Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.

The shadowing effect of initial expectation on learning asymmetry.

Evidence for positivity and optimism bias abounds in high-level belief updates. However, no consensus has been reached regarding whether learning asymmetries exist in more elementary forms of updates such as reinforcement learning (RL). In RL, the learning asymmetry concerns the sensitivity difference in incorporating positive and negative prediction errors (PE) into value estimation, namely the asymmetry of learning rates associated with positive and negative PEs. Although RL has been established as a canonical framework in characterizing interactions between agent and environment, the direction of learning asymmetry remains controversial. Here, we propose that part of the controversy stems from the fact that people may have different value expectations before entering the learning environment. Such a default value expectation influences how PEs are calculated and consequently biases subjects' choices. We test this hypothesis in two learning experiments with stable or varying reinforcement probabilities, across monetary gains, losses, and gain-loss mixed environments. Our results consistently support the model incorporating both asymmetric learning rates and the initial value expectation, highlighting the role of initial expectation in value updating and choice preference. Further simulation and model parameter recovery analyses confirm the unique contribution of initial value expectation in accessing learning rate asymmetry.

The prognostic and biology of tumour-infiltrating lymphocytes in the immunotherapy of cancer.

Tumour immunotherapy has achieved remarkable clinical success in many different types of cancer in the past two decades. The outcome of immune checkpoint inhibitors in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell within the tumour microenvironment, suggesting that the immune landscape of a tumour is highly connected to patient response and prognosis. It is critical to understanding tumour immune microenvironments for identifying immune modifiers of cancer progression and developing cancer immunotherapies. The infiltration of solid tumours by immune cells with anti-tumour activity is both a strong prognostic factor and a therapeutic goal. Recent approaches and applications of new technologies, especially single-cell mRNA analysis in dissecting tumour microenvironments have brought important insights into the biology of tumour-infiltrating immune cells, revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune response. In this review, we will discuss recent advances in the understanding of tumour infiltrated lymphocytes, their prognostic benefit, and predictive value for immunotherapy.

Resilience, Insight, Self-Compassion, and Empowerment (RISE): A Randomized Controlled Trial of a Psychoeducational Group Program for Nurses.

BACKGROUND: Nurses tend to be vulnerable to burnout and compassion fatigue due to constant workplace stressors. There is a need to provide advocacy, education, programming, and resources in the areas of positive coping and self-care to reduce burnout symptoms and promote well-being. RISE is an 8-week psychoeducational group intervention for nurses with four themes: resilience, insight, self-compassion, and empowerment. AIMS: This randomized controlled trial examined the effects of RISE on mental well-being. METHODS: The sample included 75 registered nurses who work in a hospital-based setting. Outcomes included resilience, insight, self-compassion, empowerment, stress mind-set, perceived stress, and burnout. Independent-samples t tests were conducted to compare outcomes between intervention and wait-list control groups at baseline and 1-month follow-up, as well as at 3-month follow-up. Supplemental analyses included paired-samples t tests and linear mixed models to compare the outcomes of the intervention group participants at baseline to 1-month follow-up, as well as at 3-month and 6-month follow-ups. RESULTS: Participants in the intervention group showed improved levels of insight (i.e., engagement in self-reflection), perceived stress, and burnout (i.e., emotional exhaustion) when compared with the control group and improved levels of resilience, self-compassion, stress mind-set, and perceived stress when compared with their baseline. CONCLUSIONS: This study informs how RISE affects nurse well-being and may be an effective intervention for reducing burnout and stress. This type of whole-person intervention can support nurses to improve their well-being and ability to cope amid the complex interplay of factors at the individual, unit, and organizational levels.

Employment Status of Nurses After a Psychoeducational Group Intervention: A Matched Case-Control Study.

OBJECTIVE: This matched case-control study compared the long-term employment status of direct care nurses based on participation in a psychoeducational group intervention and calculated the estimated cost savings. BACKGROUND: Chronic stress, in addition to lack of support and low autonomy, can lead to burnout among nurses. Burnout is a common reason for job dissatisfaction and turnover. Interventions combining education with therapeutic processing and peer support may lead to healing and growth in nurses already experiencing the effects of chronic stress and burnout. The COVID-19 pandemic also contributed to stress among nurses. METHODS: Fifty-four direct care nurses who participated in the intervention were paired with 54 direct care nurses who did not participate, matched on the following variables: age, gender, race, work setting, and campus. RESULTS: This study found a higher percentage of direct care nurses who participated in the intervention remained employed compared with the matched control subjects who did not participate. CONCLUSION: At a relatively low cost compared with the cost of turnover by each nurse, the psychoeducational group intervention may provide an opportunity to improve retention among nurses.

