Progress on SOX9 and its enhancers in mammalian sex determination.

The sex determination in mammals refers to the development of an initial bipotential organ, termed the bipotential gonad/genital ridge, into either a testis or an ovary at the early stages of embryonic development, under the precise regulation of transcription factors. SOX9 (SRY-box transcription factor 9) is a multifunctional transcription factor in mammalian development and plays a critical role in sex determination and subsequent male reproductive organs development. Recent studies have shown that several enhancers upstream of SOX9 also play an important role in the process of sex determination. In this review, we summarize the progress on the role of SOX9 and its gonadal enhancers in sex determination. This review will facilitate to understand the regulatory mechanism of sex determination of SOX9 and provides a theoretical basis for the further development of animal sex manipulation technologies.

Exploring the role of non-canonical splice site variants in aberrant splicing associated with reproductive genetic disorders.

Whole-exome sequencing (WES) is frequently utilized in diagnosing reproductive genetic disorders to identify various genetic variants. Canonical ±1,2 splice sites are typically considered highly pathogenic, while variants at the 5' or 3' ends of exon boundaries are often considered synonymous or missense variants, with their potential impact on abnormal gene splicing frequently overlooked. In this study, we identified five variants located at the last two bases of the exons and two canonical splicing variants in five distinct families affected by reproductive genetic disorders through WES. Minigene analysis, RT-PCR and Quantitative Real-time PCR (RT-qPCR) confirmed that all seven variants induced aberrant splicing, with six variants altering gene transcriptional expression levels. These findings underscore the crucial role of splice variants, particularly non-canonical splice sites variants, in reproductive genetic disorders, with all identified variants classified as pathogenic.

Octylammonium Iodide Induced in-situ Healing Behavior at Perovskite / Carbon Interface: the "Slow-Release Effect" Caused by Carbon Black Adsorption.

"Perovskite / Carbon" interface has remained a key bottleneck for the hole-conductor-free perovskite solar cells based on carbon-electrode (CPSCs), due to problems like loose physics contact, defects, energy mismatch, poor chemical coupling, etc. A previous study shows that octylammonium iodide (OAI) blending in carbon paste induced a kind of "in-situ healing" effect for "perovskite / carbon" interface, and improved power conversion efficiency from ≈13% to >19%. Here the beneath mechanism is further explored by careful examination of the interaction between OAI molecule and carbon black (CB) nanoparticles. It comes to show that, the famous "CB adsorption" plays a key role during the "healing" processes. Due to CB adsorption behavior, the mass ratio between OAI and CB influences much on the healing effect. By suitably adjusting the mass ratio between OAI and CB, and increasing the light harvest of perovskite, an efficiency of 19.41% is achieved for the hole-conductor-free CPSCs. Device efficiency and the charge-extraction and recombination process are tracked with the storage period, continuous improvement appears for devices assembled by relatively higher CB mass. A kind of "slow-release effect" is revealed during the OAI-induced "in-situ healing" process, which is caused by the famous "CB adsorption" behavior.

Polyvinyl Pyrrolidone Induced "Confinement Effect" on PbI2 and the Improvement on Crystallization and Thermal Stability of Perovskite.

Polyvinyl pyrrolidone is blended in PbI2 with varied concentration, so as to study the coarsening dynamics of perovskite during the two-step growth method. It is observed that polyvinyl pyrrolidone hinders the crystallization of PbI2 and helps to form a more amorphous PbI2 matrix, which then improves perovskite crystallization. As the blending concentration increases from 0 to 2 mM, average crystallite/grain size of perovskite increases from 40.29 nm/0.79 µm to 84.35 nm/1.02 µm while surface fluctuation decreases slightly from 25.64 to 23.96 nm. The observations are caused by the "confinement effect" brought by polyvinyl pyrrolidone on PbI2 . Elevating blending concentration of polyvinyl pyrrolidone results in smaller PbI2 crystallites and more amorphous PbI2 matrix, thus reducing the diffusion/reaction barrier between PbI2 and organic salt and favoring perovskite crystallization. As blending concentration increases from 0 to 2 mM, the device efficiency rises from 19.76 (± 0.60) % to 20.50 (± 0.89) %, with the optimized value up to 22.05%, which is further improved to 24.48% after n-Octylammonium iodide (OAI)-basing surface modification. The study enlarges the scope of "confinement effect" brought by polymer molecules, which is beneficial for efficient and stable perovskite solar cell fabrication.

