Miracle-dz/UniFAR-FTUs huggingface dataset:
FGF23 Suppresses Chondrocyte Proliferation in the Presence of Soluble α-Klotho both in Vitro and in Vivo*

Background: The role of elevated FGF23 in the development of growth retardation associated with X-linked hypophosphatemic rickets (XLH) remains elusive. Results: FGF23 suppresses chondrocyte proliferation in cooperation with soluble α-Klotho. Conclusion: Elevated FGF23 could have a causative role in the development of growth retardation in XLH. Significance: This may provide insights into the unrecognized function of FGF23 signaling in chondrocyte biology. Fibroblast growth factor-23 (FGF23) is well established to play crucial roles in the regulation of phosphate homeostasis. X-linked hypophosphatemic rickets (XLH) is characterized by impaired mineralization and growth retardation associated with elevated circulating FGF23 levels. Administration of phosphate and calcitriol is effective in improving growth retardation, but is not sufficient to fully reverse impaired growth, suggesting the existence of a disease-specific mechanism in the development of growth retardation in addition to dysregulated phosphate metabolism. However, the precise mechanisms of growth retardation in XLH remain elusive. Here, we postulated that FGF23 suppressed chondrocyte proliferation in the presence of soluble α-Klotho (sKL). In vitro and ex vivo studies revealed that FGF23 formed a protein complex with sKL through KL1 internal repeat and suppressed the linear growth of metatarsals in the presence of sKL, which was antagonized by co-incubation with neutralizing antibodies against FGF23 or by knocking-down FGFR3 expression. Additionally, FGF23 binding to FGFR3 was enhanced in the presence of sKL. Histologically, the length of the proliferating zone was diminished and was associated with decreased chondrocyte proliferation. FGF23/sKL suppressed Indian hedgehog (Ihh) expression and administration of Ihh protein partially rescued the suppressive effect of FGF23/sKL on metatarsal growth. Intraperitoneal administration of sKL in Hyp mice, a murine model for XLH, caused a decrease in the length of the proliferating zone associated with decreased chondrocyte proliferation without altering circulating phosphate levels. These findings suggest that suppression of chondrocyte proliferation by FGF23 could have a causative role in the development of growth retardation in XLH.
The Emerging Role of Tyrosine Kinase Inhibitors in Ovarian Cancer Treatment: A Systematic Review

ABSTRACT The present systematic review summarizes current evidence regarding the mechanisms of action, the efficacy, and the adverse effects of tyrosine kinase inhibitors (TKIs) in ovarian cancer patients. Phase II and III clinical trials were sought in the PubMed database and in the Clinical Trials.gov registry through September 30, 2015. Seventy-five clinical trials regarding TKIs targeting mainly vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, and sarcoma tyrosine kinase (Src) were yielded. The most promising results were noted with cediranib, nintedanib, and pazopanib. However, drawing universal conclusions about the potential integration of TKIs in ovarian cancer therapy remains elusive. Furthermore, emerging challenges and directions for the future research are critically discussed.
Solution structure, antibacterial activity, and expression profile of Manduca sexta moricin

In response to wounding or infection, insects produce a battery of antimicrobial peptides (AMPs) and other defense molecules to kill the invading pathogens. To study their structures, functions, and transcriptional regulation, we synthesized Manduca sexta moricin, a 42‐residue peptide (GKIPVKAIKQAGKVIGKGLRAINIAGTTHDVVSFFRPKKKKH, 4539 Da). The compound exhibited potent antimicrobial activities against a broad spectrum of Gram‐positive and Gram‐negative bacteria with a minimum inhibitory concentration of 1.4 µM. The mRNA levels of M. sexta moricin increased substantially in fat body and hemocytes after the larvae were challenged with bacterial cells. We determined the solution structure of this AMP by two‐dimensional 1H1H ‐nuclear magnetic resonance spectroscopy. The tertiary structure is composed of an eight‐turn α‐helix spanning almost the entire peptide. Insights of relationships between the structure and function are also presented. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.
The Relationship Among Genetic Heritability, Environmental Effects, and Autism Spectrum Disorders

Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental disorders that have strong heritability. To better understand the heritable factors in twins with clinically diagnosed ASD and to discuss the relationship between social impairments and genetic and environmental factors. In last 13 years, over 12,000 cases of ASD were diagnosed in the children’s development and behavior center, the authors review 37 pairs of these twins, in each pair, and at least 1 twin had been diagnosed with an ASD, and found that the concordance rate was 80% [95% confidence interval (CI) 51.9-95.7%] for monozygotic twins and 13.6% (95% CI: 2.9-34.9%) for dizygotic twins. The heritability of social impairments for ASD was 60.9% (95% CI: 47.3-74.5%). In addition, the rate of nonshared environmental factors was 39.1% (95% CI: 25.5-52.7%), and there were no shared environmental effects. Genetics and special environmental effect play an important role on ASD social impairments.
Uteroplacental insufficiency in rats induces renal apoptosis and delays nephrogenesis completion

Uteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programmes cardiorenal disease in offspring. Cross‐fostering growth‐restricted (Restricted) offspring onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine whether the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate whether cross‐fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance.
Impact of Body Mass Index on Robot-Assisted Radical Cystectomy

Background and Objectives: Obesity is a major comorbidity in the Western world and influences outcomes of patient care. A minimally invasive approach towards radical cystectomy has been increasing in popularity. We sought to determine the influence of body mass index (BMI) on robot-assisted radical cystectomy. Methods: Fifty-one consecutive patients underwent robot-assisted radical cystectomy for bladder cancer from October 2005 to April 2007 and were categorized into 3 groups based on their weight: normal (BMI <25), over-weight (BMI=25 to 29) and obese (BMI= 30 to 39.9). Effect of BMI on intraoperative, pathologic, and postoperative outcomes was assessed by retrospective review of the robot-assisted radical cystectomy database. Results: Mean BMI was 28.0, and 71% of the patients were overweight or obese. BMI did not correlate with age, sex, or American Society of Anesthesiologists (ASA) score. Overweight and obese patients had similar operative times and estimated blood loss compared with patients with normal BMI. Overweight and obese patients with bulky disease (pT3–4) had significantly higher rates of positive surgical margins (P=0.05). Complication rates were similar. Conclusion: Robotic-assisted radical cystectomy can be considered for patients of all body mass indices. Wider excision should be performed in patients with higher BMI.
Stress Management

The chapter departs from a review of scientific research in job-related stress. A model of neurodynamics explains the action mechanism of classical meditation as in-depth relaxation as effective means to cope with stress. This line of research has so far been considered alternative by the medical healthcare system, but understanding of the neurophysiological action mechanism should lead to inclusion in accordance with the normal standard of modern healthcare. A minireview of “Meditation and Prevention of Stress” by Are Holen complements the chapter.
Meta‐Analysis of the Effects of Forest Fragmentation on Interspecific Interactions

Forest fragmentation dramatically alters species persistence and distribution and affects many ecological interactions among species. Recent studies suggest that mutualisms, such as pollination and seed dispersal, are more sensitive to the negative effects of forest fragmentation than antagonisms, such as predation or herbivory. We applied meta‐analytical techniques to evaluate this hypothesis and quantified the relative contributions of different components of the fragmentation process (decreases in fragment size, edge effects, increased isolation, and habitat degradation) to the overall effect. The effects of fragmentation on mutualisms were primarily driven by habitat degradation, edge effects, and fragment isolation, and, as predicted, they were consistently more negative on mutualisms than on antagonisms. For the most studied interaction type, seed dispersal, only certain components of fragmentation had significant (edge effects) or marginally significant (fragment size) effects. Seed size modulated the effect of fragmentation: species with large seeds showed stronger negative impacts of fragmentation via reduced dispersal rates. Our results reveal that different components of the habitat fragmentation process have varying impacts on key mutualisms. We also conclude that antagonistic interactions have been understudied in fragmented landscapes, most of the research has concentrated on particular types of mutualistic interactions such as seed dispersal, and that available studies of interspecific interactions have a strong geographical bias (arising mostly from studies carried out in Brazil, Chile, and the United States).
Essential Role of the Type III Secretion System Effector NleB in Colonization of Mice by Citrobacter rodentium

ABSTRACT Attaching and effacing (A/E) pathogens are a significant cause of gastrointestinal illness in humans and animals. All A/E pathogens carry a large pathogenicity island, termed the locus for enterocyte effacement (LEE), which encodes a type III secretion system that translocates several effector proteins into host cells. To identify novel virulence determinants in A/E pathogens, we performed a signature-tagged mutagenesis screen in C57BL/6 mice by using the mouse A/E pathogen Citrobacter rodentium. Five hundred seventy-six derivatives of C. rodentium were tested in pools of 12 mutants. One attenuated mutant carried a transposon insertion in nleB, which encodes a putative effector of the LEE-encoded type III secretion system (T3SS). nleB is present in a genomic pathogenicity island that also encodes another putative effector, NleE, immediately downstream. Using translational fusions with β-lactamase (TEM-1), we showed that both NleB and NleE were translocated into host cells by the LEE-encoded T3SS of enteropathogenic Escherichia coli. In addition, deletion of the gene encoding NleB in C. rodentium resulted in reduced colonization of mice in single infections and reduced colonic hyperplasia. In contrast, the deletion of other non-LEE-encoded effector genes in C. rodentium, nleC, nleD, or nleE, had no effect on host colonization or disease. These results suggest that nleB encodes an important virulence determinant of A/E pathogens.
In Vitro Susceptibility Testing of Bedaquiline against Mycobacterium avium Complex

