Miracle-dz/UniFAR-FTUs huggingface dataset:
FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway

We recently showed that forkhead-box class O1 (FoxO1) activation protects against high glucose-induced injury by preventing mitochondrial dysfunction in the rat kidney cortex. In addition, FoxO1 has been reported to mediate putative kinase 1 (PINK1) transcription and promote autophagy in response to mitochondrial oxidative stress in murine cardiomyocytes. In this study, we ascertained whether overexpressing FoxO1 in the kidney cortex reverses preestablished diabetic nephropathy in animal models. The effect of FoxO1 on mitophagy signaling pathways was evaluated in mouse podocytes. In vivo experiments were performed in male KM mice. A mouse model of streptozotocin (STZ)-induced type 1 diabetes (T1D) was used, and lentiviral vectors were injected into the kidney cortex to overexpress FoxO1. A mouse podocyte cell line was treated with high concentrations of glucose and genetically modified using lentiviral vectors. We found aberrant mitochondrial morphology and reduced adenosine triphosphate production. These mitochondrial abnormalities were due to decreased mitophagy via reduced phosphatase/tensin homolog on chromosome 10-induced PINK1/Parkin-dependent signaling. FoxO1 upregulation and PINK1/Parkin pathway activation can individually restore injured podocytes in STZ-induced T1D mice. Our results link the antioxidative activity of FoxO1 with PINK1/Parkin-induced mitophagy, indicating a novel role of FoxO1 in diabetic nephropathy.
Mutation of foxl2 or cyp19a1a Results in Female to Male Sex Reversal in XX Nile Tilapia

It is well accepted that Forkhead box protein L2 (Foxl2) and aromatase (Cyp19a1; the enzyme responsible for estrogen synthesis) are critical for ovarian development in vertebrates. Knockouts of Foxl2 and Cyp19a1 in goat, mouse, and zebrafish have revealed similar but not identical functions across species. Functional analyses of these two genes in other animals are needed to elucidate their conserved roles in vertebrate sexual development. In this study, we established foxl2 and cyp19a1a mutant lines in Nile tilapia. Both foxl2-/- and cyp19a1a-/- XX fish displayed female-to-male sex reversal. Sf1, Dmrt1, and Gsdf were upregulated in the foxl2-/- and the cyp19a1a-/- XX gonads. Downregulation of Cyp19a1a and serum estradiol-17β level, and upregulation of Cyp11b2 and serum 11-ketotestosterone level were observed in foxl2-/- XX fish. The mutant phenotype of foxl2-/- XX individuals could be rescued by 17β-estradiol treatment from 5 to 30 days after hatching (dah). Upregulation of Star1, the enzyme involved in androgen production in tilapia, was also observed in the foxl2-/- XX gonad at 30 and 90 dah. In vitro promoter analyses consistently demonstrated that Foxl2 could suppress the transcription of star1 in a dose-dependent manner. In addition, compared with the control XX gonad, fewer germ cells were detected in the foxl2-/- XX, cyp19a1a-/- XX, and control XY gonads 10 dah. These results demonstrate that Foxl2 promotes ovarian development by upregulating Cyp19a1a expression and repressing male pathway gene expression. These results extend the study of Foxl2 and Cyp19a1a loss of function to a commercially important fish species.
Analysis and Design of Jump Coefficients in Discrete Stochastic Diffusion Models

In computational systems biology, the mesoscopic model of reaction-diffusion kinetics is described by a continuous time, discrete space Markov process. To simulate diffusion stochastically, the jump coefficients are obtained by a discretization of the diffusion equation. Using unstructured meshes to represent complicated geometries may lead to negative coefficients when using piecewise linear finite elements. Several methods have been proposed to modify the coefficients to enforce the nonnegativity needed in the stochastic setting. In this paper, we present a method to quantify the error introduced by that change. We interpret the modified discretization matrix as the exact finite element discretization of a perturbed equation. The forward error, the error between the analytical solutions to the original and the perturbed equations, is bounded by the backward error, the error between the diffusion of the two equations. We present a backward analysis algorithm to compute the diffusion coefficient from a given discretization matrix. The analysis suggests a new way of deriving nonnegative jump coefficients that minimizes the backward error. The theory is tested in numerical experiments indicating that the new method is superior and also minimizes the forward error.
Speed-Gradient Control of the Brockett Integrator

