Structural Organization Research Articles

Urban Texture Identification and Characteristic Analysis Based on Percolation Theory—A Case Study of the Second Ring Road Area in Wuhan City

The urban texture is the physical manifestation of the urban form’s evolution. In the rapid process of urbanization, protecting and reshaping the urban texture has become an essential means to sustain the overall form and vitality of cities. Previous studies in this field have primarily relied on image analysis or typological methods, lacking a quantitative approach to identify and analyze the urban texture on a large scale. Moreover, the hierarchical structure and networked organization of the urban texture are gradually being elucidated and emphasized. This study takes a complex network perspective and applies percolation theory to identify and analyze the urban texture. The hierarchical evolutionary characteristics of the urban fabric and the underlying mechanisms driving the scale-dependent differences are analyzed, and the toughness of the urban texture is evaluated based on hierarchical connections. The research findings reveal the key scale in the cross-scale evolution of urban textures, with variations in scale dependence and hierarchical evolution characteristics among different types of urban texture. The traditional urban texture displays sensitivity to scale changes, maintaining its integrity and internal connectivity at small scales. On the other hand, the texture characteristics of modern and contemporary urban areas are only discernible at larger scales. The emergence of large-scale texture clusters at specific scale levels can be explained using multiple index systems. This study has reference significance for the preservation and renewal of the urban fabric in urban renewal processes.

Structural connectivity between olfactory tubercle and ventrolateral periaqueductal gray implicated in human feeding behavior.

The olfactory tubercle (TUB), also called the tubular striatum, receives direct input from the olfactory bulb, and along with the nucleus accumbens, is one of the two principal components of the ventral striatum. As a key component of the reward system, the ventral striatum is involved in feeding behavior, but the vast majority of research on this structure has focused on the nucleus accumbens, leaving the TUB's role in feeding behavior understudied. Given the importance of olfaction in food seeking and consumption, olfactory input to the striatum should be an important contributor to motivated feeding behavior. Yet the TUB is vastly understudied in humans, with very little understanding of its structural organization and connectivity. In this study, we analyzed macrostructural variations between the TUB and the whole brain, and explored the relationship between TUB structural pathways and feeding behavior, using body mass index (BMI) as a proxy in females and males. We identified a unique structural covariance between the TUB and the periaqueductal gray (PAG), which has recently been implicated in the suppression of feeding. We further show that the integrity of the white matter tract between the two regions is negatively correlated with BMI. Our findings highlight a potential role for the TUB-PAG pathway in the regulation of feeding behavior in humans.Significance Statement Increasing evidence suggests that olfaction plays an important role in human feeding behavior. However, the neural underpinnings of this role remain relatively unexplored. Here, we examined the structural connectivity of the olfactory tubercle, which has been implicated in both olfaction and reward, using magnetic resonance imaging. We found that a unique connectivity of the olfactory tubercle with the periaqueductal gray was correlated with body mass index. Our findings highlight a potential role for this pathway in the regulation of human feeding behavior.

СТРУКТУРНАЯ ОРГАНИЗАЦИЯ МОЛЕКУЛ СОЙМОРФИНОВ

The conformational capabilities of soymorphine-5 (Thr1-Pro2-Phe3-Val4-Val5-NH2), soymorphine-6 (Tyr1-Pro2-Phe3-Val4-Val5-Asn6-NH2) and soymorphine-7 (Tyr1- Pro2-Tyr3-Val4-Val5-Asn6-Ala7-NH2) molecules have been studied by the method of theoretical conformational analysis. The potential function of the system is chosen as the sum of non-valence, electrostatic and torsion interactions and the energy of hydrogen bonds. The low-energy conformations of soymorphine-5, soymorphine-6 and soymorphine-7 molecules were found, the dihedral angles of the main and side chains of amino acid residues that make up the molecule were found, and the energy of intra- and interresidual interactions was estimated. Thus, the spatial structure of soymorphine-5, soymorphine-6 and soymorphine-7 molecules can be represented by eight structural types. It can be assumed that the molecules perform their physiological functions in these structures. Comparison of the low-energy structures of soymorphins shows that in all molecules the first four low-energy conformations are representatives of the structural types efef, efee, efff, effe for soymorphine-5, effff, efeff, efffe, effee for soymorphine-6, efffff, efeffe, efffef, effeee for soymorphine-6. soymorphine-7. On the basis of these structures, it is possible to propose their artificial analogues for synthesis. It was shown that the spatial structure of soymorphine-5, soymorphine-6 and soymorphine-7 molecules is represented by the conformations of eight shapes of the peptide skeleton. The results obtained can be used to elucidate the structural and structural-functional organization of soymorphine molecules.

