Multicomponent Synthesis of Imidazole-Based Ionizable Lipids for Highly Efficient and Spleen-Selective Messenger RNA Delivery.

The spleen emerges as a pivotal target for mRNA delivery, prompting a continual quest for specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate a pronounced preference for mRNA delivery into the spleen with exceptional transfection efficiency. We optimized IMIL structures by constructing and screening a multidimensional IMIL library containing multiple heads, tails, and linkers to perform a structure-activity correlation analysis. Following high-throughput in vivo screening, we identified A3B7C2 as a top-performing IMIL in spleen-specific mRNA delivery via the formulated LNPs, achieving a remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent in splenic dendritic cell transfection. Comparative analyses revealed that A3B7C2-based LNPs achieved a notable 2.8-fold and 12.9-fold increase in splenic mRNA transfection compared to SM102 and DLin-MC3-DMA lipid formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement in splenic mRNA expression compared to the SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues for further research in spleen-selective mRNA delivery. This work offers valuable insights for the swift discovery and rational design of ionizable lipid candidates tailored for spleen-selective transfection, thereby facilitating the application of mRNA therapeutics in spleen-related interventions.

Health state utility values of type 2 diabetes mellitus and related complications: a systematic review and meta-regression.

BACKGROUND: This study aimed to synthesize and quantitatively examine Health State Utility Values (HSUVs) for Type 2 Diabetes Mellitus (T2DM) and its complications, providing a robust meta-regression framework for selecting appropriate HSUV estimates. METHOD: We conducted a systematic review to extract HSUVs for T2DM and its complications, encompassing various influencing factors. Relevant literature was sourced from a review spanning 2000-2020, supplemented by literature from PubMed, Embase, and the Web of Science (up to March 2024). Multivariate meta-regression was performed to evaluate the impact of measurement tools, tariffs, health status, and clinical and demographic variables on HSUVs. RESULTS: Our search yielded 118 studies, contributing 1044 HSUVs. The HSUVs for T2DM with complications varied, from 0.65 for cerebrovascular disease to 0.77 for neuropathy. The EQ-5D-3L emerged as the most frequently employed valuation method. HSUV differences across instruments were observed; 15-D had the highest (0.89), while HUI-3 had the lowest (0.70) values. Regression analysis elucidated the significant effects of instrument and tariff choice on HSUVs. Complication-related utility decrement, especially in diabetic foot, was quantified. Age <70 was linked to increased HSUVs, while longer illness duration, hypertension, overweight and obesity correlated with reduced HSUVs. CONCLUSION: Accurate HSUVs are vital for the optimization of T2DM management strategies. This study provided a comprehensive data pool for HSUVs selection, and quantified the influence of various factors on HSUVs, informing analysts and policymakers in understanding the utility variations associated with T2DM and its complications.

AtNusG, a chloroplast nucleoid protein of bacterial origin linking chloroplast transcriptional and translational machineries, is required for proper chloroplast gene expression in Arabidopsis thaliana.

In Escherichia coli, transcription-translation coupling is mediated by NusG. Although chloroplasts are descendants of endosymbiotic prokaryotes, the mechanism underlying this coupling in chloroplasts remains unclear. Here, we report transcription-translation coupling through AtNusG in chloroplasts. AtNusG is localized in chloroplast nucleoids and is closely associated with the chloroplast PEP complex by interacting with its essential component PAP9. It also comigrates with chloroplast ribosomes and interacts with their two components PRPS5 (uS5c) and PRPS10 (uS10c). These data suggest that the transcription and translation machineries are coupled in chloroplasts. In the atnusg mutant, the accumulation of chloroplast-encoded photosynthetic gene transcripts, such as psbA, psbB, psbC and psbD, was not obviously changed, but that of their proteins was clearly decreased. Chloroplast polysomic analysis indicated that the decrease in these proteins was due to the reduced efficiency of their translation in this mutant, leading to reduced photosynthetic efficiency and enhanced sensitivity to cold stress. These data indicate that AtNusG-mediated coupling between transcription and translation in chloroplasts ensures the rapid establishment of photosynthetic capacity for plant growth and the response to environmental changes. Therefore, our study reveals a conserved mechanism of transcription-translation coupling between chloroplasts and E. coli, which perhaps represents a regulatory mechanism of chloroplast gene expression. This study provides insights into the underlying mechanisms of chloroplast gene expression in higher plants.

Induction and Stabilization of Columnar Mesophases in Fluorinated Polycyclic Aromatic Hydrocarbons by Arene-Perfluoroarene Interactions.

The straightforward synthesis of several Fluorinated Polycyclic Aromatic Hydrocarbons by the efficient, transition-metal-free, arene fluorine nucleophilic substitution reaction is described, and the full investigation of their liquid crystalline and optical properties reported. The key precursors for this study, i. e. 2,2'-dilithio-4,4',5,5'-tetraalkoxy-1,1'-biphenyl derivatives, were obtained in two steps from the highly selective Scholl oxidative homo-coupling of 3,4-dialkoxy-1-bromobenzene, followed by quantitative double-lithiation. In situ room temperature nucleophilic annulation with either perfluorobenzene or perfluoronaphthalene leads to 1,2,3,4-tetrafluoro-6,7,10,11-tetraalkxoytriphenylenes and 9,10,11,12,13,14-hexafluoro-2,3,6,7-tetraalkoxybenzo[f]tetraphenes, respectively, in good yields. Exploiting the same strategy, subsequent double annulations resulted in the formation of 9,18-difluoro-2,3,6,7,11,12,15,16-octa(alkoxy)tribenzo[f,k,m]tetraphenes and 9,10,19,20-tetrafluoro-2,3,6,7,12,13,16,17-octakis(hexyloxy)tetrabenzo[a,c,j,l]tetracenes, respectively. Despite the presence of only four alkoxy chains, the polar "Janus" mesogens display a columnar hexagonal mesophase over broad temperature ranges, with higher mesophase stability than the archetypical 2,3,6,7,10,11-hexa(alkoxy)triphenylenes and their hydrogenated counterparts. The improvement or induction of mesomorphism is attributed to efficient antiparallel face-to-face π-stacking driven by the establishment of non-covalent perfluoroarene-arene intermolecular interactions. The larger lipophilic discotic π-extended compounds also exhibit columnar mesomorphism, over similar temperature ranges and stability than their hydrogenated homologs. Finally, these fluorinated molecules form stringy gels in various solvents, and show interesting solvatochromic emission properties in solution as well as strong emission in thin films and gels.

Smart Temperature Sensor Design and High-Density Water Temperature Monitoring in Estuarine and Coastal Areas.

Acquiring in situ water temperature data is an indispensable and important component for analyzing thermal dynamics in estuarine and coastal areas. However, the long-term and high-density monitoring of water temperature is costly and technically challenging. In this paper, we present the design, calibration, and application of the smart temperature sensor TS-V1, a low-power yet low-cost temperature sensor for monitoring the spatial-temporal variations of surface water temperatures and air temperatures in estuarine and coastal areas. The temperature output of the TS-V1 sensor was calibrated against the Fluke-1551A sensor developed in the United States and the CTD-Diver sensor developed in the Netherlands. The results show that the accuracy of the TS-V1 sensor is 0.08 °C, while sensitivity tests suggest that the TS-V1 sensor (comprising a titanium alloy shell with a thermal conductivity of 7.6 W/(m °C)) is approximately 0.31~0.54 s/°C slower than the CTD-Diver sensor (zirconia shell with thermal conductivity of 3 W/(m °C)) in measuring water temperatures but 6.92~10.12 s/°C faster than the CTD-Diver sensor in measuring air temperatures. In addition, the price of the proposed TS-V1 sensor is only approximately 1 and 0.3 times as much as the established commercial sensors, respectively. The TS-V1 sensor was used to collect surface water temperature and air temperature in the western part of the Pearl River Estuary from July 2022 to September 2022. These data wells captured water and air temperature changes, frequency distributions, and temperature characteristics. Our sensor is, thus, particularly useful for the study of thermal dynamics in estuarine and coastal areas.

