Intermediate Stage Of Development Research Articles

Developmental hourglass: Verification by numerical evolution and elucidation by dynamical-systems theory.

Determining the general laws between evolution and development is a fundamental biological challenge. Developmental hourglasses have attracted increased attention as candidates for such laws, but the necessity of their emergence remains elusive. We conducted evolutionary simulations of developmental processes to confirm the emergence of the developmental hourglass and unveiled its establishment. We considered organisms consisting of cells containing identical gene networks that control morphogenesis and evolved them under selection pressure to induce more cell types. By computing the similarity between the spatial patterns of gene expression of two species that evolved from a common ancestor, a developmental hourglass was observed, that is, there was a correlation peak in the intermediate stage of development. The fraction of pleiotropic genes increased, whereas the variance in individuals decreased, consistent with previous experimental reports. Reduction of the unavoidable variance by initial or developmental noise, essential for survival, was achieved up to the hourglass bottleneck stage, followed by diversification in developmental processes, whose timing is controlled by the slow expression dynamics conserved among organisms sharing the hourglass. This study suggests why developmental hourglasses are observed within a certain phylogenetic range of species.

HISTONE DEACETYLASE19 Controls Ovule Number Determination and Transmitting Tract Differentiation.

The gynoecium is critical for the reproduction of flowering plants as it contains the ovules and the tissues that foster pollen germination, growth, and guidance. These tissues, known as the reproductive tract (ReT), comprise the stigma, style, and transmitting tract (TT). The ReT and ovules originate from the carpel margin meristem (CMM) within the pistil. SHOOT MERISTEMLESS (STM) is a key transcription factor for meristem formation and maintenance. In all above-ground meristems, including the CMM, local STM downregulation is required for organ formation. However, how this downregulation is achieved in the CMM is unknown. Here, we have studied the role of HISTONE DEACETYLASE 19 (HDA19) in Arabidopsis (Arabidopsis thaliana) during ovule and ReT differentiation based on the observation that the hda19-3 mutant displays a reduced ovule number and fails to differentiate the TT properly. Fluorescence-activated cell sorting coupled with RNA-sequencing revealed that in the CMM of hda19-3 mutants, genes promoting organ development are downregulated while meristematic markers, including STM, are upregulated. HDA19 was essential to downregulate STM in the CMM, thereby allowing ovule formation and TT differentiation. STM is ectopically expressed in hda19-3 at intermediate stages of pistil development, and its downregulation by RNA interference alleviated the hda19-3 phenotype. Chromatin immunoprecipitation assays indicated that STM is a direct target of HDA19 during pistil development and that the transcription factor SEEDSTICK is also required to regulate STM via histone acetylation. Thus, we identified factors required for the downregulation of STM in the CMM, which is necessary for organogenesis and tissue differentiation.

Why We Fail: An Analysis of Terminated Interventional Clinical Trials in Lymphoma

