Novel skeletal stem and progenitor cells and their regulation

The development of bone and cartilage, which provide the framework of the skeletal system, is complex. In this context stem and progenitor cells play a crucial role by producing differentiated cells. Hormones are important regulators of this process, with growth hormone (GH) acting as the major endocrine regulator of longitudinal bone growth. In the present thesis, I have studied primarily the stem and progenitor cells in the skeletal system, as well as their regulation by GH. During embryonic development, all chondrocytes and bone-forming cells originate from mesodermal or neural crest cells (NCCs). As direct descendants of the NCCs, multipotent Schwann cell precursors (SCPs) generate a variety of cell and tissue types. Employing lineage tracing, we demonstrated that during embryonic development SCPs contribute to the production of significant numbers of skeletogenic cells in bone and cartilage. These SCPs detach from the nerve fibers to become mesenchymal-type cells, which later differentiate into chondrocytes and osteocytes in the skeleton of the craniofacial region and scapula and ribs of the trunk. Our similar observations in zebrafish indicate that this process has been conserved evolutionarily. In summary, this work revealed a novel source of skeletogenic cells, as well as potential interaction between the neurological and skeletal systems during development. (Paper I) Clonal lineage tracing with multicolor reporter mouse strains, including Confetti mice, provides a powerful tool for the study of cell behavior in vivo. However, it is challenging to maintain the fluorescent signals until they can be analyzed, especially in the case of mineralized tissues. Accordingly, we optimized a protocol that employs the Confetti model to preserve the fluorescent signals in postnatal bone tissues and visualize these directly by confocal microscopy, without additional use of antibodies. (Paper II) During development, endochondral bone formation is driven primarily by a continuous supply of chondrocytes provided by the growth plate. Employing lineage tracing in multicolor reporter mice, we demonstrated that during fetal and neonatal development, the production of chondrocytes involves consumption of their progenitors, while at a later postnatal stage, these cells acquire the capacity for self-renewal. These findings indicate the formation of a novel stem cell niche that harbors the stem cells and facilitates their renewal. Moreover, we could show that the formation and maintenance of this niche depends to a large extent on formation of the SOC. We also found that the switch between symmetrical and asymmetrical division of these stem cells, hereafter referred to as epiphyseal stem cells (epSCs), is regulated by the mTORC1 signaling pathway. (Paper III) Although GH is the primary endocrine regulator of longitudinal bone growth, the effects of this hormone on our newly identified epiphyseal stem cells and their niche were unknown. Using lineage tracing, we discovered that the renewal of epSCs in the growth plate involves population asymmetry and neutral competition. GH activated the JAK-STAT pathway in epSCs and the number of these cells was reduced during continuous treatment with GH. Further analysis revealed that GH stimulates epSCs to leave their niche and generate progeny. Single-cell RNA sequencing (scRNA-seq) of all cells within the growth plate further confirmed this shift of epSCs toward differentiation into transit-amplifying cells and, at the same time, revealed that several molecular pathways are involved in the regulation of epSCs by GH, including local BMP, IGF and GAS signaling. (Paper IV) Altogether, my findings demonstrate that during development Schwann cell precursors generate chondro- and osteo-progenitors. I developed a protocol for multi-color clonal lineage tracing in mineralized tissues and applied this protocol to discover a novel stem cell niche within the epiphyseal growth plate. Finally, I characterized the dynamics and regulation of the stem cells by GH within this novel niche

Mean Field Effect on J/\psi Production in Heavy Ion Collisions

The mean field effect in quark-gluon plasma on J/\psi production in heavy ion collisions is perturbatively calculated in a transport approach. While the global nuclear modification factor R_{AA} is not sensitive to the mean field, the reduced threshold for J/\psi regeneration leads to a significant enhancement of R_{AA} at low transverse momentum at RHIC and LHC energies.Comment: 6 pages, 4 figure

Fourier-Flow model generating Feynman paths

As an alternative but unified and more fundamental description for quantum physics, Feynman path integrals generalize the classical action principle to a probabilistic perspective, under which the physical observables' estimation translates into a weighted sum over all possible paths. The underlying difficulty is to tackle the whole path manifold from finite samples that can effectively represent the Feynman propagator dictated probability distribution. Modern generative models in machine learning can handle learning and representing probability distribution with high computational efficiency. In this study, we propose a Fourier-flow generative model to simulate the Feynman propagator and generate paths for quantum systems. As demonstration, we validate the path generator on the harmonic and anharmonic oscillators. The latter is a double-well system without analytic solutions. To preserve the periodic condition for the system, the Fourier transformation is introduced into the flow model to approach a Matsubara representation. With this novel development, the ground-state wave function and low-lying energy levels are estimated accurately. Our method offers a new avenue to investigate quantum systems with machine learning assisted Feynman Path integral solving

Progressive Learning with Visual Prompt Tuning for Variable-Rate Image Compression

In this paper, we propose a progressive learning paradigm for transformer-based variable-rate image compression. Our approach covers a wide range of compression rates with the assistance of the Layer-adaptive Prompt Module (LPM). Inspired by visual prompt tuning, we use LPM to extract prompts for input images and hidden features at the encoder side and decoder side, respectively, which are fed as additional information into the Swin Transformer layer of a pre-trained transformer-based image compression model to affect the allocation of attention region and the bits, which in turn changes the target compression ratio of the model. To ensure the network is more lightweight, we involves the integration of prompt networks with less convolutional layers. Exhaustive experiments show that compared to methods based on multiple models, which are optimized separately for different target rates, the proposed method arrives at the same performance with 80% savings in parameter storage and 90% savings in datasets. Meanwhile, our model outperforms all current variable bitrate image methods in terms of rate-distortion performance and approaches the state-of-the-art fixed bitrate image compression methods trained from scratch

