Social Interaction in Petamburan as a Form of Socio-Religious Tolerance in Indonesia

Petamburan is a sub-district of Jakarta, Indonesia’s capital city, and it has been a center of attention in Indonesia because of the growth and movement of the Islamic Front Defenders (Front Pembela Islam: FPI) within it. Before the FPI was officially banned by the Indonesian government on December 30, 2020, all of its activities and controversies performed in the name of Islam and its leader had become a main attraction for Indonesia’s mainstream media. This impacts Petamburan, which is described as a conflict-prone area in terms of social and religious factors. However, the image of Petamburan from the mass media does not describe the depth of its social reality. This research proposed a core hypothesis that the Petamburan people have deep riches of social harmony in terms of religion, race, and social factors. This study used a social interaction approach and analysis that focused on interactions in the actual public spheres in Petamburan. The final result was a picture of social and religious tolerance from the wide social diversity in the Petamburan community as a form of harmonious and inclusive social life in Indonesia. Keywords: social interaction, religion, public sphere, virtual space, FP

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Individual amino acids - hungry brain and mobile gut

In every living organism amino acids are pivotally important multifunctional molecules. Single amino acids drive mayor intracellular signaling pathways controlling growth and proliferation, and enable neuronal communication in the synaptic cleft. Apart from signaling, their oxidative break down in the citric acid cycle provides energy and metabolic substrates for the cell. When several single amino acids are covalently linked and correctly folded, they form a functional protein. This certainly describes one of the most important processes in biology. All these vital functions depend on the availability of amino acids. Not surprisingly, amino acid pools are maintained within a physiological range by complex regulatory feedback mechanisms – a process termed homeostasis. A homeostatic challenge is to refill the amino acid pools without perturbing amino acid homeostasis, which might cause severe side effects. The temporal regulation of transport protein expression may solve this problem in single cell organisms, whereas eating behavior has to be balanced with the homeostatic needs and the specific available nutrient source in higher species. How this is achieved is currently under active research, but little is known in the context of individual amino acids. One reason might be that ingested proteins are broken down to twenty different individual amino acids leading to large complexity. Not only do they differ in their chemical structure, but some are also nutritionally essential. We hypothesize that, based on these structural differences; they may have distinct roles in the control of food intake and gastrointestinal function. We systematically assessed the impact of all 20 individual proteogenic amino acids on food intake and gastric function. These two functional readouts are particularly relevant in the short-term regulation of nutrient intake. Food intake determines the maximal achievable intake of nutrients, and gastric function i.e. gastric emptying and secretion dictates the concentration and the timing of nutrient release into the small intestine. Both have a direct impact on plasma nutrient concentration and the timing of nutrient appearance in plasma. Here, we show that short-term food intake was most potently reduced by oral L-arginine, L-lysine and L-glutamic acid compared to all other 17 proteogenic amino acids in the rat. As feeding behavior is controlled by neuronal circuits located in specific brain areas, we tested for neuronal activity using immunohistochemistry after L-arginine, L-lysine and L-glutamic acid application. An increased number of cFOS positive cells were detected in the blood-sensing area postrema and the nucleus of the solitary tract. To test whether circulating amino acids can directly signal to the brain to induce their anorectic effect, we administered L-arginine, L-lysine and L-glutamic acid intravenously. All three amino acids induced an anorectic response that was similar to the one induced after oral application. Surgical lesion of the area postrema abolished the anorectic responses of L-arginine and L-glutamic acid but not of L-lysine. The nucleus of the solitary tract is the main projection site of the vagus nerve which innervates the gastrointestinal tract. Surgical lesion of vagal afferents did not alter the anorectic effect of L-arginine and L-glutamic acid but of L-lysine. We presume that L-arginine and L-glutamic acid act in the area postrema to cause their anorectic response, while L-lysine stimulates hepatic vagal afferents projecting to the nucleus of the solitary tract. Interestingly, in the gastrointestinal tract all three amino acids induced gastric distension. L-arginine and L-lysine induced gastric secretion detected by changes in the alkaline tide. Gastric emptying, measured by stomach phenol red retention, was delayed after L-lysine and L-glutamic acid treatment. At the level of the small intestine, L-arginine and L-lysine accelerated phenol red dye passage into the cecum. The gastrointestinal effects of L-lysine were shown to be dose dependent in the rat and were analogously observed in healthy human subjects. The highest L-lysine dose caused self-limiting diarrhea in humans, but no other side effects were reported. The gastrointestinal effect induced by L-arginine and L-lysine was dissociated from their effect on food intake and induced conditioned taste aversion in the rat. Hence, L-arginine, L-lysine and L-glutamic acid had a remarkable specific impact on mechanism important for food processing in the gastrointestinal tract and on food intake in rats and humans. This may suggest that they act as direct sensory input to assess dietary protein content and quality in vivo. Here, we show that L-cysteine, L-lysine, L-arginine and L-tryptophan most potently delayed gastric emptying and that L-arginine and L-lysine most potently stimulated gastric secretion compared to all other proteogenic amino acids in the rat. The systematic assessment of these two key stomach functions was only feasible, because we established and validated a quantitative non-invasive high-throughput computed tomography based method. This novel method can measure simultaneously gastric emptying and secretion in rats in vivo. Future efforts aim to assess if gastric secretion and emptying induced by the candidate amino acids are conducted by a shared control mechanism, to identify its localization and potential effector molecules i.e. gastrointestinal hormones. In conclusion, we revealed remarkable amino acid specificity for two critical nutritional functions, namely food intake and gastric function. The main question arising from this work is the cellular mechanism enabling the remarkable amino acid specificity. This might give insights into how individual amino acids contribute to the control of protein intake, and how protein quality is assessed at a molecular level