A nonsmooth extension of the speed-gradient algorithms in finite form is proposed. The conditions ensuring control goal (convergence of the goal function to zero) are established. A new algorithm is applied to almost global stabilization of the Brockett integrator that has become a popular benchmark for nonsmooth and discontinuous algorithms. It is proved that the designed control law stabilizes the Brockett integrator for any initial point that does not lie on the x3-axis. Besides, it is shown that the speed-gradient algorithm ensures stabilization with an arbitrarily small control level. An important feature of the proposed control is the fact that it is continuous along trajectories of the closed-loop system.
Prenatal Stress, Glucocorticoids, and Developmental Programming of the Stress Response

The early environment has a major impact on the developing embryo, fetus, and infant. Parental adversity (maternal and paternal) and glucocorticoid exposure before conception and during pregnancy have profound effects on the development and subsequent function of the hypothalamic-pituitary-adrenal axis and related behaviors. These effects are species-, sex-, and age-specific and depend on the timing and duration of exposure. The impact of these early exposures can extend across multiple generations, via both the maternal and paternal lineage, and recent studies have begun to determine the mechanisms by which this occurs. Improved knowledge of the mechanisms by which adversity and glucocorticoids program stress systems will allow development of strategies to ameliorate and/or reverse these long-term effects.
Parallel Statistical Multiresolution Estimation for Image Reconstruction

We show that a careful parallelization of statistical multiresolution estimation (SMRE) improves the phase reconstruction in X-ray near-field holography. The central step in, and the computationally most expensive part of, SMRE methods is Dykstra's algorithm. It projects a given vector onto the intersection of convex sets. We discuss its implementation on NVIDIA's compute unified device architecture (CUDA). Compared to a CPU implementation parallelized with OpenMP, our CUDA implementation is up to one order of magnitude faster. Our results show that a careful parallelization of Dykstra's algorithm enables its use in large-scale statistical multiresolution analyses.
Oxytocin Receptor-Mediated Activation of Phosphoinositidase C and Elevation of Cytosolic Calcium in the Gonadotrope-Derived αT3-1 Cell Line.

Gonadotropes synthesize and secrete LH and FSH under the control of GnRH, which acts via phosphoinositidase C (PIC)-linked G protein coupled receptors. Additionally, gonadotropin released from the pituitary is influenced by oxytocin, a peptide that has been shown to play a role in generation of the preovulatory LH surge. Although oxytocin receptors are present in the pituitary, studies have identified their presence on lactotropes but not on gonadotropes, raising the question of which cells act as the direct target of oxytocin in gonadotrope regulation. In this study, we examined effects of oxytocin on αT3–1 cells, a gonadotrope-derived cell line. Oxytocin, vasopressin, and vasotocin each stimulated accumulation of[ 3H]inositol phosphates in cells prelabeled with[ 3H]inositol, indicating activation of PIC. The rank order of potency (oxytocin > vasotocin > vasopressin) and sensitivity to inhibition by oxytocin and vasopressin receptor antagonists, revealed the effect to be mediated by oxytocin-selective re.
Cathelicidin antimicrobial peptide LL‐37 augments interferon‐β expression and antiviral activity induced by double‐stranded RNA in keratinocytes

Cathelicidin antimicrobial peptide LL‐37 has the capacity to kill a wide range of microbes and to modify host immunity. Recently, our group observed that the activation of keratinocytes by LL‐37 and DNA greatly increases interferon (IFN)‐β through Toll‐like receptor (TLR)9. However, the effect of LL‐37 on the induction of IFN‐β through TLR3, a sensor of double‐stranded (ds) RNA, in keratinocytes is not well known.
Multidimensional Summation-by-Parts Operators: General Theory and Application to Simplex Elements

