Unpredictable Growth Research Articles

Fungal cryopreservation across 61 genera: Practical application and method evaluation

ABSTRACT Fungi occupy important environmental, cultural, and socioeconomic roles. However, biological research of this diverse kingdom has lagged behind that of other phylogenetic groups. This is partially the result of the notorious difficulty in culturing a diverse array of filamentous fungal species due to their (i) often unpredictable growth, (ii) unknown preferences for culturing conditions, and (iii) long incubation times compared with other microorganisms such as bacteria and yeasts. Given the complexity associated with concurrently culturing diverse fungal species, developing practical methods for preserving as many species as possible for future research is vital. The widely accepted best practice for preserving fungal tissue is the use of cryogenic biobanking at −165 C, allowing for the preservation and documentation of stable genetic lineages, thus enabling long-term diversity-centered research. Despite the extensive literature on fungal cryopreservation, substantial barriers remain for implementation of cryogenic biobanks in smaller mycological laboratories. In this work, we present practical considerations for the establishment of a fungal culture biobank, as well as provide evidence for the viability of 61 fungal genera in cryogenic storage. By providing a pragmatic methodology for cryogenically preserving and managing many filamentous fungi, we show that creating a biobank can be economical for independently owned and operated mycology laboratories, which can serve as a long-term resource for biodiversity, conservation, and strain maintenance.

CP-14. VOLUMETRIC ANALYSIS OF PAEDIATRIC CRANIOPHARYNGIOMAS: CLINICAL-RADIOLOGICAL CORRELATION STUDY

Abstract BACKGROUND Craniopharyngioma are heterogeneous hypothalamopituitary tumours with solid and cystic components which have a distinct natural history. Neuroimaging follow-up and the definition of progressive disease is challenging due to unpredictable growth of the inflammatory cystic component. METHODS This multicentre retrospective observational study aimed to describe the clinical-radiological correlation of craniopharyngiomas at two paediatric neurosurgery units (GOSH,UK and USP,Brazil). Craniopharyngiomas treated over a 20-year period were identified and standardized clinical outcomes recorded. Baseline MRIs were reviewed and volumetric T1-weighted images segmented by a board-certified paediatric neuroradiologist. RESULTS Of 123 patients, 92 baseline MRIs were available for image analysis (USP=32; GOSH=60). No differences between series were identified in either demography (mean age: USP=9.2±4.6; GOSH=8.2±4.1 years) or tumour characteristics, with tumours being predominantly cystic (USP=75%; GOSH=76%), localised to the sellar/suprasellar region (USP=84%; GOSH: 88%), and on pre-chiasmatic (USP=34%; GOSH=22%) or retro-chiasmatic (USP=59%; GOSH=67%) locations. Pre-chiasmatic tumours were associated with an increased prevalence of visual symptoms at presentation (p=0.006) and worse recovery of visual acuity at long-term follow-up (p=0.021). Regarding volumetric analysis, mean volumes were 16.6±25.1cm3 for the cystic component and 38.3±10cm3 for the solid component. Volumes of the solid and cystic components had no correlation with each other. Larger cystic tumour volumes were correlated with a greater prevalence of diabetes insipidus at presentation (p=0.06). Larger solid tumours were significantly related to younger ages (p=0.02) and had worse PFS in our series. In terms of long-term outcomes, high volume cystic tumours were related to worse hypothalamic outcomes. In multivariate analysis (n=92), Paris classification did not predict long-term outcomes. CONCLUSIONS Volumetric analysis of craniopharyngiomas showed significant correlation with the onset of diabetes insipidus and hypothalamic long-term outcomes. Larger cystic craniopharyngioma were more common in younger patients. The Paris classification did not predict long-term outcomes in multivariate analysis.

Optimal nitrogen source for the recovery of phycoerythrin in discolored Rhodomonas sp.

