Complex Process Research Articles

The cellular composition of chronic subdural hematoma

IntroductionThe pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence.This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH.MethodsSystemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit.ResultsOf the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017).ConclusionThis study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence.Clinical trial registrationThe study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073.

Admission plasma concentration of neutrophil gelatinase-associated lipocalin and -C-reactive protein have additive prognostic value in patients with STEMI

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by Righospitalets Forskningsfond (07IO) Lundbeck Foundation (R186-2015-2132). Background Inflammation plays an apparent critical role in patients with acute coronary syndrome (ACS) and is associated with mortality. However, the complex process is poorly understood. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker originating from mature neutrophils and renal tubular cells. It has previously been shown to be associated with mortality and acute kidney injury in ACS patients. In this study we sought to assess the potential additive prognostic value of NGAL and its relation to other markers of inflammation. Methods In 1556 consecutive ST-elevation myocardial infarction (STEMI) patients, NGAL and C-reactive protein (CRP) plasma concentration were measured at hospital admission, before acute coronary angiography. Patients were stratified to plasma concentration of both biomarkers &amp;gt;/&amp;lt; the median concentration into 4 groups (low NGAL/ low CRP (group 1), low NGAL/high CRP (2), high NGAL/low CRP (3), high NGAL/high CRP(4)). Primary outcome was 30-day all-cause mortality. Results In total, 477 (31%), 324 (21%), 316 (20%), and 439 (28%) patients were stratified in group 1-4, respectively. With 0, 1, or 2 biomarker plasma concentration above the median (group 1 – 4), patients were older (61 – 67 years old, p&amp;lt;0.0001), had more comorbidity (hypertension (40 – 53%), p=0.002; previous stroke (4.0 – 9.9%), p=0.007; peripheral arterial disease (PAD) (2.6 – 10%), p&amp;lt;0.0001; chronic kidney dysfunction (CKD) (0.6 – 11%), p&amp;lt;0.0001) and more critical per-infarction circumstances (time from symptom debut to angiography (170 – 229 minutes), p&amp;lt;0.0001; cardiogenic shock (1.3 – 14%), p&amp;lt;0.0001, cardiac arrest (0.8 – 3.4%), p=0.0002) and lower left ventricular ejection fraction (LVEF) (48 – 43%, p&amp;lt;0.0001). Increased NGAL and CRP was associated with 30-day all-cause mortality (Figure A). Only high NGAL/high CRP was independently associated with 30-day mortality in a cox proportional hazard model when adjusting for age, hypertension, previous stroke, CKD, LVEF, and cardiogenic shock (HR (95% CI) 5.19 (1.20 – 22.52), p=0.03). Both CRP and NGAL had significant predictive value of 30-day mortality (AUC ROC 0.67, p&amp;lt;0.0001 and 0.78, p&amp;lt;0.0001, respectively). Combining NGAL and CRP did, however, not increase the predictive value of NGAL alone (AUC ROC 0.77, p=0.86) (Figure B). Conclusion Combined admission NGAL and CRP plasma concentration was independently associated with 30-day all-cause mortality in STEMI patients. Adding CRP to NGAL did, however, not increase the predictive value.Figure AFigure B

Visible-Light-Promoted C3-Sulfenylindoles with Arylsulfonyl Chlorides via Electron Donor-Acceptor Complex.

In this study, we present an efficient approach for the synthesis of 3-sulfenyl indoles through an electron donor-acceptor (EDA) complex-promoted photoreaction. This sulfenylation reaction leverages sulfonyl chlorides as the sulfur source and employs PPh3 as the reductant without the need for any transition-metal catalyst or photocatalyst. At the same time, the relaxation process of the excited EDA complex was theoretically investigated at the method and multiconfiguration second-order perturbation//complete active space self-consistent field/PCM level of theory, which involves the π bond of indoles injecting an electron to the antibonding orbital of the S-Cl bond in arylsulfonyl chlorides.

Deciphering Charge Transfer Processes in Transition Metal Complexes from the Perspective of Ultrafast Electronic and Nuclear Motions.

Chemical transformations in charge transfer states result from the interplay between electronic dynamics and nuclear reorganization along excited-state trajectories. Here, we investigate the ultrafast structural dynamics following photoinduced electron transfer from the metal-metal-to-ligand charge transfer state of an electron donor, a Pt dimer complex, to a covalently linked electron acceptor group using ultrafast time-resolved wide-angle X-ray scattering and optical transient absorption spectroscopy methods to disentangle the interdependence of the excited-state electronic and nuclear dynamics. Following photoexcitation, Pt-Pt bond formation and contraction takes up to 1 ps, much slower than the corresponding process in analogous complexes without electron acceptor groups. Because the Pt-Pt distance change is slow with respect to excited-state electron transfer, it can affect the rate of electron transfer. These results have potential impacts on controlling electron transfer rates via structural alterations to the electron donor group, tuning the charge transfer driving force.

