Sequence Of Events Research Articles

Activating Iterative Revolutions of the Cancer-Immunity Cycle in Hypoxic Tumors with a Smart Nano-Regulator.

The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective anti-tumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of non-selective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two non-redundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under NIR light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to down-regulate PD-L1 and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation. This article is protected by copyright. All rights reserved.

Therapeutic Potential of Nanocarrier Mediated Delivery of Peptides for Wound Healing: Current Status, Challenges and Future Prospective.

Wound healing presents a complex physiological process that involves a sequence of events orchestrated by various cellular and molecular mechanisms. In recent years, there has been growing interest in leveraging nanomaterials and peptides to enhance wound healing outcomes. Nanocarriers offer unique properties such as high surface area-to-volume ratio, tunable physicochemical characteristics, and the ability to deliver therapeutic agents in a controlled manner. Similarly, peptides, with their diverse biological activities and low immunogenicity, hold great promise as therapeutics in wound healing applications. In this review, authors explore the potential of peptides as bioactive components in wound healing formulations, focusing on their antimicrobial, anti-inflammatory, and pro-regenerative properties. Despite the significant progress made in this field, several challenges remain, including the need for standardized characterization methods, optimization of biocompatibility and safety profiles, and translation from bench to bedside. Furthermore, developing multifunctional nanomaterial-peptide hybrid systems represents promising avenues for future research. Overall, the integration of nanomaterials made up of natural or synthetic polymers with peptide-based formulations holds tremendous therapeutic potential in advancing the field of wound healing and improving clinical outcomes for patients with acute and chronic wounds.

Using Permutation Tests to Identify Statistically Sound and Nonredundant Sequential Patterns in Educational Event Sequences

Frequent sequential pattern mining is a valuable technique for capturing the relative arrangement of learning events, but current algorithms often return excessive learning event patterns, many of which may be noise or redundant. These issues exacerbate researchers’ burden when interpreting the patterns to derive actionable insights into learning processes. This study proposed permutation tests for identifying sequential patterns whose occurrences are statistically significantly greater than the chance value and different from their superpatterns. Simulations demonstrated that the test for detecting sound patterns had a low false discovery rate and high power, while the test for detecting nonredundant patterns also showed a high accuracy. Empirical data analyses found that the patterns detected in training data were generalizable to test data.

Multimodular Wide-Band Capturing Nanohybrids: Role of Carbon Nanotubes in Slowing Charge Recombination in Supramolecular C60-BisstyrylBODIPY-(Zinc Porphyrin)2 Donor-Acceptor Molecular Cleft.

The importance of diameter-sorted single-wall carbon nanotubes (SWCNTs) noncovalently bound to a donor-acceptor molecular cleft, 1, in prolonging the lifetime of charge-separated states is successfully demonstrated. For this, using a multistep synthetic procedure, a wide-band capturing, multimodular, C60-bisstyrylBODIPY-(zinc porphyrin)2, molecular cleft 1, was newly synthesized and shown to bind diameter-sorted SWCNTs. The molecular cleft and its supramolecular assemblies were characterized by a suite of physicochemical techniques. Free-energy calculations suggested that both the (6,5) and (7,6) SWCNTs bound to 1 act as hole acceptors during the photoinduced sequential electron transfer events. Consequently, selective excitation of 1 in 1:SWCNT hybrids revealed a two-step electron transfer, leading to the formation of charge-separated states. Due to the distant separation of the cation and anion radical species within the supramolecules, improved lifetimes of the charge-separated states could be achieved. The present supramolecular strategy of improving charge separation involving SWCNTs and donor-acceptor molecular clefts highlights the potential application of these hybrid materials for various light energy harvesting and optoelectronic applications.

Dynamic rebalancing optimization for bike-sharing systems: A modeling framework and empirical comparison

Station-based Bike-sharing systems have been implemented in multiple major cities, offering a low-cost and environmentally friendly transportation alternative. As a remedy to unbalanced stations, operators typically rebalance bikes by trucks. The resulting dynamic planning has received significant attention from the Operations Research community. Due to its modeling flexibility, mixed-integer programming remains a popular choice. However, the complex planning problem requires significant simplifications to obtain a computationally tractable model. As a result, existing models have used a large variety of modeling assumptions and techniques regarding decision variables and constraints. Unfortunately, the impact of such assumptions on the solutions’ performance in practice remains generally unexplored.In this paper, we first systematically survey the literature on rebalancing problems and their modeling assumptions. We then propose a general mixed-integer programming model for multi-period rebalancing problems that can be easily adapted to different assumptions, including trip modeling, time discretization, trip distribution, and event sequences. We develop an instance generator to synthesize realistic station networks and customer trips, as well as a realistic fine-grained simulator to evaluate the operational performance of rebalancing strategies. Finally, extensive numerical experiments are carried out, both on the synthetic and real-world data, to analyze the effectiveness of various modeling assumptions and techniques. Based on our results, we identify the assumptions that empirically provide the most effective rebalancing strategies in practice. Specifically, a set of specific trip distribution constraints and event sequences ignored in the previous literature seem to provide particularly good results.

