Miracle-dz/UniFAR-FTUs huggingface dataset:
Transcriptional and Epigenomic Regulation of Adipogenesis

Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. ABSTRACT Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα are master “adipogenic” transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of adipogenesis. However, many of these novel regulators have not been validated in adipocyte development in vivo and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of adipogenesis, with a focus on factors and mechanisms shared by both white adipogenesis and brown adipogenesis. Studies on the transcriptional regulation of adipogenesis highlight the importance of investigating adipocyte differentiation in vivo rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating adipogenesis.
Study on ice nucleation temperature and water freezing in saline soils

This paper presents a computational model of the freezing point of soil and the nucleation rate of ice based on the soil volume for saline soils. Physicochemical methods and crystallization theory are used to explore the macroscopic mechanism of water freezing induced by ice crystallization, and the influence of water undercooling is discussed with regard to different soil volumes and salt contents. Growth sites, shapes, and sizes of ice crystals are determined by an assumption of heterogeneous nucleation, and the contact angle is introduced to represent a wide range of soils. The relationship between the initial contact angle and the salt content is analyzed quantitatively through an indoor cooling test and thermal difference analysis. Moreover, the van Genuchten model is applied to provide an equation for the unfrozen water content in salty soils, and the probability of ice formation is introduced to investigate the variation of contact angle during the soil freezing process. This study shows that the initial radius of an ice crystal decreases as the salt concentration decreases. The temperature of ice nucleation is determined mainly by the contact angle of ice crystals, which decreases as the soil volume increases and results in decreased supercooling.
Natural disease history of the D2-mdx mouse model for Duchenne muscular dystrophy

The C57BL/10ScSn‐Dmdmdx/J (BL10‐mdx) mouse has been the most commonly used model for Duchenne muscular dystrophy (DMD) for decades. Their muscle dysfunction and pathology is, however, less severe than in patients with DMD, which complicates preclinical studies. Recent discoveries indicate that disease severity is exacerbated when muscular dystrophy mouse models are generated on a DBA2/J genetic background. Knowledge on the natural history of animal models is pivotal for high‐quality preclinical testing. However, for BL10‐mdx mice on a DBA2/J background (D2‐mdx), limited data are available. We addressed this gap in the natural history knowledge. First, we compared histopathological aspects in skeletal muscles of young D2‐mdx, BL10‐mdx, and wild‐type mice. Pathology was more pronounced in D2‐mdx mice and differed in severity between muscles within individuals. Secondly, we subjected D2‐mdx mice to a functional test regime for 34 weeks and identified that female D2‐mdx mice outperform severely impaired males, making females less useful for functional preclinical studies. Direct comparisons between 10‐ and 34‐wk‐old D2‐mdx mice revealed that disease pathology ameliorates with age. Heart pathology was progressive, with some features already evident at a young age. This natural history study of the D2‐mdx mouse will be instrumental for experimental design of future preclinical studies. —Van Putten, M. , Putker, K. , Overzier, M. , Adamzek, W. A. , Pasteuning‐Vuhman, S. , Plomp, J. J., Aartsma‐Rus, A. Natural disease history of the D2‐mdx mouse model for Duchenne muscular dystrophy. FASEB J. 33, 8110–8124 (2019). www.fasebj. org
Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-p66Shc Signaling Pathway

Diabetes impairs the mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM), which can worsen the outcomes of HSPC transplantation and of diabetic complications. In this study, we examined the oncostatin M (OSM)–p66Shc pathway as a mechanistic link between HSPC mobilopathy and excessive myelopoiesis. We found that streptozotocin-induced diabetes in mice skewed hematopoiesis toward the myeloid lineage via hematopoietic-intrinsic p66Shc. The overexpression of Osm resulting from myelopoiesis prevented HSPC mobilization after granulocyte colony-stimulating factor (G-CSF) stimulation. The intimate link between myelopoiesis and impaired HSPC mobilization after G-CSF stimulation was confirmed in human diabetes. Using cross-transplantation experiments, we found that deletion of p66Shc in the hematopoietic or nonhematopoietic system partially rescued defective HSPC mobilization in diabetes. Additionally, p66Shc mediated the diabetes-induced BM microvasculature remodeling. Ubiquitous or hematopoietic restricted Osm deletion phenocopied p66Shc deletion in preventing diabetes-associated myelopoiesis and mobilopathy. Mechanistically, we discovered that OSM couples myelopoiesis to mobilopathy by inducing Cxcl12 in BM stromal cells via nonmitochondrial p66Shc. Altogether, these data indicate that cell-autonomous activation of the OSM-p66Shc pathway leads to diabetes-associated myelopoiesis, whereas its transcellular hematostromal activation links myelopoiesis to mobilopathy. Targeting the OSM-p66Shc pathway is a novel strategy to disconnect mobilopathy from myelopoiesis and restore normal HSPC mobilization.
NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy

Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.
Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy

Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy.
Preconception Lifestyle and Weight-Related Behaviors by Maternal Body Mass Index: A Cross-Sectional Study of Pregnant Women

Obesity is a rising global health challenge, particularly for reproductive-aged women. Our cross-sectional study of pregnant women (n = 223) examined associations between preconception body mass index (BMI) and socio-demographics, weight perceptions and lifestyle behaviors. Over half of women were overweight (33.2%) or obese (22.0%), 49.6% of which perceived their weight as normal. High proportions of women reported planning their pregnancies (70.0%) and were actively trying to lose or maintain their weight preconception (72.7%). Weight management approaches varied from reducing discretionary foods (63.7%) to professional support (8.1%). Obese women had significantly greater odds of reducing discretionary foods (odds ratio (OR) = 6.69 95% confidence interval (CI) 2.13–21.00, p = 0.001) and using structured diets (adjusted odds ratio (AOR) = 9.13 95% CI 2.90–28.81, p < 0.001) compared to normal-weight women. After adjusting for socio-demographics, compared to normal-weight women, overweight (AOR = 5.24 95% CI 2.19–12.56, p < 0.001) and obese (AOR = 2.85 95% CI 1.06–7.67, p = 0.04) women had significantly increased odds of exercising for weight management and significantly lower odds of taking folic-acid preconception (overweight: AOR = 0.40 95% CI 0.18–0.90, p = 0.01, obese: AOR = 0.38 95% CI 0.16–0.91, p = 0.03). Large proportions of women planning a pregnancy have an overweight/obese BMI, with associated suboptimal health behaviors and reduced health professional engagement preconception. Further research exploring women’s perspectives regarding preconception lifestyles is needed to inform effective preconception health promotion strategies.
Computational Simulation and Prediction on Electrical Conductivity of Oxide-Based Melts by Big Data Mining

Electrical conductivity is one of the most basic physical–chemical properties of oxide-based melts and plays an important role in the materials and metallurgical industries. Especially with the metallurgical melt, molten slag, existing research studies related to slag conductivity mainly used traditional experimental measurement approaches. Meanwhile, the idea of data-driven decision making has been widely used in many fields instead of expert experience. Therefore, this study proposed an innovative approach based on big data mining methods to investigate the computational simulation and prediction of electrical conductivity. Specific mechanisms are discussed to explain the findings of our proposed approach. Experimental results show slag conductivity can be predicted through constructing predictive models, and the Gradient Boosting Decision Tree (GBDT) model is the best prediction model with 90% accuracy and more than 88% sensitivity. The robustness result of the GBDT model demonstrates the reliability of prediction outcomes. It is concluded that the conductivity of slag systems is mainly affected by TiO2, FeO, SiO2, and CaO. TiO2 and FeO are positively correlated with conductivity, while SiO2 and CaO have negative correlations with conductivity.
Expression and Association of Tumor Necrosis Factor Receptor Associated Factor 4 (TRAF4) in Esophageal Squamous Cell Carcinoma

Background At present, there is no effective targeted therapy for esophageal squamous cell carcinoma (ESCC), and it is urgent to find new targets for the treatment of ESCC. TRAF4 has been regarded as a cause of carcinogenesis due to overexpression in many cancer types and participation in multiple signaling pathways. However, there are few studies on TRAF4 in ESCC worldwide. Its expression in ESCC and whether it affects the prognosis of patients still remain unclear. Material/Methods We detected the expressions of TRAF4, ki-67, and p53 in 100 cases of ESCC and 80 cases of adjacent normal esophageal squamous epithelium tissues by immunohistochemical technique. We further explored the relationship between TRAF4 and ESCC and its prognosis through statistical analysis. Results TRAF4 was highly expressed in ESCC tissues and was mainly expressed in the cytoplasm. Overexpression of TRAF4 in ESCC was also associated with high expression of ki-67 and p53 (P<0.05). We also found that patients with high expression of TRAF4 had significantly lower OS than in patients with low TRAF4 expression (P<0.05). Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients (P<0.05). Conclusions We found that TRAF4 was highly expressed in ESCC tissues and was mainly expressed in the cytoplasm of cancer cells. Overexpression of TRAF4 was an independent risk factor affecting the overall prognosis of patients. The results indicated that TRAF4 may become a new target for the treatment of ESCC in the future.
Inactivation of Polymyxin by Hydrolytic Mechanism

