Miracle-dz/UniFAR-FTUs huggingface dataset:
Quantification of Alterations in Cortical Bone Geometry Using Site Specificity Software in Mouse models of Aging and the Responses to Ovariectomy and Altered Loading

Investigations into the effect of (re)modeling stimuli on cortical bone in rodents normally rely on analysis of changes in bone mass and architecture at a narrow cross-sectional site. However, it is well established that the effects of axial loading produce site-specific changes throughout bones’ structure. Non-mechanical influences (e.g., hormones) can be additional to or oppose locally controlled adaptive responses and may have more generalized effects. Tools currently available to study site-specific cortical bone adaptation are limited. Here, we applied novel site specificity software to measure bone mass and architecture at each 1% site along the length of the mouse tibia from standard micro-computed tomography (μCT) images. Resulting measures are directly comparable to those obtained through μCT analysis (R2 > 0.96). Site Specificity analysis was used to compare a number of parameters in tibiae from young adult (19-week-old) versus aged (19-month-old) mice; ovariectomized and entire mice; limbs subjected to short periods of axial loading or disuse induced by sciatic neurectomy. Age was associated with uniformly reduced cortical thickness and site-specific decreases in cortical area most apparent in the proximal tibia. Mechanical loading site-specifically increased cortical area and thickness in the proximal tibia. Disuse uniformly decreased cortical thickness and decreased cortical area in the proximal tibia. Ovariectomy uniformly reduced cortical area without altering cortical thickness. Differences in polar moment of inertia between experimental groups were only observed in the proximal tibia. Aging and ovariectomy also altered eccentricity in the distal tibia. In summary, site specificity analysis provides a valuable tool for measuring changes in cortical bone mass and architecture along the entire length of a bone. Changes in the (re)modeling response determined at a single site may not reflect the response at different locations within the same bone.
Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

Abstract : Combination therapy is increasingly utilized for the treatment of metastatic breast cancer. However, co-administration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased toxicity. As adverse tissue drug concentrations are not always exposed by plasma drug concentrations, we performed studies in mice to assess both the plasma and tissue levels of the cytotoxics docetaxel and doxorubicinorubicin when administered concomitantly with the p-glycoprotein substrate/inhibitor lapatinibatinib. Both combinations are currently being investigated in clinical trials. First, we determined the tissue distribution of LAPATINIB in mice after an oral gavage dose of 60 mg/kg, which results in an exposure in mice that is equivalent to the exposure in humans when dosed at the recommended dose of 1,250 mg p.o. once daily. Next, we determined the PKs of LAPATINIB after oral gavage doses of 30 and 90 mg/kg. This completed the thorough pharmacokinetic analysis of the biodistribution of single dose LAPATINIB in mice. Following the elucidation of the pharmacokinetics of LAPATINIB in mice, we conducted time course plasma and tissue distribution studies of concomitant lapatinibatinib and docetaxel or doxorubicinorubicin. Both single and multiple dose lapatinibatinib were evaluated. These studies illustrated that lapatinibatinib, when dosed to achieve human equivalent plasma exposure in mice, did not significantly alter the plasma or tissue pharmacokinetics of doxorubicinorubicin but did increase exposure to docetaxel in the intestine, likely leading to enhanced toxicity. Thus, caution should be taken when docetaxel and lapatinibatinib are administered together, particularly to patients with compromised CYP3A activity. Finally, we developed a PBPK model of docetaxel in mice that incorporated PGP transport studying docetaxel pharmacokinetics in wild-type FVB and Mdr1a/b constitutive knockout (KO) mice.
Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways

Several studies have identified genes that are differentially expressed in atopic dermatitis (AD) compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs) reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures ‘89ADGES’, including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the ‘89ADGES’ discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein), keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16), inflammation (e.g., IL37, IL27RA, CCL18) and lipid metabolism (e.g., AKR1B10, FAD7, FAR2). Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P = <0.0006) among the 89 signature genes. Keratinocytes are known to play a major role in barrier function due to their location in the epidermis. Our result suggests that besides immune- mediated pathway, skin barrier pathways such as the keratinocyte differentiation pathway play a key role in AD pathogenesis. A better understanding of the role of keratinocytes in AD will be important for developing novel “barrier therapy” for this disease.
THE FAINTEST WISE DEBRIS DISKS: ENHANCED METHODS FOR DETECTION AND VERIFICATION