ABSTRACT We performed bedaquiline broth microdilution susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) guidelines on 103 respiratory isolates of Mycobacterium avium complex (MAC), including multidrug-resistant isolates. Approximately 90% of isolates had bedaquiline MICs of ≤0.008 μg/ml, and 102/103 isolates had MICs of ≤0.015 μg/ml. Bedaquiline has excellent potential for use in patients with MAC infections, although for reasons of its metabolism by the cytochrome P450 system, it should not be given with rifampin.
An Equation of State for Active Matter

Bird flocks, mammal herds, cellular tissue, and artificial self-propelled colloids are all examples of “active” matter—an assembly of self-driven units that take energy from the environment to produce motion [1]. Active matter is, in many ways, analogous to a gas of atoms or molecules, except that the particles are far from equilibrium, and therefore cannot be described with standard statistical physics. A thermodynamic equation of state, such as the relation between pressure and density in an ideal gas, would, however, be useful to characterize these systems. Such an equation could, in the long term, lead to a “theory” for certain forms of living matter and the principles that underlie their dynamics. Taking an important step towards this goal, Alexandre Solon at Diderot University in Paris and his colleagues have derived an equation of state for a “gas” of self-propelled colloidal spheres. The equation relates the pressure the spheres exert on a wall to the spheres’ properties, and the predictions of this equations are potentially testable in, for example, solutions of motile colloids [2].
Atrial natriuretic peptide reduces inflammation and enhances apoptosis in rat acute pancreatitis

We previously reported that atrial natriuretic peptide (ANP) reduces serum amylase and intrapancreatic trypsinogen activation in the onset of acute pancreatitis whereas secretin increases them. In the present work, we sought to establish the effect of ANP and secretin on the inflammatory response and cell death in experimental acute pancreatitis.
Studies on the oncogenicity of 3-hydroxyxanthine.

The oncogenicity of the purine N -oxide, 3-hydroxyxanthine, was tested in newborn and weanling ICR/Ha mice and in newborn, suckling, and weanling Wistar rats. Tumors were induced at the subcutaneous site of administration and occasionally in the liver; male rats were more susceptible than females. At the doses used, newborns of both species and weanling mice were less susceptible than weanling rats. The incidence of benign and malignant tumors at the subcutaneous site was dose dependent, and the latencies of the malignant tumors were generally shorter.
The diagnostic yield of commonly used investigations in pelvic gunshot wounds

BACKGROUND Patients who sustain pelvic gunshot wounds (GSWs) are at significant risk for injury owing to the density of pelvic structures. Currently, the optimal workup for pelvic GSWs is unclear. The aims of this study were to determine the diagnostic yield of tests commonly used in the investigation of pelvic GSWs and to develop a diagnostic algorithm. METHODS All patients 15 years or older presenting to the Los Angeles County + University of Southern California Medical Center (January 2008 to February 2015) who sustained one or more pelvic GSWs were retrospectively identified. Patients' demographics, clinical assessment, investigations, procedures, and outcomes were abstracted. The diagnostic yield of computed tomographic (CT) scan, cystogram, gross inspection of the urine, urinalysis, endoscopy, and digital rectal examination (DRE) in the detection of clinically significant injuries to the pelvis were calculated. RESULTS Three hundred seventy patients were included. Patients with peritonitis, hemodynamic instability, an unevaluable abdomen, or evisceration were taken to the operating room for immediate laparotomy (n = 138 [37.3%]). All others (n = 232 [62.7%]) underwent CT scan and further investigations as indicated. The sensitivity, specificity, positive predictive value, and negative predictive value of the investigations were CT scan: 1.00, 0.98, 0.74, and 1.00; cystogram: 1.00 for all parameters; gross inspection of the urine: 1.00 for all parameters; urinalysis: 1.00, 0.71, 0.17, and 1.00; endoscopy: 1.00, 0.82, 0.75, and 1.00; and DRE: 0.77, 0.99, 0.77, and 0.99. CONCLUSION In the workup of pelvic GSWs, patients with hemodynamic instability, peritonitis, evisceration, or an unevaluable abdomen should undergo immediate laparotomy, while all others should undergo CT scan. Computed tomography–positive patients should be managed for their injuries. If the CT is negative, the likelihood of a clinically significant injury is very low. If the CT is equivocal for rectal or bladder injury, endoscopy or cystogram should be used to guide definitive management. There is no role for routine urinalysis or DRE. Further prospective validation of these findings is warranted. LEVEL OF EVIDENCE Diagnostic study, level III; therapeutic study, level IV.
Early leptin intervention reverses perturbed energy balance regulating hypothalamic neuropeptides in the pre‐ and postnatal calorie‐restricted female rat offspring