Octylammonium Iodide Induced In-situ Healing at "perovskite/Carbon" Interface to Achieve 85% RH-moisture Stable, Hole-Conductor-Free Perovskite Solar Cells with Power Conversion Efficiency >19.

"Perovskite/carbon" interface is a bottle-neck for hole-conductor-free, carbon-electrode basing perovskite solar cells due to the energy mismatch and concentrated defects. In this article, in-situ healing strategy is proposed by doping octylammonium iodide into carbon paste that used to prepare carbon-electrode on perovskite layer. This strategy is found to strengthen interfacial contact and reduce interfacial defects on one hand, and slightly elevate the work function of the carbon-electrode on other hand. Due to this effect, charge extraction is accelerated, while recombination is obviously reduced. Accordingly, power conversion efficiency of the hole-conductor-free, planar perovskite solar cells is upgraded by ≈50%, or from 11.65 (± 1.59) % to 17.97 (± 0.32) % (AM1.5G, 100 mW cm-2 ). The optimized device shows efficiency of 19.42% and open-circuit voltage of 1.11 V. Meanwhile, moisture-stability is tested by keeping the unsealed devices in closed chamber with relative humidity of 85%. The "in-situ healing" strategy helps to obtain T80 time of >450 h for the carbon-electrode basing devices, which is four times of the reference ones. Thus, a kind of "internal encapsulation effect" has also been reached. The "in situ healing" strategy facilitates the fabrication of efficient and stable hole-conductor-free devices basing on carbon-electrode.

Short-term exposure to ozone may trigger the onset of Kawasaki disease: An individual-level, case-crossover study in East China.

Kawasaki disease (KD) is an acute, systemic vasculitis that primarily affects children aged under the age of 5. While environmental factors have been linked to the development of KD, the specific role of ozone (O3) pollution in triggering the disease onset remains uncertain. This study aimed to examine the associations between short-term O3 exposure and KD onset in children. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched 1808 KD patients (out of a total of 6115 eligible individuals) to pre-onset ozone exposures based on their home addresses in East China between 2013 and 2020. Our findings revealed a significant association of O3 exposure with KD onset on the day of onset (lag 0 day). However, this association attenuated and became statistically insignificant on lag 1 and lag 2 days. Each interquartile range (52.32 µg/m3) increase in O3 concentration at lag 0 day was associated with a 16.2% (95% CI: 3.6%, 30.3%) increased risk of KD onset. The E-R curve for O3 exhibited a plateau at low concentrations and then increased rapidly at concentrations ≥75 µg/m3. Notably, these associations were stronger in male children, younger children (<2 years of age) and patients experiencing KD onset during the warm season. This study provides novel epidemiological evidence indicating that short-term O3 exposure is associated with an increased risk of childhood KD onset. These findings emphasized the importance of considering this environmental risk factor in KD prevention strategies.

Associations of lipids and lipid-lowering drugs with risk of stroke: a Mendelian randomization study.

Background: Stroke is a leading cause of death worldwide, but it is unclear whether circulating lipids and lipid-lowering drugs are causally associated with stroke and its subtypes. Methods: We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-lowering drugs on stroke and its subtypes. Results: The inverse variance weighted Mendelian randomization (IVW-MR) revealed the low-density lipoprotein cholesterol (LDL-C) (OR, 1.46; 95% CI, 1.17-1.83; p = 0.0008) and apolipoprotein B (apoB) (OR, 1.46; 95% CI, 1.21-1.77; p = 0.0001) was positively correlated with large artery stroke (LAS). However, no causal effect was found in LDL-C and apoB on LAS risk when we conducted mvMR. The IVW-MR also found a suggestive evidence that decreased LDL-C levels mediated by the PCSK9 (proprotein convertase subtilisin-kexin type 9) gene were associated with a reduced risk of any stroke (AS) (OR, 1.31; 95% CI, 1.13-1.52; p = 0.0003), any ischemic stroke (AIS) (OR, 1.29; 95% CI, 1.10-1.51; p = 0.001), and LAS (OR, 1.73; 95% CI, 1.15-2.59; p = 0.008), while NPC1L1 (Niemann-Pick C1-like protein)-mediated LDL-C levels were associated with a higher risk of small vessel stroke (SVS) (OR, 6.10; 95% CI, 2.13-17.43; p = 0.0008). The SMR revealed that expression of PCSK9 was associated with risk of AS (OR, 1.15; 95% CI, 1.03-1.28; p = 0.01), AIS (OR, 1.02; 95% CI, 1.14-1.29; p = 0.03), cardioembolic stroke (CES) (OR, 1.28; 95% CI, 1.01-1.61; p = 0.04). And, a significant association was found between the expression of NPC1L1 and the risk of SVS (OR, 1.15; 95% CI, 1.00-1.32; p = 0.04). Conclusion: We cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.