Rhodomonas species are of interest as excellent aquaculture feed because of their ideal biochemical composition, especially their high protein content, resulting from the presence of intracellular phycoerythrin (PE). One of the most crucial issue with this species as a feed source is PE degradation under ambient nitrogen starvation, which leads to unpredictable growth defects and reduced nutritional value associated with cell discoloration. The aim of this study was to propose an optimal nitrogen source for the recovery of intracellular PE in discolored Rhodomonas sp. We supplied three different nitrogen sources, i.e., nitrate, ammonium, and urea, to PE-degraded cells and monitored changes in PE content and the expression of related genes. Supplementation with each nitrogen source increased cell density, with nitrate exhibiting the highest specific growth rate of 0.30 ± 0.02 day−1. The maximum PE content in each nitrogen group at 48 h after N supplementation was about 3.8 pg cell−1 with no major difference between groups. In contrast, the highest relative PE recovery rate of 5.73 ± 0.18-fold and the highest PE productivities of 0.32 ± 0.01 μg mL−1 h−1 were obtained in the nitrate group. Nitrogen transporter genes, including RhNrt2, RhAmt1, and RhDur3, were upregulated under nitrogen-starvation conditions, demonstrating the ability of this species to utilize each of the tested nitrogen sources. Furthermore, RhCpeb, which serves as a molecular indicator of PE biosynthesis, was significantly upregulated in all nitrogen-supplemented groups, with the strongest and fastest increase in expression in the nitrate group, emphasizing the potential of nitrate as the most favorable nitrogen source for PE recovery in this species. Our findings pave the way for informed strategies for the stable management and production of Rhodomonas species as high-protein feed in aquaculture.

Prediction of Deoxynivalenol Contamination in Wheat via Infrared Attenuated Total Reflection Spectroscopy and Multivariate Data Analysis.

The climate crisis further exacerbates the challenges for food production. For instance, the increasingly unpredictable growth of fungal species in the field can lead to an unprecedented high prevalence of several mycotoxins, including the most important toxic secondary metabolite produced by Fusarium spp., i.e., deoxynivalenol (DON). The presence of DON in crops may cause health problems in the population and livestock. Hence, there is a demand for advanced strategies facilitating the detection of DON contamination in cereal-based products. To address this need, we introduce infrared attenuated total reflection (IR-ATR) spectroscopy combined with advanced data modeling routines and optimized sample preparation protocols. In this study, we address the limited exploration of wheat commodities to date via IR-ATR spectroscopy. The focus of this study was optimizing the extraction protocol for wheat by testing various solvents aligned with a greener and more sustainable analytical approach. The employed chemometric method, i.e., sparse partial least-squares discriminant analysis, not only facilitated establishing robust classification models capable of discriminating between high vs low DON-contaminated samples adhering to the EU regulatory limit of 1250 μg/kg but also provided valuable insights into the relevant parameters shaping these models.

Exploration of the molecular biological mechanisms and review of postoperative radiotherapy cases in tenosynovial giant cell tumors.

Tendon Sheath Giant Cell Tumor (TGCT) is a benign tumor that primarily grows within joints and bursae. However, it has a high postoperative recurrence rate, ranging from 15% to 45%. Although radiotherapy may reduce this recurrence rate, its applicability as a standard treatment is still controversial. Furthermore, the pathogenic mechanisms of TGCT are not clear, which limits the development of effective treatment methods. The unpredictable growth and high recurrence rate of TGCT adds to the challenges of disease management. Currently, our understanding of TGCT mainly depends on pathological slice analysis due to a lack of stable cell models. In this study, we first reviewed the medical records of two female TGCT patients who had undergone radiotherapy. Then, by combining bioinformatics and machine learning, we interpreted the pathogenesis of TGCT and its associations with other diseases from multiple perspectives. Based on a deep analysis of the case data, we provided empirical support for postoperative radiotherapy in TGCT patients. Additionally, our further analysis revealed the signaling pathways of differentially expressed genes in TGCT, as well as its potential associations with osteoarthritis and synovial sarcomas.

Variation in growth rates between cultures hinders the cultivation of ammonia-oxidizing bacteria.

