Protective effects of DcR3-SUMO on lipopolysaccharide-induced inflammatory cells and septic mice.

Despite the high mortality rate associated with sepsis, no specific drugs are available. Decoy receptor 3 (DcR3) is now considered a valuable biomarker and therapeutic target for managing inflammatory conditions. DcR3-SUMO, an analog of DcR3, has a simple production process and high yield. However, its precise underlying mechanisms in sepsis remain unclear. This study investigated the protective effects of DcR3-SUMO on lipopolysaccharide (LPS)-induced inflammatory cells and septic mice. We evaluated the effects of DcR3 intervention and overexpression on intracellular inflammatory cytokine levels in vitro. DcR3-SUMO significantly reduced cytokine levels within inflammatory cells, and notably increased DcR3 protein and mRNA levels in LPS-induced septic mice, confirming its anti-inflammatory efficacy. Our in vitro and in vivo results demonstrated comparable anti-inflammatory effects between DcR3-SUMO and native DcR3. DcR3-SUMO protein administration in septic mice notably enhanced tissue morphology, decreased sepsis scores, and elevated survival rates. Furthermore, DcR3-SUMO treatment effectively lowered inflammatory cytokine levels in the serum, liver, and lung tissues, and mitigated the extent of tissue damage. AlphaFold3 structural predictions indicated that DcR3-SUMO, similar to DcR3, effectively interacts with the three pro-apoptotic ligands, namely TL1A, LIGHT, and FasL. Collectively, DcR3-SUMO and DcR3 exhibit comparable anti-inflammatory effects, making DcR3-SUMO a promising therapeutic agent for sepsis.

A two-dimensional calibration for resolving nano-positioner pedestal micro-deformation crosstalk.

This paper proposes a two-dimensional calibration method for resolving the nano-positioner pedestal micro-deformation crosstalk errors during the auction process. This refinement aims to enhance the nano-positioner's accuracy and reduce coupling crosstalk errors. The reaction force exerted by the piezoelectric actuator can cause micro-deformation in the nano-positioner sensor pedestal, causing substantial errors in uncalibrated closed-loop control. This phenomenon has been previously overlooked. According to the two-degree of freedom parallel-symmetric decoupled nano-positioner deformation characteristics, a two-dimensional calibration matrix is proposed to suppress the crosstalk between two axes caused by the micro-deformation of the sensor pedestal. Experimental results show that the calibrated closed-loop system reduces X-axis and Y-axis coupling crosstalk errors to 1/67th and 1/18th of the uncalibrated closed-loop system, respectively, concurrently enhancing the positioning accuracy to 11.8 and 17 times that of the uncalibrated closed-loop system. The calibrated closed-loop feedback control method proposed in this paper proves effective for all compact nano-positioners with pedestal deformation issues. This research provides a crucial reference for the design of nano-positioners, offering insights into enhancing their accuracy and mitigating crosstalk issues.

Nano titanium dioxide alleviates the toxic effects of tris (2-chloropropyl) phosphate on the digestive gland and hemolymph of thick-shell mussel Mytilus coruscus.

