Exogenous compound bacteria enhance the nutrient removal efficiency of integrated bioremediation systems: Functional genes and microorganisms play key roles.

With the continuous development of intensive mariculture, the application of the integrated bioremediation system of aquaculture wastewater (IBSAW) is increasingly promoted. However, the process and nutrients removal performance of the IBSAW need to be further optimized due to its immature technologies. In this study, exogenous compound bacteria (ECB) were added to IBSAW to investigate its pollutants removal efficiency and the relevant mechanisms. High-throughput sequencing and Geochip gene array were used to analyze the correlation between nutrients and bacteria, and the abundance of N and P cycling genes were quantified. Multivariable statistics, dimensionality reduction analysis, and network analysis were applied to explore the mechanisms of IBSAW operation. The results showed that the nutrients decreased significantly after adding ECB, with the brush treatment group significantly outperforming the ceramsite in removing NO3- and PO43-. Ceramsite has an advantage in removing NO2--N. The addition of ECB and different substrates significantly affected the composition of bacterial communities. The contents of nosZ and nirKS related to denitrification in the treatment groups were significantly higher than those in the control group, and the contents in the brush treatment group were significantly higher than that of ceramsite. The biomarkers Psychroserpens and Ruegeria on the biofilm of the brush treatment group were positively correlated with nirKS, while Mycobacterium, Erythrobacter and Paracoccus, Pseudohaliea in the ceramsite group were positively correlated with nirS and nirK, respectively. Therefore, it is speculated that the ECB significantly promoted the increase of denitrification bacteria by affecting the composition of bacterial communities, and the ECB combined with functional genera improved the efficiency of nutrients removal in the system. This study provided a reference for understanding the process and mechanism of nutrients removal, optimizing the wastewater purification technology of the IBSAW and improving the performance of the system.

Stability and Semiconducting Behavior of Magnesium Polysulfides by Nonequivalent sp3 Hybridizations.

The Mg/S battery has attracted enormous interest in recent years due to its high theoretical capacity, low cost, and high security. However, the understanding of many intermediate magnesium polysulfides in the Mg/S battery remains elusive. Combining extensive structural search and first-principles calculations, we investigate the phase stability, structural character, and electronic structure of magnesium polysulfides in a wide range from MgS to MgS8. The pyrite-type MgS2 (space group: Pa3̅) is predicted to be stable. Five magnesium polysulfides, MgSx (x = 3, 4, 5, 6, and 8), are found to be metastable, with formation enthalpies slightly above the convex hull. S2 dimer, "V"-like S3, and highly distorted Sx chains are found for the polysulfides with bond lengths close to or slightly longer than S8 and bond angles similar to S8. A wide range of band gaps (0.77-2.82 eV) are revealed for the polysulfides due to the contribution of the nonequivalent sp3 hybridization of the S atoms in Sx2-. Our results can help to further understand the electrochemical process in the Mg/S battery.

Operational and Intervention Effects of Targeted Tuina in Lumbar Intervertebral Disc Degeneration Model Rabbits.

Tui Na or massage therapy alleviates symptoms related to intervertebral disc degeneration (IDD). However, precise, repeatable, standardized instructions for Tuina manipulation are lacking. This study establishes IDD model rabbits induced by fibrous ring puncture, creates targeted Tuina stimulation protocols at the acupuncture points in the lumbar region, and describes in detail the operation methods and requirements of kneading, pointing, and flicking. New Zealand male white rabbits (n = 15) were selected and randomly divided into a blank group, a model group, and a Tuina group. The rabbits in the model group and the Tuina group were molded by fibrous ring puncture; the rabbits in the model group were only immobilized on the operating table without treatment. In contrast, the Tuina group used the "8N/10N, 30 cycles/min" prescription for kneading, pointing, and flicking to perform the intervention, using tactile sensory aids to monitor and regulate the intensity of the Tuina operation. Imaging diagnosis and pathological tests were used to assess the effect of Tuina in rabbits, and the results showed improved imaging features and significantly lowered pathology scores of lumbar disc degeneration in the Tuina group compared to the model group (P < 0.01). Targeted Tuina in the lumbar region may be beneficial in the alleviation of lumbar disc degeneration, but further verification is needed. By regularly performing Tuina and recording the mechanical information involved enables reproducible manipulation prescriptions and helps to observe the basic features of the underlying mechanism of Tuina for IDD.

High Coulomb Efficiency Sn-Co Alloy/rGO Composite Anode Material for Li-ion Battery with Long Cycle-Life.

