The Effects of Hand Tremors on the Shooting Performance of Air Pistol Shooters with Different Skill Levels.

Physiologic hand tremors are a critical factor affecting the aim of air pistol shooters. However, the extent of the effect of hand tremors on shooting performance is unclear. In this study, we aim to explore the relationship between hand tremors and shooting performance scores as well as investigate potential links between muscle activation and hand tremors. In this study, 17 male air pistol shooters from China's national team and the Air Pistol Sports Center were divided into two groups: the elite group and the sub-elite group. Each participant completed 40 shots during the experiment, with shooters' hand tremors recorded using three-axis digital accelerometers affixed to their right hands. Muscle activation was recorded using surface electromyography on the right anterior deltoid, posterior deltoid, biceps brachii (short head), triceps brachii (long head), flexor carpi radialis, and extensor carpi radialis. Our analysis revealed weak correlations between shooting scores and hand tremor amplitude in multiple directions (middle-lateral, ML: r2 = -0.22, p < 0.001; vertical, VT: r2 = -0.25, p < 0.001), as well as between shooting scores and hand tremor complexity (ML: r2 = -0.26, p < 0.001; VT: r2 = -0.28, p < 0.001), across all participants. Notably, weak correlations between shooting scores and hand tremor amplitude (ML: r2 = -0.27, p < 0.001; VT: r2 = -0.33, p < 0.001) and complexity (ML: r2 = -0.31, p < 0.001) were observed in the elite group but not in the sub-elite group. Moderate correlation were found between the biceps brachii (short head) RMS and hand tremor amplitude in the VT and ML directions (ML: r2 = 0.49, p = 0.010; VT: r2 = 0.44, p = 0.025) in all shooters, with a moderate correlation in the ML direction in elite shooters (ML: r2 = 0.49, p = 0.034). Our results suggest that hand tremors in air pistol shooters are associated with the skill of the shooters, and muscle activation of the biceps brachii (long head) might be a factor affecting hand tremors. By balancing the agonist and antagonist muscles of the shoulder joint, shooters might potentially reduce hand tremors and improve their shooting scores.

Environment-Sensitive Fluorescent Probe Enables Assessment of Anaplastic Lymphoma Kinase Activity in Nonsmall Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) rearrangements have been identified as key oncogenic drivers of a subset of nonsmall cell lung cancer (NSCLC). The final chimeric protein of the fusion gene can be constitutively activated, which accounts for the growth and proliferation of ALK-rearranged tumors and thus strongly associates with cancer invasion and metastasis. Diagnostic tools enabling the visualization of ALK activity in a structure-function-based approach are highly desirable to determine ALK status and guide ALK tyrosine kinase inhibitor (ALK-TKI) treatment making. Here, we describe the design, synthesis, and application of a new environment-sensitive fluorescent probe HX16 by introducing an environment-sensitive fluorophore 4-sulfonamidebenzoxadiazole to visualize ALK activity in living cancer cells and tumor tissue slices (mouse model and human biopsy sample). HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity. Using flow cytometry and confocal microscopy, HX16 enables visualization of ALK activity in various cancer cells with distinct ALK fusion genes, as well as xenograft mouse models. Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.

DNA Methyltransferase 3A: a Significant Target for the Discovery of Inhibitors as Potent Anticancer Drugs.

DNA methyltransferase (DNMT) is a conserved family of Cytosine methylases, which plays a crucial role in the regulation of Epigenetics. They have been considered promising therapeutic targets for cancer. Among the DNMT family, mutations in the DNMT3A subtype are particularly important in hematologic malignancies. The development of specific DNMT3A subtype inhibitors to validate the therapeutic potential of DNMT3A in certain diseases is a significant task. In this review, we summarized the small molecule inhibitors of DNMT3A discovered in recent years and their inhibitory activities, and classified them based on their inhibitory mechanisms.

Novel thermo and ion-responsive copolymers based on metallo-base pair directed host-guest complexation for highly selective recognition of Hg2+ in aqueous solution.