Thermomagnetic instability in superconducting lead-porous glass nanocomposites

In this paper we examine the mechanisms leading to thermomagnetic instability in nanostructured materials and study their regularities. The appearance of thermomagnetic instabilities in the superconducting state of various materials remains one of the problems of applications of superconductors. We studied the temperature and the magnetic field dependences of the magnetization m(T, H) and heat capacity C(T, H) of a nanocomposite consisting of interconnected lead filaments embedded in nanoporous glass (Pb-PG) with filament diameter d = 7 nm. Porous glass contains an arbitrarily orientated multiply connected system of pores of approximately the same size; lead in the nanocomposite forms a replica of the pore system. Thermomagnetic instability was previously observed in this material in superconducting state at T ≤ 5 K on m(H) dependencies in magnetization studies. We established that high enough external heater power P used during the heat capacity measurements in external magnetic field C(H) at T ≤ 5 K can initiate thermomagnetic instability and penetration of magnetic flux into the nanocomposite. The thermomagnetic instability is generally preceded by a sequence of small heat release events with the same magnitude as P. Another sequence of small heat release events is observed in the region close to Hc2. These events are presumably linked to the thermomagnetic instability process and are caused by small redistribution of magnetic flux in the nanocomposite.

So Let's Design a Peptide . . . A Physician's Approach.

This paper outlines a process undertaken by a physician to design a peptide aimed at impacting the extracellular matrix. From a position of very little expertise, a new peptide was designed with amino acid constituents based on the structural proteins collagen and elastin. Sequencing was also considered, given the periodic repetition observed in these proteins, and a peptide with reasonable molecular weight and physical characteristics was designed using available software. The sequence of events concerning intellectual property, functionality investigation, and eventual use of the peptide in new formulations is detailed. This may be of interest to physicians who consider this exercise out of the scope of the usual practice. J Drugs Dermatol. 2024;23(5):347-352.    doi:10.36849/JDD.7921.

Supernova Archaeology with X-Ray Binary Winds: The Case of GRO J1655−40

Supernovae are responsible for the elemental enrichment of the galaxy, and some are postulated to leave behind a black hole. In a stellar binary system, the supernova pollutes its companion, and the black hole can accrete back its own debris and emit X-rays. In this sequence of events, which is only poorly understood, winds are ejected and observed through X-ray absorption lines. Measuring abundances of elements in the wind can lead to inferences about the historical explosion and possibly identify the long-gone progenitor of the compact object. Here, we reanalyze the uniquely rich X-ray spectrum of the 2005 outburst of GRO J1655−40. We reconstruct the absorption measure distribution (AMD) of the wind and find that it increases sharply with ionization from H-like O up to H-like Ca and then flattens out. The AMD is then used to measure the relative abundances of 18 different elements. The present abundances are in partial agreement with a previous work with discrepancies mostly for low-Z elements. The overabundance of odd-Z elements hints at a high-metallicity, high-mass (≃25 M ⊙) progenitor. Interestingly, the abundances are different from those measured in the companion atmosphere, indicating that the wind entrains lingering ambient supernova debris. This can be expected since the current total stellar mass of the binary (<10 M ⊙) is much less than the progenitor mass.

A cross-attention augmented model for event-triggered context-aware story generation

Despite recent advancements, existing story generation systems continue to encounter difficulties in effectively incorporating contextual and event features, which greatly influence the quality of generated narratives. To tackle these challenges, we introduce a novel neural generation model, EtriCA, that enhances the relevance and coherence of generated stories by employing a cross-attention mechanism to map context features onto event sequences through residual mapping. This feature capturing mechanism enables our model to exploit logical relationships between events more effectively during the story generation process. To further enhance our proposed model, we employ a post-training framework for knowledge enhancement (KeEtriCA) on a large-scale book corpus. This allows EtriCA to adapt to a wider range of data samples. This results in approximately 5% improvement in automatic metrics and over 10% improvement in human evaluation. We conduct extensive experiments, including comparisons with state-of-the-art (SOTA) baseline models, to evaluate the performance of our framework on story generation. The experimental results, encompassing both automated metrics and human assessments, demonstrate the superiority of our model over existing state-of-the-art baselines. These results underscore the effectiveness of our model in leveraging context and event features to improve the quality of generated narratives.

