High-dimensional Immune Profiles and Machine Learning May Predict Acute Myeloid Leukemia Relapse Early following Transplant.

Identification of early immune signatures associated with acute myeloid leukemia (AML) relapse following hematopoietic stem cell transplant (HSCT) is critical for patient outcomes. We analyzed PBMCs from 58 patients with AML undergoing HSCT, focusing on T cell subsets and functional profiles. High-dimensional flow cytometry coupled with Uniform Manifold Approximation and Projection dimensionality reduction and PhenoGraph clustering revealed distinct changes in CD4+ and CD8+ T cell populations in 16 patients who relapsed within 1 y of HSCT. We observed increased IL-2, IL-10, and IL-17-producing CD4+ T cells, alongside decreased CD8+ T cell function early in relapsing patients. Notably, relapsing patients exhibited increased TCF-1intermediate cells, which lacked granzyme B or IFN-γ production in the CD4+ T cell compartment. We then developed a supervised machine learning algorithm that predicted AML relapse with 90% accuracy within 30 d after HSCT using high-throughput assays. The algorithm leverages condensed immune phenotypic data, alongside the ADASYN algorithm, for data balancing and 100 rounds of XGBoost supervised learning. This approach holds potential for detecting relapse-associated immune signatures months before clinical manifestation. Our findings demonstrate a distinct immunological signature potentially capable of predicting AML relapse as early as 30 d after HSCT.

Extreme field confinement in zigzag plasmonic crystals.

We propose extreme field confinement in a zigzag plasmonic crystal that can produce a wide plasmonic bandgap near the visible frequency range. By applying a periodic zigzag structure to a metal-insulator-metal plasmonic waveguide, the lowest three plasmonic crystal bands are flattened, creating a high-quality broadband plasmonic mirror over a wavelength range of 526-909 nm. Utilizing zigzag plasmonic crystals in a three-dimensional tapered metal-insulator-metal plasmonic cavity, extreme field confinement with a modal volume of less than 0.00005 λ 3 can be achieved even at resonances over a wide frequency range. In addition, by selecting the number of zigzag periods in the plasmonic crystal, critical coupling between the cavity and the waveguide can be achieved, thereby maximizing the field intensity with an enhancement factor of 105 or more. We believe that zigzag plasmonic crystals will provide a powerful platform for implementing broadband on-chip plasmonic devices.

Structural Characterization of an ACP from Thermotoga maritima: Insights into Hyperthermal Adaptation.

Thermotoga maritima, a deep-branching hyperthermophilic bacterium, expresses an extraordinarily stable Thermotoga maritima acyl carrier protein (Tm-ACP) that functions as a carrier in the fatty acid synthesis system at near-boiling aqueous environments. Here, to understand the hyperthermal adaptation of Tm-ACP, we investigated the structure and dynamics of Tm-ACP by nuclear magnetic resonance (NMR) spectroscopy. The melting temperature of Tm-ACP (101.4 °C) far exceeds that of other ACPs, owing to extensive ionic interactions and tight hydrophobic packing. The D59 residue, which replaces Pro/Ser of other ACPs, mediates ionic clustering between helices III and IV. This creates a wide pocket entrance to facilitate the accommodation of long acyl chains required for hyperthermal adaptation of the T. maritima cell membrane. Tm-ACP is revealed to be the first ACP that harbor an amide proton hyperprotected against hydrogen/deuterium exchange for I15. The hydrophobic interactions mediated by I15 appear to be the key driving forces of the global folding process of Tm-ACP. Our findings provide insights into the structural basis of the hyperthermal adaptation of ACP, which might have allowed T. maritima to survive in hot ancient oceans.

Feasibility of Bronchial Washing Fluid-Based Approach to Early-Stage Lung Cancer Diagnosis.