Transcriptome and Metabolome Analyses Provide Insights into the Flavonoid Accumulation in Peels of Citrus reticulata 'Chachi'.

The quality of Chinese medicinal materials depends on the content of bioactive components, which are affected by the environmental factors of different planting regions. In this research, integrated analysis of the transcriptome and metabolome of C. reticulata 'Chachi' was performed in two regions, and three orchards were included in the analysis. In total, only 192 compounds were found in fresh peels, and among 18 differentially accumulated flavonoid metabolites, 15 flavonoids were enriched in peels from the Xinhui planting region. In total, 1228 genes were up-regulated in peels from Xinhui, including the CHS and GST genes, which are involved in the salt stress response. Overall, based on the correlation analysis of flavonoid content and gene expression in peels of C. reticulata 'Chachi', we concluded that the authenticity of the GCRP from Xinhui may be closely related to the higher content of naringin and narirutin, and the increase in the content of these may be due to the highly saline environment of the Xinhui region.

Mycobacterium tuberculosis effector PPE36 attenuates host cytokine storm damage via inhibiting macrophage M1 polarization.

Tuberculosis caused by Mycobacterium tuberculosis remains a serious global public health threat. Macrophage polarization is crucial for the innate immunity against M. tuberculosis. However, how M. tuberculosis interferes with macrophage polarization is elusive. We demonstrated here that M. tuberculosis PPE36 (Rv2108) blocked macrophage M1 polarization, preventing the cytokine storm, and alleviating inflammatory damage to mouse immune organs. PPE36 inhibited the polarization of THP-1 cell differentiation to M1 macrophages, reduced mitochondrial dehydrogenase activity, inhibited the expression of CD16, and repressed the expression of pro-inflammatory cytokines IL-6 and TNF-α, as well as chemokines CXCL9, CXCL10, CCL3, and CCL5. Intriguingly, in the mouse infection model, PPE36 significantly alleviated the inflammatory damage of immune organs caused by a cytokine storm. Furthermore, we found that PPE36 inhibited the polarization of macrophages into mature M1 macrophages by suppressing the ERK signaling. The study provided novel insights into the function and mechanism of action of M. tuberculosis effector PPE36 both at the cellular and animal level.

Protocol for observing lipid droplet dynamics in chicken cone cells.

Chicken cone cells are an excellent model for studying the regulation of lipid droplet dynamics. Here, we present a protocol for studying cone cell lipid droplets from in vivo and ex vitro cultured retinas of chicken embryos. We describe steps for dissecting chicken retinas, electroporating retinas, culturing retinas ex vivo and in vitro, and staining lipid droplets with neutral lipid dye. This protocol is also applicable to investigating other organelles in retinas. For complete details on the use and execution of this protocol, please refer to Pan et al.1.

CgLS mediates limonene synthesis of main essential oil component in secretory cavity cells of Citrus grandis 'Tomentosa' fruits.

d-Limonene is the predominant component of essential oil from Exocarpium Citri Grandis, known for its antibacterial, antioxidant, insecticidal, and anti-inflammatory properties. The synthesis, transport, and accumulation of d-limonene in Citrus grandis 'Tomentosa' fruits are regulated by limonene synthase (LS) and its associated regulatory genes. This study addresses the gap in understanding the spatiotemporal cytological changes of LS and its regulatory genes. Through cytochemical techniques, we investigated the distribution of essential oil in the plastids, endoplasmic reticulum, and vacuoles of secretory cavity cells. We identified the LS-encoding gene CgLS via transcriptomics and demonstrated in vitro that CgLS catalyzes the formation of d-limonene from geranyl diphosphate (GPP). Transient overexpression of CgLS increased monoterpene limonene accumulation, while TRV virus-induced gene silencing reduced it. CgLS expression levels and d-limonene content showed spatiotemporal consistency with fruit development, with in situ hybridization revealing predominant expression in secretory cavity cells. Immunocytochemical localization indicated that CgLS is primarily located in the endoplasmic reticulum, plastids, and vacuoles. Our findings suggest that CgLS is translated in the endoplasmic reticulum and transported to plastids and vacuoles where d-limonene synthesis occurs. This study provides comprehensive insights into the characteristics of CgLS and its role in d-limonene synthesis at the tissue, cellular, and molecular levels in C. grandis 'Tomentosa'.

