SUMMARY Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research.

Chemical reprogramming provides a powerful platform for exploring the molecular dynamics that lead to pluripotency. Although previous studies have uncovered an intermediate extraembryonic endoderm (XEN)-like state during this process, the molecular underpinnings of pluripotency acquisition remain largely undefined. Here, we profile 36,199 single-cell transcriptomes at multiple time points throughout a highly efficient chemical reprogramming system using RNA-sequencing and reconstruct their progression trajectories. Through identifying sequential molecular events, we reveal that the dynamic early embryonic-like programs are key aspects of successful reprogramming from XEN-like state to pluripotency, including the concomitant transcriptomic signatures of two-cell (2C) embryonic-like and early pluripotency programs and the epigenetic signature of notable genome-wide DNA demethylation. Moreover, via enhancing the 2C-like program by fine-tuning chemical treatment, the reprogramming process is remarkably accelerated. Collectively, our findings offer a high-resolution dissection of cell fate dynamics during chemical reprogramming and shed light on mechanistic insights into the nature of induced pluripotency.

Psychobiotics are a group of probiotics that affect the central nervous system (CNS) related functions and behaviors mediated by the gut-brain-axis (GBA) via immune, humoral, neural, and metabolic pathways to improve not only the gastrointestinal (GI) function but also the antidepressant and anxiolytic capacity. As a novel class of probiotics, the application of psychobiotics has led researchers to focus on a new area in neuroscience. In the past five years, some psychobiotics strains were reported to inhibit inflammation and decreased cortisol levels, resulting in an amelioration of the symptoms of anxiety and depression. Psychobiotics are efficacious in improving neurodegenerative and neurodevelopmental disorders, including autism spectrum disorder (ASD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). Use of psychobiotics can improve GI function, ASD symptoms, motor functions of patients with PD and cognition in patients with AD. However, the evidence for the effects of psychobiotics on mental and neurological conditions/ disorders remains limited. Further studies of psychobiotics are needed in order to determine into their effectiveness and mechanism as treatments for various psychiatric disorders in the future.

Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF to relocalize to the nuclei. MANF interacted with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. MANF consequently inhibited p65-mediated transcriptional activation by interfering with the binding of p65 to its target genes promoters. Consistently, MANF suppressed the expressions of NF-κB-dependent target genes and the proliferation of inflammatory synoviocytes. These findings suggest that MANF may be a negative regulator of inflammation and mediate the crosstalk between the NF-κB pathway and ER stress.

YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

Deregulated expression of circular RNA (circRNA) has been determined to be important in carcinogenesis and progression; however, in the most common type of primary malignant bone tumor osteosarcoma, the roles of circRNA in cancer development still remain to be elucidated. Here, we found that circRNA UBAP2 (circUBAP2) expression is significantly increased in human osteosarcoma tissues as compared to those in matched controls. Increased circUBAP2 expression was significantly correlated with human osteosarcoma progression and prognosis. Furthermore, increased circUBAP2 could promote osteosarcoma growth and inhibit apoptosis both in vitro and in vivo. Mechanistically, circUBAP2 was found to inhibit the expression of microRNA-143 (miR-143), thus enhancing the expression and function of anti-apoptotic Bcl-2, which is a direct target of miR-143. Together, our results suggest the roles of circUBAP2 in osteosarcoma development and implicate its potential in prognosis prediction and cancer therapy.

Background: ROP18 is a Toxoplasma secreted Ser/Thr protein kinase important for acute virulence. Results: ROP18 phosphorylates host p65 at Ser-468 and target this protein to the ubiquitin-dependent degradation. Conclusion: ROP18 inhibits the host NF-B pathway by promoting p65 degradation. Significance: These findings reveal a novel molecular mechanism by which type I strain manipulates the host immune system to facilitate infection.

BackgroundThe function of the peripheral microvascular may be interrogated by measuring perfusion, tissue oxygen concentration, or venous oxygen saturation (SvO2) recovery dynamics following induced ischemia. The purpose of this work is to develop and evaluate a magnetic resonance (MR) technique for simultaneous measurement of perfusion, SvO2, and skeletal muscle T2*.MethodsPerfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT) is comprised of interleaved pulsed arterial spin labeling (PASL) and multi-echo gradient-recalled echo (GRE) sequences. During the PASL post-labeling delay, images are acquired with a multi-echo GRE to quantify SvO2 and T2* at a downstream slice location. Thus time-courses of perfusion, SvO2, and T2* are quantified simultaneously within a single scan. The new sequence was compared to separately measured PASL or multi-echo GRE data during reactive hyperemia in five young healthy subjects. To explore the impairment present in peripheral artery disease patients, five patients were evaluated with PIVOT.ResultsComparison of PIVOT-derived data to the standard techniques shows that there was no significant bias in any of the time-course-derived metrics. Preliminary data show that PAD patients exhibited alterations in perfusion, SvO2, and T2* time-courses compared to young healthy subjects.ConclusionSimultaneous quantification of perfusion, SvO2, and T2* is possible with PIVOT. Kinetics of perfusion, SvO2, and T2* during reactive hyperemia may help to provide insight into the function of the peripheral microvasculature in patients with PAD.