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Intrauterine growth restriction (IUGR) is a major problem associated with piglet growth performance. The incidence of IUGR is widespread in Rongchang pigs. The pituitary gland is important for regulating growth and metabolism, and research has identified genes associated with growth and development. The pituitary gland of newborn piglets with normal birth weight (NBW group, n = 3) and (IUGR group, n = 3) was collected for transcriptome analysis. A total of 323 differentially expression genes (DEGs) were identified (|log2(fold-change)| > 1 and q value < 0.05), of which 223 were upregulated and 100 were downregulated. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that the DEGs were mainly related to the extracellular matrix, regulation of the multicellular organismal process, tissue development and angiogenesis, which participate in the growth and immune response in IUGR piglets. Moreover, 7 DEGs including IGF2, THBS1, ITGA1, ITGA8, EPSTI1, FOSB, and UCP2 were associated with growth and immune response. Furthermore, based on the interaction network analysis of the DEGs, two genes, IGF2 and THBS1, participated in cell proliferation, embryonic development and angiogenesis. IGF2 and THBS1 were also the main genes participating in the IUGR. This study identified the core genes involved in IUGR in piglets and provided a reference for exploring the effect of the pituitary gland on piglet growth.

The expression of transcription factor Hoxb5 specifically marks the functional haematopoietic stem cells (HSC) in mice. However, our recent work demonstrated that ectopic expression of Hoxb5 exerted little effect on HSC but could convert B-cell progenitors into functional T cells in vivo. Thus, cell type- and development stage-specific roles of Hoxb5 in haematopoietic hierarchy await more extensive exploration. In this study, we aim to investigate the effect of Hoxb5 expression in multipotent blood progenitor cells.A Mx1cre/RosaHere, with a mouse strain engineered with conditional expression of Hoxb5, we unveiled that induced expression of Hoxb5 in MPP led to the generation of a de novo Sca1Our current study uncovers that Hoxb5 can empower MPP with self-renewal ability and indicates an alternative approach for generating HSC-like cells in vivo from blood lineage cells.

Objective: Despite successful antiviral therapy, the recovery of CD4+ T cells may not be complete in certain HIV-1-infected individuals. In our previous work with humanized mice infected with CXCR4-tropic HIV-1LAI (LAI), viral protein Nef was found the major factor determining rapid loss of both CD4+ T cells and CD4+CD8+ thymocytes but its effect on early T-cell development is unknown. The objective of this study is to investigate the influence of LAI Nef on the development of hematopoietic stem/progenitor cells (HSPCs) into T lymphoid cells. Design: HSPC-OP9-DL1 cell co-culture and humanized mouse model was used to investigate the objective of our study in vitro and in vivo. RNA-seq was exploited to study the change of gene expression signature after nef expression in HSPCs. Results: Nef expression in HSPCs was found to block their development into T lymphoid cells both in vitro and in the mice reconstituted with nef-expressing HSPCs derived from human cord blood. More surprisingly, in humanized mice nef expression preferentially suppressed the production of CD4+ T cells. This developmental defect was not the result of CD34+ cell loss. RNA-seq analysis revealed that Nef affected the expression of 176 genes in HSPCs, including those involved in tumor necrosis factor, Toll-like receptor, and nucleotide-binding oligomerization domain-like receptor signaling pathways that are important for hematopoietic cell development. Conclusion: Our results demonstrate that Nef compromises the development of HSPCs into T lymphoid cells, especially CD4+ T cells. This observation suggests that therapeutics targeting Nef may correct HIV-1-associated hematopoietic abnormalities, especially defects in T-cell development.

Noncoding RNAs (ncRNAs) called tsRNAs (tRNA-derived short RNAs) have the ability to regulate gene expression. The information on tsRNAs in fat tissue is, however, limited. By sequencing, identifying, and analyzing tsRNAs using pigs as animal models, this research reports for the first time the characteristics of tsRNAs in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). A total of 474 tsRNAs, 20 and 21 of which were particularly expressed in VAT and SAT, respectively, were found in WAT. According to the analysis of the tsRNA/miRNA/mRNA co-expression network, the tsRNAs with differential expression were primarily engaged in the endocrine and immune systems, which fall under the classification of organic systems, as well as the global and overview maps and lipid metropolis, which fall under the category of metabolism. This research also discovered a connection between the activity of the host tRNA engaged in translation and the production of tsRNAs. This research also discovered that tRF-Gly-GCC-037/tRF-Gly-GCC-042/tRF-Gly-CCC-016 and miR-218a/miR281b may be involved in the regulation of fatty acid metabolism in adipose tissue through SCD based on the tsRNA/miRNA/mRNA/fatty acid network. In conclusion, our findings enrich the understanding of ncRNAs in WAT metabolism and health regulation, as well as reveal the differences between SAT and VAT at the level of tsRNAs.

