Novel Conductive AgNP-Based Adhesive Based on Novel Poly (Ionic Liquid)-Based Waterborne Polyurethane Chloride Salts for E-Textiles.

The emergence of novel e-textile materials that combine the inherent qualities of the textile substrate (lightweight, soft, breathable, durable, etc.) with the functionality of micro/nano-electronic materials (conductive, dielectric, sensing, etc.) has resulted in a trend toward miniaturization, integration, and intelligence in new electronic devices. However, the formation of a conductive network by micro/nano-conductive materials on textiles necessitates high-temperature sintering, which inevitably causes substrate aging and component damage. Herein, a bis-hydroxy-imidazolium chloride salt as a hard segment to synthesize a waterborne polyurethane (WPU) adhesive is designed and prepared. When used in nano-silver-based printing coatings, it offers strong adherence for coatings, reaching 16 N cm-1; on the other hand, the introduction of chloride ions enables low-temperature (60 °C) chemical sintering to address the challenge of secondary treatment and high-temperature sintering (>150 °C). Printed into flexible circuits, the resistivity can be controlled by the content of imidazolium salts anchored in the molecular chain of the WPU from a maximum resistivity of 3.1 × 107 down to 5.8 × 10-5 Ω m, and it can conduct a Bluetooth-type finger pulse detector with such low resistivity. As a flexible circuit, it also offers high stability against washing and adhesion, which the resistivity only reduces less than 20% after washing 10 times and adhesion. Owing to the adjustability of the resistivity, we fabricated an all-textile flexible pressure sensor that accurately differentiates different external pressures (min. 10 g, ~29 Pa), recognizes forms, and detects joint motions (finger bending and wrist flexion).

An Intrinsic Self-Healable, Anti-Freezable and Ionically Conductive Hydrogel for Soft Ionotronics Induced by Imidazolyl Cross-Linker Molecules Anchored with Dynamic Disulfide Bonds.

Hydrogels are ideal materials for flexible electronic devices based on their smooth ion channels and considerable mechanical flexibility. A substantial volume of aqueous solution is required to enable the smooth flow of ions, resulting in the agony of low-temperature freezing; besides, long-term exposure to bending/tensile tress triggers fatigue issues. Therefore, it is a great challenge to prepare hydrogels with both freeze-resistance and long-term durability. Herein, a polyacrylic acid-based hydrogel with both hydrophobic interaction and dynamic reversible covalent bonding cross-linking networks is preparing (DC-hydrogel) by polymerizing a bi-functional imidazole-type ionic liquid monomer with integrated disulfide and alkene bonds (DS/DB-IL) and an octadecyl methacrylate, achieving self-healing. The DS/DB-IL anchored into the polymer backbone has a high affinity with water, reducing the freezing point of water, while the DS/DB-IL with free ions provides superior ionic conductivity to the DC-hydrogel. The polyacrylic acid with abundant carboxyl gives hydrogel good self-adhesiveness to different substrates. Ionotronics with resistance-type sensors with stable output performance are fabricated and explored its application to joint motion and health information. Moreover, hydrogel-based sensing arrays with high resolution and accuracy are fabricated to identify 2D distribution of stress. The hydrogels have great promise for various ionotronics in many fields.

Molecular evidence for the adaptive evolution in euryhaline bivalves.

