Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death.

TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.

cGAS-STING pathway agonists are promising vaccine adjuvants.

Adjuvants are of critical value in vaccine development as they act on enhancing immunogenicity of antigen and inducing long-lasting immunity. However, there are only a few adjuvants that have been approved for clinical use, which highlights the need for exploring and developing new adjuvants to meet the growing demand for vaccination. Recently, emerging evidence demonstrates that the cGAS-STING pathway orchestrates innate and adaptive immunity by generating type I interferon responses. Many cGAS-STING pathway agonists have been developed and tested in preclinical research for the treatment of cancer or infectious diseases with promising results. As adjuvants, cGAS-STING agonists have demonstrated their potential to activate robust defense immunity in various diseases, including COVID-19 infection. This review summarized the current developments in the field of cGAS-STING agonists with a special focus on the latest applications of cGAS-STING agonists as adjuvants in vaccination. Potential challenges were also discussed in the hope of sparking future research interests to further the development of cGAS-STING as vaccine adjuvants.

Influence of Cation-Size Effects of Alkaline Earth (Ae) Metals on Dimensionality and Optical Anisotropy Regulation in K4AeP2S8 Thiophosphates.

Cationic substitution demonstrates significant potential for regulating structural dimensionality and physicochemical performance owing to the cation-size effect. Leveraging this characteristic, this study synthesized a new family of K4AeP2S8 (Ae = alkaline earth elements: Mg, Ca, Sr, and Ba) thiophosphates, involving the substitution of Ae2+ cations. The synthesized compounds crystallized in distinct space groups, monoclinic P2/c (Ae = Mg) versus orthorhombic Ibam (Ae = Ca, Sr, and Ba), exhibiting intriguing dimensionality transformations from zero-dimensional (0D) [Mg2P4S16]8- clusters in K4MgP2S8 to 1D ∞[AeP2S8]4- chains in other K4AeP2S8 thiophosphates owing to the varying ionic radii of Ae2+ cations, Ae-S bond lengths, and coordination numbers of AeSn (Mg: n = 6 versus other: n = 8). Experimental investigations revealed that K4AeP2S8 thiophosphates featured wide optical bandgaps (3.37-3.64 eV), and their optical absorptions were predominantly influenced by the S 3p and P 3s orbitals, with negligible contributions from the K and Ae cations. Notably, within the K4AeP2S8 series, birefringence (Δn) increased from K4MgP2S8 (Δn = 0.034) to other K4AeP2S8 (Δn = 0.050-0.079) compounds, suggesting that infinite 1D chains more significantly influence Δn origins than 0D clusters, thus offering a feasible approach for enhancing optical anisotropy and exploring potential new birefringent materials.

A Combination of B- and N-Doped π-Systems Enabling Systematic Tuning of Electronic Structures and Properties.

Doping heteroatoms into polycyclic aromatic hydrocarbons (PAHs) may alter their structures and thereby physical properties. This study reports the construction of B/N-codoped PAHs via combining the B- and N-doped π-systems. Two π-extended B/N-codoped PAHs were synthesized through the Mallory photoreaction. Both feature a C48 BN2 π-skeleton, which is assembled by linearly fusing three substructures including B-doped and sp2 -hybridized N-doped π-moieties and one pyrene unit. In comparison to the pristine B-doped analog, their intramolecular charge transfer (ICT) states are distinctly modulated by the fused N-doped π-system and the further incorporated cyano group, leading to their tunable optical properties, as revealed by detailed theoretical and experimental analysis. Furthermore, these three molecules have sufficient Lewis acidity and can coordinate with Lewis base to form Lewis acid-base adducts, and notably, such intermolecular complexation can further dynamically modulate their ICT transitions and thereby photophysical properties, such as producing blue, green and red fluorescence.

Immunoglobulin superfamily 6 is a molecule involved in the anti-tumor activity of macrophages in lung adenocarcinoma.