The development of materials with highly selective recognition towards Hg2+ is of great significance in environmental monitoring. Herein, a novel thermo-responsive copolymer with Hg2+ recognition property is prepared via thermally-initiated copolymerization of 5'-O-Acryloyl 5-methyl-uridine (APU) and N-isopropylacrylamide (NIPAM). The chemical structure and stimuli-sensitive properties of poly(N-isopropylacrylamide-co-5-methyl-uridine) (P(NIPAM-co-APU)) linear polymers and hydrogel are thoroughly investigated. At the supramolecular level, P(NIPAM-co-APU) linear polymers could respond to both temperature and Hg2+ stimuli with highly selective recognition towards Hg2+ over other 18 metal ion species (at least 5 fold difference) and common anions. Upon capturing Hg2+ by APU units as host metal receptors, the lower critical solution temperature (LCST) of P(NIPAM-co-APU, PNU-7 and PNU-11) linear polymers are significantly shifted more than 10 °C due to the formation of stable APU-Hg2+-APU directed host-guest complexes. Accordingly, at the macroscopic level, P(NIPAM-co-APU) hydrogel display selective and robust recognition of Hg2+ under optimum conditions, and its maximum Hg2+ uptake capacity was 33.1 mg g-1. This work provides a new option for Hg2+ recognition with high selectivity, which could be facilely integrated with other smart systems to achieve satisfactory detection of environmental Hg2+.

The Src-Kinase Fyn is Required for Cocaine-Associated Memory Through Regulation of Tau.

Drug-associated context-induced relapse of cocaine-seeking behaviour requires the retrieval of drug-associated memory. Studies exploring the underlying neurobiological mechanism of drug memory formation will likely contribute to the development of treatments for drug addiction and the prevention of relapse. In our study, we applied a cocaine-conditioned place preference (CPP) paradigm and a self-administration paradigm (two drug-associated memory formation model) to confirm the hypothesis that the Src kinase Fyn critically regulates cocaine-associated memory formation in the hippocampus. For this experiment, we administered the Src kinase inhibitor PP2 into the bilateral hippocampus before cocaine-CPP and self-administration training, and the results showed that pharmacological manipulation of the Src kinase Fyn activity significantly attenuated the response to cocaine-paired cues in the cocaine-CPP and self-administration paradigms, indicating that hippocampal Fyn activity contributes to cocaine-associated memory formation. In addition, the regulation of cocaine-associated memory formation by Fyn depends on Tau expression, as restoring Tau to normal levels disrupted cocaine memory formation. Together, these results indicate that hippocampal Fyn activity plays a key role in the formation of cocaine-associated memory, which underlies cocaine-associated contextual stimulus-mediated regulation of cocaine-seeking behaviour, suggesting that Fyn represents a promising therapeutic target for weakening cocaine-related memory and treating cocaine addiction.

The effect of heel-to-toe drop of running shoes on patellofemoral joint stress during running.

BACKGROUND: Traditional running shoes with heel-to-toe drops is thought to be a contributor to increased patellofemoral joint stress, which is proposed as a mechanism of patellofemoral pain. RESEARCH QUESTION: Is there an increase in patellofemoral joint stress when running in shoes with drops compared to running in shoes without a drop? METHODS: Lower limbs kinematics and ground reaction force were collected from eighteen healthy runners during over-ground running in shoes with 15 mm, 10 mm, 5 mm drops, and without a drop. Patellofemoral joint force and stress were calculated from the kinematic and kinetic data using a biomechanical model of the patellofemoral joint. RESULTS: The peak patellofemoral joint stress was increased by more than 15% when running in shoes with 15 mm and 10 mm drops compared to running in shoes without a drop (p = 0.003, p = 0.001). The knee flexion angle was significantly increased when running in shoes with 15 mm, 10 mm and 5 mm drops (p = 0.014, p = 0.003, p = 0.002), the knee extension moment (p = 0.009, p = 0.002) and patellofemoral joint force (p = 0.003, p = 0.001) were increased when running in shoes with 15 mm and 10 mm drops, compared to running in shoes without a drop. SIGNIFICANCE: Compared to running in shoes without a drop, running in shoes with drops > 5 mm increase the peak patellofemoral joint stress significantly, which is mainly due to the increased knee extension moment.