REMOTE CARDIAC DEVICE MANAGEMENT: REAL–WORLD INSIGHTS AND CHALLENGES

Abstract Background telemedicine plays a crucial role in managing patients with Cardiac Implantable Electronic Devices (CIEDs), offering unique technical and clinical benefits. This study explores the characteristics of a real–world population of CIED recipients undergoing entirely remote follow–up. Methods and Results in a prospective evaluation of 808 consecutive CIED patients from two Italian Cardiology Centers (2021–2023), initial on–site assessments were followed by remote evaluations, either scheduled or alert–triggered. The majority received pacemakers (68.8%), with others having Implantable Defibrillators (19.3%) or Implantable Loop Recorders (11.9%). The average age was 75.6±12.6 years, and 42% were female. Most of the patients were retired (83.3%), and 73% required at least one caregiver. The EQ–5D score indicated a lower quality of life (8.9±4.3) compared to the Italian general population. During the observation period (20.6 months), 34.9% of patients were admitted to the hospital, with 50% of cases being cardiovascular–related. Heart failure was the most common cause (13.2%). Device–related issues prompted outpatients’ cardiology clinic Department evaluations in 13.4% of cases. The telemedicine program produced 2780 remote transmissions, with 23% being automatic alerts. In–clinic evaluations were 1313, with a mean duration of 19.2 minutes. Atrial fibrillation (AF) history was prevalent (40.2%), and 719 AF episodes occurred during the observation period. Conclusions Managing CIED patients via telemedicine is feasible but requires structured organization considering patient characteristics and possible outcomes. AF management is crucial, given its high prevalence. Older age and compromised quality of life are significant factors, partly mitigated by the widespread presence of caregivers. Despite remote follow–up, many patients access healthcare structures for cardiovascular reasons, emphasizing the need for distinct pathways for device–related and general care necessities.

Improvement of the organizational structure of management agricultural enterprises according to the principles of the market economy

The materials of the scientific publication define the role of marketing principles in the organization of the management structure of agricultural enterprises in the production process. The works of domestic and foreign scientists devoted to the efficiency of agricultural production, the service sector and the market were analyzed. When conducting research on the state of the organizational structure of management of agricultural enterprises based on the principle of marketing, general scientific research methods were used, in particular: a monographic method to identify the problem of adaptation of agricultural enterprises to the market environment, a method of comparative analysis to study the possibilities of adaptation to the market of agricultural enterprises of different sizes, an abstract-logical method with its methods of generalization analysis and synthesis and the method of induction and deduction for the formation of generalizations, conclusions and propositions. A system of the organizational structure of management of agricultural enterprises was established in accordance with marketing principles. The state and further development of the management structure of agricultural enterprises is determined. Presented are topical issues of forming the implementation of agrarian policy in the field of organizational structure of socio-economic and social-labor relations. The optimal system of labor organization in social and labor relations based on the principle of humanization of labor, which offers wide independence to the production enterprise, has been revealed. The conditions that determine the direction of all production and marketing activities of agricultural enterprises, which are based on the principles of marketing are analyzed. All activities of the agricultural enterprise are subject to this concept. The tactics of the marketing concept of an agricultural enterprise, based on the use of defensive and offensive positions, are also proposed. Appropriate conclusions were made that reflect the assessment of the financial condition of agricultural sector enterprises and offer the most effective method of marketing policy activation, which provides an opportunity to obtain more information about the activities of agricultural enterprises, conduct its analysis, and formulate specific proposals for production.