Resonant Akhmediev breathers

Modulation instability is a phenomenon in which a minor disturbance within a carrier wave gradually amplifies over time, leading to the formation of a series of compressed waves with higher amplitudes. In terms of frequency analysis, this process results in the generation of new frequencies on both sides of the original carrier wave frequency. We study the impact of fourth-order dispersion on this modulation instability in the context of nonlinear optics that lead to the formation of a series of pulses in the form of Akhmediev breather. The Akhmediev breather, a solution to the nonlinear Schrödinger equation, precisely elucidates how modulation instability produces a sequence of periodic pulses. We observe that when weak fourth-order dispersion is present, significant resonant radiation occurs, characterized by two modulation frequencies originating from different spectral bands. As an Akhmediev breather evolves, these modulation frequencies interact, resulting in a resonant amplification of spectral sidebands on either side of the breather. When fourth-order dispersion is of intermediate strength, the spectral bandwidth of the Akhmediev breather diminishes due to less pronounced resonant interactions, while stronger dispersion causes the merging of the two modulation frequency bands into a single band. Throughout these interactions, we witness a complex energy exchange process among the phase-matched frequency components. Moreover, we provide a precise explanation for the disappearance of the Akhmediev breather under weak fourth-order dispersion and its resurgence with stronger values. Our study demonstrates that Akhmediev breathers, under the influence of fourth-order dispersion, possess the capability to generate infinitely many intricate yet coherent patterns in the temporal domain.

Optimization of ultrasonic pretreatment and analysis of chlorogenic acid in potato leaves

Chlorogenic acid (CA) is an effective ingredient that can strengthen immunity during following the COVID-19 era. The current cost of CA is high owing to its complex purification process and low yield (approximately 2%). In this study, a one-step path orthogonal experiment was designed based on the results from Gauss calculation, which consisted of acidity, coordination, and hydrolysis in molecules. The optimized extraction conditions were 60 ℃, 60 min, 1:20 liquid ratio, and 40% ethanol in a nitrogen atmosphere controlled using a device of our own design, which led to CA yields of up to 6.35% from potato leaves. The purified CA was analyzed using high-performance liquid chromatography, thin-layer chromatography, ultraviolet–visible spectroscopy, and molecular fluorescence. This accurate and reproducible method can not only be used to obtain high yields of CA but can also be used for the quality control of active plant products and their isomers.

Integrated multi-omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex.

Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions. Skeletal muscles from 2-month-old SPEG-deficient (Speg-CKO) and wild-type (WT) mice were used for RNA sequencing (n=4 per genotype) to profile transcriptomics and mass spectrometry (n=4 for WT; n=3 for Speg-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings. We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22±3% for CMYA5 [P<0.05] and 18±3% for FSD2 [P<0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55±15% at S2902 in Speg-CKO mice; P<0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90±0.24-fold], S162 [1.61±0.37-fold] and S165 [1.66±0.13-fold]; decreased phosphorylation at S228 and S231 [39±6%], S234 [50±12%], S593 [48±3%] and S613 [66±10%]; P<0.05 for S162 and P<0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction (P<1e-15) and peroxisome proliferator-activated receptor signalling (P<9e-14). We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG-interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi-omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders.