Polarity- and Pressure-Induced Emission from a Benzophenone-Based Luminophore.

Since strong polarity usually causes emission quenching, materials with polarity-induced emission (PIE) are rarely reported despite their important applications in polar environments. Herein, an N-phenylcarbazole-substituted benzophenone derivative (BP-3-Cz) with a twisted electron donor-acceptor (D-A) structure is synthesized. The incorporation of heteroatoms into the twisted π-conjugated D-A backbone simultaneously endows BP-3-Cz with obvious polarity- and pressure-induced emission. Spectral analysis, X-ray diffraction, differential scanning calorimetry, and quantum chemical calculation results confirm that BP-3-Cz has special optical features related to the molecular conformation change and excited state turning to planarized intramolecular charge transfer with an increase in polarity or applied pressure. These findings contribute to the understanding of the PIE mechanism and the design of new PIE materials.

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study.

BACKGROUND & AIMS: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD. METHODS: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination. RESULTS: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m2 (IQR 23.8-28.1 kg/m2). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained. CONCLUSIONS: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD. LAY SUMMARY: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.

Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors.

Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.

One-pot intramolecular cyclization of 5-hydroxymethylcytosine for sequencing DNA hydroxymethylation at single-base resolution.

Here we establish a one-pot reaction to directly convert the DNA base 5-hydroxymethylcytosine (5hmC) to an intramolecular cyclization nucleobase, which loses both protons of the exocyclic N4-amino group and thus is recognized as thymine (T) by DNA polymerase. Based on this 5hmC-specific reaction, a prospective bisulfite-free strategy for 5hmC sequencing is proposed. This is also the first example to show modified DNA labeling in non-water solvent-dominant media for DNA sequencing.

The toxicity of cell therapy: Mechanism, manifestations, and challenges.

Adoptive cell therapy (ACT), including tumor-infiltrating lymphocytes (TILs), T cell receptor engineered T cell (TCR-T), and chimeric antigen receptor engineered T cell (CAR-T), has shown significant clinical benefits for cancer treatment. However, all of these ACT therapies are associated with toxicities from mild to life threatening in clinic. Common ACT-related toxicities include cytokine release syndrome (CRS) resulting from immune activation, neurological toxicity, on-target/off tumor or off-target toxicities, and toxicities associated with lymphodepletion preconditioning and high does IL-2 administration. This review summarizes clinical manifestations of adverse events associated with ACT treatment and discusses the underlying pathological mechanisms. Moreover, challenges and opportunities of managing ACT-related toxicities have been discussed to give an indication of how to improve the safety of ACT treatment without dampening the therapeutic effect.

miR-135b-dependent downregulation of S100B promotes neural stem cell differentiation in a hypoxia/ischemia-induced cerebral palsy rat model.

Cerebral palsy (CP) is frequently caused by brain injury during pregnancy, delivery, or the immediate postnatal period. The differentiation potential of neural stem cell (NSC) makes them effective in restoring injured tissues and organs with minimal risks of side effects. In this study, we identified a novel microRNA-135b (miR-135b) in CP and investigated its functional role in mediating NSC differentiation. CP models were established in Wistar rats and validated with the Y-maze test. Gain- and loss-of-function experimentation was performed on CP rats. Then NSCs were isolated and the expression patterns of miR-135b and S100B were altered in NSCs. S100B exhibited high expression in the hippocampus tissues of CP models, which was targeted by miR-135b. miR-135b elevation or S100B silencing resulted in promoted NSC differentiation, alleviated brain injury, and inhibited NSC apoptosis in hippocampus tissues of CP rats. S100B downregulation targeted by miR-135b overexpression contributed to the inactivation of the signal transducer and activator of transcription-3 (STAT3) pathway, which promoted NSC differentiation and proliferation but inhibited NSC apoptosis. Our results highlight the suppressor role played by miR-135b in CP by inducing NSC differentiation via inactivation of S100B-dependent STAT3 pathway.