Transcobalamin 2 orchestrates monocyte proliferation and TLR4-driven inflammation in systemic lupus erythematosus via folate one-carbon metabolism

BackgroundSLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear.MethodsWe collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR, and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione, and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS, and CD14 changes.ResultsElevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response.ConclusionOur study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation, and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE

Passivation mechanism of thermal atomic layer-deposited Al2O3 films on silicon at different annealing temperatures

Thermal atomic layer-deposited (ALD) aluminum oxide (Al(2)O(3)) acquires high negative fixed charge density (Q(f)) and sufficiently low interface trap density after annealing, which enables excellent surface passivation for crystalline silicon. Q(f) can be controlled by varying the annealing temperatures. In this study, the effect of the annealing temperature of thermal ALD Al(2)O(3) films on p-type Czochralski silicon wafers was investigated. Corona charging measurements revealed that the Q(f) obtained at 300°C did not significantly affect passivation. The interface-trapping density markedly increased at high annealing temperature (>600°C) and degraded the surface passivation even at a high Q(f). Negatively charged or neutral vacancies were found in the samples annealed at 300°C, 500°C, and 750°C using positron annihilation techniques. The Al defect density in the bulk film and the vacancy density near the SiO(x)/Si interface region decreased with increased temperature. Measurement results of Q(f) proved that the Al vacancy of the bulk film may not be related to Q(f). The defect density in the SiO(x) region affected the chemical passivation, but other factors may dominantly influence chemical passivation at 750°C

Associations between the size and duration of asymptomatic subchorionic hematoma and pregnancy outcomes in women with singleton pregnancies

Abstract Background The purpose of this study was to investigate the relationship between the size and duration of asymptomatic subchorionic hematoma and pregnancy outcomes in women with singleton pregnancies. Methods This was a retrospective study that enrolled 701 singleton pregnant women who were diagnosed with asymptomatic subchorionic hematoma by ultrasound at 5–10 gestational weeks. The control group recruited 640 normal pregnant women without subchorionic hematoma who were matched with subchorionic hematoma group on baseline characteristics. The pregnancy outcomes were compared between the two groups, and the associations of the size and duration of subchorionic hematoma with pregnancy outcomes were analyzed by logistic regression model. Results Compared with the normal pregnancy group, the incidence of, gestational diabetes mellitus, gestational thrombocytopenia, placenta adhesion, fetal growth restriction, macrosomia in subchorionic hematoma group were higher (all P < 0.05). After adjusting for confounding factors, the hematoma size was positively associated with the occurrence of gestational hypothyroidism (adjusted OR[95%CI]: 1.029[1.004–1.054]), intrahepatic cholestasis of pregnancy (adjusted OR[95%CI]: 1.095[1.047–1.146]), term premature rupture of membranes (adjusted OR[95%CI]: 1.044[1.005–1.085]), hypertensive disorders of pregnancy (adjusted OR[95%CI]: 1.030[1.0004-1.060]), gestational thrombocytopenia (adjusted OR[95%CI]: 1.078 [1.045–1.113]), placenta adhesion (adjusted OR[95%CI]: 1.054 [1.027–1.082]), and the duration of hematoma was positively associated with the incidence of term premature rupture of membranes (adjusted OR[95%CI]: 1.070[1.027–1.115]), gestational diabetes mellitus (adjusted OR[95%CI]: 1.938 [1.886–1.993]) and fetal growth restriction (adjusted OR[95%CI]: 1.194 [1.124–1.268]). Conclusions The presence, size and duration of a first-trimester asymptomatic subchorionic hematoma may be associated with adverse pregnancy outcomes at later gestations such as term premature rupture of membranes and fetal growth restriction

Immune checkpoint gene VSIR predicts patient prognosis in acute myeloid leukemia and myelodysplastic syndromes

Abstract Background Immune checkpoint proteins play critical functions during the immune response to cancer and have been targeted by immune checkpoint blockade therapy. V‐domain Ig suppressor of T cell activation (VSIR) is one of these immune checkpoint genes and has been investigated extensively in recent years due to its conflicting roles in cancer immunity. Specifically, in acute myeloid leukemia (AML), the prognostic value of VSIR is debated. Results In both patient tumor samples and cancer cell lines we find that VSIR has the highest expression in AML out of all cancer types and, in AML, has the highest expression out of all other immune checkpoint genes. Survival analysis indicated that AML patients with higher VSIR expression have significantly shorter survival than those patients with lower expression, even within established AML subgroups (e.g., FAB subtypes). Importantly, VSIR expression is predictive of progression from myelodysplastic syndromes (MDS) patients into AML, suggesting its potential role during the very early stage of AML development and progression. In addition to AML, VSIR also demonstrates prognostic values in other cancer types, including multiple myeloma and mesothelioma. Conclusion In summary, our analyses revealed the prognostic value of VSIR and its potential as a target for immunotherapy, especially in AML