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Positive feedback driven by transcriptional regulation has long been considered a key mechanism underlying cell lineage segregation during embryogenesis. Using the developing spinal cord as a paradigm, we found that canonical, transcription‐driven feedback cannot explain robust lineage segregation of motor neuron subtypes marked by two cardinal factors, Hoxa5 and Hoxc8. We propose a feedback mechanism involving elementary microRNA–mRNA reaction circuits that differ from known feedback loop‐like structures. Strikingly, we show that a wide range of biologically plausible post‐transcriptional regulatory parameters are sufficient to generate bistable switches, a hallmark of positive feedback. Through mathematical analysis, we explain intuitively the hidden source of this feedback. Using embryonic stem cell differentiation and mouse genetics, we corroborate that microRNA–mRNA circuits govern tissue boundaries and hysteresis upon motor neuron differentiation with respect to transient morphogen signals. Our findings reveal a previously underappreciated feedback mechanism that may have widespread functions in cell fate decisions and tissue patterning. SYNOPSIS Robust cell fate decision and precise tissue boundary formation are critical for development. This study reports a feedback mechanism involving mRNA‐microRNA interactions during cell lineage segregation in mouse spinal cord development. Robust lineage segregation of mouse Hoxa5 + and Hoxc8 + motor neurons does not require canonical transcriptional feedback loops. Mathematical modeling derives a wide range of biologically plausible parameters that allow bistability to arise from post‐transcriptional networks. An intuitive interpretation of the mathematical analysis reveals a hidden feedback mechanism involving mRNA‐microRNA interactions. In vitro and in vivo experiments validate the critical roles of two microRNAs in lineage segregation and tissue boundary formation. Graphical Abstract Robust cell fate decision and precise tissue boundary formation are critical for development. This study reports a feedback mechanism involving mRNA‐microRNA interactions during cell lineage segregation in mouse spinal cord development.

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to Krt5-expressing cells. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated targets (e.g., Krt13) and repressed proliferation-associated targets (e.g., Mki67). Thus, SOX2 is critical for foregut squamous epithelial differentiation, and its decreased expression is likely an initiating step in progression to BE and then to esophageal adenocarcinoma.

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between S0X2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-K0 (KrtSCreER/+ Sox2A,A ROSA2PdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to /Ot5-expressing cells. CUT&RUN analysis showed S0X2 bound and promoted differentiation-associated targets (e.g., Krt13) and repressed proliferation-associated targets (e.g., Mki67). Thus, S0X2 is critical for foregut squamous epithelial differentiation, and its decreased expression is likely an initiating step in progression to BE and then to esophageal adenocarcinoma.

This paper presents a wideband wireless receiver front-end for 3.1-5.0GHz band group-1 (BG-1) WiMedia application. The front-end circuits are designed in 0.18um standard CMOS process. The experimental results show the maximum conversion power gain is 45.5dB; minimum noise figure is 2.9dB. Input return loss is lower than -9.3dB and output return loss is lower than -6.8dB. The maximum LO conversion power is 0dBm. 3dB working frequency is 1.9GHz (3.1GHz-5.0GHz) Total power consumption is 24.3mW including LNA, mixer and all buffers. Total chip area is 1.27mm2 including dummy and pads.

The main functions of the Power Control and Distribution Unit (PCDU) in FORMOSAT-5 satellite are to condition energy from the solar arrays and distribute power for all subsystems on the satellite. The Power Relay (PR) module, one of the major modules in the PCDU is to manage the switchover of redundant DC-DC converter sections, secondary power distribution and power protections. The PR module controls power protections which are under voltage (UV) protection and Undervoltage-Lockout (UVLO) detection. UVLO detection monitors primary power voltage with majority voting in PR FPGA. UV detector switches nominal DC-DC converter to redundant DC-DC section, when under voltage happens. Power protection circuits all can be realized by Inverting Bistable Multivibrator. This paper describes protection methods for power and the reliable circuit design implementation.