Ammonia-oxidizing bacteria, key players in the nitrogen cycle, have been the focus of extensive research. Numerous novel species have been isolated and their growth dynamics were studied. Despite these efforts, controlling their growth to obtain diverse physiological findings remains a challenge. These bacteria often fail to grow, even under optimal conditions. This unpredictable growth pattern could be viewed as a survival strategy. Understanding this heterogeneous behavior could enhance our ability to culture these bacteria. In this study, the variation in the growth rate was quantified for the ammonia-oxidizing bacterium Nitrosomonas mobilis Ms1. Our findings revealed significant growth rate variation under low inoculum conditions. Interestingly, higher cell densities resulted in more stable cultures. A comparative analysis of three Nitrosomonas species showed a correlation between growth rate variation and culture failure. The greater the variation in growth rate, the higher the likelihood of culture failure.

Investigation of the Water Basins of Kalafgan District with GIS Analysis

The rapid and unpredictable growth of the population, the development of cultivation, and the lack of surface and underground water management have caused problems in the irrigation and hydrological system in Kalafgan city. In this region, the lack of sufficient water diversion dams and the canalization system, at the same time as the rapid development of cultivation and agriculture, have caused problems for the residents of this city. To solve the water shortage, there is a need to increase the number of water diversion dams, manage surface water, and determine and identify water sources and drainage patterns. Determining and stabilizing the location construction of suitable dams and channels in the regional study is determined by using a geographic information system. One of the effective sciences in the field of earth and environmental science studies is the use of geographic information systems, which is very useful in the accurate estimation of hydrometric parameters of watersheds. In this research, as an example of hydrometric studies of the water basins of Kalafgan city in the geographic information system, the digital elevation model (DEM) has been used with the help of geographic information system software for the studied basin.

Agent-Based and Continuum Models for Spatial Dynamics of Infection by Oncolytic Viruses

The use of oncolytic viruses as cancer treatment has received considerable attention in recent years, however the spatial dynamics of this viral infection is still poorly understood. We present here a stochastic agent-based model describing infected and uninfected cells for solid tumours, which interact with viruses in the absence of an immune response. Two kinds of movement, namely undirected random and pressure-driven movements, are considered: the continuum limit of the models is derived and a systematic comparison between the systems of partial differential equations and the individual-based model, in one and two dimensions, is carried out. In the case of undirected movement, a good agreement between agent-based simulations and the numerical and well-known analytical results for the continuum model is possible. For pressure-driven motion, instead, we observe a wide parameter range in which the infection of the agents remains confined to the center of the tumour, even though the continuum model shows traveling waves of infection; outcomes appear to be more sensitive to stochasticity and uninfected regions appear harder to invade, giving rise to irregular, unpredictable growth patterns. Our results show that the presence of spatial constraints in tumours’ microenvironments limiting free expansion has a very significant impact on virotherapy. Outcomes for these tumours suggest a notable increase in variability. All these aspects can have important effects when designing individually tailored therapies where virotherapy is included.

Tekstas kaip gyvatvorė

Text as ahedgerow Text, what it is and what it is like, has always been a topic of discussion in philology. In turn, the variety of description of text and the interconnected definitions of work and document have been enormous, and specifying them never ends. As we operate in abstract nouns qualifying human activity, the conceptual metaphor that we choose considerably affects the direction of thinking. The article proposes a critical overview of commonly used images of text: net, structure, fluid water, forest, garden etc., and suggests a new metaphor, ‘text as a hedgerow’. This concept differs particularly from former organicist imagination drawing on the vitality of a wild plant, in that it directs the view to the meeting point of spontaneity and reasoning, the involuntary and the planned, the natural and the acculturated or tamed. Besides the spontaneous pull towards the sun (in the case of literature, towards fame), the image of a hedgerow implies conscious grafting, orderly pruning, and planned shaping. Even more important is the tension between the function prescribed by the author, the editor or the reader, and uninhibited and unpredictable growth. The natural structures of branching out and leafing, determined by vegetative conditions that enact the tendencies of syntactic connectivity, and the tension of form imposed by the pruner, are always complicated.