The influence of perceived stress in acute coronary syndromes presentation

Abstract Funding Acknowledgements None. Introduction Acute coronary syndrome (ACS) is the result of a complex pathophysiological process, influenced by multiple factors, including stress. The 10-item Perceived Stress Scale (PSS-10) is a validated instrument to estimate stress levels in clinical practice and may be useful in the assessment of ACS (Figure 1). Purpose We aimed to assess if perceived stress had influence on the presentation of an ACS as a ST-elevation myocardial infarction (STEMI) or a non-ST-elevation myocardial infarction (NSTEMI), at admission, during hospitalization for this event, and at follow-up. Methods Single-center prospective study engaging patients hospitalized for ACS from 20/03/2019 to 31/03/2020. The PSS-10 was completed during the hospitalization period. Patients were divided into two groups, according to the type of ACS: group A – STEMI patients - and group B - NSTEMI patients. Follow-up of these patients (regarding death, readmissions for cardiac causes and readmissions for other causes) was carried out until December 11, 2022. Logistic regression was performed to assess if stress was a predictor of NSTEMI. Results A total of 166 patients were included: 52 in group A and 94 in group B. In group A, mean age was 63 ± 18 years and 34.60% were women, while in group B mean age was 66 ± 20 years, and 38.70% were female. Group B presented more with preserved ejection fraction (79.30% vs 60.40% in group A, p=0.018). There were no other statistically significant differences regarding clinical presentation, or intrahospital complications between the two groups. PSS-10 score in group A was 17.17 ± 8.62, while group B scored 20.83 ± 6.10 (p=0.039). The follow-up of these two groups did not show significant differences in terms of death (7.70% in group A vs 16.10% in group B, p=0.149), readmissions for other causes (19.20% in group A vs 28.00% in group B, p=0.243) or readmissions for cardiac causes (group A 9.60% and group B 22.60%, p=0.051). Logistic regression revealed that perceived stress was a predictor of NSTEMI (odds ratio (OR) 1.006, p=0.025, confidence interval (CI) 1.001-1.011). There were no statistically significant differences in follow-up between the two groups. Conclusions This is the first prospective study carried out in the Portuguese population regarding this thematic, which showed that perceived stress was a predictor of NSTEMI and can influence patients with ACS manifestations.Figure 1

Drug discovery and development in the era of artificial intelligence: From machine learning to large language models

Drug Research and Development (R&D) is a complex and difficult process, and current drug R&D faces the challenges of long time span, high investment, and high failure rate. Machine learning, with its powerful learning ability to characterize big data and complex networks, is increasingly effective to improve the efficiency and success rate of drug R&D. Here we review some recent examples of the application of machine learning methods in six areas: disease gene prediction, virtual screening, drug molecule generation, molecular attribute prediction, and prediction of drug combination synergism. We also discuss the advantages of integrative learning in multi-attribute prediction. Integrative models based on base learners constructed from data of different dimensions on the one hand fully utilize the information contained in these data, and on the other hand improve the average prediction performance. Finally, we envision a new paradigm for drug discovery and development: a large language model acts as a central hub to organize public resources into a knowledge base, validating the knowledge with computational software and smaller predictive models, as well as high-throughput automated screening platforms based on organoidal technologies, to speed up development and reduce the differences in efficacy between disease models and humans to improve the success rate of a drug.

Encoding of self-initiated actions in axon terminals of the mesocortical pathway.

The initiation of goal-directed actions is a complex process involving the medial prefrontal cortex and dopaminergic inputs through the mesocortical pathway. However, it is unclear what information the mesocortical pathway conveys and how it impacts action initiation. In this study, we unveiled the indispensable role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. To investigate the role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. We designed a lever-press task in which mice internally determine the timing of the press, receiving a larger reward for longer waiting periods. Our study revealed that self-initiated actions depend on dopaminergic signaling mediated by D2 receptors, whereas sensory-triggered lever-press actions do not involve D2 signaling. Microprism-mediated two-photon calcium imaging further demonstrated ramping activity in mesocortical axon terminals approximately 0.5s before the self-initiated lever press. Remarkably, the ramping patterns remained consistent whether the mice responded to cues immediately for a smaller reward or held their response for a larger reward. We conclude that mesocortical dopamine axon terminals encode the timing of self-initiated actions, shedding light on a crucial aspect of the intricate neural mechanisms governing goal-directed behavior.

Smoothing in linear multicompartment biological processes subject to stochastic input

Many physical and biological systems rely on the progression of material through multiple independent stages. In viral replication, for example, virions enter a cell to undergo a complex process comprising several disparate stages before the eventual accumulation and release of replicated virions. While such systems may have some control over the internal dynamics that make up this progression, a challenge for many is to regulate behavior under what are often highly variable external environments acting as system inputs. In this work, we study a simple analog of this problem through a linear multicompartment model subject to a stochastic input in the form of a mean-reverting Ornstein-Uhlenbeck process, a type of Gaussian process. By expressing the system as a multidimensional Gaussian process, we derive several closed-form analytical results relating to the covariances and autocorrelations of the system, quantifying the smoothing effect discrete compartments afford multicompartment systems. Semianalytical results demonstrate that feedback and feedforward loops can enhance system robustness, and simulation results probe the intractable problem of the first passage time distribution, which has specific relevance to eventual cell lysis in the viral replication cycle. Finally, we demonstrate that the smoothing seen in the process is a consequence of the discreteness of the system, and does not manifest in systems with continuous transport. While we make progress through analysis of a simple linear problem, many of our insights are applicable more generally, and our work enables future analysis into multicompartment processes subject to stochastic inputs. Published by the American Physical Society 2024

Practice What You Preach!

