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The present work reports the evaluation of a sliding mode observer (SMO) for a passive interferometric fiber-optic gyroscope (IFOG). To achieve that, the experimental setup was designed and evaluated to provide two out-of-phase signals as required by the SMO system employed. This led to the operation of the IFOG-SMO implemented in a passive mode with a 3 × 3 optical fiber directional coupler, which dismissed the use of optical phase modulators, such as piezoelectric or electro-optic devices. Simulations were performed and provided a qualitative analysis of the dependence of the system gain as a function of the sigmoid factor and sample rate, which resulted in a method for tuning the gain value according to the expected input signal. The experimental results show proper working of the IFOG-SMO and the capability for measuring large and small amplitude angular velocities and the expansion of the full scale. This is, to the best of our knowledge, the first time a sliding mode control technique has been employed and evaluated for an interferometric fiber-optic gyroscope.

Histone deacetylase 6 (HDAC6), a member of the HDAC family whose major substrate is α-tubulin, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. Overexpression of HDAC6 correlates with tumorigenesis and improved survival; therefore, HDAC6 may be used as a marker for prognosis. Previous work demonstrated that in multiple myeloma cells, inhibition of HDAC6 results in apoptosis. Furthermore, HDAC6 is required for the activation of heat-shock factor 1 (HSF1), an activator of heat-shock protein encoding genes (HSPs) and CYLD, a cylindromatosis tumor suppressor gene. HDAC6 contributes to cancer metastasis since its upregulation increases cell motility in breast cancer MCF-7 cells and its interaction with cortactin regulates motility. HDAC6 also affects transcription and translation by regulating the heat-shock protein 90 (Hsp90) and stress granules (SGs), respectively. This review will discuss the role of HDAC6 in the pathogenesis and treatment of cancer.

Dissolved organic nitrogen (DON) supports a significant amount of heterotrophic production in the ocean. Yet, to date, the identity and diversity of microbial groups that transform DON are not well understood. To better understand the organisms responsible for transforming high molecular weight (HMW)-DON in the upper ocean, isotopically labeled protein extract from Micromonas pusilla , a eukaryotic member of the resident phytoplankton community, was added as substrate to euphotic zone water from the central California Current system. Carbon and nitrogen remineralization rates from the added proteins ranged from 0.002 to 0.35 μmol C l −1 per day and 0.03 to 0.27 nmol N l −1 per day. DNA stable-isotope probing (DNA-SIP) coupled with high-throughput sequencing of 16S rRNA genes linked the activity of 77 uncultivated free-living and particle-associated bacterial and archaeal taxa to the utilization of Micromonas protein extract. The high-throughput DNA-SIP method was sensitive in detecting isotopic assimilation by individual operational taxonomic units (OTUs), as substrate assimilation was observed after only 24 h. Many uncultivated free-living microbial taxa are newly implicated in the cycling of dissolved proteins affiliated with the Verrucomicrobia, Planctomycetes, Actinobacteria and Marine Group II (MGII) Euryarchaeota. In addition, a particle-associated community actively cycling DON was discovered, dominated by uncultivated organisms affiliated with MGII, Flavobacteria, Planctomycetes, Verrucomicrobia and Bdellovibrionaceae. The number of taxa assimilating protein correlated with genomic representation of TonB-dependent receptor (TBDR)-encoding genes, suggesting a possible role of TBDR in utilization of dissolved proteins by marine microbes. Our results significantly expand the known microbial diversity mediating the cycling of dissolved proteins in the ocean.