Regime shifts in the thermal dynamics of offshore China due to accelerated global warming.

Thermal dynamics play a pivotal role in offshore ecosystems, influencing a multitude of ecological and biogeochemical processes. Assessing how water temperature (WT) responds to climate change is vital for the sustainable development of marine ecosystems. Despite the scarcity of long-term sea surface temperature (SST) data, this study reconstructs SSTs from 1973 to 2020 in China's coastal zones using the data-driven Air2water model. A probabilistic approach was applied to investigate the joint dependency structures between air temperature (AT) and WT at offshore oceanic stations in China, focusing on variations during periods of decelerated and accelerated warming. The results indicate that the Air2water model performs well in reconstructing SSTs of the coastal zone of China. Furthermore, the joint probability of AT-WT events, characterized by bimodal distributions, tends to increase during accelerated warming. This suggests intensified extreme SST events in the coastal zone of China due to global warming, with the significant warming primarily related with regional oscillations, atmospheric dynamics, and the complex temperature trends in the regional marine environment. These findings highlight the escalating impact of global warming on marine ecosystems in China's coastal regions, underscoring the urgency of developing adaptive strategies to mitigate these effects.

Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours.

An effective nanotherapeutic transport from the vasculature to the tumour is crucial for cancer treatment with minimal side effects. Here we demonstrate that, in addition to the endothelial barrier, the tumour vascular basement membrane surrounding the endothelium acts as a formidable mechanical barrier that entraps nanoparticles (NPs) in the subendothelial void, forming perivascular NP pools. Breaking through this basement membrane barrier substantially increases NP extravasation. Using inflammation triggered by local hyperthermia, we develop a cooperative immunodriven strategy to overcome the basement membrane barrier that leads to robust tumour killing. Hyperthermia-triggered accumulation and inflammation of platelets attract neutrophils to the NP pools. The subsequent movement of neutrophils through the basement membrane can release the NPs entrapped in the subendothelial void, resulting in increased NP penetration into deeper tumours. We show the necessity of considering the tumour vascular basement membrane barrier when delivering nanotherapeutics. Understanding this barrier will contribute to developing more effective antitumour therapies.

An integrated multi-omics approach reveals polymethoxylated flavonoid biosynthesis in Citrus reticulata cv. Chachiensis.

Citrus reticulata cv. Chachiensis (CRC) is an important medicinal plant, its dried mature peels named "Guangchenpi", has been used as a traditional Chinese medicine to treat cough, indigestion, and lung diseases for several hundred years. However, the biosynthesis of the crucial natural products polymethoxylated flavonoids (PMFs) in CRC remains unclear. Here, we report a chromosome-scale genome assembly of CRC with the size of 314.96 Mb and a contig N50 of 16.22 Mb. Using multi-omics resources, we discover a putative caffeic acid O-methyltransferase (CcOMT1) that can transfer a methyl group to the 3-hydroxyl of natsudaidain to form 3,5,6,7,8,3',4'-heptamethoxyflavone (HPMF). Based on transient overexpression and virus-induced gene silencing experiments, we propose that CcOMT1 is a candidate enzyme in HPMF biosynthesis. In addition, a potential gene regulatory network associated with PMF biosynthesis is identified. This study provides insights into PMF biosynthesis and may assist future research on mining genes for the biosynthesis of plant-based medicines.

Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.

The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals. We show that Tak1, a key kinase in innate immune/inflammatory signaling, activates the Hippo pathway by inducing the lysosomal degradation of Cka, an essential subunit of the STRIPAK PP2A complex that suppresses Hippo signaling. Suppression of STRIPAK results in the activation of Hippo pathway through Tao-Hpo signaling. We further show that Tak1-mediated Hippo signaling is involved in processes ranging from cell death to phagocytosis and innate immune memory. Our findings thus reveal a molecular connection between innate immune/inflammatory signaling and the evolutionally conserved Hippo pathway, thus contributing to our understanding of infectious, inflammatory and malignant diseases.