Marine bivalves inhabiting intertidal and estuarine areas are frequently exposed to salinity stress due to persistent rainfall and drought. Through prolonged adaptive evolution, numerous bivalves have developed eurysalinity, which are capable of tolerating a wide range of salinity fluctuations through the sophisticated regulation of physiological metabolism. Current research has predominantly focused on investigating the physiological responses of bivalves to salinity stress, leaving a significant gap in our understanding of the adaptive evolutionary characteristics in euryhaline bivalves. Here, comparative genomics analyses were performed in two groups of bivalve species, including 7 euryhaline species and 5 stenohaline species. We identified 24 significantly expanded gene families and 659 positively selected genes in euryhaline bivalves. A significant co-expansion of solute carrier family 23 (SLC23) facilitates the transmembrane transport of ascorbic acids in euryhaline bivalves. Positive selection of antioxidant genes, such as GST and TXNRD, augments the capacity of active oxygen species (ROS) scavenging under salinity stress. Additionally, we found that the positively selected genes were significantly enriched in KEGG pathways associated with carbohydrates, lipids and amino acids metabolism (ALDH, ADH, and GLS), as well as GO terms related to transmembrane transport and inorganic anion transport (SLC22, CLCND, and VDCC). Positive selection of MCT might contribute to prevent excessive accumulation of intracellular lactic acids during anaerobic metabolism. Positive selection of PLA2 potentially promote the removal of damaged membranes lipids under salinity stress. Our findings suggest that adaptive evolution has occurred in osmoregulation, ROS scavenging, energy metabolism, and membrane lipids adjustments in euryhaline bivalves. This study enhances our understanding of the molecular mechanisms underlying the remarkable salinity adaption of euryhaline bivalves.

Autophagy contributes to increase the content of intracellular free amino acids in hard clam (Mercenaria mercenaria) during prolonged exposure to hypersaline environments.

Marine bivalves in intertidal zones and land-based seawater ponds are constantly subjected to a wide range of salinity fluctuations due to heavy rainfall, intense drought, and human activities. As osmoconformers, bivalves rely primarily on rapid release or accumulation of free amino acids (FAAs) for osmoregulation. Euryhaline bivalves are capable of withstanding hyposaline and hypersaline environments through regulation of physiology, metabolism, and gene expression. However, current understanding of the molecular mechanisms underlying osmoregulation and salinity adaptation in euryhaline bivalves remains largely limited. In this study, RNA-seq, WGCNA and flow cytometric analysis were performed to investigate the physiological responses of hard clams (Mercenaria mercenaria) to acute short-term hyposalinity (AL) and hypersalinity (AH), and chronic long-term hyposalinity (CL) and hypersalinity (CH) stress. We found that amino acids biosynthesis was significantly inhibited and aminoacyl-tRNA biosynthesis was augmented to decrease intracellular osmolarity during hyposaline exposure. Under CH, numerous autophagy-related genes (ATGs) were highly expressed, and the autophagy activity of gill cells were significantly up-regulated. A significant decrease in total FAAs content was observed in gills after NH4Cl treatment, indicating that autophagy was crucial for osmoregulation in hard clams during prolonged exposure to hypersaline environments. To prevent premature or unnecessary apoptosis, the expression of cathepsin L was inhibited under AL and AH, and inhibitors of apoptosis was augmented under CL and CH. Additionally, neuroendocrine regulation was involved in salinity adaption in hard clams. This study provides novel insights into the physiological responses of euryhaline marine bivalves to hyposaline and hypersaline environments.

Scaphopoda is the sister taxon to Bivalvia: Evidence of ancient incomplete lineage sorting.

The almost simultaneous emergence of major animal phyla during the early Cambrian shaped modern animal biodiversity. Reconstructing evolutionary relationships among such closely spaced branches in the animal tree of life has proven to be a major challenge, hindering understanding of early animal evolution and the fossil record. This is particularly true in the species-rich and highly varied Mollusca where dramatic inconsistency among paleontological, morphological, and molecular evidence has led to a long-standing debate about the group's phylogeny and the nature of dozens of enigmatic fossil taxa. A critical step needed to overcome this issue is to supplement available genomic data, which is plentiful for well-studied lineages, with genomes from rare but key lineages, such as Scaphopoda. Here, by presenting chromosome-level genomes from both extant scaphopod orders and leveraging complete genomes spanning Mollusca, we provide strong support for Scaphopoda as the sister taxon of Bivalvia, revitalizing the morphology-based Diasoma hypothesis originally proposed 50 years ago. Our molecular clock analysis confidently dates the split between Bivalvia and Scaphopoda at ~520 Ma, prompting a reinterpretation of controversial laterally compressed Early Cambrian fossils, including Anabarella, Watsonella, and Mellopegma, as stem diasomes. Moreover, we show that incongruence in the phylogenetic placement of Scaphopoda in previous phylogenomic studies was due to ancient incomplete lineage sorting (ILS) that occurred during the rapid radiation of Conchifera. Our findings highlight the need to consider ILS as a potential source of error in deep phylogeny reconstruction, especially in the context of the unique nature of the Cambrian Explosion.

