Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?

The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the thermodynamic hypothesis of folding is far from strong. Furthermore, physical theory-based approaches to the prediction of protein folds and their folding pathways so far have invariably failed except for some very small proteins, despite decades of intensive theory development and the enormous increase of computer power. The recent spectacular successes in protein structure prediction owe to evolutionary modeling of amino acid sequence substitutions enhanced by deep learning methods, but even these breakthroughs provide no information on the protein folding mechanisms and pathways. We discuss an alternative view of protein folding, under which the native state of most proteins does not occupy the global free energy minimum, but rather, a local minimum on a fluctuating free energy landscape. We further argue that ΔG of folding is likely to be positive for the majority of proteins, which therefore fold into their native conformations only through interactions with the energy-dependent molecular machinery of living cells, in particular, the translation system and chaperones. Accordingly, protein folding should be modeled as it occurs in vivo, that is, as a non-equilibrium, active, energy-dependent process.

Caring for Patients in a Coma Following a Traumatic Brain Injury in Iran

The study described here is the process of caring for patients in a coma following a traumatic brain injury (TBI) in Iran. The data that were analyzed come from in-depth semistructured interviews of 20 key participants and associated memos and field notes. The MAXQDA 10 qualitative analysis software was used to assist with the coding of the data. Ten catagories and 26 subcategories were identified from the primary analysis, which fit well into four themes. The main themes that were identified were chaos and confusion, inconsistent quality, multilateral support, and improving care. The processes of caring for persons in a coma following a TBI were found to be an ever-changing, multidimensional, context-dependent process.

Interpreting and knowledge mediation in the healthcare setting: What do we really mean by “accuracy”?

This paper explores the concept of “accuracy” in the context of interpreter-mediated healthcare interaction by reporting on a study of simulated doctor-patient consultations involving professional Australian Sign Language (Auslan)/English interpreters. Wadensjö’s (1998) taxonomy of renditions is used to analyse the ways interpreters convey health information. Our data reveals that interpreters frequently produce reduced and expanded renditions that are not detrimental to the message or the interaction. There has previously been little discussion of how qualified interpreters make these decisions, and we suggest that achieving accuracy in the healthcare setting may be a more dynamic and context-dependent process than previously suggested. While the use of role-plays can on the one hand can be considered a delimiting factor (due to their artificial nature), they also allow a systematic comparison of different interpreters, thus providing more robust evidence for healthcare interpreter training.

Activation of proline metabolism maintains ATP levels during cocaine-induced polyADP-ribosylation

Cocaine is a commonly abused drug worldwide. Acute as well as repeated exposure to cocaine activates persistent cellular and molecular changes in the brain reward regions. The effects of cocaine are predominantly mediated via alterations in neuronal gene expression by chromatin remodeling. Poly(ADP-ribose) polymerase-1 (PARP-1) catalyzed PARylation of chromatin has been reported as an important regulator of cocaine-mediated gene expression. PARP-1 dependent ADP-ribosylation is an energy-dependent process. In this study, we investigated the cellular energy response to cocaine-induced upregulation of PARP-1 expression. Exposure of differentiated SH-SY5Y cells to varying concentrations of cocaine resulted in the induction of PARP-1 dependent PARylation of p53 tumor suppressor. Further analysis revealed that PARylation of p53 by cocaine treatment resulted in nuclear accumulation of p53. However, induction and nuclear accumulation of p53 did not correlate with neuronal apoptosis/cell death upon cocaine exposure. Interestingly, cocaine-induced p53 PARylation resulted in the induction of proline oxidase (POX)—a p53 responsive gene involved in cellular metabolism. Given that cocaine-induced p53 PARylation is an energy-dependent process, we observed that cocaine-induced PARP-1/p53/POX axes alters cellular energy metabolism. Accordingly, using pharmacological and genetic studies of PARP-1, p53, and POX, we demonstrated the contribution of POX in maintaining cellular energy during neuronal function. Collectively, these studies highlight activation of a novel metabolic pathway in response to cocaine treatment.