The low cycle performance and low Coulomb efficiency of tin-based materials confine their large-scale commercial application for lithium-ion batteries. To overcome the shortage of volume expansion of pristine tin, Sn-Co alloy/rGO composites have been successfully synthesized by chemical reduction and sintering methods. The effects of sintering temperature on the composition, structure and electrochemical properties of Sn-Co alloy/rGO composites were investigated by experimental study and first-principles calculation. The results show that Sn-Co alloys are composed of a large number of CoSn and trace CoSn2 intermetallics, which are uniformly anchored on graphene nanosheets. The sintering treatment effectively improves the electrochemical performance, especially for the first Coulomb efficiency. The first charge capacity of Sn-Co alloy/rGO composites sintered at 450 °C is 675 mAh·g-1, and the corresponding Coulomb efficiency reaches 80.4%. This strategy provides a convenient approach to synthesizing tin-based materials for high-performance lithium-ion batteries.

Epidemiological characteristics, virulence potential, antimicrobial resistance profiles, and phylogenetic analysis of Aeromonas caviae isolated from extra-intestinal infections.

Objective: Aeromonas caviae (A. caviae) is one of the major etiological agents in human intestinal infections reported to be associated with a broad spectrum of extra-intestinal infections with increasing incidence over recent years. Although previous studies have established its significance as a causative agent of both bloodstream and gastrointestinal infections, the characteristics of A. caviae that cause extra-intestinal infections remain unilluminated.In this single-center retrospective study, we investigated epidemiological characteristics, antimicrobial resistance genes and phenotypes, virulence genes, and phyloevolution of 47 clinical A. caviae isolated from patients with extra-intestinal infections from 2017 to 2020. Methods: A. caviae strains were identified by biochemical tests and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/MS), ultimately confirmed to species level by whole-genome sequencing (WGS). Antimicrobial resistance and virulence genes were identified using the Comprehensive Antibiotic Resistance Database (CARD) and the virulence factor database (VFDB), respectively. Phylogenetic analysis of 47 clinical strains was performed by combining with 521 A. caviae strains from NCBI database. Results: A. caviae was an opportunistic pathogen in immunocompromised patients, especially those with underlying hepatobiliary diseases and malignancies. 19 out of 47 isolates were identified as multidrug resistance (MDR) strains. Piperacillin-tazobactam, levofloxacin, gentamicin, amikacin with a resistance rate of less than 10% remained as options to treat extra-intestinal infections. 24 out of 47 isolates exhibited non-susceptibility to cephalosporins and cephamycins, all of which carried ß-lactamase gene, including bla MOX, bla PER-3, bla OXA, bla NDM, and bla CphA. Most stains (98%, 46/47) carried at least one of the virulence genes, but extra-intestinal infections had a low mortality rate. Phylogenetic analysis indicated the risk of nosocomial transmission but revealed no outbreak. However, the emergence of MDR and ß-lactamase resistance genes in extra-intestinal isolates of A. caviae is becoming an increasing risk to public health and requires attention. Conclusions: This study strengthen our understanding of A.caviae isolated from extra-intestinal infections. It may contribute to the management of extra-intestinal infections as well as the prevention and control of drug resistance.

Hollow nanotube arrays of nickle-cobalt metal sulfide for high energy density supercapacitors.

High energy density is still difficult to achieve using existing metal sulfides because of their low specific capacitance. To improve capacitance, a series of nickel and cobalt metal sulfides with different Ni/Co ratios were synthesized by a two-step hydrothermal method. Using the combining method of experimental research and first-principles calculation, the morphology, structural stability, electronic structure and electrochemical properties of metal sulfides were investigated systematically. The results show that the morphology of metal sulfides gradually grows from two-dimensional structure to nanotube arrays, and finally to nanorod arrays, as the Ni/Co ratios decrease. Among them, the NC24 sample with the Ni/Co ratio of 1 : 2 is a hollow nanotube array composed of NiCo2S4, which shows excellent electrochemical performance. The specific capacity of the NC24 sample reaches 1527C g-1 at 1 A g-1, and the capacity retention is 93.81% at 10 A g-1 after 2000 cycles. Furthermore, a symmetrical supercapacitor assembled from the NiCo2S4 nanotube array shows a high energy density of 67.5 W h kg-1. This strategy develops a nanotube array of metal sulfides and expands its application in a high energy density supercapacitor.

Anti-IgLON5 disease: a novel topic beyond neuroimmunology.

Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.

Self-Assembly of Copolymers Containing Crystallizable Blocks: Strategies and Applications.

