Miracle-dz/UniFAR-FTUs huggingface dataset:
Sphingosine‐1‐phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans

The bioactive sphingolipid sphingosine‐1‐phosphate (S1P) and the kinase that produces it have been implicated in inflammatory bowel diseases in mice and humans; however, little is known about the role of the 2 S1P‐specific phosphohydrolase isoforms, SGPP1 and SGPP2, which catalyze dephosphorylation of S1P to sphingosine. To elucidate their functions, we generated specific knockout mice. Deletion of Sgpp2, which is mainly expressed in the gastrointestinal tract, significantly reduced dextran sodium sulfate (DSS)‐induced colitis severity, whereas deletion of ubiquitously expressed Sgpp1 slightly worsened colitis. Moreover, Sgpp1 deletion enhanced expression of multifunctional proinflammatory cytokines, IL‐6, TNF‐α, and IL‐1β, activation of the transcription factor signal transducer and activator of transcription 3, and immune cell infiltration into the colon. Conversely, Sgpp2‐null mice failed to mount a DSS‐induced systemic inflammatory response. Of interest, Sgpp2 deficiency suppressed DSS‐induced intestinal epithelial cell apoptosis and improved mucosal barrier integrity. Furthermore, down‐regulation of Sgpp2 attenuated LPS‐induced paracellular permeability in cultured cells and enhanced expression of the adherens junction protein E‐cadherin. Finally, in patients with ulcerative colitis, SGPP2 expression was elevated in colitis tissues relative to that in uninvolved tissues. These results indicate that induction of SGPP2 expression contributes to the pathogenesis of colitis by promoting disruption of the mucosal barrier function. SGPP2 may represent a novel therapeutic target in inflammatory bowel disease. —Huang, W. ‐C. , Liang, J., Nagahashi, M. , Avni, D. , Yamada, A. , Maceyka, M. , Wolen, A. R. , Kordula, T. , Milstien, S. , Takabe, K. , Oravecz, T. , Spiegel, S. Sphingosine‐1‐phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. FASEB J. 30, 2945‐2958 (2016). www.fasebj. org
The Scientific and Clinical Application of Elastic Resistance

Gain a solid base in the science behind elastic resistance exercise and learn the latest clinical applications for rehabilitation and fitness. "The Scientific and Clinical Application of Elastic Resistance" is the most comprehensive guide to elastic resistance exercise.With this expansive reference, students and clinicians will learn how to deliver the most effective clinical and home exercise programs for patients and clients as well as tailor individual programs to improve physical conditioning and sport-specific abilities.The book's 430 photographs show how to perform a variety of exercises using elastic resistance bands and tubing. The companion CD-ROM (which can be purchased separately from the link below when it is available) contains all the exercises in the book, making it one of the most complete collections of elastic resistance exercises available. The CD-ROM is set up in the PhysioTools platform and allows users to order, edit, and download exercise programs, as well as-sort exercises by body part, sport/activity, or special population for quick reference;-develop protocols of elastic resistance exercises; and -provide clean-printed handouts with instructions for patients. "The Scientific and Clinical Application of Elastic Resistance" presents a broad range of easy-to-access information organized into five parts: scientific applications, exercise applications for different areas of the body, training applications, sport-specific applications for 10 different sports, and special populations.
The Effect of a Talux® Prosthetic Foot on Gait Parameters and Limb Loading of Nonvascular Transtibial Amputees

