Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

OBJECTIVES: Anti-IL-6 receptor antibodies are clinically efficacious in the management of rheumatoid arthritis (RA) with an associated increase in regulatory T cells (Tregs); however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyze the relationship between these Treg subsets and the clinical outcome of RA. METHODS: We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. RESULTS: The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs, and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. CONCLUSIONS: Blocking IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favorable treatment course, and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

SMART-SLE: serology monitoring and repeat testing in systemic lupus erythematosus-an analysis of anti-double-stranded DNA monitoring.

OBJECTIVE: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive. METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare. RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009). CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State In Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

Association depressive symptoms with memory function and social capital before and during COVID-19 in community-dwelling older adults in rural Japan: A retrospective study with a longitudinal data.

OBJECTIVES: This study aimed to investigate the impact of memory function and social capital on depressive symptoms during the COVID-19 pandemic among older adults in rural Japan. METHODS: A retrospective study with longitudinal data was conducted during COVID-19 from May 2021 to November 2021 (T2) in Kurogawa, Japan. The candidate population for this study was 145 with the following requirements: (1) older individuals aged 65 years or above who were registered in the Kurogawa study, and (2) those with previous data (from November 2016 to February 2020; T1 as pre-pandemic). Memory function was assessed using the Wechsler Memory Scale-Revised Logical Memory II delayed recall part A (LM II-DR). Depressive symptoms were assessed using the Japanese version of the 15-item Geriatric Depression Scale (GDS-15). Social capital was evaluated through civic participation, social cohesion, and reciprocity. Fear of the COVID-19 infection (FCV-19S) was evaluated. RESULTS: The final analysis included 96 participants (mean age = 81.0 years, SD = 4.8) Multivariate analysis for GDS-15 score by Mixed Model Repeated Measures (MMRM) revealed significant associations between LM II-DR (ß = -0.13, 95% CI: -0.21-0.05, p = 0.002) and FCV-19S during COVID-19 (ß = 0.08, 95% CI: 0.01-0.15, p = 0.02) with GDS-15 score. However, civic participation, social cohesion and reciprocity were not associated with GDS-15 score. CONCLUSIONS: Among older adults in rural Japan, memory function and fear of the COVID-19 infection were significantly associated with depressive symptoms in MMRM analysis. However, social capital was not associated with depressive symptoms. This highlights the need to address memory function and fear of the COVID-19 infection in interventions for older adults during crises like the COVID-19 pandemic.

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles.

A stereoselective N-alkenylation of azoles with alkynes and iodine(III) electrophile is reported. The reaction between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl group in the product can be leveraged as a versatile synthetic handle, allowing for the preparation of hitherto inaccessible types of densely functionalized N-vinylazoles.

Volatile Organic Compound Detection by Graphene Field-Effect Transistors Functionalized with Fly Olfactory Receptor Mimetic Peptides.

An olfactory receptor mimetic peptide-modified graphene field-effect transistor (gFET) is a promising solution to overcome the principal challenge of low specificity graphene-based sensors for volatile organic compound (VOC) sensing. Herein, peptides mimicking a fruit fly olfactory receptor, OR19a, were designed by a high-throughput analysis method that combines a peptide array and gas chromatography for the sensitive and selective gFET detection of the signature citrus VOC, limonene. The peptide probe was bifunctionalized via linkage of a graphene-binding peptide to facilitate one-step self-assembly on the sensor surface. The limonene-specific peptide probe successfully achieved highly sensitive and selective detection of limonene by gFET, with a detection range of 8-1000 pM, while achieving facile sensor functionalization. Taken together, our target-specific peptide selection and functionalization strategy of a gFET sensor demonstrates advancement of a precise VOC detection system.

Role of interferons (IFNs) in the differentiation of T peripheral helper (Tph) cells.