ROS-induced moderate autophagy of haemocytes confers resistance of Mercenaria mercenaria to air exposure stress.

Air exposure (AE) is a significant environmental stressor that can lead to desiccation, hypoxia, starvation, and disruption of cellular homeostasis in marine bivalves. Autophagy is a highly conserved catabolic pathway that facilitates the degradation of damaged macromolecules and organelles, thereby supporting cellular stress responses. To date, autophagy-mediated resistance mechanisms to AE stress remain largely elusive in bivalves. In this study, we performed a multi-tool approach to investigate the autophagy-related physiological regulation in hard clams (Mercenaria mercenaria) under different duration of AE (T = 0, 1, 5, 10, 20, 30 days). We observed that autophagy of haemocytes was significantly activated on day 5. However, autophagy activity began to significantly decline from day 10 to day 30. Autophagy was significantly inhibited after antioxidant treatment, indicating that reactive oxygen species (ROS) was an endogenous inducer of autophagy. A significant decline in the survival rate of hard clams was observed after injection of ammonium chloride or carbamazepine during AE stress, suggesting that moderate autophagy was conducive for clam survival under AE stress. We also observed DNA breaks and high levels of apoptosis in haemocytes on day 10. Activation of apoptosis lagged behind autophagy, and the relationship between autophagy and apoptosis might shift from antagonism to synergy with the duration of stress. This study provides novel insights into the stress resistance mechanisms in marine bivalves.

Location optimization of fresh food e-commerce front warehouse.

The ongoing emergence of COVID-19 and the maturation of cold chain technology, have aided in the rapid development of the fresh produce e-commerce industry. Taking into account the characteristics of consumers' demand for fresh products, this paper constructs a location allocation model of a front warehouse for fresh e-commerce with the objective of minimizing the total cost. An improved immune optimization algorithm is proposed in this paper, and the effectiveness of the proposed algorithm is demonstrated by a real case study. The results show that the improved immune optimization algorithm outperforms the traditional genetic algorithm in terms of solution accuracy; the proposed location model can effectively help fresh produce e-commerce enterprises open new front-end warehouses when demand is increasing, as well as provide optimal economic decision-making for front warehouse layout.

Chromosome-level genome assembly of the caenogastropod snail Rapana venosa.

The carnivorous gastropod Rapana venosa (Valenciennes, 1846) is one of the most notorious ecological invaders worldwide. Here, we present the first high-quality chromosome-scale reference R. venosa genome obtained via PacBio sequencing, Illumina paired-end sequencing, and high-throughput chromosome conformation capture scaffolding. The assembled genome has a size of 2.30 Gb, with a scaffold N50 length of 64.63 Mb, and is anchored to 35 chromosomes. It contains 29,649 protein-coding genes, 77.22% of which were functionally annotated. Given its high heterozygosity (1.41%) and large proportion of repeat sequences (57.72%), it is one of the most complex genome assemblies. This chromosome-level genome assembly of R. venosa is an important resource for understanding molluscan evolutionary adaption and provides a genetic basis for its biological invasion control.

Integrated mRNA and miRNA transcriptomic analysis reveals the response of Rapana venosa to the metamorphic inducer (juvenile oysters).