Introduction: Clinical trials serve as the cornerstone for advancing therapeutic and clinical strategies in Lymphoma. Learning from prematurely terminated trials provides valuable insights for researchers and drug developers. This study analyses interventional clinical trials in lymphoma terminated between 2010 and 2023, aiming to identify common factors contributing to their failure and improve future research in Lymphoma. Methods The study identified clinical trials in Lymphoma registered in the US between 01/01/2010, and 01/07/2023, using the InovaSight platform. The analysis included trials investigating drugs in phases I-III with at least one recruited patient. Phase 4 studies, early access programs, and trials examining medical devices were excluded, as were trials terminated early due to positive efficacy signals. Natural language processing (NLP) & classification algorithms were used to categorize trials into distinct phases of clinical development and were also applied to identify reasons for trial termination from official registrations and relevant publications. These reasons were then characterized using the InovaSight trial ontology for thematic analysis. Enriching features, including mechanism of action information, design characteristics, target enrolment, and inclusion criteria, were generated and linked for each eligible trial. The analysis was conducted using the InovaSight drug development platform, which employs responsible artificial intelligence to expedite the development of novel therapeutics for haematological malignancies. Results: A total of 306 trials met the inclusion criteria, with phase II trials being most frequently withdrawn (49.3%), followed by phase I (42.5%) and phase III (8.2%). The trials spanned from 2010-01-31 to 2021-12-15. Among terminated studies, single-arm trials were most frequent (64%), followed by two-armed designs (21.2%) and three or more arms (14.7%). A concentration of mechanisms of action were observed across all phases (further described in poster). Reasons for early termination included enrolment issues, sponsor decisions, lack of efficacy, safety concerns, funding withdrawal, investigator-related issues, study irrelevance, drug supply problems, COVID-19, and unspecified reasons. The most common reason for early termination was enrolment issues in Phase I and Phase II studies, and sponsor decisions in Phase III studies. Detailed results are presented in Figure 1. Discussion: Our analysis identified a total of 306 trials that met the inclusion criteria, encompassing different phases of clinical development. Interestingly, phase II trials were the most frequently withdrawn, followed by phase I and phase III trials. This observation suggests that a considerable number of trials face challenges during the intermediate stages of development, which could be attributed to various factors such as safety concerns, lack of efficacy, or financial constraints. Our analysis revealed a concentration of similar mechanisms of action across all trial phases. This finding suggests that certain therapeutic areas or drug targets may be more prone to early termination. Exploring the underlying reasons for this pattern could provide valuable insights for future trial planning and design (This is further elucidated in the full presentation). Among the various reasons for early termination, enrolment issues emerged as the most common factor in both Phase I and Phase II studies. This highlights the critical need for in depth and principled approaches to study feasibility assessment routed in an evidence-based methodology. In contrast, sponsor decisions were the leading cause of termination in Phase III trials. This finding suggests that late-stage trials are more susceptible to decisions made by the trial sponsors, which could be influenced by factors such as financial considerations or market dynamics. The results underscore the importance of careful trial planning, patient recruitment strategies, and effective collaboration between sponsors, investigators, and regulatory bodies. Understanding the challenges and factors contributing to trial termination can aid in optimizing future trial designs, mitigating risks, and improving the efficiency of drug development processes.

Transgenic Mouse Model for Translational Immunotherapy Studies on Multiple Myeloma

Background Genetically engineered mouse models that recapitulate key immunological features of human multiple myeloma may lend themselves to preclinical design and testing of novel immune therapies that target members of the tumor necrosis factor (TNF) receptor superfamily in addition to BCMA. One model of this sort are double-transgenic IL6Myc mice that spontaneously develop myeloma-like plasma cell tumors (PCTs) with full genetic penetrance (100% tumor incidence) and relatively short latency (4-5 months) in presence of an intact innate and adaptive immune system (Rutsch et. al. Blood 2010). IL6Myc mice exhibit serum M-spikes, respond to proteasome inhibition, and develop osteolytic lesions mimicking myeloma bone disease (Duncan K et. al. Blood Cancer J 2013, Sun F et. al. Haematologica 2020). Here, we examined changes in the immune tumor microenvironment during PCT progression in IL6Myc mice. We found that neoplastic plasma cell development was accompanied by accumulation of inhibitory T cells, T cell exhaustion, and elevated serum levels of MIP-3α and MCP-5. A subset of aberrant plasma cells expressed the TNF receptors, TACI and BAFF-R, which, together with their ligands, APRIL and BAFF, may serve as immunotherapeutic targets in myeloma not responding to BCMA-targeted treatment (Wong DP et. al. Nat Commun 2022, Braunstein M et. al. Expert Rev Hematol 2021). Materials and methods Double-transgenic IL6Myc mice were bred by intercrossing homozygous transgenic C.iMyc ΔEμ (Duncan K et. al. Blood Cancer J 2013) and heterozygous transgenic C.IL6 mice (Kovalchuk AL. et. al. Proc Natl Acad Sci USA 2002). Age-matched IL6Myc mice were investigated at an early (5-7 weeks), intermediate (10-12 weeks) and late (14-17 weeks) stage of PCT development using flow cytometry (Cytek Aurora) and serum cytokine levels (Bio-Plex) as main research tools. Results Bone marrow (BM) plasma cells, defined as CD45-gated B220 -CD138 + cells, increased during PCT development, as one might have expected: 10.5 ± 5.8% and 26.8 ± 6.4% ( p< 0.05) in early- and late-stage mice, respectively. The proportion of B220 +CD19 + B cells fell accordingly: 29.6 ± 4.1% vs 5.5 ± 4.9% ( p< 0.0001). Consistent with the notion that the BM microenvironment of PCT-bearing mice is immunosuppressive, there was a 2-fold elevation of TGF-β expressing T cells and a 4-fold elevation of IL-10 expressing T cells in the BM when late-stage mice were compared to early-stage mice. A sizeable fraction of aberrant plasma cells expressed TACI and BAFF-R in addition to BCMA ( Figure 1, left). Spleens of IL6Myc mice undergoing tumor development contained increasing numbers of FoxP3 + regulatory T cells (8.6 ± 2.1% at early stage vs 14.0 ± 4.6% at late stage, p< 0.05) and CD11b +Ly-6G/C + myeloid-derived suppressor cells (21.2 ± 9.2% vs 51.6 ± 10.1%, p< 0.01). Exhausted T cells, detected via expression of PD-1, TIM-3, LAG-3 and TIGIT, increased in sync with PCT progression ( Figure 1, right). Elevated serum levels of inflammatory cytokines, including MIP-3α (95.3 ± 41.9 pg/ml in early-stage mice vs 514 ± 279 pg/ml in late-stage mice, p< 0.01) and MCP-5 (121 ± 43.9 pg/ml vs 284 ± 70.5 pg/ml, p< 0.05), agreed with flow-based tissue data. Conclusion Neoplastic plasma cell development in IL6Myc mice takes place in an immune suppressed tumor microenvironment similar to that promoting human myeloma. IL6Myc-driven PCTs may provide a good experimental model system for novel immunotherapeutic approaches that target TACI and BAFF-R or their ligands, APRIL and BAFF. Previous work to that end holds great promise but has been challenging thus far (Goodman DB et. al. Sci Transl Med 2022, Lee L et. al. J Immunother Cancer 2023).

