Dual targeting of TIGIT and PD-1 with a novel small molecule for cancer immunotherapy.

Immune checkpoint inhibitors have unveiled promising clinical prospects in cancer treatment. Nonetheless, their effectiveness remains restricted, marked by consistently low response rates and affecting only a subset of patients. The co-blockade of TIGIT with PD-1 has exhibited substantial anti-tumor effects. Notably, there is a dearth of reports on small-molecule inhibitors concurrently targeting both TIGIT and PD-1. In this study, we employed Microscale Thermophoresis (MST) to screen our laboratory's existing repository of small molecules. Our findings illuminated Gln(TrT) 's affinity for both TIGIT and PD-1, affirming its potential to effectively inhibit TIGIT/PVR and PD-1/PD-L1 pathways. In vitro co-culture experiments substantiated Gln(TrT)'s proficiency in restoring Jurkat T-cell functionality by blocking both TIGIT/PVR and PD-1/PD-L1 interactions. In the MC38 murine tumor model, Gln(TrT) emerges as a pivotal modulator, promoting the intratumoral infiltration and functional competence of CD8+ T cells. Furthermore, whether used as a monotherapy or in conjunction with radiotherapy, Gln(TrT) substantially impedes MC38 tumor progression, significantly extending the survival of murine subjects.

Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy.

BACKGROUND: Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative. METHODS: SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model. RESULTS: SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8+ T and M1-type macrophages into tumor sites, while also priming the function of CD8+ T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy. CONCLUSION: Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy.

Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy.

The immune checkpoint TIGIT/PVR blockade exhibits significant antitumor effects through activation of NK and CD8+ T cell-mediated cytotoxicity. Immune checkpoint blockade (ICB) could induce tumor ferroptosis through IFN-γ released by immune cells, indicating the synergetic effects of ICB with ferroptosis in inhibiting tumor growth. However, the development of TIGIT/PVR inhibitors with ferroptosis-inducing effects has not been explored yet. In this study, the small molecule Hemin that could bind with TIGIT to block TIGIT/PVR interaction was screened by virtual molecular docking and cell-based blocking assay. Hemin could effectively restore the IL-2 secretion from Jurkat-hTIGIT cells. Hemin reinvigorated the function of CD8+ T cells to secrete IFN-γ and the elevated IFN-γ could synergize with Hemin to induce ferroptosis in tumor cells. Hemin inhibited tumor growth by boosting CD8+ T cell immune response and inducing ferroptosis in CT26 tumor model. More importantly, Hemin in combination with PD-1/PD-L1 blockade exhibited more effective antitumor efficacy in anti-PD-1 resistant B16 tumor model. In summary, our finding indicated that Hemin blocked TIGIT/PVR interaction and induced tumor cell ferroptosis, which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

Boosting CO2 electrocatalysis through electrical double layer regulations.

Interfacial investigation for fine-tuning microenvironment has recently emerged as a promising method to optimize the electrochemical CO2 reduction system. The electrical double layer located at the electrode-electrolyte interface presents a particularly significant impact on electrochemical reactions. However, its effect on the activity and selectivity of CO2 electrocatalysis remains poorly understood. Here, we utilized two-dimensional mica flakes, a material with a high dielectric constant, to modify the electrical double layer of Ag nanoparticles. This modification resulted in a significant enhancement of current densities for CO2 reduction and an impressive Faradaic efficiency of 98% for CO production. Our mechanistic investigations suggest that the enhancement of the electrical double layer capacitance through mica modification enriched local CO2 concentration near the reaction interface, thus facilitating CO2 electroreduction.

Alloferon-1 ameliorates estrogen deficiency-induced osteoporosis through dampening the NLRP3/caspase-1/IL-1ß/IL-18 signaling pathway.

Alloferon-1 is an insect polypeptide that has anti-inflammatory, antitumor and antiviral activity. This study aimed to determine the effects of alloferon-1 on estrogen deficiency-induced osteoporosis and explore the associated mechanism using a murine model of ovariectomy (OVX)-induced osteoporosis. Results showed that alloferon-1 prevented ovariectomy­induced body weight gain, bone loss and bone mineral content reduction, affected biochemical markers of bone turnover, and restored the microstructure of bone trabeculae. Moreover, alloferon-1 suppressed the expression of the ovariectomy­mediated inflammatory cytokines in the vertebrae bone tissues, including nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (Caspase-1), interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) which were determined by immunofluorescence staining and western blot. Overall, the present study provides evidence for the effectiveness of alloferon-1 against estrogen deficiency-induced osteoporosis, suggesting an alternative drug or an auxiliary modulator for the treatment of postmenopausal osteoporosis (PMOP).