In the marine environment, nanoparticles play a role in adsorbing and catalytically degrading organic pollutants, thereby mitigating their toxic effects on aquatic organisms. This study aimed to investigate the impact of nano titanium dioxide (nTiO2) and tris (2-chloropropyl) phosphate (TCPP) on the hemolymph and digestive function of the thick-shell mussel Mytilus coruscus. Mussels were divided into a control group, a group exposed to TCPP alone, a group exposed to a combination of TCPP and 0.5 mg/L nTiO2, and a group exposed to a combination of TCPP and 1 mg/L nTiO2. After 14 days of exposure, oxidative stress responses, including superoxide dismutase (SOD) activity and malondialdehyde (MDA) content, immune defense responses, including acid phosphatase (ACP) and alkaline phosphatase (AKP) activities, and gene expression, including HSP70 expression, were measured in the hemolymph and digestive glands of the mussels. Compared to the control group, mussels solely exposed to 100 µg/L TCPP exhibited a significant reduction in SOD activity in the hemolymph. When TCPP was co-exposed with 0.5 mg/L nTiO2, there were significant increases in MDA content and AKP activity in both the digestive gland and hemolymph compared to the control group. Upon co-exposure of TCPP with 1 mg/L nTiO2, MDA content and AKP activity in the digestive gland significantly decreased, while SOD, ACP, and AKP activity in the hemolymph significantly increased and MDA content significantly decreased, returning to the control group levels. Furthermore, in the combined exposure, HSP70 gene expression significantly decreased as the nTiO2 concentration increased from 0.5 mg/L to 1 mg/L. In summary, TCPP impacted the hemolymph and digestive function of mussels, whereas a concentration of 1 mg/L nTiO2 effectively alleviated the toxic effects of TCPP. This study is crucial for assessing the ecological risks of nanoparticles and emerging organic pollutants in marine environments, and provides new insights into the interaction between nTiO2 and TCPP, as well as the influence of nTiO2 concentration on mitigating TCPP toxicity.

Positive effects of rutin on egg quality, lipid peroxidation and metabolism in post-peak laying hens.

Excessive fat deposition due to impaired fat metabolism in chickens is a major problem in the poultry industry. Nutritional interventions are effective solutions, but current options are limited. A safe phytochemical, rutin, has shown positive effects in animals, but its effect on lipid metabolism in poultry remains unknown. Hence, this study is to investigate the effects of rutin on egg quality, serum biochemistry, fat deposition, lipid peroxidation and hepatic lipid metabolism in post-peak laying hens. A total of 360 Taihang laying hens (49-week-old) were randomly divided into five groups and fed a basal diet (control group, 0%) and a basal diet supplemented with 300 (0.03%), 600 (0.06%), 900 (0.09%), and 1,200 (0.12%) mg rutin/kg feed, respectively. The results showed that eggshell strength was significantly (p < 0.05) higher in the dietary rutin groups, whereas yolk percentage (p < 0.05), total cholesterol (TC) (p < 0.01) and yolk fat ratio (p < 0.01) decreased linearly (p < 0.05) in the dietary rutin groups. Importantly, dietary rutin reduced serum triglyceride (TG) and TC levels, decreased abdominal lipid deposition and liver index (p < 0.05), and which concomitantly decreased hepatic lipid (TG, TC, and free fatty acid) accumulation (p < 0.05). An increase (p < 0.05) in total antioxidant capacity and superoxide dismutase activity and a decrease (p < 0.05) in malondialdehyde levels were also found. At the same time, the activities of hepatic lipase, acetyl-CoA carboxylase and malic enzyme in the liver were decreased (p < 0.05). Dietary rutin also increased (p < 0.05) the expression of fatty acid oxidation-related genes (carnitine palmitoyl transferase 1, peroxisome proliferator-activated receptor α, farnesoid X receptor). Additionally, it decreased fatty acid synthesis genes (sterol regulatory element binding protein-1c, acetyl-CoA carboxylase α, stearoyl-CoA desaturase 1) (p < 0.05). In conclusion, the addition of rutin (0.06-0.12%) to the diet improved the fat metabolism and increased liver antioxidant capacity in post-peak laying hens, and these positive changes improved egg quality to some extent.

Combined toxicity of polyvinyl chloride microplastics and copper to marine jacopever (Sebastes schlegelii).