The Talux® prosthetic foot is designed to combine the benefit provided by a dynamic response foot with the advantage of added dorsiflexion, plantarflexion, inversion, and eversion, thus closely simulating the normal human foot. Patients have found that the design also accommodates for small changes in heel height. Previous studies comparing the Talux with other prosthetic feet did not report the similarities between the prosthetic and the sound side. The aim of the study was twofold: to determine the similarities in gait parameters between the prosthetic and sound sides and to determine how much change in heel height can be accommodated by the Talux prosthetic foot. To achieve this aim, we evaluated selected gait parameters. We compared the spatial and temporal gait parameters, hip, knee, and ankle kinematics, and knee kinetics on the prosthetic versus sound side, and we compared the parameters when patients were walking with different lifts under the heels in 10 nonvascular amputees wearing the Talux. We found similarities between the prosthetic and sound sides of the subjects in the majority of the gait parameters except for 1) longer step length and shorter step time, 2) more extended knee at initial and mid stance, and 3) larger range of knee motion in swing phase of walking, all on the prosthetic side. The vertical ground reaction forces were only 10% higher on the prosthetic side. The change in the heel height from 0 to 24 mm was accommodated for most of the parameters except for the increased knee flexion at initial and mid stance on the prosthetic side without any effect on the sound side. Of significance was that the major differences between the Talux and the sound side foot were only found during swing phase when there was no interaction between the prosthetic foot and the ground. This data suggests that the dynamic properties of the Talux foot mimic the properties of the anatomical foot.
Heparin‐binding epidermal growth factor‐like growth factor promotes neuroblastoma differentiation

High‐risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin‐binding epidermal growth factor–like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high‐stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK‐N‐AS, SK‐N‐BE2, and SH‐SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF‐induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up‐regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis. —Gaviglio, A. L. , Knelson, E. H. , Blobe, G. C. Heparin‐binding epidermal growth factor‐like growth factor promotes neuroblastoma differentiation. FASEB J. 31, 1903–1915 (2017). www.fasebj. org
In vivo study of the role of α6‐containing nicotinic acetylcholine receptor in retinal function using subtype‐specific RDP‐MII(E11R) toxin

Although a6‐contaning (a6*) nicotinic acetylcholine receptors (nAChRs) are densely expressed in the visual system, their role is not well known. We have characterized a family of toxins that are antagonists for a6b2* receptors and used one of these [RDP‐MII(E11R)] to localize a6* nAChRs and investigate their impact on retinal function inadult Long‐Evans rats. Thea6*nAChRsinretinal tissuewere localized using either a fluorescently tagged [RDP‐MII(E11R)] or anti‐a6‐specific antibodies and found to be predominantly at the level of the ganglion cell layer. After intraocular injection of RDP‐MII(E11R) in one eye and vehicle or inactiveMII in contralateral eyes as controls, we recorded flash electroretinograms (F‐ERGs), pattern ERGs (P‐ERGs), and cortical visual‐evoked potential (VEPs). There was no significant difference in F‐ERG between the RDP‐MII(E11R)‐treated and control eyes. In contrast, P‐ERG response amplitude was significantly reduced in the RDP‐MII(E11R)‐injected eye. Blocking a6* nAChRs at retinal level also decreased the VEP amplitude recorded in the visual cortex contralateral to the injected eye. Because both the cortical and inner retina output were affected by RDP‐MII(E11R), whereas photoreceptor output was preserved, we conclude that the reduced visual response was due to an alteration in the function of a6* nAChRs present in the ganglion cell layer. —Barloscio, D. , Cerri, E. , Domenici, L. , Longhi, R. , Dallanoce, C. , Moretti, M. , Vilella, A. , Zoli, M. , Gotti, C. , and Origlia, N. In vivo study of the role of α6‐containing nicotinic acetylcholine receptor in retinal function using subtype‐specific RDP‐MII(E11R) toxin. FASEB J. 31, 192–202 (2017) www.fasebj. org
Basal cell nevus syndrome (gorlin syndrome) confirmed by PTCH mutations and deletions

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, is a rare autosomal dominant disorder characterized by variable manifestations, including multiple basal cell carcinomas, odontogenic keratocysts of the jaw, skeletal anomalies including scoliosis and bifid ribs, palmar and plantar pits, calcification of the falx cerebri, and biparietal frontal bossing. We report a case of a 9-year-old boy with the clinical features of basal cell nevus syndrome, in which a PTCH gene mutation was confirmed by DNA testing.
Klotho expression in long bones regulates FGF23 production during renal failure

