The function of the co-chaperone ERdj4 in diverse (patho-)physiological conditions

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a well-orchestrated cellular response to reduce the protein burden within the ER. This unfolded protein response (UPR) is controlled primarily by three transmembrane proteins, IRE1α, ATF6, and PERK, the activity of which is controlled by BiP, the ER-resident Hsp70 protein. Binding of BiP to co-chaperones via their highly conserved J-domains stimulates the intrinsic ATPase activity of BiP, thereby providing the energy necessary for (re-)folding of proteins, or for targeting of misfolded proteins to the degradation pathway, processes specified and controlled by the respective co-chaperone. In this review, our aim is to elucidate the function of the co-chaperone ERDJ4, also known as MDG1, MDJ7, or DNAJB9. Knockout and knockin experiments clearly point to the central role of ERDJ4 in controlling lipogenesis and protein synthesis by promoting degradation of SREBP1c and the assembly of the protein complex mTORC2. Accumulating data reveal that ERDJ4 controls epithelial-to-mesenchymal transition, a central process during embryogenesis, in wound healing, and tumor development. Overexpression of ERdj4 has been shown to improve engraftment of transplanted human stem cells, possibly due to its ability to promote cellular survival in stressed cells. High ERDJ4-plasma levels are specific for fibrillary glomerulonephritis and serve as a diagnostic marker. As outlined in this review, the functions of ERDJ4 are manifold, depending on the cellular (patho-) physiological state, the cellular protein repertoire, and the subcellular localization of ERDJ4.

Experimental Study and Improving the Productivity of Assembly line Balancing in Teleja Garment Manufacturing in Ethiopia

This study is designed to assess and improve apparel sewing section efficiency and productivity throughout line balancing. Apparel industry is one of the oldest and among the most global industry, being primarily concerned with the design and production of cloth and their supply. The central process in apparel manufacturing is the joining together of components which is known as the sewing process , which is the most labour intensive type of manufacturing process .Proper utilization of resources in garment sewing section is more critical to enhance the performance of the apparel industry by reducing production cost and minimizing wastage. For effective utilization of resources in the sewing section, good line balancing is important to increase productivity and production efficiency. This research was a design to analyse and improve the assembling line in the case of Telaje garment manufacturing and sales plc. The study was first conduct observations in the production floor and start work with the selection of sewing line in the garment production process. Among the nine lines of the factory select one on the production floor and one garment ordered product known as five pocket men’s jeans trousers are selected. For this study, both qualitative and quantitative research approaches were employed. Both primary and secondary data sources are used to detail the collected relevant data to understand the current efficiency scenario of the factory. The main challenges to minimizing line efficiency and productivity with the expected performance measurement are improper utilization of resources and improper implementation of line balancing in sewing section, therefore this thesis work shows that the bottleneck process and consequence solution will be searched, and finally significantly improving the productivity by 418 unit products/ day and, hence the efficiency will increase from 28.83% to 50.04% of the line

Image of the destination in knowledge management for the reactivation of the tourism economy in the face of Covid-19

The image of the destination is a central process in the tourism agenda. The establishment of a model or explanatory includes predictive variables the satisfactory experience in terms of transfer, stay and return. In this way, the objective of this work is to demonstrate the axes, trajectories and relationships between the determining variables of the destination image in order to anticipate knowledge management scenarios aimed at reactivating the tourist economy. A correlation work was carried out to with a selection of sources indexed to international repositories, considering the search for keywords in the period of the pandemic. The results show homogeneous random effects that suggest risk thresholds for the decision - making of the tourist experience based on its predictors, although these findings correspond to a data tracking and processing system that can be developed according to the prevalence of the literature.

Restructuring insight: An integrative review of insight in problem-solving, meditation, psychotherapy, delusions and psychedelics

Occasionally a solution arrives as a sudden understanding - an insight. Insight has been considered as an “extra” ingredient of creative thinking and problem-solving. Here we propose that insight is a central process in seemingly distinct areas of research. Drawing on literature from a variety of fields, we show that besides being a common topic in problem-solving literature, insight is also a core component in psychotherapy, essential for some forms of meditation, a key process underlying the emergence of primary delusions in schizophrenia, and a factor that drives the positive outcomes of psychedelic therapy. Our goal is to bridge these different views and research traditions. In each case, we discuss the prerequisites and consequences of insight. We examine evidence for common prerequisites of insight experiences, comprising a tension within knowledge structures and a plastic state of mind. We discuss a framework for explaining insight across these fields and highlight the clinical relevance of studying insight. This integrative review provides a better understanding of insight, a central feature of our minds.

Employability as a Guiding Outcome in Veterinary Education: Findings of the VetSet2Go Project

This paper presents a mini-review of employability as a guiding outcome in veterinary education—its conceptualisation, utility, core elements and dimensions, and pedagogical approaches—through a summary of the findings of a major international project with the same aims (the VetSet2Go project). Guided by a conception of the successful veterinary professional as one capable of navigating and sustainably balancing the (sometimes competing) needs and expectations of multiple stakeholders, the project integrated multiple sources of evidence to derive an employability framework representing the dimensions and capabilities most important to veterinary professional success. This framework provides a useful complement to those based in narrower views of competency and professionalism. One notable difference is its added emphasis on broad success outcomes of satisfaction and sustainability as well as task-oriented efficacy, thus inserting “the self” as a major stakeholder and bringing attention to resilience and sustainable well-being. The framework contains 18 key capabilities consistently identified as important to employability in the veterinary context, aligned to five broad, overlapping domains: veterinary capabilities (task-oriented work performance), effective relationships (approaches to others), professional commitment (approaches to work and the broader professional “mission”), psychological resources (approaches to self), plus a central process of reflective self-awareness and identity formation. A summary of evidence supporting these is presented, as well as recommendations for situating, developing, and accessing these as learning outcomes within veterinary curricula. Though developed within the specific context of veterinarian transition-to-practise, this framework would be readily adaptable to other professions, particularly in other health disciplines.