Marine organisms commonly encounter co-stress resulting from the coexistence of microplastics (MPs) and heavy metals pollution in marine environments. Nevertheless, the combined effects and toxicity mechanisms of MPs and heavy metals on marine organisms remain unclear. This study integrated growth, physiological, morphological, and biochemical markers to assess the individual and combined toxicity of polyvinyl chloride MPs (PVC MPs, 1 × 104 particles/L) and copper (Cu, 200 µg/L) on marine jacopever (Sebastes schlegelii). The results revealed that co-exposure to MPs and Cu had a more detrimental impact on jacopever compared to the single-exposure groups, as evidenced by the enhanced growth inhibition, respiratory stress, and hepatotoxicity. This phenomenon may be attributed to PVC MPs accelerating the accumulation of Cu in jacopever liver. Therefore, peroxidation damage occurred in the co-exposed liver and may result in liver dysfunction. These findings contribute valuable insights into the risks associated with the coexistence of MPs and heavy metal pollution in marine ecosystems.

Inhibitory mechanisms of decoy receptor 3 in cecal ligation and puncture-induced sepsis.

Despite its high mortality, specific and effective drugs for sepsis are lacking. Decoy receptor 3 (DcR3) is a potential biomarker for the progression of inflammatory diseases. The recombinant human DcR3-Fc chimera protein (DcR3.Fc) suppresses inflammatory responses in mice with sepsis, which is critical for improving survival. The Fc region can exert detrimental effects on the patient, and endogenous peptides are highly conducive to clinical application. However, the mechanisms underlying the effects of DcR3 on sepsis are unknown. Herein, we aimed to demonstrate that DcR3 may be beneficial in treating sepsis and investigated its mechanism of action. Recombinant DcR3 was obtained in vitro. Postoperative DcR3 treatment was performed in mouse models of lipopolysaccharide- and cecal ligation and puncture (CLP)-induced sepsis, and their underlying molecular mechanisms were explored. DcR3 inhibited sustained excessive inflammation in vitro, increased the survival rate, reduced the proinflammatory cytokine levels, changed the circulating immune cell composition, regulated the gut microbiota, and induced short-chain fatty acid synthesis in vivo. Thus, DcR3 protects against CLP-induced sepsis by inhibiting the inflammatory response and apoptosis. Our study provides valuable insights into the molecular mechanisms associated with the protective effects of DcR3 against sepsis, paving the way for future clinical studies. IMPORTANCE: Sepsis affects millions of hospitalized patients worldwide each year, but there are no sepsis-specific drugs, which makes sepsis therapies urgently needed. Suppression of excessive inflammatory responses is important for improving the survival of patients with sepsis. Our results demonstrate that DcR3 ameliorates sepsis in mice by attenuating systematic inflammation and modulating gut microbiota, and unveil the molecular mechanism underlying its anti-inflammatory effect.

Bioaccumulation of polycyclic aromatic hydrocarbons and their human health risks depend on the characteristics of microplastics in marine organisms of Sanggou Bay, China.

Microplastics pose a threat to marine environments through their physical presence and as vectors of chemical pollutants. However, the impact of microplastics on the accumulation and human health risk of chemical pollutants in marine organisms remains largely unknown. In this study, we investigated the microplastics and polycyclic aromatic hydrocarbons (PAHs) pollution in marine organisms from Sanggou Bay and analyzed their correlations. Results showed that microplastic and PAHs concentration ranged from 1.23 ± 0.23 to 5.77 ± 1.10 items/g, from 6.98 ± 0.45 to 15.07 ± 1.25 µg/kg, respectively. The microplastic abundance, particularly of fibers, transparent and color plastic debris, correlates strongly with PAH contents, indicating that microplastics increase the bioaccumulation of PAHs and microplastics with these characteristics have a significant vector effect on PAHs. Although consuming seafood from Sanggou Bay induce no carcinogenic risk from PAHs, the presence of microplastics in organisms can significantly increases incremental lifetime cancer risk of PAHs. Thus, microplastics can serve as transport vectors for PAHs with implications for the potential health risks to human through consumption. This study provides new insight into the risks of microplastics in marine environments.

The ecological risk and fate of microplastics in the environmental matrices of marine ranching area in coastal water.