The wide application of Cyber Physical System (CPS) makes the security of CPS more and more concerned. As the key factors affecting the safety of CPS, space and time have also become the current research hotspot. The space and time safety of CPS requires that CPS arrives at the specified place at the specified time, time and space should meet the safety requirements of the CPS in the current CPS environment. We call the behavior space-time compositions. In order to solve the problem that CPS lacks the method of modeling and verification of space-time compositions, a hybrid Architecture Analysis & Design Language (AADL) modeling and model transformation method for CPS space-time compositions verification is proposed. Firstly, space-time description capability is extended in the AADL behavior annex and Hybrid AADL (HAADL) is proposed. Secondly, differential equations and space-time compositions vector are introduced in Process Algebra to propose Hybrid Space-Time Communication Sequential Processes (HS-TCSP). Furthermore, the Hybrid AADL is transformed to HS-TCSP. Finally, an example of an aircraft collision avoidance system is used to verify the effectiveness of the method.

Hematopoietic stem cells (HSC) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSC are poised to be immediately activated in certain conditions and can return to quiescence after homeostasis has been regained. At present, the molecular networks of regulating the threshold of HSC dormancy, if existing, remain largely unknown. Here, we show that deletion of Nupr1, a gene preferentially expressed in HSC, activated quiescent HSC under homeostasis, which conferred a competitive engraftment advantage for these HSC without compromising their stemness or multi-lineage differentiation capacity in serial transplantation settings. Following an expansion protocol, the Nupr1-/- HSC proliferated more robustly than their wild-type counterparts in vitro. Nupr1 inhibits the expression of p53 and rescue of this inhibition offsets the engraftment advantage. Our data reveal a new role for Nupr1 as a regulator of HSC quiescence, which provides insights for accelerating the engraftment efficacy of HSC transplantation by targeting the HSC quiescence-controlling network.

Numerous efforts have been attempted to regenerate T cells in culture dish from pluripotent stem cells (PSCs). However, in vitro generated T cells exhibited extremely low activity and compromised immunocompetency in vivo. Here, we describe a two-step protocol for regenerating functional T cells using an inducible Runx1-Hoxa9-PSC (iR9-PSCs) line. The procedure mainly includes generation of induced hematopoietic progenitor cells (iHPCs) in vitro, transplantation, and development of functional induced T cells (iT) in vivo via transplantation. The entire induction process in vitro requires 21 days before iHPCs transplantation. The development of mature T cells in vivo takes 4 to 6 weeks post-transplantation. We provide a simple and reproducible approach for functional T cell regeneration from iR9-PSCs for research purpose.

How transplanted haematopoietic stem cells (HSCs) behave soon after they reside in a preconditioned host has not been studied due to technical limitations. Here, using single-cell RNA sequencing, we first obtained the transcriptome-based classifications of 28 haematopoietic cell types. We then applied them in conjunction with functional assays to track the dynamic changes of immunophenotypically purified HSCs in irradiated recipients within the first week after transplantation. Based on our transcriptional classifications, most homed HSCs in bone marrow and spleen became multipotent progenitors and, occasionally, some HSCs gave rise to megakaryocytic-erythroid or myeloid precursors. Parallel in vitro and in vivo functional experiments supported the paradigm of robust differentiation without substantial HSC expansion during the first week. Therefore, this study uncovers the previously inaccessible kinetics and fate choices of transplanted HSCs in myeloablated recipients at early stage, with implications for clinical applications of HSCs and other stem cells.