(Thermo)mechanical and chemical characteristics of photochemically crosslinked acrylates from bio‐ and fossil‐based origin

AbstractThe acrylates with oligomers and monomers from (partially) bio‐based feedstock become available at (semi‐)industrial scale, which can be processed through photochemical crosslinking for applications in coatings, additive manufacturing, electronics, or inks. Although fossil‐ and bio‐based acrylates may have a similar chemical composition, it requires good understanding of processing and structure–property relationships as minor changes in microstructure may strongly alter the performance. A comparative study on mechanical properties and chemical structure of bio‐ and fossil‐based acrylates with different functionalities and backbone structures reveals higher ductility of bio‐based acrylates, in relation with a more complex organization of the intrinsic molecular structure. The latter is confirmed by mechanical testing and visco‐elastic characteristics (dynamic mechanical analysis) yielding lower stiffness and higher dampening of bio‐based acrylates, in parallel with a lower glass transition temperature (differential scanning calorimetry). The complex molecular arrangements include a nanoscale morphology with ordered structure (X‐ray diffraction), conformational changes (infrared spectroscopy), and a residual high‐molecular weight fraction (size exclusion chromatography). The visco‐elastic calculations indicate only 4% to 5% lower crosslinking density and around 10% higher mean molar mass of the polymer chains segments between chemical crosslinks and trapped chain entanglements, which explain the unique structure and performance of bio‐based acrylates.

Topological analysis of 3D digital ovules identifies cellular patterns associated with ovule shape diversity.

Tissue morphogenesis remains poorly understood. In plants, a central problem is how the 3D cellular architecture of a developing organ contributes to its final shape. We address this question through a comparative analysis of ovule morphogenesis, taking advantage of the diversity in ovule shape across angiosperms. Here, we provide a 3D digital atlas of Cardamine hirsuta ovule development at single cell resolution and compare it to an equivalent atlas of Arabidopsis thaliana. We introduce nerve-based topological analysis as a tool for unbiased detection of differences in cellular architectures and corroborate identified topological differences between two homologous tissues by comparative morphometrics and visual inspection. We find that differences in topology, cell volume variation and tissue growth patterns in the sheet-like integuments and the bulbous chalaza, are associated with differences in ovule curvature. In contrast, the radialized, conical ovule primordia and nucelli exhibit similar shapes despite differences in internal cellular topology and tissue growth patterns. Our results support the notion that the structural organization of a tissue is associated with its susceptibility to shape changes during evolutionary shifts in 3D cellular architecture.

Neuronal LRP4 directs the development, maturation, and cytoskeletal organization of Drosophila peripheral synapses.

Tissue morphogenesis remains poorly understood. In plants, a central problem is how the 3D cellular architecture of a developing organ contributes to its final shape. We address this question through a comparative analysis of ovule morphogenesis, taking advantage of the diversity in ovule shape across angiosperms. Here, we provide a 3D digital atlas of Cardamine hirsuta ovule development at single cell resolution and compare it to an equivalent atlas of Arabidopsis thaliana. We introduce nerve-based topological analysis as a tool for unbiased detection of differences in cellular architectures and corroborate identified topological differences between two homologous tissues by comparative morphometrics and visual inspection. We find that differences in topology, cell volume variation and tissue growth patterns in the sheet-like integuments and the bulbous chalaza, are associated with differences in ovule curvature. In contrast, the radialized, conical ovule primordia and nucelli exhibit similar shapes despite differences in internal cellular topology and tissue growth patterns. Our results support the notion that the structural organization of a tissue is associated with its susceptibility to shape changes during evolutionary shifts in 3D cellular architecture.