The debate surrounding "source" and "sink" of microplastics (MPs) in coastal water has persisted for decades. While the transportation of MPs is influenced by surface runoff and currents, the precise transport patterns remain inadequately defined. In this study, the typical coastal habitat - marine ranching in Haizhou Bay (Jiangsu Province, China) were selected as a case study to assess the ecological risk of MPs. An enhanced framework was employed to assess the entire community characteristics of MPs in various environmental compartments, including surface water (SW), middle water (MW), bottom water (BW), sea bottom sediment (SS), and intertidal sediment (IS). The results of the assessment showed a low risk in the water column and a high risk in the sediment. PERMANOVA based on size and polymer of MPs revealed significant differences between IS and other compartments (SW, MW, BW, and SS) (P < 0.001). The co-occurrence network analysis for MP size indicated that most sites occupied central positions, while the analysis for MP polymer suggested that sites near the marine ranching area held more central positions, with sites in MW, BW, and SS being somewhat related to IS. Generalized additive model (GAM) demonstrated that MP concentration in the water correlated with Chla and nutrients, whereas MPs in sediment exhibited greater susceptibility to dissolved oxygen (DO) and salinity. We believe that except for the natural sedimentation and re-suspension of MPs in the vertical direction, MPs in bottom water may migrate to the surface water due to upwelling mediated by artificial reefs. Additionally, under the combined influence of surface runoff, currents, and tides, MPs may migrate horizontally, primarily occurring between middle and bottom water and sediments. The study recommends limiting and reducing wastewater and sewage discharge, as well as regulating fishing and aquaculture activities to control the sources and sinks of MPs in coastal water. Moreover, it advocates the implementation and strengthening of marine monitoring activities to gain a better understanding of the factors driving MP pollution in marine ranching area.

Mycobacterial CpsA activates type I IFN signaling in macrophages via cGAS-mediated pathway.

Type I interferon (IFN) production is crucial in tuberculosis pathogenesis, yet the bacterial factors initiating this process are incompletely understood. CpsA, protein of Mycobacterium marinum and Mycobacterium tuberculosis, plays a key role in maintaining bacterial virulence and inhibiting host cell LC3-associated phagocytosis. By utilizing CpsA full deletion mutant studies, we re-verified its essential role in infection-induced pathology and revealed its new role in type I IFN expression. CpsA deficiency hindered IFN production in infected macrophages in vitro as well as zebrafish and mice in vivo. This effect was linked to the cGAS-TBK1-IRF3 pathway, as evidenced by decreased TBK1 and IRF3 phosphorylation in CpsA-deficient bacterial strain-infected macrophages. Moreover, we further show that CpsA deficiency cause decreased cytosolic DNA levels, correlating with impaired phagosomal membrane rupture. Our findings reveal a new function of mycobacterial CpsA in type I IFN production and offer insight into the molecular mechanisms underlying mycobacterial infection pathology.

[Characteristics of Microplastic Pollution in Sediment of Silty Coast in Culture Bay].

Microplastic pollution is a central issue of great concern in the current environmental field. Microplastic pollution in marine environmental media is widely reported, but the characteristics of microplastic pollution in deep sediments are rarely reported. Based on this, three sampling points were set up on the muddy coast near the Haizhou Bay, a typical aquaculture sea area, to analyze the characteristics of microplastic pollution in sediment column samples. The study showed that the abundance of microplastics in the sediments of the study area was(0.12 ± 0.07)n·g-1, which was at the medium pollution level. The total amount of microplastics in the sediment column was 3.43-6.00 times the abundance of microplastics in the surface sediment (5 cm). The abundance of microplastics in the sediment column samples showed regional differences. There was no significant difference in the abundance of microplastics in the sediment at different depths, but the index decreased with the increase in depth. The relationship between sediment moisture content, depth, and microplastics indicated that the abundance of microplastics in sediment was related to the physical properties of the sediment. Transparent and black microplastics accounted for the highest proportion in each station. Fiber was the most common form of microplastics in the sediment, and microplastics with small particle size accounted for the majority. The density of microplastics did not prevent its appearance in the sediment. The pollution characteristics of microplastics varied greatly in different depths of sediments.

