Elucidating the spatial organization and control of information processing in cell signalling networks: from network and enzymatic building blocks to concrete systems

Cells function and survive by making decisions in response to dynamic environments. The core controllers of decision-making are highly complex intracellular networks of proteins and genes, which harbour sophisticated information processing capabilities. The effect of spatial organization and control of signaling networks is typically ignored. However, the role of space in signalling networks is being increasingly recognized. While there are some experimental and modelling efforts that incorporate spatial aspects in specific cellular contexts, the role of spatial regulation of signalling across different cell networks remains largely unexplored. In this thesis, we utilize a combination of mathematical modeling, systems engineering and in silico synthetic approaches to understand the spatial organization and control of signaling networks at multiple levels. We examine spatial effects in representative networks and enzymatic building blocks, including typical network modules, covalent modification cycles and enzymatic modification cascades and pathways. We complement these studies by dissecting the role of spatial regulation in the concrete context of the Caulobacter cell cycle, which involves specific combinations of these building blocks. In another investigation, we examine the organization of spatially regulated signaling networks underlying chemotaxis. We explicitly examine the effects of diffusion and its interplay with spatially varying signals and localization/compartmentalization of signalling entities and gain key insights into the interplay of these factors. At the network level, examining typical network modules reveals how introduction of diffusion/global entities may significantly distort temporal characteristics and introduce new types of signal transduction characteristics. At the enzymatic level, dissecting spatial regulation in enzymatic modules highlights the subtle effect and new facets that arise due to the interweaving of cycle kinetics and diffusion. The var- ious ways in which spatial compartmentalization affects pathway behaviour is revealed in the study of various types of signaling pathways. The study of spatial regulation of these enzymatic/network building blocks provides a systematic basis for understanding how spatial control can affect the spatiotemporal interactions driving Caulobacter cell cycle and we use an in-silico synthetic approach to create a platform for further understanding the functioning of the networks controlling this process. In a different study, we use a design approach to shed light on different signalling configurations of chemotactic networks that allow cells to exhibit both attractive and repulsive behaviour, in light of known signalling characteristics seen in cells. Our results uncover the various capabilities, constraints and trade-offs associated with the spatial control of information processing in signalling networks, which come to the surface only if spatial factors are explicitly considered. Overall, using a focused multipronged approach reveals different facets of spatial regulation of signalling at multiple levels and in different contexts. Combining mathematical modelling, systems engineering and synthetic design approaches creates a powerful framework, which may be used to elucidate spatial control of information processing in multiple contexts and design synthetic systems that could fruitfully exploit spatial organization and regulation.Open Acces

Pilgrim Experience and Revisit Intention Post COVID-19: An Exploratory Study of Amarnath Holy Shrine in Jammu and Kashmir, India

The present preliminary study seeks to explore the pilgrim tourist experience and their revisit intentions post-COVID pandemic. Data were collected at the Amarnath Holy Shrine in Jammu and Kashmir, India, using a combination of primary and secondary sources, including seven in-depth semi-structured telephone interviews with pilgrims using the snowball sampling technique. Five main themes were found regarding revisiting intentions, including ease of registration, safety and security, health facilities, accommodation facilities, food and beverage services, and connectivity of the destinations. The study highlights that despite COVID-19, most respondents agree to return to visit the holy Amarnath Cave as they felt that they would not be affected by COVID-19 in the future. This research has implications for tourists’ safety and security concerns at religious sites, including highlighting the need for proper infrastructure development to enhance the sustainability of religious destinations. Regarding social impacts, the local administration must make efforts to carry out the pilgrimage in a sustainable way post-COVID-19, following new procedures to ensure the safety and health of the tourist and the local community. The Shrine board and Local administration must formally implement these standards via formal Standards of Procedure (SOP)

PERENCANAAN DESAIN PENAMBANGAN LAPISAN BATUBARA PADA SEAM 20 PT. PRIBUMI RESOURCE, SITE DESA SEMAMBU, KECAMATAN SUMAY, KABUPATEN TEBO, PROVINSI JAMBI