A blood-based approach such as circulating tumor DNA remains challenging in diagnosis for early-stage disease. Bronchial washing (BW) is a minimally invasive procedure that yields fluids that may contain tumor DNA. Therefore, we prospectively enrolled 12 patients with early-stage non-small cell lung cancer without endoscopically visible tumors. Somatic mutations were analyzed using ultra-deep next-generation sequencing in 48 paired specimens (primary tumor tissue, normal tissue, BW supernatant, and BW precipitate). In primary tumors, 130 missense mutations/indels (5-16 per patient) and 20 driver mutations (0-3 per patient) were found. Concordance of driver mutations between BW fluids and primary tumors was 95.0%. The allele frequencies for missense mutations/indels in BW supernatants significantly correlated with those in primary tumors and were higher than those in BW precipitates. These findings suggest that BW supernatants are reflective of tumor-associated mutations and could be used for early-stage lung cancer diagnosis.

Nanolayer-embedded pseudo-photonic crystals.

In recent years, novel high-performance nanophotonic devices have been realized by applying ultrathin two-dimensional nanolayer materials to nanophotonics. In this paper, we propose nanolayer-embedded compact pseudo-photonic crystals (PPCs) that enable strong interaction between ultrathin nanolayers and photonic crystal modes. In typical two-dimensional slab photonic crystals, the transverse-magnetic (TM) photonic crystal bandgap is not well formed, making it difficult to operate the TM photonic crystal waveguide modes. However, by utilizing the low-frequency TM PPC bands, a long propagation TM waveguide mode, a slow TM waveguide mode, and a TM photonic bandgap are all readily available. In particular, the insertion of a nanometer-thick low-refractive-index layer in the vertical center of TM PPC waveguide can localize the electric fields tightly in nanometer space, causing strong field interaction with the inserted nanolayer material. Using the TM slow light near PPC band edges, field interaction with the nanolayer is significantly enhanced. We can also realize nanolayer-embedded high-quality-factor (Q-factor > 104) PPC cavities using the TM PPC bandgap. We believe that the proposed TM PPCs will play an important role in the strong interaction of ultrathin nanolayer materials with photonic crystal modes.

Ultrahigh Nonlinear Responses from MXene Plasmons in the Short-Wave Infrared Range.

Surface plasmons in 2D materials such as graphene exhibit exceptional field confinement. However, the low electron density of majority of 2D materials, which are semiconductors or semimetals, has limited their plasmons to mid-wave or long-wave infrared regime. This study demonstrates that a 2D Ti3C2Tx MXene with high electron density can not only support strong plasmon confinement with an acoustic plasmon mode in the short-wave infrared region, but also provide ultrahigh nonlinear responses. The acoustic MXene plasmons (AMPs) in the MXene (Ti3C2Tx)-insulator (SiO2)-metal (Au) nanostructure generate in the 1.5-6.0 µm wavelength range, exhibiting a two orders of magnitude reduction in wavelength compared to wavelength in free space. Furthermore, AMP resonators with patterned Au rods exhibit a record-high nonlinear absorption coefficient of 1.37 × 10-2 m W-1 at wavelength of 1.56 µm, ≈3 orders of magnitude greater than the highest value recorded for other 2D materials. These results indicate that MXenes can overcome fundamental plasmon wavelength limitations of previously studied 2D materials, providing groundbreaking opportunities in nonlinear optical applications, including all-optical processing and ultrafast optical switching.

Orally Administrated Inflamed Colon-Targeted Nanotherapeutics for Inflammatory Bowel Disease Treatment by Oxidative Stress Level Modulation in Colitis.