Circulating levels of bone‐derived fibroblast growth factor 23 (FGF23) increase early during acute and chronic kidney disease and are associated with adverse outcomes. Membrane‐bound Klotho acts as a permissive coreceptor for FGF23, and its expression was recently found in osteoblasts/osteocytes. We hypothesized that Klotho in bone cells is part of an autocrine feedback loop that regulates FGF23 expression during renal failure. Thus, we induced renal failure in mice with targeted deletion of Klotho in long bones. Uremic wild‐type (KLfl/fl) and knockout (Prx1‐Cre;KLfl/fl) mice both responded with reduced body weight, kidney atrophy, hyperphosphatemia, and increased bone turnover. Importantly, long bones of Prx1‐Cre;KLfl/fl mice but not their axial skeleton failed to increase FGF23 expression as observed in uremic KLfl/fl mice. Consequently, Prx1‐Cre;KLfl/fl mice had significantly lower serum FGF23 and parathyroid hormone levels, and higher renal 1‐α‐hydroxylase expression, serum 1,25‐dihydroxyvitamin D, and calcium levels than KLfl/fl mice. These results were confirmed in two independent models of renal failure, adenine diet induced and 5/6 nephrectomy. Moreover, FGF23‐treated bone cells required Klotho to increase FGF23 mRNA and ERK phosphorylation. In summary, our novel findings show that Klotho in bone is crucial for inducing FGF23 production upon renal failure. We propose the presence of an autocrine feedback loop in which Klotho senses the need for FGF23. —Kaludjerovic, J., Komaba, H. , Sato, T. , Erben, R. G. , Baron, R. , Olauson, H. , Larsson, T. E. , Lanske, B. Klotho expression in long bones regulates FGF23 production during renal failure. FASEB J. 31, 2050–2064 (2017). www.fasebj. org
Early suppression of adipocyte lipid turnover induces immunometabolic modulation in cancer cachexia syndrome

Cancer cachexia is a multifactorial syndrome characterized by body weight loss, atrophy of adipose tissue (AT) and systemic inflammation. However, there is limited information regarding the mechanisms of immunometabolic response in AT from cancer cachexia. Male Wistar rats were inoculated with 2 × 107 of Walker 256 tumor cells [tumor bearing (TB) rats]. The mesenteric AT (MeAT) was collected on d 0, 4, 7 (early stage), and 14 (cachexia stage) after tumor cell injection. Surgical biopsies for MeAT were obtained from patients who had gastrointestinal cancer with cachexia. Lipolysis showed an early decrease in glycerol release in TB d 4 (TB4) rats in relation to the control, followed by a 6‐fold increase in TB14 rats, whereas de novo lipogenesis was markedly lower in the incorporation of glucose into fatty acids in TB14 rats during the development of cachexia. CD11b and CD68 were positive in TB7 and TB14 rats, respectively. In addition, we found cachexia stage results similar to those of animals in MeAT from patients: an increased presence of CD68+, iNOS2+, TNFα+, and HSL+ cells. In summary, translational analysis of MeAT from patients and an animal model of cancer cachexia enabled us to identify early disruption in Adl turnover and subsequent inflammatory response during the development of cancer cachexia. —Henriques, F. S. , Sertié, R. A. L. , Franco, F. O. , Knobl, P., Neves, R. X. , Andreotti, S. , Lima, F. B. , Guilherme, A. , Seelaender, M. , Batista, M. L. , Jr. Early suppression of adipocyte lipid turnover induces immunometabolic modulation in cancer cachexia syndrome. FASEB J. 31, 1976–1986 (2017). www.fasebj. org
A novel role for myeloid cell‐specific neuropilin 1 in mitigating sepsis