P11.74.A Plexiform Neurofibromas prevalence and treatment modalities in a referral comprehensive cancer center

Abstract Background Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, with an incidence of 1/3500. Plexiform neurofibromas (PN) are benign tumors that can occur along the nerve sheath throughout the body, with unpredictable growth and with risk of malignant transformation. Symptoms will depend on their size and location, and include pain, deformity and functional impairment. There is a great variability in the PN severity and impact on quality-of-life (QOL). An unknown percentage of NF1 patients may need treatment, either medical and/or surgical. Objectives To assess the frequency of PN in a NF1 population followed in a comprehensive cancer center. Material and Methods Retrospective study. All patients with NF1 and PN followed in our center, between 31/12/2000 and 31/12/2021. Results Of 438 NF1 patients, 185 had PN (42%). 52 NF1 patients with PN were children (≤ 18). The most common symptoms were pain in 71 people (38,4%), deformity in 70 (37,8%) and functional impairment in 69 (37,3%). Several patients had a combination of these symptoms. Different treatment modalities were used for PN: medical, surgical or both. In this study, 54 patients (29,1%) were treated with MEK inhibitors (selumetinib), 74 patients (40%) were treated surgically and 12,4% (23) needed a combined approach (medical and surgical treatment). Conclusion PN are frequent in NF1 patients. A significant percentage is symptomatic and will require treatment, surgical, medical or both. There is no standard of care for PN NF1. The timing and sequence of medical and surgical treatment is yet to be defined.

Long-term facial symmetry after pediatric mandibular reconstruction using the vascularized fibula free flap: A photogrammetric analysis

The fibula free flap is the standard of care in the reconstruction of large mandibular defects in pediatric patients, enabling adequate restoration of the facial contour. However, the unpredictable growth potential of the reconstructed mandible could influence the preservation of the initially restored symmetry over time. Being mindful of the importance of facial appearance during developmental stages, this study aimed to evaluate the long-term facial symmetry after mandible reconstruction using this technique in growing patients. A photogrammetric analysis of facial symmetry using the "Asymmetry Index" (AI) was performed from preoperative and postoperative frontal photographs in 17 pediatric patients (9 males and 8 females) who underwent mandibular reconstruction with the vascularized fibula free flap and had a minimum follow-up of 5 years. Comparisons between preoperative and postoperative measurements-as well as postoperative comparisons between condyle-reconstructed and condyle-preserved patients-were conducted. The mean follow-up was 76.9 (± 19.0) months (range, 60-120). The average age at intervention was 9.23 (± 3.8) years. Mean AI was 15.31 (± 1.81) preoperatively and 3.59 (± 0.97) postoperatively. Differences between preoperative and postoperative measurements were statistically significant in all the assessed parameters (p<0.001). Postoperative differences between the condyle-reconstructed and the condyle-preserved groups were not significant (p>0.05). No secondary procedures were required to enhance symmetry in the late postoperative period. Mandibular reconstruction using the vascularized fibula free flap provides adequate restoration of facial symmetry that could be predictably maintained throughout the developmental period in children and adolescents, regardless of the need for condylar reconstruction.

Reproductive resilience: putting pollen grains in two baskets.

To ensure reproductive success, flowering plants produce an excess of pollen to fertilize a limited number of ovules. Pollen grains mature into two distinct subpopulations - those that display high metabolic activity and elevated reactive oxygen species (ROS) levels immediately after hydration (high-ROS/active), and those that maintain an extended period of dormancy with low metabolic activity (low-ROS/inactive/arrested/dormant). We propose that the dormant pollen serves as a backup to provide a second chance for successful fertilization when the 'first wave' of pollen encounters an unpredictable growth condition such as heat stress. This model provides a framework for considering the role of dormancy in reproductive stress tolerance as well as strategies for mitigating pollen thermovulnerability to daytime and night-time warming that is associated with global climate change.