At the Basis of Brain Malformations: Brain Plasticity, Developmental Neurobiology, and Considerations for Rehabilitation

AbstractFrom early age in the human brain occurs plasticity process that influences its development. The functioning of the brain is governed by its neuronal connectivity and the synaptic dynamics of these connections. A neuron, over thousands of synapses, can receive a large number of inputs and produce different outputs leading to the consolidation and integration of memory. Synaptic plasticity is the set of experience-dependent changes in neuronal pathways that support acquired habits. It is the ability of the nervous system to reshape connectivity between neurons, changing the functional and structural organization of neuronal circuits that allows us to adapt to the multiple and continuous changes in the environment and leading to processes such as cognitive development and the ability to learn. Synaptic plasticity is mainly due to short- and long-term mechanisms. Short-term synaptic plasticity refers to changes in synaptic strength that occurs very quickly (from one-thousandth of a second to 5 minutes) and are temporary and decay over minutes (maximum 30 minutes). Long-term synaptic plasticity is defined by a long-lasting, activity-dependent change in synaptic efficacy, last from hours up to a lifetime (from 30 minutes to weeks, months, and years) and is thought to constitute the basis of learning and memory. A significant difference occurs in the nature of the change; short-term plasticity adds only a functional change, whereas long-term plasticity causes not only functional but also structural changes. Aside from genetic factors and metabolic processes, brain development is mediated also by environmental factors. Interaction with the environment plays a key role in the development and growth of neural networks and neuroplasticity. Environmental interactions that can modify and increase the development of neural networks and intelligence in children are several and are herein discussed.

Assessing PERT integration: a European survey on pulmonary embolism response teams

Abstract Funding Acknowledgements None. Background In recent years, the establishment of multidisciplinary pulmonary embolism response teams (PERTs) has become more prevalent in response to the growing challenges in managing acute pulmonary embolism (PE). A survey was conducted to assess the availability and structure of PERTs in selected European PE reference centers. Methods A survey was circulated among leading European PE centers to obtain data on their current PE treatments, the existence and features of PERTs, their activation methods, and their structural organization. Additionally, data regarding PE treatment priority relative to acute coronary syndrome and the availability of outpatient PE follow-up programs was collected. Results Overall, 26 selected reference centers for PE from 13 European countries participated at this survey and in more than four fifth (80.8%) of the centers PERT is already implemented. Although 76.9% of the centers handle over 40 PE cases annually, less than half (42.8%) of their PE cases are discussed in a PERT meeting. Figure 1A illustrates the risk classifications for which PERTs are typically consulted. The most common method of activating PERTs is through phone calls (47.6%), followed by mobile apps (38.1%) and pagers (4.8%). In almost 60% PERT is leading from the Department of Cardiology followed by Pulmonology (18.2%), Critical Care Medicine (9.1%), General Internal Medicine (4.6%), Angiology (4.6%) and Radiology (4.6%) (Figure 1B and 1C). Regarding advanced treatment the majority of European expert centers for PE offers catheter-directed thrombolysis (78.3%) and catheter-based thrombectomy (78.3%) and the opportunity of surgical embolectomy (65.2%). Notably, over 46% of centers prioritize ST-elevation infarction over high-risk PE (Figure 1D). The follow-up of patients with PE is organized in 34.6% in a dedicated PE clinic, in 23.1%in the clinic of the physician leading PERT and in 7.7% no PE follow-up is available. Conclusion The findings confirm the widespread adoption of PERTs in European PE reference centers. However, there is a discernible trend of prioritizing myocardial infarction over PE with hemodynamic instability, even when mortality rates are comparable for high-risk PE cases. This emphasizes the pressing need for awareness campaigns to enlighten physicians about the significant mortality rates linked with unstable PE, aiming for enhanced management and intervention for this thrombotic disease.

Response Item Network (ResIN): A network-based approach to explore attitude systems