Inflammatory bowel disease (IBD) is characterized by an inappropriate and persistent inflammatory immune response and is often accompanied by excessive reactive oxygen species (ROS) production. For effective IBD treatment, there is a high demand for safe and targeted therapy that can be orally administered. In this study, we aimed to propose the use of inflamed colon-targeted antioxidant nanotherapeutics (ICANs) for in situ oxidative stress level modulation in colitis. ICANs consist of mesoporous silica nanoparticles (MSNs) with surface-attached ROS-scavenging ceria nanoparticles (CeNPs), which are further coated with poly(acrylic acid) (PAA) to facilitate preferential adherence to inflamed colon tissues through electrostatic interaction. We achieved a high ROS-scavenging property that remained effective even after artificial gastrointestinal fluid incubation by optimization of the molecular weight and PAA-coating pH. The orally administered ICANs demonstrated enhanced adherence to inflamed colon tissues in an acute inflammation mouse model of IBD induced by dextran sulfate sodium. This targeted delivery resulted in gut microenvironment modulation by regulating redox balance and reducing inflammatory cell infiltration, thereby suppressing the colitis-associated immune response. These findings highlight the potential of noninvasive ICANs as a promising candidate for treating inflammatory intestinal diseases by oxidative stress level modulation in colitis.

Bone-Adhesive Anisotropic Tough Hydrogel Mimicking Tendon Enthesis.

Tendon consists of soft collagen, yet it is mechanically strong and firmly adhered to the bone owing to its hierarchically anisotropic structure and unique tendon-to-bone integration (enthesis), respectively. Despite the recent advances in biomaterials, hydrogels simultaneously providing tendon-like high mechanical properties and strong adhesion to bone-mimicking enthesis is still challenging. Here, a strong, stiff, and adhesive triple-network (TN) anisotropic hydrogel that mimics a bone-adhering tendon is shown. The tough adhesive TN hydrogel is developed by combining imidazole-containing polyaspartamide (providing multiple hydrogen bonds to the bone surface) and energy-dissipative alginate-polyacrylamide double-network. To mimic the anisotropic structure and high mechanical properties of tendons, the bone-adhered TN hydrogel is linearly stretched and subsequently fixed via secondary cross-linking. The resulting hydrogel exhibits high tensile modulus and strength while maintaining a high bone adhesion without chemical modification of the bone surface. Furthermore, a bone-ligament-bone structure with strong bone adhesion reminiscent of the natural ligament is realized.

T cell exhaustion is associated with cognitive status and amyloid accumulation in Alzheimer's disease.

Studies over the last 100 years have suggested a link between inflammation, infectious disease, and Alzheimer's Disease (AD). Understanding how the immune system changes during the development of AD may facilitate new treatments. Here, we studied an aging cohort who had been assessed for AD pathology with amyloid positron emission tomography and cognitive testing, and conducted high dimensional flow cytometry on peripheral blood mononuclear and cerebrospinal fluid cells. Participants were assigned a classification of being amyloid negative cognitively normal, amyloid positive cognitively normal (APCN), or amyloid positive mild cognitive impairment (APMCI), an early stage of AD. We observed major alterations in the peripheral innate immune system including increased myeloid and plasmacytoid dendritic cells in the blood of APMCI participants. When the adaptive immune system was examined, amyloid positive participants, regardless of cognitive status, had increased CD3+ T cells. Further analyses of CD4+ and CD8+ T cells revealed that APMCI participants had an increase in more differentiated phenotype T cells, such as effector memory and effector memory CD45RA expressing (TEMRA), compared to those with normal cognition. When T cell function was measured, we observed that T cells from APCN participants had increased IFNγ+GzB- producing cells compared to the other participants. In contrast, we demonstrate that APMCI participants had a major increase in T cells that lacked cytokine production following restimulation and expressed increased levels of PD-1 and Tox, suggesting these are exhausted cells. Rejuvenation of these cells may provide a potential treatment for AD.

Anisotropic Hydrogels with a Multiscale Hierarchical Structure Exhibiting High Strength and Toughness for Mimicking Tendons.