Over evolutionary time, Wolbachia has been repeatedly transferred between host species contributing to the widespread distribution of the symbiont in arthropods. For novel infections to be maintained, Wolbachia must infect the female germ line after being acquired by horizontal transfer. Although mechanistic examples of horizontal transfer exist, there is a poor understanding of factors that lead to successful vertical maintenance of the acquired infection. Using Anopheles mosquitoes (which are naturally uninfected by Wolbachia) we demonstrate that the native mosquito microbiota is a major barrier to vertical transmission of a horizontally acquired Wolbachia infection. After injection into adult Anopheles gambiae , some strains of Wolbachia invade the germ line, but are poorly transmitted to the next generation. In Anopheles stephensi , Wolbachia infection elicited massive blood meal-induced mortality, preventing development of progeny. Manipulation of the mosquito microbiota by antibiotic treatment resulted in perfect maternal transmission at significantly elevated titers of the w AlbB Wolbachia strain in A . gambiae , and alleviated blood meal-induced mortality in A. stephensi enabling production of Wolbachia -infected offspring. Microbiome analysis using high-throughput sequencing identified that the bacterium Asaia was significantly reduced by antibiotic treatment in both mosquito species. Supplementation of an antibiotic-resistant mutant of Asaia to antibiotic-treated mosquitoes completely inhibited Wolbachia transmission and partly contributed to blood meal-induced mortality. These data suggest that the components of the native mosquito microbiota can impede Wolbachia transmission in Anopheles . Incompatibility between the microbiota and Wolbachia may in part explain why some hosts are uninfected by this endosymbiont in nature.

BackgroundAnti-MDA5 antibody positive dermatomyositis (MDA5-DM) is characterized by high mortality due to rapid progressive ILD. MDA5 is a cytosolic protein and a family of RIG-I like receptor, which functions as a virus RNA sensor and induces the production of such as type-1 IFN. Although little is known about the pathogenesis of MDA5-DM, it is notable that the similarities were reported between COVID-19 infection and MDA5-DM. It may suggest that there is a common underlying autoinflammatory mechanism. We reported that in MDA5-DM, (1) RIG-I-like receptor signaling is enhanced and (2) antiviral responses such as type 1 IFN signaling are also enhanced as compare with anti-ARS-antibody positive DM, and (3) the key for survival is suppression of RIG-I-like and IFN signaling (EULAR2022, POS0390). We also found that a significant role for uncontrolled macrophage in the pathogenesis of ILD by our autopsy case. Recently, it has been reported that tacrolimus (TAC) and cyclophosphamide (CY) combination therapy (TC-Tx) has improved the prognosis of cases with early onset of the disease, but there are cases that cannot be saved. Therefore, we devised BRT therapy (BRT-Tx). The Tx combines baricitinib (BAR), which inhibits GM-CSF and IFN-mediated signaling and effectively suppresses uncontrolled macrophages, with rituximab (RTX) and TAC, which rapidly inhibits B and T cell interaction and ultimately prevents anti-MDA5 antibody production.ObjectivesTo determine the differences in gene expression between BRT and TC-Tx for MDA5-DM in peripheral blood.MethodsTotal of 6 MDA5-DM (TC: 3, BRT: 3) were included and all of them had multiple poor prognostic factors. Peripheral whole blood was collected at just before and 2-3 months after the treatment. RNA was extracted, and quantified using a next-generation sequencer. Differentially Expressed Genes (DEGs) were identified by pre vs. post treatment. Gene Ontology (GO), clustering and Gene Set Variation Analysis (GSVA) were performed to DEGs. As one BRT case was added since our last year’s report, we also reanalyzed the surviving vs. fatal cases. The IFN signature was scored separately for Types 1, 2, and 3, and the changes between pre- and post-treatment were investigated.ResultsTwo of three cases with TC died during treatment, while all three cases on BRT recovered. The cluster analysis of the DEGs separated deaths from survivors, not by type of treatment. Comparing surviving and dead cases, GO analysis revealed that the immune system via immunoglobulins and B cells was significantly suppressed in surviving cases. GO analysis of DEGs in each therapeutic group showed that expression of B cell-related genes such as lymphocyte proliferation and B cell receptor signaling pathway were significantly suppressed in BRT-Tx. On the other hand, TC-Tx significantly suppressed such pathways as cell proliferation and cell surface receptor signaling, and was less specific for the target cells than BRT-Tx. The changes in IFN signature score after treatment showed an increase in type 2 and 3 IFN scores in all fatal cases and an increase in type 1 IFN score in one fatal case.ConclusionBRT-Tx significantly suppressed gene expression associated with B cells, while TC-Tx was characterized by low specificity of therapeutic targets and suppression of total cell proliferation. Comparison of surviving and dead cases revealed that the combination of RTX contributed to the success of treatment, as suppression of the immune system mediated by immunoglobulins and B cells is the key for survival. Analysis of the IFN signature revealed an increase in IFN score after treatment in fatal cases, indicating that the combination of BAR is beneficial. The superiority of BRT-Tx seems clear from the fact that all patients survived with BRT-Tx while only one/three patients survived with TC-Tx.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsMoe Sakamoto: None declared, Yu Nakai: None declared, Yoshiharu Sato: None declared, Yoshinobu Koyama Speakers bureau: Abbvie, Asahikasei, Ayumi, BMS, Esai, Eli-Lilly, Mitsubishi Tanabe, Grant/research support from: Abbvie, GSK.

