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Abstract Spin- and charge- stripe order has been extensively studied in the superconducting cuprates, among which underdoped La2−x Sr x CuO4 (LSCO) is an archetype with static spin stripes at low temperatures. An intriguing, but not completely understood, phenomenon in LSCO is that the stripes are tilted away from the high-symmetry Cu-Cu directions. Using high-resolution neutron scattering on LSCO with x = 0.12, we find two coexisting phases at low temperatures, one with static spin stripes and the other with fluctuating ones, both sharing the same tilt angle. Our numerical calculations using the doped Hubbard model elucidate the tilting’s origin, attributing it to anisotropic next-nearest neighbor hopping $${t}^{{\prime} }$$ t ′ , consistent with the material’s slight orthorhombicity. Our results underscore the model’s success in describing specific details of the ground state of this real material and highlight the role of $${t}^{{\prime} }$$ t ′ in the Hamiltonian, revealing the delicate interplay between stripes and superconductivity across theoretical and experimental contexts.

Porcine respiratory coronavirus (PRCV) is a member of the species Alphacoronavirus 1 within the genus Alphacoronavirus of the family Coronaviridae. A few studies have been conducted on the prevalence of PRCV since its first identification in 1997, but there have been no recent studies on the prevalence and genetic characterization of the virus in Korea. In this study, the seroprevalence of PRCV was determined in Korean pig farms using a commercially available TGEV/PRCV differential enzyme-linked immunosorbent assay kit. The farm-level seroprevalence of PRCV was determined to be 68.6% (48/70), similar to previous reports in Korea, suggesting that PRCV is still circulating in Korean pig herds nationwide. Among the 20 PRCV-seropositive farms tested in this study, PRCV RNAs were detected in 17 oral fluid samples (28.3%) from nine farms (45.0%), while TGEV RNAs were not detected in any sample. To investigate the genetic characteristics of Korean PRCV strains, genetic and phylogenetic analyses were conducted on PRCV spike gene sequences obtained in this study. The three Korean PRCV strains (KPRCV2401, KPRCV2402, and KPRCV2403) shared 98.5–100% homology with each other and 96.2–96.6% and 91.6–94.5% homology with European and American strains, respectively. A 224-amino acid deletion was found in the S gene of both Korean and European PRCVs but not in that of American PRCVs, suggesting a European origin for Korean PRCVs. Phylogenetic analysis showed that Korean PRCVs are more closely related to European PRCVs than American PRCVs but clustered apart from both, suggesting that Korean PRCV has evolved independently since its emergence in Korean PRCVs. The results of this study will help expand knowledge on the epidemiology and molecular biology of PRCV currently circulating in Korea.

Abstract To further elucidate the expression, regulation and function of Signaling Lymphocytic Activation Molecule Family (SLAMF) protein members in human monocytes and macrophages. Un-differentiated monocytic THP-1 cell (u-THP-1) and differentiated THP-1 macrophage (d-THP-1) were used as culture models in the study. Responses of cells to the differentiation agents phorbol ester (25 ng/ml) and TLR (Toll-like receptor) ligands were assessed. RT-PCR and Western blot analysis were used to determine mRNA and protein level. Pro-inflammatory cytokine mRNA expression levels and phagocytosis were used as functional markers. Data analyzed using t-test, one-way or two-way ANOVA followed by post hoc test. SLAMFs were differentially expressed in THP-1 cells. Differentiation of u-THP-1 to d-THP-1 led to significantly higher SLAMF7 mRNA and protein levels than other SLAMF. In addition, TLR stimuli increased SLAMF7 mRNA expression but not protein expression. Importantly, SLAMF7 agonist antibody and TLR ligands synergistically increased the mRNA expression levels of IL-1β, IL-6 and TNF-α, but had no effect on phagocytosis. SLAMF7 knocked-down in d-THP-1 significantly lowered TLR-induced mRNA expressions of pro-inflammatory markers. SLAM family proteins are differentially regulated by differentiation and TLRs. SLAMF7 enhanced TLR-mediated induction of pro-inflammatory cytokines in monocytes and macrophages but not phagocytosis.

Susan Young,1,2 Kelly Cocallis3 1Psychology Services Limited, London, UK; 2Department of Psychology, Reykjavik University, Reykjavik, Iceland; 3Health Psychology, Northumbria Healthcare NHS Foundation Trust, Northumberland, UKCorrespondence: Susan Young, Psychology Services Limited, London, UK, Email psychltd@aol.comAbstract: The scientific literature on psychosexual functioning shows a range of outcomes for individuals with neurodiversity. The aim of this article was to synthesize and critically evaluate evidence regarding psychosexual selfhood (orientation), behaviors and experiences in individuals with autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) to prioritize further research and identify interventions to reduce risk. A systematic review of the literature that compared sexual orientation, behavior and experiences of individuals with ASD or ADHD with those of neurotypical peers was performed in AMED, CINAHL, MEDLINE, PsycARTICLES and PsycINFO, Psychology and Behavioural Sciences Collection, Child Development and Adolescent Studies databases (supplemented by hand-searching of reference lists). Seventeen ASD and nineteen ADHD studies met inclusion criteria. Overall, the studies reviewed suggest poorer psychosexual functioning for individuals with ASD or ADHD compared to neurotypical peers, including a lack of satisfaction in their sexual relationships, sexual dysfunction, risky sexual behaviors, and victimization. This appears to be more marked for females. Individuals with ASD were more likely to identify with a non-heterosexual orientation compared with neurotypical peers. The study identifies gaps in our knowledge relating to risky sexual behaviors (in particular, those relating to sexual health and vulnerability to sexual victimization and perpetration). The public health implications of the findings are discussed. Future research is needed to clarify the mechanisms by which individuals with neurodevelopmental disorders may be at increased risk of adverse psychosexual outcomes and identify interventions that may mediate outcomes.Keywords: ADHD, ASD, neurodiversity, sexual behavior, outcomes

Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor receptors, and triggers cell differentiation/survival signaling pathways. To identify signaling molecules involved in the progression of liver diseases, we performed reverse-phase protein microarray (RPMA)-based screening of hepatocytes isolated from humanized mice after acute HCV infection. Acute viral infection in humanized liver mice significantly decreased the level of hepatocyte p-Gab1. Moreover, hepatoma cells upon HCV infection decreased Gab1 mRNA at later times of infection (D3 to D5) and p-Gab1 level was inversely related to the production of TGF-β. In contrast, the level of p-Gab1 was increased in CCL4-induced fibrotic liver. Hepatoma cells showed elevation of p-Gab1, along with an increase in STAT3 and ERK activation, upon treatment with HGF (ligand of HGF receptor/c-Met) and CCL4. In Gab1 knockdown hepatoma cells, cell proliferative signaling activity was reduced but the level of activated caspase-3 was increased. These findings suggest that hepatocyte Gab1 expression may play a role in promoting liver fibrosis progression by triggering ERK activation and inhibiting apoptosis. It implies that the Gab1-mediated signaling pathway would be a promising therapeutic target to treat chronic liver diseases.

Abstract Escherichia coli (E. coli) cells are present in fecal materials that can be the main source for disease‐causing agents in water. As a result, E. coli is recommended as a water quality indicator. We have developed an innovative platform to detect E. coli for monitoring water quality on-site by integrating paper-based sample preparation with nucleic acid isothermal amplification. The platform carries out bacterial lysis and DNA enrichment onto a paper pad through ball-based valves for fluid control, with no need of laboratory equipment, followed by loop-mediated isothermal amplification (LAMP) in a battery-operated coffee mug, and colorimetric detection. We have used the platform to detect E. coli in environmental water samples in about 1 h, with a limit of quantitation of 0.2 CFU/mL, and 3 copies per reaction. The platform was confirmed for detecting multiple E. coli strains, and for water samples of different salt concentrations. We validated the functions of the platform by analyzing recreational water samples collected near the Atlantic Ocean that contain different concentrations of salt and bacteria.

Immune mediated graft loss still represents a major risk to transplant recipients. Creative approaches to immunosuppression that exploit the recipient's own alloregulatory mechanisms could reduce the need for pharmacologic immunosuppression and potentially induce immune tolerance. In the process of studying recipient derived myeloid derived suppressor cells (MDSCs), we identified key alloregulatory MDSC mechanisms, mediated by isolatable proteins IL-4, IL-34, and IL-10. We sought to purify these proteins and fuse them for subsequent infusion into transplant recipients as a means of inducing an alloregulatory response. In this introductory investigation, we leveraged molecular engineering technology to create a fusion protein (FP) of three cytokine coding sequences of IL-4, IL-34, and IL-10 and demonstrated their expressions by Western Blot analysis. Following purification, we tested whether FP IL-4/IL-34/IL-10 (FP1) can protect heart transplant allografts. Injection of FP1 significantly prolonged allogeneic cardiac graft survival in a dose-dependent fashion and the increase of graft survival time exceeded survival attributable to IL-34 alone. In vitro, MDSCs cells were expanded by FP1 treatment. However, FP1 did not directly inhibit T cell proliferation in vitro. In conclusion, newly developed FP1 improves the graft survival in cardiac transplantation mouse model. Significant additional work to optimize FP1 or include other novel proteins could supplement current treatment options for transplant patients.

Increasingly complex and long-range donor organ allocation routes coupled with implementation of unmanned aerial vehicles (UAVs) have prompted investigations of the conditions affecting organs once packaged for shipment. Our group has previously demonstrated that different modes of organ transport exert unique environmental stressors, in particular vibration. Using a mouse heart transplant model, we demonstrated that vibrational forces exert tangible, cellular effects in the form of cardiomyocyte apoptosis and cytoskeletal derangement. Functionally, these changes translated into accelerated allograft loss. Notably, administration of an apoptosis inhibitor, Z-VAD-FMK, helped to ameliorate the detrimental cellular and functional effects of mechanical vibration in a dose-dependent manner. These findings constitute one of the first reports of the negative impact of transit environment on transplant outcomes, a contributing mechanism underpinning this effect, and a potential agent to prophylax against this process. Given current limitations in measuring donor organ transit environments in situ, further study is required to better characterize the impact of transport environment and to potentially improve the care of donor organs during shipment. Clinical and Translational Impact Statement: We show that apoptosis inhibitor, Z-VAD-FMK, ameliorated transport-related vibrational stress in murine heart transplants, which presents a potential therapeutic or preservation solution additive for future use in transporting donor organs.

Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.

Abstract Fretting in the partial-slip and gross-slip regimes under a constant normal load is considered. The tangential force—displacement relations for the forward and backward motions are described based the generalized Cattaneo—Mindlin theory of tangential contact and Masing’s hypothesis on modelling the force—displacement hysteretic loop. Besides the critical force and displacement parameters (characterizing the triggering of sliding), the model includes one dimensionless fitting parameter that tunes the tangential contact stiffness of the friction—contact interface. Explicit expressions are derived for the main tribological parameters of the fretting loop, including the slip index and the signal index. The presented phenomenological modelling approach has been applied to the analysis of two sets of experimental data taken from the literature. It has been shown that the experimentally observed simple relation of a rational type between the slip index and the slip ratio corresponds to the gross-slip asymptotics of the corresponding model-based predicted relation. The known quantitative criteria for the transition from the partial slip regime to the gross slip regime are expressed in terms of the stiffness parameter, and a novel geometric transition criterion is formulated.

Abstract Kagome lattice Heisenberg antiferromagnets are known to be highly sensitive to perturbations caused by the structural disorder. NMR is a local probe ideally suited for investigating such disorder-induced effects, but in practice, large distributions in the conventional one-dimensional NMR data make it difficult to distinguish the intrinsic behavior expected for pristine kagome quantum spin liquids from disorder-induced effects. Here we report the development of a two-dimensional NMR data acquisition scheme applied to Zn-barlowite (Zn0.95Cu0.05)Cu3(OD)6FBr kagome lattice, and successfully correlate the distribution of the low energy spin excitations with that of the local spin susceptibility. We present evidence for the gradual growth of domains with a local spin polarization induced by 5% Cu2+ defect spins occupying the interlayer non-magnetic Zn2+ sites. These spin-polarized domains account for ~60% of the sample volume at 2 K, where gapless excitations induced by interlayer defects dominate the low-energy sector of spin excitations within the kagome planes.

Halide perovskites display physical properties that are of both practical and fundamental interest. At high pressure, the low-temperature electrical transport in one such compound, CsPbI3, is now shown to be due to Cs-mediated electron-electron interactions resulting in Fermi-liquid-like behaviour.

Abstract Etrolizumab is an IgG1‐humanized monoclonal anti‐β7 integrin antibody. Phase III trials with induction and/or maintenance phases were conducted in patients with moderately‐to‐severely active ulcerative colitis (UC) who were either previously treated with tumor necrosis factor (TNF) inhibitors (HICKORY) or were TNF inhibitor naïve (HIBISCUS I/II, LAUREL, and GARDENIA). A total of eight exposure‐response analyses were conducted for two clinical outcomes (remission and endoscopic improvement) at the end of induction for studies HIBISCUS I/II (combined) and HICKORY and at the end of maintenance for studies HICKORY and LAUREL. Trough concentration at week 4 (Ctrough,wk4) of induction was selected as the exposure metric. Exposure‐response (ER) modeling was conducted using logistic regression. A full covariate model was used to examine the impact of covariates on clinical outcomes. Linear models with a single intercept for placebo and active treatments adequately described the data for all eight analyses. The etrolizumab exposure‐response slope was significant (p

Abstract Etrolizumab is an IgG1‐humanized monoclonal antibody that specifically targets the β7 subunit of α4β7 and α4Eβ7 integrins, and it has been evaluated for the treatment of moderately‐to‐severely active ulcerative colitis (UC). Population pharmacokinetic (PK) analysis was performed to characterize etrolizumab PK properties in patients with moderately‐to‐severely active UC and evaluate covariate impacts on exposure. The population PK model was developed based on etrolizumab serum concentrations from patients with moderately‐to‐severely active UC enrolled in six studies (one phase I, one phase II, and four phase III) and validated using another phase III clinical trial. Stepwise covariate modeling was used to evaluate the impact of 23 prespecified covariates. Etrolizumab PK was best described by a two‐compartment model with first‐order absorption, with clearance decreasing over time. Population typical values were 0.260 L/day for clearance (CL) during the first dosing internal, 2.61 L for central volume, 71.2% for bioavailability, and 0.193/day for absorption rate. CL reduced over the study duration, the typical maximum reduction was 26% with an onset half‐life of 4.8 weeks. Consequently, the predicted mean terminal half‐life was shorter after a single dose (13.0 days) compared to that at steady‐state (17.1 days). Baseline body weight and albumin were the most impactful covariates for etrolizumab exposure. Final population PK model well characterized the PK properties of etrolizumab in patients with moderately‐to‐severely active UC and identified influential covariate effects.