Interleukin (IL)-21-producing T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. In this study, we investigated the relationship between Tph cells and interferons (IFNs) in several autoimmune diseases because our previous study demonstrated that type I IFNs promote the differentiation of IL-21-producing Tph-like cells. The frequency of Tph cells in the blood as well as serum IFN-α2a and IFN-λ1 were markedly elevated in patients with active systemic lupus erythematosus (SLE) compared to other autoimmune diseases or healthy controls. Notably, the frequency of Tph cells was positively correlated with the SLE disease activity index, serum IFN-α and serum IFN-λ1 in SLE patients. Additionally, we found that type III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3) promote the differentiation of programmed cell death-1 (PD-1)+ CXCR5 -CD4+ T cells and enhance the secretion of IL-21, IFN-γ and CXCL13. IFN-λ1, like IFN-α, up-regulated the mRNA expression of IL21, IFNG, CXCL13, CD244, SLAMF7, GZMB, PRF1, CCR5 and PRDM1, whereas it down-regulated that of CXCR5 and BCL6, reflecting a Tph-related gene expression pattern. IFN-α in combination with IFN-λ1, IFN-λ2 or IFN-λ3 significantly increased the differentiation of PD-1+CXCR5- Tph-like cells and the secretion of Tph-related cytokines as compared with each IFN alone, suggesting a cooperative interaction. From these findings, it is highly probable that type III IFNs in addition to type I IFNs play a key role in the differentiation of Tph cells and that high levels of IFN-α and IFN-λ1 trigger the differentiation and expansion of Tph cells in SLE.

Stereoselective Approach to Multisubstituted Enolates from Unactivated Alkynes: Oxyalkylidenation of Alkynyl Ketone Enolates with Aldehydes.

The preparation of multisubstituted enolates with precise regio- and stereocontrol is a nontrivial task when conventional deprotonation methods are used on the corresponding carbonyl compounds. We describe herein an approach to preparing stereodefined enolates by leveraging the stereoselective oxyfunctionalization of unactivated alkynes, particularly in the context of the alkynylogous aldol reaction. trans-Iodo(III)acetoxylation of alkynes and subsequent Sonogashira coupling allow for the facile preparation of multisubstituted enynyl acetates, which can be deacetylated by MeLi into the corresponding enolates. The alkynyl enolates react with aldehydes to afford γ,δ-unsaturated ß-diketones through a cascade of alkynylogous aldol addition, intramolecular Michael addition, and ring opening of the oxetene intermediate.

Differences in the strength of inhibition of interleukin-6 signalling by subcutaneous sarilumab and tocilizumab in rheumatoid arthritis patients.

OBJECTIVES: To assess differences in the strength of inhibition of IL-6/STAT3 signalling induced by subcutaneously (sc) administered tocilizumab (TCZ) and sarilumab (SAR). METHODS: Data were collected on patients with rheumatoid arthritis (RA) who achieved low disease activity (Clinical Disease Activity Index [CDAI]≤10) following treatment with weekly or bi-weekly administration of 162 mg sc of TCZ (TCZ qw group, n=8; TCZ q2w group, n=8), bi-weekly doses of 200 mg sc of SAR (SAR q2w group, n=7), or MTX (n=8) as a control. The clinical characteristics of each group were collected, and the serum concentrations of IL-6 and soluble IL-6 receptor (sIL-6R) were measured using ELISA. Whole blood samples from each group were stimulated with 100 ng/ml of IL-6. The proportion of phosphorylated (p)STAT3-positive CD4+ T cells was measured using phosflow cytometric analysis. RESULTS: The proportion of pSTAT3-positive CD4+ T cells following stimulation with 100 ng/ml of recombinant human IL-6 was significantly different among the groups (median 1.8% [0.9-3.0] vs. 7.7% [2.9-8.0] vs. 12.5% [11.4-16.6] vs. 71.5% [68.0-78.5] for the TCZ qw, SAR q2w, TCZ q2w, and MTX control groups, respectively; p<0.01 for all comparisons). CONCLUSIONS: SAR 200 mg q2w showed significantly stronger inhibition of IL-6/STAT3 signalling than TCZ sc q2w but weaker inhibition than TCZ sc qw. The results of this study may be useful for adjusting the IL-6 blockade treatment for patients with RA.

Deep remission within 12 months prevents renal flare and damage accrual in lupus nephritis.

OBJECTIVES: To evaluate the significance of achieving deep remission by induction therapy in lupus nephritis (LN) patients. METHODS: We assessed consecutive patients undergoing induction therapy for active LN. Achievement of complete renal response (CR) was defined as a urine protein creatinine ratio (UPCR) ≤0.5 g/gCr, and deep remission (DR) was defined as a UPCR ≤0.15 g/gCr with stabilisation of serum creatinine levels assessed every 2-3 months. We compared renal flare and damage accrual rates among patients with CR, CR without DR, and DR at 3, 6, and 12 months and later. RESULTS: Fifty-nine Asian patients were enrolled, and the median observation period was 48.6 months. Of these, 55 patients achieved CR, and 33 achieved DR within 12 months of receiving induction therapy. The patients with DR within 12 months experienced a significantly lower rate of subsequent renal flare (p<0.001) and damage accrual (p=0.046) than those without CR, those with DR after 12 months, and those with no DR but CR within 12 months. In addition, younger age, shorter disease duration, lower urine protein at baseline, and earlier renal response were associated with DR within 12 months. CONCLUSIONS: Achievement of DR within 12 months after induction therapy should be a treatment target for active LN, as it has implications for preventing renal flare and damage accrual.