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Innate lymphoid cells (ILCs) play important roles in regulating tissue homeostasis and innate immune responses. Generation of ILCs after engraftment of pluripotent stem cell (PSC)-derived hematopoietic progenitors (iHPCs) has not yet been reported. Here, we document that ILCs exist in Rag2

Memristors are emerging and being considered to be used as candidates to realize multiple bio-synaptic plasticities and to act in the developed neuromorphic computing systems. Simulating the human visual neural network is an effective way to build a new generation of artificial visual systems and a realistic method to break the von Neumann bottleneck. In this article, we report for the first time a newly proposed and fabricated oxide-based optoelectronic synaptic device with a structure of ITO/Ag:SrTiO3/CuAlO2/ITO, and demonstrate its diverse synaptic plasticities. It is found that the device can respond light stimulation from visible to near-IR (450 nm-905 nm) wavelengths, and also can exhibit interestingly various synaptic behaviors including short-term plasticity (STP), paired-pulse facilitation (PPF), long-term plasticity (LTP) and the transition from STP to LTP, respectively. More importantly, our optoelectronic synaptic device has successfully simulated several artificial vision properties as image memory, image preprocessing and color recognition. It is worth acknowledging that our optoelectronic synaptic device has a simple structure of ITO/Ag:SrTiO3/CuAlO2/ITO and an excellent synaptic behavior, showing a potential to be used in the artificial vision and neuromorphic computing systems in the near future.

The expression of transcription factor Hoxb5 specifically marks the functional hematopoietic stem cells (HSC) in mice. However, our recent work demonstrated that ectopic expression of Hoxb5 exerted little effect on HSC but could convert B cell progenitors into functional T cells in vivo. Thus, cell type- and development stage-specific roles of Hoxb5 in hematopoietic hierarchy await more extensive exploration. Here, with a mouse strain engineered with conditional expression of Hoxb5, we unveiled that induced expression of Hoxb5 in mouse multipotent progenitor cells (MPP) led to the generation of a de novo Sca1+cKit+Mac1+CD48+ (Mac1+CD48+SK) cell type, which has the ability to repopulate long-term multi-lineage hematopoiesis in serial transplant recipients. RNA-seq analyses showed that Mac1+CD48+SK cells exhibited an acquired machinery of DNA replication and cell division, which resembled nature fetal liver HSC cells (FL HSC). In short, our current study uncovers that Hoxb5 is able to empower MPP with self-renewal potential, thereby providing new strategies to reprogram blood progenitor cells into HSC-like cells.

Regeneration of functional B lymphopoiesis from pluripotent stem cells (PSCs) is challenging, and reliable methods have not been developed. Here, we unveiled the guiding role of three essential factors, Lhx2, Hoxa9, and Runx1, the simultaneous expression of which preferentially drives B lineage fate commitment and in vivo B lymphopoiesis using PSCs as a cell source. In the presence of Lhx2, Hoxa9, and Runx1 expression, PSC-derived induced hematopoietic progenitors (iHPCs) immediately gave rise to pro/pre-B cells in recipient bone marrow, which were able to further differentiate into entire B cell lineages, including innate B-1a, B-1b, and marginal zone B cells, as well as adaptive follicular B cells. In particular, the regenerative B cells produced adaptive humoral immune responses, sustained antigen-specific antibody production, and formed immune memory in response to antigen challenges. The regenerative B cells showed natural B cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study exhibits de novo evidence that B lymphopoiesis can be regenerated from PSCs via an HSC-independent approach, which provides insights into treating B cell-related deficiencies using PSCs as an unlimited cell resource.

We propose an Exploration Strategy Improved Deep Deterministic Policy Gradient algorithm called ESI-DDPG for lane keeping tasks in autonomous driving. The actor network in DDPG outputs a policy which is deterministic, so it is necessary to add noise to actions so that the autonomous vehicle can fully explore the environment and learn the optimal policy. However, the initial weight of exploration noise is large, which makes the autonomous vehicle carry out a lot of invalid exploration in the early training stage. Therefore, we combine the Stanley method to make a weighted correction to the exploration noise, so that the exploration of the vehicle tends to be in the right direction and the training efficiency can be improved. In addition, due to the good sample data obtained in the training process, the driving policy finally learned is better. We choose TORCS as the experiment platform and the results show that, compared with DDPG, TD3 and SAC, our proposed algorithm can learn the driving policy faster and the final policy has smaller trajectory error while driving.

