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The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM's function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR) internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs) that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation), all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-β receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, TβRIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. TβRIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. TβRIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. TβRIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for TβRIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.

The enzyme cyclooxygenase (COX)-1 is constitutive whereas COX-2 is regulated in virtually all tissues. To assess whether this dogma holds true in the pancreatic islet, we examined basal and interleukin (IL)-1-regulated expression of COX-2 in HIT-T15 cells, Syrian hamster and human islets, and other Syrian hamster tissues. We found that COX-2, and not COX-1, gene expression is dominant in pancreatic islet tissue under both basal and IL-1-stimulated conditions. Control tissues (liver, spleen, and kidney) showed the expected predominance of COX-1 gene expression. Basal and IL-1-stimulated prostaglandin E2synthesis were blocked by a specific COX-2 inhibitor. IL-1 stimulation had a biphasic effect on COX-2 mRNA levels with an initial mild increase at 2-4 hr followed by a more dramatic decrease below basal level by 24 hr. The IL-1-induced increase in COX-2 mRNA levels was accompanied by a parallel increase in NF-κ B binding to COX-2 promoter elements. The subsequent decrease in COX-2 mRNA levels was accompanied by a parallel decrease in NF-IL-6 binding activity and COX-2 promoter activity. Specific mutation of the NF-IL-6 binding motif within the COX-2 promoter reduced basal promoter activity by 50% whereas mutation of the NF-κ B motif had no effect. These studies provide documentation of NF-IL-6 in the pancreatic islet and that COX-2, rather than COX-1, is dominantly expressed. They suggest coordinate regulation by IL-1 of COX-2 mRNA, NF-κ B, and NF-IL-6 and raise the issue of whether intrinsically high levels of COX-2 gene expression predisposes the normal islet for microenvironmentally induced overproduction of islet prostaglandin E2.

Describing the current state of gamification, Chamorro-Premuzic, Winsborough, Sherman, and Hogan (2016) provide a troubling contradiction: They offer examples of a broad spectrum of gamification interventions, but they then summarize the entirety of gamification as “the digital equivalent of situational judgment tests.” This mischaracterization grossly oversimplifies a rapidly growing area of research and practice both within and outside of industrial–organizational (I-O) psychology. We agree that situational judgment tests (SJTs) can be considered a type of gamified assessment, and gamification provides a toolkit to make SJTs even more gameful. However, the term gamification refers to a much broader and potentially more impactful set of tools than just SJTs, which are incremental, versatile, and especially valuable to practitioners in an era moving toward business-to-consumer (B2C) assessment models. In this commentary, we contend that gamification is commonly misunderstood and misapplied by I-O psychologists, and our goals are to remedy such misconceptions and to provide a research agenda designed to improve both the science and the practice surrounding gamification of human resource processes.

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-receptor (TGFBR3) decreases with advanc-ing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, T[beta]RIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. T[beta]RIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. T[beta]RIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. T[beta]RIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for T[beta]RIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.

A new era in cancer therapy is emerging with the development of tumor-specific agents exhibiting less toxicity. Since the advent of imatinib, several tumor-directed treatment options have been developed. However, therapies not directed specifically at a tumor target also have potential benefits. The 26S proteasome is a critical regulator of cell homeostasis through the degradation of key signaling molecules including p21, p27, and p53. Additionally, the proteasome degrades I-κB which inhibits the activity of NF-κB, an important promoter of cell proliferation. Blocking function of the proteasome disrupts tumor growth by shifting the balance of the cell from proliferation to apoptosis. In vitro, the proteasome inhibitor, bortezomib, inhibits NF-κB activity and prevents growth of several malignant cell types including multiple myeloma. Given the central role of NF-κB in the pathogenesis of multiple myeloma, bortezomib was a good candidate for use in therapy. Treatment of heavily pre-treated patients with bortezomib led to response rates of 30%-40%. More importantly, bortezomib led to improvements in bone metabolism, a major cause of morbidity in multiple myeloma. This effect was seen independent of the response of the myeloma. This finding correlates with in vitro studies which demonstrate increased BMP2 expression and osteoblast number after exposure to bortezomib. Moreover, bortezomib blocks NF-κB-mediated angiogenesis and tumor cell metastasis. While tumor-targeted treatments have an important role in the future of cancer therapy, these examples show that it is important not to lose sight of the benefits of less-specific agents in the treatment of malignant neoplasms.

Hidradenitis suppurativa is a painful, chronic inflammatory skin disease. In two double-blind, placebo-controlled trials, treatment with adalimumab resulted in significantly increased rates of clinical response at week 12. Rates of serious adverse events were similar between groups. Hidradenitis suppurativa, also known as acne inversa, is a painful, chronic inflammatory skin disease 1 – 3 characterized by multifocal, recurrent nodules, abscesses, and fistulas, predominantly affecting the axillary, inguinal, breast-fold, and anogenital regions. 4 The prevalence of self-reported disease is 1% in Western Europe. 1 , 5 The average interval from the onset of symptoms to diagnosis is 7.2 years. 6 Women are affected 2 to 5 times as frequently as men, and the disease may be more common in blacks than in whites. 1 , 7 Disease severity ranges from mild (localized lesions) to severe (multiple areas of widely dispersed lesions, including interconnected sinus tracts and . . .

Nicotinamide adenine dinucleotide (NAD + ) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD + precursors to augment NAD + bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD + precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD + metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group. Declining NAD + levels have been linked to aging-associated pathologies. Here the authors present results of a double-blind, randomized crossover trial on 30 healthy middle-aged individuals to show that nicotinamide riboside effectively elevates NAD + levels in humans, appears to be well tolerated, and may have potential to improve cardiovascular parameters.

The presence of cell-free microRNAs (miRNAs) has been detected in a range of body fluids. The miRNA content of plasma/serum in particular has been proposed as a potential source of novel biomarkers for a number of diseases. Nevertheless, the quantification of miRNAs from plasma or serum is made difficult due to inefficient isolation and lack of consensus regarding the optimal reference miRNA. The effect of haemolysis on the quantification and normalisation of miRNAs in plasma has not been investigated in great detail. We found that levels of miR-16, a commonly used reference gene, showed little variation when measured in plasma samples from healthy volunteers or patients with malignant mesothelioma or coronary artery disease. Including samples with evidence of haemolysis led to variation in miR-16 levels and consequently decreased its ability to serve as a reference. The levels of miR-16 and miR-451, both present in significant levels in red blood cells, were proportional to the degree of haemolysis. Measurements of the level of these miRNAs in whole blood, plasma, red blood cells and peripheral blood mononuclear cells revealed that the miRNA content of red blood cells represents the major source of variation in miR-16 and miR-451 levels measured in plasma. Adding lysed red blood cells to non-haemolysed plasma allowed a cut-off level of free haemoglobin to be determined, below which miR-16 and miR-451 levels displayed little variation between individuals. In conclusion, increases in plasma miR-16 and miR-451 are caused by haemolysis. In the absence of haemolysis the levels of both miR-16 and miR-451 are sufficiently constant to serve as normalisers.