Rapid Adaptation Research Articles

ІНКРЕМЕНТНИЙ ПІДХІД ДО ПЛАНУВАННЯ РОБОТИ СТУДЕНТІВ НАД СПІЛЬНИМ ПРОГРАМНИМ ПРОЄКТОМ

As of today, well-known product and outsourcing IT companies use Agile models for the software development life cycle (SDLC), the advantages of which include rapid adaptation to changes, continuous feedback, improved product quality, increased team engagement, focus on customer value, transparency and control, as well as the reduction of internal and external risks. All Agile models are iterative, meaning the development process is divided into separate, similar iterations, which have different names in different models. Familiarization with and practical application of modern Agile models by students at the first (bachelor’s) level of higher education in the field of information technology is an important task for future IT specialists. To achieve this task, the most popular Agile model, Scrum, was chosen, which is also incremental, meaning that each iteration delivers additional functionality that is ready for use. The main roles of participants and their responsibilities, artifacts, and ceremonies of the Scrum process are reviewed. The article proposes applying the Scrum model for iterative and incremental software development that will solve a multi-criteria optimization problem using a game-theoretic approach. The formulation and general algorithm for solving the multi-criteria optimization problem using a game-theoretic approach are presented, as well as an example of formulating the Product Backlog, which contains twelve functional requirements to be implemented by the student Scrum team over twelve iterations (sprints). The recommended process for dividing students into Scrum teams and assigning roles to participants is described. An example of incremental implementation based on the Scrum model of the SDLC for solving the multi-criteria optimization problem using a game-theoretic approach is also provided.

Stiffening of the Cytoplasm in Response to Intracellularly Applied Forces.

Cells constantly encounter mechanical forces that regulate various cellular functions, such as migration, division, and differentiation. Understanding how cells respond to forces at the intracellular level is essential for elucidating the mechanical adaptability of living cells. This study investigates how the cytoplasm alters its mechanical properties in response to forces applied inside a cell. The mechanical properties were measured through in situ characterization using magnetic tweezers to apply mechanical forces on magnetic beads internalized into cells. The findings reveal that the cytoplasm stiffens within seconds when force is applied to the cytoplasm. Macromolecular crowding and cytoskeletal structures, particularly F-actin, were found to significantly contribute to cytoplasm stiffening. The stiffening response was also observed across multiple length scales by using magnetic beads of varying diameters. These results highlight the rapid adaptation of the cytoplasm to mechanical forces applied to the inside of a cell.

High-fat and high-sugar diets induce rapid adaptations of fat storage in the house fly Musca domestica L.

Dietary change can be a strong evolutionary force and lead to rapid adaptation in organisms. High-fat and high-sugar diets can challenge key metabolic pathways, negatively affecting other life-history traits and inducing pathologies such as obesity and diabetes. In this study we use experimental evolution to investigate the plastic and evolutionary responses to nutritionally unbalanced diets. We reared replicated lines of larvae of the housefly Musca domestica on a fat-enriched (FAT), a sugar-enriched (SUG), and a control (CTRL) diet for thirteen generations. We measured development time in each generation, and larval growth and fat accumulation in generation 1, 7, and 13. Subsequently all lines were reared for one generation on the control diet to detect any plastic and evolutionary changes. In the first generation, time to pupation decreased on a fat-rich diet and increased on a sugar-rich diet. The fat-rich diet increased fat accumulation and, to a lesser extent, dry weight of the larvae. Multigenerational exposure to the unbalanced diets caused compensatory changes in development time, dry weight, as well as absolute and relative fat content, although pattern and timing depended on diet and trait. When put back on a control diet, many of the changes induced by the unbalanced diets disappeared, indicating that diet has large plastic effects. Nevertheless, fat-evolved lines still grew significantly larger than the sugar-evolved lines, and sugar-evolved lines had consistently lower fat content. This can be an effect of parental diet or an evolutionary change in nutrient metabolism as a consequence of multigenerational exposure to unbalanced diets.