Optical time-stretch imaging flow cytometry in the compressed domain.

Imaging flow cytometry based on optical time-stretch (OTS) imaging combined with a microfluidic chip attracts much attention in the large-scale single-cell analysis due to its high throughput, high precision, and label-free operation. Compressive sensing has been integrated into OTS imaging to relieve the pressure on the sampling and transmission of massive data. However, image decompression brings an extra overhead of computing power to the system, but does not generate additional information. In this work, we propose and demonstrate OTS imaging flow cytometry in the compressed domain. Specifically, we constructed a machine-learning network to analyze the cells without decompressing the images. The results show that our system enables high-quality imaging and high-accurate cell classification with an accuracy of over 99% at a compression ratio of 10%. This work provides a viable solution to the big data problem in OTS imaging flow cytometry, boosting its application in practice.

Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle.

BACKGROUND: Malnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient-sensing mechanisms in the pathogenesis of steatosis. METHODS: Plin2, a lipid droplet (LD) protein-inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4-UAS system, we used the Drosophila melanogaster wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. Drosophila Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid-binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH-7 and SNU-475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell-free systems in amino acid-binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis. RESULTS: As a lipolysis inhibitor, Plin2 was significantly elevated in liver (P < 0.05) and muscle (P < 0.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid-dependent manner. Ubr1 uses two canonical substrate-binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto-inhibition. In the absence of amino acids, or when the amino acid-binding capacity of Ubr1 is diminished, Ubr1-mediated Plin2 degradation is inactivated, leading to steatosis. CONCLUSIONS: We identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.

Simultaneous expression of three reporter proteins from a porcine reproductive and respiratory syndrome virus-based vector.

The mechanism of discontinuous transcription for the synthesis of a series of sub-genomic mRNAs to express the structural proteins of porcine reproductive and respiratory syndrome virus (PRRSV) potentially allows for the simultaneous expression of multiple foreign genes. This can occur by insertion of multiple novel independent transcription units between the ORF sequences of the PRRSV genome. Here, an expression cassette consisting of a red fluorescent protein (RFP) gene flanked at its 3' end by transcription-regulating sequences (TRS) and an expression cassette consisting of an iLOV gene flanked at its 5' end by TRS, was constructed. The resulting expression cassette containing a RFP and an iLOV gene were introduced between ORF1b and 2 as well as ORF7 and 3'UTR, respectively, in an infectious PRRSV cDNA clone. Transfection of the resulting clone (pGX-12RFP-73iLOV) into cells resulted in the recovery of a recombinant virus (rGX-12RFP-73iLOV). Simultaneous expression of RFP and iLOV was observed in MARC-145 cells infected with rGX-RFP-iLOV. To test the ability of the PRRSV genome to express all three reporter genes simultaneously, an expression cassette containing the Gluc gene and one containing the iLOV gene were also inserted in between ORF1b and 2 as well as ORF7 and 3'UTR, respectively. This was performed in a recently obtained infectious PRRSV cDNA clone carrying a RFP gene in nsp2. Transfection of the construct (pGX-R-Gluc-iLOV) carrying the three reporter genes into cells allowed the rescue of the recombinant reporter virus (rGX-R-Gluc-iLOV) which showed similar growth characteristics to the parental virus but yielded 100-fold less infectious viruses. Fluorescence microscopy of cells infected with rGX-R-Gluc-iLOV demonstrated the presence of both RFP and iLOV genes. Gluc activities in supernatants harvested at different time points from cells infected with recombinant viruses carrying Gluc showed increased levels of Gluc activity as the infection progressed. This indicated that Gluc gene as well as its activity were acceptable parameters to monitor viral propagation. Our results indicate that it is possible to introduce at least three foreign proteins simultaneously in a PRRSV-based vector and such studies will prove invaluable in our future understanding of these viruses.

Improved Thermal Stability and Film Uniformity of Halide Perovskite by Confinement Effect brought by Polymer Chains of Polyvinyl Pyrrolidone.

