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Abstract Recently, new centrifugation protocols for the preparation of platelet-rich fibrin (PRF) have been introduced in an attempt to further improve the beneficial impact of these 2nd generation platelet concentrate membranes. This in-vitro study aimed to compare the biological and physical characteristics of three types of PRF membranes using two different centrifuges with adapted relative centrifugal forces (RCF): leucocyte- and platelet-rich fibrin, advanced platelet-rich fibrin, and advanced platelet-rich fibrin+. Release of growth factors, macroscopic dimensions, cellular content and mechanical properties of the respective membranes, prepared from blood of the same individual were explored. Furthermore, the impact of timing (blood draw-centrifugation and centrifugation-membrane preparation) was assessed morphologically as well as by electron microscopy scanning. No statistically significant differences amongst the three PRF modifications could be observed, neither in their release of growth factors or the cellular content, nor in clot/membrane dimensions. The difference between both centrifuges were negligible when the same g-force was used. A lower g-force, however, reduced membrane tensile strength. Timing in the preparation process had a significant impact. Adaptation of RCF only had a minimal impact on the final characteristics of PRF membranes.

The benefits of incorporating process information in a large-scale assessment with the complex micro-level evidence from the examinees (i.e., process log data) are well documented in the research across large-scale assessments and learning analytics. This study introduces a deep-learning-based approach to predictive modeling of the examinee's performance in sequential, interactive problem-solving tasks from a large-scale assessment of adults' educational competencies. The current methods disambiguate problem-solving behaviors using network analysis to inform the examinee's performance in a series of problem-solving tasks. The unique contribution of this framework lies in the introduction of an "effort-aware" system. The system considers the information regarding the examinee's task-engagement level to accurately predict their task performance. The study demonstrates the potential to introduce a high-performing deep learning model to learning analytics and examinee performance modeling in a large-scale problem-solving task environment collected from the OECD Programme for the International Assessment of Adult Competencies (PIAAC 2012) test in multiple countries, including the United States, South Korea, and the United Kingdom. Our findings indicated a close relationship between the examinee's engagement level and their problem-solving skills as well as the importance of modeling them together to have a better measure of students' problem-solving performance.

We used a process-based model to examine the role of spatial heterogeneity of surface and sub-surface water on the carbon budget of the wetlands of the West Siberian Lowland over the period 1948–2010. We found that, while surface heterogeneity (fractional saturated area) had little overall effect on estimates of the region's carbon fluxes, sub-surface heterogeneity (spatial variations in water table depth) played an important role in both the overall magnitude and spatial distribution of estimates of the region's carbon fluxes. In particular, to reproduce the spatial pattern of CH4 emissions recorded by intensive in situ observations across the domain, in which very little CH4 is emitted north of 60° N, it was necessary to (a) account for CH4 emissions from unsaturated wetlands and (b) use spatially varying methane model parameters that reduced estimated CH4 emissions in the northern (permafrost) half of the domain (and/or account for lower CH4 emissions under inundated conditions). Our results suggest that previous estimates of the response of these wetlands to thawing permafrost may have overestimated future increases in methane emissions in the permafrost zone.

Abstract Inducing necroptosis in cancer cells has emerged as an effective strategy to overcome drug resistance. However, while organic small molecules have been extensively studied for this purpose, metal-based compounds have received relatively little attention as triggers of necroptosis. The development of ruthenium (II) hybrid compounds, particularly those containing triazene (Ru-TRZ), highlights a novel avenue for modulating necroptotic cell death. Here we show that incorporating a methyltriazene moiety, a known alkylating warhead, confers superior mitochondrial-targeting properties and enhances cell death compared to amide-containing counterparts. Ru-hybrid TRZ2 exhibits also antitumor efficacy against in vivo drug-resistant cancer cells. Mechanistically, we demonstrate that Ru-TRZ hybrids induce apoptosis. In addition, by activating downstream RIPK3-driven cell death, TRZ2 proficiently restrains normal mitochondrial function and activity, leading to cancer cell necroptosis. Finally, TRZ2 synergizes anti-proliferative activity and cell death effects induced by conventional drugs. In conclusion, Ru-TRZ2 stands as a promising ruthenium-based chemotherapeutic agent inducing necroptosis in drug resistant cancer cells.