First-principles model of optimal translation factors stoichiometry

Enzymatic pathways have evolved uniquely preferred protein expression stoichiometry in living cells, but our ability to predict the optimal abundances from basic properties remains underdeveloped. Here we report a biophysical, first-principles model of growth optimization for core mRNA translation, a multi-enzyme system that involves proteins with a broadly conserved stoichiometry spanning two orders of magnitude. We show that predictions from maximization of ribosome usage in a parsimonious flux model constrained by proteome allocation agree with the conserved ratios of translation factors. The analytical solutions, without free parameters, provide an interpretable framework for the observed hierarchy of expression levels based on simple biophysical properties, such as diffusion constants and protein sizes. Our results provide an intuitive and quantitative understanding for the construction of a central process of life, as well as a path toward rational design of pathway-specific enzyme expression stoichiometry.

Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5

Rotating cilia at the vertebrate left-right organizer (LRO) generate an asymmetric leftward flow, which is sensed by cells at the left LRO margin. Ciliary activity of the calcium channel Pkd2 is crucial for flow sensing. How this flow signal is further processed and relayed to the laterality-determining Nodal cascade in the left lateral plate mesoderm (LPM) is largely unknown. We previously showed that flow down-regulates mRNA expression of the Nodal inhibitor Dand5 in left sensory cells. De-repression of the co-expressed Nodal, complexed with the TGFß growth factor Gdf3, drives LPM Nodal cascade induction. Here, we show that post-transcriptional repression of dand5 is a central process in symmetry breaking of Xenopus, zebrafish and mouse. The RNA binding protein Bicc1 was identified as a post-transcriptional regulator of dand5 and gdf3 via their 3′-UTRs. Two distinct Bicc1 functions on dand5 mRNA were observed at pre- and post-flow stages, affecting mRNA stability or flow induced translational inhibition, respectively. To repress dand5, Bicc1 co-operates with Dicer1, placing both proteins in the process of flow sensing. Intriguingly, Bicc1 mediated translational repression of a dand5 3′-UTR mRNA reporter was responsive to pkd2, suggesting that a flow induced Pkd2 signal triggers Bicc1 mediated dand5 inhibition during symmetry breakage.

Heme stimulates platelet mitochondrial oxidant production via the activation of toll-like receptor 4 signaling to mediate targeted granule secretion

Hemolysis is a pathological component of many diseases and is associated with thrombosis and vascular dysfunction. Hemolytic products, including cell-free hemoglobin and free heme directly activate platelets. However, the effect of hemolysis on platelet degranulation, a central process in not only thrombosis, but also inflammatory and mitogenic signaling, remains less clear. Our group showed that hemoglobin-induced platelet activation involved the production of mitochondrial reactive oxygen species (mtROS). However, the molecular mechanism by which extracellular hemolysis induces platelet mtROS production, and whether the mtROS regulate platelet degranulation remains unknown. Here, we demonstrate using isolated human platelets that cell free heme is a more potent agonist for platelet activation than hemoglobin, and stimulates the release of a specific set of molecules from the α-granule of platelets, including the glycoprotein thrombospondin-1 (TSP-1). We uncover the mechanism of heme-mediated platelet mtROS production which is dependent on the activation of platelet TLR4 signaling and leads to the downstream phosphorylation of complex-V by the serine kinase Akt. Notably, inhibition of platelet TLR4 or Akt, or scavenging mtROS prevents heme-induced granule release in vitro. Further, heme-dependent granule release is significantly attenuated in vivo in mice lacking TLR4 or those treated with the mtROS scavenger MitoTEMPO. These data elucidate a novel mechanism of TLR4-mediated mitochondrial regulation, establish the mechanistic link between hemolysis and platelet degranulation, and begin to define the heme and mtROS-dependent platelet secretome. These data have implications for hemolysis-induced thrombo-inflammatory signaling and for the consideration of platelet mitochondria as a therapeutic target in hemolytic disorders.

Non-Invasive Differentiation of M1 and M2 Activation in Macrophages Using Hyperpolarized 13C MRS of Pyruvate and DHA at 1.47 Tesla

Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical proinflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of macrophages in multiple diseases, the ability to noninvasively differentiate between M1 and M2 activation states would be highly valuable for monitoring disease progression and therapeutic responses. Since M1/M2 activation patterns are associated with differential metabolic reprogramming, we hypothesized that hyperpolarized 13C magnetic resonance spectroscopy (HP 13C MRS), an innovative metabolic imaging approach, could distinguish between macrophage activation states noninvasively. The metabolic conversions of HP [1-13C]pyruvate to HP [1-13C]lactate, and HP [1-13C]dehydroascorbic acid to HP [1-13C]ascorbic acid were monitored in live M1 and M2 activated J774a.1 macrophages noninvasively by HP 13C MRS on a 1.47 Tesla NMR system. Our results show that both metabolic conversions were significantly increased in M1 macrophages compared to M2 and nonactivated cells. Biochemical assays and high resolution 1H MRS were also performed to investigate the underlying changes in enzymatic activities and metabolite levels linked to M1/M2 activation. Altogether, our results demonstrate the potential of HP 13C MRS for monitoring macrophage activation states noninvasively.