The Role of Data Capabilities in Developing Public Sector Dynamic Capabilities: Lessons from the COVID-19 Pandemic

ABSTRACT For public sector organizations, adapting to unexpectedly changing circumstances has become a substantial challenge. The COVID-19 pandemic provides a fruitful ground for exploring how organizations operate and change under intense circumstances. This article draws on the case of Estonian public sector organizations to understand the way data capabilities were used to improve operational routines related to pandemic response. Certain data capabilities helped organizations to carry out tasks related to the pandemic response, which impelled rapid adaptation of routines. However, it remains a challenge to embrace long-term changes going beyond temporary fixes of the pandemic and to develop dynamic capabilities.

Orthographic and phonological processing in the left ventral occipitotemporal cortex during Chinese word reading.

The left ventral occipitotemporal cortex (lvOT) has been consistently identified as a crucial structure in word reading, and its function varies across subregions. Nevertheless, the specific function of the lvOT and its subregions remains controversial because the obvious grapheme-to-phoneme correspondence rules of alphabetic languages make it difficult to disentangle the contributions of orthography and phonology to neural activations. To explore information processing in lvOT subregions, the present study manipulated the orthography and phonology in a factorial design and used the fMRI rapid adaptation paradigm. The results revealed a posterior-to-anterior functional gradient in lvOT in Chinese word reading and specified that the functional transition from sublexical to lexical processing occurred in the middle subregion close to the classic VWFA. More importantly, we found that the middle and posterior subregions of lvOT are responsible for processing both orthographic and phonological information during Chinese word reading. These results elaborated the function of the lvOT in Chinese word reading.

ADAPTIVE METHOD OF FORMING COMPLEX SIGNALS ENSEMBLES BASED ON MULTI-LEVEL RECURRENT TIME-FREQUENCY SEGMENT MODELING

The article investigates the implementation of an adaptive method for forming ensembles of complex signals based on multilevel recurrent time-frequency segmentation. It addresses the key challenges faced by cognitive wireless networks operating in dynamic radio frequency environments with high levels of interference, necessitating rapid adaptation to changes in the spectral characteristics of signals. The study substantiates the need for adaptive filters and specific transformations to enhance signal processing quality, particularly in environments with high variability in frequency characteristics and significant noise interference. The proposed method of multilevel recurrent time-frequency segmentation allows for the modification of time segment durations and the use of segments of varying lengths, providing flexibility in signal processing and adaptation to current conditions. This adaptability enables optimal signal processing for each individual case, taking into account short-term impulses, long-term fluctuations, and various types of noise and distortions. This approach effectively separates frequency components and reduces interference between them, which is crucial for maintaining high signal quality and communication stability in cognitive networks. It has been proven that the use of adaptive filters such as LMS (Least Mean Squares) and RLS (Recursive Least Squares), as well as fast Fourier Transform (STFT), wavelet, and Hilbert transforms at different stages of multilevel time-frequency segmentation, significantly enhances signal interference resistance and energy efficiency. Comparative analysis of signal metrics before and after filtering and transformation shows an increase in signal quality by 14,3–24,5% and a reduction in noise levels by 21,7–29,6%. The wavelet transform, in particular, proved to be highly effective, allowing for precise extraction of useful frequency components from the noise background and improving signal parameters through dynamic adjustment to specific radio environment conditions. Experimental results confirm the effectiveness of the proposed method, demonstrating its ability to ensure consistently high-quality processing of complex signal ensembles even in dynamic cognitive radio environments.