Rencana PT. Pribumi Resource membuka lokasi penambangan baru untuk memenuhi target produksi pada tahun-tahun berikutnya dengan rancangan pit 1 dan pit 2 memiliki stripping ratio 1 : 3 didapatkan batas penambangan pada pit 1 yaitu 83 mdpl memiliki cadangan batubara 1.243.682,61 ton dan volume overburden 4.065.484,85 BCM, batas penambangan pada pit 2 yaitu 102 mdpl memiliki cadangan batubara 1.192.565,29 ton dan volume overburden 3.259.338,33 BCM. Perhitungan umur tambang selama 6 tahun dengan rincian pada tahun ke-1 overburden yang dibongkar 941.473 BCM dengan batubara 427.248 ton, pada tahun ke-2 overburden yang dibongkar 1.534.408 BCM dengan batubara 472.642 ton, pada tahun ke-3 overburden yang dibongkar 1.449.964 BCM dengan batubara 251.301 ton, pada tahun ke-4 overburden yang dibongkar 1.180.409 BCM dengan batubara 431.919 ton, pada tahun ke-5 overburden yang dibongkar 883.256 BCM dengan batubara 270.842 ton dan pada tahun ke-6 overburden yang dibongkar 1.170.376 BCM dengan batubara 472.850 ton. Rancangan Disposal ada dua rancangan dengan kapasitas 2.692.729 BCM dan 2.690.459 BCM. Rancagan jalan tambang yang menghubungkan area pit dan area disposal dengan kemiringan 8% hingga 12% dengan maksimal panjang jalan 1,2 km. Kebutuhan jumlah alat untuk produksi batubarara sebanyak 2 unit excavator Komatsu PC 200-7 dan 4 unit dump truck Hino FM 350 PL (Mining) dengan match factor 0,6. Sedangkan kebutuhan jumlah alat untuk produksi overburden sebanyak 4 unit excavator Komatsu PC 200-7 dan 12 unit dump truck Hino FM 350 PL (Mining) dengan match factor 0,78. Kata Kunci: Survey, Stripping Ratio, Cadangan, Rancangan Pit, Disposal, Jalan Tambang, Kebutuhan Ala

MultiPathGAN: Structure Preserving Stain Normalization using Unsupervised Multi-domain Adversarial Network with Perception Loss

Histopathology relies on the analysis of microscopic tissue images to diagnose disease. A crucial part of tissue preparation is staining whereby a dye is used to make the salient tissue components more distinguishable. However, differences in laboratory protocols and scanning devices result in significant confounding appearance variation in the corresponding images. This variation increases both human error and the inter-rater variability, as well as hinders the performance of automatic or semi-automatic methods. In the present paper we introduce an unsupervised adversarial network to translate (and hence normalize) whole slide images across multiple data acquisition domains. Our key contributions are: (i) an adversarial architecture which learns across multiple domains with a single generator-discriminator network using an information flow branch which optimizes for perceptual loss, and (ii) the inclusion of an additional feature extraction network during training which guides the transformation network to keep all the structural features in the tissue image intact. We: (i) demonstrate the effectiveness of the proposed method firstly on H\&E slides of 120 cases of kidney cancer, as well as (ii) show the benefits of the approach on more general problems, such as flexible illumination based natural image enhancement and light source adaptation

Artificial intelligence approach for tomato detection and mass estimation in precision agriculture

Funding: This study was carried out with the support of “Research Program for Agricultural Science & Technology Development” (Project No: PJ013891012020), National Institute of Agricultural Sciences, Rural Development Administration, Republic of Korea.Application of computer vision and robotics in agriculture requires sufficient knowledge and understanding of the physical properties of the object of interest. Yield monitoring is an example where these properties affect the quantified estimation of yield mass. In this study, we propose an image-processing and artificial intelligence-based system using multi-class detection with instance-wise segmentation of fruits in an image that can further estimate dimensions and mass. We analyze a tomato image dataset with mass and dimension values collected using a calibrated vision system and accurate measuring devices. After successful detection and instance-wise segmentation, we extract the real-world dimensions of the fruit. Our characterization results exhibited a significantly high correlation between dimensions and mass, indicating that artificial intelligence algorithms can effectively capture this complex physical relation to estimate the final mass. We also compare different artificial intelligence algorithms to show that the computed mass agrees well with the actual mass. Detection and segmentation results show an average mask intersection over union of 96.05%, mean average precision of 92.28%, detection accuracy of 99.02%, and precision of 99.7%. The mean absolute percentage error for mass estimation was 7.09 for 77 test samples using a bagged ensemble tree regressor. This approach could be applied to other computer vision and robotic applications such as sizing and packaging systems and automated harvesting or to other measuring instruments.Publisher PDFPeer reviewe