A novel chemosensor for sensitive and facile detection of strontium ions based on ion-imprinted hydrogels modified with guanosine derivatives.

A novel chemosensor is developed for the sensitive and facile detection of trace strontium ions (Sr2+) based on the ion-imprinted hydrogels. With Sr2+ as the templates, the ion-imprinted hydrogels are synthesized by copolymerizing the ion-responsive units 5'-O-acryloyl-2',3'-O-isopropylidene guanosine (APG) and the thermo-responsive units N-isopropylacrylamide (NIPAM). In the presence of Sr2+, APG units can self-assemble to form planar G-quartets via the complexation with Sr2+, which are introduced into the gel network during polymerization. Then Sr2+ templates can be removed by multiple repeated washing. When re-exposed to Sr2+, the relaxed G-quartets can recognize Sr2+, leading to the weakening of electrostatic repulsion between the four oxygen atoms in the G-quartets and inducing the shrinkage of the hydrogels. In this work, the Sr2+-imprinted chemosensors are designed as the grating systems for detecting trace Sr2+. Based on the array of hydrogel strings synthesized on a nano-scale, the smart grating systems thus constructed can convert and amplify the Sr2+ concentration signals to the easily-measurable optical signals. With the Sr2+-imprinted hydrogel gratings, trace Sr2+ (10-11 M) in an aqueous solution can be detected sensitively. Moreover, the proposed Sr2+-imprinted chemosensors can be integrated with other smart systems for developing various detectors with high performance.

Two-photon ratiometric fluorescent probe for imaging of hypochlorous acid in acute lung injury and its remediation effect.

Acute lung injury (ALI) is a pulmonary inflammatory disease with high morbidity and mortality rates. However, owing to the unknown etiology and rapid progression of the disease, the diagnosis of ALI is full of challenges with no effective treatment. Since the inflammatory response and oxidative stress played vital roles in the development of ALI, we herein developed the largest emission cross-shift (△λ = 145 nm) two-photon ratiometric fluorescent probe of TPRS-HOCl with high selectivity and short response time toward hypochlorous acid (HOCl) for exploring the relevance between the degree of ALI and HOCl concentration in the development process of the disease. In addition, the inhibition effect of HOCl during different treatment periods was also evaluated. Moreover, the tendency of imaging results was basically in accordance with that of hematoxylin and eosin (H&E) staining and the treatment effect became better in the early stage when using N-acetylcysteine (NAC), demonstrating the sensitivity of TPRS-HOCl toward ALI response. Thus, TPRS-HOCl has great potential to diagnose ALI in the early stage and guide for effective treatment.

The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations.

EGFR mutations are an ongoing challenge in the treatment of NSCLC, and demand continuous updating of EGFR TKI drug candidates. Pyrrolopyrimidines are one group of versatile scaffolds suitable for tailored drug development. However not many precedents of this type of pharmacophore have been investigated in the realm of third generation of covalent EGFR-TKIs. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives able to block mutant EGFR activity in a covalent manner were synthesized, through optimized Buchwald-Hartwig C-N cross coupling reactions. Their preliminary bioactivity and corresponding inhibitory mechanistic pathways were investigated at molecular and cellular levels. Several compounds exhibited increased biological activity and enhanced selectivity compared to the control compound. Notably, compound 12i selectively inhibits HCC827 cells harboring the EGFR activating mutation with up to 493-fold increased efficacy compared to in normal HBE cells. Augmented selectivity was also confirmed by kinase enzymatic assay, with the test compound selectively inhibiting the T790 M activating mutant EGFRs (IC50 values of 0.21 nM) with up to 104-fold potency compared to the wild-type EGFR (IC50 values of 22 nM). Theoretical simulations provide structural evidence of selective kinase inhibitory activity. Thus, this series of pyrrolo[2,3-d]pyrimidine derivatives could serve as a starting point for the development of new EGFR-TKIs.

Differences in Gait Stability and Acceleration Characteristics Between Healthy Young and Older Females.