Community Health Workers’ Challenges during COVID-19: An Intersectionality Study

Abstract Accredited social health activists (ASHAs) and auxiliary nurse midwives (ANMs) as community health workers (CHWs) have been crucial in providing health assistance and information during the COVID-19 pandemic. These CHWs face various challenges, such as discrimination, long hours of work, and low wages, which were exacerbated during the pandemic. The study uses an intersectionality framework to understand CHWs’ marginalization and challenges. A qualitative study with ASHAs and ANMs was conducted in selected primary health centers (PHCs) and subcenters in Suryapet district, Telangana, in 2021. The in-depth interviews of 60 CHWs were analyzed using the software Atlas-ti. The inductive thematic analysis highlighted several challenges faced by CHWs. These challenges include barriers such as discrimination based on class and caste, pay parity, increased workload, lack of training, inadequate safety equipment, and instances of assaults and mistreatment. CHWs, who are often rural women with minimal education, face stigmatization and attacks from community members. They struggled with maintaining records and understanding online training and dealt with rapid adaptation to technology. The study highlights the importance of implementing policies and support systems to protect and empower community health workers. This includes training, fair compensation, safety equipment, and measures against discrimination and violence.

Comprehensive Optimization of a Freeze-Drying Process Achieving Enhanced Long-Term Stability and In Vivo Performance of Lyophilized mRNA-LNPs

The success of mRNA vaccines against SARS-CoV-2 has prompted interest in mRNA-based pharmaceuticals due to their rapid production, adaptability, and safety. Despite these advantages, the inherent instability of mRNA and its rapid degradation in vivo underscores the need for an encapsulation system for the administration and delivery of RNA-based therapeutics. Lipid nanoparticles (LNPs) have proven the most robust and safest option for in vivo applications. However, the mid- to long-term storage of mRNA-LNPs still requires sub-zero temperatures along the entire chain of supply, highlighting the need to develop alternatives to improve mRNA vaccine stability under non-freezing conditions to facilitate logistics and distribution. Lyophilization presents itself as an effective alternative to prolong the shelf life of mRNA vaccines under refrigeration conditions, although a complex optimization of the process parameters is needed to maintain the integrity of the mRNA-LNPs. Recent studies have demonstrated the feasibility of freeze-drying LNPs, showing that lyophilized mRNA-LNPs retain activity and stability. However, long-term functional data remain limited. Herein, we focus on obtaining an optimized lyophilizable mRNA-LNP formulation through the careful selection of an optimal buffer and cryoprotectant and by tuning freeze-drying parameters. The results demonstrate that our optimized lyophilization process maintains LNP characteristics and functionality for over a year at refrigerated temperatures, offering a viable solution to the logistical hurdles of mRNA vaccine distribution.

Photo-tunable hydrogels reveal cellular sensing of rapid rigidity changes through the accumulation of mechanical signaling molecules.

Cells use traction forces to sense mechanical cues in their environment. While the molecular clutch model effectively explains how cells exert more forces on stiffer substrates, it falls short in addressing their adaptation to dynamic mechanical fluctuations prevalent in tissues and organs. Here, using hydrogel with photo-responsive rigidity, we show that cells' response to rigidity changes is frequency dependent. Strikingly, at certain frequencies, cellular traction forces exceed those on static substrates 4-fold stiffer, challenging the established molecular clutch model. We discover that the discrepancy between the rapid adaptation of traction forces and the slower deactivation of mechanotransduction signaling proteins results in their accumulation, thereby enhancing long-term cellular traction in dynamic settings. Consequently, we propose a new model that melds immediate mechanosensing with extended mechanical signaling. Our study underscores the significance of dynamic rigidity in the development of synthetic biomaterials, emphasizing the importance of considering both immediate and prolonged cellular responses.

Distinct evolutionary trajectories following loss of RNA interference in Cryptococcus neoformans.

