Miracle-dz/UniFAR-FTUs huggingface dataset:
Neural differentiation, selection and transcriptomic profiling of human neuromesodermal progenitor-like cells in vitro

ABSTRACT Robust protocols for directed differentiation of human pluripotent cells are required to determine whether mechanisms operating in model organisms are relevant to our own development. Recent work in vertebrate embryos has identified neuromesodermal progenitors as a bipotent cell population that contributes to paraxial mesoderm and spinal cord. However, precise protocols for in vitro differentiation of human spinal cord progenitors are lacking. Informed by signalling in amniote embryos, we show here that transient dual-SMAD inhibition, together with retinoic acid (dSMADi-RA), provides rapid and reproducible induction of human spinal cord progenitors from neuromesodermal progenitor-like cells. Using CRISPR-Cas9 to engineer human embryonic stem cells with a GFP-reporter for neuromesodermal progenitor-associated gene Nkx1.2 we facilitate selection of this cell population. RNA-sequencing was then used to identify human and conserved neuromesodermal progenitor transcriptional signatures, to validate this differentiation protocol and to reveal new pathways/processes in human neural differentiation. This optimised protocol, novel reporter line and transcriptomic data are useful resources with which to dissect molecular mechanisms regulating human spinal cord generation and allow the scaling-up of distinct cell populations for global analyses, including proteomic, biochemical and chromatin interrogation. Summary: The first transcriptome profiling of human neuromesodermal progenitor-like cells, generation of human spinal cord progenitors from these cells and a GFP-reporter for Nkx1.2 in human embryonic stem cells.
Examining the role of social support and spirituality on the general health perceptions of Hispanic cancer survivors

Although cancer survival rates continue to improve, overall disparities persist for ethnic minority survivors, who have a disproportionately high risk of experiencing poor quality of life, despite documented higher levels of self‐reported spirituality. Yet little is known about the relationship between spirituality and social support and health outcomes among Hispanic survivors. This study examined (1) differences between Hispanic and non‐Hispanic white survivors on health, social support, and spirituality and (2) the potential mediating roles of mental health and emotional distress on general health perceptions.
Camptothecin exhibits topoisomerase1-independent KMT1A suppression and myogenic differentiation in alveolar rhabdomyosarcoma cells

Alveolar rhabdomyosarcoma (aRMS) is an aggressive subtype of the most common soft tissue cancer in children. A hallmark of aRMS tumors is incomplete myogenic differentiation despite expression of master myogenic regulators such as MyoD. We previously reported that histone methyltransferase KMT1A suppresses MyoD function to maintain an undifferentiated state in aRMS cells, and that loss of KMT1A is sufficient to induce differentiation and suppress malignant phenotypes in these cells. Here, we develop a chemical compound screening approach using MyoD-responsive luciferase reporter myoblast cells to identify compounds that alleviate suppression of MyoD-mediated differentiation by KMT1A. A screen of pharmacological compounds yielded the topoisomerase I (TOP1) poison camptothecin (CPT) as the strongest hit in our assay system. Furthermore, treatment of aRMS cells with clinically relevant CPT derivative irinotecan restores MyoD function, and myogenic differentiation in vitro and in a xenograft model. This differentiated phenotype was associated with downregulation of the KMT1A protein. Remarkably, loss of KMT1A in CPT-treated cells occurs independently of its well-known anti-TOP1 mechanism. We further demonstrate that CPT can directly inhibit KMT1A activity in vitro. Collectively, these findings uncover a novel function of CPT that downregulates KMT1A independently of CPT-mediated TOP1 inhibition and permits differentiation of aRMS cells.
Alterations in β-catenin/E-cadherin complex formation during the mechanotransduction of Saos-2 osteoblastic cells

Mechanical load application promotes bone formation, while reduced load leads to bone loss. However, the underlying mechanisms that regulate new bone formation are not fully understood. Wnt/β-catenin signaling has an important role in bone formation, bone growth and remodeling. The aim of the present study was to investigate whether mechanical stimuli regulated bone formation through the Wnt/β-catenin signaling pathway. Saos-2 osteoblastic cells were subjected to mechanical strain using a Flexcell strain loading system. The results demonstrated that 12% cyclical tensile stress significantly stimulated Saos-2 cell proliferation, increased the activity of alkaline phosphatase and promoted the formation of mineralized nodules, as determined by MTT and p-nitrophenyl phosphate assays and Alizarin Red S staining, respectively. Furthermore, western blot analysis demonstrated that, following mechanical strain, increased phosphorylation of glycogen synthase kinase-3β and nuclear β-catenin expression was observed in cells, compared with static control culture cells. Results of reporter gene and reverse transcription-polymerase chain reaction assays also demonstrated that mechanical strain significantly increased T-cell factor reporter gene activity and the mRNA expression of cyclooxygenase (COX)-2, cyclin D1, c-fos and c-Jun in Saos-2 cells. Co-immunoprecipitation analysis revealed that elongation mechanical strain activated Wnt/β-catenin signaling and reduced β-catenin and E-cadherin interaction in Saos-2 cells. In conclusion, the results of the current study indicate that mechanical strain may have an important role in the proliferation and differentiation of osteoblasts. The disassociation of the β-catenin/E-cadherin complex in the osteoblast membrane under stretch loading and the subsequent translocation of β-catenin into the nucleus may be an intrinsic mechanical signal transduction mechanism.
On Tighter Generalization Bound for Deep Neural Networks: CNNs, ResNets, and Beyond