Owing to their anisotropic and hierarchical structure, tendons exhibit an outstanding mechanical performance despite the low polymer concentration and softness of the constituent materials. Here, we propose a tendon-mimicking, strong, and tough hydrogel with a multiscale hierarchical and anisotropic structure. An isotropic, precursor double-network hydrogel is transformed into an anisotropic hydrogel by stretching, solvent exchange, and subsequent fixation via ionic crosslinking. Solvent exchange induces densification of the stretched polymer network, enhancement of linear alignment of polymer chains, and microphase separation, leading to anisotropic toughening of the hydrogel. The resulting anisotropic hydrogels show high strength and toughness, which vary over a wide range (1.2-3.3 MPa of strength and 4.9-8.8 MJ/m3 of toughness, respectively), controlled by the degree of pre-stretching. Furthermore, a hierarchical architecture is constructed by braiding the anisotropic hydrogel strands into a rope, resulting in an improved mechanical performance (4.7 MPa of strength in a four-strand hydrogel rope) compared to separated unbraided strands of a hydrogel (2.3 MPa of strength). The higher hierarchical hydrogel cable, prepared by braiding four hydrogel ropes, can withstand a heavy load even up to 13 kg. These results represent that a hierarchical assembly of anisotropic hydrogels exhibits high mechanical performance and a hierarchically anisotropic structure, which are reminiscent of tendons.

Light Engineering in Nanometer Space.

Significant advances have been made in photonic integrated circuit technology, similar to the development of electronic integrated circuits. However, the miniaturization of cavity resonators, which are the essential components of photonic circuits, still requires considerable improvement. Over the past decades, various optical cavities have been utilized to implement next-generation light sources in photonic circuits with low energy, high data traffic, and integrable physical sizes. Nevertheless, it has been difficult to reduce the size of most commercialized cavities beyond the diffraction limit while maintaining high performance. Herein, recent advancements in subwavelength metallic cavities that can improve performance, even with the use of lossy plasmonic modes, are reviewed. The discussion is divided in three parts according to light engineering methods: subwavelength metal-clad cavities engineered using intermediate dielectric cladding; implementation of plasmonic cavities and waveguides using plasmonic crystals; and development of deep-subwavelength plasmonic waveguides and cavities using geometric engineering. A direction for further developments in photonic integrated circuit technology is also discussed, along with its practical application.

A Simple and Accurate Liquid Chromatography-Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Busulfan in Plasma.

OBJECTIVE: Busulfan, frequently used as a conditioning regimen for hematopoietic stem cell transplantation, has a narrow therapeutic range and wide intra-and interpatient variabilities. Therefore, therapeutic drug monitoring of busulfan is necessary to ensure that the drug concentrations of patients are within a targeted therapeutic range. In this study, we developed a simple and accurate method for measuring busulfan concentrations using liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: Separation and detection of busulfan was performed using T3 column equipped with LC-MS/MS. Busulfan was isolated from 50 µL human plasma after mixing with busulfan-2H8 (internal standard) solution, calibrator, and quality-control material. The sample was eluted and gradated with a mobile phase composed of ammonium acetate, formic acid, and water or methanol. The busulfan concentration was quantified using a six-point standard curve. Busulfan and busulfan-2H8 were detected in positive-ion multiple-reaction-monitoring mode. According to the Clinical and Laboratory Standards Institute guideline, we verified the precision, linearity, limit of detection (LOD), limit of quantification (LOQ), and carryover. RESULTS: Busulfan and busulfan-2H8 were detected at m/z 264.1>151.1 and 272.2>159.1. The total run time was 3 min. Both intra-and inter-assay coefficients of variation were <3%. The calibration curve was linear at 25-5,000 ng/mL. The LOD and LOQ were 2.5 ng/mL and 25 ng/mL, respectively. The recoveries ranged from 92.0-104.8% and the carryover was-0.02%. CONCLUSIONS: Our method for busulfan reduces total run time and has excellent analytical performance. It will be a useful method for therapeutic drug monitoring of busulfan in clinical laboratories.

Analysis of natural recombination in porcine endogenous retrovirus envelope genes.