Perception of the National Entrepreneurship Conditions – Differences Across Time and Expert Specialization

Creating an external context that will have nourishing effect on the entrepreneurial activities seems to be timely, path and location dependent process. The systemic explorations of the national entrepreneurial context (environment) are still relatively underrepresented. The paper explores strengths and weaknesses of the national entrepreneurship conditions in Croatia and how stable these conditions are in the longer time frame. The aim of the study is to provide more detailed insight on the differences in perceptions among experts engaged in Global Entrepreneurship Monitor (GEM) and along the time. Findings indicate deterioration of the national entrepreneurial conditions in Croatia. Experts’ perceptions of national entrepreneurial conditions diverge between experts who have and those who do not have prior entrepreneurial experiences. The time also matters – perceptual difference in evaluating the quality of national entrepreneurship conditions is observed across 2015–2018.

Classical macrophage polarisation is limited by human β-defensin 3 via an autocrine IL-4 dependent process.

Human β-defensin 3 (HBD3), is an anti-microbial host-defence peptide, that can rapidly enter macrophages to modulate TLR4 responses to lipopolysaccharide. However, the molecular mechanisms by which HBD3 exerts this anti-inflammatory influence remain unclear. Here, we show mice deleted for the orthologue of HBD3 have an increased acute lipopolysaccharide response in vivo. Furthermore, we found that HBD3 limited the response of macrophages to classical activation, and contemporaneously drove expression of IL-4. An increase in markers of alternative activation, and a change in metabolic flux was also observed. Consistent with these results, HBD3 enhanced the IL-4 activation of macrophages. Finally, we demonstrate that the ability of HBD3 to limit macrophage classical activation requires IL-4Rα. These data reveal a previously unrecognised role for HBD3 in influencing the polarisation state of macrophages to enable a state conducive for repair and resolution.

PULP STONES: A REVIEW

Pulp stones are seen to be a fairly common nding in most routine radiographs but they have been given relatively less attention in research as well as textbooks. New investigations have been done in abundance when it comes to their prevalence as well as etiological factors. Despite numerous studies, their formation still remains a riddle for endodontists and researchers alike. Historical perspective of pulp stones being an age dependent process are now being questioned as more studies report their prevalence in young population. This review article evaluates the recent studies pertaining to pulpal calcications where newer etiological factors as well as molecular factors have been highlighted in their formation. Their signicance has been largely studied correlating their occurrence with various other systemic calcications.

Neural Circuitry–Neurogenesis Coupling Model of Depression

Depression is characterized by the disruption of both neural circuitry and neurogenesis. Defects in hippocampal activity and volume, indicative of reduced neurogenesis, are associated with depression-related behaviors in both humans and animals. Neurogenesis in adulthood is considered an activity-dependent process; therefore, hippocampal neurogenesis defects in depression can be a result of defective neural circuitry activity. However, the mechanistic understanding of how defective neural circuitry can induce neurogenesis defects in depression remains unclear. This review highlights the current findings supporting the neural circuitry-regulated neurogenesis, especially focusing on hippocampal neurogenesis regulated by the entorhinal cortex, with regard to memory, pattern separation, and mood. Taken together, these findings may pave the way for future progress in neural circuitry–neurogenesis coupling studies of depression.

Learning the same motor task twice impairs its retention in a time- and dose-dependent manner

Anterograde interference emerges when two differing tasks are learned in close temporal proximity, an effect repeatedly attributed to a competition between differing task memories. However, recent development alternatively suggests that initial learning may trigger a refractory period that occludes neuroplasticity and impairs subsequent learning, consequently mediating interference independently of memory competition. Accordingly, this study tested the hypothesis that interference can emerge when the same motor task is being learned twice, that is when competition between memories is prevented. In a first experiment, the inter-session interval (ISI) between two identical motor learning sessions was manipulated to be 2 min, 1 h or 24 h. Results revealed that retention of the second session was impaired as compared to the first one when the ISI was 2 min but not when it was 1 h or 24 h, indicating a time-dependent process. Results from a second experiment replicated those of the first one and revealed that adding a third motor learning session with a 2 min ISI further impaired retention, indicating a dose-dependent process. Results from a third experiment revealed that the retention impairments did not take place when a learning session was preceded by simple rehearsal of the motor task without concurrent learning, thus ruling out fatigue and confirming that retention is impaired specifically when preceded by a learning session. Altogether, the present results suggest that competing memories is not the sole mechanism mediating anterograde interference and introduce the possibility that a time- and dose-dependent refractory period—independent of fatigue—also contributes to its emergence. One possibility is that learning transiently perturbs the homeostasis of learning-related neuronal substrates. Introducing additional learning when homeostasis is still perturbed may not only impair performance improvements, but also memory formation.