Regulating Lithium Deposition Behaviors by Functional PVDF‐HFP/NaTi2(PO4)3 Composite Separator

AbstractThe unpredictable growth of lithium (Li) dendrite is one of the crux issues in the commercial application of the Li‐metal batteries (LMBs). Herein, a flexible PVDF‐HFP/LiClO4/NaTi2(PO4)3 (NTP) layer modified polypropylene (PP) separators are designed to achieve homogeneous nucleation and growth of Li. The introduction of NTP particles not only reduces the crystallinity of the polymer but also generates a rapid Li+ migration pathway at the interface, which is conducive to regulating the Li+ flux and guiding the uniform Li deposition by improving ionic conductivity. In addition, because of the high electrolyte wettability and the enhanced mechanical strength of the functionalized separator, the mass transport capability is promoted and the penetration of Li dendrite can be avoided. Consequently, the modified separators with 20 wt% NTP (PP@PHNTP‐20) endow Cu||Li batteries with an excellent average Coulombic efficiency of ≈99%. Furthermore, the long‐term reversible Li plating/stripping can be achieved in the Li symmetric battery, and the LiFePO4 (LFP) ||Li batteries with PP@PHNTP‐20 present high capacity retention and improved C‐rate performance in a carbonate‐based electrolyte without additives.

ВЛИЯНИЕ НЕКОТОРЫХ ПАРАМЕТРОВ ЭКСПЕРИМЕНТАЛЬНОГО ПРОТИВООБЛЕДЕНИТЕЛЬНОГО КОМПЛЕКСА «ФИЛЬТР» НА ЭФФЕКТИВНОСТЬ ЗАЩИТЫ ЭНЕРГЕТИЧЕСКИХ УСТАНОВОК ОТ СНЕГА

Unpredictable growth of ice crust on filters installed in air cleaning devices at the inlet to air supply channels to aircraft drives during operation of gas compressor stations in heavy snowfalls can lead to accidents and downtime. To combat ice growths, an experimental complex "FILTER" was developed. The developed experimental complex makes it possible to conduct interdisciplinary studies of the behavior of snow and ice covers on gas-permeable and deformable surfaces of various types, providing gas-dynamic conditions similar to those that occur near air-cleaning devices. These include precipitation in the form of snow, high relative humidity, negative temperatures at which snow and ice cover forms on the inlet filters. Studies have been carried out on the release of an ice crust formed on protective gas-permeable and deformable surfaces of various types. For its destruction, the energy of a gas-dynamic jet was used. The general design scheme of the experimental anti-icing complex "FIL-TER", the results of experiments and their analysis are presented. Thus, on the experimental anti-icing complex, an assessment was made of the effect on the efficiency of protection of a model power plant from an ice crust of the following parameters: air supply pressure to the nozzle (varied in the range 0.1–0.6 MPa), (changed in the range 7.75–13.5 m/s), the diameter of the gas-tight area and the material of the gas-permeable deformable surface. The most effective combination of parameters is determined. It was found that of the considered gas-permeable deformable surfaces, the option with a plastic mesh demonstrated the highest efficien-cy with the following flow parameters: jet pressure P ≥ 0.5 MPa, air flow velocity 13.5 m/s, gas-tight area diameter 50 mm.

A key management scheme using (p, q)-lucas polynomials in wireless sensor network

Wireless Sensor Network (WSN) has witnessed an unpredictable growth for the last few decades. It has many applications in various critical sectors such as real-time monitoring of nuclear power plant, disaster management, environment, military area etc. However, due to the distributed and remote deployment of sensor nodes in such networks, they are highly vulnerable to different security threats. The sensor network always needs a proficient key management scheme to secure data because of resource-constrained nodes. Existing polynomial based key management schemes are simple, but the computational complexity is a big issue. Lucas polynomials, Fibonacci polynomials, Chebychev polynomials are used in Engineering, Physics, Combinatory and Numerical analysis etc. In this paper, we propose a key management scheme using (p, q)-Lucas polynomial to improve the security of WSN. In (p, q)-Lucas polynomial, p represents a random base number while q represents a substitute value of × in the polynomial. The value of p is unique, and q is different according to communication between nodes. Analysis of the proposed method on several parameters such as computational overhead, efficiency and storage cost have been performed and compared with existing related schemes. The analysis demonstrates that the proposed (p, q)-Lucas polynomial based key management scheme outperforms over other polynomials in terms of the number of keys used and efficiency.