Inferring microbial community assembly in an urban river basin through geo-multi-omics and phylogenetic bin-based null-model analysis of surface water.

Understanding the community assembly process is a central issue in microbial ecology. In this study, we analyzed the community assembly of particle-associated (PA) and free-living (FL) surface water microbiomes in 54 sites from the headstream to the river mouth of an urban river in Japan, the river basin of which has the highest human population density in the country. Analyses were conducted from two perspectives: (1) analysis of deterministic processes considering only environmental factors using a geo-multi-omics dataset and (2) analysis of deterministic and stochastic processes to estimate the contributions of heterogeneous selection (HeS), homogeneous selection (HoS), dispersal limitation (DL), homogenizing dispersal (HD), and drift (DR) as community assembly processes using a phylogenetic bin-based null model. The variation in microbiomes was successfully explained from a deterministic perspective by environmental factors, such as organic matter-related, nitrogen metabolism, and salinity-related parameters, using multivariate statistical analysis, network analysis, and habitat prediction. In addition, we demonstrated the dominance of stochastic processes (DL, HD, and DR) over deterministic processes (HeS and HoS) in community assembly from both deterministic and stochastic perspectives. Our analysis revealed that as the distance between two sites increased, the effect of HoS sharply decreased while the effect of HeS increased, particularly between upstream and estuary sites, indicating that the salinity gradient could potentially enhance the contribution of HeS to community assembly. Our study highlights the importance of both stochastic and deterministic processes in community assembly of PA and FL surface water microbiomes in urban riverine ecosystems.

Computational estimation of sediment symbiotic bacterial structures of seagrasses overgrowing downstream of onshore aquaculture.

Coastal seagrass meadows are essential in blue carbon and aquatic ecosystem services. However, this ecosystem has suffered severe eutrophication and destruction due to the expansion of aquaculture. Therefore, methods for the flourishing of seagrass are still being explored. Here, data from 49 public coastal surveys on the distribution of seagrass and seaweed around the onshore aquaculture facilities are revalidated, and an exceptional area where the seagrass Zostera marina thrives was found near the shore downstream of the onshore aquaculture facility. To evaluate the characteristics of the sediment for growing seagrass, physicochemical properties and bacterial ecological evaluations of the sediment were conducted. Evaluation of chemical properties in seagrass sediments confirmed a significant increase in total carbon and a decrease in zinc content. Association analysis and linear discriminant analysis refined bacterial candidates specified in seagrass overgrown- and nonovergrown-sediment. Energy landscape analysis indicated that the symbiotic bacterial groups of seagrass sediment were strongly affected by the distance close to the seagrass-growing aquaculture facility despite their bacterial population appearing to fluctuate seasonally. The bacterial population there showed an apparent decrease in the pathogen candidates belonging to the order Flavobacteriales. Moreover, structure equation modeling and a linear non-Gaussian acyclic model based on the machine learning data estimated an optimal sediment symbiotic bacterial group candidate for seagrass growth as follows: the Lachnospiraceae and Ruminococcaceae families as gut-inhabitant bacteria, Rhodobacteraceae as photosynthetic bacteria, and Desulfobulbaceae as cable bacteria modulating oxygen or nitrate reduction and oxidation of sulfide. These observations confer a novel perspective on the sediment symbiotic bacterial structures critical for blue carbon and low-pathogenic marine ecosystems in aquaculture.

Multi-omics analysis on an agroecosystem reveals the significant role of organic nitrogen to increase agricultural crop yield.

Both inorganic fertilizer inputs and crop yields have increased globally, with the concurrent increase in the pollution of water bodies due to nitrogen leaching from soils. Designing agroecosystems that are environmentally friendly is urgently required. Since agroecosystems are highly complex and consist of entangled webs of interactions between plants, microbes, and soils, identifying critical components in crop production remain elusive. To understand the network structure in agroecosystems engineered by several farming methods, including environmentally friendly soil solarization, we utilized a multiomics approach on a field planted with Brassica rapa We found that the soil solarization increased plant shoot biomass irrespective of the type of fertilizer applied. Our multiomics and integrated informatics revealed complex interactions in the agroecosystem showing multiple network modules represented by plant traits heterogeneously associated with soil metabolites, minerals, and microbes. Unexpectedly, we identified soil organic nitrogen induced by soil solarization as one of the key components to increase crop yield. A germ-free plant in vitro assay and a pot experiment using arable soils confirmed that specific organic nitrogen, namely alanine and choline, directly increased plant biomass by acting as a nitrogen source and a biologically active compound. Thus, our study provides evidence at the agroecosystem level that organic nitrogen plays a key role in plant growth.