While increased mutation rates typically have negative consequences in multicellular organisms, hypermutation can be advantageous for microbes adapting to the environment. Previously, we identified two hypermutator Cryptococcus neoformans clinical isolates that rapidly develop drug resistance due to transposition of a retrotransposon, Cnl1. Cnl1-mediated hypermutation is caused by a nonsense mutation in the gene encoding a novel RNAi component, Znf3, combined with a tremendous transposon burden. To elucidate adaptative mechanisms following RNAi loss, two bioinformatic pipelines were developed to identify RNAi loss-of-function mutations in a collection of 387 sequenced C. neoformans isolates. Remarkably, several RNAi-loss isolates were identified that are not hypermutators and have not accumulated transposons. To test if these RNAi loss-of-function mutations can cause hypermutation, the mutations were introduced into a non-hypermutator strain with a high transposon burden, which resulted in a hypermutator phenotype. To further investigate if RNAi-loss isolates can become hypermutators, in vitro passaging was performed. Although no hypermutators were found in two C. neoformans RNAi-loss strains after short-term passage, hypermutation was observed in a passaged C. deneoformans strain with increased transposon burden. Consistent with a two-step evolution, when an RNAi-loss isolate was crossed with an isolate containing a high Cnl1 burden, F1 hypermutator progeny inheriting a high transposon burden were identified. In addition to Cnl1 transpositions, insertions of a novel gigantic DNA transposon KDZ1 (~11 kb), contributed to hypermutation in the progeny. Our results suggest that RNAi loss is relatively common (7/387, ~1.8%) and enables distinct evolutionary trajectories: hypermutation following transposon accumulation or survival without hypermutation.

Assessing the Impacts of Adaptation to Native-Range Habitats and Contemporary Founder Effects on Genetic Diversity in an Invasive Fish.

Species invading non-native habitats can cause irreversible environmental damage and economic harm. Yet, how introduced species become widespread invaders remains poorly understood. Adaptation within native-range habitats and rapid adaptation to new environments may both influence invasion success. Here, we examine these hypotheses using 7058 SNPs from 36 native, 40 introduced and 19 farmed populations of tench, a fish native to Eurasia. We examined genetic structure among these populations and accounted for long-term evolutionary history within the native range to assess whether introduced populations exhibited lower genetic diversity than native populations. Subsequent to infer genotype-environment correlations within native-range habitats, we assessed whether adaptation to native environments may have shaped the success of some introduced populations. At the broad scale, two glacial refugia contributed to the ancestry and genomic diversity of tench. However, native, introduced and farmed populations of admixed origin exhibited up to 10-fold more genetic diversity (i.e., observed heterozygosity, expected heterozygosity and allelic richness) compared to populations with predominantly single-source ancestry. The effects of introduction to a new location were also apparent as introduced populations exhibited fewer private alleles (mean = 9.9 and 18.9 private alleles in introduced and native populations, respectively) and higher population-specific Fst compared to native populations, highlighting their distinctiveness relative to the pool of allelic frequencies across tench populations. Finally, introduced populations with varying levels of genetic variation and similar genetic compositions have become established and persisted under strikingly different climatic and ecological conditions. Our results suggest that lack of prior adaptation and low genetic variation may not consistently hinder the success of introduced populations for species with a demonstrated ability to expand their native range.

LEADERSHIP BEHAVIORAL DEVELOPMENT OF MILLENNIAL LEADERS AS A CHANGE AGENT IN THE DIGITAL TRANSFORMATION ORGANIZATION

<p>The digital transformation era and Industry 4.0 provide ample opportunities for this generation to thrive with their rapid technological adaptation and openness to new ideas. This research examines millennial leadership behavioral development to enable them to effectively become change agents in digital organizations, using the case study of William Tanuwijaya at Tokopedia. Through a review of literature from international sources during 2020–2023, this study discusses millennial leadership theories and change management, highlighting the urgency and importance of adaptive leadership capable of managing change in the face of digital organizational challenges. The research findings indicate that millennial leadership styles vary according to organizational contexts. Millennials are confronted with change management, where organizational readiness to adapt is critical to success. Adaptive leadership, a key strategy in managing change, is crucial. Through William Tanuwijaya's leadership at Tokopedia, millennial leadership characteristics prioritizing social and environmental issues, sustainability, and the implementation of sustainable values are evident, alongside collaboration with the government to create an inclusive environment and focus on innovation and digital transformation in the economy. Leaders like William Tanuwijaya start by building teams consisting of celebrities or public figures in Indonesia to promote Tokopedia and strengthen the company's image while formulating the company's vision and initiatives, motivating employees, overcoming obstacles such as improving work efficiency, implementing successful minor changes, ensuring smooth change integration, and making change an integral part of the organizational culture and system.<strong></strong></p>