Human representation of multimodal distributions as clusters of samples.

Behavioral and neuroimaging evidence shows that human decisions are sensitive to the statistical regularities (mean, variance, skewness, etc.) of reward distributions. However, it is unclear what representations human observers form to approximate reward distributions, or probability distributions in general. When the possible values of a probability distribution are numerous, it is cognitively costly and perhaps unrealistic to maintain in mind the probability of each possible value. Here we propose a Clusters of Samples (CoS) representation model: The samples of the to-be-represented distribution are classified into a small number of clusters and only the centroids and relative weights of the clusters are retained for future use. We tested the behavioral relevance of CoS in four experiments. On each trial, human subjects reported the mean and mode of a sequentially presented multimodal distribution of spatial positions or orientations. By varying the global and local features of the distributions, we observed systematic errors in the reported mean and mode. We found that our CoS representation of probability distributions outperformed alternative models in accounting for subjects' response patterns. The ostensible influence of positive/negative skewness on the over/under estimation of the reported mean, analogous to the "skewness preference" phenomenon in decisions, could be well explained by models based on CoS.

Single-strand DNA-scaffolded copper nanoclusters for the determination of inorganic pyrophosphatase activity and screening of its inhibitor.

A fluorescence method for the determination of inorganic pyrophosphatase (PPase) activity has been established based on copper nanoclusters (CuNCs). The polythymine of 40 mer (T40) acts as a template for the reduction reaction from Cu2+ to Cu0 by ascorbic acid (AA). This reaction leads to the formation of fluorescent CuNCs with excitation/emission peaks at 340/640 nm. However, the higher binding affinity between inorganic pyrophosphate (PPi) and Cu2+ hinders the effective formation of CuNCs. This shows low fluorescence intensity. PPase catalyzes the hydrolysis of PPi into Pi during which free Cu2+ ions are produced. This facilitates the formation of fluorescent CuNCs. Thus, the fluorescence intensity was restored. The fluorescence enhancement of the system has a linear relationship with PPase activity in the range 0.3 to 20 mU·mL-1, and the detection limit is0.2 mU·mL-1. The relative intensity (I/I0) at 640 nm for the analytical solution versus system is also employed to screen the inhibitor for PPase with high efficiency. Graphical abstract Schematic representation of a fluorescent assay for the determination of inorganic pyrophosphatase activity and screening its inhibitor based on single-strand polythymine-scaffolded copper nanoclusters.

DNA-scaffold copper nanoclusters integrated into a cerium(III)-triggered Fenton-like reaction for the fluorometric and colorimetric enzymatic determination of glucose.

A fluorometric and colorimetric method are described for the determination of hydrogen peroxide and glucose by integrating copper nanoclusters (CuNCs) into a Fenton-like reaction. The mechanism mainly depends on the fast formation of long-strand DNA-templated CuNCs with strong red fluorescence (with excitation/emission maxima at 340/640 nm) in the absence of H2O2. The DNA can be cleaved into short-oligonucleotide fragments by hydroxy radicals as formed in the Ce(III)-triggered Fenton-like reaction in the presence of H2O2. As a result, short-strand DNA loses the ability as a template for the formation of CuNCs. This leads to a decrease of fluorescence. The colorimetric assay, in turn, is based on the oxidation of colorless Ce(III) ions to the distinctly yellow Ce(IV) ions (with an absorption maximum at 400 nm) by H2O2. Compared with those assays based on the use of enzyme mimics, this method does not require any chromogenic substrates such as ABTS and TMB. Based on the dual-signal readout platform, we successfully achieved the detection of H2O2 and glucose. LODs are as low as 0.266 µM and 2.92 µM. The methods were applied to the sensitive determination of glucose by using glucose oxidase (GOx) which catalyzes the oxidization of glucose to produce H2O2. The practical application was demonstrated by determination of glucose in human serum, with apparent recoveries of 98.4-101.9% and 99.1-105.6%, respectively. The concentration of glucose ranges from 1 to 500 µM and 50 to 600 µM based on the dual-signal readout platform, respectively. This fluorometric and colorimetric dual-mode strategy will pave a new avenue for constructing effective assays for H2O2-related analytes in biochemical and clinical applications. Graphical abstractSchematic representation of a fluorometric and colorimetric dual-readout strategy for the sensitive determination of hydrogen peroxide and glucose. The assay has been designed by integrating copper nanoclusters into a Ce(III)-triggered Fenton-like reaction.