Metamorphosis, as a critical developmental event, controls the population dynamics of most marine invertebrates, especially some carnivorous gastropods that feed on bivalves, whose population dynamics not only affect the maintenance of the ecological balance but also impact the protection of bivalve resources; therefore, the metamorphosis of carnivorous gastropods deserve attention. Here, we investigated the mechanism underlying the response of the carnivorous gastropod Rapana venosa to its metamorphic inducer juvenile oysters through integrated analysis of miRNA and mRNA profiles. According to the results, we speculated that the AMPK signaling pathway may be the critical regulator in the response to juvenile oysters in R. venosa competent larvae. The NF-kB and JAK-STAT signaling pathways that regulated apoptosis were also activated by the metamorphic inducer, which may result in the degeneration of the velum. Additionally, the significant changes in the expression of the SARP-19 precursor gene and protein cibby homolog 1-like gene may indicate that these signaling pathways also regulate growth and development during metamorphosis. This study provides further evidence that juvenile oysters can induce metamorphosis of R. venosa at the transcriptional level, which expands our understanding of the metamorphosis mechanism in carnivorous gastropods.

Effect of heat and hypoxia stress on mitochondrion and energy metabolism in the gill of hard clam.

Aquatic animals suffer from heat and hypoxia stress more frequently due to global climate change and other anthropogenic activities. Heat and hypoxia stress can significantly affect mitochondrial function and energy metabolism. Here, the response and adaptation characteristics of mitochondria and energy metabolism in the gill of the hard clam Mercenaria mercenaria under heat (35 °C), hypoxia (0.2 mg/L), and heat plus hypoxia stress (35 °C, 0.2 mg/L) after 48 h exposure were investigated. Mitochondrial membrane potentials were depolarized under environmental stress. Mitochondrial fusion, fission and mitophagy played a key role in maintain mitochondrion function. The AMPK subunits showed different expression under environmental stress. Acceleration of enzyme activities (phosphofructokinase, pyruvate kinase and lactic dehydrogenase) and accumulation of anaerobic metabolites in glycolysis and TCA cycle implied that the anaerobic metabolism might play a key role in providing energy. Accumulation of amino acids might help to increase tolerance under heat and heat combined hypoxia stress. In addition, urea cycle played a key role in amino acid metabolism to prevent ammonia/nitrogen toxicity. This study improved our understanding of the mitochondrial and energy metabolism responses of marine bivalves exposed to environmental stress.

Molecular response and developmental speculations in metamorphosis of the veined rapa whelk, Rapana venosa.

Metamorphosis is the short developmental stage characterized by dramatic ontogenetic changes that occurs in most animals. However, this important process remains largely unclear in marine invertebrates. In this study, we performed the sequential RNA sequencing of a representative mollusk, the rapa whelk (Rapana venosa), that is undergoing metamorphosis and conducted differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to investigate the overall and dynamic transcriptome responses. The results revealed that the expression of cytochrome P450 2A and 3A were upregulated during metamorphosis, while the expression of H/ACA ribonucleoproteins increased 4 h after metamorphosis induction (M4 stage), indicating that R. venosa mainly responded to the pelagobenthic changes. At the M24 stage, the enrichment of V-type proton ATPase and insulin indicated the complete development of secretory organs and initiation of hormone secretion. Furthermore, at the M48 stage, the enrichment of zinc metalloproteinase and conotoxin indicated a well-developed predation system that requires exogenous nutrition. Finally, during the PL stage, the genes associated with growth control were highly enriched, implying that R. venosa had completed metamorphosis and has entered the period of rapid growth. Therefore, our study provides useful transcriptomic resources for R. venosa and contributes new insights that may assist in elucidating the mechanisms underlying metamorphosis in marine invertebrates.

Highly selective NH3 gas sensor based on Co(OH)2/Ti3C2T x nanocomposites operating at room temperature.