Bio-inspired design of NiFeP nanoparticles embedded in (N,P) co-doped carbon for boosting overall water splitting.

The design and synthesis of cost-effective and stable bifunctional electrocatalysts for water splitting via a green and sustainable fabrication way remain a challenging problem. Herein, a bio-inspired method was used to synthesize NiFeP nanoparticles embedded in (N,P) co-doped carbon with the added carbon nanotubes. The obtained Ni0.8Fe0.2P-C catalyst displayed excellent hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances in both alkaline and alkaline simulated seawater solutions. The optimal Ni0.8Fe0.2P-C/NF only needs overpotentials of 45 and 242 mV to reach the current density of 10 mA cm-2 under HER and OER working conditions in 1.0 M KOH solution, respectively. First-principles calculations revealed the presence of a strong interaction between the carbon layer and metal phosphide nanoparticles. Benefiting from this and carbon nanotubes modification, the fabricated Ni0.8Fe0.2P-C presents impressive stability, working continuously for 100 h without collapse. A low alkaline cell voltage of 1.56 V for the assembled Ni0.8Fe0.2P-C/NF//Ni0.8Fe0.2P-C/NF electrocatalyzer could afford a current density of 10 mA cm-2. Moreover, when integrated with a photovoltaic device, the bifunctional Ni0.8Fe0.2P-C electrocatalyst demonstrates application potential for sustainable solar-driven water electrolysis.

Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy.

PD-1/PD-L1 blockade has achieved substantial clinical results in cancer treatment. However, the expression of other immune checkpoints leads to resistance and hinders the efficacy of PD-1/PD-L1 blockade. T cell immunoglobulin and mucin domain 3 (TIM-3), a non-redundant immune checkpoint, synergizes with PD-1 to mediate T cell dysfunction in tumor microenvironment. Development of small molecules targeting TIM-3 is a promising strategy for cancer immunotherapy. Here, to identify small molecule inhibitors targeting TIM-3, the docking pocket in TIM-3 was analyzed by Molecular Operating Environment (MOE) and the Chemdiv compound database was screened. The small molecule SMI402 could bind to TIM-3 with high affinity and prevent the ligation of PtdSer, HMGB1, and CEACAM1. SMI402 reinvigorated T cell function in vitro. In the MC38-bearing mouse model, SMI402 inhibited tumor growth by increasing CD8+ T and natural killing (NK) cells infiltration at the tumor site, as well as restoring the function of CD8+ T and NK cells. In conclusions, the small molecule SMI402 shows promise as a leading compound which targets TIM-3 for cancer immunotherapy.

Hydrogen Isotope Separation Using Graphene-Based Membranes in Liquid Water.

Hydrogen isotope separation has been effectively achieved electrochemically by passage of gaseous H2/D2 through graphene/Nafion composite membranes. Nevertheless, deuteron nearly does not exist in the form of gaseous D2 in nature but as liquid water. Thus, it is a more feasible way to separate and enrich deuterium from water. Herein, we have successfully transferred monolayer graphene to a rigid and porous polymer substrate, PITEM (polyimide track-etched membrane), which could avoid the swelling problem of the Nafion substrate as well as keep the integrity of graphene. Meanwhile, defects in the large area of CVD graphene could be successfully repaired by interfacial polymerization resulting in a high separation factor. Moreover, a new model was proposed for the proton transport mechanism through monolayer graphene based on the kinetic isotope effect (KIE). In this model, graphene plays a significant role in the H/D separation process by completely breaking the O-H/O-D bond, which can maximize the KIE, leading to increased H/D separation performance. This work suggests a promising application for using monolayer graphene in the industry and proposes a pronounced understanding of proton transport in graphene.

Alloferon-1 ameliorates acute inflammatory responses in λ-carrageenan-induced paw edema in mice.