SUMMARYRegeneration of humoral immunity from pluripotent stem cells (PSCs) is a crucial aim in translational medicine. However, reconstitution of complete, sustained, and functional B lymphopoiesis from PSCs has not yet been developed. Here, we successfully achieved regenerative B lymphopoiesis in B-cell deficient animals transplanted with PSC-derived hematopoietic progenitors (iHPCs) guided by synergistic expression ofRunx1, Hoxa9, andLhx2. Upon transplantation, the iHPCs immediately gave rise to pro/pre-B cells in recipients’ bone marrow, which were able to further differentiate into the entire B cell lineages, including innate B-1a, B-1b, MZ B cells, as well as adaptive FO B cells. In responding to antigen stimuli, the regenerative B cells produced adaptive humoral immune responses, sustained a prolonged antigen-specific antibody production, and formed immune-memory. Particularly, the regenerative B cells in spleen showed developing patterns of immunoglobulin chain-switch and hyper-mutation via a cross-talk with the host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study providesde novoevidence that B lymphopoiesis can be regenerated from PSCs via a HSC-independent approach, which provides insights into treating B-cell related humoral deficiencies using PSCs as unlimited cell resource.

Objective: The QingYu pig is well known for its excellent meat quality attributes in Sichuan province, China. In order to improve its production efficiency, the determination of genetic factors contributing to quantifiable economic traits of livestock is important. Moreover, the cross-breeding of QingYu pigs with western breeds possessing strong growth attributes is an efficient way to improve the performance of this breed.Methods: Here, the genetic parameters of several important reproductive traits of QingYu pigs were estimated, include total number born (TNB), number born alive, litter birth weight, individual birth weight, number of piglets weaned, litter weaning weight, and individual weaning weight. The data was analyzed using the ASReml 3.0 software (NSW Inc., Sydney, Australia). Furthermore, the effects of crossing Berkshire with QingYu (BQ) pigs on carcass and meat quality traits, as well as the effects of slaughter weight on carcass and meat quality of BQ were characterized.Results: QingYu pigs exhibited superior reproductive traits. The TNB available to QingYu pigs was more than 8 per parity. The observed repeatability of the reproductive traits of the QingYu pigs was between 0.10 and 0.23. The significantly correlated genetic and phenotypic of reproduction traits were consistent. Interestingly, the BQ pigs exhibited improved carcass quality, with a significant increase in loin muscle area, lean percentage and reduction in sebum percentage. As a result, BQ had higher L45min, lower cooking scores, and lower drip loss. In addition, the loin muscle area, body length, and sebum percentage were significantly higher in 90 and 100 kg animals. Cooking loss showed a significant increase at 80 kg, and marbling increased significantly from 90 kg.Conclusion: The results of this study suggest that QingYu pigs exhibit excellent reproductive properties and heritability of these traits. Crossing with Berkshire is an efficient strategy to improve the carcass and meat quality of QingYu pigs for commercial operations. Furthermore, it appears as though the optimal slaughter weight of BQ pigs is at approximately 90 kg.

Though understanding the gas production behavior from methane hydrate in sediments by depressurization are critical for the utilization of gas hydrate resource and has been widely studied, very few researches are reported using natural marine sediments as porous matrices. Significant differences have been found between the natural sediments and widely used coarse sands; difficulties could be commonly encountered in the formation and production process arising from the fine grain sizes and thereby low permeability. In this work, gas production behavior in hydrate-bearing natural marine sediments from the South China Sea was investigated by depressurization with different gas production pressures (2 MPa, 3 MPa and 4 MPa)and pressure gradients (1 MPa, 2 MPa and 4 MPa). Results show that the gas production process consists of two main stages: the rapid free gas liberation stage when the pressure and temperature drop quickly; the hydrate decomposition stage when the gas production slows down and temperature remains relatively stable and then rises to the backpressure driven by heat transfer from the ambient. A high pressure gradient and low production pressure were found to efficiently facilitate the gas production process. The minimum temperature during production significantly varies, under the combined effects of fast gas release and hydrate decomposition, which could play a crucial role in the production behavior. Furthermore, the difference in the thermal conductivity of the natural marine sediments with common coarse grains seriously affects the heat transfer and gas production behavior, with heat transfer from the ambient to the production well with a radial temperature gradient. The inhomogeneity of hydrate saturation vertically resulting from the low permeability of natural sediments also results in a non-uniform temperature distribution during production, which could locally trigger the secondary hydrate formation and freezing thereby hindering the gas production. Therefore, significant differences could be present in the natural sediments, making this work helpful in understanding the production behavior from natural hydrate deposits.

The immunophilins are an important group of regulatory molecules in the immune system. FKBP5, expressed throughout mammals and in fish and birds, functions in both physiological and pathogenic path...