Ammonia (NH3) is a common air pollutant and is a biomarker for kidney disease. Therefore, the preparation of ammonia gas sensors with high sensitivity, good selectivity and low operating temperature is of great importance for health protection. Using the in situ electrostatic self-assembly approach, a chemoresistive gas sensor based on Co(OH)2/Ti3C2T x hybrid material was created in this study. The prepared samples were characterized by XRD, XPS, TEM, BET and other testing methods for structure, surface topography and elements. These samples were fabricated into sensors, and the gas sensing properties of the materials were investigated under different test conditions. The results show that the gas response value of the C/M-2 sensor is up to about 14.7%/100 ppm, which is three times the response value of the sensor made of pure MXene to NH3. In addition, the Co(OH)2/Ti3C2T x hybrid sensors exhibit excellent repeatability, high sensitivity under low concentration (less than 5 ppm), fast response/recovery time (29 s/49 s) and long-time stability, which indicates their promising utility in the IoT field.

Metabolomics and biochemical assays reveal the metabolic responses to hypo-salinity stress and osmoregulatory role of cAMP-PKA pathway in Mercenaria mercenaria.

Hypo-salinity events frequently occur in marine ecosystem due to persistent rainfall and freshwater inflow, reducing the cytosol osmolarity and triggering cellular stress responses in aquatic organisms. Euryhaline bivalves have developed sophisticated regulatory mechanisms to adapt to salinity fluctuations over a long period of evolution. In this study, we performed multiple biochemical assays, widely targeted metabolomics, and gene expression analysis to investigate the comprehensive metabolic responses to hypo-salinity stress and osmoregulation mechanisms in hard clam Mercenaria mercenaria, which is a euryhaline bivalve species widely cultured in China. During hypo-salinity stress, increased vacuoles appeared in gill filaments. The Na+ and Cl- concentrations in gills significantly decreased because of the up-regulation of Na+/K+-ATPase (NKA) activity. The cAMP content dramatically decreased at 5 d post hypo-salinity stress. Meanwhile, the gene expression levels of adenylate cyclase, proteinkinase A, and sodium and calcium channel proteins were evidently down-regulated, suggesting that cAMP-PKA pathway was inhibited to prevent ambient inorganic ions from entering the gill cells. Antioxidant metabolites, such as serine and Tyr-containing dipeptides, were significantly up-regulated to resist oxidative stress. Glycerolipid metabolism was strengthened to stabilize membrane structure when hypo-salinity stress was prolonged to 5 days. At 1 d post hypo-salinity stress, an increase in alanine and lactate contents marked the initiation of anaerobic metabolism. Acylcarnitines accumulation indicated that fatty acids ß-oxidation was promoted to provide energy for osmoregulation. The potential biomarkers of hypo-salinity stress were identified in hard clams. This study provides novel insights into the metabolic regulatory mechanisms to hypo-salinity stress in euryhaline bivalves.

Identification and characterization of olfactory receptor genes and olfactory perception in rapa whelk Rapana venosa (Valenciennes, 1846) during larval settlement and metamorphosis.

The rapa whelk Rapana venosa, an economically important marine fishery resource in China but a major invader all over the world, changes from a phytophagous to a carnivorous form following settlement and metamorphosis. However, the low settlement and metamorphosis rates (<1%) of larvae limit the abundance of R. venosa. This critical step (settlement and metamorphosis) remains poorly characterized but may be related to how larvae perceive the presence of shellfish, their new source of food. Here, we report that larvae may use olfactory perception to sense shellfish. Olfactory receptor (OR) genes are involved in odor sensing in animals. We identified a total of 463 OR genes, which could be grouped into nine clades based on phylogenetic analysis. When assessing the attraction of larvae at different developmental stages to oyster odor, R. venosa showed active settlement and metamorphosis behavior only at the J4 stage (competent larva, 1000-1500 µm shell length) and in the presence of shellfish odor at the same time. Expression of OR gene family members differed between stage 2 (four-spiral whorl stage) and stage 1 (single- to three-spiral whorl stage), indicating significant changes in the olfactory system during larval development. These findings broaden our understanding of olfactory perception, settlement, and metamorphosis in gastropods and can be used to improve R. venosa harvesting, as well as the sustainable development and utilization of this resource.