Human tropic Porcine Endogenous Retroviruses (PERVs) are the major concern in zoonosis for xenotransplantation because PERVs cannot be eliminated by specific pathogen-free breeding. Recently, a PERV A/C recombinant with PERV-C bearing PERV-A gp70 showed a higher infectivity (approximately 500-fold) to human cells than PERV-A. Additionally, the chance of recombination between PERVs and HERVs is frequently stated as another risk of xenografting. Overcoming zoonotic barriers in xenotransplantation is more complicated by recombination. To achieve successful xenotransplantation, studies on the recombination in PERVs are important. Here, we cloned and sequenced proviral PERV env sequences from pig gDNAs to analyze natural recombination. The envelope is the most important element in retroviruses as a pivotal determinant of host tropisms. As a result, a total of 164 PERV envelope genes were cloned from pigs (four conventional pigs and two miniature pigs). Distribution analysis and recombination analysis of PERVs were performed. Among them, five A/B recombinant clones were identified. Based on our analysis, we determined the minimum natural recombination frequency among PERVs to be 3%. Although a functional recombinant envelope clone was not found, our data evidently show that the recombination event among PERVs may occur naturally in pigs with a rather high possibility.

When Bitcoin encounters information in an online forum: Using text mining to analyse user opinions and predict value fluctuation.

Bitcoin is an online currency that is used worldwide to make online payments. It has consequently become an investment vehicle in itself and is traded in a way similar to other open currencies. The ability to predict the price fluctuation of Bitcoin would therefore facilitate future investment and payment decisions. In order to predict the price fluctuation of Bitcoin, we analyse the comments posted in the Bitcoin online forum. Unlike most research on Bitcoin-related online forums, which is limited to simple sentiment analysis and does not pay sufficient attention to note-worthy user comments, our approach involved extracting keywords from Bitcoin-related user comments posted on the online forum with the aim of analytically predicting the price and extent of transaction fluctuation of the currency. The effectiveness of the proposed method is validated based on Bitcoin online forum data ranging over a period of 2.8 years from December 2013 to September 2016.

Predicting Virtual World User Population Fluctuations with Deep Learning.

This paper proposes a system for predicting increases in virtual world user actions. The virtual world user population is a very important aspect of these worlds; however, methods for predicting fluctuations in these populations have not been well documented. Therefore, we attempt to predict changes in virtual world user populations with deep learning, using easily accessible online data, including formal datasets from Google Trends, Wikipedia, and online communities, as well as informal datasets collected from online forums. We use the proposed system to analyze the user population of EVE Online, one of the largest virtual worlds.

Development of a novel viral DNA vaccine against human papillomavirus: AcHERV-HP16L1.

In this study, we developed a novel DNA vaccine for HPV; a recombinant baculovirus bearing human endogenous retrovirus (HERV) envelope protein, which cannot replicate in mammals, was used as a nano-carrier for HPV-16L1 DNA vaccine (AcHERV-HP16L1). For in vivo test, mice were injected intramuscularly with 107 particles of the constructs, with two boosts at 2-week intervals. Compared with Gardasil (25 microL/dose), the AcHERV-HP16L1 immunized mice showed similar high levels of humoral immunity in IgG/IgA and in neutralization of HPV pseudovirions. Combined immunization (prime with AcHERV-HP16L1 and boost with Gardasil) induced slightly higher neutralizing activity. As compared to the group treated with Gardasil, the mice immunized with AcHERV-HP16L1 showed 450- and 490-fold increase in the IFN-gamma at 5 and 20 weeks after the first priming, respectively. The combined immunization conferred lower T cell immunity than AcHERV-HP16L1 treatment. The advantages of our novel AcHERV-HP16L1 vaccine over Gardasil include higher cellular immunogenicity, considerably lower production cost, and comparable safety. Therefore, we suggest that AcHERV-HP16L1 can be developed as an efficient prophylactic vaccine and therapeutic vaccine.