Dam inundation duration as a dominant constraint on riparian vegetation recovery.

The identification of limiting factors is essential for the ecological restoration of riparian ecosystems degraded by the damming of rivers, but remains unclear. Here, we quantitatively assessed the relative importance of environmental factors and revealed the main limiting factors for riparian vegetation restoration and their influencing mechanisms, using riparian plant and environmental data of seven large reservoirs in southwest China. We found that inundation duration had a significantly greater effect on riparian vegetation distribution, cover and diversity than environmental factors such as inundation depth, rainfall, humidity, temperature, sunshine hours, aspect, slope, surface relief, soil pH, available nitrogen (AN), available phosphorus (AP), and available potassium (AK); vegetation cover, species richness, complexity and dominance were highly significantly negatively correlated with inundation duration (p < 0.01); inundation for 5 months is close to the tolerance limit of most plants and poses a significant limiting effect on the vegetation restoration in the reservoir riparian. Therefore, the inundation duration should be highlighted in riparian vegetation restoration. Meanwhile, incorporating the riparian inundation into the river ecological scheduling objectives to shorten the inundation duration and thus radically alleviate the limitation is a new opportunity for vegetation restoration in the reservoir riparian.

[Advances in the Treatment of Glucocorticoid Resistance and Relapsed Immune Thrombocytopenia --Review].

Immune thrombocytopenia (ITP) is an immune-mediated acquired hemorrhagic autoimmune disease. At present, the first-line therapeutic drugs for ITP include glucocorticoids and intravenous immunoglobulins. However, about 1/3 of the patients had no response to the first-line treatment, or relapsed after dose reduction or withdrawal of glucocorticoids. In recent years, with the gradual deepening of the understanding on the pathogenesis of ITP, the drugs targeting different pathogenesis continually emerge, including immunomodulators, demethylating agents, spleen tyrosine kinase (SYK) inhibitors and neonatal Fc receptor (FcRn) antagonist. However, most of these drugs are in clinical trials. This review summarized briefly the recent advances in the treatment of glucocorticoids resistance and relapsed ITP, so as to provide reference for the clinical treatments.

Research Progress on Factors Affecting Oil-Absorption Performance of Cement-Based Materials.

With the wide application of petroleum resources, oil substances have polluted the environment in every link from crude oil extraction to utilization. Cement-based materials are the main materials in civil engineering, and the study of their adsorption capacity for oil pollutants can expand the scope of functional engineering applications of cement-based materials. Based on the research status of the oil-wet mechanism of different kinds of oil-absorbing materials, this paper lists the types of conventional oil-absorbing materials and introduces their application in cement-based materials while outlining the influence of different oil-absorbing materials on the oil-absorbing properties of cement-based composites. The analysis found that 10% Acronal S400F emulsion can reduce the water absorption rate of cement stone by 75% and enhance the oil-absorption rate by 62%. Adding 5% polyethylene glycol can increase the oil-water relative permeability of cement stone to 1.2. The oil-adsorption process is described by kinetic and thermodynamic equations. Two isotherm adsorption models and three adsorption kinetic models are explained, and oil-absorbing materials and adsorption models are matched. The effects of specific surface area, porosity, pore interface, material outer surface, oil-absorption strain, and pore network on the oil-absorption performance of materials are reviewed. It was found that the porosity has the greatest influence on the oil-absorbing performance. When the porosity of the oil-absorbing material increases from 72% to 91%, the oil absorption can increase to 236%. In this paper, by analyzing the research progress of factors affecting oil-absorption performance, ideas for multi-angle design of functional cement-based oil-absorbing materials can be obtained.

Body color plasticity of Diaphorina citri reflects a response to environmental stress.