Hypercoagulability occurs in 15% of patients with malignancy and represents a clinical spectrum ranging from abnormal coagulation tests but no clinically evident thromboembolic disease, to arterial and venous thrombosis, migratory thrombophlebitis, nonbacterial thrombotic endocarditis (NBTE) and disseminated intravascular coagulation. The combination of increased procoagulant activity and decreased fibrinolytic activity accelerates the prothrombotic potential of endothelial cells in malignancy. NBTE is a rare manifestation of cancer-induced hypercoagulability and is commonly seen with mucin-producing adenocarcinomas, but rarely seen with ovarian clear cell carcinoma (OCCC). Cerebrovascular embolization ranges from 14–91% in NBTE. We report a rare case of a 62-year-old female presenting with occipital stroke as a consequence of NBTE in OCCC. Association of NBTE in OCCC has only been reported in 2 cases so far, but presentation with stroke has never been reported in the literature.

Abstract The benefits of incorporating process information in a large-scale assessment with the complex micro-level evidence from the examinees (i.e., process log data) are well documented in the research across large-scale assessments and learning analytics. This study introduces a deep-learning-based approach to predictive modeling of the examinee’s performance in sequential, interactive problem-solving tasks from a large-scale assessment of adults' educational competencies. The current methods disambiguate problem-solving behaviors using network analysis to inform the examinee's performance in a series of problem-solving tasks. The unique contribution of this framework lies in the introduction of an “effort-aware” system. The system considers the information regarding the examinee’s task-engagement level to accurately predict their task performance. The study demonstrates the potential to introduce a high-performing deep learning model to learning analytics and examinee performance modeling in a large-scale problem-solving task environment collected from the OECD Programme for the International Assessment of Adult Competencies (PIAAC 2012) test in multiple countries, including the United States, South Korea, and the United Kingdom. Our findings indicated a close relationship between the examinee's engagement level and their problem-solving skills as well as the importance of modeling them together to have a better measure of students’ problem-solving performance.

Abstract Secure Multiparty Computation (SMC) enables multiple parties to cooperate securely without compromising their privacy. SMC has the potential to offer solutions for privacy obstacles in vehicular networks. However, classical SMC implementations suffer from efficiency and security challenges. To address this problem, two quantum communication technologies, Quantum Key Distribution (QKD) and Quantum Oblivious Key Distribution were utilised. These technologies supply symmetric and oblivious keys respectively, allowing fast and secure inter‐vehicular communications. These quantum technologies are integrated with the Faster Malicious Arithmetic Secure Computation with Oblivious Transfer (MASCOT) protocol to form a Quantum Secure Multiparty Computation (QSMC) platform. A lane change service is implemented in which vehicles broadcast private information about their intention to exit the highway. The proposed QSMC approach provides unconditional security even against quantum computer attacks. Moreover, the communication cost of the quantum approach for the lane change use case has decreased by 97% when compared to the classical implementation. However, the computation cost has increased by 42%. For open space scenarios, the reduction in communication cost is especially important, because it conserves bandwidth in the free‐space radio channel, outweighing the increase in computation cost.

Methicillin-resistant Staphylococcus aureus (M RSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes aiming to promote the accumulation of RFB at infected sites and consequently enhance the therapeutic potency. Two clinical isolates of MRSA, MRSA-C1 and MRSA-C2, were used to test the developed formulations, as well as the positive control, vancomycin (VCM). RFB in free and liposomal forms displayed high antibacterial activity, with similar potency between tested formulations. In MRSA-C1, minimal inhibitory concentrations (MIC) for Free RFB and liposomal RFB were 0.009 and 0.013 μg/mL, respectively. Minimum biofilm inhibitory concentrations able to inhibit 50% biofilm growth (MBIC50) for Free RFB and liposomal RFB against MRSA-C1 were 0.012 and 0.008 μg/mL, respectively. Confocal microscopy studies demonstrated the rapid internalization of unloaded and RFB-loaded liposomes in the bacterial biofilm matrix. In murine models of systemic MRSA-C1 infection, Balb/c mice were treated with RFB formulations and VCM at 20 and 40 mg/kg of body weight, respectively. The in vivo results demonstrated a significant reduction in bacterial burden and growth index in major organs of mice treated with RFB formulations, as compared to Control and VCM (positive control) groups. Furthermore, the VCM therapeutic dose was two fold higher than the one used for RFB formulations, reinforcing the therapeutic potency of the proposed strategy. In addition, RFB formulations were the only formulations associated with 100% survival. Globally, this study emphasizes the potential of RFB nanoformulations as an effective and safe approach against MRSA infections.