BACKGROUND: Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily and has been implicated in various diseases. However, the specific role of IGSF6 in the anti-tumor immunity within lung adenocarcinoma (LUAD) remains unclear. METHODS: We analyzed the IGSF6 expression in LUAD using data from TCGA, and we performed qRT-PCR and western blotting to validate these findings using tissue samples obtained from LUAD patients. Images of IHC staining were obtained from HPA. To assess the clinical relevance of IGSF6 expression, we utilized UALCAN and SPSS to analyze its association with major clinical features of LUAD. Additionally, we employed ROC curves and survival analysis to evaluate the potential diagnostic and prognostic value of IGSF6 in LUAD. To gain insights into the functional implications of IGSF6, we performed enrichment analysis using the R software clusterProfiler package. Moreover, we utilized TIMER2.0 and TISIDB to investigate the relationship between IGSF6 and immune infiltrates in LUAD. The proportion of tumor-infiltrating immune cells in LUAD was assessed using FCM, and their correlation with IGSF6 expression in tumor tissues was analyzed. The localization of IGSF6 protein on macrophages was confirmed using the HPA and FCM. To determine the regulatory role of IGSF6 on macrophage activity in LUAD, we employed ELISA, FCM, and tumor-bearing models. RESULTS: We discovered that both IGSF6 mRNA and protein levels were significantly decreased in LUAD. Additionally, we observed a negative correlation between IGSF6 expression and TNM stages as well as pathologic stages in LUAD. Notably, IGSF6 exhibited high sensitivity and specificity in diagnosing LUAD, and was positively associated with the survival rate of LUAD patients. Furthermore, IGSF6 expression was closely linked to gene sets involved in immune response. IGSF6 expression showed a positive correlation with immune infiltrates exhibiting anti-tumor activity, particularly M1 macrophages. We confirmed the predominant localization of the IGSF6 protein on the membrane of M1 macrophages. Importantly, the knockdown of IGSF6 resulted in a reduction in the anti-tumor activity of M1 macrophages, thereby promoting tumor progression. CONCLUSION: IGSF6 is a molecule that is essential for the anti-tumor activity of macrophages in LUAD.

CircRNA CDR1as: a novel diagnostic and prognostic biomarker for gastric cancer.

BACKGROUND: Circular RNA (circRNA) CDR1as is emerging as a vital tumour regulator. This study aimed to investigate its diagnostic and prognostic value and molecular mechanisms for gastric cancer (GC). METHODS: CDR1as expression in GC and adjacent normal tissues (n = 82), paired plasma (n = 65) and plasma exosome samples (n = 68) from GC patients and healthy controls were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Correlations between CDR1as level and clinicopathological factors of GC patients were analysed. Its diagnostic and prognostic value was evaluated by receiver operating characteristic (ROC) curves and Cox regression analysis combined with Kaplan-Meier plots. CDR1as-regulated proteins and signalling pathways were identified by quantitative proteomics and bioinformatic analysis. RESULTS: CDR1as was downregulated in GC tissues and associated with tumour size and neural invasion. Plasma- and exosome-derived CDR1as was upregulated in GC patients while plasma-derived CDR1as level was related to lymphatic metastasis. Area under ROC curve (AUC) of tissue-, plasma- and exosome-derived CDR1as was 0.782, 0.641, 0.536 while combination of plasma CDR1as, serum CEA and CA19-9 increased AUC to 0.786. Distal metastasis, TNM stage and tissue-derived CDR1as level were independent predictors for overall survival (OS) of patients. MiRNA signalling networks and glycine, serine and threonine metabolism were regulated by CDR1as and HSPE1 might be a key protein. CONCLUSIONS: CDR1as is a crucial regulator and promising biomarker for GC diagnosis and prognosis.

CDR1as level in tumour tissues and plasma of GC patients was associated with tumour progression. The findings indicate that CDR1as is involved in GC progression and is a potential diagnostic and prognostic biomarker.

Noncentrosymmetric Na6Pb3P4S16 and Centrosymmetric K2MIIP2S6 (MII = Mg and Zn) Displaying Multiple Membered-Ring Configurations and Strong Optical Anisotropy.