Our aim was to evaluate differences in gait acceleration intensity, variability, and stability of feet and trunk between older females (OF) and young females (YF) using inertial sensors. Twenty OF (mean age 68.4, SD 4.1 years) and 18 YF (mean age 22.3, SD 1.7 years) were asked to walk straight for 100 meters at their preferred speed, while wearing inertial sensors on their heels and lower back. We calculated spatiotemporal measures, foot and trunk acceleration characteristics, their variability, and trunk stability using the local divergence exponent (LDE). Two-way ANOVA (such as the factors foot and age), Student's t-test and Mann-Whitney U test were used to compare statistical differences of measures between groups. Cohen's d effects were calculated for each variable. Foot maximum vertical (VT) acceleration and amplitude, trunk-foot VT acceleration attenuation, and their variability were significantly smaller in OF than in YF. In contrast, trunk mediolateral (ML) acceleration amplitude, maximum VT acceleration, amplitude, and their variability were significantly larger in OF than in YF. Moreover, OF showed lower stability (i.e., higher LDE values) in ML acceleration, ML, and VT angular velocity of the trunk. Even though we measured healthy OF, these participants showed lower VT foot accelerations with higher VT trunk acceleration, lower trunk-foot VT acceleration attenuation, less gait stability, and more variability of the trunk, and hence, were more likely to fall. These findings suggest that instrumented gait measurements may help for early detection of changes or impairments in gait performance, even before this can be observed by clinical eye or gait speed.

Anomeric 5-Aza-7-deaza-2'-deoxyguanosines in Silver-Ion-Mediated Homo and Hybrid Base Pairs: Impact of Mismatch Structure, Helical Environment, and Nucleobase Substituents on DNA Stability.

Nucleoside configuration (α-d vs. ß-d), nucleobase substituents, and the helical DNA environment of silver-mediated 5-aza-7-deazaguanine-cytosine base pairs have a strong impact on DNA stability. This has been demonstrated by investigations on oligonucleotide duplexes with silver-mediated base pairs of α-d and ß-d anomeric 5-aza-7-deaza-2'-deoxyguanosines and anomeric 2'-deoxycytidines incorporated in 12-mer duplexes. To this end, a new synthetic protocol has been developed to access the pure anomers of 5-aza-7-deaza-2'-deoxyguanosine by glycosylation of either the protected nucleobase or its salt followed by separation of the glycosylation products by crystallization and chromatography. Thermal stability measurements were performed on duplexes with α-d/α-d and ß-d/ß-d homo base pairs or α-d/ß-d and ß-d/α-d hybrid pairs within two sequence environments, positions 6 or 7, of oligonucleotide duplexes. The respective Tm stability increases observed after silver ion addition differ significantly. Homo base pairs with ß-d/ß-d or α-d/α-d nucleoside combinations are more stable than α-d/ß-d hybrid base pairs. The positional switch of silver-ion-mediated base pairs has a significant impact on stability. Nucleobase substituents introduced at the 5-position of the dC site of silver-mediated base pairs affect base pair stability to a minor extent. Our investigation might lead to applications in the construction of bioinspired nanodevices, in DNA diagnostics, or metal-DNA hybrid materials.

Acyclic Janus-AT Nucleoside Host Channels Precisely Lock Water into Single-File Wires with Local Rotational Flexibility.

Confining polar water molecules to particular geometries demands sophisticated intermolecular interactions, and not many small synthetic molecules have accomplished such a task. Herein, regioisomeric acyclic Janus-AT nucleosides (1 and 2), with a self-complementary fused genetic alphabet and conformationally flexible side chains, have been selectively synthesized. 1 and 2 adopt disparate base-pair motifs from the π-π stacked hydrophobic base moieties and distinct hydrogen bond (HB) interconnections from the hydrophilic sugar residues, which in turn lead to divergent, intricate intermolecular interaction networks with different capacities to confine water molecules. Under the precise control of the host framework of the N8 -regioisomer, separate ordered single-file water wires can be locked through special three-HB clamps into unique inter- and intra-wire geometrical alignments. Localized dynamic synchronized rotations within the fixed framework coordinated by both the host hydroxy groups and guest water molecules were observed in a temperature-induced reversible single-crystal-to-single-crystal transition (SCSCT).