Biofilms provide an ecological advantage against many environmental stressors, such as pH and temperature, making it the most common life‐cycle stage for many bacteria. These protective characteristics make eradication of bacterial biofilms challenging. This is especially true in the health sector where biofilm formation on hospital or patient equipment, such as respirators, or catheters, can quickly become a source of anti‐microbial resistant strains. Biofilms are complex structures encased in a self‐produced polymeric matrix containing numerous components such as polysaccharides, proteins, signalling molecules, extracellular DNA and extracellular RNA. Biofilm formation is tightly controlled by several regulators, including quorum sensing (QS), cyclic diguanylate (c‐di‐GMP) and small non‐coding RNAs (sRNAs). These three regulators in particular are fundamental in all stages of biofilm formation; in addition, their pathways overlap, and the significance of their role is strain‐dependent. Currently, ribonucleases are also of interest for their potential role as biofilm regulators, and their relationships with QS, c‐di‐GMP and sRNAs have been investigated. This review article will focus on these four biofilm regulators (ribonucleases, QS, c‐di‐GMP and sRNAs) and the relationships between them.

The exploration of the interference prompted by commensal bac-teria over fungal pathogens is an interesting alternative to develop new ther-apies. In this work we scrutinized how the presence of the poorly studied vag-inal species Lactobacillus gasseri affects relevant pathophysiological traits of Candida albicans and Candida glabrata. L. gasseri was found to form mixed biofilms with C. albicans and C. glabrata resulting in pronounced death of the yeast cells, while bacterial viability was not affected. Reduced viability of the two yeasts was also observed upon co-cultivation with L. gasseri under plank-tonic conditions. Either in planktonic cultures or in biofilms, the anti-Candida effect of L. gasseri was augmented by acetate in a concentration-dependent manner. During planktonic co-cultivation the two Candida species counter-acted the acidification prompted by L. gasseri thus impacting the balance be-tween dissociated and undissociated organic acids. This feature couldn’t be phenocopied in single-cultures of L. gasseri resulting in a broth enriched in acetic acid, while in the co-culture the non-toxic acetate prevailed. Altogether the results herein described advance the design of new anti-Candida thera-pies based on probiotics, in particular, those based on vaginal lactobacilli spe-cies, helping to reduce the significant burden that infections caused by Can-dida have today in human health.

Cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells are a highly effective immunotherapy for relapsed and refractory B-cell malignancies, but their utility can be limited by the development of immune effector cell-associated neurotoxicity syndrome (ICANS). The recent discovery of CD19 expression on the pericytes in the blood–brain barrier (BBB) suggests an important off-target mechanism for ICANS development. In addition, the release of systemic cytokines stimulated by the engagement of CD19 with the CAR T cells can cause endothelial activation and decreased expression of tight junction molecules, further damaging the integrity of the BBB. Once within the brain microenvironment, cytokines trigger a cytokine-specific cascade of neuroinflammatory responses, which manifest clinically as a spectrum of neurological changes. Brain imaging is frequently negative or nonspecific, and treatment involves close neurologic monitoring, supportive care, interleukin antagonists, and steroids. The goal of this review is to inform readers about the normal development and microstructure of the BBB, its unique susceptibility to CD19 CAR T cells, the role of individual cytokines on specific elements of the brain’s microstructural environment, and the clinical and imaging manifestations of ICANS. Our review will link cellular pathophysiology with the clinical and radiological manifestations of a complex clinical entity.