Kwadwo Osei Bonsu,1 Stephanie Young,1,2 Tiffany Lee,1,2 Hai Nguyen,1 Rufaro S Chitsike3,4 1School of Pharmacy, Memorial University of Newfoundland and Labrador, St John’s, NL, A1B 3V6, Canada; 2Pharmacy Program, Eastern Region Health Authority, St John’s, NL, A1B 3V6, Canada; 3Division of Medicine (Hematology), Memorial University of Newfoundland and Labrador, St John’s, NL, A1B 3V6, Canada; 4Division of Hematology, Eastern Region Health Authority, St John’s, NL, A1B 3V6, CanadaCorrespondence: Kwadwo Osei Bonsu, School of Pharmacy, Memorial University of Newfoundland and Labrador, 300 Prince Philip Drive, St John’s, NL, A1B 3V6, Canada, Email koseibonsu@mun.caBackground: Poor medication adherence puts patients who require antithrombotic therapy at greater risk of complications. We started a multidisciplinary Adult Outpatient Thrombosis Service in 2017 in a Canadian health authority and were interested in the level of medication adherence in the population attending.Aim(S): The aim of this study is to assess adherence to antithrombotic medications for patients attending a multidisciplinary Thrombosis Service.Methods: We conducted a cross-sectional survey of outpatients seen at the Thrombosis Service between 2017 and 2019 using the 12-item validated Adherence to Refills and Medications Scale (ARMS) to assess adherence to antithrombotic (anticoagulants and antiplatelet) therapy. Linear regression analysis examined the factors associated with adherence to antithrombotic therapy.Results: Of 1058 eligible patients, 53.2% responded to the survey. Seventeen were excluded from the analysis for missing more than 6 responses to the 12 items on the ARMS. About 55% (n = 297) were on direct oral anticoagulants (DOACs), 19% (n = 102) on warfarin, 5.0% (n = 27) on low molecular weight heparin, 3.3% (n = 18) on antiplatelet therapy and 18% (n = 96) were no longer on antithrombotic therapy. Nearly half (47%, n = 253) had taken antithrombotic therapy for 1– 5 years while 28% (n = 150) and 25% (n = 137) had taken antithrombotic treatments for < 1 and > 5 years, respectively. Most patients (87%, n = 475) were ≥ 50 years and half (51%, n = 277) were male. The mean adherence score was 13.9 (SD± 2.2) and 88% (n = 481) of participants were adherent to antithrombotic treatment (ARMS = 12– 16). Multivariable linear regression showed that patients with post-graduate education had 0.4% lower adherence to antithrombotic therapy as compared with elementary education (β = 0.0039, p = 0.048). Patients with prior antithrombotic agent use > 5 years had 0.5% lower adherence to antithrombotic treatment compared to patients with < 1 year (β = 0.0047, p = 0.0244).Conclusion: Self-reported adherence to antithrombotic therapy was high (88%) within a multidisciplinary Thrombosis Service. Patients with advanced education and prolong duration of antithrombotic therapy were more likely to have lower self-reported adherence to antithrombotic treatment.Keywords: medication adherence, self-reported adherence, multidisciplinary care, thrombosis service, anticoagulation management program, antithrombotic therapy

Non-alcoholic fatty liver disease (NAFLD) is an important public health problem with growing numbers of NAFLD patients worldwide. Pathological conditions are different in each stage of NAFLD due to various factors. Preclinical and clinical studies provide evidence for a crucial role of immune cells in NAFLD progression. Liver-resident macrophages, kupffer cells (KCs), and monocytes-derived macrophages are the key cell types involved in the progression of NAFLD, non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). Their unique polarization contributes to the progression of NAFLD. KCs are phagocytes with self-renewal abilities and play a role in regulating and maintaining homeostasis. Upon liver damage, KCs are activated and colonized at the site of the damaged tissue. The secretion of inflammatory cytokines and chemokines by KCs play a pivotal role in initiating NAFLD pathogenesis. This review briefly describes the role of immune cells in the immune system in NAFLD, and focuses on the pathological role and molecular pathways of KCs and recruited macrophages. In addition, the relationship between macrophages and insulin resistance is described. Finally, the latest therapeutics that target KCs and macrophages are summarized for the prevention and treatment of NAFLD.

Fibroblastic reticular cells (FRCs) play important roles in tolerance by producing laminin α4 (Lama4) and altering lymph node (LN) structure and function. The present study revealed the specific roles of extracellular matrix Lama4 in regulating LN conduits using FRC-specific KO mouse strains. FRC-derived Lama4 maintained conduit fiber integrity, as its depletion altered conduit morphology and structure and reduced homeostatic conduit flow. Lama4 regulated the lymphotoxin β receptor (LTβR) pathway, which is critical for conduit and LN integrity. Depleting LTβR in FRCs further reduced conduits and impaired reticular fibers. Lama4 was indispensable for FRC generation and survival, as FRCs lacking Lama4 displayed reduced proliferation but upregulated senescence and apoptosis. During acute immunization, FRC Lama4 deficiency increased antigen flow through conduits. Importantly, adoptive transfer of WT FRCs to FRC Lama4–deficient mice rescued conduit structure, ameliorated Treg and chemokine distribution, and restored transplant allograft acceptance, which were all impaired by FRC Lama4 depletion. Single-cell RNA sequencing analysis of LN stromal cells indicated that the laminin and collagen signaling pathways linked crosstalk among FRC subsets and endothelial cells. This study demonstrated that FRC Lama4 is responsible for maintaining conduits by FRCs and can be harnessed to potentiate FRC-based immunomodulation.