Polymyxins are nonribosomal peptide antibiotics used as the last-resort drug for treatment of multidrug-resistant Gram-negative bacteria. However, strains that are resistant to polymyxins have emerged in many countries. ABSTRACT Polymyxins are nonribosomal peptide antibiotics used as the last-resort drug for treatment of multidrug-resistant Gram-negative bacteria. However, strains that are resistant to polymyxins have emerged in many countries. Although several mechanisms for polymyxin resistance have been well described, there is little knowledge on the hydrolytic mechanism of polymyxin. Here, we identified a polymyxin-inactivating enzyme from Bacillus licheniformis strain DC-1 which was produced and secreted into the medium during entry into stationary phase. After purification, sequencing, and heterologous expression, we found that the alkaline protease Apr is responsible for inactivation of polymyxins. Analysis of inactivation products demonstrated that Apr cleaves polymyxin E at two peptide bonds: one is between the tripeptide side chain and the cyclic heptapeptide ring, the other between l-Thr and l-α-γ-diaminobutyric acid (l-Dab) within the cyclic heptapeptide ring. Apr is highly conserved among several genera of Gram-positive bacteria, including Bacillus and Paenibacillus. It is noteworthy that two peptidases S8 from Gram-negative bacteria shared high levels of sequence identity with Apr. Our results indicate that polymyxin resistance may result from inactivation of antibiotics by hydrolysis.
Proteome analysis of the salivary pellicle formed on titanium alloys containing niobium and zirconium

Abstract The chemical composition of biomaterials can drive their biological responses; therefore, this in vitro study aimed to evaluate the proteomic profile of the salivary pellicle formed on titanium (Ti) alloys containing niobium (Nb) and zirconium (Zr). The experimental groups consisted of Ti35NbxZr (x = 5 and 10 wt%) alloys, and commercially pure titanium (cpTi); titanium aluminium vanadium (Ti6Al4V) alloys were used as controls. The physical and chemical characteristics of the Ti materials were analysed. The proteomic profile was evaluated by liquid chromatography coupled with tandem mass spectrometry. Bacterial adhesion (2 h) of mixed species (Streptococcus sanguinis and Actinomyces naeslundii) was investigated as colony-forming units (n = 6). This paper reports the finding that salivary pellicle composition can be modulated by the composition of the Ti material. The Ti35NbxZr group showed a significant ability to adsorb proteins from saliva, which can favour interactions with cells and compatibility with the body.
Malignancy in Giant Cell Tumor of Bone: A Review of the Literature

Background: Primary and recurrent giant cell tumor of bone is typically benign; however, rarely giant cell tumor of bone can undergo malignant transformation. Malignancy in giant cell tumor of bone may be primary (adjacent to benign giant cell tumor of bone at first diagnosis) or secondary (at the site of previously treated giant cell tumor of bone). Malignant giant cell tumor of bone has a poor prognosis; it is important to distinguish malignant from benign lesions to facilitate appropriate management. The true incidence of malignant giant cell tumor of bone is not known, probably owing to inaccurate diagnosis and inconsistent nomenclature. We have analyzed current data to provide a robust estimate of the incidence of malignancy in giant cell tumor of bone. Methods: A literature search was performed to source published reports of primary and secondary cases of malignant giant cell tumor of bone. Studies that reported a denominator were used to estimate the incidence of malignancy. Results: We identified 4 large series of patients with malignant giant cell tumor of bone that provided data on 2315 patients with giant cell tumor of bone. Across these studies, the cumulative incidence of malignancy was 4.0%; the cumulative incidence of primary malignancy was 1.6% compared with 2.4% for secondary malignancy. Our analyses confirmed that most malignant giant cell tumor of bone is secondary and occurs following radiation. In addition, data from 8 small series showed that 4.8% of patients with giant cell tumor of bone who received radiation therapy developed secondary malignancy. Conclusions: Malignant giant cell tumor of bone is rare, and its identification is hindered by a lack of clear diagnostic criteria. For optimal care of patients with giant cell tumor of bone, we recommend: comprehensive histologic sampling to ensure accurate diagnoses; watchful follow-up, particularly for patients treated with radiation; and timely treatment of local recurrence.
Longitudinal Cognitive and Behavioral Presentation of Adult Female with Kabuki Syndrome