Belief network analysis (BNA) refers to a class of methods designed to detect and outline structural organizations of complex attitude systems. BNA can be used to analyze attitude-structures of abstract concepts such as ideologies, worldviews, and norm systems that inform how people perceive and navigate the world. The present manuscript presents a formal specification of the Response-Item Network (or ResIN), a new methodological approach that advances BNA in at least two important ways. First, ResIN allows for the detection of attitude asymmetries between different groups, improving the applicability and validity of BNA in research contexts that focus on intergroup differences and/or relationships. Second, ResIN’s networks include a spatial component that is directly connected to item response theory (IRT). This allows for access to latent space information in which each attitude (i.e. each response option across items in a survey) is positioned in relation to the core dimension(s) of group structure, revealing non-linearities and allowing for a more contextual and holistic interpretation of the attitudes network. To validate the effectiveness of ResIN, we develop a mathematical model and apply ResIN to both simulated and real data. Furthermore, we compare these results to existing methods of BNA and IRT. When used to analyze partisan belief-networks in the US-American political context, ResIN was able to reliably distinguish Democrat and Republican attitudes, even in highly asymmetrical attitude systems. These results demonstrate the utility of ResIN as a powerful tool for the analysis of complex attitude systems and contribute to the advancement of BNA.

The Dynamics of Civil Society Organisations and Cooperative Societies around Cocoa Governance Based on North-South Cooperation in Côte d'Ivoire

The cocoa sector in Côte d'Ivoire has around 3,000 cooperatives, whose stated objective is to fight for an improvement in the living conditions of producers by acting for a better marketing price for their produce. Despite their large numbers, these cooperatives struggle to integrate and influence decision-making bodies so that the needs of producers can be taken into account. It is against this backdrop that two non-governmental organisations, INADES [ ], and INKOTA-Netzwerk, launched a collaborative initiative in 2019 involving international civil society organisations, human rights organisations and cooperatives, with a view to helping them build an advocacy framework to have a greater impact on decision-making in the sector through the establishment in 2020, of the "Ivorian platform for sustainable cocoa". And this desire to bring together agricultural cooperatives as well as the Ivorian civil society (south) and their partners (north) so that they can play their full part in the decision-making process within this sector has been the subject of a study. The results, findings, observations and information gathered as part of this research are set out in this article. The data was collected through documentary research and semi-directive interviews with Inades-Formation managers, civil society organisations that are members of the platform, cooperative group managers and trade union structure managers. In terms of results, the pooling of synergies between civil society organisations in the north and south, which began in 2020 under the slogan "Ivorian platform for sustainable cocoa", has led to the development and publication of an advocacy guide. This activity has also helped improve the administrative and economic organisation of cooperative structures. In addition, the information and capacity-building sessions carried out by international civil society organisations have enabled cooperatives to revitalise their influence in the process of political and ......

HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Structural Reconstruction of E. coli Ubi Metabolon Using an AlphaFold2-Based Computational Framework.

Ubiquinone (UQ) is a redox polyisoprenoid lipid found in the membranes of bacteria and eukaryotes that has important roles, notably one in respiratory metabolism, which sustains cellular bioenergetics. In Escherichia coli, several steps of the UQ biosynthesis take place in the cytosol. To perform these reactions, a supramolecular assembly called Ubi metabolon is involved. This latter is composed of seven proteins (UbiE, UbiG, UbiF, UbiH, UbiI, UbiJ, and UbiK), and its structural organization is unknown as well as its protein stoichiometry. In this study, a computational framework has been designed to predict the structure of this macromolecular assembly. In several successive steps, we explored the possible protein interactions as well as the protein stoichiometry, to finally obtain a structural organization of the complex. The use of AlphaFold2-based methods combined with evolutionary information enabled us to predict several models whose quality and confidence were further analyzed using different metrics and scores. Our work led to the identification of a "core assembly" that will guide functional and structural characterization of the Ubi metabolon.

Barriers to and Facilitators of Key Stakeholders Influencing Successful Digital Implementation of Remote Monitoring Solutions: Mixed Methods Analysis.

Implementation of remote monitoring solutions and digital alerting tools in health care has historically been challenging, despite the impetus provided by the COVID-19 pandemic. To date, a health systems-based approach to systematically describe barriers and facilitators across multiple domains has not been undertaken. We aimed to undertake a comprehensive mixed methods analysis of barriers and facilitators for successful implementation of remote monitoring and digital alerting tools in complex health organizations. A mixed methods approach using a modified Technology Acceptance Model questionnaire and semistructured interviews mapped to the validated fit among humans, organizations, and technology (HOT-fit) framework was undertaken. Likert frequency responses and deductive thematic analyses were performed. A total of 11 participants responded to the questionnaire and 18 participants to the interviews. Key barriers and facilitators could be mapped onto 6 dimensions, which incorporated aspects of digitization: system use (human), user satisfaction (human), environment (organization), structure (organization), information and service quality (technology), and system quality (technology). The recommendations proposed can enhance the potential for future remote sensing solutions to be more successfully integrated in health care practice, resulting in more successful use of "virtual wards." ClinicalTrials.gov NCT05321004; https://www.clinicaltrials.gov/study/NCT05321004.