Three thiophosphates including noncentrosymmetric Na6Pb3P4S16 and centrosymmetric K2MIIP2S6 (MII = Mg and Zn) were successfully synthesized in vacuum-sealed silica tubes. Note that interesting multiple six membered-rings (6-MRs) including 6-NaS6-MRs and 6-KSn-MRs (n = 6 and 7) formed by A+-centered polyhedra were discovered in the structures of title thiophosphates and these MR-composed three-dimensional (3D) tunnels show great possibility to facilitate the filling of various structural blocks (such as zero-dimensional (0D) Pb3S10 trimers or one-dimensional (1D) (MIISn)n chains). Na6Pb3P4S16 exhibits the strongest nonlinear optical (NLO) response (5.4 × AgGaS2) with phase-matching (PM) behavior among the known Pb-based PM NLO sulfides, which is much larger than that of Pb3P2S8 (3.5 × AgGaS2); it was verified that such large second harmonic generation (SHG) response in Na6Pb3P4S16 can be attributed to the huge contribution of stereochemically active PbS4 units based on the SHG-density and dipole-moment calculations. Moreover, title thiophosphates show large birefringences (Δn = 0.102-0.21), which indicates that incorporation of [P2S6] dimers or polarized PbS4 units into structures provides positive benefits for the onset of strong optical anisotropy.

Potential Immunoregulatory Mechanism of Plant Saponins: A Review.

Saponins are extracted from different parts of plants such as seeds, roots, stems, and leaves and have a variety of biological activities including immunomodulatory, anti-inflammatory effects, and hypoglycemic properties. They demonstrate inherent low immunogenicity and possess the capacity to effectively regulate both the innate and adaptive immune responses. Plant saponins can promote the growth and development of the body's immune organs through a variety of signaling pathways, regulate the activity of a variety of immune cells, and increase the secretion of immune-related cytokines and antigen-specific antibodies, thereby exerting the role of immune activity. However, the chemical structure of plant saponins determines its certain hemolytic and cytotoxicity. With the development of science and technology, these disadvantages can be avoided or reduced by certain technical means. In recent years, there has been a significant surge in interest surrounding the investigation of plant saponins as immunomodulators. Consequently, the objective of this review is to thoroughly examine the immunomodulatory properties of plant saponins and elucidate their potential mechanisms, with the intention of offering a valuable point of reference for subsequent research and advancement within this domain.

Construction of Optimal Frequency Hopping Sequence Set with Low-Hit-Zone.

In quasi-synchronous frequency-hopping multiple access (QS-FHMA) systems, low-hit-zone (LHZ) frequency-hopping sequence (FHS) sets have been well-applied to reduce mutual interference (MI). In this paper, we propose three constructions of LHZ FHS sets with new parameters via interleaving techniques. The obtained sequences can be verified that they are optimal with respect to the Peng-Fan-Lee bound.

Diradical B/N-Doped Polycyclic Hydrocarbons.

Heterocyclic diradicaloids with atom-precise control over open-shell nature are promising materials for organic electronics and spintronics. Herein, we disclose quinoidal π-extension of a B/N-heterocycle for generating B/N-type organic diradicaloids. Two quinoidal π-extended B/N-doped polycyclic hydrocarbons that feature fusion of the B/N-heterocycle motif with the antiaromatic s-indacene or dicyclopenta[b,g]naphthalene core were synthesized. This quinoidal π-extension and B/N-heterocycle leads to their open-shell electronic nature, which stands in contrast to the multiple-resonance effect of conventional B/N-type emitters. These B/N-type diradicaloids have modulated (anti)aromaticity and enhanced diradical characters comparing with the all-carbon analogues, as well as intriguing properties, such as magnetic activities, narrow energy gaps and highly red-shifted absorptions. This study thus opens the new space for both of B/N-doped polycyclic π-systems and heterocyclic diradicaloids.

Diradicaloid Boron-Doped Molecular Carbons Achieved by Pentagon-Fusion.

Molecular carbons (MCs) are molecular cutouts of carbon materials. Doping with heteroatoms and constructing open-shell structures are two powerful approaches to achieve unexpected and unique properties of MCs. Herein, we disclose a new strategy to design open-shell boron-doped MCs (BMCs), namely by pentagon-fusion of an organoborane π-system. We synthesized two diradicaloid BMC molecules that feature C24 B and C38 B π-skeletons containing a pentagonal ring. A thorough investigation reveals that such pentagon-fusion not only leads to their local antiaromaticity, but also incorporates an internal quinoidal substructure and thereby induces open-shell singlet diradical states. Moreover, their fully fused structures enable efficient π conjugation, which is expanded over the whole frameworks. Consequently, some intriguing physical properties are achieved, such as narrow energy gaps, very broad light absorptions, and superior photothermal capability, along with excellent photostability. Notably, the solid of the C38 B molecule exhibits absorption that covers the range of 300-1200 nm and an efficiency of 93.5 % for solar-driven water evaporation, thus demonstrating the potential of diradicaloid BMCs as high-performance organic photothermal materials.

Pushing OECTs toward Wearable: Development of a Miniaturized Analytical Control Unit for Wireless Device Characterization.

Organic electrochemical transistors (OECTs) have emerged as a next-generation biosensing technology because of their water-stability, cost-effectiveness, and ability to obtain high sensitivity at low operation voltage (mV). However, a miniaturized readout unit that can wirelessly characterize the overall performance of an OECT is still missing, which hinders the assembling of truly wearable OECT systems for continuous health-monitoring applications. In this work, we present a coin-sized analytical unit for remote and wireless OECT characterization, namely, a personalized electronic reader for electrochemical transistors (PERfECT). It has been verified that PERfECT can measure the transfer, output, hysteresis, and transient behavior of OECTs with resolution and sampling rate on par with the bulky equipment used in laboratories. PERfECT is also capable of characterizing other low-voltage transistors. An integrated board for multiplexed OECT characterizations (32 channels) has also been demonstrated. This work provides a missing building block for developing next-generation OECT-based bioelectronics for digital wearable applications.

Clinical profile of fatal familial insomnia: phenotypic variation in 129 polymorphisms and geographical regions.

OBJECTIVE: Elucidate the core clinical and genetic characteristics and identify the phenotypic variation between different regions and genotypes of fatal familial insomnia (FFI). METHODS: A worldwide large sample of FFI patients from our case series and literature review diagnosed by genetic testing were collected. The prevalence of clinical symptoms and genetic profile were obtained, and then the phenotypic comparison between Asians versus non-Asians and 129Met/Met versus 129Met/Val were conducted. RESULTS: In total, 131 cases were identified. The age of onset was 47.51±12.53 (range 17-76) years, 106 patients died and disease duration was 13.20±9.04 (range 2-48) months. Insomnia (87.0%) and rapidly progressive dementia (RPD; 83.2%) occurred with the highest frequency. Hypertension (33.6%) was considered to be an objective indicator of autonomic dysfunction. Genotype frequency at codon 129 was Met/Met (84.7%) and Met/Val (15.3%), and allele frequency was Met (92.4%) and Val (7.6%).129 Met was a risk factor (OR: 3.728, 95% CI: 2.194 to 6.333, p=0.000) for FFI in the non-Asian population. Comparison of Asians and non-Asians revealed clinical symptoms and genetic background to show some differences (p<0.05). In the comparison of 129 polymorphisms, a longer disease duration was found in the 129 MV group, with alleviation of some clinical symptoms (p<0.05). After considering survival probability, significant differences in survival time between genotypes remained (p<0.0001). CONCLUSIONS: Insomnia, RPD and hypertension are representative key clinical presentations of FFI. Phenotypic variations in genotypes and geographic regions were documented. Prion protein gene 129 Met was considered to be a risk factor for FFI in the non-Asian population, and 129 polymorphisms could modify survival duration.

Tuning Diradical Properties of Boron-Containing π-Systems by Structural Isomerism.

Tuning diradical character is an important topic for organic diradicaloids. Herein, we report the precise borylation enabling structural isomerism as an effective strategy to modulate diradical character and thereby properties of organic diradicaloids. We synthesized a new B-containing polycyclic hydrocarbon that has the indeno[1,2-b]fluorene π-skeleton with the ß-carbons bonding to two boron atoms. Detailed theoretical and experimental results show that this bonding pattern leads to its distinctive electronic structures and properties in comparison to that of its isomeric molecule. This molecule has the efficient conjugation between boron atoms and π-skeleton, resulting in downshifted LUMO and HOMO levels. Moreover, it exhibits smaller diradical character and thereby inhibited diradical properties, such as significantly blue-shifted light absorption, larger energy bandgap and weak para-magnetic resonance. Notably, this B-containing polycyclic hydrocarbon possesses much stronger Lewis acidity and its Lewis acid-base adducts display enhanced diradical character, demonstrating the positive effects of Lewis coordination on modulating diradical performance.