Site-Selective C-H Alkenylation of N-Heteroarenes by Ligand-Directed Co/Al and Co/Mg Cooperative Catalysis.

We report herein the design and development of Co/Al and Co/Mg bimetallic catalysts, supported by a phosphine/secondary phosphine oxide (PSPO) bifunctional ligand, for the site-selective C-H alkenylation of nitrogen-containing heteroarenes with alkynes. These catalysts enable the alkenylation of pyridine, pyridone, and imidazo[1,2-a]pyridine derivatives at the C-H site proximal to the Lewis basic nitrogen or oxygen atom, which represents a selectivity profile distinct from that of the previously developed cobalt-diphosphine/aluminum catalyst. The alkenylated products were obtained in moderate to good yields using various heterocycles and differently substituted internal alkynes. Kinetic isotope effect experiments suggest the irreversibility of the C-H activation step, the relevance of which to the rate-limiting step depends on the reaction conditions. Density functional theory calculations indicate that ligand-to-ligand hydrogen transfer is the common mechanism of C-H activation.

Ethanol induces heat tolerance in plants by stimulating unfolded protein response.

KEY MESSAGE: Ethanol priming induces heat stress tolerance by the stimulation of unfolded protein response. Global warming increases the risk of heat stress-related yield losses in agricultural crops. Chemical priming, using safe agents, that can flexibly activate adaptive regulatory responses to adverse conditions, is a complementary approach to genetic improvement for stress adaptation. In the present study, we demonstrated that pretreatment of Arabidopsis with a low concentration of ethanol enhances heat tolerance without suppressing plant growth. We also demonstrated that ethanol pretreatment improved leaf growth in lettuce (Lactuca sativa L.) plants grown in the field conditions under high temperatures. Transcriptome analysis revealed a set of genes that were up-regulated in ethanol-pretreated plants, relative to water-pretreated controls. Binding Protein 3 (BIP3), an endoplasmic reticulum (ER)-stress marker chaperone gene, was among the identified up-regulated genes. The expression levels of BIP3 were confirmed by RT-qPCR. Root-uptake of ethanol was metabolized to organic acids, nucleic acids, amines and other molecules, followed by an increase in putrescine content, which substantially promoted unfolded protein response (UPR) signaling and high-temperature acclimation. We also showed that inhibition of polyamine production and UPR signaling negated the heat stress tolerance induced by ethanol pretreatment. These findings collectively indicate that ethanol priming activates UPR signaling via putrescine accumulation, leading to enhanced heat stress tolerance. The information gained from this study will be useful for establishing ethanol-mediated chemical priming strategies that can be used to help maintain crop production under heat stress conditions.

Ethanol-Mediated Novel Survival Strategy against Drought Stress in Plants.

Water scarcity is a serious agricultural problem causing significant losses to crop yield and product quality. The development of technologies to mitigate the damage caused by drought stress is essential for ensuring a sustainable food supply for the increasing global population. We herein report that the exogenous application of ethanol, an inexpensive and environmentally friendly chemical, significantly enhances drought tolerance in Arabidopsis thaliana, rice and wheat. The transcriptomic analyses of ethanol-treated plants revealed the upregulation of genes related to sucrose and starch metabolism, phenylpropanoids and glucosinolate biosynthesis, while metabolomic analysis showed an increased accumulation of sugars, glucosinolates and drought-tolerance-related amino acids. The phenotyping analysis indicated that drought-induced water loss was delayed in the ethanol-treated plants. Furthermore, ethanol treatment induced stomatal closure, resulting in decreased transpiration rate and increased leaf water contents under drought stress conditions. The ethanol treatment did not enhance drought tolerance in the mutant of ABI1, a negative regulator of abscisic acid (ABA) signaling in Arabidopsis, indicating that ABA signaling contributes to ethanol-mediated drought tolerance. The nuclear magnetic resonance analysis using 13C-labeled ethanol indicated that gluconeogenesis is involved in the accumulation of sugars. The ethanol treatment did not enhance the drought tolerance in the aldehyde dehydrogenase (aldh) triple mutant (aldh2b4/aldh2b7/aldh2c4). These results show that ABA signaling and acetic acid biosynthesis are involved in ethanol-mediated drought tolerance and that chemical priming through ethanol application regulates sugar accumulation and gluconeogenesis, leading to enhanced drought tolerance and sustained plant growth. These findings highlight a new survival strategy for increasing crop production under water-limited conditions.