Craniopharyngiomas

Craniopharyngiomas are rare epithelial tumours situated primarily in the sellar/parasellar region, occurring along the path of the craniopharyngeal duct. Whilst classed as histologically benign tumours, their unpredictable growth pattern and proximity to vital structures including the optic chiasm, hypothalamus, and pituitary gland renders them a considerable threat, with significant associated morbidity and increase in mortality. Occurring both in child and adulthood, their clinical manifestations are broad, commonly with symptoms/signs secondary to hypothalamic-pituitary dysfunction, raised intracranial pressure and visual compromise. They have two distinct histological subtypes (adamantinomatous and papillary), with unique patterns of age distribution, and genetic and molecular make-up. With increasing understanding of their genetic pathogenesis including BRAF V600E mutations in the papillary subtype, and β-catenin mutations in the adamantinomatous, further research provides hope for the discovery of targeted medical therapy that can exploit molecular changes occurring as a result of such alterations. Until then, primary treatment consists of surgery with or without radiotherapy, with intracystic aspiration, chemotherapy or irradiation being alternative options in selected patients. Long term management by an experienced multidisciplinary team is essential, given the breadth of complications, including hypothalamic morbidity, visual compromise, cognitive and neuropsychological sequelae and impairment to quality of life.

Numerical simulation for growing Large-scale and High-quality Zinc germanium phosphide crystals

The mid-infrared nonlinear crystals have shown great promise for the usage in the fields of sum frequency generation, optical parametric amplifier and optical parametric oscillator. These motivations are empowered by high-quality ZnGeP2 optical devices with high second-order dielectric susceptibility, thermal conductivity and hardness. However, the rapid development of large-sized ZnGeP2 single crystals with high optical quality is limited by traditional time-consuming and unpredictable growth route. Herein, for the first time, a strategy of comprehensive unsteady computer modeling is implemented to stimulate the Vertical Bridgman growth process of large-sized ZnGeP2 single crystal by the Crystal Growth Simulator (CGSim) software. The accurate simulations of temperature field, crystal growth rate, crystallization interface shape and thermal stress evolution are achieved by using this established numerical model. The accuracy and feasibility have been confirmed by the agreement between stimulated and experimental results of the temperature field curves and crystallization interface shape. The optimal parameters for growing large-sized (Φ = 60 mm) ZnGeP2 single crystal are determined: pulling speed of 0.3 mm/h, temperature gradient of 5 K/cm and slow cooling regime. The large-sized (Φ = 60 mm) ZnGeP2 single crystal with better quality is thus successfully obtained in the crystal-growth experiment in our lab, further verifying the accuracy of the constructed numerical model. Our work provides a new way to predict and guide the growth of large ZnGeP2 single crystal and other similar single crystals.

Does no-intraoperative correction of chin deviation prevent costochondral graft overgrowth in pediatric temporomandibular joint ankylosis management - an intermediate outcome study

The use of costochondral graft is controversial for pediatric temporomandibular joint reconstruction due to its unpredictable growth. The height of the cartilage is directly responsible for the growth capacity of costochondral graft. Even after keeping the cartilage in costochondral graft to a recommended height, overgrowth has been reported. Traditionally during costochondral graft fixation, chin deviation is corrected intraoperatively. The investigators hypothesized that this intraoperative manipulation of mandible to correct chin deviation and maintaining the chin in new position causes excessive stress and strain in the muscular functional matrix. The authors believe that this may be the reason for excessive growth trigger on the grafted side. This study intends to prove the hypothesis of no-intraoperative correction of chin deviation can prevent overgrowth of the costochondral graft. We implied this technique in pediatric temporomandibular joint ankylosis patients managed with osteoarthrectomy and reconstructed with costochondral graft. Patients with at least a follow-up of 30-months were included in the study. The study sample consisted of 20 patients. All the patients had adequate growth with improvement in facial asymmetry. The results of the present study supports our hypothesis of no-intraoperative correction of chin deviation as a technique to prevent overgrowth of costochondral graft. We recommend this technique to allow catch-up of growth rather than acceleration of growth. This change in technique needs more research, randomized controlled trial for reliability and long-term results.