Evaluation of startups through Internet platforms

The situation in the venture capital market is continually changing, as evidenced by the statistics on the use of venture investment pools. Experienced investors, reducing their risks, give preference to firmly established startups that are at intermediate and late stages of development, as well as those in the sphere of IT development and high technologies. This approach leads to a situation when investors do not notice quite a number of interesting, impressive and promising projects at their early and seed stages. In this regard, it is relevant to consider some methods aimed at the evaluation of startups at different stages of their development. The traditional methods of evaluating projects with no operational history are not suitable. The instruments for preparing startup business plans as well as discounting and compounding tools are relevant up to the entry point of the search for financial resources. In a real situation, a perspective innovative startup risks to be taken over as a result of the only available way of mobilising resources – through the inclusion of investors in the startup owners (shareholders) pool. Other traditional sources – internal funds and bank loans – limit a startup’s resource, most often at the seed stage, due to their limited scope and high cost of borrowed capital. As a rule, the borrowed capital in the form of bank loan is basically unavailable for startup initiation due to no ways to ensure repayment guarantees, while the possibility of relying on a business plan for a startup in the process of raising bank funds is a common misconception. In recent years, the impact of the development of specific Internet resources on the structure of investment in economy has been tangible. In addition to innovative ideas in entrepreneurship, a number of instruments specific of new processes in investing are being realised. Business angels, accelerators, startup-oriented Internet resources are shifting to the mechanisms of remote assessment of startup potential and its subsequent funding.

The underestimation and evolutionary significance of post-imaginal growth in the termitophilous Termitogastrina: Insights from a new species of Xenogaster from Brazil (Staphylinidae: Aleocharinae: Corotocini)

Xenogaster Wasmann is a Neotropical genus of termitophilous rove beetles with 11 known species. During recent surveys in Southeastern Brazil, we collected a new species of this genus, Xenogaster lugens Pires-Silva and Zilberman sp. nov., herein described. This new species is known only from an intermediate stage of development, which prompted a discussion about the range and underestimation of the phenomenon of post-imaginal growth in Termitogastrina (Corotocini). A redescription of X. pilosula Seevers, and comparisons between its stenogastric and physogastric stages are also presented and used in the final discussion on the taxonomical and evolutionary significance of this phenomenon under the frame of the knowledge of post-imaginal growth in the subtribe and also Corotocini in general.