Unveiling the Role of Protein Kinase C θ in Porcine Epidemic Diarrhea Virus Replication: Insights from Genome-Wide CRISPR/Cas9 Library Screening.

Porcine epidemic diarrhea virus (PEDV), a member of the Alpha-coronavirus genus in the Coronaviridae family, induces acute diarrhea, vomiting, and dehydration in neonatal piglets. This study aimed to investigate the genetic dependencies of PEDV and identify potential therapeutic targets by using a single-guide RNA (sgRNA) lentiviral library to screen host factors required for PEDV infection. Protein kinase C θ (PKCθ), a calcium-independent member of the PKC family localized in the cell membrane, was found to be a crucial host factor in PEDV infection. The investigation of PEDV infection was limited in Vero and porcine epithelial cell-jejunum 2 (IPEC-J2) due to defective interferon production in Vero and the poor replication of PEDV in IPEC-J2. Therefore, identifying suitable cells for PEDV investigation is crucial. The findings of this study reveal that human embryonic kidney (HEK) 293T and L929 cells, but not Vero and IPEC-J2 cells, were suitable for investigating PEDV infection. PKCθ played a significant role in endocytosis and the replication of PEDV, and PEDV regulated the expression and phosphorylation of PKCθ. Apoptosis was found to be involved in PEDV replication, as the virus activated the PKCθ-B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) axis in HEK293T and L929 cells to increase viral endocytosis and replication via mitochondrial apoptosis. This study demonstrated the suitability of HEK293T and L929 cells for investigating PEDV infection and identified PKCθ as a host factor essential for PEDV infection. These findings provide valuable insights for the development of strategies and drug targets for PEDV infection.

The combined effects of microplastics and bisphenol-A on the innate immune system response and intestinal microflora of the swimming crab Portunus trituberculatus.

Microplastics (MPs) and bisphenol-A (BPA) have been shown to have toxic effects on aquatic organisms. However, data on the combined effects of MPs and BPA on the innate immune system response and intestinal microorganisms of crabs are limited. Here, Portunus trituberculatus were exposed to BPA (at a concentration of 100 µg/L), MPs (microbeads of polystyrene with a particle size of 1 µm and at a concentration of 1 × 106 particles/L) or BPA+MPs for 21 days were tested at the tissue, cellular, and molecular levels. The results showed that neither the single nor combined exposure of MPs and BPA had a significant impact on the growth of crabs. However, intestinal histology study found that the intestinal villi of crabs in the BPA treated group, MP treated group and MP+BPA treated group appeared abnormal. Overall, compared with the control group and the single pollutant exposure group, co-exposure to the MP and BPA generally led to a significant increase in MDA and SOD activity and a significant decrease in CAT activity, and the activation of MyD88, Crustin-1, TARF6, Cu/Zn-SOD, Lyz, Toll-2 and NOX gene expression levels were significantly up-regulated. Co-exposure induced disorders of the intestinal microbial community of crabs, resulting in an increase in the abundance of harmful bacteria and a decrease in the abundance of beneficial bacteria. This study shows that the combined exposure of MPs and BPA can exacerbate the intestinal toxicity of a single pollutant to P. trituberculatus.

Research Advances on Swine Acute Diarrhea Syndrome Coronavirus.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a virulent pathogen that causes acute diarrhea in piglets. The virus was first discovered in Guangdong Province, China, in 2017 and has since emerged in Jiangxi, Fujian, and Guangxi Provinces. The outbreak exhibited a localized and sporadic pattern, with no discernable temporal continuity. The virus can infect human progenitor cells and demonstrates considerable potential for cross-species transmission, representing a potential risk for zoonotic transmission. Therefore, continuous surveillance of and comprehensive research on SADS-CoV are imperative. This review provides an overview of the temporal and evolutionary features of SADS-CoV outbreaks, focusing on the structural characteristics of the virus, which serve as the basis for discussing its potential for interspecies transmission. Additionally, the review summarizes virus-host interactions, including the effects on host cells, as well as apoptotic and autophagic behaviors, and discusses prevention and treatment modalities for this viral infection.