Circulating CD15+ LOX-1+ PMN-MDSCs are a potential biomarker for the early diagnosis of non-small-cell lung cancer.

AIMS: Non-small-cell lung cancer (NSCLC) is the most common clinical lung cancer. Polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs), which are the major population of MDSCs, are involved in NSCLC progression. Recently, it was found that lectin-type oxidized LDL receptor 1 (LOX-1) could identify human PMN-MDSCs. However, the role of CD15+ LOX-1+ PMN-MDSCs in NSCLC early diagnosis has not been revealed. Here, we tried to confirm the application of the newly identified CD15+ LOX-1+ PMN-MDSCs in the early diagnosis of NSCLC. METHODS: Flow cytometry (FCM) was used to detect the proportion of CD15+ LOX-1+ PMN-MDSCs in the peripheral blood (PB) of healthy controls (HC) and NSCLC patients. The correlation of CD15+ LOX-1+ PMN-MDSC frequency with levels of cytokeratin 19-fragments (CYFRA21-1), carcinoembryonic antigen (CEA), and carbohydrate antigen 125 (CA125) was analysed. Receiver operating characteristic (ROC) curve was used to estimate the diagnostic efficacy of CD15+ LOX-1+ PMN-MDSCs for NSCLC. Additionally, the association of CD15+ LOX-1+ PMN-MDSC frequency with NSCLC prognosis/recurrence after surgery was explored. RESULTS: The proportion of CD15+ LOX-1+ PMN-MDSCs increased in PB of NSCLC patients. CD15+ LOX-1+ PMN-MDSC proportion was positively correlated with levels of CEA, CA125 and CYFRA21-1. Detection of PMN-MDSC percentage in PB owed high sensitivity and specificity for NSCLC diagnosis. The proportion of CD15+ LOX-1+ PMN-MDSCs decreased in patients after surgery. The frequency of CD15+ LOX-1+ PMN-MDSCs was lower in NSCLC patients without recurrence compared to those with recurrence after surgery. CONCLUSIONS: Circulating CD15+ LOX-1+ PMN-MDSCs are a potential diagnostic marker for NSCLC, and are associated with NSCLC prognosis and recurrence after surgery.

Fas, Caspase-8, and Caspase-9 pathway-mediated bile acid-induced fetal cardiomyocyte apoptosis in intrahepatic cholestasis pregnant rat models.

AIM: Intrahepatic cholestasis of pregnancy (ICP) is a specific complication in the middle and late pregnancy and has been recognized as one of the high-risk pregnancy for sudden fetal death. In this study, we aimed to investigate the role of Fas, Caspase-8, and Caspase-9 pathways in the internal relations of fetal myocardial apoptosis in ICP rat models, thus resulting in fetal intrauterine death. Furthermore, we researched whether ursodeoxycholic acid (UDCA) promoted benefits in fetal cardiomyocyte apoptosis. MATERIALS AND METHODS: To establish ICP rat models, on the 15th day of pregnancy, rats were injected 17α-ethynyl estradiol (EE2). Meanwhile, in experimental group, pregnant rats were treated with EE2 + UDCA. All rats were sacrificed on the 21st day of pregnancy. The expression levels of Fas, Caspase-8, and Caspase-9 were examined by western blot and real-time polymerase chain reaction analysis. Fetal rat cardiac tissues were removed and stained for pathological evaluation. In addition, we observed fetal myocardial structure by using transmission electron microscopy. RESULTS: We detected high concentrations of bile acids and transaminase in the fetal circulation. And we found increased expression levels of Fas, Caspase-8, and Caspase-9 proteins and mRNA in the fetal cardiomyocyte in EE2-treated group but not in control- or EE2 + UDCA-treated groups. Furthermore, compared to controls, EE2-treated rats exhibited severe fetal myocardial structure damage and the apoptotic bodies by using transmission electron microscopy. UDCA reversed the impairment of fetal cardiomyocytes. CONCLUSION: Our study has led to research into the association between activation of Fas, Caspase-8, and Caspase-9 pathways and bile acid-induced fetal cardiomyocyte apoptosis, which may be one of the mechanisms on fetal cardiac death in ICP. More importantly, UDCA may improve the adverse outcome of fetus.