Novel swine orthopneumovirus (SOV) infections have been identified in pigs in the USA and some European countries but not in Asian countries, including South Korea, to date. The current study reports the first SOV infections in four domestic pig farms located in four provinces across South Korea. The detection rate of SOV in oral fluid samples using qRT-PCR was 4.4% (14/389), indicating the presence of the virus in pigs at commercial farms in Korea. Two complete genome sequences and one glycoprotein (G) gene sequence were obtained from SOV-positive samples. The complete genome analysis of KSOV-2201 and KSOV-2202 strains showed 98.2 and 95.4% homologies with a previously reported SOV, and the phylogenetic tree exhibited a high correlation with a previously reported SOV strain from the US and a canine pneumovirus (CPnV) strain from China. Based on the genetic analysis of the viral G gene, the murine pneumonia virus (MPV)-like orthopneumoviruses (MLOVs) were divided into two genogroups (G1 and G2). Seventeen CPnVs and two feline pneumoviruses were grouped into G1, while the Korean SOV strains identified in this study were grouped into G2 along with one SOV and two CPnVs. These results will contribute to expanding our understanding of the geographical distribution and genetic characteristics of the novel SOV in the global pig population.

Shamar Young,1 Ranjan Ragulojan,1 Ting Chen,1 Joshua Owen,1 Donna D’souza,1 Tina Sanghvi,2 Jafar Golzarian,1 Siobhan Flanagan1 1University of Minnesota, Department of Radiology, Division of Interventional Radiology, Minneapolis, MN, 55455, USA; 2Minneapolis VA Medical Center, Department of Radiology, Minneapolis, MN, 55455, USACorrespondence: Shamar Young, Tel +1 612-624-6189, Email youn1862@umn.eduObjective: To evaluate the dynamic changes of lymphocytes following transarterial radioembolization (TARE) for hepatocellular carcinoma (HCC) and their relationship to normal liver dose (NLD).Materials and Methods: A total of 93 patients who underwent 102 treatments were retrospectively reviewed. Absolute lymphocyte counts pretreatment and at 1, 3, 6, and 12 months were evaluated. Kaplan–Meier, Spearman correlation, receiver operating characteristic (ROC) curve, and area under the curve (AUC) analyses were performed.Results: The mean absolute lymphocyte count at baseline was 1.25 ± 0.79 103/μL which was significantly greater than 1 (0.71 ± 0.47 103/μL, p< 0.0001), 3 (0.79 ± 0.77 103/μL, p=0.0003), and 6 (0.81 ± 0.44 103/μL, p=0.0001) months, but not significantly different than 12 (0.92 ± 0.8 103/μL, p=0.12) months post treatment. There was a modest negative correlation between NLD and lymphocyte count at 1 month (rho= − 0.216, p=0.03), which strengthened at 3 months post treatment (rho= − 0.342, p=0.008). AUC of ROC analysis between absolute lymphocyte count ≤ 1 103/μL or > 1 103/μL at 1, 3, 6, and 12 months post treatment was 0.625, 0.676, 0.560, and 0.794, respectively. Univariate analysis of overall survival when separating patients by a lymphocyte count of ≤ 1 103/μL and > 1 103/μL demonstrated a significant difference at 1 (HR: 0.56, 95% CI: 0.33– 0.95, p=0.03), 3 (HR: 0.41, 95% CI: 0.18– 0.94, p=0.035) and 6 (HR: 0.36, 95% CI: 0.17– 0.77, p=0.008) months post treatment, but not pretreatment or at 12 months.Conclusion: NLD may correlate with lymphocyte depression at 1 and 3 months and lymphopenia may portend a worse overall survival in the post treatment setting.Keywords: hepatocellular carcinoma, transarterial radioembolization, lymphocytes