Potential marine benthic colonisers of offshore wind farms in the English channel: A functional trait-based approach

Offshore wind farms (OWFs) have gained attention as a promising alternative to conventional energy sources. However, their installation and operation may have multiple ecological impacts on the marine environment, including the “reef effect”. The reef effect is the colonisation of wind turbines and other artificial substrates by benthic organisms, which has a major impact on marine biodiversity as it changes community assemblages and ecosystem functioning. We conducted a two-step study to predict the reef effect of a future OWF (Dunkirk, northern France). First, we explored similarities between colonisers of existing OWFs and those of other hard substrates (oil and gas platforms (O&GP) and hard substrates in the English Channel (HSEC)). We then analysed functional traits to determine a trait profile of potential colonisers of Dunkirk's OWF. Statistical analyses revealed that OWF and O&GP communities were more similar to each other than to that of HSEC. Comparing the three communities revealed that they shared 157 taxa, which could be potential colonisers of Dunkirk's future OWF. The functional profile revealed that OWF colonisers were species ranging from 10 to 100 mm in size, with gonochoric reproduction, pelagic and planktotrophic larvae, a life span of less than 2 years or 5–20 years, were sessile, and were carnivores or suspension feeders. Functional trait analysis revealed that during their intermediate stage of development, OWF benthic communities have a functional richness and diversity (0.68 and 0.53, respectively) similar to those of HSEC communities (0.54 and 0.50, respectively). However, based on using O&GP as a long-term view of the colonisation of OWFs, functional richness and diversity could decrease during the climax stage (0.07 and 0.42, respectively).

Sympetaly in the mimosoid clade (Leguminosae, Caesalpinioideae): An unusual trait in the rosid group

Sympetaly is a notable feature within the mimosoid clade (Leguminosae: Caesalpinioideae), specially as it is uncommon in rosids. The way the petals are organized, forming a tubular corolla by the union of the petals directly affects the perception of pollinators. This study examines whether the petal union leading to a sympetalous corolla in the mimosoid clade is widespread and whether there is variation in type and extent. For this purpose, floral buds and flowers of 16 species from 13 genera were collected, fixed, and processed for analysis by light and scanning electron microscopy. Most species studied display a pentamerous sympetalous corolla with free lobes. The petal primordia are individualized and emerge simultaneously on the floral apex, alternating with the sepal primordia. Petals remain free at the beginning of the intermediate stages of development, and subsequently, the petals curve and approach each other, and their margins touch. Epidermal papillae are found on the petals’ apical margin interconnecting the lobes, which enclose the inner organs of the floral bud. The structure of the sympetalous corolla is variable regarding the type and extent of the union. Four different types of sympetaly were found and classified as follows: 1. full connation - petals fully united along their length; 2. connation-coherence - petals genuinely united in the basal portion and coherent in the median and apical portion; 3. full coherence - petals intertwined with papillae throughout; and 4. partial coherence - free petals at the base and intertwined with papillae in the middle and apical portion. Thus, sympetaly of mimosoid legumes results from postgenital union of the petals at the apical, median, and basal regions during their development by tissue union (connation), intertwining of epidermal papillae (coherence), or both processes. The mucilage cells found along the petals guarantee the stabilization and flexibility of the tubes, in addition to contributing to the protection of the internal organs of the flower. Although more studies on floral development are needed to understand the evolution of this unusual trait, connation appears to be a derived trait within mimosoids.

Early-life experience reorganizes neuromodulatory regulation of stage-specific behavioral responses and individuality dimensions during development.

Early-life experiences may promote stereotyped behavioral alterations that are dynamic across development time, but also behavioral responses that are variable among individuals, even when initially exposed to the same stimulus. Here, by utilizing longitudinal monitoring of Caenorhabditis elegans individuals throughout development we show that behavioral effects of early-life starvation are exposed during early and late developmental stages and buffered during intermediate stages of development. We further found that both dopamine and serotonin shape the discontinuous behavioral responses by opposite and temporally segregated functions across development time. While dopamine buffers behavioral responses during intermediate developmental stages, serotonin promotes behavioral sensitivity to stress during early and late stages. Interestingly, unsupervised analysis of individual biases across development uncovered multiple individuality dimensions that coexist within stressed and unstressed populations and further identified experience-dependent effects on variation within specific individuality dimensions. These results provide insight into the complex temporal regulation of behavioral plasticity across developmental timescales, structuring shared and unique individual responses to early-life experiences.