An investigation of spatial signal transduction in cellular networks

<p>Abstract</p> <p>Background</p> <p>Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to signalling may play an important role in other apparently purely temporal signal transduction processes. It is increasingly being recognized that a conceptual basis for studying spatial signal transduction in signalling networks is necessary.</p> <p>Results</p> <p>In this work we examine spatial signal transduction in a series of standard motifs/networks. These networks include coherent and incoherent feedforward, positive and negative feedback, cyclic motifs, monostable switches, bistable switches and negative feedback oscillators. In all these cases, the driving signal has spatial variation. For each network we consider two cases, one where all elements are essentially non-diffusible, and the other where one of the network elements may be highly diffusible. A careful analysis of steady state signal transduction provides many insights into the behaviour of all these modules. While in the non-diffusible case for the most part, spatial signalling reflects the temporal signalling behaviour, in the diffusible cases, we see significant differences between spatial and temporal signalling characteristics. Our results demonstrate that the presence of diffusible elements in the networks provides important constraints and capabilities for signalling.</p> <p>Conclusions</p> <p>Our results provide a systematic basis for understanding spatial signalling in networks and the role of diffusible elements therein. This provides many insights into the signal transduction capabilities and constraints in such networks and suggests ways in which cellular signalling and information processing is organized to conform to or bypass those constraints. It also provides a framework for starting to understand the organization and regulation of spatial signal transduction in individual processes.</p

Theatre of Social Commitment: A Study of Edward Bond’s Select Plays

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Evaluation of the Cross-Protective Efficacy of a Chimeric Porcine Reproductive and Respiratory Syndrome Virus Constructed Based on Two Field Strains

One of the major hurdles to porcine reproductive and respiratory syndrome (PRRS) vaccinology is the limited or no cross-protection conferred by current vaccines. To overcome this challenge, a PRRS chimeric virus (CV) was constructed using an FL12-based cDNA infectious clone in which open reading frames (ORFs) 3–4 and ORFs 5–6 were replaced with the two Korean field isolates K08-1054 and K07-2273,respectively. This virus was evaluated as a vaccine candidate to provide simultaneous protection against two genetically distinct PRRS virus (PRRSV) strains. Thirty PRRS-negative three-week-old pigs were divided into five groups and vaccinated with CV, K08-1054, K07-2273, VR-2332, or a mock inoculum. At 25 days post-vaccination (dpv), the pigs in each group were divided further into two groups and challenged with either K08-1054 or K07-2273. All of the pigs were observed until 42 dpv and were euthanized for pathological evaluation. Overall, the CV-vaccinated group exhibited higher levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-12 (IL-12) expression and of serum virus-neutralizing antibodies compared with the other groups after vaccination and also demonstrated better protection levels against both viruses compared with the challenge control group. Based on these results, it was concluded that CV might be an effective vaccine model that can confer a broader range of cross-protection to various PRRSV strains

Oksidacijski stres, hematološko-biokemijski nalaz, elementi u tragovima i vitamini u pasa s cinkom izlječivom dermatozom.

The aim of this study was to examine the hemato-biochemical alterations and evaluate the oxidative stress indices in the blood of dogs with zinc responsive dermatosis. The study included 9 dogs with clinically established diagnosis of zinc responsive dermatosis and 6 dogs as a healthy control. The clinical disease was characterized by alopecia, erythema, hyperkeratotic foot pads and scaling around the eyes, chin, eyes, head and legs. The MDA levels were significantly (P<0.01) higher, whereas superoxide dismutase and catalase activity were significantly (P<0.01) lower when compared to healthy control dogs. Hematology revealed significant neutrophilia and lymphopenia, along with anemia. Biochemical examination revealed a significant (P<0.05) decrease in albumin, A:G ratio and glucose levels, and a significant increase (P<0.05) in globulin level. Plasma zinc, vitamin A and C were significantly decreased, however copper levels were increased. In conclusion, zinc responsive dermatosis is accompanied by oxidative stress and anemia, and affected animals are susceptible to infection.Istraživanje je provedeno radi određivanja hematološko-biokemijskih poremećaja i prosudbe pokazatelja oksidacijskog stresa u krvi pasa s cinkom izlječivom dermatozom. U istraživanje je bilo uključeno devet pasa s kliničkom dijagnozom dermatoze izlječive cinkom i šest zdravih kontrolnih pasa. Klinički se bolest očitovala alopecijom, eritemom, hiperkeratozom mekuši, ljuštenjem oko očiju, po bradi, glavi i nogama. Razine malondialdehida bile su značajno veće (P<0,01), dok je aktivnost superoksidne dismutaze i katalaze bila značajno manja (P<0,01) u usporedbi sa zdravom kontrolnom skupinom pasa. Hematološki nalazi pokazali su znatnu neutrofiliju, limfopeniju i anemiju. Biokemijskom pretragom ustanovljen je značajan pad koncentracije albumina (P<0,05), omjera A:G i razine glukoze te značajno povećanje razine globulina (P<0,05). Cink u plazmi, vitamin A i C bili su značajno smanjeni dok su razine bakra bile povećane. Zaključuje se da je dermatoza izlječiva cinkom također popraćena oksidacijskim stresom, anemijom, a zahvaćene životinje osjetljivije su na infekciju