X-Rays from a Central “Exhaust Vent” of the Galactic Center Chimney

Using deep archival observations from the Chandra X-ray Observatory, we present an analysis of linear X-ray-emitting features located within the southern portion of the Galactic center chimney and oriented orthogonal to the Galactic plane, centered at coordinates l = 0.°08, b = −1.°42. The surface brightness and hardness ratio patterns are suggestive of a cylindrical morphology, which may have been produced by a plasma outflow channel extending from the Galactic center. Our fits of the feature’s spectra favor a complex two-component model consisting of thermal and recombining plasma components, possibly a sign of shock compression or heating of the interstellar medium by outflowing material. Assuming a recombining plasma scenario, we further estimate the cooling timescale of this plasma to be on the order of a few hundred to thousands of years, leading us to speculate that a sequence of accretion events onto the Galactic black hole may be a plausible quasi-continuous energy source to sustain the observed morphology.

Labour market trajectories and unemployment of older workers in Europe after the Great Recession

AbstractMany European countries want to overcome the early exit from labour market which was widespread since the 1970s through pension reform and labour policies. The extension of working life is hindered by factors that the literature overlooks. This article focuses on the discontinuity of the late‐career caused by unemployment. The aim is to investigate whether older workers are at risk of unemployment and what are the transitions after spells of unemployment. The labour market trajectories of workers over 50s in 11 European countries from 2006 to 2019 were analysed, specifically after the Great Recession and before the Covid‐19 epidemic. It is based on longitudinal survey data from the generated Survey of Health, Ageing and Retirement in Europe Job Episodes Panel. Event history analysis and sequence analysis were performed. Older employees are unlikely to face unemployment. The transition rate highlights the difficulty for older workers into re‐employment. A low education level increases the risk of unemployment and remaining unemployed. Data by country confirm the trend towards overcoming the transition from unemployment to early exit. Divergences concern the higher risk of being trapped in unemployment in Southern European countries such as Greece and Italy.

Queering a Trans Life Story: The Unnatural Potential of Weak Narrativity in succubus in my pocket

ABSTRACT: Discussing similarities between antimimetic and queer/trans narratives, as well as interlacing subjects of interest in the respective fields of unnatural and queer/trans narratology, this article suggests the importance of experimental texts for theorizing trans narratives. It presents its arguments by focusing on one case study, a mixed genre manuscript written in 2004 and published in 2015, succubus in my pocket by the late trans poet kari edwards (1954–2006). My approach mines queer narratology (Susan Lanser), trans poetics (Trace Peterson), unnatural narratology (Brian Richardson), and the study of narrative poetry (Brian McHale) for conceptual tools to discuss how an extremely antimimetic narrative entwines transgressions of narrative expectations with transgressions of expectations about sex and gender. The work invites narrative interpretations of sequential events based on causal expectations while consistently refuting default interpretive strategies. This article shows how weak narrativity can be deployed as a critique of narrative sense-making processes in general and, more particularly, of conventional progression in narratives about trans lives.

Dynamically driven correlations in elastic net models reveal sequence of events and causality in proteins.

An explicit analytic solution is given for the Langevin equation applied to the Gaussian Network Model of a protein subjected to both a random and a deterministic periodic force. Synchronous and asynchronous components of time correlation functions are derived and an expression for phase differences in the time correlations of residue pairs is obtained. The synchronous component enables the determination of dynamic communities within the protein structure. The asynchronous component reveals causality, where the time correlation function between residues i and j differs depending on whether i is observed before j or vice versa, resulting in directional information flow. Driver and driven residues in the allosteric process of cyclophilin A and human NAD-dependent isocitrate dehydrogenase are determined by a perturbation-scanning technique. Factors affecting phase differences between fluctuations of residues, such as network topology, connectivity, and residue centrality, are identified. Within the constraints of the isotropic Gaussian Network Model, our results show that asynchronicity increases with viscosity and distance between residues, decreases with increasing connectivity, and decreases with increasing levels of eigenvector centrality.

