Detecting and Predicting Economic Accelerations,Recessions, and Normal Growth Periods in Real‐Time

The dichotomous characterization of the business cycle in recessions and expansions has been central in the literature over the last 50 years. However, there are various reasons to question the adequacy of this dichotomous, recession/expansion approach for our understanding of the business cycle dynamics, as well as for the prediction of future business cycle developments. In this context, the contribution of this paper to the literature is twofold. First, since a positive rate of growth at the level of economic activity can be considered as the normal scenario in modern economies due to both population and technological growth, it proposes a new non‐parametric algorithm for the detection and dating of economic acceleration periods, trend or normal growth periods, and economic recessions. Second, it uses an ordered probit framework for the estimation and forecasting of these three business cycle phases, applying an automatized model selection approach using monthly macroeconomic and financial data on the German economy. The empirical results show that this approach has superior out‐of‐sample properties under real‐time conditions compared to alternative probit models specified individually for the prediction of recessions and/or economic accelerations. Copyright © 2016 John Wiley & Sons, Ltd.     

More than just scanning: the importance of cap-independent mRNA translation initiation for cellular stress response and cancer

The scanning model for eukaryotic mRNA translation initiation states that the small ribosomal subunit, along with initiation factors, binds at the cap structure at the 5′ end of the mRNA and scans the 5′ untranslated region (5′UTR) until an initiation codon is found. However, under conditions that impair canonical cap-dependent translation, the synthesis of some proteins is kept by alternative mechanisms that are required for cell survival and stress recovery. Alternative modes of translation initiation include cap- and/or scanning-independent mechanisms of ribosomal recruitment. In most cap-independent translation initiation events there is a direct recruitment of the 40S ribosome into a position upstream, or directly at, the initiation codon via a specific internal ribosome entry site (IRES) element in the 5′UTR. Yet, in some cellular mRNAs, a different translation initiation mechanism that is neither cap- nor IRES-dependent seems to occur through a special RNA structure called cap-independent translational enhancer (CITE). Recent evidence uncovered a distinct mechanism through which mRNAs containing N ⁶-methyladenosine (m⁶A) residues in their 5′UTR directly bind eukaryotic initiation factor 3 (eIF3) and the 40S ribosomal subunit in order to initiate translation in the absence of the cap-binding proteins. This review focuses on the important role of cap-independent translation mechanisms in human cells and how these alternative mechanisms can either act individually or cooperate with other cis-acting RNA regulons to orchestrate specific translational responses triggered upon several cellular stress states, and diseases such as cancer. Elucidation of these non-canonical mechanisms reveals the complexity of translational control and points out their potential as prospective novel therapeutic targets.     

Proteomic interaction profiling reveals KIFC1 as a factor involved in early targeting of F508del-CFTR to degradation

Misfolded F508del-CFTR, the main molecular cause of the recessive disorder cystic fibrosis, is recognized by the endoplasmic reticulum (ER) quality control (ERQC) resulting in its retention and early degradation. The ERQC mechanisms rely mainly on molecular chaperones and on sorting motifs, whose presence and exposure determine CFTR retention or exit through the secretory pathway. Arginine-framed tripeptides (AFTs) are ER retention motifs shown to modulate CFTR retention. However, the interactions and regulatory pathways involved in this process are still largely unknown. Here, we used proteomic interaction profiling and global bioinformatic analysis to identify factors that interact differentially with F508del-CFTR and F508del-CFTR without AFTs (F508del-4RK-CFTR) as putative regulators of this specific ERQC checkpoint. Using LC–MS/MS, we identified kinesin family member C1 (KIFC1) as a stronger interactor with F508del-CFTR versus F508del-4RK-CFTR. We further validated this interaction showing that decreasing KIFC1 levels or activity stabilizes the immature form of F508del-CFTR by reducing its degradation. We conclude that the current approach is able to identify novel putative therapeutic targets that can be ultimately used to the benefit of CF patients.     

Extrapineal melatonin: sources,regulation, and potential functions

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.