Hepatitis E virus (HEV) infection is a global health concern, with a large number of new infections reported every year. In developing countries with poor sanitation condition, HEV1 and HEV2 are mainly transmitted by the fecal-oral route due to water contamination. HEV3 and HEV4 are zoonotic diseases in humans consuming undercooked pork, mainly in developed countries. Usually, HEV infection is an acute self-limited course, and chronic infection can occur in immunocompromised individuals. The diagnosis of HEV infection relies on sero - logical tests, including RNA and anti-HEV antibodies. Currently, ribavirin is a proven effective drug; the treatment options for immunocompromised and pregnant individuals are limited. To date, only China has approved vaccines for HEV prevention. Therefore, more research is needed to understand the etiology.

Adipogenesis plays a key role in increasing fat mass, which is a main characteristic for obesity, and involves preadipocyte proliferation and differentiation. Recently, more and more evidences suggested that microRNAs (miRNAs) is an important member of the regulatory network of adipogenesis. In this study, miR-143a-3p was highly expressed in adipose tissues of obese mice, and was up-regulated at the middle and last stage of 3T3-L1 adipocyte differentiation. Using mouse 3T3-L1 cells line, which is an ideal model in vitro for the study of adipogenesis, we observed that overexpression of miR-143a-3p inhibited the preadipocyte proliferation, and enhanced the preadipocyte differentiation. In contrast, the inhibition of miR-143a-3p expression promoted the preadipocyte proliferation, and inhibited the preadipocyte differentiation. Further analysis suggested that miR-143a-3p mediating preadipocyte differentiation might be involved in fatty acid metabolism. In addition, we found that miR-143-3p and PPARγ, an activator of miR-143a-3p transcription, could regulate each other. Compared with miR-143a-3p, MAPK7 played an opposite role in the proliferation and differentiation of adipocyte. Further analysis indicated that MAPK7 is a target gene of miR-143a-3p in 3T3-L1 cells, and inhibition of MAPK7 recede the effect of miR-143a-3p on preadipocyte proliferation and differentiation. Taken together, these results indicated that as a regulator of PPARγ, miR-143a-3p play an important role in adipogenesis via regulating MAPK7 and fatty acid.

Betaine is a natural compound present in commonly consumed foods and may have a potential role in the regulation of glucose and lipids metabolism. However, the underlying molecular mechanism of its action remains largely unknown. Here, we show that supplementation with betaine contributes to improved high-fat diet (HFD)-induced gut microbiota dysbiosis and increases anti-obesity strains such as Akkermansia muciniphila, Lactobacillus, and Bifidobacterium. In mice lacking gut microbiota, the functional role of betaine in preventing HFD-induced obesity, metabolic syndrome, and inactivation of brown adipose tissues are significantly reduced. Akkermansia muciniphila is an important regulator of betaine in improving microbiome ecology and increasing strains that produce short-chain fatty acids (SCFAs). Increasing two main members of SCFAs including acetate and butyrate can significantly regulate the levels of DNA methylation at host miR-378a promoter, thus preventing the development of obesity and glucose intolerance. However, these beneficial effects are partially abolished by Yin yang (YY1), a common target gene of the miR-378a family. Taken together, our findings demonstrate that betaine can improve obesity and associated MS via the gut microbiota-derived miR-378a/YY1 regulatory axis, and reveal a novel mechanism by which gut microbiota improve host health.

The traditional chamber reservation, which relies on manual summary, manual arrangement and other ways, is not only takes time and effort but also causes low office efficiency. To provide efficient, reliable and scientific chamber reservation, depending on modern technology is the research direction. This article develops and designs a chamber reservation system that based on SSH framework and b-s model by internet technology. The chamber reservation system based on SSH framework has the functions, which contain remote reservation, automatic arrangement and remote query. The system can not only be used conveniently, but also improve validly office efficiency.

