Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.

Lordship and Humanity Principles for The Peace of Indonesia: An Integrative Study of Theology and Ideology

This study is stimulated by the background of the gap regarding the understanding and application between the Indonesian ideology of Pancasila and theology (religion) among both Muslims and Christians. This research aimed to study the integration between Christian theology and the Indonesian ideology of Pancasila. This research was based upon the naturalistic paradigm with a qualitative approach and integrative research method to find a model for solving religious intolerance and violence, which is often manipulated by political interests. This integrative study, especially integral dialectical synthesis, is to find a holistic knowledge of the doctrine of the principle of One Lordship, just and civilized humanity according to Christian theology and ideology of Pancasila as a model of integration. The integrative study between theology and ideology confirms that each of the five principles of Pancasila is theological, and even a mandate that believers (the Christians community) must obey. The relationship between Christian theology and the ideology of Pancasila is an integrative relationship because God and humanity are also integrative. These findings suggest that all Christians live in love and respect to their fellow humans, both Christian and non-Christian. Loving God and others means loving the Indonesian people by participating in overcoming the nation's problems and building the Indonesian nation's welfare for the welfare of the nation is our (all Indonesian citizens) wellbeing.

Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain

ATP-sensitive potassium (K-ATP) channels are ubiquitously expressed on the plasma membrane of cells in several organs, including the heart, pancreas, and brain, and they govern a wide range of physiological processes. In pancreatic β-cells, K-ATP channels composed of Kir6.2 and SUR1 play a key role in coupling blood glucose and insulin secretion. A tryptophan residue located at the cytosolic end of the transmembrane helix is highly conserved in eukaryote and prokaryote Kir channels. Any mutation on this amino acid causes a gain of function and neonatal diabetes mellitus. In this study, we have investigated the effect of mutation on this highly conserved residue on a KirBac channel (prokaryotic homolog of mammalian Kir6.2). We provide the crystal structure of the mutant KirBac3.1 W46R (equivalent to W68R in Kir6.2) and its conformational flexibility properties using HDX-MS. In addition, the detailed dynamical view of the mutant during the gating was investigated using the in silico method. Finally, functional assays have been performed. A comparison of important structural determinants for the gating mechanism between the wild type KirBac and the mutant W46R suggests interesting structural and dynamical clues and a mechanism of action of the mutation that leads to the gain of function.

Neural mechanism of experience-dependent sensory gain control in C. elegans

Animals' sensory systems adjust their responsiveness to environmental stimuli that vary greatly in their intensity. Here we report the neural mechanism of experience-dependent sensory adjustment, especially gain control, in the ASH nociceptive neurons in Caenorhabditis elegans. Using calcium imaging under gradual changes in stimulus intensity, we find that the ASH neurons of naive animals respond to concentration increases in a repulsive odor 2-nonanone regardless of the magnitude of the concentration increase. However, after preexposure to the odor, the ASH neurons exhibit significantly weak responses to a small gradual increase in odor concentration while their responses to a large gradual increase remain strong. Thus, preexposure changes the slope of stimulus-response relationships (i.e., gain control). Behavioral analysis suggests that this gain control contributes to the preexposure-dependent enhancement of odor avoidance behavior. Mathematical analysis reveals that the ASH response consists of fast and slow components, and that the fast component is specifically suppressed by preexposure. In addition, genetic analysis suggests that G protein signaling is required for the fast component. Thus, our integrative study demonstrates how prior experience dynamically modulates stimulus-response relationships in sensory neurons, eventually leading to adaptive modulation of behavior.

Integrative Study Supports the Role of Trehalose in Carbon Transfer From Fungi to Mycotrophic Orchid

Orchids rely on mycorrhizal symbiosis, especially in the stage of mycoheterotrophic protocorms, which depend on carbon and energy supply from fungi. The transfer of carbon from fungi to orchids is well-documented, but the identity of compounds ensuring this transfer remains elusive. Some evidence has been obtained for the role of amino acids, but there is also vague and neglected evidence for the role of soluble carbohydrates, probably trehalose, which is an abundant fungal carbohydrate. We therefore focused on the possible role of trehalose in carbon and energy transfer. We investigated the common marsh orchid (Dactylorhiza majalis) and its symbiotic fungus Ceratobasidium sp. using a combination of cultivation approaches, high-performance liquid chromatography, application of a specific inhibitor of the enzyme trehalase, and histochemical localization of trehalase activity. We found that axenically grown orchid protocorms possess an efficient, trehalase-dependent, metabolic pathway for utilizing exogenous trehalose, which can be as good a source of carbon and energy as their major endogenous soluble carbohydrates. This is in contrast to non-orchid plants that cannot utilize trehalose to such an extent. In symbiotically grown protocorms and roots of adult orchids, trehalase activity was tightly colocalized with mycorrhizal structures indicating its pronounced role in the mycorrhizal interface. Inhibition of trehalase activity arrested the growth of both symbiotically grown protocorms and trehalose-supported axenic protocorms. Since trehalose constitutes only an inconsiderable part of the endogenous saccharide spectrum of orchids, degradation of fungal trehalose likely takes place in orchid mycorrhiza. Our results strongly support the neglected view of the fungal trehalose, or the glucose produced by its cleavage as compounds transported from fungi to orchids to ensure carbon and energy flow. Therefore, we suggest that not only amino acids, but also soluble carbohydrates are transported. We may propose that the soluble carbohydrates would be a better source of energy for plant metabolism than amino acids, which is partially supported by our finding of the essential role of trehalase.

Online Opinion Expression about Women Serving as Judges among University Students in Egypt and Kuwait: An Integrative Study of the Spiral of Silence and Uses and Gratifications

This study integrates the Spiral of Silence and Uses and Gratifications theories to examine the willingness of university students to express on Twitter their opinions about a controversial issue, women serving as judges in Kuwait and Egypt. The analysis of a survey of 640 respondents showed that they used Twitter for information seeking, opinion formation, opinion reinforcement, and social utility in discussions, and for its democratizing capability. Democratization was the only motive to predict the expression of opinion online. When the Kuwaiti and Egyptian samples were analyzed separately, the democratization motive predicted opinion expression for the Kuwaiti students but not for the Egyptian students. Interaction effects between motivations and size of the respondent's social network on Twitter were found to predict the online expression of opinion. For example, the variable assessing the size of a respondent's social network interacted with information seeking motivation and also with opinion reinforcement to predict opinion expression online.

Memory and Memories: An Interdisciplinary Approach

Only humans seem to have the ability to project themselves into their past or future. This mental phenomenon, called autonoetic consciousness, proves the interrelation of memory, imagination, emotion, intelligence and consciousness as a way of creating self-images. The current paper constitutes an integrative study on memory from a theoretical perspective. The first part presents the most known neuroscientific viewpoints on the memory process, along with the pathological case of patient HM, who lost his memory following the removal of his hippocampus. The second part provides a humanistic perspective on recollection to demonstrate its compatibility with the neurological processes of storing information and forming memories. The final part conveys the phenomenon of recollection from the perspective of identity crisis in Kazuo Ishiguro’s novels, as a case study in memory literature. According to memory theories to date, identity cannot exist outside the process of recording and recalling past experiences. Despite the fallible nature of recollection, human beings return to their past in order to give a healthy meaning to their present.

Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.