Summation-by-parts (SBP) finite-difference discretizations share many attractive properties with Galerkin finite-element methods (FEMs), including time stability and superconvergent functionals; however, unlike FEMs, SBP operators are not completely determined by a basis, so the potential exists to tailor SBP operators to meet different objectives. To date, application of high-order SBP discretizations to multiple dimensions has been limited to tensor product domains. This paper presents a definition for multi-dimensional SBP finite-difference operators that is a natural extension of one-dimensional SBP operators. Theoretical implications of the definition are investigated for the special case of a diagonal norm (mass) matrix. In particular, a diagonal-norm SBP operator exists on a given domain if and only if there is a cubature rule with positive weights on that domain and the polynomial-basis matrix has full rank when evaluated at the cubature nodes. Appropriate simultaneous-approximation terms are developed to impose boundary conditions weakly, and the resulting discretizations are shown to be time stable. Concrete examples of multi-dimensional SBP operators are constructed for the triangle and tetrahedron; similarities and differences with spectral-element and spectral-difference methods are discussed. An assembly process is described that builds diagonal-norm SBP operators on a global domain from element-level operators. Numerical results of linear advection on a doubly periodic domain demonstrate the accuracy and time stability of the simplex operators.
Retention of corneodesmosomes and increased expression of protease inhibitors in dandruff

Dandruff is a common, relapsing and uncomfortable scalp condition affecting a large proportion of the global population. The appearance of flakes on the scalp and in the hair line, and associated itch are thought to be consequences of a damaged skin barrier, altered corneocyte cohesion and abnormal desquamation in dandruff. The balance between skin proteases and protease inhibitors is essential for driving the key events, including corneodesmosome degradation, in the desquamation process and to maintain stratum corneum (SC) barrier integrity.
Randomized QR with Column Pivoting

The dominant contribution to communication complexity in factorizing a matrix using QR with column pivoting is due to column-norm updates that are required to process pivot decisions. We use randomized sampling to approximate this process which dramatically reduces communication in column selection. We also introduce a sample update formula to reduce the cost of sampling trailing matrices. Using our column selection mechanism, we observe results that are comparable in quality to those obtained from the QRCP algorithm, but with performance near unpivoted QR. We also demonstrate strong parallel scalability on shared-memory multiple core systems using an implementation in Fortran with OpenMP. This work immediately extends to produce low-rank truncated approximations of large matrices. We propose a truncated QR factorization with column pivoting that avoids trailing matrix updates which are used in current implementations of level-3 BLAS QR and QRCP. Provided the truncation rank is small, avoiding trailing ma.
Managing Lower Lid Herniated Fat Pad Without Excision

Because of a congenital predisposition and advancing age, the globe may come down, reducing the space between the globe and the orbital floor. Because of the cone-shaped bony orbit, the orbital fat is projected forward, creating a hernia of the lower eyelid no matter how strong the orbital septum may be. Preoperatively, our patients never have excess orbital fat nor do they have shallow orbits, because when we reduce these fat hernias, we never produce an exophthalmia. The orbital fat volume, which will involute with age, is constant in early life. Even if a herniated fat pad appears at an early age, there is no exophthalmia before it manifests itself. A good canthopexy can raise the globe because the Lockwood suspensory ligament is attached to it. This can reduce the herniated fat pad somewhat. We often combine it with the use of the capsulopalpebral fascia attaching it to the orbital rim. We prefer the transcon-junctival approach. These methods will delay enophthalmia. We get natural-looking improvements without excising skin or fat pads.
Adaptive Coarse Spaces for FETI-DP in Three Dimensions

An adaptive coarse space approach including a condition number bound for dual primal finite element tearing and interconnecting (FETI-DP) methods applied to three dimensional problems with coefficient jumps inside subdomains and across subdomain boundaries is presented. The approach is based on a known adaptive coarse space approach enriched by a small number of additional local edge eigenvalue problems. These edge eigenvalue problems serve to make the method robust and permit a condition number bound which depends only on the tolerance of the local eigenvalue problems and some properties of the domain decomposition. The introduction of the edge eigenvalue problems thus turns a well-known condition number indicator for FETI-DP and balancing domain decomposition by constraints (BDDC) methods into a condition number estimate. Numerical results are presented for linear elasticity and heterogeneous materials supporting our theoretical findings. The problems considered include those with random coefficients an.
A 4th-Order Particle-in-Cell Method with Phase-Space Remapping for the Vlasov-Poisson Equation

Numerical solutions to the Vlasov--Poisson system of equations have important applications to both plasma physics and cosmology. In this paper, we present a new particle-in-cell (PIC) method for solving this system that is 4th-order accurate in both space and time. Our method is a high-order extension of one presented previously [B. Wang, G. H. Miller, and P. Colella, SIAM J. Sci. Comput. , 33 (2011), pp. 3509--3537]. It treats all of the stages of the standard PIC update---charge deposition, force interpolation, the field solve, and the particle push---with 4th-order accuracy, and includes a 6th-order accurate phase-space remapping step for controlling particle noise. We demonstrate the convergence of our method on a series of one- and two- dimensional electrostatic plasma test problems, comparing its accuracy to that of a 2nd-order method. As expected, the 4th-order method can achieve accuracy comparable to that of the 2nd-order method and with considerably fewer resolution elements.
What the Eczema Area and Severity Index score tells us about the severity of atopic dermatitis: an interpretability study

The Eczema Area and Severity Index (EASI) is an investigator‐assessed instrument measuring the severity of clinical signs in atopic dermatitis (AD). The EASI was identified as one of the best‐validated outcome measures for AD; however, no previous studies address how to interpret the EASI score for clinical use.
Growth Hormone and Dexamethasone Stimulate Lipolysis and Activate Adenylyl Cyclase in Rat Adipocytes by Selectively Shifting Giα2 to Lower Density Membrane Fractions.

GH, in the presence of glucocorticoid, produces a delayed increase in lipolysis in rat adipose tissue, but the biochemical mechanisms that account for this action have not been established. Other lipolytic agents rapidly activate adenylyl cyclase (AC) and the resulting production of cAMP initiates a chain of reactions that culminates in the activation of hormone-sensitive lipase. We compared responses of segments of rat epididymal fat or isolated adipocytes to 30 ng/ml GH and 0.1 μg/ml dexamethasone (Dex) with 0.1 ng/ml isoproterenol (ISO), which evoked a similar increase in lipolysis. All measurements were made during the fourth hour after the addition of GH+Dex or immediately after the addition of ISO to cells or tissues that had been preincubated for 3 h without hormone. Although no significant increases in cAMP were discernible in homogenates of GH+Dex-treated tissues, RP-cAMPS (RP-adenosine 3′5′-phosphothioate), a competitive inhibitor of cAMP, was equally effective in decreasing lipolysis induced by.
Proteolysis of Human Prolactin: Resistance to Cathepsin D and Formation of a Nonangiostatic, C-Terminal 16K Fragment by Thrombin1.

The N-terminal 16K fragments of rat and human PRLs possess angiostatic activity. 16K PRL has also been detected in vivo in both humans and rats. Based on an in vitro study, cathepsin D, an acid protease, has been implicated in the generation of rat 16K PRL. However, the proteolytic cleavage of human PRL has not been demonstrated. Our objective was to identify an enzyme that is capable of forming an angiostatic human 16K PRL. To confirm the angiostatic action of rat 16K PRL, the fragment was generated by incubating 23K PRL with rat mammary microsomal fraction at pH 3.2. Upon incubation with human umbilical vein endothelial cells (HUVEC), rat 16K PRL, but not 23K PRL, inhibited basal- and basic fibroblast growth factor-stimulated cell proliferation. Intact rat and human PRLs were then incubated with cathepsin D or acidified microsomal pellets of MCF-7 human breast cancer cells. Analysis by SDS-PAGE showed cleavage of rat, but not human, PRL. Next, hormones were incubated with thrombin at pH 7.4. As shown by.
Luteinizing Hormone-Releasing Hormone (LHRH) Biosynthesis and Secretion in Embryonic LHRH Neurons.

Evidence indicates that LH-releasing hormone (LHRH) neurons can exhibit neuroendocrine secretory properties before entrance into the central nervous system. In this study, we evaluated LHRH biosynthesis and secretion in embryonic LHRH neurons maintained in nasal explants. Using ELISA and calcium imaging techniques, peptide content and single neuron activities were examined. LHRH neurons maintained for 7–10 days in vitro were found to possess a similar amount of LHRH/cell as the equivalent aged LHRH cells in vivo (postnatal day 1). LHRH peptide was measured in the medium of these relatively young cultures, and 40 mm KCl stimulated a 4-fold increase in LHRH secretion. KCl enhanced medium also resulted in a significant increase in LHRH content per culture (24.5 pg vs. 32.3). A similar effect was observed after muscimol-enhanced media (32.2 pg). Both agents also stimulated a substantial rise in intracellular calcium. Pretreatment of cultures with tetrodotoxin partially blocked the affects of muscimol on both .
Molecular Analysis of the Inhibition of Monocyte Chemoattractant Protein-1 Gene Expression by Estrogens and Xenoestrogens in MCF-7 Cells1.

Xenoestrogens (XEs) are a diverse group of chemicals that mimic estrogenic actions and may have adverse effects on human health. The influence of these compounds on cytokine production or immune system function remains unclear. In this study we have examined the effects of 17β-estradiol (E2) and XEs on chemoattractant cytokine (chemokine) production and analyzed the molecular mechanism. Monocyte chemoattractant protein-1 (MCP-1), also termed monocyte chemotactic and activating factor, is a member of the chemokine family and attracts mainly blood monocytes. Human mammary tumor cell line MCF-7 cells produce a large quantity of MCP-1 in response to interleukin-1α (IL-1α). Addition of E2 to MCF-7 cells inhibited MCP-1 production in a dose-dependent manner. XEs, bisphenol A, and NP also inhibited MCP-1 production, although the potency was 3–4 orders of magnitude lower than that of E2. E2, bisphenol A, and NP inhibited MCP-1 messenger RNA expression in MCF-7 cells. Two closely located nuclear factor-κB sites, A.
Idelalisib for the treatment of B-cell malignancies

Introduction: The standard of care for B-cell malignancies is chemotherapy or chemo-immunotherapy, which can manage, but not cure, these diseases. However, myelotoxicity and secondary malignancies limit their use. The B-cell receptor (BCR) plays a critical role in malignant B-cell proliferation and survival; inhibition of pivotal signaling nodes in the BCR pathway provides novel mechanisms for targeted therapy. Among these nodes, the phosphoinositide 3-kinase p110δ catalytic subunit (PI3Kδ) is particularly attractive. P110δ expression is restricted to hematopoietic cells and is highly expressed in B lymphocytes. Idelalisib (Zydelig) is an orally bioavailable ATP-competitive kinase inhibitor that targets PI3Kδ with high potency and selectivity. Idelalisib was approved in 2014 both in the US and EU in combination with rituximab for relapsed chronic lymphocytic leukemia (CLL) and as monotherapy for patients with relapsed follicular lymphoma and small lymphocytic lymphoma. Additionally approval was granted in the EU for first line use in poor prognosis CLL with 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. Areas covered: We describe idelalisib’s discovery and selectivity in biochemical and cellular assays and the outcomes of clinical trials in CLL, indolent NHL, and mantle cell lymphoma. Expert opinion: Idelalisib will shape the future clinical landscape of B-cell malignancies.
Identification of the Oxidative 3α-Hydroxysteroid Dehydrogenase Activity of Rat Leydig Cells as Type II Retinol Dehydrogenase.

Dihydrotestosterone (DHT) is the most potent naturally occurring androgen, and its production in the testis may have important consequences in developmental and reproductive processes. In the rat testis, three factors can contribute to intracellular DHT levels: 1) synthesis of DHT from T by 5α-reductase, 2) conversion of DHT to 5α-androstane-3α,17β-diol (3α-DIOL) by the reductive activity of 3α-hydroxysteroid dehydrogenase (3α-HSD), and 3) conversion of 3α-DIOL by an oxidative 3α-HSD activity. While the type I 3α-HSD enzyme (3α-HSD1 or AKR1C9) is an oxidoreductase in vitro and could theoretically be responsible for factors 2 and 3, we have shown previously that rat Leydig cells have two 3α-HSD activities: a cytosolic NADP(H)- dependent activity, characteristic of 3α-HSD1, and a microsomal NAD(H)-dependent activity. The two activities were separable by both developmental and biochemical criteria, but the identity of the second enzyme was unknown. To identify the microsomal NAD(H)-dependent 3α-HSD in rat Le.
A Model of Planar Borehole Propagation

Drilling geometrically complex boreholes in the subsurface has been made possible with the development of downhole tools that steer the bit. This paper proposes a model of borehole propagation that can be used not only to predict the bit trajectory, here restricted to a vertical plane, but also to assess the conditions leading to abnormal situations. The model is formulated from considerations involving (a) a bit/rock interaction law that relates the force and moment on the bit to its penetration into the rock, (b) kinematic relationships that describe the local borehole geometry from the bit motion, and (c) a beam model of the bottom-hole assembly (BHA) that expresses the force and moment at the bit as functions of both the loads applied on the BHA and the geometrical constraints imposed by the stabilizers that center the BHA in the borehole. The coupling between the model components leads to the formulation of a delay differential equation that governs the evolution of the borehole inclination, with spa.