Toward an understanding of the role of structural organization and point defects in the formation of functional pure and Tm3+-doped (Ca3-xSrx)(VO4)2 for diode-pumped and SRS lasers

Whitlockite-type polycrystalline and single-crystal (Ca3−xSrx)(VO4)2 solid solutions were successfully obtained by solid-state synthesis and Czochralski method, respectively. Synchrotron powder X-ray diffraction allowed to reveal actual compositions of polycrystalline (Ca3−xSrx)(VO4)2 solid solutions with х = 0.3, 0.54, 0.9, 1.2, 1.35 refined by Rietveld method, which are slightly different from the initial ones. Synchrotron X-ray single-crystal diffraction analysis of Czochralski-grown undoped (Ca1.8Sr1.2)(VO4)2 (CSVO) revealed its actual composition (Ca2.982(11)Sr0.031)(VО4)2. Difference between initial and refined compositions is analyzed and discussed. In the CSVO structure, Sr2+ ions partially occupy monocapped Ca2 and two-capped Ca3 trigonal prismatic sites and Ca2+ ions are in the Ca5 and Ca5A sites, forming two independent strongly distorted tetrahedral Ca5O4 and octahedral Ca5AO6 oxygen environments. Synchrotron X-ray single-crystal diffraction analysis together with X-ray absorption spectroscopic study of (Сa2.4Sr0.6)(VO4)2 doped with 0.5 and 1.0 wt% Tm2O3 (СSVO:0.5Tm and CSVO:1.0Tm) allowed to establish the absence of cations in the Ca5A site, the localization of Sr2+ ions in the Ca2 and Ca3 sites and additionally in octahedral Ca4 site together with Tm3+ ions, forming an individual eight-coordinated environment, in the refined compositions (Ca2.776(7)Sr0.210(4)Tm3+0.008(1))(VO4)2 and (Ca2.855(7)Sr0.140(7)Tm3+0.009(1)□0.022(7))(VO4)2, respectively, with vacancies (marked by a square,□) in the two-capped Ca1 trigonal prismatic site in the CSVO:1.0Tm structure. Additional interstitial oxygen, participating in the formation of the Tm3+ environment, found in the residual electron density, together with vacancies in the Ca1 site provides electroneutrality to CSVO:0.5Tm and CSVO:1.0Tm crystals. Several structural models of the coordination environment of Tm3+ ions were analyzed and the most correct one was proposed.

SANS and SAXS: A Love Story to unravel structural evolution of soy proteins and polysaccharide fibres during high moisture extrusion for meat alternatives

Plant-based meat alternatives are seeing considerable interest due to their potential to reduce environmental burden and enhance population health. The food industry, therefore, seeks routes to provide the consumer with whole-cut plant-based products that closely resemble meat products. High-moisture extrusion (HME) of plant proteins enables the industrial manufacturing of meat-like products with highly hierarchical structural organisation of fibres. The major bottleneck in serving the growing market for these products is a lack of insight into how multiscale structures evolve during shear processing. Furthermore, it remains an open question of how two biopolymers, one being a plant protein and the other being a polysaccharide, contribute to the anisotropic structure formation during HME. This study shows how the complementary use of small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS) can add clarity to these matters, benefiting from the different contrasts in scattering length density (SLD) encountered with each of these methods. It is demonstrated that two biopolymers have differences in the development of structural anisotropy. The protein fibril alignment starts in the extruder section with its further development along the cooling die. On the other hand, for polysaccharide fibres, the strongest local alignment has been found in the transition zone.