Shamar Young,1 Isa Cam,1 Mehmet Gencturk,1 Nathan Rubin,2 Donna D’souza,1 Siobhan Flanagan,1 Jafar Golzarian,1 Tina Sanghvi3 1University of Minnesota, Department of Radiology, Division of Interventional Radiology, Minneapolis, MN, 55455, USA; 2Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; 3Minneapolis VA Medical Center, Department of Radiology, Minneapolis, MN, USACorrespondence: Shamar YoungUniversity of Minnesota, Department of Radiology, Division of Interventional Radiology, 420 Delaware St SE, Minneapolis, MN, 55455, USATel +612-624-6189Email youn1862@umn.eduBackground: The purpose of this study is to determine and compare the ability of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), aspartate-aminotransferase-to-lymphocyte ratio (ALRI), systemic-inflammation index (SII) and lymphocyte count to predict oncologic outcomes in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE).Materials and Methods: A single-center retrospective review of 296 patients who were treated for 457 HCCs was performed. Pre- and post-treatment laboratory and treatment outcome variables were collected. Objective radiologic response (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Patients were categorized into above and below median scores and compared.Results: The median pretreatment NLR, PLR, ALRI, SII, and lymphocyte count were 2.7 (range: 0.4– 55), 88.3 (range: 0.1– 840), 71.8 (range: 0.1– 910), 238.1 (range: 0.1– 5150.8), and 1 (range: 0.1– 5.2) 103/μL, respectively. Patients with above median ALRI scores were less likely to achieve an ORR as compared to those with below median ALRI values (132 (132/163, 81%) vs 150 (150/163, 92%), p = 0.004). On univariate analysis, patients with above median pretreatment NLR (HR 1.41, 95% CI: 1.09– 1.83, p = 0.01) and below median lymphocyte count (HR 0.69, 95% CI: 0.53– 0.92, p = 0.01) had significantly worse PFS. The relationship between PFS and NLR (p = 0.08) as well as lymphocytes (p = 0.20) no longer remained on multivariate analysis. On univariate analysis, below median pretreatment NLR (HR 1.72, 95% CI: 1.2– 2.45, p = 0.003) and ALRI (HR 1.52, 95% CI: 1.05– 2.2); p = 0.03) as well as above median lymphocyte count (HR 0.48, 95% CI: 0.34– 0.7, p < 0.0001) were associated with improved OS. The significant relationship between lymphocytes and OS remained on multivariate analysis (HR 0.50, 95% CI: 0.28– 0.9, p = 0.02), but the relationship with NLR (p = 0.94) did not persist.Conclusion: NLR is predictive of PFS and OS in patients with HCC undergoing TACE and may be superior to other inflammatory scores (PLR, ALRI, and SII) in this setting. However, lymphocyte count may be most predictive of OS.Keywords: hepatocellular carcinoma, chemoembolization, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, aspartate-aminotransferase-to-lymphocyte ratio, systemic-inflammation index

Porcine deltacoronavirus (PDCoV) is an emerging coronavirus that causes diarrhea in nursing piglets. Since its first outbreak in the United States in 2014, this novel porcine coronavirus has been detected worldwide, including in Korea. However, no PDCoV case has been reported since the last report in 2016 in Korea. In June 2022, the Korean PDCoV strain KPDCoV-2201 was detected on a farm where sows and piglets had black tarry and watery diarrhea, respectively. We isolated the KPDCoV-2201 strain from the intestinal samples of piglets and sequenced the viral genome. Genetically, the full-length genome and spike gene of KPDCoV-2201 shared 96.9–99.2% and 95.8–98.8% nucleotide identity with other global PDCoV strains, respectively. Phylogenetic analysis suggested that KPDCoV-2201 belongs to G1b. Notably, the molecular evolutionary analysis indicated that KPDCoV-2201 evolved from a clade different from that of previously reported Korean PDCoV strains and is closely related to the emergent Peruvian and Taiwanese PDCoV strains. Furthermore, KPDCoV-2201 had one unique and two Taiwanese strain-like amino acid substitutions in the receptor-binding domain of the S1 region. Our findings suggest the possibility of transboundary transmission of the virus and expand our knowledge about the genetic diversity and evolution of PDCoV in Korea.

Myeloid-derived suppressor cells (MDSCs) are generated under biological stress such as cancer, inflammatory tissue damage, and viral infection. In recent years, with occurrence of global infectious diseases, new discovery on MDSCs functions has been significantly expanded during viral infection and COVID-19. For a successful viral infection, pathogens viruses develop immune evasion strategies to avoid immune recognition. Numerous viruses induce the differentiation and expansion of MDSCs in order to suppress host immune responses including natural killer cells, antigen presenting cells, and T-cells. Moreover, MDSCs play an important role in regulation of immunopathogenesis by balancing viral infection and tissue damage. In this review article, we describe the overview of immunomodulation and genetic regulation of MDSCs during viral infection in the animal model and human studies. In addition, we include up-to-date review of role of MDSCs in SARS-CoV-2 infection and COVID-19. Finally, we discuss potential therapeutics targeting MDSCs.

Abstract Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain‐of‐function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti‐tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.

Introduction: The Mayo Clinic Endoscopic Subscore is a commonly used grading system to assess the severity of ulcerative colitis. Correctly grading colonoscopies using the Mayo Clinic Endoscopic Subscore is a challenging task, with suboptimal rates of interrater and intrarater variability observed even among experienced and sufficiently trained experts. In recent years, several machine learning algorithms have been proposed in an effort to improve the standardization and reproducibility of Mayo Clinic Endoscopic Subscore grading. Methods: Here we propose an end-to-end fully automated system based on deep learning to predict a binary version of the Mayo Clinic Endoscopic Subscore directly from raw colonoscopy videos. Differently from previous studies, the proposed method mimics the assessment done in practice by a gastroenterologist, that is, traversing the whole colonoscopy video, identifying visually informative regions and computing an overall Mayo Clinic Endoscopic Subscore. The proposed deep learning–based system has been trained and deployed on raw colonoscopies using Mayo Clinic Endoscopic Subscore ground truth provided only at the colon section level, without manually selecting frames driving the severity scoring of ulcerative colitis. Results and Conclusion: Our evaluation on 1672 endoscopic videos obtained from a multisite data set obtained from the etrolizumab Phase II Eucalyptus and Phase III Hickory and Laurel clinical trials, show that our proposed methodology can grade endoscopic videos with a high degree of accuracy and robustness (Area Under the Receiver Operating Characteristic Curve = 0.84 for Mayo Clinic Endoscopic Subscore ⩾ 1, 0.85 for Mayo Clinic Endoscopic Subscore ⩾ 2 and 0.85 for Mayo Clinic Endoscopic Subscore ⩾ 3) and reduced amounts of manual annotation. Plain language summary Patient, caregiver and provider thoughts on educational materials about prescribing and medication safety Artificial intelligence can be used to automatically assess full endoscopic videos and estimate the severity of ulcerative colitis. In this work, we present an artificial intelligence algorithm for the automatic grading of ulcerative colitis in full endoscopic videos. Our artificial intelligence models were trained and evaluated on a large and diverse set of colonoscopy videos obtained from concluded clinical trials. We demonstrate not only that artificial intelligence is able to accurately grade full endoscopic videos, but also that using diverse data sets obtained from multiple sites is critical to train robust AI models that could potentially be deployed on real-world data.