Pre‐ and postnatal calorie restriction is associated with postnatal growth restriction, reduced circulating leptin concentrations, and perturbed energy balance. Hypothalamic regulation of energy balance demonstrates enhanced orexigenic (NPY, AgRP) and diminished anorexigenic (POMC, CART) neuropeptide expression (PN21), setting the stage for subsequent development of obesity in female Sprague‐Dawley rats. Leptin replenishment during the early postnatal period (PN2‐PN8) led to reversal of the hypothalamic orexigenic:anorexigenic neuropeptide ratio at PN21 by reducing only the orexigenic (NPY, AgRP), without affecting the anorexigenic (POMC, CART) neuropeptide expression. This hypothalamic effect was mediated via enhanced leptin receptor (ObRb) signaling that involved increased pSTAT3/STAT3 but reduced PTP1B. This was further confirmed by an increase in body weight at PN21 in response to intracerebroventricular administration of antisense ObRb oligonucleotides (PN2‐PN8). The change in the hypothalamic neuropeptide balance in response to leptin administration was associated with increased oxygen consumption, carbon dioxide production, and physical activity, which resulted in increased milk intake (PN14) with no change in body weight. This is in contrast to the reduction in milk intake with no effect on energy expenditure and physical activity observed in controls. We conclude that pre‐ and postnatal calorie restriction perturbs hypothalamic neuropeptide regulation of energy balance, setting the stage for hyperphagia and reduced energy expenditure, hallmarks of obesity. Leptin in turn reverses this phenotype by increasing hypothalamic ObRb signaling (sensitivity) and affecting only the orexigenic arm of the neuropeptide balance. © 2015 Wiley Periodicals, Inc.
Glomerulocystic disease

Glomerulocystic disease is a rare cause of cystic kidney diseases and can occur at any age. It is characterized by cystic dilatation of the Bowman’s capsule and normal tubules, and needs to be differentiated from other cystic renal diseases. It commonly presents as renal failure. We present a case of a 52-year-old female, with renal failure who was subsequently found to have glomerulocystic disease on renal biopsy.
Cultural Integration in Cross-Border Mergers & Acquisitions

Billions of dollars are involved in the execution of mergers and acquisitions between companies, especially when they take place between different cultures. In literature it can be found that a culture difference is a potential catalyst to the success or to the failure of a merger or acquisition. In this work these cultural differences are studied in more depth. In a literature review, different theories in this area are related and this will give insight into the following aspects: culture conflict; cooperation between two company top managers; misunderstanding and lower performances; polarization, negative evaluations of counter-parts, anxiety and ethnocentrism between members of the acquiring and acquired top management. The research consists of both a literature study and interviews with different companies. Results of the literature study show that cultural differences, especially of national nature, play an important role in the integration process. It appears that cultural differences not always have a negative impact, but they can also positively influence the integration process. From the interviews, it became clear that every relevant aspect of the integration process as found in literature is subjected to the influence of cultural differences. Also strategies are presented that can be applied to bridge the cultural differences and to turn the negative influence to their advantage. This can be accomplished by adopting tools to facilitate the cultural integration, leadership, cultural learning and information system. Moreover, in an era of globalization, this study contributes to company management practice by expanding across national boundaries through transformation into a new organizational culture.
Ferroportin1 and hephaestin overexpression attenuate iron‐induced oxidative stress in MES23.5 dopaminergic cells

Elevated iron was found in the substantia nigra (SN) of patients with Parkinson's disease (PD). Our previous in vivo experiments suggested that decreased ferroportin1 (FPN1) and hephaestin (HP) expression might account for the cellular iron accumulation and resulting dopaminergic neurons loss in the SN of PD animal models. In the present study, we investigated whether increased FPN1 and/or HP expression could attenuate iron‐induced oxidative stress in the dopaminergic MES23.5 cell line. We generated MES23.5 cells with stable overexpression of FPN1 and/or HP. Our study showed that overexpression of FPN1 and/or HP increased iron efflux, lowered cellular iron level, suppressed reactive oxygen species production, and restored mitochondrial transmembrane potential, similar to the effects seen for the iron chelator deferoxamine. These results suggest that FPN1 and/or HP might directly contribute to iron efflux process from neurons in conditions of overexpression, thus prevent cellular iron accumulation and eventually protect cells from iron‐induced oxidative stress. J. Cell. Biochem. 110: 1063–1072, 2010. Published 2010 Wiley‐Liss, Inc.
Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia.

AIMS Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia. MATERIALS & METHODS A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale. RESULTS Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone. CONCLUSION These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients.