Miracle-dz/UniFAR-FTUs huggingface dataset:
Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis

Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of diabetic nephropathy and renal fibrosis; however, the causative role of sustained EGFR activation is unclear. Here, we generated a novel kidney fibrotic mouse model of persistent EGFR activation by selectively expressing the EGFR ligand, human heparin‐binding EGF‐like growth factor (hHB‐EGF), in renal proximal tubule epithelium. hHB‐EGF expression increased tyrosine kinase phosphorylation of EGFR and the subsequent activation of downstream signaling pathways, including ERK and AKT, as well as the profibrotic TGF‐β1/SMAD pathway. Epithelial‐specific activation of EGFR was sufficient to promote spontaneous and progressive renal tubulointerstitial fibrosis, as characterized by increased collagen deposition, immune cell infiltration, and α‐smooth muscle actin (α‐SMA)–positive myofibroblasts. Tubule‐specific EGFR activation promoted epithelial dedifferentiation and cell‐cycle arrest. Furthermore, EGFR activation in epithelial cells promoted the proliferation of α‐SMA+ myofibroblasts in a paracrine manner. Genetic or pharmacologic inhibition of EGFR tyrosine kinase activity or downstream MEK activity attenuated the fibrotic phenotype. This study provides definitive evidence that sustained activation of EGFR in proximal epithelia is sufficient to cause spontaneous, progressive renal tubulointerstitial fibrosis, evident by epithelial dedifferentiation, increased myofibroblasts, immune cell infiltration, and increased matrix deposition. —Overstreet, J. M. , Wang, Y. , Wang, X. , Niu, A. , Gewin, L. S. , Yao, B. , Harris, R. C. , Zhang, M. ‐Z. Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis. FASEB J. 31,4407‐4421 (2017). www.fasebj. org
Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization

Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+ influx in alveolar macrophages from wild‐type, but not MCU+/‒, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU‐mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+ suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis. —Gu, L. , Larson‐Casey, J. L. , Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization. FASEB J. 31, 3072–3083 (2017). www.fasebj. org
Differential regulation of renal Klotho and FGFR1 in normal and uremic rats

In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)‐23. Abnormal regulation of the FGFR1‐Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)‐1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a highphosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti‐FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β‐cateniv together with a reduction in Klotho. Wnt/β‐catenin inhibition with Dkk‐1 prevented the P‐induced down‐regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β‐catenin pathway. —Muñoz‐Castañeda, J. R. , Herencia, C. , Pendón‐Ruiz de Mier M. V. , Rodriguez‐Ortiz, M. E. , Diaz‐Tocados, J. M. , Vergara, N. , Martínez‐Moreno, J. M. , Salmerón M. D. , Richards, W. G. , Felsenfeld, A. , Kuro‐O, M. , Almadén Y. , Rodríguez, M. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. FASEB J. 31, 3858–3867 (2017). www.fasebj. org—Muñoz‐Castañeda, Juan R. , Herencia, Carmen, Pendón‐Ruiz de Mier, Maria Victoria, Rodriguez‐Ortiz, Maria Encarnación, Diaz‐Tocados, Juan M. , Vergara, Noemi, Martínez‐Moreno, Julio M. , Salmerón, Maria Dolores, Richards, William G. , Felsenfeld, Arnold, Kuro‐O, Makoto, Almadén, Yolanda, Rodríguez, Mariano Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. FASEB J. 31, 3858–3867 (2017)
Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development

Low nephron endowment at birth has been associated with an increased risk for developing hypertension and chronic kidney disease. We demonstrated in an earlier study that conditional deletion of the microRNA (miRNA)‐processing enzyme Dicer from nephron progenitors results in premature depletion of the progenitors and increased expression of the proapoptotic protein Bim (also known as Bcl‐2L11). In this study, we generated a compound mouse model with conditional deletion of both Dicer and Bim, to determine the biologic significance of increased Bim expression in Dicer‐deficient nephron progenitors. The loss of Bim partially restored the number of nephron progenitors and improved nephron formation. The number of progenitors undergoing apoptosis was significantly reduced in kidneys with loss of a single allele, or both alleles, of Bim compared to mutant kidneys. Furthermore, 2 miRNAs expressed in nephron progenitors (miR‐17 and miR‐106b) regulated Bim levels in vitro and in vivo. Together, these data suggest that miRNA‐mediated regulation of Bim controls nephron progenitor survival during nephrogenesis, as one potential means of regulating nephron endowment. —Cerqueira, D. M. , Bodnar, A. J., Phua, Y. L. , Freer, R. , Hemker, S. L. , Walensky, L. D. , Hukriede, N. A. , Ho, J. Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development. FASEB J. 31, 3540–3554 (2017). www.fasebj. org
How minerals may influence the development and expression of immunity to endoparasites in livestock

This review attempts to explain how dietary mineral intake may affect the immune system, with particular reference to gastrointestinal nematode infestations of livestock, and considers its significance for other gut infections as well as for other species. Of the 56 minerals found in mammalian tissues, 16 are currently considered to be essential, and a further 13 probably essential, for cell and tissue function. To date, eight of these have been shown to affect the function of the mammalian immune system directly. Nine others have roles in physiological pathways such as neurological or endocrine function, or protein or carbohydrate metabolism, which in turn regulate the immune system. The remainder may in the future be shown to have immunologically specific roles. The pathogenesis of mineral effects on immunity involves a number of pathways and molecular mechanisms. Major areas requiring further investigation are the relationship between deficiency of minerals and in vivo immune‐mediated protection against disease, in particular diseases of the mucosa, and the mechanisms by which the minerals or their deficiency exert their effect on immunity. Research is also required into the possibility that animals in the process of acquiring gut immunity have higher requirements for minerals.
The Influence of Instruction about the Method of Urine Collection and Storage on the Incidence or Prevalence of Urinary Tract Infection

A study of 66 children, including 46 (69.7 percent) females and aged between four weeks and 15 years with significant bacteriuria was undertaken over a four-month period to determine the effects of instructions received about the methods of urine collection and storage on the prevalence of urinary tract infection. The commonest clinical presentation was fever (65.2 per cent). Only 23(35.1 per cent) of the patients had specific symptoms suggestive of urinary tract infection(UTI). The method of urine collection was explained to 68.2 per cent of the patients and/or their relations. This instruction was given mostly by the attending physicians (80.0 per cent). Despite the explanation, 14 (21.2 per cent) of the patients collected the urine samples wrongly and 48 (72.7 per cent) stored the samples longer than one hour. Significant bacteriuria was more prevalent in 72.7 per cent of patients who submitted their urine samples to the laboratory later than one hour after collection. There is a need for health care workers to effectively educate patients and/or their relations on the proper methods of urine collection and storage in order to reduce the frequency of making a false diagnosis of UTI with its consequent financial wastage. Nigerian Journal of Paediatrics 2001; 28:39. pp 39-42
NRF1 coordinates with DNA methylation to regulate spermatogenesis

Spermatogenesis is a highly coordinated process that requires tightly regulated gene expression programmed by transcription factors and epigenetic modifiers. In this study, we found that nuclear respiratory factor (NRF)‐1, a key transcription factor for mitochondrial biogenesis, cooperated with DNA methylation to directly regulate the expression of multiple germ cell–specific genes, including Asz1. In addition, conditional ablation of NRF1 in gonocytes dramatically down‐regulated these germline genes, blocked germ cell proliferation, and subsequently led to male infertility in mice. Our data highlight a precise crosstalk between transcriptional regulation by NRF1 and epigenetic modulation during germ cell development and unequivocally demonstrate a novel role of NRF1 in spermatogenesis. —Wang, J., Tang, C. , Wang, Q. , Su, J., Ni, T. , Yang, W. , Wang, Y. , Chen, W. , Liu, X. , Wang, S. , Zhang, J., Song, H. , Zhu, J., Wang, Y. NRF1 coordinates with DNA methylation to regulate spermatogenesis. FASEB J. 31, 4959–4970 (2017). www.fasebj. org
Periprosthetic Fractures around the Shoulder

Shoulder arthroplasty is being performed with increasing volumes worldwide. This inevitability means that complications will be encountered with greater frequency. Periprosthetic fractures around the shoulder are an uncommon but daunting complication related to this type of surgery. This article represents a detailed review of the epidemiology, risk factors, classification and management of these complex injuries.
Unidirectional Binding of Clostridial Collagenase to Triple Helical Substrates*

Histotoxic clostridia produce collagenases responsible for extensive tissue destruction in gas gangrene. The C-terminal collagen-binding domain (CBD) of these enzymes is the minimal segment required to bind to collagen fibril. Collagen binding efficiency of CBD is more pronounced in the presence of Ca2+. We have shown that CBD can be functional to anchor growth factors in local tissue. A 1H-15N HSQC NMR titration study with three different tropocollagen analogues ((POG)10)3, ((GPOG)7PRG)3, and (GPRG(POG)7C-carbamidomethyl)3, mapped a saddle-like binding cleft on CBD. NMR titrations with three nitroxide spin-labeled analogues of collagenous peptide, (PROXYL-G(POG)7PRG)3, (PROXYL-G(POG)7)3, and (GPRG(POG)7C-PROXYL)3 (where PROXYL represents 2,2,5,5-tetramethyl-l-pyrrolidinyloxy), unambiguously demonstrated unidirectional binding of CBD to the tropocollagen analogues. Small angle x-ray scattering data revealed that CBD binds closer to a terminus for each of the five different tropocollagen analogues, which in conjunction with NMR titration studies, implies a binding mode where CBD binds to the C terminus of the triple helix.
Interleukin-1 Receptor-associated Kinase 2 Is Critical for Lipopolysaccharide-mediated Post-transcriptional Control*

IRAK2, a member of the interleukin-1 receptor-associated kinase (IRAK) family, has been implicated in Toll-like receptor (TLR)-mediated signaling. We generated IRAK2-deficient mice to examine its function in detail. These mice are resistant to lipopolysaccharide-induced septic shock, because of impaired TLR4-mediated induction of pro-inflammatory cytokines and chemokines. Although IRAK2 deficiency did not affect TLR4-mediated NFκB activation, a reduction of lipopolysaccharide (LPS)-mediated mRNA stabilization contributed to the reduced cytokine and chemokine production observed in bone marrow-derived macrophages from IRAK2-deficient mice. Furthermore, the ratios of LPS-induced cytokine and chemokine mRNAs in translation-active (polysomal) versus translation-inactive (free ribosomes) pools were reduced in IRAK2-deficient macrophages compared with wild type macrophages. Importantly, LPS-induced phosphorylation of MKK3/6, MNK1, and eIF4E was significantly reduced in IRAK2-deficient macrophages compared with wild type macrophages. Moreover, LPS stimulation induced an interaction of IRAK2 with TRAF6, MKK3/6, and MK2, implicating a critical role for mitogen-activated protein kinase signaling in LPS-induced IRAK2-mediated post-transcriptional control. These results reveal that IRAK2 is required for LPS-mediated post-transcriptional control of cytokine and chemokine expression, which plays an essential role in TLR4-induced septic shock.
Animal models of ocular angiogenesis: from development to pathologies

Pathological angiogenesis in the eye is an important feature in the pathophysiology of many vision‐threatening diseases, including retinopathy of prematurity, diabetic retinopathy, and age‐related macular degeneration, as well as corneal diseases with abnormal angiogenesis. Development of reproducible and reliable animal models of ocular angiogenesis has advanced our understanding of both the normal development and the pathobiology of ocular neovascularization. These models have also proven to be valuable experimental tools with which to easily evaluate potential antiangiogenic therapies beyond eye research. This review summarizes the current available animal models of ocular angiogenesis. Models of retinal and choroidal angiogenesis, including oxygen‐induced retinopathy, laser‐induced choroidal neovascularization, and transgenic mouse models with deficient or spontaneous retinal/choroidal neovascularization, as well as models with induced corneal angiogenesis, are widely used to investigate the molecular and cellular basis of angiogenic mechanisms. Theoretical concepts and experimental protocols of these models are outlined, as well as their advantages and potential limitations, which may help researchers choose the most suitable models for their investigative work. —Liu, C. ‐H. , Wang, Z. , Sun, Y. , Chen, J. Animal models of ocular angiogenesis: from development to pathologies. FASEB J. 31, 4665–4681 (2017). www.fasebj. org
Characterization of a Novel Gain of Function Glucocorticoid Receptor Knock-in Mouse*

Glucocorticoids (GCs) exert profound influences on many physiologic functions by virtue of their diverse roles in growth, development, and maintenance of homeostasis. We previously created a novel gain of function in the human glucocorticoid receptor (hGR), hGRM604L, which is active at GC concentrations 5–10-fold lower than wild-type GR. To gain a greater insight into GC physiology in vivo, we inserted this mutant GR (GRM610L in mice) into mice via homologous recombination. Mice expressing the allele are phenotypically normal with respect to GC function. However, corticosterone levels, ACTH levels, and adrenocortical size are markedly reduced, suggesting they are phenotypically normal because the mutant GR alters the basal regulation of the hypothalamic-pituitary-adrenal axis. We demonstrate via physiologic and immunologic studies that GRM610L mice have increased sensitivity to GCs in vivo. Sensitivity to the actions of endogenous GCs may be an important factor underlying the development of many human diseases including hypertension, obesity, and diabetes. Our model may provide a new and powerful tool for the study of GC physiological and pathological processes in vivo.
Psychosocial needs of HIV-positive children on antiretrovirals: A survey of South African children's homes

Although the distribution of antiretroviral therapy (ART) is still far from adequate, where such therapy is accessible, HIV has largely been transformed from a fatal to chronic infection. The South African government began a national ART rollout in 2003, providing ART free to medically qualifying individuals. Institutions caring for HIV-positive children have since seen a significant increase in the life expectancies of the children for whom they care. These institutions are experiencing a major transformation from their original role as a hospice for sick and dying patients to a children's home raising relatively healthy children with a chronic illness. This anthropologically based research was done in Johannesburg, South Africa, using a social survey and semi-structured interviews conducted with administrators and caregivers from local children's homes. The specific aim was to assess the current state of children's homes caring for HIV-positive children and the psychosocial challenges they face. The 23 homes included in this study cared for a total of 1091 children; 35% of the children were HIV positive with 73% on ART. The majority of homes were facing new and important challenges. Disclosing a child's HIV infection was difficult with only 35% of homes reporting a formal disclosure policy. Education was a concern with most homes expressing a serious need for access to more remedial and special needs schools. Caring for the psychological well-being of children was a challenge with 39% of homes having no access to any form of counseling. Finally, a majority of homes (65%) did not have a plan in place for the children's eventual move from the institution. This study concludes that the provision of antiretrovirals would be best accompanied by a number of medical, psychological, educational, and social services that help prepare HIV-positive children for futures they only recently have been able to expect.
Functional Interactions between Mldp (LSDP5) and Abhd5 in the Control of Intracellular Lipid Accumulation*

Cellular lipid metabolism is regulated in part by protein-protein interactions near the surface of intracellular lipid droplets. This work investigated functional interactions between Abhd5, a protein activator of the lipase Atgl, and Mldp, a lipid droplet scaffold protein that is highly expressed in oxidative tissues. Abhd5 was highly targeted to individual lipid droplets containing Mldp in microdissected cardiac muscle fibers. Mldp bound Abhd5 in transfected fibroblasts and directed it to lipid droplets in proportion to Mldp concentration. Analysis of protein-protein interactions in situ demonstrated that the interaction of Abhd5 and Mldp occurs mainly, if not exclusively, on the surface of lipid droplets. Oleic acid treatment rapidly increased the interaction between Abhd5 and Mldp, and this effect was suppressed by pharmacological inhibition of triglyceride synthesis. The functional role of the Abhd5-Mldp interaction was explored using a mutant of mouse Abhd5 (E262K) that has greatly reduced binding to Mldp. Mldp promoted the subcellular colocalization and interaction of Atgl with wild type, but not mutant, Abhd5. This differential interaction was reflected in cellular assays of Atgl activity. In the absence of Mldp, wild type and mutant Abhd5 were equally effective in reducing lipid droplet formation. In contrast, mutant Abhd5 was unable to prevent lipid droplet accumulation in cells expressing Mldp despite considerable targeting of Atgl to lipid droplets containing Mldp. These results indicate that the interaction between Abhd5 and Mldp is dynamic and essential for regulating the activity of Atgl at lipid droplets containing Mldp.
Dynamin-dependent Membrane Drift Recruits AMPA Receptors to Dendritic Spines*

The surface expression and localization of AMPA receptors (AMPARs) at dendritic spines are tightly controlled to regulate synaptic transmission. Here we show that de novo exocytosis of the GluR2 AMPAR subunit occurs at the dendritic shaft and that new AMPARs diffuse into spines by lateral diffusion in the membrane. However, membrane topology restricts this lateral diffusion. We therefore investigated which mechanisms recruit AMPARs to spines from the shaft and demonstrated that inhibition of dynamin GTPase activity reduced lateral diffusion of membrane-anchored green fluorescent protein and super-ecliptic pHluorin (SEP)-GluR2 into spines. In addition, the activation of synaptic N-methyl-d-aspartate (NMDA) receptors enhanced lateral diffusion of SEP-GluR2 and increased the number of endogenous AMPARs in spines. The NMDA-invoked effects were prevented by dynamin inhibition, suggesting that activity-dependent dynamin-mediated endocytosis within spines generates a net inward membrane drift that overrides lateral diffusion barriers to enhance membrane protein delivery into spines. These results provide a novel mechanistic explanation of how AMPARs and other membrane proteins are recruited to spines by synaptic activity.
Transient Neurologic Signs in Infancy and Motor Outcomes at 4 1/2 Years in Children Born Biologically At Risk

This study was designed to investigate the effects of transient neurologic signs evident in infancy on motor outcomes in 41/2-year-old children born biologically at risk. Children who appeared neurologically normal at each of the 4-month, 12-month, and 24-month visits in the Neonatal Intensive Care Unit Follow-Up Clinic were assigned to the neurologically normal (NN) group (n = 42). Children who appeared to have neuromotor abnormalities at either or both the 4-month and 12-month visits, and who were then rated as “normal” at the 24-month visit, were assigned to the transient neurological signs (TNS) group (n = 19). The groups were compared on motor and cognitive measures at the 41/2-year clinic visit. No significant differences between groups were found except on the measure of pencil prehension, in which the TNS group scored significantly lower (p < .01) than the NN group. A more thorough assessment of fine motor skills at the preschool level may be indicated when following the neurodevelopmental course of children born biologically at risk.