Sepsis—typically caused by an uncontrolled and amplified host systemic inflammatory response to microbial infection—is a life‐threatening complex clinical disorder and remains a major cause of infection‐related deaths in the intensive care unit. Emerging evidence suggests that neuropilin 1 (Nrp1), an originally defined coreceptor for class 3 semaphorins and VEGF, plays important roles in the immune system; however, the function and regulation of macrophage Nrp1 in host immune defense against bacterial infection remain unknown. To address this problem, we generated myeloid cell–specific Nrp1‐knockout (Nrp1myel‐KO) mice and applied 2 stringent animal models of sepsis: cecal ligation and puncture as well as intraperitoneal injection of LPS. Here, we reported that myeloid cell–specific Nrp1‐deficient mice exhibited enhanced susceptibility to cecal ligation and puncture– and LPS‐induced sepsis, which correlated with significantly decreased survival rates and heightened levels of proinflammatory cytokines in both peritoneal lavage and serum. Mechanistically, LPS specifically attenuated the expression of Nrp1 in macrophages, which was mediated by TLR4–NF‐κB p50 and ‐65 pathways. By using isolated primary macrophages, loss of Nrp1 consistently resulted in increased production of proinflammatory cytokines, including iNOS, TNF‐α, and IL‐6. Together, these findings demonstrate a novel role of macrophage Nrp1 in sepsis. —Dai, X. Okon, I. , Liu, Z. , Wu, Y. , Zhu, H. , Song, P., Zou, M. ‐H. A novel role for myeloid cell–specific neuropilin 1 in mitigating sepsis. FASEB J. 31, 2881–2892 (2017). www.fasebj. org
Antenatal haemoglobin A1c and risk of large-for-gestational-age infants in a multi-ethnic cohort of women with gestational diabetes.

Gestational diabetes mellitus (GDM) is a risk factor for delivering a large-for-gestational-age (LGA) infant. Haemoglobin A1c (A1C) is an indicator of glycaemic control. The objective of this study was to test whether higher A1C quartile at the time of diagnosis of GDM is associated with increased risk of delivering a LGA or macrosomic infant. Women with singleton pregnancies treated for GDM at a large diabetes and pregnancy programme located in Charlotte, North Carolina, were eligible for inclusion in this retrospective cohort study. Clinical information, including A1C at diagnosis, treatment, prior medical and obstetric history, and birth data were abstracted from medical records. LGA was defined as birthweight >90th percentile for gestational age and sex and macrosomia as birthweight >4000 g. Logistic regression was used to analyse the association of A1C at GDM diagnosis with risk of delivering LGA or macrosomic infants. This study included 502 women. Prevalences of LGA and macrosomia were 4% and 6% respectively. After adjustment there was no detectable trend of increased risk for LGA (P for trend = 0.12) or macrosomia (P for trend = 0.20) across increasing quartiles of A1C at GDM diagnosis. A1C at GDM diagnosis may not be linearly associated with LGA or macrosomia, possibly because of the mediating effect of strict glycaemic control in this clinical setting.
Interaction of Tim23 with Tim50 Is Essential for Protein Translocation by the Mitochondrial TIM23 Complex*

The TIM23 complex is the major translocase of the mitochondrial inner membrane responsible for the import of essentially all matrix proteins and a number of inner membrane proteins. Tim23 and Tim50, two essential proteins of the complex, expose conserved domains into the intermembrane space that interact with each other. Here, we describe in vitro reconstitution of this interaction using recombinantly expressed and purified intermembrane space domains of Tim50 and Tim23. We established two independent methods, chemical cross-linking and surface plasmon resonance, to track their interaction. In addition, we identified mutations in Tim23 that abolish its interaction with Tim50 in vitro. These mutations also destabilized the interaction between the two proteins in vivo, leading to defective import of preproteins via the TIM23 complex and to cell death at higher temperatures. This is the first study to describe the reconstitution of the Tim50-Tim23 interaction in vitro and to identify specific residues of Tim23 that are vital for the interaction with Tim50.
Distinct Mechanisms of Regulation by Ca2+/Calmodulin of Type 1 and 8 Adenylyl Cyclases Support Their Different Physiological Roles*

Nine membrane-bound mammalian adenylyl cyclases (ACs) have been identified. Type 1 and 8 ACs (AC1 and AC8), which are both expressed in the brain and are stimulated by Ca2+/calmodulin (CaM), have discrete neuronal functions. Although the Ca2+ sensitivity of AC1 is higher than that of AC8, precisely how these two ACs are regulated by Ca2+/CaM remains elusive, and the basis for their diverse physiological roles is quite unknown. Distinct localization of the CaM binding domains within the two enzymes may be essential to differential regulation of the ACs by Ca2+/CaM. In this study we compare in detail the regulation of AC1 and AC8 by Ca2+/CaM both in vivo and in vitro and explore the different role of each Ca2+-binding lobe of CaM in regulating the two enzymes. We also assess the relative dependence of AC1 and AC8 on capacitative Ca2+ entry. Finally, in real-time fluorescence resonance energy transfer-based imaging experiments, we examine the effects of dynamic Ca2+ events on the production of cAMP in cells expressing AC1 and AC8. Our data demonstrate distinct patterns of regulation and Ca2+ dependence of AC1 and AC8, which seems to emanate from their mode of regulation by CaM. Such distinctive properties may contribute significantly to the divergent physiological roles in which these ACs have been implicated.
Advances in the use of genetically engineered parasites to study immunity to Toxoplasma gondii