In an earlier study, we reported nearly 100 previously unknown dusty debris disks around Hipparcos main-sequence stars within 75 pc by selecting stars with excesses in individual WISE colors. Here, we further scrutinize the Hipparcos 75 pc sample to (1) gain sensitivity to previously undetected, fainter mid-IR excesses and (2) remove spurious excesses contaminated by previously unidentified blended sources. We improve on our previous method by adopting a more accurate measure of the confidence threshold for excess detection and by adding an optimally weighted color average that incorporates all shorter-wavelength WISE photometry, rather than using only individual WISE colors. The latter is equivalent to spectral energy distribution fitting, but only over WISE bandpasses. In addition, we leverage the higher-resolution WISE images available through the unWISE.me image service to identify contaminated WISE excesses based on photocenter offsets among the W3- and W4-band images. Altogether, we identify 19 previously unreported candidate debris disks. Combined with the results from our earlier study, we have found a total of 107 new debris disks around 75 pc Hipparcos main-sequence stars using precisely calibrated WISE photometry. This expands the 75 pc debris disk sample by 22% around Hipparcos main-sequence stars and by 20% overall (including non-main-sequence and non-Hipparcos stars).
Two photon microscopy for studies of xenobiotics in human skin

For successful uptake and distribution of drugs from transdermal formulations, it is important to understand the skin barrier function. Innovative advances in modern microscopy have provided valuable tools to study the interaction between the skin and xenobiotics. Two-photon microscopy (TPM) allows non-invasive visualization of fluorescent compounds in the skin. The advantages of TPM over conventional confocal microscopy are better light penetration into highly scattering and absorbing tissue such as human skin, improved detection efficiency, limited out of focus photobleaching and reduced phototoxic effects. We present TPM as an alternative non-invasive in vitro method to study chemical penetration enhancement of fluorescent model drugs. The permeability of sulforhodamine B (SRB) through human epidermis was measured with vertical diffusion cells. The absorption was visualized using TPM after 24 h passive diffusion. We have evaluated variations in physicochemical parameters controlling dermal drug uptake induced by the penetration enhancer oleic acid according to methods previously described by Yu et al. Optical sectioning by TPM was compared with cryosectioning. Oleic acid significantly increased penetration of sulforhodamine. TPM images demonstrate a four-fold increase in the partition coefficient. In addition, a six-fold increase in the concentration gradient was found over stratum corneum. Better light penetration and detection efficiency increase maximum imaging depth in TPM compared to conventional confocal microscopy, however loss of signal due to scattering and absorption is still significant and will affect distribution profiles generated by optical sectioning. A true concentration profile cannot be established without better knowledge about signal losses in the skin.
Local Distribution and the Symmetry Gap: Approximability of Multiway Partitioning Problems

We study the approximability of multiway partitioning problems, examples of which include Multiway Cut, Node-weighted Multiway Cut, and Hypergraph Multiway Cut. We investigate these problems from the point of view of two possible generalizations: as Min-CSPs, and as Submodular Multiway Partition problems. These two generalizations lead to two natural relaxations that we call respectively the Local Distribution LP, and the Lovasz relaxation. The Local Distribution LP is generally stronger than the Lovasz relaxation, but applicable only to Min-CSP with predicates of constant size. The relaxations coincide in some cases such as Multiway Cut where they are both equivalent to the CKR relaxation. We show that the Lovasz relaxation gives a (2--2/k)-approximation for Submodular Multiway Partition with k terminals, improving a recent 2-approximation [2]. We prove that this factor is optimal in two senses: (1) A (2--2/k -- e)-approximation for Submodular Multiway Partition with k terminals would require exponentially many value queries (in the oracle model), or imply NP = RP (for certain explicit submodular functions). (2) For Hypergraph Multiway Cut and Node-weighted Multiway Cut with k terminals, both special cases of Submodular Multiway Partition, we prove that a (2--2/k -- e)-approximation is NP-hard, assuming the Unique Games Conjecture. Both our hardness results are more general: (1) We show that the notion of symmetry gap, previously used for submodular maximization problems [19, 6], also implies hardness results for submodular minimization problems. (2) Assuming the Unique Games Conjecture, we show that the Local Distribution LP gives an optimal approximation for every Min-CSP that includes the Not-Equal predicate. Finally, we connect the two hardness techniques by proving that the integrality gap of the Local Distribution LP coincides with the symmetry gap of the multilinear relaxation (for a related instance). This shows that the appearance of the same hardness threshold for a Min-CSP and the related submodular minimization problem is not a coincidence.
Inflammatory bowel disease and laterality: is left handedness a risk?