Alloferon-1 have been proposed as an effective peptide to enhance antitumoral immunity, antiviral defense and anti-inflammatory activity. This work aimed to assess anti-inflammatory effects of alloferon-1 against acute inflammation and histopathological deformations in λ-carrageenan-induced paw edema in mice. Systemic pretreatment with alloferon-1 (22.0 mg/kg) intraperitoneally injected mice showed a significant reduction in paw thickness and vascular permeability. Alloferon-1 prevented λ-carrageenan-evoked exudation and the neutrophil influx to the mouse pleura and the neutrophil migration into carrageenan-stimulated mouse air pouches based on the histopathological changes in the paw tissues. Administration of alloferon-1 also suppressed the expression of the inflammatory cytokines in the inflamed paw tissues such as tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP1), interleukin-5 (IL-5), etc. detected by Luminex liquid chip. Collectively, the present study provides evidences for the marked anti-inflammatory effects of alloferon-1 which might represent new therapeutic options for the treatment of acute inflammatory diseases.

The surface structure, stability, and catalytic performances toward O2 reduction of CoP and FeCoP2.

The systematic atomistic level investigation of low-index surface structures, stabilities, and catalytic performances of CoP and FeCoP2 towards the O2 reduction reaction (ORR) is vital for their applications. Employing first-principles calculations, it is revealed that CoP and FeCoP2 present the same surface stability in the order of (101) ≈ (011) > (111) > (001) > (110) > (010) > (100). They also possess a similar Wulff equilibrium crystal shape with (101) and (011) exposing the largest surface area. From the electronic view, FeCoP2 presents improved electronic conductivity compared with CoP. From the energy view, whether FeCoP2 delivers improved electrocatalytic activity toward the ORR with respect to CoP depends on the reactive surfaces and sites. Among the 4 surfaces considered, only CoP(101), FeCoP2(101) and FeCoP2(011) delivered ORR performances theoretically when the bridge metal-metal site acts as the reactive center, which makes CoP(011) the only exception. CoP(101)-bCo-Co and FeCoP2(011)-bFe-Co exhibit a larger thermodynamic limiting potential than FeCoP2(101)-bCo-Co, suggesting their higher performances toward the ORR. The last step of HO* desorption as the rate-limiting step accounts for 3/4. The third step of transformation from O* to HO* as the most sluggish step accounts for 1/4. The work function, d-band center, Bader charge, and electronic localization function calculations are performed to reveal the HO adsorption nature. The present work provides fundamental insight into the effect of Fe doping into CoP, the determination of the catalyst surface and the key species adsorption nature to guide the rational design of high-performance materials.

Deep Subdomain Learning Adaptation Network: A Sensor Fault-Tolerant Soft Sensor for Industrial Processes.

Sensor faults are non-negligible issues for soft sensor modeling. However, existing deep learning-based soft sensors are fragile and sensitive when considering sensor faults. To improve the robustness against sensor faults, this article proposes a deep subdomain learning adaptation network (DSLAN) to develop a sensor fault-tolerant soft sensor, which is capable of handling both sensor degradation and sensor failure simultaneously. Primarily, domain adaptation works for process data with sensor degradation in industrial processes. Being founded on the basic structure of deep domain adaptation, a novel subdomain learner is added to automatically learn the subdomain division, enabling DSLAN adaptable to multimode industrial processes. Notably, the subdomain structure of each sample follows a categorical distribution parameterized by output of the subdomain learner. Based on the designed subdomain learner, a new probabilistic local maximum mean discrepancy (PLMMD) is presented to measure the difference in distribution between source and target features. In addition, a generator for failure data imputation is integrated in the framework, making DSLAN handle sensor failure simultaneously. Finally, the Tennessee Eastman (TE) benchmark process and two real industrial processes are used to verify the effectiveness of the proposed method. With the fault tolerance ability, soft sensing technology will take a step toward practical applications.

Single-metal-atom catalysts supported on graphdiyne catalyze CO oxidation.

Single-metal-atom catalysts supported on graphdiyne (GDY) exhibit great potential for catalyzing low temperature CO oxidation in solving the increasingly serious environmental problems caused by CO emissions due to the high catalytic activity, clear structure, uniform metal distribution and low cost. First principle calculations were employed to study CO oxidation activities of four M@GDY single-atom catalysts (M = Pt, Rh, Cu, and Ni). For each catalyst, five possible reaction mechanisms including bi-molecular and tri-molecular reactions were discussed. According to the calculated reaction barriers, the preferred reaction pathway is via the bi-molecular Langmuir-Hinshelwood (BLH) ((CO + O2)* → OCOO* → CO2 + O*) route to yield the first CO2 molecule with 0.55, 0.51, and 0.53 eV as the energy barriers of the rate-limiting steps of Pt@GDY, Rh@GDY, and Cu@GDY, respectively, whereas for Ni@GDY, it switches to the tri-molecular Eley-Rideal (TER1) ((2CO)* + O2→ OCOOCO* → 2CO2) mechanism with the reaction barrier of the rate-limiting step being 1.27 eV. Based on the energy difference in the initial states of the five reaction mechanisms, TER1 is generally viable. No matter it is based on the calculated reaction barrier or the energy of the initial state of each mechanism, the non-noble Cu@GDY is supposed to be an efficient catalyst as the noble ones. The electronic properties are calculated to explain the bonding strength and origin of the catalytic performance. The GDY support plays an important role in the electron transfer process.