Abstract 1138: PRMT5 inhibition downregulates MYB and NOTCH1 signaling, key molecular drivers of adenoid cystic carcinoma

Abstract Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands, characterized by slow and unpredictable growth, unrelenting relapse and high rates of metastasis. Poor response to chemotherapy and targeted drugs has resulted in there being no approved therapies to date, which contributes to poor prognosis with less than a 20% 5-year survival rate in patients with high-risk ACC. A vast majority of ACC tumors are known to have recurrent chromosomal translocation t(6;9) or t(8;9) resulting in MYB/MYBL1-NFIB fusions, and high levels of MYB protein expression. Furthermore, a subset of ACC tumors expresses NOTCH1 activating mutations (20-25%) and hyperactive NOTCH signaling in both primary and recurrent/metastatic tumors. A previous report has demonstrated that an inhibitor of PRMT5 (protein arginine methyltransferase) shows favorable responsiveness in patients with advanced ACC in a phase I clinical trial. Here, we investigate mechanistic aspects as to how PRMT5 inhibition potentially regulates the unique molecular drivers of ACC tumor growth. Due to a limited number of validated in vitro cellular models, we selected a group of head and neck cancer cell lines, including those originating from salivary gland, along with MYB and NOTCH1-driven leukemia models, to evaluate the effects of PRMT5 inhibition on MYB and NOTCH regulated genes. Treatment with PRT543, a potent and selective PRMT5 inhibitor, decreased expression of MYB and its associated downstream gene GATA3, as well as ACC-related genes such as SOX4 and POU3F2. Furthermore, PRT543 downregulated MYB signaling (MYB, FOXM1, NIK and SKI) as well as MYB alternative isoforms MYB-9A and MYB-10A in MYB expressing leukemia cells. Intriguingly, treatment with PRT543 also downregulated the transcription factor, HSF4, that is uniquely linked to regulation by N-terminal truncated MYB, a variant driven by an alternative promoter (TSS2) and reported as being active in ACC tumors. In addition to regulation of MYB, we also show that PRT543 downregulates NOTCH1 expression as well as multiple NOTCH1 target genes in leukemia cells which harbor a NOTCH1 active mutation. Given these results, we investigated the ability of PRT543 to inhibit the growth of ACC PDX tumor models in vivo and demonstrate that PRT543 significantly inhibits the growth of ACC PDX tumors in vivo. We confirmed that PRT543 downregulates levels of global symmetric dimethylarginine (sDMA, a substrate of PRMT5) in the treated tumors. Further studies with PRT543 in ex vivo and in vivo ACC models are ongoing. Collectively, these findings provide a strong molecular rationale for exploring PRT543 as a potential therapeutic option for ACC tumors. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831). Citation Format: Jack Carter, Koichi Ito, Venkat Thodima, Neha Bhagwat, Joseph Rager, Nicole Spardy Burr, Jeffrey Kaufman, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. PRMT5 inhibition downregulates MYB and NOTCH1 signaling, key molecular drivers of adenoid cystic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1138.

Increasing the capacity of water distribution networks using fitness function transformation

Even the most carefully designed water distribution network (WDN) can suffer from local capacity deficiencies as a result of the quick and unpredictable growth of the urbanization of new industrial sites. To solve this problem, this paper focuses on the identification of the best possible location for a new pipeline within an existing WDN, which maximizes the node-wise capacity. To determine the optimal solution, a parameter, namely pressure sensitivity, is defined, which can localize nodes with local capacity problems computationally efficiently. During our research, a fitness function transformation technique was defined, which increases the effectivity of the optimization on a larger scale by the formulation of a feasible fitness function. Combining this technique with an extended version of the genetic algorithm, the topology of eleven real-life WDN was optimized. A scrutiny is performed on three networks, highlighting typical deficiencies.