Skeletal myogenesis is a highly ordered and complex biological process that is mediated by numerous regulatory factors. In previous studies, it has been demonstrated that microRNAs (miRs) and long non-coding RNAs (lncRNAs) serve key roles in skeletal myogenesis. The present study showed that the expression levels of miR-23a-5p showed a dynamic change from decrease to increase during C2C12 myoblast proliferation and differentiation. Functional analysis using 5-ethynyl-2′-deoxyuridine proliferation and Cell Counting Kit-8 detection assays indicated that overexpression of miR-23a-5p significantly promoted C2C12 myoblast proliferation compared with the negative control. In addition, in C2C12 myoblasts transfected with miR-23a-5p mimics, increased expression levels of regulators associated with cell proliferation (Cyclin E, CCND1 and Cyclin B) were observed compared with the negative control. By contrast, overexpression of miR-23a-5p decreased the expression levels of specific-myogenesis factors (MyoD, MyoG and Myf5) and decreased C2C12 myoblast differentiation. Luciferase activity assays indicated that miR-23a-5p suppressed the luciferase activity of lncDum. Further analysis demonstrated that miR-23a-5p not only showed an opposite expression level pattern compared with lncDum, which was first increased and then decreased, but also had an opposite effect on the proliferation and differentiation of C2C12 myoblasts compared with lncDum which inhibited cell proliferation and promoted cell differentiation. Taken together, these results indicated that miR-23a-5p may mediate the proliferation and differentiation of C2C12 myoblasts, which may be involved in lncDum regulation.

Objectives Exploring approaches of extending the haematopoiesis time window of MPPs and lineage‐committed progenitors might produce promising therapeutic effects. NUP98‐HOXA10hd (NA) fusion protein can expand long‐term haematopoietic stem cells (HSCs) and promote engraftment competitiveness without causing obvious oncogenesis. Our objectives were to investigate the roles of NA fusion protein in MPP and downstream lineage‐committed progenitor context. Material and Methods 300 sorted MPPs (Lin−CD48−c‐kit+Sca1+CD135+CD150−) were mixed with 5 × 105 total BM helper/competitor cells and injected into irradiated recipients. For secondary transplantation, 5 × 106 total BM cells from primary recipient mice were injected into lethally irradiated recipients. NA‐MPP recipient mice were sacrified for flow cytometric analysis of bone marrow progenitors at indicated time points. Sorted MPPs and myeloid progenitors were used for RNA‐seq library preparation. Results We showed that NA‐expressing MPPs achieved significantly longer multi‐lineage haematopoiesis (>44‐week) than natural MPPs (20‐week). NA upregulated essential genes regulating long‐term haematopoiesis, cell cycle, epigenetic regulation and responses to stress in MPPs. These molecular traits are associated with the earlier appearance of a Sca1‐c‐kit+ myeloid progenitor population, and more abundant cellularity of lineage‐committed progenitor as well as bone marrow nucleated cells. Further, the NA‐derived primary bone marrow cells, which lack NA‐LSK cells, successfully repopulated secondary multi‐lineage haematopoiesis over 20 weeks. Conclusions This study unveiled that NA fusion protein promotes MPP and lineage‐committed progenitor engraftment via extending long‐term multi‐lineage haematopoiesis., Yong Dong et al. show that MPPs overexpressing NUP98‐HOXA10hd fusion protein (NA) generate abundant lineage committed progenitors and sustain long‐term multi‐lineage hematopoiesis in transplant setting. Overexpression of NA in MPPs offer promising means to involve MPPs in clinical transplant settings.

Hematopoietic stem cells (HSCs) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSCs poise to be immediately activated on urgent conditions and can return to quiescence after regaining homeostasis. To date, the molecular networks of regulating the threshold of HSC dormancy, if exist, remain largely unknown. Here, we unveiled that deletion of Nupr1, a gene preferentially expressed in HSCs, activated the quiescence HSCs under homeostatic status, which conferred engraftment competitive advantage on HSCs without compromising their stemness and multi-lineage differentiation abilities in serial transplantation settings. Following an expansion protocol, the Nupr1-/- HSCs proliferate more robustly than their wild type counterparts in vitro. Nupr1 inhibits the expression of p53 and the rescue of which offsets the engraftment advantage. Our data unveil the de novo role of Nupr1 as an HSC quiescence-regulator, which provides insights into accelerating the engraftment efficacy of HSC transplantation by targeting the HSC quiescence-controlling network.

Tumor-associated antigen (TAA) T-cell receptor (TCR) gene-engineered T cells exhibit great potential in antitumor immunotherapy. Considering the high costs and low availability of patient-derived peripheral blood T cells, substantial efforts have been made to explore alternatives to natural T cells. We previously reported that enforced expression of Hoxb5 converted B cells into induced T (iT) cells in vivo. Here, we successfully regenerated naive OT1 (major histocompatibility complex I restricted ovalbumin antigen) iT cells (OT1-iT) in vivo by expressing Hoxb5 in pro-pre-B cells in the OT1 transgenic mouse. The OT1-iT cells can be activated and expanded in vitro in the presence of tumor cells. Particularly, these regenerated OT1-iT cells effectively eradicated tumor cells expressing the TAA (ovalbumin) both in vitro and in vivo. This study provides insights into the translational applications of blood lineage-transdifferentiated T cells in immunotherapy.