Functionalized Silver-Ion-Mediated α-dC/ß-dC Hybrid Base Pairs with Exceptional Stability: α-d-5-Iodo-2'-Deoxycytidine and Its Octadiynyl Derivative in Metal DNA.

Silver-mediated α-dC-Ag+ -ß-dC hybrid base pairs decorated with 5-iodo- or 5-octadiynyl residues are well accommodated in duplex DNA. A strong Tm increase and favorable thermodynamic data for duplex DNA were observed after addition of silver ions. The phenomenon is particularly obvious when both nucleobases of the base pairs are functionalized. Neither the position of the base pair, nor the type of 5-substituent had a negative influence. On the contrary, functionalization of conventional silver-mediated ß-dC-Ag+ -ß-dC homo base pairs showed a negative impact induced by the bulky substituents. To this end, cytosine modified 12-mer oligodeoxynucleotides were prepared by solid-phase synthesis employing new α-anomeric 2'-deoxycytidine phosphoramidites. A multigram scale synthesis was developed for 5-iodo-α-d-2'-deoxycytidine (1) employing the direct glycosylation of cytosine with Hoffer's α-d-halogenose followed by separation of anomeric DMT nucleosides. Regarding base-pair stability and functionalization silver-mediated α/ß-dC hybrid base pairs were found to be superior to ß/ß-dC homo pairs. According to their extraordinary properties, they might find applications in DNA diagnostics, material science, or nanotechnology.

Antiviral activities of Janus-type nucleosides and their related oxime-intermediates.

Herpes simplex virus (HSV) infection has been recognized as the most common mucosal disease in humans, manifesting as a life-threatening infection especially for patients with compromised immunity. When combined with the emergence of resistance due to the long-term use of classical antiviral agents, these threats make novel therapeutics for HSV a clinically necessity. We therefore designed and synthesized a series of Janus-type nucleosides by combining the natural genetic alphabets into a singular nucleoside structural unit. We also synthesized a series of new compounds and systematically evaluated their antiviral activity and structure-antiviral activity relationship. The results indicated that both nucleosides and their related intermediates exhibited high anti-HSV-1 activity. Compounds HY17 and HY19, in particular, possessed excellent anti-HSV-1 activity with IC50 values of 0.05 and 0.04 µg/mL, respectively. They also showed broad-spectrum antiviral activity against a multitude of diverse viruses, such as HSV-2, influenza virus A (H3N2), CVB3, HBV, HCV, and HPV. These results suggest that once their mechanisms are fully elucidated, these compounds will prove to be promising candidates as antiviral agents.

Supermacrocyclic Assemblies by Hydrogen-Bond Codes of C7-Phenol Pyrazolo and Pyrrolo Derivatives of Adenine.

Hydrogen bond (HB) mediated base pair motifs are versatile scaffolds of diverse supramolecular constructs. Here, we report that two new four- and six-membered supermacrocyclic assemblies with intriguing geometries could self-assemble from two new adenine derivatives, APN (1) and APC (2). The conversion of a conventional HB acceptor, N8 of 1, to a non-conventional HB donor, C8-H of 2, had a pronounced impact on the overall intricate HB network and self-assembly patterns, epitomizing the subtleties in design and exploitation of such base-pair motifs as promising tectons for building supramolecular architectures.

Highly Efficient Method for Suzuki Reactions in Aqueous Media.

Herein, we report the crystal structure and characterization of mono-6-(l-aminopropanol)-deoxy-ß-cyclodextrin (L n @ß-CD). A highly efficient, in situ generated catalyst, PdCl2(L n @ß-CD), was synthesized for palladium-catalyzed cross-coupling reactions under mild reaction conditions, and the use of this catalyst in Suzuki cross-couplings was investigated. Low palladium loadings of 0.01 mol % PdCl2(L n @ß-CD) (Pd accounted for approximately 8.4% of the catalyst by mass) were found to be highly efficient for Suzuki cross-couplings in water and afforded the corresponding biaryl compounds in excellent yields. The catalyst can be recycled and reused.

The readout of base-pair information in adenine-thymine α-D-Arabinonucleosides.

