METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling.

Infertility is a worldwide reproductive health problem and there are still many unknown etiologies of infertility. In recent years, increasing evidence emerged and confirmed that epigenetic regulation played a leading role in reproduction. However, the function of m6A modification in infertility remains unknown. Here we report that METTL3-dependent m6A methylation plays an essential role in female fertility via balancing the estrogen and progesterone signaling. Analysis of GEO datasets reveal a significant downregulation of METTL3 expression in the uterus of infertile women with endometriosis or recurrent implantation failure. Conditional deletion of Mettl3 in female reproductive tract by using a Pgr-Cre driver results in infertility due to compromised uterine endometrium receptivity and decidualization. m6A-seq analysis of the uterus identifies the 3'UTR of several estrogen-responsive genes with METTL3-dependent m6A modification, like Elf3 and Celsr2, whose mRNAs become more stable upon Mettl3 depletion. However, the decreased expression levels of PR and its target genes, including Myc, in the endometrium of Mettl3 cKO mice indicate a deficiency in progesterone responsiveness. In vitro, Myc overexpression could partially compensate for uterine decidualization failure caused by Mettl3 deficiency. Collectively, this study reveals the role of METTL3-dependent m6A modification in female fertility and provides insight into the pathology of infertility and pregnancy management.

Transcription factor TOX maintains the expression of Mst1 in controlling the early mouse NK cell development.

Rationale: TOX is a DNA-binding factor required for the development of multiple immune cells and the formation of lymph nodes. However, the temporal regulation mode of TOX on NK cell development and function needs to be further explored. Methods: To investigate the role of TOX in NK cells at distinct developmental phases, we deleted TOX at the hematopoietic stem cell stage (Vav-Cre), NK cell precursor (CD122-Cre) stage and late NK cell developmental stage (Ncr1-Cre), respectively. Flow cytometry was used to detect the development and functional changes of NK cell when deletion of TOX. RNA-seq was used to assess the differences in transcriptional expression profile of WT and TOX-deficient NK cells. Published Chip-seq data was exploited to search for the proteins directly interact with TOX in NK cells. Results: The deficiency of TOX at the hematopoietic stem cell stage severely retarded NK cell development. To a less extent, TOX also played an essential role in the physiological process of NKp cells differentiation into mature NK cells. Furthermore, the deletion of TOX at NKp stage severely impaired the immune surveillance function of NK cells, accompanied by down-regulation of IFN-γ and CD107a expression. However, TOX is dispensable for mature NK cell development and function. Mechanistically, by combining RNA-seq data with published TOX ChIP-seq data, we found that the inactivation of TOX at NKp stage directly repressed the expression of Mst1, an important intermediate kinase in Hippo signaling pathway. Mst1 deficient at NKp stage gained the similar phenotype with Toxfl/flCD122Cre mice. Conclusion: In our study, we conclude that TOX coordinates the early mouse NK cell development at NKp stage by maintaining the expression of Mst1. Moreover, we clarify the different dependence of the transcription factor TOX in NK cells biology.

An in-memory computing architecture based on a duplex two-dimensional material structure for in situ machine learning.

The growing computational demand in artificial intelligence calls for hardware solutions that are capable of in situ machine learning, where both training and inference are performed by edge computation. This not only requires extremely energy-efficient architecture (such as in-memory computing) but also memory hardware with tunable properties to simultaneously meet the demand for training and inference. Here we report a duplex device structure based on a ferroelectric field-effect transistor and an atomically thin MoS2 channel, and realize a universal in-memory computing architecture for in situ learning. By exploiting the tunability of the ferroelectric energy landscape, the duplex building block demonstrates an overall excellent performance in endurance (>1013), retention (>10 years), speed (4.8 ns) and energy consumption (22.7 fJ bit-1 µm-2). We implemented a hardware neural network using arrays of two-transistors-one-duplex ferroelectric field-effect transistor cells and achieved 99.86% accuracy in a nonlinear localization task with in situ trained weights. Simulations show that the proposed device architecture could achieve the same level of performance as a graphics processing unit under notably improved energy efficiency. Our device core can be combined with silicon circuitry through three-dimensional heterogeneous integration to give a hardware solution towards general edge intelligence.

Three-dimensional monolithic micro-LED display driven by atomically thin transistor matrix.

Two-dimensional materials are promising candidates for future electronics due to unmatched device performance at atomic limit and low-temperature heterogeneous integration. To adopt these emerging materials in computing and optoelectronic systems, back end of line (BEOL) integration with mainstream technologies is needed. Here, we show the integration of large-area MoS2 thin-film transistors (TFTs) with nitride micro light-emitting diodes (LEDs) through a BEOL process and demonstrate high-resolution displays. The MoS2 transistors exhibit median mobility of 54 cm2 V-1s -1, 210 µA µm-1 drive current and excellent uniformity. The TFTs can drive micrometre-sized LEDs to 7.1 × 107 cd m-2 luminance under low voltage. Comprehensive analysis on driving capability, response time, power consumption and modulation scheme indicates that MoS2 TFTs are suitable for a range of display applications up to the high resolution and brightness limit. We further demonstrate prototypical 32 × 32 active-matrix displays at 1,270 pixels-per-inch resolution. Moreover, our process is fully monolithic, low-temperature, scalable and compatible with microelectronic processing.

Sub-thermionic, ultra-high-gain organic transistors and circuits.

The development of organic thin-film transistors (OTFTs) with low power consumption and high gain will advance many flexible electronics. Here, by combining solution-processed monolayer organic crystal, ferroelectric HfZrOx gating and van der Waals fabrication, we realize flexible OTFTs that simultaneously deliver high transconductance and sub-60 mV/dec switching, under one-volt operating voltage. The overall optimization of transconductance, subthreshold swing and output resistance leads to transistor intrinsic gain and amplifier voltage gain over 5.3 × 104 and 1.1 × 104, respectively, which outperform existing technologies using organics, oxides and low-dimensional nanomaterials. We further demonstrate battery-powered, integrated wearable electrocardiogram (ECG) and pulse sensors that can amplify human physiological signal by 900 times with high fidelity. The sensors are capable of detecting weak ECG waves (undetectable even by clinical equipment) and diagnosing arrhythmia and atrial fibrillation. Our sub-thermionic OTFT is promising for battery/wireless powered yet performance demanding applications such as electronic skins and radio-frequency identification tags, among many others.