Abstract Measures of the functional and structural properties of blood vessels can be used to assess preclinical stage of vascular disorders. Recent experimental and population studies show that arterial stiffening precedes development of high blood pressure, and can be used to predict future cardiovascular events. Arterial stiffness was also shown to be reversible in several experimental models of various conditions. Since reversing arterial stiffness could prevent development of hypertension and other clinical conditions, understanding the biological mechanisms of arterial stiffening and investigating potential therapeutic interventions to modulate arterial stiffness are important research topics. For research and application in general clinical settings, it is an important step to develop reliable devices and a standardized arterial stiffness measurement protocol.

Abstract The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia–Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.

We report classical swine fever outbreaks occurring in naive pig herds on Jeju Island, South Korea, after the introduction of the LOM vaccine strain. Two isolates from sick pigs had >99% identity with the vaccine stain. LOM strain does not appear safe; its use in the vaccine should be reconsidered.

Bioactive herbicidal compounds produced by soil microorganisms might be used to creating a bioherbicide for biological weed control. A total of 1,300 bacterial strains were isolated and screened for herbicidal activity against grass and broadleaf weeds. Among primarily selected 102 strains, the herbicidal activity of bacterial fermentation broths from the following three isolates strain-101, strain-128, and strain-329 reduced the growth of D. sanguinalis by 66.7%, 78.3%, and 100%, respectively as compared with control. Phylogenetic analysis of 16S rRNA gene sequencing determined that the strain-329 has 99% similarity to Streptomyces anulatus (HBUM 174206). The potential bioherbicidal efficacy of Streptomyces strain-329 was tested on grass and broadleaf weeds for phytotoxic activity through pre- and post-emergence applications. At pre-emergence application, the phytotoxic efficacy to D. sanguinalis and S. bicolor on seed germination were 90.4% and 81.3%, respectively at the 2x concentration, whereas in the case of Solanum nigrum, 85.2% phytotoxic efficacy was observed at the 4x concentration. The efficacy of Streptomyces strain-329 was substantially higher at post-emergence application, presenting 100% control of grass and broadleaf weeds at the 1x concentration. Two herbicidal compounds coded as 329-C1 and 329-C3 were extracted and purified by column chromatography and high-performance liquid chromatography methods. The active compound 329-C3 slightly increased leaf electrolytic leakage and MDA production as concentration-dependent manner. These results suggest that new Streptomyces sp. strain-329 produced bioherbicidal metabolites and may provide a new lead molecule for production an efficient bioherbicide to regulate grass and broadleaf weeds.

Background: In the present study, we examined superoxide-mediated excitatory nociceptive transmission on at-level neuropathic pain following spinal thoracic 10 contusion injury (SCI) in male Sprague Dawley rats. Methods: Mechanical sensitivity at body trunk, neuronal firing activity, and expression of superoxide marker/ionotropic glutamate receptors (iGluRs)/CamKII were measured in the T7/8 dorsal horn, respectively. Results: Topical treatment of superoxide donor t-BOOH (0.4 mg/kg) increased neuronal firing rates and pCamKII expression in the naïve group, whereas superoxide scavenger Tempol (1 mg/kg) and non-specific ROS scavenger PBN (3 mg/kg) decreased firing rates in the SCI group (* p < 0.05). SCI showed increases of iGluRs-mediated neuronal firing rates and pCamKII expression (* p < 0.05); however, t-BOOH treatment did not show significant changes in the naïve group. The mechanical sensitivity at the body trunk in the SCI group (6.2 ± 0.5) was attenuated by CamKII inhibitor KN-93 (50 μg, 3.9 ± 0.4) or Tempol (1 mg, 4 ± 0.4) treatment (* p < 0.05). In addition, the level of superoxide marker Dhet showed significant increase in SCI rats compared to the sham group (11.7 ± 1.7 vs. 6.6 ± 1.5, * p < 0.05). Conclusions: Superoxide and the pCamKII pathway contribute to chronic at-level neuropathic pain without involvement of iGluRs following SCI.