Novel antidiabetic nutrients identified by in vivo screening for gastric secretion and emptying regulation in rats

Diabetes mellitus is a disease characterized by elevated blood glucose levels and represents a worldwide health issue. Postprandial hyperglycemia is considered a major predictor of diabetic complications, and its reduction represents a specific treatment target in Type 1 and 2 diabetes. Since postprandial glucose excursions depend to a large extent on gastric secretion and emptying, amylin and glucagon-like peptide 1 analogs are prescribed to reduce them. Although gastric function is considered mainly sensitive to ingested calories, its chemospecificity is not well understood. To identify ingestible nutrients reducing postprandial hyperglycemia, we applied intragastrically more than 40 individual nutrients at an isomolar dose to rats and quantified their impact on gastric secretion and emptying using a novel in vivo computed tomography imaging method. We identified l-tryptophan, l-arginine, l-cysteine, and l-lysine as the most potent modulators with effective strength comparable to a supraphysiological dose of amylin. Importantly, all identified candidates reduced postprandial glucose excursion within an oral glucose tolerance test in healthy and diabetic rats. This clinical beneficial effect originated predominantly from their impact on gastric function, as none of the candidates altered plasma glucose concentrations induced by intraperitoneal or intraduodenal glucose tolerance tests. Overall, these data demonstrate a remarkable chemospecificity of stomach function, unveil a strong role of the stomach for glycemic control and identifies nutrients with antidiabetic potential

Simultaneous assessment of gastric emptying and secretion in rats by a novel computed tomography based method

Gastric emptying and gastric secretion are major physiological functions of the stomach. The assessment of these functions in particular in small animals is challenging; no method currently available allows the simultaneous measurement of both functions, and methods used are lethal or invasive and often limited by spatial, temporal or quantitative resolution. Here, we report the establishment and validation of a quantitative non-invasive high-throughput computed tomography based method to measure simultaneously liquid gastric emptying and secretion in rats in vivo. The imaging strategy enables to visualize stomach anatomy, and to quantify stomach volume and stomach contrast agent content. The method was validated by comparing the results to classical lethal methods (stomach phenol red content, stomach wet weight). Additionally, we showed that the use of a mild anesthetic does not interfere with normal gastric function thereby enabling high-resolution temporal studies within single animals. These combined advantages were applied to reevaluate the impact of cholecystokinin (CCK), histamine and oral glucose on gastric function with high temporal resolution. CCK inhibited gastric emptying for 20 min leading to the accumulation of gastric juice in the stomach. The CCK antagonist devazepide blocked this effect. Histamine stimulated gastric secretion and delayed emptying. Oral glucose solution emptied at a fix rate of 24-31 cal/min and stimulated gastric secretion. These results confirm previous observations and add volumetric changes as a new dimension. As computed tomography scanners become broadly available this method is an excellent approach to measure the combined gastric functional readout and to reduce number of animals used

Elements of a stochastic 3D prediction engine in larval zebrafish prey capture

© 2019, eLife Sciences Publications Ltd. All rights reserved. The computational principles underlying predictive capabilities in animals are poorly understood. Here, we wondered whether predictive models mediating prey capture could be reduced to a simple set of sensorimotor rules performed by a primitive organism. For this task, we chose the larval zebrafish, a tractable vertebrate that pursues and captures swimming microbes. Using a novel naturalistic 3D setup, we show that the zebrafish combines position and velocity perception to construct a future positional estimate of its prey, indicating an ability to project trajectories forward in time. Importantly, the stochasticity in the fish’s sensorimotor transformations provides a considerable advantage over equivalent noise-free strategies. This surprising result coalesces with recent findings that illustrate the benefits of biological stochasticity to adaptive behavior. In sum, our study reveals that zebrafish are equipped with a recursive prey capture algorithm, built up from simple stochastic rules, that embodies an implicit predictive model of the world

High-throughput screening for selective appetite modulators: a multibehavioral and translational drug discovery strategy

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species