The occurrence of pollutants in organisms and water of inland mariculture systems: Shrimp aquaculture is a procession of Microplastics accumulation.

Microplastics (MPs) pollution in the ocean was widely concerned, but the current study on MPs pollution in the mariculture system is relatively lacking. This study researched the MPs pollution characteristics in water and shrimp at different stages of the pond and industrial aquaculture. The study shows that in the same aquaculture stage, MPs abundance in shrimp and water in pond aquaculture mode is higher than that in industrial aquaculture mode. The MPs pollution characteristics in shrimp and water show significant consistency. The hazard index of MPs in pond water and industrial models are 122 (Level Ⅲ) and 540 (Level Ⅲ), respectively, indicating that industrial aquaculture models may suffer from more severe MPs stress. The aquaculture period and mode significantly affected the MPs abundance of water and shrimp, but there was no interaction between the aquaculture period and mode. MPs abundance in shrimp show a significant relationship with the length of crustacean and weight. This study further enhanced the understanding of MPs pollution of water and organisms in different aquaculture modes at different stages, and warned MPs is widely spread in mariculture systems.

Characterization and risk assessment of microplastics in laver from the Yueqing Bay.

Microplastics (MPs) pollution is regarded as a global challenge for ocean. As an important food source of human, macroalgae could suffer MP pollution and transmit MPs into human via food web. However, few studies have revealed the relationship of MP pollution between macroalgae and its habitat. In order to evaluate the trapping and accumulation of MPs in macroalgae and surface water, the present study investigated MP pollution in a typical aquaculture macroalgae species, laver (Porphyra haitanensis) in the Yueqing Bay. The results indicated MP abundance in laver (1.45 ± 0.26 items/g) was at a medium level while MP abundance in surface water (0.21 ± 0.15 item/m3) was at a relatively low level worldwide. Distribution trend and characteristics of MPs in laver and surface water showed highly similarity. Besides, heavy metal elements (Fe and Zr) were detected on the surface of MPs trapped by laver. Pollution load index (PLI) in surface water of the whole bay was low, indicating MP pollution was not serious in the Yueqing Bay. Due to the discharging of domestic sewage in recent years, fiber-shaped, textile MPs accounted for most in laver and surface water of the Yueqing Bay. These results indicated that MPs in surface water could be trapped by P. haitanensis, thus macroalgae cultivation might be a potential way to alleviate seawater MP pollution in the nearshore areas.

A case study on microplastics pollution characteristics in fouling organisms in typical aquaculture bay, China.

Microplastics (MPs) and fouling organisms are prevalent in oceans worldwide. The study aims to investigate the pollution characteristics of MPs in fouling organisms. The study found significant inter-specific differences in the MPs abundance, while the length of MPs is consistent. The average number of MPs in N. exigua is 0.00 ± 0.00. There is a correlation between MPs abundance and weight in sessile group, while gastropods don't. Direct observation has demonstrated that the radulae of N. radula can envelop MPs. Fiber and blue are the predominant forms and colors of MPs found in fouling organisms. It is noteworthy that all film and fragment MPs observed were of a blue hue and had a size limitation of 500 µm. The characteristics of MPs between sessile organisms are more similar than those between gastropods. This study has improved our understanding of the pollution characteristics of MPs in fouling organisms, specifically gastropods.

Distribution and characteristics of microplastics in 16 benthic organisms in Haizhou Bay, China: Influence of habitat, feeding habits and trophic level.