The vastly spreading COVID-19 pneumonia is caused by SARS-CoV-2. Lymphopenia and cytokine levels are tightly associated with disease severity. However, virus-induced immune dysregulation at cellular and molecular levels remains largely undefined. Here, the leukocytes in the pleural effusion, sputum, and peripheral blood biopsies from severe and mild patients were analyzed at single-cell resolution. Drastic T cell hyperactivation accompanying elevated T cell exhaustion was observed, predominantly in pleural effusion. The mechanistic investigation identified a group of CD14+ monocytes and macrophages highly expressing CD163 and MRC1 in the biopsies from severe patients, suggesting M2 macrophage polarization. These M2-like cells exhibited up-regulated IL10, CCL18, APOE, CSF1 (M-CSF), and CCL2 signaling pathways. Further, SARS-CoV-2-specific T cells were observed in pleural effusion earlier than in peripheral blood. Together, our results suggest that severe SARS-CoV-2 infection causes immune dysregulation by inducing M2 polarization and subsequent T cell exhaustion. This study improves our understanding of COVID-19 pathogenesis.

Background Borrelia burgdorferi is a tick-borne spirochete that causes Lyme borreliosis (LB). After an initial tick bite, it spreads from the deposition site in the dermis to distant tissues of the host. It is generally believed that this spirochete disseminates via the hematogenous route. Borrelia persica causes relapsing fever and is able to replicate in the blood stream. Currently the exact dissemination pathway of LB pathogens in the host is not known and controversially discussed. Methods In this study, we established a strict intravenous infection murine model using host-adapted spirochetes. Survival capacity and infectivity of host-adapted B. burgdorferi sensu stricto (Bbss) were compared to those of B. persica (Bp) after either intradermal (ID) injection into the dorsal skin of immunocompetent mice or strict intravenous (IV) inoculation via the jugular vein. By in vitro culture and PCR, viable spirochetes and their DNA load in peripheral blood were periodically monitored during a 49/50-day course post-injection, as well as in various tissue samples collected at day 49/50. Specific antibodies in individual plasma/serum samples were detected with serological methods. Results Regardless of ID or IV injection, DNA of Bp was present in blood samples up to day 24 post-challenge, while no Bbss was detectable in the blood circulation during the complete observation period. In contrast to the brain tropism of Bp, Bbss spirochetes were found in ear, skin, joint, bladder, and heart tissue samples of only ID-inoculated mice. All tested tissues collected from IV-challenged mice were negative for traces of Bbss. ELISA testing of serum samples showed that Bp induced gradually increasing antibody levels after ID or IV inoculation, while Bbss did so only after ID injection but not after IV inoculation. Conclusions This study allows us to draw the following conclusions: (i) Bp survives in the blood and disseminates to the host’s brain via the hematogenous route; and (ii) Bbss, in contrast, is cleared rapidly from the blood stream and is a tissue-bound spirochete.

Ju, Z. et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat. Med. 13, 742–747 (2007). CAS Article Google Scholar De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell. 12, 247–256 (2013). Article Google Scholar Murnane, J. P. & Sabatier, L. Chromosome rearrangements resulting from telomere dysfunction and their role in cancer. Bioessays 26, 1164–1174 (2004). CAS Article Google Scholar Niyongere, S. et al. Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML. Leukemia 33, 205–216 (2019). CAS Article Google Scholar Download references We thank the Dr. Jian Mao (School of Medicine, Hangzhou Normal University) for technical assistance. This work was supported by Grants 2016YFA0100602, 2017YFA0103302, 2018YFA0109300 from the National Key Research and Development Program of China; Grants 81525010, 91749203, 81871116, 81501214, 91749117, 81770155, and 81771502 from the National Natural Science Foundation of China; Grants LQ14C070002 from the Natural Science Foundation of Zhejiang Province of China; Grant 2018GZR110103002 from Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory and Grant 2017ZT07S347 from the Program for Guangdong Introducing Innovative and Enterpreneurial Teams. This work was supported by the Science Foundation for Distinguished Young Scholars of Guangdong Province (2019B151502008) to Hu Wang. These authors contributed equally: Ying Wang, Jin-ping Zheng Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China Ying Wang, Junyi Wang, Lingjie Xu, Hu Wang & Zhenyu Ju Department of Public Health and Preventive Medicine, Changzhi Medical College, Changzhi, Shanxi, 046000, P. R. China Jin-ping Zheng Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China Ying Luo, Hu Wang & Zhenyu Ju CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Jinyong Wang Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA John M. Sedivy Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China Zhangfa Song You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar Y.W., JP.Z., H.W., Y.L., JY.W., and LJ.X. carried out the experiments. Y.W., JP.Z., H.W., JinY W., J.M.S., ZF.S., and ZY.J. analyzed the data. Y.W., JP.Z., H.W., J.M.S., and ZY.J. wrote the paper. Correspondence to Ying Wang or Zhangfa Song or Hu Wang or Zhenyu Ju. The authors declare no competing interests. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Wang, Y., Zheng, J., Luo, Y. et al. L1 drives HSC aging and affects prognosis of chronic myelomonocytic leukemia. Sig Transduct Target Ther 5, 205 (2020). https://doi.org/10.1038/s41392-020-00279-4 Download citation Received: 26 March 2020 Revised: 27 July 2020 Accepted: 30 July 2020 Published: 19 September 2020 DOI: https://doi.org/10.1038/s41392-020-00279-4