Iodide-assisted silver nanoplates for colorimetric determination of chromium(III) and copper(II) via an aggregation/fusion/oxidation etching strategy.

The authors have studied the role of different ligands on the surfaces of silver nanoplates for regulating their analytical applications. Citrate-capped silver nanoplates are applied for the detection of chromium ions (Cr3+) based on aggregation of silver nanoplates. Cr3+ can cause aggregation through high affinity between Cr3+ and carboxylate groups of citrates, resulting in a color change from dark yellow to purple and at last colorless. The detection limit is 8.0 nM. This system shows excellent selectivity in the presence of a variety of other metal ions. Further, silver nanoplates coupled with iodide ions are employed for the colorimetric determination of copper ions (Cu2+) based on a new strategy of fusion/oxidation etching nanoplates. When Cu2+ is introduced into this silver nanoplate system, Cu2+ can oxidize I- to iodine (I2), which can further oxidize silver to form silver iodide (AgI). Simultaneously, the solution color changes from dark yellow to colorless. The lower limit detection is 0.27 µM. This assay exhibits excellent selectivity for Cu2+ over other environmental metal ions. It is perceived that this design concept will open up a fresh insight of simple, rapid and reliable detection of other heavy metal ions in drinking water and environmental samples. Graphical abstract Iodide-assisted silver nanoplates can be used for the colorimetric and visual ldetermination of Cr3+ and Cu2+ based on an aggregation/fusion/oxidation etching mechanism. These systems allows selective and sensitive determination of the ions in real samples.

DNA-templated copper nanoclusters as a fluorescent probe for fluoride by using aluminum ions as a bridge.

A selective fluorescent on-off-on probe has have designed for the detection of fluoride (F-) ions based on DNA-templated copper nanocluster (CuNCs) and by using aluminum(III) ions as a bridge. A 40-mer polythymine acts as a template for the reduction of Cu(II) to Cu(0) by ascorbic acid. This result is the formation of red fluorescent CuNCs, with excitation/emission peaks at 340/640 nm. After addition of Al3+ ions, the fluorescence of CuNCs is quenched because the interaction of Al3+ and DNA disturbs the formation of DNA-templated CuNCs. Fluorescence is restored on addition of fluoride to the system. This is due to the desorption of Al3+ from the DNA and the formation of the Al(OH)3F- complex. This system displays a fast fluorometric response to fluoride, with high selectivity over other anions. Fluorescence increases linearly in the 2 to 150 µM F- concentration range, and the detection limit is 1.0 µM. This probe has been successfully used for the detection of F- ions in four brands of toothpaste. The method is rapid, cost-effective, selective, and does not require toxic solvents and reagents. Graphical abstract Schematic presentation of a method for fluorometric determination of fluoride by using DNA-templated copper nanoclusters (CuNCs) and using aluminum(III) as a bridge. The red fluorescence of the CuNCs is quenched in the presence of Al(III) ions but restored after addition of fluoride.

Potential exposure to metals and health risks of metal intake from Tieguanyin tea production in Anxi, China.

The metal content of Tieguanyin tea from Anxi, Southeast China, was studied. Leaching experiments were designed based on the local tea-drinking habits, and tea infusions were prepared using three types of water and two methods of soaking tea. Twelve metals (Cd, As, Cr, Pb, Se, Sb, Ag, Tl, Cu, Zn, Be, and Ba) were measured by inductively coupled plasma mass spectrometry (ICP-MS), and a human health risk assessment was performed. The results showed that the quality of water used for steeping tea has a direct effect on the leaching concentrations of metals in the tea infusion and this effect can be reduced by using pure water or commercially available drinking water. Further, the two tea-soaking methods used by local residents can reduce the metal intake. The health risk assessment determined that the carcinogenic risk values of Cr, As, and Pb (Cr > Pb > As) were within an acceptable range (10-7-10-4); therefore, the concentrations of these metals in tea infusions do not pose substantial carcinogenic risk to tea drinkers. The results also indicate that the high concentrations of Tl in the tea infusions pose a substantial noncarcinogenic risk and may result from the dissolution characteristics of Tl and the water quality.