Controlled cultivation of different stages of Pyropia orbicularis (Rhodophyta; Bangiales) from the South Pacific coast

The species of the genus Pyropia have a diplohaplontic life cycle, in which there is a gametophytic phase (n) or blade, and a microscopic sporophytic phase (2n), known as conchocelis, as well as intermediate stages of development. Pyropia species, together with Porphyra species, belong to the group of the most commercialized and produced macroalgae worldwide, mainly due to their high nutritional value and high content of bioactive compounds with antioxidant and anti-inflammatory activity. The interest in cultivating and exploiting this marine resource has increased in recent years; nevertheless, despite the development of cultivation techniques and technologies for these species, there are still difficulties involved in their successful cultivation, mainly related to the great interspecific and intraspecific variability in the required culture conditions. In this work, we study the life cycle development of Pyropia orbicularis, a species endemic to the South Pacific, to determine the effect of abiotic culture parameters, such as the temperature and photoperiod, on the formation and development of early and late life cycle stages, such as conchocelis formation, cochoesporangial filaments, conchospore release and blade growth. Our results demonstrate that the conchocelis phase grew rapidly under 8:16 h (L:D) photoperiod conditions at both 15 °C and 20 °C. The lower temperatures favored the formation of conchosporangia and conchospores; the rate of their development was increased at 15 °C. The development of the blades in the suspended culture system was constant during the experimental period, generating blades of the same color and shape as those from natural populations. Our results reflect the adaptation of P. orbicularis to the seasonal environmental conditions it is exposed to and the importance of maintaining optimal abiotic parameters for the success of its culture. This work is the first to describe the full life cycle development of P. orbicularis under controlled conditions, which has important implications for commercial production.

In-planta transient transformation of avocado (Persea americana) by vacuum agroinfiltration of aerial plant parts

Avocado, Persea americana Mill, is one of the most traded tropical fruits in the international market. To date, stable and transient transformation has only been achieved for of zygotic embryos and not of adult plant tissue, which limits functional genomics research. We provide the first transient Agrobacterium-mediated transformation methodology in avocado leaves that overcomes the recalcitrance to transformation of this species. We investigated the effect of Agrobacterium strain, leaf stage, wounding pre-treatment, the phytohormone jasmonic acid, and vacuum infiltration on transient transformation of avocado leaves. Using the Agrobacterium strain LBA4404 and the RUBY reporter a transformation frequency of up to 27% was obtained for avocado detached leaves. The transformation efficiency depended on the age of the leaf, with an intermediate stage of leaf development showing the highest efficiency of transient reporter gene expression. Microwounding pre-treatment facilitates agroinfiltration and coupled with leaf age are the primary factors influencing competence for transient transformation. Jasmonic acid did not significantly affect transient transformation in the absence of microwounding. However, microwounding and 250 µM of jasmonic acid acted synergistically to significantly enhance transient expression. Using this methodology with localized vacuum agroinfiltration, transient transformation of attached avocado leaves was achieved. This method unlocks the use of Agrobacterium-mediated transient transformation as a tool for explore gene function and metabolic pathways in both, detached and attached avocado leaves.

Testing geometry and 3D perception in children following vision restoring cataract-removal surgery.