BACKGROUND Left handedness has been associated with inflammatory bowel disease (IBD) and autoimmune diseases. AIMS To determine whether left handedness is associated with IBD in two prospective national birth cohorts. METHODS Subjects with Crohn's disease (CD) and ulcerative colitis (UC) were identified from two national longitudinal birth cohorts at age 26 years (1970 British Cohort Study (BCS70), born in 1970) and age 33 years (National Child Development Study (NCDS), born in 1958). Laterality was determined at age 10 (BCS70) or seven (NCDS) years, based on hand preference for writing and foot preference for kicking a ball (BCS70 only). Multiple logistic regression was used to assess the relationship of handedness with CD, UC, and IBD in the cohorts combined and adjusted for sex. RESULTS Both cohorts combined showed increased adjusted relative odds of 2.13 (95% confidence interval (CI) 0.97–4.65; p=0.059), 2.13 (95% CI 0.92–4.91; p=0. 077), and 2.13 (95% CI 1.20–3.78; p=0.010) for CD, UC, and IBD, respectively in left handers. CONCLUSIONS The study suggests a link between IBD and left handedness which may be genetic and/or environmental in origin.
Cromoglycate and other antiallergic drugs: a possible mechanism of action.

variant of the clinical spectrum caused by spontaneous dissection of the internal carotid artery in the neck. To date the symptoms and signs in five of the eight patients have regressed completely. We suggest that patients with this clinical presentation in whom the angiographic findings are compatible with a dissection should undergo exploration of the internal carotid artery and biopsy to establish the diagnosis. It is interesting that Tews'0 in a retrospective survey of patients with this syndrome could identify 10 patients who had had a dissecting aneurysm of the internal carotid artery.
Stabilizing distributed queuing systems using feedback based on diversity

The Huberman-Hogg model of computational ecosystems is applied to resources with queues. The previous theoretical results indicate that instabilities, due to delayed information, can be controlled by adaptive mechanisms, particularly schemes which employ diverse past horizons. A stochastic learning automaton, with rewards based on queuing parameters, is implemented to test the theoretical results. The effects of the learning step size and horizon are shown for systems with various delays and traffic intensities. The instabilities are controlled with appropriate choices of parameters and reward mechanism. Long horizons permit nonadaptive agents to achieve similar results, with the possible loss of responsiveness to dynamic environments.
Cortical reorganization following anterior temporal lobectomy in patients with temporal lobe epilepsy

Background: Functional MRI was used to study the impact of temporal lobe epilepsy (TLE) and anterior temporal lobectomy (ATL) on the cortical language network in patients with medically refractory TLE. Methods: Nineteen patients with medically refractory TLE and 11 healthy control subjects were enrolled in this study. Ten patients underwent left ATL (mean age 35.2 ± 3.8 years), and 9 underwent right ATL (mean age 35.9 ± 2.6 years). The subjects silently generated verbs in response to a series of visually presented nouns inside the scanner. Correlation analysis was performed between the subjects' performance on the clinical language tests and their neural response in the a priori cortical regions. Results: Preoperative data revealed that the patients with TLE showed increased neural activity in the right inferior frontal gyri (IFG) and middle frontal gyri (MFG). The right TLE patients demonstrated strong correlation between their language performance and the level of cortical activation within the typical language areas. However, such a correlation was absent in the left TLE patients. After the ATL surgery, the left TLE patients showed reduced activation in the left MFG and right IFG, whereas no difference was observed in the right TLE patients. In the right TLE patients, the correlation between language performance and neural response shifted from the typical language areas to the anterior cingulate cortex. Conclusion: This study demonstrates that the cortical language network is affected differently by the left and right temporal lobe epilepsy and is reorganized after anterior temporal lobectomy.
Renal and Systemic Hemodynamic Responses to Intravenous Infusion of Leukotriene C4 in the Rat