Contemporary urban planning is a highly complex process, often spanning many years and involving many different types of stakeholders. Western countries and cities are increasingly conducting construction and involvement processes along the same lines. However, there continue to be significant cultural and geographical differences in how designers, planners, developers, and citizens understand those concepts. This paper aims to give a practitioner’s perspective on how the design and planning process works in a Danish context. It does so by contextualizing Danish planning and elaborating on the tricky choices faced by designers and planners, elaborating on the specific philosophy of SLA. It then finishes by going through some of the projects that SLA designed to give the reader an understanding of the involvement process, design, and learnings.

Mesoscopic precursor anomaly characteristics of red sandstone under uniaxial compression after cyclic high-temperatures

The deformation and failure characteristics of rock caused by periodic changes of temperature are not only significantly different from that under normal temperature, but also significantly different from that produced by a single high-temperature event. Here, using a three-dimensional digital image correlation (3D-DIC) integrated test system, mechanical and micro-damage tests of red sandstone are performed under cycles of high-temperature and natural-cooling with a temperature range of 25°C to 300°C and the number of cycles varying between 0 and 25. Macroscopic, mesoscopic and microscopic characteristics such as rock strength, deformation, strain field and fracture morphology are examined and their evolution with the number of heating-cooling cycles is discussed. Using the time-history evolution of the differentiation rate of the precursor anomaly (En), the characteristic coefficient (K) and the damage variable (DF), three kinds of characteristic time points are put forward to quantify the incubation and development time of precursor abnormal characteristics and are used to divide the whole process of deformation and failure. These time points are the precursor abnormal differentiation time (PADT) tE, the precursor abnormal startup time (PAST) tK, and the precursor abnormal failure time (PAFT) tD. Test results show that: (1) The action of cyclic high-temperature natural-cooling not only shows the strengthening effect of temperature, but also shows the strengthening effect of a certain number of cycles. (2) The evolution sequence of the three precursor abnormal characteristic moments is PADT, PAST and PAFT in turn, and this sequence can intuitively describe the whole complex process of rock deformation and failure, and there are wave peaks in the evolution curve with the number of high-temperature cycle. (3) The effect of high temperature (i.e., 300°C) cyclic heating on rock properties is similar to the threshold effect of a single high-temperature heating event.

Challenges in facilitators’ professional development – complexities within a scaling up process as reasons for dropout

In-service courses for teachers are often provided by so called facilitators who function as teacher trainers and whose tasks in the education system are multifaceted. The professional development (PD) of facilitators is of great importance, and the complex process of scaling up might lead to unexpected constraints, and influence the effectiveness of a program. In general, more research is needed concerning facilitators’ PD with respect to their different roles and functions. In this paper, a project will be presented that focused on qualifying facilitators for the topic “inclusive mathematics” and accompanied the process of scaling up. In the end, unexpectedly, five out of 15 facilitators did not finish the program. Therefore, the challenges and concrete reasons for dropout were investigated in detail. The paper will present a case analysis, where Facilitators’ multifaceted roles, functions, and tasks emerged as the central category. Moreover, conclusions for professionalization programs and research will be derived and discussed.

ΔNp63 regulates Sfrp1 expression to direct salivary gland branching morphogenesis

Branching morphogenesis is a complex process shared by many organs including the lungs, kidney, prostate, as well as several exocrine organs including the salivary, mammary and lacrimal glands. This critical developmental program ensures the expansion of an organ’s surface area thereby maximizing processes of cellular secretion or absorption. It is guided by reciprocal signaling from the epithelial and mesenchymal cells. While signaling pathways driving salivary gland branching morphogenesis have been relatively well-studied, our understanding of the underlying transcriptional regulatory mechanisms directing this program, is limited. Here, we performed in vivo and ex vivo studies of the embryonic mouse submandibular gland to determine the function of the transcription factor ΔNp63, in directing branching morphogenesis. Our studies show that loss of ΔNp63 results in alterations in the differentiation program of the ductal cells which is accompanied by a dramatic reduction in branching morphogenesis that is mediated by dysregulation of WNT signaling. We show that ΔNp63 modulates WNT signaling to promote branching morphogenesis by directly regulating Sfrp1 expression. Collectively, our findings have revealed a novel role for ΔNp63 in the regulation of this critical process and offers a better understanding of the transcriptional networks involved in branching morphogenesis.