Advancing Persistent Character Generation: Comparative Analysis of Fine-Tuning Techniques for Diffusion Models

In the evolving field of artificial intelligence, fine-tuning diffusion models is crucial for generating contextually coherent digital characters across various media. This paper examines four advanced fine-tuning techniques: Low-Rank Adaptation (LoRA), DreamBooth, Hypernetworks, and Textual Inversion. Each technique enhances the specificity and consistency of character generation, expanding the applications of diffusion models in digital content creation. LoRA efficiently adapts models to new tasks with minimal adjustments, making it ideal for environments with limited computational resources. It excels in low VRAM contexts due to its targeted fine-tuning of low-rank matrices within cross-attention layers, enabling faster training and efficient parameter tweaking. DreamBooth generates highly detailed, subject-specific images but is computationally intensive and suited for robust hardware environments. Hypernetworks introduce auxiliary networks that dynamically adjust the model’s behavior, allowing for flexibility during inference and on-the-fly model switching. This adaptability, however, can result in slightly lower image quality. Textual Inversion embeds new concepts directly into the model’s embedding space, allowing for rapid adaptation to novel styles or concepts, but is less effective for precise character generation. This analysis shows that LoRA is the most efficient for producing high-quality outputs with minimal computational overhead. In contrast, DreamBooth excels in high-fidelity images at the cost of longer training. Hypernetworks provide adaptability with some tradeoffs in quality, while Textual Inversion serves as a lightweight option for style integration. These techniques collectively enhance the creative capabilities of diffusion models, delivering high-quality, contextually relevant outputs.

Adaptation of French general practitioners for the management of nursing home patients during COVID-19 in 2020: a multilevel analysis.

To describe French general practioners' (GPs) adaptation strategies to ensure follow-up care of nursing home patients during the first wave of COVID-19 (May 2020) and to identify factors associated with each strategy. A national cross-sectional study was conducted with online questionnaires in May 2020 among GPs practicing in France (metropolitan and overseas) and usually providing nursing home visits before pandemic. The outcome was defined as the GPs' adaptation strategies for managing nursing home patients and was categorized into four groups: Maintenance of Nursing Home Visits NHV (reference), Stopping NHV, Numeric adaptation (teleconsultations only), Mixed adaptation (NHV and teleconsultations). The probability of adaptation strategies was analyzed by multilevel logistic models in which the GPs represented level 1 and the counties level 2. We applied three random-intercept multilevel logistic models with the county of GP's practice as random effect. This analysis included 2,146 responses by GPs coming from 98 French counties. Overall, 40.4% of GPs maintained NHV, while other strategies were: Stopping visits (24.1%), Numeric adaptation (15.4%), Mixed adaptation (20.1%). Several individual (age, training GP, perceived status of being at high risk of severe COVID, compliance with temporary delegation of the patient's management) and territorial factors (excess mortality rate due to COVID-19, GPs' density, proportion of over-75s, presence of reinforcement measures for nursing home patients) were identified as associated with each strategy. This study highlights a rapid adaptation of general practice to keep supporting nursing home patients. Heterogeneity of adaptation strategies could reflect both the lack of national guidelines and the heterogeneity among GPs' usual practices. Policymakers should take actions at a territorial level (subnational) to strengthen support to nursing home patients considering adaptations to the local context of the pandemic outbreak and perspective of local actors.