An Antimicrobial Peptide-Mimetic Methacrylate Random Copolymer Induces Domain Formation in a Model Bacterial Membrane.

To address the emerging issue of drug-resistant bacteria, membrane-active synthetic polymers have been designed and developed to mimic host-defense antimicrobial peptides (AMPs) as antibiotic alternatives. In this study, we investigated the domain formation induced by synthetic polymer mimics of AMPs using model membranes to elucidate the biophysical principles that govern their membrane-active mechanisms. To that end, lipid vesicles mimicking Escherichia coli (E. coli) membrane were prepared using an 8:2 (molar ratio) mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), sodium salt (POPG). Our studies using differential scanning calorimetry (DSC) and fluorescence microscopy indicated that cationic amphiphilic methacrylate random copolymers induced the phase separation to form POPE- or POPG-rich domains. A rhodamine-labeled polymer also showed the binding to separated domains in the membrane. Based on these results, we propose the mechanism that the copolymers induce domain formation by clustering of anionic POPG lipids similar to natural AMPs. In addition, the time-course of polymer binding to the GUV membrane was sigmoidal, suggesting the positive feedback loop in the membrane binding. We also hypothesize that this cooperative binding of the polymer is driven by the domain formation. This study demonstrates the potential of the amphiphilic copolymers to modulate the lipid organization of cell membranes, which may provide a new strategy to design membrane-active antimicrobial agents.

Lupus low disease activity state within 12 months is associated with favourable outcomes in severely active systemic lupus erythematosus.

OBJECTIVES: To demonstrate the significance of the time to attain lupus low disease activity state (LLDAS) after remission induction therapy in patients with severely active SLE. METHODS: We enrolled 79 patients starting prednisolone ≥0.4 mg/kg/day for active lupus with a BILAG 2004 index of A ≥ 1 or B ≥ 2, or for severe flare based on the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI). The time to LLDAS attainment was divided into ≤6, 6-12 and >12 months and non-LLDAS; associations between the timing of LLDAS and flares, damage accrual and ≥50% LLDAS attainment were examined. RESULTS: The mean SLEDAI was 17; median starting dose of prednisolone, 0.95 mg/kg/day; and mean observational period, 39.7 months. Six (7.6%) and 41 (51.9%) patients achieved LLDAS within 6 and 12 months. Patients with a shorter time to LLDAS achievement were more likely to spend ≥50% of the time in LLDAS and had a lower cumulative prednisolone dose; no differences were observed in damage accrual. Patients requiring longer than 12 months to achieve LLDAS had a higher prevalence of thrombocytopenia and those with non-LLDAS had lower renal function and a higher starting dose of prednisolone and steroid pulse therapy than those who achieved LLDAS within 12 months. CONCLUSION: Achieving LLDAS within 12 months of induction therapy may be favourable in patients with severely active SLE. The low frequency of LLDAS attainment in high-risk populations highlights the need for a new strategy for SLE treatment.

Integrated Multi-Omics Analysis Reveals Differential Effects of Fructo-Oligosaccharides (FOS) Supplementation on the Human Gut Ecosystem.

Changes in the gut ecosystem, including the microbiome and the metabolome, and the host immune system after fructo-oligosaccharide (FOS) supplementation were evaluated. The supplementation of FOS showed large inter-individual variability in the absolute numbers of fecal bacteria and an increase in Bifidobacterium. The fecal metabolome analysis revealed individual variability in fructose utilization in response to FOS supplementation. In addition, immunoglobulin A(IgA) tended to increase upon FOS intake, and peripheral blood monocytes significantly decreased upon FOS intake and kept decreasing in the post-FOS phase. Further analysis using a metagenomic approach showed that the differences could be at least in part due to the differences in gene expressions of enzymes that are involved in the fructose metabolism pathway. While the study showed individual differences in the expected health benefits of FOS supplementation, the accumulation of "personalized" knowledge of the gut ecosystem with its genetic expression may enable effective instructions on prebiotic consumption to optimize health benefits for individuals in the future.