P21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells.

The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.

Investigation of the effect of anisotropy on Generalized Forming Limit Diagram

In contemporary industrial practices, various methods are employed to subject raw metal sheets to deformation in order to fabricate requisite components. These sheets exhibit a defined capacity for deformation during the forming process. Over recent decades, a plethora of experimental and numerical methodologies have emerged to ascertain these forming limits. Initially, a forming limit diagram (FLD) was devised, predicated on the phenomenon of necking, under the assumption that forming takes place under plane-stress conditions. However, in certain complex processes like hydroforming and incremental forming, necking can manifest at sites where normal and through-thickness shear stresses act upon the sheet in addition to the in-plane stresses, rendering the plane-stress assumption inadequate for predicting forming limits in such scenarios. Thus, it becomes imperative to derive a diagram that can accurately forecast forming limits in these processes. This study aims to establish a Generalized Forming Limit Diagram (GFLD) through numerical means. GFLDs were constructed utilizing two distinct yield functions, namely Von-Mises and Hill48, for isotropic and anisotropic states, respectively. The findings reveal that normal compressive stress and through-thickness shear strain augment the formability of sheet metals. Furthermore, the outcomes illustrate that accounting for anisotropy introduces variances between diagrams in some regions of the FLD curve while the discrepancies are minor within the central regions.

Diagnostic Tool for Early Detection of Rheumatic Disorders Using Machine Learning Algorithm and Predictive Models

Background: Rheumatic diseases are chronic diseases that affect joints, tendons, ligaments, bones, muscles, and other vital organs. Detection of rheumatic diseases is a complex process that requires careful analysis of heterogeneous content from clinical examinations, patient history, and laboratory investigations. Machine learning techniques have made it possible to integrate such techniques into the complex diagnostic process to identify inherent features that lead to disease formation, development, and progression for remedial measures. Methods: An automated diagnostic tool using a multilayer neural network computational engine is presented to detect rheumatic disorders and the type of underlying disorder for therapeutic strategies. Rheumatic disorders considered are rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus. The detection system was trained and tested using 70% and 30% respectively of labelled synthetic dataset of 100,000 records containing both single and multiple disorders. Results: The detection system was able to detect and predict underlying disorders with accuracy of 97.48%, sensitivity of 96.80%, and specificity of 97.50%. Conclusion: The good performance suggests that this solution is robust enough and can be implemented for screening patients for intervention measures. This is a much-needed solution in environments with limited specialists, as the solution promotes task-shifting from the specialist level to the primary healthcare physicians.

Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer

Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial–mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT. Utilizing a high throughput screen of FDA-approved compounds, we uncovered a novel role of the topoisomerase inhibitor, Teniposide, in reversing EMT. Here, we demonstrate Teniposide as a potent modulator of the EMT program, specifically through an IRF7–NMI mediated response. Furthermore, Teniposide significantly reduces the expression of the key EMT transcriptional regulator, Zinc Finger E-Box Binding Homeobox 2 (ZEB2). ZEB2 downregulation by Teniposide inhibited RNA polymerase I (Pol I) activity and rRNA biogenesis. Importantly, Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells. We have uncovered a novel role of Teniposide, which when used at a very low concentration, mitigates mesenchymal-like invasive phenotype. Overall, its ability to target EMT and rRNA biogenesis makes Teniposide a viable candidate to be repurposed as a therapeutic option to restrict breast cancer metastases.

Shell analysis by different methods of dynamic relaxation

Shell analysis is a complex process. So far, many equations and theories have been proposed. With the increasing processing power of computers, numerical and approximate solutions were developed. The dynamic relaxation scheme is one of these methods. This procedure is an explicit technique for solving simultaneous equations. The fictitious mass and damping are added to the system of static structural equations in the dynamic relaxation technique to obtain a fictitious dynamic system. In this paper, 12 well-known dynamic relaxation processes were used for the linear analysis of shells. It is found that so far, the ability of many solutions of dynamic relaxation in the linear analysis of shells has not been shown. In each approach, the mass, damping and time step matrices are obtained based on the researchers’ work. Twelve samples are analysed. Most of these are examples of well-known benchmarks in non-linear analysis. The number of iterations and the analysis time gives the score of each technique. Then, the final rank of each method was obtained. Numerical solutions show that minimising the residual energy was the best process for linear shell analysis. Also, minimising the error of displacement, Zhang, Qiang and the power iteration methods behaved very similarly to each other.