Optimizing the Speed and Explosive Power Performance of Football Players: The Effect of a Six-Week Neuromuscular Training

Background. Football players require high levels of speed and explosive power to perform effectively on the field, making these physical attributes critical for success. Neuromuscular training has been proposed as a method to enhance these performance metrics. Objectives. The purpose of the present study was to examine the effect of neuromuscular training on the speed and explosive power performance of football players. Materials and methods. A total of thirty male football players (aged 20 to 26 years) from Imphal West District, Imphal, Manipur, India, who had participated in national-level competitions, were selected for the study. The subjects were randomly assigned into two equal groups: an experimental group (n = 15) and a control group (n = 15). Both groups were assessed before the intervention for speed and explosive power performance using the 50 m dash speed test and the standing broad jump test to determine the baseline significance of the selected variables. Following the initial assessments, the experimental group underwent a supervised neuromuscular training program, while the control groupreceived no special training. The neuromuscular training was conducted over a period of six weeks, with sessions held five days a week (Monday to Friday), each lasting 60 minutes. Results. The experimental group confirmed significant improvements in both speed and explosive power compared to the control group (p < 0.05). The mean and standard deviation of speed for the experimental group were 7.15 ± 0.71 in the pre-test and 6.54 ± 0.61 in the post-test. For explosive power, the values were 2.36 ± 0.32 in the pre-test and 2.55 ± 0.39 in the post-test. The notable enhancements in speed and explosive power performance in the experimental group are likely attributed to the six-week neuromuscular training program, which facilitated rapid physical adaptation among the football players. Conclusions. Implementing the six-week neuromuscular training program effectively enhanced the speed and explosive power performance of football players. This type of training has been demonstrated to be highly effective for optimizing these performance metrics in football players.

GAME DEVELOPMENT PROJECT MANAGEMENT USING SCRUM FRAMEWORK: HYPERCASUAL GAME CASE STUDY 'RUSH RUNNER'

The research aims to explore and implement an effective Project Management approach in Game Development using the Scrum Framework. A case study was conducted on the development of a hypercasual game titled "Rush Runner." With a focus on rapid iterations, continuous feedback, and adaptation to changes, the Scrum methodology was used to manage the game development workflow from planning to publication. Concrete steps were taken to adapt to user needs and evolving demands as an integral part of the development process. The research findings indicate that the implementation of Scrum had a positive impact on productivity, quality, and user satisfaction in hypercasual game development. Furthermore, the integration of Project Management and the Scrum approach optimized overall time, cost, and quality. These findings provide valuable insights for practitioners and researchers in the field of game development to understand the importance of an adaptive and responsive Project Management approach to market changes and user needs.

Changes in DNA methylation contribute to rapid adaptation in bacterial plant pathogen evolution.

Adaptation is usually explained by beneficial genetic mutations that are transmitted from parents to offspring and become fixed in the adapted population. However, genetic mutation analysis alone is not sufficient to fully explain the adaptive processes, and several studies report the existence of nongenetic (or epigenetic) inheritance that can enable adaptation to new environments. In the present work, we tested the hypothesis of the role of DNA methylation, a form of epigenetic modification, in adaptation of the plant pathogen Ralstonia pseudosolanacearum to the host during experimental evolution. Using SMRT-seq technology, we analyzed the methylomes of 31 experimentally evolved clones obtained after serial passages on 5 different plant species during 300 generations. Comparison with the methylome of the ancestral clone revealed a list of 50 differential methylated sites (DMSs) at the GTWWAC motif. Gene expression analysis of the 39 genes targeted by these DMSs revealed limited correlation between differential methylation and differential expression of the corresponding genes. Only 1 gene showed a correlation, the RSp0338 gene encoding the EpsR regulator protein. The MSRE-qPCR technology, used as an alternative approach for DNA methylation analysis, also found the 2 DMSs upstream RSp0338. Using site-directed mutagenesis, we demonstrated the contribution of these 2 DMSs in host adaptation. As these DMSs appeared very early in the experimental evolution, we hypothesize that such fast epigenetic changes can allow rapid adaptation to the plant stem environment. In addition, we found that the change in DNA methylation upstream RSp0338 remains stable at least for 100 generations outside the host and thus can contribute to long-term adaptation to the host plant. To our knowledge, this is the first study showing a direct link between bacterial epigenetic variation and adaptation to a new environment.