Polyvinyl pyrrolidone (PVP) is doped to PbI2 and organic salt during two-step growth of halideperovskite. It is observed that PVP molecules can interact with both PbI2 and organic salt, reduce the aggregation and crystallization of the two, and then slow down the coarsening rate of perovskite. As doping concentration increases from 0 to 1 mM in organic salt, average crystallite size of perovskite decreases monotonously from 90 to 34 nm; Surface fluctuation reduces from 259.9 to 179.8 nm at first, and then increases; Similarly, surface roughness decreases from 45.55 to 26.64 nm at first, and then rises. Accordingly, a kind of "confinement effect" is resolved to crystallite growth and surface fluctuation/roughness, which helps to build compact and uniform perovskite film. Density of trap states (t-DOS) is cut down by ≈60% at moderate doping  (0.2 mM). Due to the "confinement effect", power conversion efficiency of perovskite solar cells is improved from 19.46 (±2.80) % to 21.50 (±0.99) %, and further improved to 24.11% after surface modification. Meanwhile, "confinement effect" strengthens crystallite/grain boundaries and improves thermal stability of both film and device. T80 of device increases to 120 h, compared to 50 h for reference ones.

Improved Crystallization of Lead Halide Perovskite in Two-Step Growth Method by Polymer-Assisted "Slow-Release Effect".

Fast reaction between organic salt and lead iodide always leads to small perovskite crystallites and concentrated defects. Here, polyacrylic acid is blended with organic salt, so as to regulate the crystallization in a two-step growth method. It is observed that addition of polyacrylic acid retards aggregation and crystallization behavior of the organic salt, and slows down the reaction rate between organic salt and PbI2 , by which "slow-release effect" is defined. Such effect improves crystallization of perovskite. X-ray diffraction study shows that, after addition of 2 mm polyacrylic acid, average crystallite size of perovskite increases from ≈40 to ≈90 nm, meanwhile, grain size increases. Thermal admittance spectroscopy study shows that trap density is reduced by nearly one order (especially for deep energy levels). Due to the improved crystallization and reduced trap density, charge recombination is obviously reduced, while lifetime of charge carriers in perovskite film and devices are prolonged, according to time-resolved photoluminescence and transient photo-voltage decay curve tests, respectively. Accordingly, power conversion efficiency of the device is promoted from 19.96 (±0.41)% to 21.84 (±0.25)% (with a champion efficiency of 22.31%), and further elevated to 24.19% after surface modification by octylammonium iodide.

Wounds under diabetic milieu: The role of immune cellar components and signaling pathways.

A major challenge in the field of diabetic wound healing is to confirm the body's intrinsic mechanism that could sense the immune system damage promptly and protect the wound from non-healing. Accumulating literature indicates that macrophage, a contributor to prolonged inflammation occurring at the wound site, might play such a role in hindering wound healing. Likewise, other immune cell dysfunctions, such as persistent neutrophils and T cell infection, may also lead to persistent oxidative stress and inflammatory reaction during diabetic wound healing. In this article, we discuss recent advances in the immune cellular components in wounds under the diabetic milieu, and the role of key signaling mechanisms that compromise the function of immune cells leading to persistent wound non-healing.

Identification of potential targets of cinnamon for treatment against Alzheimer's disease-related GABAergic synaptic dysfunction using network pharmacology.

Cinnamon aqueous extract's active substance base remains unclear and its mechanisms, mainly the therapeutic target of anti-Alzheimer's disease (AD)-related GABAergic synaptic dysfunction, remain unclear. Here, 30 chemical components were identified in the aqueous extract of cinnamon using LC/MS; secondly, we explored the brain-targeting components of the aqueous extract of cinnamon, and 17 components had a good absorption due to the blood-brain barrier (BBB) limitation; thirdly, further clustering analysis of active ingredient targets by network pharmacology showed that the GABA pathway with GABRG2 as the core target was significantly enriched; then, we used prominent protein-protein interactions (PPI), relying on a protein-metabolite network, and identified the GABRA1, GABRB2 and GABRA5 as the closest targets to GABRG2; finally, the affinity between the target and its cognate active compound was predicted by molecular docking. In general, we screened five components, methyl cinnamate, propyl cinnamate, ( +)-procyanidin B2, procyanidin B1, and myristicin as the brain synapse-targeting active substances of cinnamon using a systematic strategy, and identified GABRA1, GABRB2, GABRA5 and GABRG2 as core therapeutic targets of cinnamon against Alzheimer's disease-related GABAergic synaptic dysfunction. Exploring the mechanism of cinnamon' activities through multi-components and multiple targets strategies promise to reduce the threat of single- target and symptom-based drug discovery failure.

Dynamic moist air monitor in a micro area with extremely high figure-of-merit.