Ribosomes are critical for cell function; their synthesis (known as ribosome biogenesis; \"RiBi\") is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cells in adult tissue. Here, we generated mice with conditional deletion of , an essential gene for RiBi and translation, to investigate effects of RiBi blockade We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis. We observed a surprising latency of several weeks between deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death, which was associated with translocation of ribosomal proteins RPL5 and RPL11 into acinar cell nucleoplasm. Indeed, deletion of could rescue acinar cells from apoptotic cell death; however, acinar cells remained morphologically and functionally abnormal. Moreover, the deletion of did not rescue the lethality of inducible, globally deleted in adult mice nor did it rescue embryonic lethality of global deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion of in acinar cells blocked -oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless of mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translation .

Paligenosis is a conserved cellular plasticity program that allows mature cells to reenter the cell cycle in response to tissue injury. Paligenosis progresses via three stages: autodegradation (with dramatic increase in autophagy and lysosomes), induction of metaplastic or fetal-like genes, and cell cycle entry. Hippo signaling, particularly the downstream effector YAP1, regulates cellular plasticity, but its role in paligenosis has not been studied. Here we first examine paligenosis in digestive-enzyme-secreting chief cells in mouse stomach. We identify Serine/Threonine Kinase 38 (STK38) as a non-canonical YAP1 kinase that phosphorylated and deactivated YAP1 in uninjured chief cells. During paligenosis, STK38 was degraded by autophagy in stage 1, dephosphorylating and activating YAP1. YAP1 activation was necessary and sufficient for the paligenosis that converts chief cells into metaplastic, proliferating progenitors. Additionally, we show STK38, like canonical Hippo kinases, interact with NF2. We also observed the same pattern of YAP1 induction via autophagic destruction of STK38 in other tissues and cell types, suggesting a universal logic model for how the massive autophagy activated in differentiated cells during tissue damage can consequently activate Hippo effectors to induce plasticity for tissue regeneration.

Health and disaster risk reduction are important and necessary components in building a smart city,especially when climate change may increase the frequency of extreme temperatures and the health risks of urban dwellers.However,limited knowledge is available about the best way to disseminate weather warnings and health protection information.This study explores the weather information acquisition patterns of the Hong Kong public and examines the sociodemographic predictors of these patterns to establish the potential public health implications of smart city development.A population-based,stratified crosssectional,random digit dialing telephone survey was conducted among the Cantonese-speaking population aged over 15 years in Hong Kong in early 2016.Analyses were conducted based on 1017 valid samples,with a response rate of 63.6%.Cold Weather Warnings were well disseminated in Hong Kong,with 95.7% of the respondents reporting awareness of the public warnings.Television and smartphone apps were the two most important channels for weather information acquisition.Age and education level are the main social-demographic variables associated with the current utilization and future preference of smartphone technology.Among those who were not using a preferredchannel to acquire weather information,61.3% considered switching to a smartphone app.Moreover,the patterns of individual health protection measures and self-reported health impacts were significantly different between smartphone app users and non-users.Weather information dissemination should be tailored to the sociodemographic characteristics of the users.

Recognition of viral dsRNA by Toll-like receptor 3 （TLR3） leads to induction of interferons （IFNs） and proinflam- matory cytokines, and innate antiviral response. Here we identified the RNA-binding protein Mex3B as a positive regulator of TLR3-mediated signaling by expression cloning screens. Cells from Mex3b-/- mice exhibited reduced production of IFN-β in response to the dsRNA analog poly（I：C） but not infection with RNA viruses. Mex3b-/- mice injected with poly（I：C） was more resistant to poly（I：C）-induced death. Mex3B was associated with TLR3 in the endo- somes. It bound to dsRNA and increased the dsRNA-binding activity ofTLR3. Mex3B also promoted the proteolytic processing of TLR3, which is critical for its activation. Mutants of Mex3B lacking its RNA-binding activity inhibited TLR3-mediated IFN-β induction. These findings suggest that Mex3B acts as a coreceptor of TLR3 in innate antivirai response.

Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β （IL-Iβ） and IL-18 and triggers pyroptosis. Caspase-1 and -11 （or -4/5 in human） in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-me- diated inflammatory responses. Here we report that gasdermin D （GSDMD） is another crucial component of in- flammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical in- flammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the pre- dicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-Iβ secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd-/- cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd-/- cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.