Genome-wide identification of the TIFY gene family in three cultivated Gossypium species and the expression of JAZ genes.

TIFY proteins are plant-specific proteins containing TIFY, JAZ, PPD and ZML subfamilies. A total of 50, 54 and 28 members of the TIFY gene family in three cultivated cotton species-Gossypium hirsutum, Gossypium barbadense and Gossypium arboretum-were identified, respectively. The results of phylogenetic analysis showed that these TIFY genes were divided into eight clusters. The different clusters of gene family members often have similar gene structures, including the number of exons. The results of quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed that different JAZ genes displayed distinct expression patterns in the leaves of upland cotton under treatment with Gibberellin (GA), methyl jasmonate (MeJA), Jasmonic acid (JA) and abscisic acid (ABA). Different groups of JAZ genes exhibited different expression patterns in cotton leaves infected with Verticillium dahliae. The results of the comparative analysis of TIFY genes in the three cultivated species will be useful for understanding the involvement of these genes in development and stress resistance in cotton.

Ultrasensitive detection of pepsinogen I and pepsinogen II by a time-resolved fluoroimmunoassay and its preliminary clinical applications.

A fast and highly sensitive assay for pepsinogen I (PG I) and pepsinogen II (PG II) by using time-resolved fluoroimmunoassay (TRFIA) detection technique has been developed for the determination of serum PG I and PG II against gastrointestinal diseases. On the noncompetitive assay, one monoclonal antibody (McAb) coated on wells was directed against a specific antigenic site on the PG I or PG II. The McAb, called as labelling McAb, was prepared with the europium-chelate of N-(p-isothiocyanatobenzyl)-diethylenetriamine-N,N,N,N-tetraacetic acid and directed against a different antigenic site on the PG I or PG II molecule. After bound/free separation by washing, the fluorescence counts of bound Eu(3+)-McAb were measured. The levels of PG in sera from patients or healthy volunteers were determined by PG I and PG II TRFIA using the autoDELFIA(1235) system. The measurement ranges of PG I-TRFIA were 3.5-328.0 microg L(-1) and those of PG II-TRFIA were 2.0-55.0 microg L(-1). The within-run and between-run CVs of the PG I-TRFIA were 1.9% and 4.7%, respectively, and those of PG II-TRFIA were 2.1% and 3.8%, respectively. The recovery rates of PG I-TRFIA and PG II-TRFIA were 102.7% and 104.6%, respectively. The detection limitations of PG I and PG II were 0.05 microg L(-1) and 0.02 microg L(-1), respectively. The dilution experiments showed the percentage of expected value of PG I-TRFIA was 93.2-102.3% and of PG II-TRFIA was 97.3-110.6%. The cross-reacting rate between PG I and PG II was negligible. The linear correlation of radioimmunoassay (RIA) and TRFIA measurements resulted in a correlation coefficient as 0.926 of PG I and as 0.959 of PG II. The europium-labelling McAbs were stable for at least one year at -20 degrees C, and the results of the TRFIA with same reagents were reproducible over one year as well. The means of 1600 healthy volunteers were 162.4+/-52.1 microg L(-1) for serum PG I, 11.7+/-6.8 microg L(-1) for serum PG II, and 13.8+/-7.4 for the PG I/PG II ratio. The normal ranges of Serum PG I levels for healthy volunteers were 58.2-266.6 microg L(-1), and those of serum PG II levels were less than 25.3 microg L(-1). The availability of a highly sensitive, reliable, and convenient PG-TRFIA method for quantifying PG will allow investigations into the possible diagnostic value of this analysis in various clinical conditions, including gastric carcinoma, duodenal ulcer, gastric ulcer and gastritis. The sensitivity and reproducibility of the assay were satisfactory for clinical applications.