We studied the systemic and renal hemodynamic effects of leukotriene C4 (2 μg/ per min for 5 minutes, iv) in the rat. During the period of its infusion, leukotriene C4 produced a significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, as measured by electromagnetic flow probes. These effects were abolished by FPL55712, a putative antagonist of sulfidopeptide leukotrienes, but not by saralasin or indomethacin. Leukotriene C4 also resulted in an average loss of 20% in plasma volume which, during the postinfusion period, perpetuated the low cardiac output state and thus provoked the release of angiotensin II. This vasoactive peptide sustained the elevation in systemic vascular resistance and the reduction in renal blood flow over a 70-minute postinfusion observation period. Consequently, glomerular filtration rate fell by approximately 50%. These angiotensin II-mediated effects were abolished by saralasin. Indomethacin prevented the leukotriene C4-induced loss of plasma volume and, thus, allowed for the significant recovery of cardiac output and renal blood flow during the postinfusion period, thereby preserving glomerular filtration rate. We conclude that leukotriene C4 exerts direct systemic and renal vasoconstrictor, as well as cardiodepressant effects, during the period of its infusion. By virtue of its vasopermeability enhancing effect, leukotriene C4 also results in an immediate loss of plasma volume, an effect which requires the presence of secondarily generated cyclooxygenase products and which perpetuates the hemodynamic abnormalities observed beyond the period of leukotriene C4 infusion.
Vascular gene expression and phenotypic correlation during differentiation of human embryonic stem cells

The study of the cascade of events of induction and sequential gene activation that takes place during human embryonic development is hindered by the unavailability of postimplantation embryos at different stages of development. Spontaneous differentiation of human embryonic stem cells (hESCs) can occur by means of the formation of embryoid bodies (EBs), which resemble certain aspects of early embryos to some extent. Embryonic vascular formation, vasculogenesis, is a sequential process that involves complex regulatory cascades. In this study, changes of gene expression along the development of human EBs for 4 weeks were studied by large‐scale gene screening. Two main clusters were identified—one of down‐regulated genes such as POU5, NANOG, TDGF1/Cripto (TDGF, teratocarcinoma‐derived growth factor‐1), LIN28, CD24, TERF1 (telomeric repeat binding factor‐1), LEFTB (left–right determination, factor B), and a second of up‐regulated genes such as TWIST, WNT5A, WT1, AFP, ALB, NCAM1. Focusing on the vascular system development, genes known to be involved in vasculogenesis and angiogenesis were explored. Up‐regulated genes include vasculogenic growth factors such as VEGFA, VEGFC, FIGF (VEGFD), ANG1, ANG2, TGFβ3, and PDGFB, as well as the related receptors FLT1, FLT4, PDGFRB, TGFβR2, and TGFβR3, other markers such as CD34, VCAM1, PECAM1, VE‐CAD, and transcription factors TAL1, GATA2, and GATA3. The reproducibility of the array data was verified independently and illustrated that many genes known to be involved in vascular development are activated during the differentiation of hESCs in culture. Hence, the analysis of the vascular system can be extended to other differentiation pathways, allocating human EBs as an in vitro model to study early human development. Developmental Dynamics 232:487–497, 2005. © 2004 Wiley‐Liss, Inc.
Delineation of the Innate and Adaptive T-Cell Immune Outcome in the Human Host in Response to Campylobacter jejuni Infection

Background Campylobacter jejuni is the most prevalent cause of bacterial gastroenteritis worldwide. Despite the significant health burden this infection presents, molecular understanding of C. jejuni-mediated disease pathogenesis remains poorly defined. Here, we report the characterisation of the early, innate immune response to C. jejuni using an ex-vivo human gut model of infection. Secondly, impact of bacterial-driven dendritic cell activation on T-cell mediated immunity was also sought. Methodology Healthy, control paediatric terminal ileum or colonic biopsy tissue was infected with C. jejuni for 8–12 hours. Bacterial colonisation was followed by confocal microscopy and mucosal innate immune responses measured by ELISA. Marked induction of IFNγ with modest increase in IL-22 and IL-17A was noted. Increased mucosal IL-12, IL-23, IL-1β and IL-6 were indicative of a cytokine milieu that may modulate subsequent T-cell mediated immunity. C. jejuni-driven human monocyte-derived dendritic cell activation was followed by analyses of T cell immune responses utilising flow cytometry and ELISA. Significant increase in Th-17, Th-1 and Th-17/Th-1 double-positive cells and corresponding cytokines was observed. The ability of IFNγ, IL-22 and IL-17 cytokines to exert host defence via modulation of C. jejuni adhesion and invasion to intestinal epithelia was measured by standard gentamicin protection assay. Conclusions Both innate and adaptive T cell-immunity to C. jejuni infection led to the release of IFNγ, IL-22 and IL-17A; suggesting a critical role for this cytokine triad in establishing host anti-microbial immunity during the acute and effectors phase of infection. In addition, to their known anti-microbial functions; IL-17A and IL-17F reduced the number of intracellular C. jejuni in intestinal epithelia, highlighting a novel aspect of how IL-17 family members may contribute to protective immunity against C. jejuni.
MIF Signal Transduction Initiated by Binding to CD74

Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 K d, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.