Excitation Wavelength Dependent Fluorescence of an ESIPT Triazole Derivative for Amine Sensing and Anti-Counterfeiting Applications.

Excitation wavelength dependent (Ex-De) emission materials have potential applications in anti-counterfeiting labels and bioimaging. Nevertheless, few purely organic chromophores are used in these areas. In this study, multiple excited states were incorporated into a molecule that was excited state intramolecular proton transfer (ESIPT) active, with the goal of manipulating the relaxation pathways of the excited states. The triazole derivative exhibits Ex-De photoluminescence (PL), and the maximum PL wavelength is located at 526 nm and 593 nm under a series of excitation wavelengths. Spectral identification indicates that the excimer and ESIPT processes are responsible for the green (526 nm) and orange (593 nm) fluorescence, respectively. Importantly, the quick response code and test strip prepared with this triazole derivative can be used for anti-counterfeiting and food spoilage detection applications, respectively. This research opens the door for developing novel Ex-De materials for anti-counterfeiting purposes.

Dispersion-aggregation-dispersion colorimetric detection for mercury ions based on an assembly of gold nanoparticles and carbon nanodots.

Mercury is a common heavy metal element in natural systems and is highly toxic to the human body. Herein, a novel colorimetric detection of Hg2+ ions is proposed based on the aggregation of gold nanoparticles (AuNPs) induced by carbon quantum dots (CDs) with the assistance of glutathione (GSH). In this sensing system, the AuNP/CDs composite forms through Au-N bonds. Simultaneously, the color of the solution turns from wine red to blue. The well-dispersed AuNPs can be restored after the addition of GSH, because GSH competes with CDs to bind onto the surface of AuNPs and protect AuNPs from aggregation. In the presence of Hg2+ ions, GSH can chelate with Hg2+ to form a complex, which subsequently enables CDs to facilitate the aggregation of the AuNPs again. Therefore, according to the red-to-blue color change, a colorimetric sensor is established for the sensitive and selective detection of Hg2+ with a detection limit of 7.5 nM. Moreover, this sensor is successfully used to detect Hg2+ spiked in environmental water. This very simple and cost-effective strategy will promote the development of a colorimetric sensor for the determination of other metal ions in biological and environmental fields.

Transport of imidazolium-based ionic liquids with different anion/cation species in sand/soil columns.

Ionic liquids (ILs) have been widely used as environmentally friendly solvents to replace volatile organic solvents in the chemistry industries. They have a high water solubility and potential risk to organisms in the soil-water environment. At present, most studies focused on the batch sorption of ILs in soil and neglected the investigation of IL transports in soil, which results in a lack of understanding of the structure-dependent mobility of ILs in the environment. Laboratory-scale sand/soil column experiments were performed to study the transport of imidazolium-based ILs, such as [C4mim][OTF], [C4mim][TOS], [C4mim][MeSO3], [C4mim][BF4], [C2mim][BF4], and [C6mim][BF4] including different counteranions and alkyl chain lengths of IL cations. Batch experiments were also carried out to compare the difference of sorption distribution coefficient (Kd) between the batch and column experiments. A one-dimensional convective-dispersive model using CXTFIT code was created based on the measured breakthrough curves (BTCs) to estimate the column transport parameters. For the anion, [BF4-], the Kd of ILs in both batch and column experiments increased with increasing alkyl chain lengths of the IL cation. In batch tests, counteranions showed no influence on the Kd of [C4mim][OTF], [C4mim][TOS], [C4mim][MeSO3], [C4mim][BF4], [C2mim][BF4], and [C6mim][BF4]. However, in column tests, the BTCs of 1-butyl-3-methylimidazolium-based ILs were anion dependent as evidenced by the change of retardation factor (R) for different counteranions. Furthermore, the effects of transport distance (11cm, 15cm, 19cm, and 24cm) on the mobility of ILs were estimated. The longer distances signified an increase in the contact time and more binding sites for ILs and therefore, the smoother shapes of BTCs in column experiments.