As neuroscience and rehabilitative techniques advance, age-old questions concerning the visual experience of those who gain sight after blindness, once thought to be philosophical alone, take center stage and become the target for scientific inquiries. In this study, we employ a battery of visual perception tasks to study the unique experience of a small group of children who have undergone vision-restoring cataract removal surgery as part of the Himalayan Cataract Project. We tested their abilities to perceive in three dimensions (3D) using a binocular rivalry task and the Brock string task, perceive visual illusions, use cross-modal mappings between touch and vision, and spatially group based on geometric cues. Some of the children in this study gained a sense of sight for the first time in their lives, having been born with bilateral congenital cataracts, while others suffered late-onset blindness in one eye alone. This study simultaneously supports yet raises further questions concerning Hubel and Wiesel's critical periods theory and provides additional insight into Molyneux's problem, the ability to correlate vision with touch quickly. We suggest that our findings present a relatively unexplored intermediate stage of 3D vision development. Importantly, we spotlight some essential geometrical perception visual abilities that strengthen the idea that spontaneous geometry intuitions arise independently from visual experience (and education), thus replicating and extending previous studies. We incorporate a new model, not previously explored, of testing children with congenital cataract removal surgeries who perform the task via vision. In contrast, previous work has explored these abilities in the congenitally blind via touch. Taken together, our findings provide insight into the development of what is commonly known as the visual system in the visually deprived and highlight the need to further empirically explore an amodal, task-based interpretation of specializations in the development and structure of the brain. Moreover, we propose a novel objective method, based on a simple binocular rivalry task and the Brock string task, for determining congenital (early) vs. late blindness where medical history and records are partial or lacking (e.g., as is often the case in cataract removal cases).

Circ_0000284: A risk factor and potential biomarker for prehypertension and hypertension.

CircRNAs have been shown to be involved in the development of certain diseases, but their application in prehypertension and hypertension remains unclear. We aimed to explore the potential role of circ_0000284 in revealing the molecular regulatory mechanisms of prehypertension and hypertension. We enrolled a total of 100 patients with normal blood pressure, 100 patients with prehypertension and 100 patients with hypertension. The expression of circ_0000284 among the groups was detected by real-time fluorescence quantitative polymerase chain reaction (qRT‒PCR). Multivariate logistic models were constructed combining conventional risk factors with circ_0000284. A receiver operating characteristic curve (ROC) was used to analyze the diagnostic value of circRNAs in the clinical model. Spearman correlation was used to analyze the correlation of circ_0000284 and the biochemical characteristics of all subjects. The results showed that circ_0000284 was differentially expressed among the normal blood pressure group, prehypertensive group and hypertensive group and showed a significantly upregulated trend in the progression to hypertension (P < 0.05). The ROC curve revealed a high diagnostic ability of circ_0000284 in hypertension in the clinical model (AUC = 0.812). Circ_0000284 also presented a certain ability for early diagnosis of prehypertension (AUC = 0.628). Spearman correlation showed that circ_0000284 was positively correlated with Na and CKMB. Our study suggested that upregulated expression of circ_0000284 was an independent risk factor for prehypertension and hypertension. Circ_0000284 was a potential fingerprint for the early diagnosis of hypertension and distinguished the intermediate stage of hypertension development. Moreover, our study provided new insight into the correlation between circ_0000284 and cardiac injury in the progression to hypertension.

Feasibility of Advanced Vehicle Control Systems (AVCS) for Transit Buses

In the course of developing automated vehicle-roadway systems, opportunities to deploy vehicle control systems at intermediate stages of development may emerge. Some of these systems may provide a significant efficiency or safety enhancement to existing operations with manually-driven vehicles. Under certain circumstances, transit buses provide an ideal testbed for such systems. The work presented here represents a feasibility study for the application of Advanced Vehicle Control Systems (AVCS) to transit bus operations. The paper explores past and present research relevant to automatic control for buses and describes specific operations that could be better performed by AVCS-assisted or controlled vehicles.The study concludes with a series of recommendations for proceeding toward a deployment phase. For transit bus operations, the most suitable deployment opportunities for AVCS exist on exclusive busways (bus-only roads) or large bus servicing facilities used for daily maintenance operations. Busways would provide an excellent testing ground for a lateral control/lane keeping system. Such a system would provide immediate utility on the existing busway and would serve as a building block for more highly automated systems in the future. Maintenance operations in service garages require dedicated drivers to move vehicles through a routine servicing sequence. By fully automating the movement of buses within such facilities, labor costs could be dramatically reduced.