The Use of Fast-Acting Insulin Topical Solution on Skin to Promote Surgical Wound Healing in Cats.

Wound healing is a complex biological process involving a coordinated sequence of events aimed at restoring tissue integrity and function. Recent advancements in wound care have introduced novel therapies, with topical insulin application emerging as a promising strategy for promoting tissue healing. This study, involving 60 female cats (n = 60) undergoing elective spaying, aimed to evaluate the effects of topical fast-acting insulin on the healing process of surgical wounds. Each surgical suture was divided into two regions: the control zone (Zcr) without insulin application and the study zone (Zst), where insulin was applied topically for 10 min every 24 h over eight consecutive days. Assessment of suture healing was conducted using an adapted scale at two time points post-surgery: T1 (day 2) and T2 (day 8). Statistically significant differences were registered in the final healing scale scores between Zcr and Zst (p < 0.022), as well as for the parameter of regional fluid (p-value = 0.017). Additionally, at T2, all Zst regions exhibited wound closure, whereas Zcr did not, although not in a statistically significant manner. The observed discrepancy at T2 between the Zcr and Zst regions may suggest a potential benefit of utilizing insulin. No side effects resulting from the insulin topical application performed by the tutors were recorded in the Zst suture group. This study represents the first exploration of the benefits of topical insulin application for surgical wound healing in cats.

The development of a model of decision-making during an act of serious violence using the Critical Decision Method

ABSTRACT To date, psychological theories of aggression have shown limited applicability to the first-hand experience of real-world violence. Examining the experiences of those directly involved in violent offending, may enable professionals to develop a strengthened and more refined understanding. The current study aimed to develop a theoretical model of offender experiences of decision-making, during the commission of a violent offence. The Critical Decision Method (CDM) for cognitive task analysis was conducted within a British prison, with nine participants who had been convicted of a serious violent offence. Interview transcripts were analysed using constructivist Grounded Theory (CGT). Seven themes were interpreted from participant narratives: (i) predisposing influences, (ii) environment, (iii) emotion, (iv) triggering events, (v) decision to act, (vi) identity and (vii) severity of harm caused to the victim. Participants’ narratives were found to focus upon a process of decision-making which followed a sequence of events, from the impact of early experiences, through to the in-the-moment decisions, that led to acting in a violent manner. This study provides novel insights into the experience of violent decision-making. Participants emphasised the role of emotion and identity. A range of clinical implications are discussed which highlight the important role of emotion regulation and identity transformation in the rehabilitation of violent offenders.

Multi-physics analysis of SBLOCA by coupled Neutronics/Thermal-Hydraulics full plant model

With the development of computational tools, the accident analysis would be performed by best estimate approaches. The employment of multi-physics codes would be considered as new calculation procedure to obtain high valuable results by improving calculations with specialized codes. The small break loss of coolant accident (SBLOCA) is an accident that has typically been analyzed using system codes with a limited number of Thermal-Hydraulics (TH) channels in the core region, neglecting the use of multi-physics calculations. This approach results in insufficient accuracy and resolution in both neutronics and TH calculations within the core zone. To address this issue, this study proposes the implementation of a Neutronics/Thermal-Hydraulics coupling with one-to-one mapping in the core zone, achieved through the development of a comprehensive plant TH model. This approach aims to enhance the accuracy and resolution of calculations, enabling the identification of local phenomena, parameters, and feedback during accident simulations, and the incorporation of these effects on the macroscopic cross-sections at each time step. The results of SBLOCA simulation reveals the effects of conservative/best estimate approach on the sequence of events, the initiation time of the safety systems, the critical controlled parameters of the power plant, and the precise understanding of the accident. Also, it was found that the radial power distribution becomes disrupted and loses its symmetry immediately after the SCRAM leading to different characteristics of steam generators (SGs) and natural circulation flow rate in each loop of primary side.

Microbial Symphony: Exploring the Role of the Gut in Osteoarthritis-Related Pain. A Narrative Review.