Structurally modified nucleosides are central players in the field of nucleic acid chemistry. Adenine-thymine (AT) pyrimido[4,5-d]pyrimidine furanosyl and pyranosyl arabinonucleosides have been synthesized for the first time. Single-crystal X-ray diffraction analysis reveals novel base pairs that, in synergy with the sugar residues, direct the emergence of distinct networks containing channels and cavities. The microscopic noncovalent connections can be translated into macroscopic levels in which robust organogels are formed by the furanoside but not the pyranoside. The influences of the sugars are also displayed by the different shaped superstructures of the free nucleosides in solution. The readout of the information in the base moiety is therefore tailored by the sugar configuration, and the interplays exert subtle effects on the structures, from solid to gel and to the solution state. The potential for forming these appealing base pairs and higher structures enables these intriguing nucleosides to serve as unique building blocks in various areas or to construct innovative nucleic acid structures.

Complex self-assembly of pyrimido[4,5-d]pyrimidine nucleoside supramolecular structures.

Supramolecular self-assembly is not only one of the chemical roots of biological structure but is also drawing attention in different industrial fields. Here we study the mechanism of the formation of a complex flower-shaped supramolecular structure of pyrimido[4,5-d]pyrimidine nucleosides by dynamic light scattering, scanning electron microscopy, differential scanning calorimetry, nuclear magnetic resonance and X-ray analysis. Upon removing the hydroxyl group of sugars, different flower-shaped superstructures can be produced. These works demonstrate that complex self-assembly can indeed be attained through hierarchical non-covalent interactions of single molecules. Furthermore, chimerical structures built from molecular recognition by these monomers indicate their potential in other fields if combined with other chemical entities.

A requirement of dendritic cell-derived interleukin-27 for the tumor infiltration of regulatory T cells.

Tregs (Foxp3+CD4+) are enriched in tumors to foster a tolerant microenvironment that inhibits antitumor immune response. IL-27 is reported to regulate the development and function of Tregs in vitro and in vivo; however, the effects of endogenous IL-27 on Tregs in the tumor microenvironment remain elusive. We demonstrated that in the absence of DC-derived IL-27, Tregs were decreased significantly in transplanted B16 melanoma, transplanted EL-4 lymphoma, and MCA-induced fibrosarcoma by using IL-27p28 conditional KO mice. Further studies revealed that IL-27 promoted the expression of CCL22, which is established to mediate the recruitment of peripheral Tregs into tumors. Tumor-associated DCs were identified as the major source of CCL22 in tumor sites, and IL-27 could induce CCL22 expression in an IL-27R-dependent manner. Intratumoral reconstitution of rmCCL22 or rmIL-27, but not rmIL-27p28, significantly restored the tumor infiltration of Tregs in IL-27p28 KO mice. Correlated with a decreased number of Tregs, tumor-infiltrating CD4 T cells were found to produce much more IFN-γ in IL-27p28 KO mice, which highlighted the physiological importance of Tregs in suppressing an antitumor immune response. Overall, our results identified a novel mechanism of action of IL-27 on Tregs in the context of cancers.

IL-4 induces a suppressive IL-10-producing CD8+ T cell population via a Cdkn2a-dependent mechanism.

CD8(+) T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL-10-producing CD8(+) T cells that were induced by IL-4. These IL-10(+)CD8(+) T cells possessed a strong inhibitory effect on the CD4(+) T cell proliferation in an IL-10-dependent and cell contact-dependent fashion. In comparison with IL-10(-)CD8(+) T cells, IL-10(+)CD8(+) T cells expressed an array of Th2-like cytokines (IL-4, IL-5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL-4-induced IL-10 production significantly. Furthermore, CD8(+) T cells from Cdkn2a(-/-) mice produced a significantly lower amount of IL-10, and the effect was limited to CD8(+) T cells but not observed in CD4(+) T cells and APCs. Finally, IL-10(+)CD8(+) T cells played a protective role in the TNBS-induced murine colitis model, indicating a critical role of this population of CD8(+) T cells in regulatory immune responses. Taken together, we have defined a population of IL-10-producing CD8(+) Tregs induced by IL-4 and mediated by Cdkn2a.