Nd1-S is the nuclear-localizing short variant form of Nd1 (Ivns1abp) encoding a Kelch family transcription factor. While the function of Nd1 has been investigated in the context of metastasis and doxorubicin-induced cardiotoxicity, little is known about its role in hematopoiesis. In this study, we investigated the function of Nd1-S in hematopoiesis by transplanting the Nd1-S-overexpressing murine hematopoietic stem and progenitor cells (HSPCs) into recipient mice (Nd1-S mice). Enforced expression of Nd1-S led to erythroid and megakaryocyte dysplasia, demonstrated by dramatically decreased red blood cells and platelets, and megakaryocytes in the peripheral blood and bone marrow of the Nd1-S mice. Moreover, phenotypic megakaryocyte-erythroid progenitors (MEPs) accumulated in these Nd1-S mice with aberrant morphology and defective colony-forming capability. Furthermore, these phenotypic MEPs showed impaired pathways regulating erythroid differentiation and megakaryocyte development. Therefore, our study provides de novo evidence that overexpression of Nd1-S in HSPCs leads to erythroid and megakaryocyte dysplasia in vivo by targeting MEPs.

Obtaining T cells by reprogramming is one of the major goals in regenerative medicine. Here, we describe a protocol for generating functional T cells from Hoxb5-expressing pro/pre-B cells in vivo. This protocol includes the construction of Hoxb5 recombinant plasmids, retroviral packaging, isolation and viral transduction of pro/pre-B cells, cell transplantation, and phenotypic analysis of induced T cells. The procedure is reproducible and straightforward, providing an approach for generating induced T cells for translational research. Keywords: Hoxb5, Retrovirus, Pro/pre-B cells, T cells

Obesity due to excessive lipid accumulation is closely associated with metabolic diseases such as type 2 diabetes, insulin resistance and inflammation. Therefore, a detailed understanding of the molecular mechanisms that underlie adipogenesis is crucial to develop treatments for diseases related to obesity. Here, we found that the microRNA-204-5p (miR-204-5p) was expressed at low levels in fat tissues from obese mice fed long-term with a high-fat diet (HFD). Overexpression or inhibition of miR-204-5p in vitro in 3T3-L1 preadipocytes significantly inhibited or promoted 3T3-L1 proliferation, respectively, an effect mediated by regulating cell proliferation factors. miR-204-5p also induced preadipocyte apoptosis by directly targeting the 3' UTR region of Bcl-2, reducing the constitutive suppression of Bcl-2 on p53-dependent apoptosis. Interestingly, overexpression of miR-204-5p during adipocyte differentiation significantly increased the number of oil red O+ cells, triglyceride accumulation and the expression of markers associated with adipocyte differentiation. In contrast, inhibition of miR-204-5p had the opposite effect on 3T3-L1 adipocyte differentiation. Luciferase activity assays and qRT-PCR showed that miR-204-5p regulates adipocyte differentiation by negatively regulating KLF3, a negative regulator of lipogenesis. Taken together, our findings showed that miR-204-5p inhibits proliferation and induces apoptosis of preadipocytes by regulating Bcl-2, but also promotes adipocyte differentiation by targeting KLF3.