In Bolivia, lateritic soils are common in humid tropical regions and can be used in the construction industry as an alternative to materials that cause a negative environmental impact, such as cement. The production of Portland cement causes environmental issues like significant greenhouse gas emissions and air pollution. To address this problem, geopolymers have been introduced as an alternative binder with low CO2 emissions. In this regard, geopolymers based on lateritic clays have been studied mineralogically, chemically, and on their compressive strength separately. However, there are still no studies on lateritic clays present in Bolivia and their mechanical, mineralogical, and chemical properties combined in a geopolymer. Therefore, this present research proposes the evaluation of a geopolymer made from laterite clays. Compression and flexural tests were carried out, along with mineralogical and chemical analyses on mortar and geopolymer cubes and prisms. The results indicate that the laterite clay-based geopolymer has lower compressive strength compared to Portland cement IP (cement type I with the addition of pozzolana) mortar. However, the flexural strength tests show a slight increase in the case of the geopolymer.

Migraine is a complex and heterogenous disorder whose disease mechanisms remain disputed. This narrative review summarizes functional MRI (fMRI) and diffusion tensor imaging (DTI) findings and interprets their association with migraine symptoms and subtype to support and expand our current understanding of migraine pathophysiology. Our PubMed search evaluated and included fMRI and DTI studies involving comparisons between migraineurs vs healthy controls, migraineurs with vs without aura, and episodic vs chronic migraineurs. Migraineurs demonstrate changes in functional connectivity (FC) and regional activation in numerous pain-related networks depending on migraine phase, presence of aura, and chronicity. Changes to diffusion indices are observed in major cortical white matter tracts extending to the brainstem and cerebellum, more prominent in chronic migraine and associated with FC changes. Reported changes in FC and regional activation likely relate to pain processing and sensory hypersensitivities. Diffuse white matter microstructural changes in dysfunctional cortical pain and sensory pathways complement these functional differences. Interpretations of reported fMRI and DTI measure trends have not achieved a clear consensus due to inconsistencies in the migraine neuroimaging literature. Future fMRI and DTI studies should establish and implement a uniform methodology that reproduces existing results and directly compares migraineurs with different subtypes. Combined fMRI and DTI imaging may provide better pathophysiological explanations for nonspecific FC and white matter microstructural differences.

In recent years, the phenomenon referred to as projectification has escalated. Projects have increasingly started to displace certain types of operations in businesses across the globe. In essence, it means that project work has intensified due to an increase in the freelance and independent work economy. This represents a reflection of changing times and changing organizations. This article aims to present a general overview of the evolution of projects and the future trends in using this particular way of working. The methodology is a literature review that helps identify critical events and key agents in the process.

This article analyzes some of the current topics in the world of work, especially the Great Labor Discontent and the Great Resignation. The general objective is to present the conditions surrounding the Great Resignation that allow a better understanding of the changes that are taking place in the workplace. The general background and the main characteristics of the great discontent are presented, and the positive effects that these changes are generating are analyzed, as well as emerging movements such as the return of boomerang employees. The study is based on a literature review and stems from the analysis of news, research, and publications of consulting companies, as well as the most relevant publications that have been developed on the subject to date. JEL Codes: J50, J24, J64, J81 Received: 06/01/2023. Accepted: 06/06/2023. Published: 19/07/2023.

The diencephalon is a complex midline structure consisting of the hypothalamus, neurohypophysis, subthalamus, thalamus, epithalamus, and pineal body. Tumors arising from each of these diencephalic components differ significantly in terms of biology and prognosis. The aim of this comprehensive review is to describe the epidemiology, clinical symptoms, imaging, histology, and molecular markers in the context of the 2021 WHO classification of central nervous system neoplasms. We will also discuss the current management of each of these tumors.