Navigating the Fourth Industrial Revolution: Generational Differences, COVID-19 Impact, and Knowledge Sharing in the Modern Workplace

This systematic literature review examines the intricate interplay between generational differences, the Fourth Industrial Revolution (4IR), and the unanticipated effects of the COVID-19 pandemic on the contemporary world of work. In response to the pandemic, organizations worldwide rapidly reevaluated their work processes, embracing digital technologies and remote work. This unforeseen shift underscored the world's capacity for rapid adaptation to unforeseen challenges. However, the 4IR extends beyond technological advancements, involving non-technological aspects such as evolving business models, workforce well-being, job security, and the changing nature of work. Understanding these dimensions is vital in shaping the modern workforce. Generational differences add another layer of complexity. Each generation, from Baby Boomers to Millennials, brings distinct worldviews and work values. This review explores how different generations perceive and adapt to the evolving nature of work, especially in the context of the 4IR. In addition, the 4IR highlights the critical role of knowledge in driving innovation and competitiveness. Knowledge-sharing practices within organizations have become pivotal in staying ahead in this era of rapid technological change. By addressing both technological and non-technological dimensions of the 4IR and considering generational perspectives, this review offers a comprehensive understanding of how these forces intersect and influence the modern workplace. It provides insights and recommendations to guide organizations, policymakers, and individuals in navigating the complexities of the modern world of work, harnessing 4IR opportunities, and addressing its multifaceted challenges.

The Role Of Knowledge Management In Increasing Organizational Flexibility To Face The Changes Brought By The Industrial Revolution 4.0

The importance of knowledge management integration in increasing organisational flexibility in the midst of the Industrial Revolution 4.0, which demands rapid adaptation and responsiveness, requires organisations to continue to innovate in the dynamics of change. The purpose of this study is to explore the relationship between knowledge management and organisational flexibility and provide practical recommendations to optimise the application of knowledge management to improve organisational responsiveness. The research method uses a qualitative approach with literature study as the main source of data. The results revealed that effective integration between knowledge management and organisational flexibility can provide a significant competitive advantage. However, in its implementation, there are obstacles such as cultural resistance and technological limitations. The conclusion of this study confirms that a thorough and integrated application of knowledge management is the key to increasing organisational flexibility in the digital era. The implication of these findings is the need for organisational commitment to build a culture of knowledge sharing, adopt technologies that support knowledge management and align strategies with overall business objectives to ensure success in the face of change and maintain competitiveness in a dynamic market.

Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.

Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer. Previously, we and others have identified that SMARCA4-mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). Despite initial excitements, therapeutics targeting metabolic pathways such as OXPHOS have largely been disappointing due to rapid adaptation of cancer cells to inhibition of single metabolic enzymes or pathways, suggesting novel combination strategies to overcome adaptive responses are urgently needed. Here, we performed a functional genomics screen using CRISPR-Cas9 library targeting genes with available FDA approved therapeutics and identified ROCK1/2 as a top hit that sensitizes cancer cells to OXPHOS inhibition. We validate these results by orthogonal genetic and pharmacologic approaches by demonstrating that KD025 (Belumosudil), an FDA approved ROCK inhibitor, has highly synergistic anti-cancer activity in vitro and in vivo in combination with OXPHOS inhibition. Mechanistically, we showed that this combination induced a rapid, profound energetic stress and cell cycle arrest that was in part due to ROCK inhibition-mediated suppression of the adaptive increase in glycolysis normally seen by OXPHOS inhibition. Furthermore, we applied global phosphoproteomics and kinase-motif enrichment analysis to uncover a dynamic regulatory kinome upon combination of OXPHOS and ROCK inhibition. Importantly, we found converging phosphorylation-dependent regulatory cross-talk by AMPK and ROCK kinases on key RHO GTPase signaling/ROCK-dependent substrates such as PPP1R12A, NUMA1 and PKMYT1 that are known regulators of cell cycle progression. Taken together, our study identified ROCK kinases as critical mediators of metabolic adaptation of cancer cells to OXPHOS inhibition and provides a strong rationale for pursuing ROCK inhibitors as novel combination partners to OXPHOS inhibitors in cancer treatment.