Successful Urgent TAVI for Critical Aortic Valve Stenosis after ECMO Implantation.

Transcatheter aortic valve implantation (TAVI) has evolved to be the treatment of choice for patients with severe aortic stenosis and high perioperative risk. Cardiogenic shock is one of the most severe complications during the TAVI procedure, especially as the prognosis of cardiogenic shock secondary to aortic stenosis is very poor. This situation can be challenging, while extracorporeal membranous oxygenation (ECMO) can be a treatment option. Here, we reported on an 88-year-old female patient who had been diagnosed as non-ST-elevation myocardial infarction (NSTEMI) and critical aortic valve stenosis (AS) with a logistic Euroscore of 25%. Percutaneous coronary angioplasty (PCI) was performed smoothly and developed tachy-brady arrhythmia of atrial fibrillation then cardiac arrest at the beginning of the TAVI procedure. A v-a ECMO was installed at her left femoral side. Afterward, the TAVI procedure was completed accordingly; her consciousness recovered and Levosimendan therapy enhanced her left-ventricular ejection fraction (LVEF) from 22% to 40%. Five days after TAVI, ECMO was replaced by intra-aortic balloon pumping (IABP) and it was removed 3 days later. A minor complication of this therapy, e.g., muscular weakness in her left leg, was noted. The patient underwent rehabilitation for about 2 months, and was discharged from hospital with a wheel chair and clear consciousness. At the 24 month follow-up she was in good recovery and was able to walk upstairs to the second floor again. Our experience suggests that one indication of prophylactic use of ECMO is for patients with an unstable hemodynamic condition.

Genome-wide analysis of the hard clam mitogen-activated protein kinase kinase gene family and their transcriptional profiles under abiotic stress.

Mitogen-activated protein kinase kinase (MAPKK) was the hub component of the Mitogen-activated protein kinase (MAPK) signaling pathway and played an important role in the cellular response to environmental stress. In this study, we identified five MmMAPKK genes in hard clam Mercenaria mercenaria and found that all MmMAPKK genes contain a conserved protein kinase domain. The MmMAPKK genes derived from dispersed duplication were unevenly distributed in three chromosomes. Although the genome size was highly variable among different bivalve mollusks, the number of MAPKK genes was relatively stable. Phylogenetic analysis showed that bivalve MAPKK was divided into five clades, and amino acid sequences of MAPKK from the same clade consisted of similar conserved motifs. The syntenic analysis demonstrated that MmMAPKKs had the highest number of homologous gene pairs with Cyclina sinensis. MmMAPKKs were ubiquitously expressed in all examined tissues, and all MmMAPKK genes were highly expressed in the ovary. MmMAPKK genes showed stress-specific expression under envirionmental stress. MmMAPKK7 showed an upregulated in heat and heat plus hypoxia stress while MmMAPKK1 showed an upregulated in hypoxic stress groups. Dynamic changes of MmMAPKK7, MmMAPKK6 and MmMAPKK1 in hemocytes were observed in response to air exposure. MmMAPKK4 significantly downregulated after air exposure for five days. MmMAPKK7 and MmMAPKK6 might participate in adaptation to low salinity stress. Our results provided useful information about MAPKK and laid a foundation for further studies on MAPKK evolution in the bivalve.

Symbiotic microbiome and metabolism profiles reveal the effects of induction by oysters on the metamorphosis of the carnivorous gastropod Rapana venosa.