Chemometrics aided energy dispersive X-ray fluorescence and scattering for diagnostic modeling of trace biometals as cancer biomarkers

Direct analysis of biometals in biomedical samples by energy dispersive X-ray fluorescence (EDXRF) for disease diagnostics has hardly been fully explored due to dark matrix analytical challenges. In this study, we exploited multivariate chemometrics modeling of cancer diagnostics in model human tissue simulates and cultures using selected biometals’ (Mn, Fe, Cu, Zn and Se) fluorescence and Compton scatter profiles. PCA successfully reduced the correlated data dimension to uncorrelated datasets for the characterization of the cell cultures. Artificial neural network (ANN) enhanced the classification of cancer staging and the development of a multivariate calibration strategy for the quantification of trace elements. ANN characterized cancer into early, intermediate, and advanced stages of development. Low concentrations of Fe (101 ± 28 ppm), Zn (59 ± 4 ppm) and Cu (21 ± 1 ppm) were evident in SV10 due to the lag phase stage of cancer development. Further, strong correlation (0.976) was evident in early-stage cancer between Zn and Se but with strong negative correlations between Mn and Se (−0.973) and between Mn and Zn (−0.900) probably due to their antioxidant effects. The results show predictable and systematic associations between the concentrations of Fe, Cu, Zn, Se and Mn as cancer biomarkers with the potential to be used for cancer diagnosis at the early stage of development.

The Relevance of Diachronic Approach to Grammaticalization Research

The present paper proves the relevance of the diachronic approach to grammaticalization research. The article contains defi nitions of the concept of grammaticalization and makes a distinction between diachronic and historical grammar. The theoretical review is based on research carried out by such scholars as I.A. Baudouin de Courtenay, W. von Humboldt, E. Kuryłowicz, B. Heine, Ch. Lehmann, E. Traugott, J. Bybee and others. Grammaticalization is defi ned as a process whereby lexical units turn into grammatical units or the latest increase their grammatical status. It is noted that a diachronic approach to this process enables researchers to identify the grammaticalization sources, fi nd out the patterns and possible ways of development of universal grammaticalization paths in diff erent languages and prove the unidirectionality hypothesis. This approach also provides the explanatory value of a linguistic theory, allows us to identify the cognitive and communicative factors, analyze the dynamics of grammatical changes and fi nd out the similarities between languages in the most explicit way. Based on the example of the English grammaticalized construction be going to, it is proved that the grammaticalization process is gradual and requires a diachronic approach for a more comprehensive analysis of intermediate stages of development of grammatical units.

Abstract 1611: Temporal recapitulation of genome instability in an iPSC model of osteosarcoma

Abstract Osteosarcoma (OS) is characterized by widespread genomic instability, with cellular transformation associated with extensive structural (SV) and copy number variation (CNV). TP53 and RB1 mutations contribute to the initiation and maintenance of genome instability, which serves as a key driver of relapse. Significant effort has been made to model OS genome instability; however, current models have limited capacity to recapitulate genomic instability in real time. To model OS initiation and development, TP53 and RB1 mutations were installed in human iPSC using CRISPR/Cas9, followed by differentiation to mesenchymal (iMSC) and osteoblast (iOB) lineages in vitro. Functional assays of transformation were then conducted at intermediate stages of development for each genotype. Compared to isogenic WT controls, TP53-/- and TP53-/-/RB1-/- iOB exhibited increased proliferation, whereas anchorage independent growth was only observed in TP53-/-/RB1-/- iOB. Overexpression of cMYC and hRAS significantly increased the magnitude of these results in iOB. In contrast to iOB, TP53-/-/RB1-/- iMSC did not form colonies without cMYC and hRAS overexpression. To evaluate this phenomenon in vivo, iMSC and iOB were injected into the calcaneal bone of immunodeficient mice. Consistent with our in vitro observations, TP53-/-/RB1-/- and TP53-/-/RB1-/-+cMYC/hRAS iOB, and TP53-/-/RB1-/-+cMYC/hRAS iMSC gave rise to tumors. Histological evaluation of MSC-derived tumors revealed a largely undifferentiated pleomorphic phenotype, with a progressive increase in complexity in tumors derived from later stage iOB. Global gene expression signatures of xenografted tumors bore a striking similarity to OS patient samples compared to other pediatric tumors. In follow-on experiments, a progressive increase in cytogenetic abnormalities were observed in mutant but not WT iMSC, which became more pronounced in mutant iOB and correlated with a transformed phenotype. We are currently evaluating the temporal kinetics of this process, including through the use of low-coverage whole genome sequencing to elucidate the existence of recurrent patterns. These data highlight the utility of our iPSC approach as a novel model of OS, allowing for the first time the ability to study the evolution of genome instability in real time. We envision that this approach may uncover heretofore undiscovered common patterns underlying the seemingly chaotic nature of OS genomes, providing new opportunities for therapeutic intervention. Citation Format: Kelsie Lynn Becklin, Rebecca Madden, Lauren Mills, Nicole Thue, Nathan Carroll, Anthony DeFeo, Branden Moriarity, Beau Webber. Temporal recapitulation of genome instability in an iPSC model of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1611.