Microplastics (MPs) are widely found in the ocean and cause a serious risk to marine organisms. However, fewer studies have been conducted on benthic organisms. This study conducted a case study on the pollution characteristics of MPs on 16 marine benthic organisms in Haizhou Bay, and analyzed the effects of habitat, trophic level, and feeding mode on the MPs pollution characters. The results showed that MPs were detected in all 16 organisms with an average abundance of 8.84 ± 9.14 items/individual, which is in the middle-high level in the international scale. Among the detected MPs, the main material was cellophane. This study showed that benthic organisms can be used as indicator organisms for MPs pollution. MPs in organisms can be affected by their habitat, trophic level, and feeding mode. Comprehensive analysis of MPs in benthic organisms will contribute to fully understand the characterization and source resolution of MPs pollution.

A tuning fork gyroscope with drive-sense orthogonal thin-walled holes for high sensitivity.

A tuning fork gyroscope (TFG) with orthogonal thin-walled round holes in the driving and sensing directions is proposed to improve sensitivity. The thin walls formed by through holes produce stress concentration, transforming the small displacement of tuning fork vibration into a large concentrated strain. When piezoelectric excitation or detection is carried out here, the driving vibration displacement and detection output voltage can be increased, thereby improving sensitivity. Besides, quadrature coupling can be suppressed because the orthogonal holes make the optimal excitation and detection positions in different planes. The finite element method is used to verify the benefits of the holes, and the parameters are optimized for better performance. The experimental results show that the sensitivity of the prototype gyroscope with a driving frequency of 890.68 Hz is 100.32 mV/(°/s) under open-loop driving and detection, and the rotation rate can be resolved at least 0.016 (°/s)/Hz, which is about 6.7 times better than that of the conventional TFG. In addition, the quadrature error is reduced by 2.7 times. The gyroscope has a simple structure, high reliability, and effectively improves sensitivity, which is helpful to guide the optimization of piezoelectric gyroscopes and derived MEMS gyroscopes.

Mitigating aberrant Cdk5 activation alleviates mitochondrial defects and motor neuron disease symptoms in spinal muscular atrophy.

Spinal muscular atrophy (SMA), the top genetic cause of infant mortality, is characterized by motor neuron degeneration. Mechanisms underlying SMA pathogenesis remain largely unknown. Here, we report that the activity of cyclin-dependent kinase 5 (Cdk5) and the conversion of its activating subunit p35 to the more potent activator p25 are significantly up-regulated in mouse models and human induced pluripotent stem cell (iPSC) models of SMA. The increase of Cdk5 activity occurs before the onset of SMA phenotypes, suggesting that it may be an initiator of the disease. Importantly, aberrant Cdk5 activation causes mitochondrial defects and motor neuron degeneration, as the genetic knockout of p35 in an SMA mouse model rescues mitochondrial transport and fragmentation defects, and alleviates SMA phenotypes including motor neuron hyperexcitability, loss of excitatory synapses, neuromuscular junction denervation, and motor neuron degeneration. Inhibition of the Cdk5 signaling pathway reduces the degeneration of motor neurons derived from SMA mice and human SMA iPSCs. Altogether, our studies reveal a critical role for the aberrant activation of Cdk5 in SMA pathogenesis and suggest a potential target for therapeutic intervention.

Significance of the cGAS-STING Pathway in Health and Disease.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a significant role in health and disease. In this pathway, cGAS, one of the major cytosolic DNA sensors in mammalian cells, regulates innate immunity and the STING-dependent production of pro-inflammatory cytokines, including type-I interferon. Moreover, the cGAS-STING pathway is integral to other cellular processes, such as cell death, cell senescence, and autophagy. Activation of the cGAS-STING pathway by "self" DNA is also attributed to various infectious diseases and autoimmune or inflammatory conditions. In addition, the cGAS-STING pathway activation functions as a link between innate and adaptive immunity, leading to the inhibition or facilitation of tumorigenesis; therefore, research targeting this pathway can provide novel clues for clinical applications to treat infectious, inflammatory, and autoimmune diseases and even cancer. In this review, we focus on the cGAS-STING pathway and its corresponding cellular and molecular mechanisms in health and disease.