The self-assembly of copolymers containing crystallizable blocks in solution has received increasing attention in the past few years. Various strategies including crystallization-driven self-assembly (CDSA) and polymerization-induced CDSA (PI-CDSA) have been widely developed. Abundant self-assembly morphologies are captured and advanced applications have been attempted. In this review, the synthetic strategies including the mechanisms and characteristics are highlighted and a survey on the advanced applications of crystalline nano-assemblies is collected. This review is hoped to depict a comprehensive outline for self-assembly of copolymers containing crystallizable blocks in recent years and to prompt the development of the self-assembly technology in interdisciplinary fields.

Rapid Naked-Eye Detection of a Liver Disease Biomarker by Discovering Its Monoclonal Antibody to Functionalize Engineered Red-Colored Bacteria Probes.

Glycocholic acid (GCA) is a biomarker for liver diseases, but few facile naked-eye detection methods have been reported to detect it till now. To tackle this challenge, we first prepared a novel monoclonal mouse antibody (mAb) of GCA by a hybridoma technique. The anti-GCA mAb exhibited high specificity, making its cross-reactivity with seven structurally and functionally related GCA analogs negligible. Using this anti-GCA mAb and an engineered red-colored bacterial strain (Staphylococcus aureus, S. aureus), we developed a simple naked-eye visualized method for GCA detection. Toward this goal, S. aureus bacteria were turned red by 5-cyano-2,3-ditolyl tetrazolium chloride treatment and heat treated to an unculturable state, rendering the bacteria as an optical detection probe powerful in in vitro diagnostics. Through the natural binding ability of protein A on the surface of S. aureus and the Fc fragment of a mouse antibody, the anti-GCA antibody was simply conjugated onto S. aureus. Then, the engineered S. aureus served as a red-colored bioprobe for detecting GCA through a coagglutination test. In the presence of GCA, the bioprobes aggregated into dense red-colored eye-visible clusters, enabling the sensitive detection of GCA with a concentration of 0.05-0.10 µg/mL. This naked-eye visualization method only takes a few minutes to detect GCA and avoids the use of expensive equipment. It represents a rapid, convenient, and simple method for detecting GCA to diagnose liver diseases.

Understanding the anchoring and catalytic effect of the Co@C2N monolayer in lithium-selenium batteries: a first-principles study.

The practical applications of lithium-selenium (Li-Se) batteries are impeded due to the low utilization of active selenium, sluggish kinetics, and volume change. The development of highly efficient host materials to suppress high-order polyselenide shuttling and accelerate Li2Se conversion is essential for Li-Se batteries. Herein, a theoretical design of a Co@C2N monolayer as a host material for ultra-high areal capacity Li-Se batteries is proposed by first-principles calculations. The investigations of the lowest energy configurations, binding energies, and the charge transfer indicate that the Co@C2N monolayer could alleviate the reciprocating motion of high-order polyselenides and improve the cycling performance. Further electronic property calculations show that the semi-metallic characteristics of the Co@C2N monolayer material are retained even after chemical adsorption with Se8 or Li2Sen molecules, which is beneficial for the utilization of active selenium. In addition, the crucial catalytic role of the Co@C2N monolayer is investigated and the results indicate that the Co@C2N monolayer could facilitate the formation and decomposition of Li2Se molecules during the discharge and charge processes. Our present work would not only provide a deep understanding on the anchoring and catalytic effect of the Co@C2N monolayer, but also demonstrate a general principle for the rational design and screening of advanced materials for high energy density Li-Se batteries.

Symptoms Based on Deficiency Syndrome in Traditional Chinese Medicine Might Be Predictor of Frailty in Elderly Community Dwellers.

BACKGROUND: The most widely used frailty phenotype and frailty indexes are either time-consuming or complicated, thus restricting their generalization in clinical practice; and therefore, an easier and faster screening tool is needed to be developed. OBJECTIVE: To select sensitive symptoms in traditional Chinese medicine (TCM) and study whether they can improve the risk prediction of frailty. METHODS: This is a cross-sectional study enrolling 2249 Chinese elderly community dwellers. Data were collected via face-to-face inquiries, anthropometric measurements, laboratory tests, and community health files. Frailty was the main outcome measure, and it was evaluated by Fried's frailty phenotype (FP). The ordinal logistic regression model was used to identify the factors associated with frailty. The risk assessment plot was used to compare the discriminative ability for frailty among models with and without TCM symptoms. RESULTS: The identified sensitive influential factors for frailty included age, education level, dietary habits, chronic obstructive pulmonary disease, diabetes, cerebral infarction, osteoporosis, cold limbs, lethargy and laziness in speaking and moving, weakness of lower limbs, slow movement, dry mouth and throat, and glazed expression. The risk prediction for "frailty cumulative components ≥1" was not significantly increased, while for "frailty cumulative components ≥2", a new model developed with the above selected TCM symptoms had a higher AUC than the baseline model without it (0.79 VS 0.81, P=0.002). And the NRI and IDI for the new model were 41.4% (P=0.016) and 0.024% (P=0.041), respectively. CONCLUSION: This research might provide an easier and faster way for early identification and risk prediction of frailty in elderly community dwellers.