A label-free ratiometric method to detect Hg2+ based on structural change of DNA.

In this work, a simple ratiometric method has been designed to detect Hg2+ based on the structural change between double-stranded DNA (dsDNA) and its G-quadruplex structure. When Hg2+ was added, the designed G-quadruplex structure could change into the corresponding dsDNA by forming the T-Hg2+ -T mismatch. This kind of variation resulted in a decrease in the fluorescence of the G-quadruplex/N-methyl mesoporphyrin IX (NMM) complex and an increase in the fluorescence from the dsDNA/SYBR Green I (SG I) pair. The secondary excitation wavelength of SG I was used to excite NMM and SG I simultaneously. The titration experiment indicated that the new method had a linear response within 0.7-2.5 µM Hg2+ with a limit of detection of 9.3 nM. Because using the T-Hg2+ -T mismatch to recognize Hg2+ was very specific, the selectivity of the new method was also satisfactory. The recoveries ranged from 92.8% to 110.2% suggested that this new method could achieve a potential application for Hg2+ detection in real environmental samples.

Characterization and enhanced extracellular overexpression of a new salt-activated alginate lyase.

BACKGROUND: Alginate lyases (EC 4.4.2.3/4.4.2.11) have been applied to produce alginate oligosaccharides, which have physiological advantages such as prebiotic and antidiabetic effects, and are of benefit in the food and pharmaceutical industries. Extracellular production of recombinant proteins in Escherichia coli presents advantages including simplified downstream processing and high productivity; however, the presence of certain signal peptides does not always ensure successful secretion, which make the extracellular production of alginate lyase in E. coli rarely reported but of great significance. RESULTS: A PL7 family alginate lyase, Aly01, with its native signal peptide from Vibrio natriegens SK42.001, was identified, characterized, and extracellularly expressed in E. coli. The enzyme specifically released trisaccharide from alginate and was strictly NaCl activated. Green fluorescent protein (GFP) was fused with the Aly01 signal peptide and successfully secreted in E. coli to expand the feasibility of using this signal peptide to produce other heterologous proteins extracellularly. Through a synergistic strategy of utilizing Terrific Broth (TB) medium supplemented with 120 mmol L-1 glycine and 10 mmol L-1 calcium, the lag phase of protein secretion was reduced to 3 h from 12 h; meanwhile calcium remedied glycine-related cell growth impairment, leading to further enhancement of overall enzyme productivity, reaching a maximum of 4.55 U mL-1 . CONCLUSION: A new salt-activated alginate lyase, Aly01, was identified and characterized. E. coli employed its signal peptide and extracellularly expressed both Aly01 and a GFP, which indicated the signal peptide of Aly01 could be a powerful tool for extracellular production of other heterologous proteins in E. coli. © 2021 Society of Chemical Industry.

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFD-induced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogen-activated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD.

Basic Research and Clinical Reports Associated with Low Serum IgG4 Concentrations.

Elevated IgG4 concentrations in serum have received a great deal of attention recently, whereas the significance of decreased IgG4 levels was frequently neglected in spite of its close relation with infectious and noninfectious inflammations. In this review, based on the structural and functional characteristics of IgG4, we bring together case reports and research related to low levels of IgG4 and try to scratch the importance of decreased IgG4 concentrations in serum. As with elevated IgG4 levels, low serum IgG4-related diseases can be involved in multiple systems such as infection in the respiratory system, stroke in the circulatory system, and glomerulonephritis in the urinary system. Both genetic and immune dysregulation can contribute to decreased IgG4 levels. In the light of animal experiments, we believe that the mystery of low IgG4 can be revealed as long as enough attention is acquired.