We establish a margin based data dependent generalization error bound for a general family of deep neural networks in terms of the depth and width, as well as the Jacobian of the networks. Through introducing a new characterization of the Lipschitz properties of neural network family, we achieve significantly tighter generalization bounds than existing results. Moreover, we show that the generalization bound can be further improved for bounded losses. Aside from the general feedforward deep neural networks, our results can be applied to derive new bounds for popular architectures, including convolutional neural networks (CNNs) and residual networks (ResNets). When achieving same generalization errors with previous arts, our bounds allow for the choice of larger parameter spaces of weight matrices, inducing potentially stronger expressive ability for neural networks. Numerical evaluation is also provided to support our theory.
SOME TESTS ON CREEP AND SHRINKAGE OF RECYCLED LIGHTWEIGHT AGGREGATE CONCRETE

Tests have been performed on four concrete mixtures made with aggregates originating from crushed lightweight aggregate concrete. The watercement ratio and the amount of recycled aggregates were varied. Two mixtures contained natural sand while two other mixtures did not. The results show the expected influence of water-cement ratio on strength, stiffness, shrinkage and creep. The higher the amount of recycled aggregates, the lower are strength and stiffness and the higher are shrinkage strain and creep.
Internet of Things Forensics: The Need, Process Models, and Open Issues

The Internet of Things (IoT) brings a set of unique and complex challenges to the field of digital forensics. To take advantage of the volume and variety of data captured by and stored in ubiquitous IoT services, forensic investigators need to draw upon evidence-acquisition methods and techniques from all areas of digital forensics and possibly create new IoT-specific investigation processes. Although a number of conceptual process models have been developed to address the unique characteristics of the IoT, many challenges remain unresolved.
Association of Insulin Resistance with Lower Bone Volume and Strength Index of the Proximal Femur in Nondiabetic Postmenopausal Women

Background Type 2 diabetes mellitus is associated with an increased risk of osteoporotic fracture despite relatively preserved bone mineral density (BMD). Although this paradox might be attributed to the influence of insulin resistance (IR) on bone structure and material properties, the association of IR with femur bone geometry and strength indices remains unclear. Methods Using data from the Cardiovascular and Metabolic Disease Etiology Research Center cohort study, we conducted a cross-sectional analysis among nondiabetic postmenopausal women. IR was estimated using the homeostasis model assessment of IR (HOMA-IR). Compartment-specific volumetric BMD (vBMD) and bone volume of proximal femur were measured using quantitative computed tomography. The compressive strength index (CSI), section modulus (Z), and buckling ratio of the femoral neck were calculated as bone strength indices. Results Among 1,008 subjects (mean age, 57.3 years; body mass index [BMI], 23.6 kg/m2), BMI, waist circumference, and vBMD of the femoral neck and total hip increased in a linear trend from the lowest (<1.37) to highest (≥2.27) HOMA-IR quartile (P<0.05 for all). The HOMA-IR showed an independent negative association with total bone volume (standardized β=−0.12), cortical volume (β=−0.05), CSI (β=−0.013), and Z (β=−0.017; P<0.05 for all) of the femoral neck after adjustment for age, weight, height, physical activity, and vitamin D and high-sensitivity C-reactive protein levels. However, the association between HOMA-IR and vBMD was attenuated in the adjusted model (femoral neck, β=0.94; P=0.548). Conclusions Elevated HOMA-IR was associated with lower cortical bone volume and bone strength indices in nondiabetic postmenopausal women, independent of age and body size.
Individual differences in decoding skill, print exposure, and cortical structure in young adults

ABSTRACT This exploratory study investigated relations between individual differences in cortical grey matter structure and young adult readers’ cognitive profiles. Whole-brain analyses revealed neuroanatomical correlations with word and nonword reading ability (decoding), and experience with printed matter. Decoding was positively correlated with grey matter volume (GMV) in left superior temporal sulcus, and thickness (GMT) in right superior temporal gyrus. Print exposure was negatively correlated with GMT in left inferior frontal gyrus (pars opercularis) and left fusiform gyrus (including the visual word form area). Both measures also correlated with supramarginal gyrus (SMG), but in spatially distinct subregions: decoding was positively associated with GMV in left anterior SMG, and print exposure was negatively associated with GMT in left posterior SMG. Our comprehensive approach to assessment both confirms and refines our understanding of the novel relation between the structure of pSMG and proficient reading, and unifies previous research relating cortical structure and reading skill.
Fast and Scalable Bayesian Deep Learning by Weight-Perturbation in Adam