Body color polyphenism is common in Diaphorina citri. Previous studies compared physiological characteristics in D. citri, but the ecological and biological significance of its body color polyphenism remains poorly understood. We studied the ecological and molecular effects of stressors related to body color in D. citri. Crowding or low temperature induced a high proportion of gray morphs, which had smaller bodies, lower body weight, and greater susceptibility to the insecticide dinotefuran. We performed transcriptomic and metabolomics analysiis of 2 color morphs in D. citri. Gene expression dynamics revealed that the differentially expressed genes were predominantly involved in energy metabolism, including fatty acid metabolism, amino acid metabolism, and carbohydrate metabolism. Among these genes, plexin, glycosidase, phospholipase, take out, trypsin, and triacylglycerol lipase were differentially expressed in 2 color morphs, and 6 hsps (3 hsp70, hsp83, hsp90, hsp68) were upregulated in gray morphs. The metabolome data showed that blue morphs exhibited a higher abundance of fatty acid and amino acid, whereas the content of carbohydrates was elevated in gray morphs. This study partly explains the body color polyphenism of D. citri and provides insights into the molecular changes of stress response of D. citri.

Centrins control chicken cone cell lipid droplet dynamics through lipid-droplet-localized SPDL1.

As evolutionarily conserved organelles, lipid droplets (LDs) carry out numerous functions and have various subcellular localizations in different cell types and species. In avian cone cells, there is a single apically localized LD. We demonstrated that CIDEA (cell death inducing DFFA like effector a) and microtubules promote the formation of the single LD in chicken cone cells. Centrins, which are well-known centriole proteins, target to the cone cell LD via their C-terminal calcium-binding domains. Centrins localize on cone cell LDs with the help of SPDL1-L (spindle apparatus coiled-coil protein 1-L), a previously uncharacterized isoform of the kinetochore-associated dynein adaptor SPDL1. The loss of CETN3 or overexpression of a truncated CETN1 abrogates the apical localization of the cone cell LD. Simulation analysis showed that multiple LDs or a single mispositioned LD reduces the light sensitivity. Collectively, our findings identify a role of centrins in the regulation of cone cell LD localization, which is important for the light sensitivity of cone cells.

A dRASSF-STRIPAK-Imd-JAK/STAT axis controls antiviral immune response in Drosophila.

Host antiviral immunity suffers strong pressure from rapidly evolving viruses. Identifying host antiviral immune mechanisms has profound implications for developing antiviral strategies. Here, we uncover an essential role for the tumor suppressor Ras-association domain family (RASSF) in Drosophila antiviral response. Loss of dRassf in fat body leads to increased vulnerability to viral infection and impaired Imd pathway activation accompanied by detrimental JAK/STAT signaling overactivation. Mechanistically, dRASSF protects TAK1, a key kinase of Imd pathway, from inhibition by the STRIPAK PP2A phosphatase complex. Activated Imd signaling then employs the effector Relish to interfere with the dimerization of JAK/STAT transmembrane receptor Domeless, therefore preventing excessive JAK/STAT signaling. Moreover, we find that RASSF and STRIPAK PP2A complex are also involved in antiviral response in human cell lines. Our study identifies an important role for RASSF in antiviral immunity and elucidates a dRASSF-STRIPAK-Imd-JAK/STAT signaling axis that ensures proper antiviral responses in Drosophila.

Hepatic CDP-diacylglycerol synthase 2 deficiency causes mitochondrial dysfunction and promotes rapid progression of NASH and fibrosis.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis (NASH). The factors promoting the progression of steatosis to NASH are still unclear. Recent studies suggest that mitochondrial lipid composition is critical in NASH development. Here, we showed that CDP-DAG synthase 2 (Cds2) was downregulated in genetic or diet-induced NAFLD mouse models. Liver-specific deficiency of Cds2 provoked hepatic steatosis, inflammation and fibrosis in five-week-old mice. CDS2 is enriched in mitochondria-associated membranes (MAMs), and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE levels. Overexpression of phosphatidylserine decarboxylase (PISD) alleviated the NASH-like phenotype in Cds2f/f;AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in hepatocytes. Additionally, dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha (PPARα) attenuated mitochondrial defects and ameliorated the NASH-like phenotype in Cds2f/f;AlbCre mice. Finally, Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and obesity. Thus, Cds2 modulates mitochondrial function and NASH development.