In the rapidly changing moisture air, conventional relative humidity (RH) sensors are often difficult to respond in time and accurately due to the limitation of flow rate and non-uniform airflow distribution. In this study, we numerically demonstrate that humidity changes on micro-zones can be monitored in real time using a Bloch surface wave (BSW) ubiquitous in one-dimensional photonic crystals (1DPC). This phenomenon can be observed by leakage radiation microscope (LRM). After theoretically deriving the angular resolution limit of LRM, we obtained the minimum BSW angular change on a practical scheme that can be observed in the momentum space to complete the detection, and realized the dynamic real-time monitoring of small-scale humidity change in experiment for the first time. This monitoring method has extremely high figure of merit (FOM) without hysteresis, which can be used in humidity sensing and refractive index sensing as well as the research on turbulence.

Construction of a Traceability System for Food Industry Chain Safety Information Based on Internet of Things Technology.

The continuous development of the social economy, has stimulataed an increase in the satndard of living and increased the deman for consumption resulting in the demand for high-quality and safe food has continued to increase. The so-called food safety means that the food that people eat under certain conditions will not harm human health. Frequent food safety incidents have highlighted the seriousness of my country's food safety problems and exposed loopholes in my country's food safety supervision. This article aims to study the construction of the Internet of Things technology in the food industry chain safety information traceability system, research on the RFID technology, GPS technology, and sensor technology in the Internet of things technology, and also conduct some research on the modules of the food industry chain safety information traceability system. This paper proposes to integrate the Internet of Things technology into the construction of the food industry chain safety information traceability system. First, a detailed analysis of some of the technologies that may be used is carried out, and then through the investigation of people on food safety and other aspects, and the food traceability system satisfaction survey. The experimental results in this article show that 40% of women pay more attention to food safety. Of course, in the satisfaction survey of the food safety traceability system based on the Internet of Things technology, it has been recognized by more than 20% of the people.

Analyzing dynamic impacts of deagriculturalization on CO2 emissions in selected Asian economies: a tale of two shocks.

The study investigates the symmetric and asymmetric impact of agriculturalization on CO2 emissions in a sample of selected Asian economies for time period 1985 to 2019. For empirical analysis, the study adopted panel linear and nonlinear autoregressive distributed lag (ARDL) approaches. The long-run findings of panel ARDL reveal that agriculturalization contributes to environmental quality by mitigating CO2 emissions. The panel nonlinear results clearly indicate that the effects of agriculturalization on CO2 emissions are asymmetric. The findings demonstrate that agriculturalization improves environmental quality and de-agriculturalization mitigates environmental quality. Our empirical results are also robust to alternative model specifications. Based on these findings, the study recommends that the relevant authorities should formulate reforms in the agriculture sector that controls and reduces carbon emissions in Asian economies.

Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.

Effects of immunoglobulin plus prednisolone in reducing coronary artery lesions in patients with Kawasaki disease: study protocol for a phase III multicenter, open-label, blinded-endpoints randomized controlled trial.

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis of unclear etiology that mainly affects infants and young children. Strategies to reduce the incidence and severity of coronary artery lesions (CALs), the determinant factor in the long-term prognosis of KD, are currently a focus of studies on KD. Corticosteroids, preferred in the treatment of the majority of vasculitides, are controversial in the treatment of acute KD. In this trial, we will evaluate whether the addition of prednisolone to standard intravenous immunoglobulin (IVIG) plus aspirin therapy can reduce the occurrence of CAL in Chinese patients with KD. METHODS: This is a multicenter, prospective, open-label, randomized controlled trial, which is expected to be conducted in more than 20 hospitals in China and aims to assess the efficacy and safety of IVIG + prednisolone treatment versus standard treatment. Patients with KD who fulfill the inclusion and exclusion criteria will be recruited and randomized (1:1) to receive either a large dose of IVIG (2 g/kg over 12-24 h with a maximum dose of 60 g) + aspirin 30 mg/kg/d or IVIG (2 g/kg over 12-24 h) + aspirin 30 mg/kg/d + prednisolone (2 mg/kg/d with a maximum dose of 60 mg tapered over 15 days after normalization of C-reactive protein concentration). The primary outcome will be the occurrence of CAL at 1 month of illness. The follow-up duration for each participant will be set as 1 year. Patients and treating physicians will be unmasked to group allocation. DISCUSSION: This will be the first multicenter randomized controlled trial to evaluate the efficacy of IVIG + aspirin + prednisolone in Chinese pediatric patients with KD, which may provide high-level evidence for improving the initial treatment for acute KD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04078568 . Registered on 16 August 2018.

The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity.

The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes1,2. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression.