence and type.

Metastasis contributes to over 90 percent of cancer mortalities and may be influenced by the extracellular matrix (ECM). ECM microenvironments differ in matrix organization, cell-matrix adhesions, and fiber rigidity, which may affect cancer migration and, thus, should be investigated. To understand the interactions between cancer cells and the ECM, we simulate local invasion through ECM organizations of varying determinants. Randomly curved organizations of normal ovarian stroma exhibit minimal local invasion. In contrast, wave-like and parallel linear structures in reorganized ECM organizations provide contact guidance, which increases cancer invasiveness. ECM organizations with strong cell-matrix attachments generate cell pseudopodia, which aid in increasing invasion rate, while weaker attachments prevent the cells from attaching to the fibers and forming pseudopodia, limiting local invasion. ECM organizations with rigid fibers elongate the cell body, allowing them to form cell protrusions and spread rapidly. Conversely, soft fibers stimulate cell rounding and limit migration. Optimizing cell-matrix adhesions and fiber rigidity results in below 10 percent local invasion and reinforces the importance of using computational modeling to discover novel approaches to restricting cancer movement.

Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8+ T-cell responses against Epstein–Barr virus (EBV) and Hepatitis B virus (HBV), and that T cells primed by CD137L-DCs more effectively lyse EBV+ and HBV+ target cells. The chemokine profile of CD137L-DCs identifies them as inflammatory DCs, and they polarize CD8+ T cells to a Tc1 phenotype. Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L-DCs possessing a stronger T cell activation ability. CD137L-DCs are effective in crosspresentation. PGE2 as a maturation factor is required for enhancing migration of CD137L-DCs but does not significantly reduce their potency. This study shows that CD137L-DCs have a superior ability to activate T cells and to induce potent Tc1 responses against the cancer-causing viruses EBV and HBV which suggest CD137L-DCs as promising candidates for DC-based tumor immunotherapy.

Background: Although remission is the goal of treatment in early rheumatoid arthritis (ERA), there is a lack of a sensitive biomarker for evaluating stringent clinical remission. Calprotectin is a potential biomarker for this purpose as it plays a critical role in synovial inflammation, cartilage destruction and bone resorption and its levels are reflective of local joint inflammation.1,2 Objectives: The study compares calprotectin with acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in discriminating stringent clinical remission from low disease activity (LDA) to moderate disease activity (MDA) in patients with ERA. Methods: A cross-sectional study was conducted on ERA patients from the Singapore Early Arthritis Cohort study. Serum calprotectin, ESR and CRP levels were measured. Receiver operating characteristics curves were used to compare the biomarkers in determining remission according to the Disease Activity Score in 28 Joints with ESR and CRP (DAS28ESR and DAS28CRP), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI). Results: Eighty ERA patients were included: 72.5% female, 61.3% Chinese, 66.3% seropositive, mean (S.D.) age 54.1 (12.2) and disease duration 2.3 (0.9) years. Calprotectin was significantly correlated with the DAS28ESR (rs=0.509, P-value Conclusion: Calprotectin is a sensitive biomarker for evaluating stringent clinical remission and can potentially be integrated into treat-to-target algorithms to guide management in ERA patients with apparently quiescent disease activity. References [1] Bae SC, Lee YH. Calprotectin levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis. Postgrad Med 2017;129(5):531-7. [2] Kopec-Medrek M, Widuchowska M, Kucharz EJ. Calprotectin in rheumatic diseases: a review. Reumatologia 2016;54(6):306-9. Acknowledgement: This work was supported by the National University Hospital University Medicine Cluster Junior Research Award (JRA/Nov17/U002). Disclosure of Interests: Yuhan Zou: None declared, Manjari Lahiri Grant/research support from: Grant support from Pfizer. I am the site PI for the Singapore National Biologics Register which is funded by multiple pharmaceutical companies; however I do not directly receive any funds for this., Consultant for: Advisory board for Elli Lilly, Lay Kheng Teoh: None declared, Bhushan Dharmadhikari: None declared, Nien Yee Kow: None declared, Anselm Mak: None declared, Peter Cheung: None declared

6535 Background: Epstein-Barr virus (EBV) is associated with non-keratinising (NK) NPC, a disease prevalent in Southeast Asia, and provides a potential target for dendritic cell (DC) vaccine therapy. CD137 ligand (CD137L) expressed on antigen presenting cells costimulates CD137 expressing T cells upon receptor/ligand interaction. CD137L signalling differentiates monocytes to CD137L-DC, a novel type of DC, which are more potent than classical DC in stimulating autologous T cells. Here, we explore the safety and efficacy of autologous CD137L-DC pulsed with EBV peptides spanning Epstein Barr nuclear antigen 1, latent membrane protein 1 (LMP1) and LMP2 (CD137L-DC-EBV-VAX) in patients with locally recurrent or metastatic NPC. Methods: In this single centre, phase I study, eligible patients (pts) with locally recurrent or metastatic NK-NPC and clinical benefit (CB) from their prior treatment (stable disease [SD], partial [PR] or complete response[CR]), underwent apheresis to isolate monocytes which were differentiated to CD137L-DC through CD137L agonist exposure. CD137L-DC were pulsed with EBV antigens during maturation to obtain CD137L-DC-EBV-VAX which was administered intradermally every 2 weeks (w) for up to 7 injections following site preconditioning with Tetanus and Diphtheria vaccine. Results: 14 pts were enrolled of which 2 progressed rapidly and did not begin treatment. Mean age was 58 years. Median lines of prior treatment for metastatic NPC was 1 (range 1-6), the most common being cisplatin and gemcitabine. 9 pts received 7 vaccine doses (range 2-7) with a mean administered cell count of 23.9x106. CB was seen in 5 cases (42%) with 1 PR and 4 SD beyond 1 year. Median progression free survival (mPFS) was 26w (95% CI, 23-43). The lowest PFS (8w) was in a pt with 6 prior lines of treatment including a checkpoint inhibitor. Mean pretreatment neutrophil: lymphocyte ratio (NLR) was 3.4 and a value of less than 3 was associated with prolonged mPFS (42 vs 14w, p = 0.01). Enzyme linked immune absorbent spot (ELISPOT) analysis in 5 pts with CB showed a rise in interferon-γ secreting peripheral T cells prior to the 3rd vaccine versus baseline. Treatment was well tolerated with only 4 cases of grade 1 related adverse events reported, most commonly injection site reaction (3pts). Conclusions: CD137L-DC-EBV-VAX is safe and exhibits promising efficacy when administered following CB from chemotherapy. A rise in activated peripheral blood mononuclear cells after 2 vaccinations in selected patients showing benefit suggests immunological correlates with efficacy. Clinical trial information: NCT03282617 .

Graphene and its derivatives having at least one dimension in nanoscale range have attracted tremendous attention in recent years due to their unique electronic, optical, chemical, and mechanical properties. This chapter is about graphene quantum dots (GQDs) that are zero-dimensional graphene derivatives with one to few layers of graphene sheet having size range less than 20nm. This chapter is an overview of synthesis of GQDs by top-down and bottom-up approaches, as well as detailed methods of synthesis of GQDs by acidic oxidation of carbon fibers. Owing to their extremely small size, quantum confinement, edge effect, biocompatibility, low toxicity, photostability as well as water solubility they are excellent candidates for understanding biological systems and cellular processes at the molecular scale. These are also suitable nanomaterials to replace inorganic semiconducting nanoparticles (e.g., CdS, CdSe, ZnS, and Si) which are toxic to biological systems.

Graphene and its derivatives having at least one dimension in nanoscale range have attracted tremendous attention in recent years due to their unique electronic, optical, chemical, and mechanical properties. This chapter is about graphene quantum dots (GQDs) that are zero-dimensional graphene derivatives with one to few layers of graphene sheet having size range less than 20nm. This chapter is an overview of synthesis of GQDs by top-down and bottom-up approaches, as well as detailed methods of synthesis of GQDs by acidic oxidation of carbon fibers. Owing to their extremely small size, quantum confinement, edge effect, biocompatibility, low toxicity, photostability as well as water solubility they are excellent candidates for understanding biological systems and cellular processes at the molecular scale. These are also suitable nanomaterials to replace inorganic semiconducting nanoparticles (e.g., CdS, CdSe, ZnS, and Si) which are toxic to biological systems.

Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8

The importance of monocyte-derived dendritic cells (DCs) is evidenced by the fact that they are essential for the elimination of pathogens. Although in vitro DCs can be generated by treatment of monocytes with GM-CSF and IL-4, it is unknown what stimuli induce differentiation of DCs in vivo. CD137L-DCs are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. We demonstrate that the gene signature of in vitro generated CD137L-DCs is most similar to those of GM-CSF and IL-4-generated immature DCs and of macrophages. This is reminiscent of in vivo inflammatory DC which also have been reported to share gene signatures with monocyte-derived DCs and macrophages. Performing direct comparison of deposited human gene expression data with a CD137L-DC dataset revealed a significant enrichment of CD137L-DC signature genes in inflammatory in vivo DCs. In addition, surface marker expression and cytokine secretion by CD137L-DCs resemble closely those of inflammatory DCs. Further, CD137L-DCs express high levels of adhesion molecules, display strong attachment and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study characterizes the gene expression profile of CD137L-DCs and identifies significant similarities of CD137L-DCs with in vivo inflammatory monocyte-derived DCs and macrophages.

We read with great interest the publication by Kang and colleagues ([1][1]). The authors describe that agonistic anti-CD137 (TNFRSF9, 4-1BB) antibodies enhance antitumor T-cell responses in murine xenograft models that is consistent with the findings of many other groups and that corresponds to the

CD137 is expressed on activated T cells and NK cells, among others, and is a potent co-stimulator of antitumor immune responses. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), and CD137L reverse signaling into APC enhances their activity. CD137–CD137L interactions as main driver of type 1, cell-mediated immune responses explains the puzzling observation that CD137 agonists which enhance antitumor immune responses also ameliorate autoimmune diseases. Upon co-stimulation by CD137, Th1 CD4+ T cells together with Tc1 CD8+ T cells and NK cells inhibit other T cell subsets, thereby promoting antitumor responses and mitigating non-type 1 auto-immune diseases.