The patient is a 61-year-old male with a diagnosis of relapse classical Hodgkin lymphoma, treated with ABVD, ICE, and achieved remission. He underwent autologous stem cell transplantation and 3 months later found to have a PET-positive neck node concerning for relapsed disease of Hodgkin lymphoma. Biopsy proved the lesion was HPV-associated squamous cell carcinoma and not relapse Hodgkin disease. Iatrogenic immunosuppression such as bone marrow transplantation can cause substantial increase risk for viral-associated tumors and therefore tissue biopsies are necessary to make that distinction to avoid inappropriate treatment. Keywords: Hodgkin lymphoma, HPV, Squamous cell carcinoma, Transplantation

Enteropathogenic and enterohemorrhagic Escherichia coli are important enteric pathogens that induce hemorrhagic colitis or even fatal hemolytic uremic syndrome. Emerging evidence shows that some bio-actives derived from fruits and vegetables may serve as alternatives to antibiotics for overcoming multidrug resistant E. coli infections. In this study, the Citrobacter rodentium (Cr) infection model was utilized to mimic E. coli-induced acute intestinal inflammation, and the effects of a cruciferous vegetable-derived cancer protective compound, indole-3-carbinol (I3C), on the immune responses of Cr-susceptible C3H/HeN mice were investigated. Dietary I3C significantly inhibited the loss of body weight and the increase in spleen size in Cr infected mice. In addition, I3C treatment reduced the inflammatory response to Cr infection by maintaining anti-inflammatory cytokine IL-22 mRNA levels while reducing expression of other pro-inflammatory cytokines including IL17A, IL6, IL1β, TNF-α, and IFN-γ. Moreover, the serum cytokine levels of IL17, TNF-α, IL12p70, and G-CSF also were down-regulated by I3C in Cr-infected mice. Additionally, dietary I3C specifically enhanced the Cr-specific IgG response to Cr infection. In general, dietary I3C reduced the Cr-induced pro-inflammatory response in susceptible C3H/HeN mice and alleviated the physiological changes and tissue damage induced by Cr infection but not Cr colonization.

The lifelong efforts of Paul A. M. Dirac were to construct localized quantum systems in the Lorentz covariant world. In 1927, he noted that the time-energy uncertainty should be included in the Lorentz-covariant picture. In 1945, he attempted to construct a representation of the Lorentz group using a normalizable Gaussian function localized both in the space and time variables. In 1949, he introduced his instant form to exclude time-like oscillations. He also introduced the light-cone coordinate system for Lorentz boosts. Also in 1949, he stated the Lie algebra of the inhomogeneous Lorentz group can serve as the uncertainty relations in the Lorentz-covariant world. It is possible to integrate these three papers to produce the harmonic oscillator wave function which can be Lorentz-transformed. In addition, Dirac, in 1963, considered two coupled oscillators to derive the Lie algebra for the generators of the O(3,2) de Sitter group, which has ten generators. It is proven possible to contract this group to the inhomogeneous Lorentz group with ten generators, which constitute the fundamental symmetry of quantum mechanics in Einstein’s Lorentz-covariant world.

The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A “clickable” non-natural amino acid—p-azido-l-phenylalanine (AzF)—was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide–alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives.

Intestinal inflammation is associated with an increased risk of developing colorectal cancer and may result from dysregulated responses to commensal bacteria or exposure to bacterial pathogens. Dietary modulation of intestinal inflammation may protect against development of colon cancer. However, the precise diet-derived components and underlying mechanisms remain elusive. Citrobacter rodentium (Cr) induces acute intestinal inflammation and has been used to study the role of inflammation in the susceptibility to colon cancer. Here we examine the effects of indole-3-carbinol (I3C), a dietary compound with anticarcinogenic properties, on intestinal immune and inflammatory responses to Cr infection and adhesion to colonic cells in vitro. C57BL/6J mice were fed a diet with/without 1 μmol/g I3C and infected with Cr. Compared to infected mice fed with a control diet, consumption of a 1 μmol I3C/g diet significantly reduced fecal excretion of Cr, Cr colonization of the colon, and reduced colon crypt hyperplasia. Furthermore, expression of Cr-induced inflammatory markers such as IL-17A, IL-6, and IL1β were attenuated in infected mice fed with the I3C diet, compared to mice fed a control diet. The expression of cytotoxic T cell markers CD8 and FasL mRNA were increased in I3C-fed infected mice. In-vitro, I3C inhibited Cr growth and adhesion to Caco-2 cells. I3C alleviates Cr-induced murine colitis through multiple mechanisms including inhibition of Cr growth and adhesion to colonic cells in vitro and enhancement of cytotoxic T cell activity.

Purpose. Research has documented an inverse relationship between body mass index (BMI) and school achievement but has failed to empirically explain it. We tested whether this association among adolescents can be explained in part by student engagement. Methods. A self-report survey about health and school behaviors was completed by 196 high school students; BMI and achievement data were obtained from school records. Three forms of engagement were assessed: behavioral, presenteeism, and affective. Associations of engagement with BMI and achievement were examined, and mediation analyses were conducted. Results. The simple relationship between BMI and achievement was confirmed and demonstrated that BMI was negatively related to academic achievement. Higher BMI was also significantly correlated with lower classroom participation. Mediation tests showed the significant relationship between BMI and achievement was reduced after accounting for behavioral engagement but not affective engagement. Conclusions. These novel findings shed light on why heavier students often experience lower academic achievement. Intervention studies targeting barriers to classroom engagement among overweight and obese youth are needed so that their academic potential is not compromised.