Patient: Female, 27 Final Diagnosis: Kabuki syndrome Symptoms: Cognitive impairment Medication: — Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background: Kabuki syndrome (KS) is a rare disease with an estimated prevalence of approximately 1: 32 000. While the clinical presentation of KS is heterogeneous, manifestations may include: characteristic facial features, postnatal growth retardation, and skeletal abnormalities. With regards to the cognitive profile, most individuals with KS have an Intellectual Disability, but the magnitude of the impairment ranges from mild to severe, and verbal abilities are generally stronger than nonverbal abilities (i.e., visual spatial and visual perception abilities). Given the low incidence of KS, there is limited literature illustrating the longitudinal development of individuals with the condition. This report presents the cognitive and behavioral trajectory of an individual with KS. Case Report: The patient in this case report was a 27-year-old female with KS. Her cognitive profile had remained in the average range over time, but consistent with the limited KS literature, her verbal abilities were significantly higher than her nonverbal abilities. Specifically, our patient demonstrated significant deficits in visual motor and visual perceptual skills. With regards to her core language skills, her expressive skills were average, yet her receptive skills were below average. Throughout the majority of her schooling, her academic achievement skills were mildly delayed. Notably, her performance on cognitive and academic assessments remained stable over time. During young adulthood, she developed significant internalizing symptoms, particularly depressive symptoms. Conclusions: This is the first case report to illustrate the presentation of an individual with KS from toddlerhood through young adulthood. The patient’s clinical presentation across time was relatively consistent with the KS literature to date; notable patterns of language, motor, cognitive and behavioral deficits illustrate the considerable heterogeneity that exists within the syndrome. This case report, particularly, illustrates the persistence of the cognitive profile over time and also the co-occurring psychiatric symptoms that might emerge.
OPTIMAL PAIR-WISE SUS ALGORITHM AS PROPORTIONAL FAIR ALGORITHM FOR MU-MIMO-OFDM SYSTEMS

In this paper, we research proportional fairness of the optimal pair-wise semi-orthogonal user selection (SUS) algorithm used in the MU-MIMO-OFDM system compliant with IEEE 802.11ac standard. Zero-forcing beamforming (ZFBF) is applied in the system as a precoding technique in order to cancel user interferences. Two different scenarios are considered: homogeneous and heterogeneous. Beside the proportional fairness, a throughput performance of the MU-MIMO-OFDM system is analyzed for both scenarios too. Simulation results show that the optimal pair-wise SUS algorithm is an excellent solution to realize the trade-off between the proportional fairness among users and the achieved system throughput.
T-Cell–Specific PTPN2 Deficiency in NOD Mice Accelerates the Development of Type 1 Diabetes and Autoimmune Comorbidities

Genome-wide association studies have identified PTPN2 as an important non-MHC gene for autoimmunity. Single nucleotide polymorphisms that reduce PTPN2 expression have been linked with the development of various autoimmune disorders, including type 1 diabetes. The tyrosine phosphatase PTPN2 attenuates T-cell receptor and cytokine signaling in T cells to maintain peripheral tolerance, but the extent to which PTPN2 deficiency in T cells might influence type 1 diabetes onset remains unclear. NOD mice develop spontaneous autoimmune type 1 diabetes similar to that seen in humans. In this study, T-cell PTPN2 deficiency in NOD mice markedly accelerated the onset and increased the incidence of type 1 diabetes as well as that of other disorders, including colitis and Sjögren syndrome. Although PTPN2 deficiency in CD8+ T cells alone was able to drive the destruction of pancreatic β-cells and the onset of diabetes, T-cell–specific PTPN2 deficiency was also accompanied by increased CD4+ T-helper type 1 differentiation and T-follicular-helper cell polarization and increased the abundance of B cells in pancreatic islets as seen in human type 1 diabetes. These findings causally link PTPN2 deficiency in T cells with the development of type 1 diabetes and associated autoimmune comorbidities.