Dynamic linkages of empowering and transformational leadership with knowledge sharing in project teams

ABSTRACT Previous research has studied the effect of leadership on knowledge sharing and has consistently found empowering and transformational leader behaviours to be important. However, there is lack of theoretical guidance on how the influence of leadership on knowledge sharing unfolds over time. This paper proposes a conceptual model that identifies key antecedents of knowledge sharing across different stages of life span of a project team. The conceptual model focuses on the influence of empowering and transformational leaders in each stage of team development. This paper argues that the influence of empowering and transformational leadership on knowledge sharing varies over time in a curvilinear manner such that the influence is limited during the initial and final stages but is relatively high in the intermediate stages of team development. This paper identifies the key mediators of the relationship between empowering/transformational leadership and knowledge sharing in project teams at different stages.

Structure of the upper crust at the axis segmentation stage of rift evolution as revealed by gravity data: Case study of the Gedemsa magmatic segment, Main Ethiopian Rift

The upper crustal structure of the individual tectono-magmatic segments within the Main Ethiopian Rift is poorly understood. The Gedemsa tectono-magmatic segment (GTMS) is considered to be within an intermediate stage of rift development with magma-assisted rifting contributing to overall extension. The interpretation of gravity data from Global Gravity Model plus2013 has provided an insight on the nature and structure of the shallow upper crust beneath the GTMS within the Central Main Ethiopian Rift. A detailed investigation of the structure of the shallow upper crust based on 2D gravity models, 3D geologic interpretation maps, and residual and upward continued gravity anomaly maps indicate the occurrence of dense, mafic intrusions at depths between 10-20 km and 5–10 km beneath the Tullu Moye-Gedemsa and Boku volcanic centers, respectively. The gravity data indicate at deeper depths, the GTMS (25 km wide and 60 km long) is elongated parallel to the Main Ethiopian Rift axis. Our 2D gravity modeling indicates that the Quaternary faults within the Wonji Fault Belt are closely associated with the dense magmatic intrusions as the faults aid in transporting melt from the deeper crustal melt areas to the shallow magma chambers.

International experiences and the development of intercultural sensitivity among university students

International cultural immersion experiences are deemed one of the most effective ways to prepare multicultural and global citizens. The purpose of the study was to determine: (1) first-year and final-year university students’ levels of Intercultural Sensitivity (henceforth IS); (2) if there was a relationship between IS and experiences of intercultural contact; and (3) the variables that might predict the development of IS. A longitudinal method and a correlational-predictive design was used. The sample comprised 1645 (52.5% women and 47.5% men) undergraduate students from 8 public universities and one private university in Andalusia (Spain) with a mean age of 23.29 (SD = 4.99). The Intercultural Development Inventory (IDI) was used to measure IS, and the Intercultural Experiences Inventory (IEI) was administered to explore students' intercultural experiences. Findings highlighted that there is little change in the IDI scores among first-year and final-year students, and most students were found to be in the intermediate stages of intercultural development (the minimization stage according to Bennett’s model, characterized by the widespread belief that everyone is quite similar). The lack of development found in the students’ IS could have something to do with the lack of opportunity to reflect and think about cultural differences. Positive correlations were found between IS and mobility experiences and intercultural friendships, and negative correlations were found with the number of intercultural interactions and language knowledge. Having mobility experiences, being female, and having friends from other cultures were predictive variables of IS. Finally, the educational implications are discussed.