Septin 7 interacts with Numb to preserve sarcomere structural organization and muscle contractile function.

Here, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.

Septin 7 interacts with Numb to preserve sarcomere structural organization and muscle contractile function

Here, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.

Abstract PO5-21-05: An Endocrine Resistant-Related Gene Signature Revealing the Tumor Microenvironment to Predict the Prognosis of Hormone Receptor-Positive Breast Cancer Patients

Abstract Key words: breast cancer; hormone receptor-positive; predictive model; prognosis; endocrine therapy; drug resistance Hormone receptor positive (HR+) breast cancer is the most common type of breast cancer, accounting for approximately 70% of all breast cancer, in whom endocrine therapy plays a vital role. However, the limited effectiveness of endocrine therapy due to intricate mechanisms of drug resistance poses a significant challenge in treating certain patients. Therefore, it is imperative to identify novel indicators of endocrine resistance and develop new models for predicting recurrence-free survival (RFS) in patients with HR+ breast cancer. In this study, we successfully established an endocrine resistance-related risk model based on multicenter RNA sequencing data. This model could represent tumor microenvironment characteristics and provide valuable insights into predicting the prognosis of HR+ breast cancer patients. A seven gene risk model reflecting endocrine therapy resistance in 208 early HR+ breast cancer patients from two centers was constructed by LASSO analysis and multivariate cox regression. Based on the median value of risk score, patients were divided into high-risk group and low-risk group. Compared with the low-risk group, the high-risk group exhibited a significantly worse prognosis, which showed consistent across two external validation cohorts (TCGA-BRCA and METABRIC cohort). Time dependent ROC curve showed excellent capacity of gene model in predicting 1,3 and 5-year RFS. The IC50 analysis revealed that patients in low-risk group exhibited greater sensitivity to endocrine drugs, such as tamoxifen, fulvestrant and palbociclib, which strongly suggested that the identified gene signature can effectively differentiate between endocrine-resistant and -sensitive status. Gene-set enrichment analysis revealed regulation of cell killing, positive regulation of inflammatory response and T cell mediated cytotoxicity were enriched in low risk group, suggesting immune activation and a higher immune infiltration status. Conversely, the high-risk group demonstrated associations with collagen metabolic process, extracellular matrix structural constituent and collagen fibril organization, which were the indicative of the location and function of cancer-associated fibroblasts (CAFs). As expected, ssGSEA results revealed elevated expression levels of immune cells (e.g., natural killer cells, tumor-infiltrating lymphocytes, CD8+ T cells) and immune functions (e.g., T cell co-stimulation, inflammation-promoting, cytolytic activity) in the low-risk group. However, three diverse acknowledged methods (TIDE, EPIC and MCP-counter) consistently identified CAFs as predominantly content in the high-risk groups. Furthermore, considering that CD8+ T cell is the primary cell type responsible for exerting cytotoxic effects, we observed a negative correlation between CD8+ T cells and CAFs. This suggests that CAFs may inhibit the infiltration of CD8+ T cells, thereby weakening their cytotoxic capabilities, leading to a shorter RFS in high-risk patient groups. In conclusion, a novel gene signature constructed with 7 endocrine resistance response-related genes can be used for prognostic prediction and reflecting the tumor microenvironment status in HR+ early breast cancer. The low-risk group exhibited enhanced anti-tumor immunity, resulting in a favorable prognosis. In contrast, the high-risk group displayed pronounced infiltration of CAFs, indicating their potential to impede immune cell infiltration and impact the efficacy of endocrine drugs through the formation of physical barriers and recruitment of immunosuppressive factors. Consequently, patients in the high-risk group experienced a worse prognosis. Therefore, inhibiting these genes may be a therapeutic option for overcoming endocrine therapy resistance in HR+ breast cancer patients. Citation Format: Xiyu Kang, Jiaxiang Liu, Xin Wang. An Endocrine Resistant-Related Gene Signature Revealing the Tumor Microenvironment to Predict the Prognosis of Hormone Receptor-Positive Breast Cancer Patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-05.