BackgroundTo date, there are no head-to-head clinical trials directly comparing the effects between IL-6i and JAKi on bone destruction in RA. In recent years, a series of JAK inhibitors (JAKi) have been introduced, all of which have JAK1 inhibitory activity, and inhibition of IL-6 signaling plays an important role in their pharmacological actions. IL-6 inhibitors (IL-6i) have been also commonly used for rheumatoid arthritis (RA), and several anti-receptor antibodies are in clinical application. Recent studies have revealed the molecular basis of the immune cell-fibroblast-bone triad interactions in RA bone destruction[1-3].ObjectivesTo examine changes in peripheral blood gene expression after IL-6i or JAKi treatment, which inhibit common pathways, and to estimate their respective effects on the bone immune system.MethodsPeripheral blood gene expression changes in 38 RA patients (Tocilizumab (TCZ)=13, Tofacitinib (TOF)=15, Baricitinib (BAR)=10) were analyzed before and 3 months after the initiation of treatment using next generation sequencing. Changes in gene expression of molecules involved in bone immunity were analyzed before and after each treatment.ResultsComparison of L-6i and JAKi showed that JAKi treatment significantly suppressed RANKL expression in peripheral blood. At the same time, significant suppression of RANK, ETS1, and IL-34 gene expression was also observed with JAKi treatment. Comparison of TOF and BAR treatment showed significant suppression of IL-4 expression in TOF and significant suppression of MMP-2 and IL-12 expression in BAR.ConclusionJAKi suppressed RANKL expression significantly compared to IL-6i, suggesting that JAKi is more potent than IL-6i in suppressing bone destruction. Furthermore, assuming that the promoter regions of RANK in synovial osteoclasts and ETS1 in fibroblasts are similar to those in peripheral blood, the following prediction emerges. Namely, JAKi suppresses RANK and ETS1 expression more than IL-6i, suggesting that JAKi may be favorable for preventing bone destruction in terms of (1) suppressing osteoclast differentiation and (2) suppressing tissue-destructive fibroblast generation.References[1]N. Komatsu, H. Takayanagi, Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nature reviews. Rheumatology 18, 415-429 (2022).[2]M. Tsukasaki, H. Takayanagi, Osteoclast biology in the single-cell era. Inflamm Regen 42, 27 (2022).[3]M. Yan et al., ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Nature Immunol 23, 1330-1341 (2022).Acknowledgements:NIL.Disclosure of InterestsYoshinobu Koyama Speakers bureau: Abbvie, Asahikasei, Ayumi, BMS, Esai, Eli-Lilly, Mitsubishi Tanabe, Grant/research support from: Abbvie, GSK, Yoshiharu Sato: None declared, Moe Sakamoto: None declared, Yu Nakai: None declared.

Biomass-burning aerosols have a significant effect on global and regional aerosol climate forcings. To model the magnitude of these effects accurately requires knowledge of the size distribution of the emitted and evolving aerosol particles. Current biomass-burning inventories do not include size distributions, and global and regional models generally assume a fixed size distribution from all biomass-burning emissions. However, biomass-burning size distributions evolve in the plume due to coagulation and net organic aerosol (OA) evaporation or formation, and the plume processes occur on spacial scales smaller than global/regional-model grid boxes. The extent of this size-distribution evolution is dependent on a variety of factors relating to the emission source and atmospheric conditions. Therefore, accurately accounting for biomass-burning aerosol size in global models requires an effective aerosol size distribution that accounts for this sub-grid evolution and can be derived from available emission-inventory and meteorological parameters. In this paper, we perform a detailed investigation of the effects of coagulation on the aerosol size distribution in biomass-burning plumes. We compare the effect of coagulation to that of OA evaporation and formation. We develop coagulation-only parameterizations for effective biomass-burning size distributions using the SAM-TOMAS large-eddy simulation plume model. For the most-sophisticated parameterization, we use the Gaussian Emulation Machine for Sensitivity Analysis (GEM-SA) to build a parameterization of the aged size distribution based on the SAM-TOMAS output and seven inputs: emission median dry diameter, emission distribution modal width, mass emissions flux, fire area, mean boundary-layer wind speed, plume mixing depth, and time/distance since emission. This parameterization was tested against an independent set of SAM-TOMAS simulations and yields R2 values of 0.83 and 0.89 for Dpm and modal width, respectively. The size distribution is particularly sensitive to the mass emissions flux, fire area, wind speed, and time, and we provide simplified fits of the aged size distribution to just these input variables. The simplified fits were tested against 11 aged biomass-burning size distributions observed at the Mt. Bachelor Observatory in August 2015. The simple fits captured over half of the variability in observed Dpm and modal width even though the freshly emitted Dpm and modal widths were unknown. These fits may be used in global and regional aerosol models. Finally, we show that coagulation generally leads to greater changes in the particle size distribution than OA evaporation/formation does, using estimates of OA production/loss from the literature.

Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide ‘degron’ from hypoxia-inducible factor-1α, which binds to the Von –Hippel–Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-α (ERα; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERα in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERα-dependent breast cancer cells by inducing G 1 arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERα expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G 1 arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERα and AR, respectively.

The most significant vector of tick-borne pathogens in the United States is Ixodes scapularis Say (the blacklegged tick). Previous studies have identified significant genetic, behavioral and morphological differences between northern vs. southern populations of this tick. Because tick-borne pathogens are dependent on their vectors for transmission, a baseline understanding of the vector population structure is crucial to determining the risks and epidemiology of pathogen transmission. We investigated population genetic variation of I. scapularis populations in the eastern United States using a multilocus approach. We sequenced and analyzed the mitochondrial COI and 16S genes and three nuclear genes (serpin2, ixoderin B and lysozyme) from wild specimens. We identified a deep divergence (3-7%) in I. scapularis COI gene sequences from some southern specimens, suggesting we had sampled a different Ixodes species. Analysis of mitochondrial 16S rRNA sequences did not support this hypothesis and indicated that all specimens were I. scapularis. Phylogenetic analysis and analysis of molecular variance (AMOVA) supported significant differences between northern vs. southern populations. Demographic analysis suggested that northern populations had experienced a bottleneck/expansion event sometime in the past, possibly associated with Pleistocene glaciation events. Similar to other studies, our data support the division of northern vs. southern I. scapularis genetic lineages, likely due to differences in the demographic histories between these geographic regions. The deep divergence identified in some COI gene sequences highlights a potential hazard of relying solely on COI for species identification (\"barcoding\") and population genetics in this important vector arthropod.

Megawatt-scale gyrotrons operating in the relatively low frequency range of 14–35 GHz are required for electron Bernstein wave heating, electron cyclotron heating, and electron cyclotron current drive experiments in specific low-magnetic field fusion devices. In this study, a 14 GHz 1 MW gyrotron was developed based on a design concept that incorporates direct RF beam coupling through a built-in corrugated waveguide. This approach minimizes the RF transmission path and enhances the transmission efficiency. In the initial experimental test, an output power of 1.05 MW was achieved with a pulse width of 2 ms at 14.018 GHz. This represents the first instance of a 1.05 MW output in the 14 GHz gyrotron, demonstrating its potential use in fusion reactor and devices. The study also details the development of a novel 28 GHz 0.4 MW continuous wave gyrotron designed for the Q-shu University Experiments with Steady-state Spherical Tokamak. This gyrotron utilizes a double-disk sapphire window and a depressed collector. Experimental results at the output window demonstrated a maximum power of 1.24 MW with a pulse width of 2 ms as well as a maximum total efficiency with a collector potential depression of 53.1% with a output power of 0.52 MW and a pulse width of 8 ms. Additionally, a 28/35 GHz dual-frequency gyrotron was employed to evaluate the cooling performance of the double-disk sapphire window—an essential component for high-power gyrotrons at low frequencies. By comparing the experimental data, including an output power of 0.13 MW at a pulse width of 30 s at 28 GHz, with simulation results, the feasibility of achieving 0.4 MW CW operation at 28 GHz was confirmed.