Uncertainty computation in deep learning is essential to design robust and reliable systems. Variational inference (VI) is a promising approach for such computation, but requires more effort to implement and execute compared to maximum-likelihood methods. In this paper, we propose new natural-gradient algorithms to reduce such efforts for Gaussian mean-field VI. Our algorithms can be implemented within the Adam optimizer by perturbing the network weights during gradient evaluations, and uncertainty estimates can be cheaply obtained by using the vector that adapts the learning rate. This requires lower memory, computation, and implementation effort than existing VI methods, while obtaining uncertainty estimates of comparable quality. Our empirical results confirm this and further suggest that the weight-perturbation in our algorithm could be useful for exploration in reinforcement learning and stochastic optimization.
Computed Tomographic Features of Primary Small Cell Neuroendocrine Tumors of the Gallbladder

Purpose This study aimed to report the computed tomography (CT) imaging features of primary small cell neuroendocrine tumors of the gallbladder (PSCNETGs). Materials and Methods The CT examinations of 9 patients (5 women, 4 men; median age, 57 years) with histopathologically proven PSCNETG were reviewed. Computed tomographic images were analyzed with respect to morphologic features of primary tumors and accompanying lymph nodes. Results All PSCNETGs were visible on CT, with a median largest axial diameter of 60 mm (Q1, 30 mm; Q3 mm, 82; range, 25–86 mm). These tumors presented with extraluminal growth (8/9; 89%), heterogeneous enhancement (8/9; 89%), gallbladder replacement greater than 50% (5/9; 56%), hepatic metastases (5/9; 56%), and direct liver involvement by tumor (4/9; 44%). Enlarged lymph nodes were present in all patients (9/9; 100%) with a median largest axial diameter of 39 mm (Q1, 23 mm; Q3, 48 mm; range, 12–62 mm). Vessel encasement by lymph nodes was present in 6 (67%) of 9 patients. Conclusion Primary small cell neuroendocrine tumors of the gallbladder predominantly presents as a large, heterogeneous gallbladder mass with extraluminal growth in association with large metastatic lymph nodes and intrahepatic metastases.
Platelet activation parameters and platelet-leucocyte-conjugate formation in glioblastoma multiforme patients

Patients with glioblastoma multiforme (GBM) suffer from an increased incidence of vascular thrombotic events. However, key influencing factors of the primary hemostasis have not been characterized in GBM patients to date. Thus, the present study determines the activation level of circulating platelets in GBM patients, in-vitro reactivity to agonist-induced platelet stimulation and the formation of circulating platelet-leucocyte conjugates as well as the plasma levels of the proinflammatory lipid mediator sphingosine-1-phosphate (S1P). The endogenous thrombin potential (ETP) was determined as global marker for hemostasis. The 21 GBM patients and 21 gender and age matched healthy individuals enrolled in this study did not differ in mean total platelet count. Basal surface expression of platelet CD63 determined by flow cytometry was significantly increased in GBM patients compared to controls as was observed for the concentration of soluble P-selectin in the plasma of GBM patients. While the ETP was not affected, the immunomodulatory lipid S1P was significantly decreased in peripheral blood in GBM. Interestingly, monocyte expression of PSGL-1 (CD162) was decreased in GBM patient blood, possibly explaining the rather decreased formation of platelet-monocyte conjugates. Our study reveals an increased CD63 expression and P-selectin expression/ secretion of circulating platelets in GBM patients. In parallel a down-modulated PSGL-1 expression in circulating monocytes and a trend towards a decreased formation of heterotypic platelet-monocyte conjugates in GBM patients was seen. Whether this and the observed decreased plasma level of the immunomodulatory S1P reflects a systemic anti-inflammatory status needs to be addressed in future studies.
Adaptive Near-Optimal Control of Uncertain Systems With Application to Underactuated Surface Vessels

In this paper, a unified online adaptive near-optimal control framework is proposed for linear and nonlinear systems with parameter uncertainty. Under this framework, auxiliary systems converging to the unknown dynamics are constructed to approximate and compensate the parameter uncertainty. With the aid of the auxiliary system, future outputs of the controlled system are predicted recursively. By utilizing a predictive time-scale approximation technique, the nonlinear dynamic programming problem for optimal control is significantly simplified and decoupled from the parameter learning dynamics: the finite-horizon integral-type objective function is simplified into a quadratic one relative to the control action and there is no need to solve time-consuming Hamilton equations. Theoretical analysis shows that closed-loop systems are asymptotically stable. It is also proved that the proposed adaptive near-optimal control law asymptotically converges to the optimal. The efficacy of the proposed framework and the theoretical results are validated by an application to underactuated surface vessels.
Detection of Significant Association Between Variants in Cannabinoid Receptor 1 Gene (CNR1) and Personality in African–American Population