Most marine mollusks have a pelagic larval phase, and they need to undergo metamorphosis to develop into adults. Metamorphosis is affected by many factors, including abiotic factors such as temperature, salinity and illumination as well as biological factors such as food and microorganisms. In our previous study, we found that the metamorphosis of Rapana venosa requires induction by juvenile oysters, which are the food source of R. venosa. However, the regulatory mechanism of this induction is largely unknown. In the present study, we evaluated the impacts of induction by juvenile oysters on competent larvae of R. venosa. Competent larvae were experimentally divided into two pools, and scallop shells without juvenile oysters and scallop shells with juvenile oysters were added for 2 h and 12 h to monitor alterations in critical gene expression, symbiotic microbiota and metabolomic responses. The carboxypeptidase gene was increased while the cellulase gene was decreased, which may mean that the food habit transition was induced by juvenile oysters. Meanwhile, critical genes in the neuroendocrine system were also significantly altered in juvenile oysters. Furthermore, dramatic changes in the symbiotic microbiota and metabolism profiles were observed, with many of them associated with the digestive system and neuroendocrine system. In conclusion, juveniles as food resources may induce metamorphosis in R. venosa by regulating the neuroendocrine system and promoting the development of the digestive system and changes in digestive enzymes. This study may provide evidence that induction by juvenile oysters can promote food habit transition and metamorphosis in R. venosa by regulating the metabolome and microbiome and further altering the digestive and neuroendocrine systems of R. venosa, which expands our understanding of the regulatory mechanism of metamorphosis in R. venosa. However, further studies are needed to explore the specific substance inducing metamorphosis released by juvenile oysters.

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Metabolic response of Mercenaria mercenaria under heat and hypoxia stress by widely targeted metabolomic approach.

In the context of global climatic changes, marine organisms have been exposed to environmental stressors including heat and hypoxia. This calls for the design of multi-stressors to uncover the impact of oceanic factors on aquatic organisms. So far, little is known about the metabolic response of marine organisms, especially bivalves, to the combined effects of heat and hypoxia. In this study, we employed widely targeted metabolomic analysis to study the metabolic response of gills in hard clam, a heat- and hypoxia-tolerant bivalve. A total of 810 metabolites were identified. Results showed that the heat group (HT) and heat plus hypoxia group (HL) had a higher number of differential metabolites than the hypoxia group (LO). Glycolysis was affected by the heat and heat plus hypoxia stress. Moreover, anaerobic metabolic biomarkers were accumulated marking the onset of anaerobic metabolism. Environmental stresses may affect Tricarboxylic acid (TCA) cycle. Accumulation of carnitine and glycerophospholipid may promote fatty acid ß oxidation and maintain cell membrane stability, respectively. The high content of oxidized lipids (i.e., Leukotriene) in HL and HT groups implied that the organisms were under ROS stress. The significantly differential metabolites of organic osmolytes and vitamins might relieve ROS stress. Moreover, accumulation of thermoprotective osmolytes (monosaccharide, Trimethylamine N-oxide (TMAO)) accumulation was helpful to maintain protein homeostasis. This investigation provided new insights into the adaptation mechanisms of hard clam to heat, hypoxia and combined stress at the metabolite level and highlighted the roles of molecules and protectants.

RNA-Seq analysis and WGCNA reveal dynamic molecular responses to air exposure in the hard clam Mercenaria mercenaria.

Intertidal bivalves are constantly exposed to air due to daily and seasonal tidal cycles. The hard clam Mercenaria mercenaria is an economically important bivalve species and often subjected to air exposure for more than 10 days during long-distance transportation. Hard clam exhibits remarkable tolerance to air exposure. In this study, we performed RNA sequencing on hemocytes of M. mercenaria exposed to air for 0, 1, 5, 10, 20 and 30 days. The overall and dynamic molecular responses of hard clams to air exposure were revealed by different transcriptomic analysis strategies. As a result, most cytochrome P450 1A and 3A, and monocarboxylate transporter family members were up-regulated during air exposure. Additionally, the dominant molecular process in response to 5-d, 10-d, 20-d and 30-d air exposure was refolding of misfolded proteins in endoplasmic reticulum, lysosome-mediated degradation of phospholipids, protein metabolism and reorganization of cytoskeleton, and activation of anti-apoptotic process, respectively. Our results facilitated comprehensive understanding of the tolerance mechanisms of intertidal bivalves to air exposure.