Studying in vivo biology and the host immune response to Toxoplasma gondii has yielded many insights into the pathogenesis of this parasitic organism. It is recognized that this infection in immune competent hosts elicits a strong Th1‐type response, which is characterized by the generation of parasite‐specific CD4+ and CD8+ T cells that produce IFN‐γ and provide protective immunity. One of the problems associated with studying resistance to Toxoplasma has been the lack of reagents to track parasite‐specific T cell responses with a high degree of specificity. To overcome this difficulty, it is possible to use a combination of transgenic parasites that are engineered to express well‐characterized heterologous reporters or antigens, and T cell hybridomas or naïve T cells that express a T cell receptor specific for the processed peptide. These approaches have provided new insights into parasite dissemination, antigen presDelivered as OEentation, as well as immune regulation.
Intersectin 2 controls actin cap formation and meiotic division in mouse oocytes through the Cdc42 pathway

Intersectins (ITSNs), an evolutionarily conserved adaptor protein family, have been implicated in multiple biologic processes; however, their functions in mammalian oocytes have not been addressed. Here, we report delayed meiotic resumption and defective cytokinesis upon specific depletion of ITSN2 in mouse oocytes. In particular, abnormal spindle, misaligned chromosomes, and loss of cortical actin cap are readily observed in LTSN2‐depleted oocytes. Similarly, a small molecule that targets the Cdc42–ITSN interaction also disrupts oocyte maturation and actin polymerization. Moreover, we find that ITSN2 depletion reduces the activity of Cdc42 in oocytes and, of note, that forced expression of the dominant‐positive mutant of Cdc42, in part, prevents the effects of ITSN2 knockdown on actin cap formation. In addition, the localization of WASP and Arp2, the downstream effector proteins of Cdc42, is altered in ITSN2‐depleted oocytes accordingly. In summary, our data support a model in which ITSN2 depletion induces the inactivation of Cdc42, which, in turn, influences the distribution and function of Arp2/3 and WASP, consequently disrupting oocyte polarity establishment and meiotic division. —Zhang, J., Ma, R. , Li, L. , Wang, L. , Hou, X. , Han, L. , Ge, J., Li, M. , Wang, Q. Intersectin 2 controls actin cap formation and meiotic division in mouse oocytes through the Cdc42 pathway. FASEB J. 31, 4277–4285 (2017). www.fasebj. org
Genetics and visceral leishmaniasis: of mice and man

Ninety per cent of the 500 000 annual new cases of visceral leishmaniasis (VL) occur in India/Bangladesh/Nepal, Sudan and Brazil. Importantly, 80–90% of human infections are sub‐clinical or asymptomatic, usually associated with strong cell‐mediated immunity. Understanding the environmental and genetic risk factors that determine why two people with the same exposure to infection differ in susceptibility could provide important leads for improved therapies. Recent research using candidate gene association analysis and genome‐wide linkage studies (GWLS) in collections of families from Sudan, Brazil and India have identified a number of genes/regions related both to environmental risk factors (e.g. iron), as well as genes that determine type 1 vs. type 2 cellular immune responses. However, until now all of the allelic association studies carried out have been underpowered to find genes of small effect sizes (odds ratios or OR < 2), and GWLS using multicase pedigrees have only been powered to find single major genes, or at best oligogenic control. The accumulation of large DNA banks from India and Brazil now makes it possible to undertake genome‐wide association studies (GWAS), which are ongoing as part of phase 2 of the Wellcome Trust Case Control Consortium. Data from this analysis should seed research into novel genes and mechanisms that influence susceptibility to VL.