First-principles calculations on the deposition behavior of LixNay (x + y ≤ 5) clusters during the hybrid storage of Li and Na atoms on graphene.

A new strategy of sodium ion batteries with the hybrid storage of Li and Na ions has attracted much attention in the field of large-scale energy storage. For revealing the mechanism of hybrid storage of Li and Na atoms in carbon materials, the lowest energy configuration, adsorption energy, differential charge density and density of states of LixNay clusters on graphene, as a structural unit of carbon materials, were calculated and investigated based on first principles density functional theory. The calculation results show that the deposition behavior of single Li or Na atoms on graphene is similar, and both are preferentially deposited at the hollow of graphene (H-site). The Li atom is deposited preferentially over the Na atom, and the deposition height of the Li atom is lower. When the total number of metal atoms x + y ≥ 3, LixNay clusters are deposited on graphene in the form of a stereotypical atomic cluster, in which the Li atom is usually at the bottom of the LixNay cluster, while the Na atom is usually at the top of the cluster. The electronic structure analysis shows that the electrons of the LixNay cluster are transferred to the anti-bonding π orbitals adjacent to graphene. The 2s orbitals of Li atoms and the 2s and 2p orbitals of Na atoms are hybridized with the 2p orbitals of C atoms. Therefore, the Li-C bonds or Na-C bonds formed between Li or Na atoms and C atoms of graphene are usually ionic bonds with partial covalent bond properties. Meanwhile, the Li-Li, Na-Na or Li-Na bonds formed inside LixNay clusters are usually multiple metal-metal bonds.

Development of enzyme-free single-step immunoassays for glycocholic acid based on palladium nanoparticle-mediated signal generation.

Palladium nanoparticles (PdNPs) are composed mainly of inert noble metals, and their outstanding properties have attracted wide attention. PdNPs are not only capable of mimicking the oxidase-like characteristics of natural bio-enzymes, but they also present a clear black band in the test zone. In this work, the synthesized PdNPs promoted a transformation of colorless tetramethylbenzidine (TMB) to a blue oxidation product of TMB, providing a Km value of 0.09 mM for TMB, and revealing the good catalytic performance of the synthesized PdNPs. For both signal generation and amplification, PdNPs effectively replaced natural bio-enzymes as a new labeling tag. Thus, the PdNP-based enzyme-free single-step immunoassays were successfully developed for efficient and sensitive detection of glycocholic acid (GCA). Under optimal conditions, a noticeable linear relationship was identified by the enzyme-linked immunosorbent assay (ELISA) over a range of 8-2390 ng/mL, while the visual limit of detection (vLOD) in the constructed lateral flow immunoassay (LFA) was 10 ng/mL for GCA. The recovery rate in spiked urine samples obtained by the ELISA ranged from 84.2 to 117.9%, which was consistent with the results in LFA. The present work demonstrates the potential of PdNPs as labeling matrices in enzyme-free single-step immunoassays.

A highly sensitive electrochemical biosensor for microRNA122 detection based on a target-induced DNA nanostructure.

Specific and sensitive biomarker detection is significant for the early diagnosis of cancers. Herein, a highly sensitive electrochemical biosensor employing a tetrahedral DNA nanostructure (TDN) probe and multiple signal amplification strategies has been constructed, and successfully applied to microRNA-122 (miR-122) detection. The platform consisted of a TDN probe anchoring on a gold nanoparticle-coated gold electrode and multiple signal amplification procedures combining the electrodeposition of gold nanoparticles, hybridization chain reaction (HCR), and horseradish peroxidase enzymatic catalysis (HPEC). In the presence of the target, the hairpin structure of the helper probe could be opened and trigger the HCR through the hybridization of H1 and H2 probes, and then avidin-HRP was attached on the surface of the gold electrode that can produce an electro-catalytic signal. We used TDN probe as the scaffold to increase the reactivity and multiple signal amplification greatly improve the sensitivity of this biosensor. This biosensor offers an excellent sensitivity (a limit of detection of 0.74 aM) and differentiation ability for single and multiple mismatches. This multiplexing biosensor for trace microRNA detection shows promising applications in the early diagnosis of cancer.

Codonopsis pilosula Polysaccharides Alleviate Aß 1-40-Induced PC12 Cells Energy Dysmetabolism via CD38/NAD+ Signaling Pathway.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia and has a complex pathogenesis with no effective treatment. Energy metabolism disorders, as an early pathological event of AD,have attracted attention as a promising area of AD research. Codonopsis pilosula Polysaccharides are the main effective components of Codonopsis pilosula, which have been demonstrated to regulate energy metabolism. METHODS: In order to further study the roles and mechanisms of Codonopsis pilosula polysaccharides in AD, this study used an Aß1-40-induced PC12 cells model to study the protective effects of Codonopsis pilosula polysaccharides and their potential mechanisms in improving energy metabolism dysfunction. RESULTS: The results showed that Aß1-40 induced a decrease in PC12 cells viability, energy metabolism molecules (ATP, NAD+, and NAD+/NADH) and Mitochondrial Membrane Potential (MMP) and an increase in ROS. Additionally, it was found that Aß1-40 increased CD38 expression related to NAD+ homeostasis, whereas Silent Information Regulation 2 homolog1 (SIRT1, SIRT3), Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and SIRT3 activity were decreased. Codonopsis pilosula polysaccharides increased NAD+, NAD+/NADH, SIRT3, SIRT1, and PGC-1α related to NAD+, thus partially recovering ATP. CONCLUSION: Our findings reveal that Codonopsis pilosula polysaccharides protected PC12 cells from Aß1-40-induced damage, suggesting that these components of the Codonopsis pilosula herb may represent an early treatment option for AD patients.

Enhanced performance of a surface plasmon resonance-based immunosensor for the detection of glycocholic acid.

The concentration of glycocholic acid (GCA) in urine and blood is an important biomarker for liver cancer. Monitoring of GCA depends to a large extent on the availability of appropriate analytical techniques. In this work, based on the immobilization of GCA-OVA onto the sensor chip surface, a label-free competitive inhibition immunoassay for the determination of GCA with the surface plasmon resonance (SPR) technique was developed. The proposed SPR immunosensor is simple to prepare, recyclable and exhibits excellent sensitivity to GCA (a linear range of 13.3-119.4 ng mL-1 and a limit of detection (LOD) of 2.5 ng mL-1), which was 14 times lower than that of the traditional immunoassay. Excellent recoveries and correlation between these two methods were observed (R2 = 0.995). Hence, it can be proved that the SPR immunosensor could be used to achieve rapid and sensitive quantitative detection of GCA in real urine samples and meet clinical needs.

Design, synthesis and biological evaluation of novel pleuromutilin derivatives as potent anti-MRSA agents targeting the 50S ribosome.

A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC50 = 3.95 µM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.

A Pt-Ir nanocube amplified lateral flow immunoassay for dehydroepiandrosterone.

The traditional gold-nanoparticle-based lateral flow immunoassay (LFIA) cannot satisfy the requirements for the sensitive detection of dehydroepiandrosterone (DHEA) in human urine. To enhance the sensitivity of the LFIA, platinum-iridium nanocubes (Pt-Ir NCs) with high catalytic efficiency and stability were synthesized and labelled with polyclonal antibody (pAb) to form a pAb-Pt-Ir probe. For the detection of DHEA, a novel LFIA with Pt-Ir NCs as an optical label and an enhanced LFIA in which the peroxidase-like activity of the Pt-Ir NCs was triggered by the introduction of the chromogenic substrate 3-amino-9-ethyl-carbazole (AEC) were developed and compared with a LFIA with platinum nanocubes (PtNCs) as an optical label. The visual limit of detection was 0.5 ng mL-1 for Pt-Ir-LFIA and 0.05 ng mL-1 for AEC-enhanced Pt-Ir-LFIA, in comparison to 100 ng mL-1 for PtNCs-LFIA and 50 ng mL-1 for AEC-enhanced PtNCs-LFIA. The average recoveries from spiked urine samples ranged from 90.8% to 110.4%, with a coefficient of variation below 12.6%, suggesting the accuracy and reliability of our developed immunoassay. Achieving excellent sensitivity, specificity, and reproducibility, Pt-Ir-LFIA provided a promising platform for monitoring DHEA.

Bicyclic Ligand-Biased Agonists of S1P1: Exploring Side Chain Modifications to Modulate the PK, PD, and Safety Profiles.

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.