One of the most common musculoskeletal disorders, osteoarthritis (OA), causes worldwide disability, morbidity, and poor quality of life by degenerating articular cartilage, modifying subchondral bone, and inflaming synovial membranes. OA pathogenesis pathways must be understood to generate new preventative and disease-modifying therapies. In recent years, it has been acknowledged that gut microbiota (GM) can significantly contribute to the development of OA. Dysbiosis of GM can disrupt the "symphony" between the host and the GM, leading to a host immunological response that activates the "gut-joint" axis, ultimately worsening OA. This narrative review summarizes research supporting the "gut-joint axis" hypothesis, focusing on the interactions between GM and the immune system in its two main components, innate and adaptive immunity. Furthermore, the pathophysiological sequence of events that link GM imbalance to OA and OA-related pain is broken down and further investigated. We also suggest that diet and prebiotics, probiotics, nutraceuticals, exercise, and fecal microbiota transplantation could improve OA management and represent a new potential therapeutic tool in the light of the scarce panorama of disease-modifying osteoarthritis drugs (DMOADs). Future research is needed to elucidate these complex interactions, prioritizing how a particular change in GM, i.e., a rise or a drop of a specific bacterial strain, correlates with a certain OA subset to pinpoint the associated signaling pathway that leads to OA.

The nature of chronic rejection after lung transplantation: a murine orthotopic lung transplant study.

Chronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation. 40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling. Chronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset. Against the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD.

OA17 An unusual cause of unilateral retroperitoneal fibrosis

Abstract Background/Aims Retroperitoneal fibrosis (RPF) is a rare condition, with an incidence of around 1 per 200,000 to 500,000 per year. It is distinguished by fibro-inflammatory changes in the retroperitoneum, which typically surrounds the abdominal aorta. Idiopathic RPF is common, whilst secondary causes can result from drug therapies, infection, malignancy, or surgery. Early symptoms include dull, poorly-localised back or flank pain, and lower limb swelling. The classical focal mass of primary retroperitoneal fibrosis is typically situated over the distal aorta, anterior to the L4 and L5 vertebra. External compression of the ureter can result in hydronephrosis due to prevention of normal ureteric urinary peristalsis. Management options are limited, generally involving immunosuppression and urological surgery, often necessitating cross-specialty, multidisciplinary input. Methods We report the case of a young gentleman with no past medical or family history who presented with abdominal pain, vomiting, septic shock and metabolic acidosis. To exclude acute abdominal pathology, computed tomography (CT) abdomen and pelvis was performed. Incidentally, this found chronic inflammatory changes in the descending colon and right retroperitoneal soft tissue thickening causing severe right hydroureteronephrosis. This incidental finding of retroperitoneal fibrosis on CT scan prompted an exploration into infective, inflammatory, and malignant aetiological causes of retroperitoneal fibrosis. Results Following initial stabilisation, urological opinion was sought, which concluded that surgical intervention for ureteric stenting was unnecessary. This decision was supported by the absence of obstruction from fibrosis and the lack of signs indicating infection. No medical explanation was found for the initial presentation in extremis. Rheumatological advice was sought for consideration of biopsy and immunosuppressive therapy for this suspected primary retroperitoneal fibrosis. Upon inquiry, the patient divulged a historical occurrence of retroperitoneal fluid accumulation secondary to a paravertebral mass that mandated laparoscopic drainage four years ago overseas. Histopathological analysis of the mass confirmed the presence of tuberculosis (TB), which was treated. His recovery was complicated at that time by right-sided hydronephrosis and fibrosis necessitating decompression. This sequence of events was deemed by a radiologist to also account for the observed bowel findings in the right flank. Conclusion This case report is the first of its kind to document TB, or any infective aetiology, as being the primary cause of unilateral retroperitoneal fibrosis. Unilateral retroperitoneal fibrosis is incredibly rare, and there are only four English language case reports in the literature. Idiopathic RPF typically presents as bilateral concentric tissue around the abdominal aorta, whilst secondary causes can lead to unconventional imaging patterns, as seen in this case. It was only upon direct inquiry that the patient disclosed a prior diagnosis of TB affecting the lumbar spine. This case highlights the importance of meticulous history taking and systematic exclusion of secondary causes of RPF, prior to contemplating invasive biopsies and steroid therapy. Disclosure D. Li: None. M. Renju: None.

AmplificationTimeR: An R Package for Timing Sequential Amplification Events.

Few methods exist for timing individual amplification events in regions of focal amplification. Current methods are also limited in the copy number states that they are able to time. Here we introduce AmplificationTimeR, a method for timing higher level copy number gains and inferring the most parsimonious order of events for regions that have undergone both single gains and whole genome duplication. Our method is an extension of established approaches for timing genomic gains. We can time more copy number states, and in states covered by other methods our results are comparable to previously published methods. AmplificationTimer is freely available as an R package hosted at https://github.com/Wedge-lab/AmplificationTimeR. Supplementary data are available at Bioinformatics online.