ABSTRACT: Pullorum disease is described worldwide and is caused by Salmonella enterica subspecies enterica serovar Gallinarum biovar Pullorum (S. Pullorum). S. Pullorum infection is important in commercial poultry, provoking a systemic disease with high mortality rates. Its occurrence requires notification, and when it is diagnosed in commercial breeding flocks, its eradication is demanded. The aim of this study was to report a severe outbreak of Pullorum disease in young Guinea fowl (Numida meleagris), resulting in 100% mortality of keets (n=290) within the first two weeks of age. All examined keets had enlarged liver, kidneys and spleen (5/5), and the affected tissues were submitted to histological and bacteriological examination. On histopathology, random paratyphoid nodules characterized by areas of necrosis with fibrin and a moderate infiltrate of macrophages and heterophils were observed in the liver. In kidneys, discrete areas of necrosis associated with moderate multifocal infiltrates of lymphocytes, and plasma cells were observed. In the spleen, a moderate infiltrate of macrophages was noticed. Isolation of colonies suggestive of S. Pullorum from liver and spleen was performed in selective agars and, after biochemical tests, confirmed by specific duplex-PCR. The antimicrobial susceptibility test of the isolated strain revealed resistance to only sulfamethoxazole + trimethoprim among the tested antimicrobials. The S. Pullorum isolate recovered in the present study was highly pathogenic to N. meleagris and may represent a risk to other avian species, including industrial poultry.

Random prime numbers are an essential resource for many asymmetric cryptographic protocols. However, despite the emerging popularity of quantum random number generators (QRNGs) as sources of secure randomness, physical prime number generators have not yet been explored. In this work, we experimentally implement and characterize a vacuum-based probabilistic prime number generation scheme with an error probability of 3.5×10−15. By removing the quantum source (QS), an additional scheme based on electronic noise is derived, and a comparative analysis for increasing prime lengths is made. We observed that the QS significantly outperforms the classical scheme for small prime generation, where increases up to 585.0% in the diversity of unique primes obtained are seen. Moreover, we propose a length-agnostic statistical test for prime number sequences and apply it to the output of the uniformized randomness source, which was successful in revealing underlying biases in the output prime distributions. The resultant sequences were subsequently submitted to the NIST statistical test suite, where the quantum and classical sources passed, respectively, 86.96% and 45.34% of the total test set applied.

Abstract Optical homodyne detection is widely adopted in continuous-variable quantum key distribution for high-rate field measurement quadratures. Besides that, those detection schemes have been being implemented for single-photon statistics characterization in the field of quantum tomography. In this work, we propose a discrete-variable quantum key distribution (DV-QKD) implementation that combines the use of phase modulators for high-speed state of polarization (SOP) generation, with a conjugate homodyne detection scheme which enables the deployment of high speed QKD systems. The channel discretization relies on the application of a detection threshold that allows to map the measured voltages as a click or no-click. Our scheme relies also on the use of a time-multiplexed pilot tone—quantum signal architecture which enables the use of a Bob locally generated local oscillator and opens the door to an effective polarization drift compensation scheme. Besides that, our results shows that for higher detection threshold values we obtain a very low quantum bit error rate (QBER) on the sifted key. Nevertheless, due to huge number of discarded qubits the obtained secure key length abruptly decreases. From our results, we observe that optimizing the detection threshold and considering a system operating at 500 MHz symbol generation clock, a secure key rate of approximately 46.9 Mbps, with a sifted QBER of $$1.5\%$$ 1.5 % over 40 km of optical fiber. This considering the error correction and privacy amplification steps necessary to obtain a final secure key.

Migraine is a complex and common disorder that affects patients around the world. Despite recent advances in this field, the exact pathophysiology of migraine is still not completely understood. Structural MRI sequences have revealed a variety of changes to brain parenchyma associated with migraine, including white matter lesions, volume changes, and iron deposition. This Review highlights different structural imaging findings in various types of migraine and their relationship to migraine characteristics and subtypes in order to improve our understanding of migraine, its pathophysiologic mechanisms, and how to better diagnose and treat it.

Migraine is a complex headache characterized by changes in functional connectivity and cerebral perfusion. The perfusion changes represent a valuable domain for targeted drug therapy. Arterial spin labeling is a noncontrast imaging technique of quantifying cerebral perfusion changes in the migraine setting. In this narrative review, we will discuss the pathophysiology of the different categories of migraine, as defined by the International Classification of Headache Disorders-3 and describe a category-based approach to delineating perfusion changes in migraine on arterial spin labeling images. We will also discuss the use of arterial spin labeling to differentiate migraine from stroke and/or seizures in the adult and pediatric populations. Our systematic approach will help improve the understanding of the complicated vascular changes that occur during migraines and identify potential areas of future research.

Extracellular vesicles (EVs) comprise a broad range of secreted cell-derived membrane vesicles. Beyond their more well-characterized role in cell communication, in recent years, EVs have also been shown to play important roles during infection. Viruses can hijack the biogenesis of exosomes (which are small EVs) to promote viral spreading. Additionally, these exosomes are also important mediators in inflammation and immune responses during both bacterial and viral infections. This review summarizes these mechanisms while also describing the impact of bacterial EVs in regulating immune responses. Finally, the review also focuses on the potential and challenges of using EVs, in particular, to tackle infectious diseases.

Cancer is a result of abnormal cell proliferation. This pathology is a serious health problem since it is a leading cause of death worldwide. Current anti-cancer therapies rely on surgery, radiation, and chemotherapy. However, these treatments still present major associated problems, namely the absence of specificity. Thus, it is urgent to develop novel therapeutic strategies. Nanoparticles, particularly dendrimers, have been paving their way to the front line of cancer treatment, mostly for drug and gene delivery, diagnosis, and disease monitoring. This is mainly derived from their high versatility, which results from their ability to undergo distinct surface functionalization, leading to improved performance. In recent years, the anticancer and antimetastatic capacities of dendrimers have been discovered, opening new frontiers to dendrimer-based chemotherapeutics. In the present review, we summarize the intrinsic anticancer activity of different dendrimers as well as their use as nanocarriers in cancer diagnostics and treatment.

Human induced pluripotent stem cells (hiPSCs) can be efficiently differentiated into cardiomyocytes (CMs), which can be used for cardiac disease modeling, for drug screening, and to regenerate damaged myocardium. Implementation of xeno-free culture systems is essential to fully explore the potential of these cells. However, differentiation using xeno-free adhesion matrices often results in low CM yields and lack of functional CM sheets, capable of enduring additional maturation stages. Here, we established a xeno-free CM differentiation platform using TeSR/Synthemax, including a replating step and integrated with two versatile purification/enrichment metabolic approaches. Results showed that the replating step was essential to reestablish a fully integrated, closely-knit CM sheet. In addition, replating contributed to increase the cTnT expression from 65% to 75% and the output from 2.2 to 3.1 CM per hiPSC, comparable with the efficiency observed when using TeSR/Matrigel. In addition, supplementation with PluriSin1 and Glu-Lac+ medium allowed increasing the CM content over 80% without compromising CM sheet integrity or functionality. Thus, this xeno-free differentiation platform is a reliable and robust method to produce hiPSC-derived CMs, increasing the possibility of using these cells safely for a wide range of applications.

Human iPSC-derived self-organized cardiac tissues can be valuable for the development of platforms for disease modeling and drug screening, enhancing test accuracy and reducing pharmaceutical industry financial burden. However, current differentiation systems still rely on static culture conditions and specialized commercial microwells for aggregation, which hinders the full potential of hiPSC-derived cardiac tissues. Herein, we integrate cost-effective and reproducible manual aggregation of hiPSC-derived cardiac progenitors with Matrigel encapsulation and a dynamic culture to support hiPSC cardiac differentiation and self-organization. Manual aggregation at day 7 of cardiac differentiation resulted in 97% of beating aggregates with 78% of cTnT-positive cells. Matrigel encapsulation conjugated with a dynamic culture promoted cell migration and the creation of organized structures, with observed cell polarization and the creation of lumens. In addition, encapsulation increased buoyancy and decreased coalescence of the hiPSC-derived cardiac aggregates. Moreover, VEGF supplementation increased over two-fold the percentage of CD31-positive cells resulting in the emergence of microvessel-like structures. Thus, this study shows that the explored culture parameters support the self-organization of hiPSC-derived cardiac microtissues containing multiple cardiac cell types. Additional stimuli (e.g., BMP) in long-term scalable and fully automatized cultures can further potentiate highly structured and mature hiPSC-derived cardiac models, contributing to the development of reliable platforms for high-throughput drug screening and disease modeling.