Background: Several studies have revealed significant associations between single nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 (CNR1) gene and a broad spectrum of psychiatric disorders such as major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Personality traits that are highly related to susceptibility to these conditions have been associated with the CNR1 variants in subjects of Caucasian origin. However, there are no reported studies regarding the effects of CNR1 polymorphisms on personality traits in the African-American (AA) population. Methods: We performed an imputation-based association analysis for 26 CNR1 variants with five dimensions of personality in 3,046 AAs. Results: SNPs rs806372 and rs2180619 showed a significant association with extraversion after Bonferroni correction for multiple testing (p < 0.0019). Further, several extraversion-associated SNPs were significantly associated with conscientiousness, agreeableness, and openness. SNP priority score analysis indicated that SNPs rs806368, rs806371, and rs2180619 play a role in the modulation of personality and psychiatric conditions. Conclusion: CNR1 is important in determining personality traits in the AA population.
Antioxidants retard the ageing of mouse oocytes

The aim of the present study was to verify the effects of heavy metal coupling agents (sodium citrate and EDTA) and antioxidants (acetyl carnitine and lipoic acid) on the number of oocytes, as well as the ageing of mitochondria, chromosomes and spindles in mice. C57BL/6 female mice were randomly classified into four groups (n=12 per group): i) Heavy metal coupling agent; ii) antioxidant; iii) mixed group; and iv) the normal control group. For the treatments, heavy metal coupling agents and antioxidants were added to the drinking water provided to the mice. Following 3, 6, 9 and 12 months of treatment, the number of oocytes and mitochondrial membrane potential were determined, and chromosome and spindle structures were observed. With increasing age, the experimental mice in the four groups showed significantly decreased numbers of oocytes, reduced mitochondrial activity, and increased rates of spindle and chromosome abnormalities, which indicated age-induced ageing of mouse oocytes; thus, a mouse ageing oocyte model had been successfully established. For mice of the same age, more oocytes, higher mitochondrial activity, and lower spindle and chromosome malformation rates were detected in the antioxidant and mixed groups when compared with the normal control groups. Furthermore, no significant difference in the number of oocytes, mitochondrial activity or chromosome malformation rates was observed between the heavy metal coupling agent group and normal control group, which was possibly due to less metal being absorbed during the breeding process. Therefore, the results demonstrated that the antioxidants acetyl carnitine and lipoic acid may serve a role in delaying oocyte ageing.
Acyclic peptides incorporating the d‐Phe‐2‐Abz turn motif: Investigations on antimicrobial activity and propensity to adopt β‐hairpin conformations

Three linear peptides incorporating d‐Phe‐2‐Abz as the turn motif are reported. Peptide 1, a hydrophobic β‐hairpin, served as a proof of principle for the design strategy with both NMR and CD spectra strongly suggesting a β‐hairpin conformation. Peptides 2 and 3, designed as amphipathic antimicrobials, exhibited broad spectrum antimicrobial activity, with potency in the nanomolar range against Staphylococcus aureus. Both compounds possess a high degree of selectivity, proving non‐haemolytic at concentrations 500 to 800 times higher than their respective minimal inhibitory concentrations (MICs) against S. aureus. Peptide 2 induced cell membrane and cell wall disintegration in both S. aureus and Pseudomonas aeruginosa as observed by transmission electron microscopy. Peptide 2 also demonstrated moderate antifungal activity against Candida albicans with an MIC of 50 μM. Synergism was observed with sub‐MIC levels of amphotericin B (AmB), leading to nanomolar MICs against C. albicans for peptide 2. Based on circular dichroism spectra, both peptides 2 and 3 appear to exist as a mixture of conformers with the β‐hairpin as a minor conformer in aqueous solution, and a slight increase in hairpin population in 50% trifluoroethanol, which was more pronounced for peptide 3. NMR spectra of peptide 2 in a 1:1 CD3CN/H2O mixture and 30 mM deuterated sodium dodecyl sulfate showed evidence of an extended backbone conformation of the β‐strand residues. However, inter‐strand rotating frame Overhauser effects (ROE) could not be detected and a loosely defined divergent hairpin structure resulted from ROE structure calculation in CD3CN/H2O. The loosely defined hairpin conformation is most likely a result of the electrostatic repulsions between cationic strand residues which also probably contribute towards maintaining low haemolytic activity.