Responses of intraspecific metabolic scaling to temperature and activity differ between water- and air-breathing ectothermic vertebrates.

Metabolism underpins all life-sustaining processes and varies profoundly with body size, temperature and locomotor activity. A current theory explains some of the size-dependence of metabolic rate (its mass exponent, b) through changes in metabolic level (L). We propose two predictive advances that: (a) combine the above theory with the evolved avoidance of oxygen limitation in water-breathers experiencing warming, and (b) quantify the overall magnitude of combined temperatures and degrees of locomotion on metabolic scaling across air- and water-breathers. We use intraspecific metabolic scaling responses to temperature (523 regressions) and activity (281 regressions) in diverse ectothermic vertebrates (fish, reptiles and amphibians) to show that b decreases with temperature-increased L in water-breathers, supporting surface area-related avoidance of oxygen limitation, whereas b increases with activity-increased L in air-breathers, following volume-related influences. This new theoretical integration quantitatively incorporates different influences (warming, locomotion) and respiration modes (aquatic, terrestrial) on animal energetics.

Complexity Reduction in Analyzing Independence between Statistical Randomness Tests Using Mutual Information.

The advantages of using mutual information to evaluate the correlation between randomness tests have recently been demonstrated. However, it has been pointed out that the high complexity of this method limits its application in batteries with a greater number of tests. The main objective of this work is to reduce the complexity of the method based on mutual information for analyzing the independence between the statistical tests of randomness. The achieved complexity reduction is estimated theoretically and verified experimentally. A variant of the original method is proposed by modifying the step in which the significant values of the mutual information are determined. The correlation between the NIST battery tests was studied, and it was concluded that the modifications to the method do not significantly affect the ability to detect correlations. Due to the efficiency of the newly proposed method, its use is recommended to analyze other batteries of tests.

Case Report: A prenatal diagnosis of osteogenesis imperfecta in a patient with a novel pathogenic variant in COL1A2.

Osteogenesis imperfecta is considered a rare genetic condition which is characterized by bone fragility. In 85% of cases, it is caused by mutations in COL1A1 and COL1A2 genes which are essential to produce type I collagen. We report the case of a female neonate delivered to a 27-year-old women at San Bartolomé Teaching Hospital with a family history of clavicle fracture. A prenatal control with ultrasound was performed to the mother at 29 weeks. A fetus with altered morphology and multiple fractures was found. Therefore, a prenatal diagnosis of osteogenesis imperfecta was performed. The neonate was born with a respiratory distress syndrome and an acyanotic congenital heart disease. Therefore, she remained in NICU until her death. We highlight the importance of prenatal diagnosis, genetic counseling and a multidisciplinary evaluation in this type of pathologies and report a new probably pathogenic variant in the COL1A2 gene detected by exomic sequencing in amniotic fluid.

The 2022 Massive Open Online Course (MOOC) to train physiotherapists in the management of people with spinal cord injuries: a qualitative and quantitative analysis of learners' experiences and its impact.

STUDY DESIGN: Observational. OBJECTIVES: To determine the learners' experience and the impact of a Massive Open Online Course (MOOC) conducted to teach physiotherapists about the management of people with spinal cord injuries (SCI). METHODS: A SCI MOOC for physiotherapists was run in 5 different languages at the end of 2022. Qualitative and quantitative data were collected from different sources including registration details, pre- and post-MOOC Knowledge Assessments, a post-MOOC Evaluation, social media posts and online tracking of websites and emails. The data were used to answer four key questions: (i) what was the reach of the MOOC, (ii) what did participants think about the MOOC (iii) did the MOOC change participants' knowledge and/or confidence, and (iv) did the MOOC change participants' clinical practice or the way they teach others? RESULTS: 25,737 people from 169 countries registered for the MOOC. 98% of participants who completed the Evaluation (n = 2281) rated the MOOC as either "good" or "very good". Participants' knowledge improved by a median (IQR) of 25% (10 to 45%) (n = 4016 participants) on the MOOC Knowledge Assessment. Participants reported changes in confidence, and intentions to change clinical practice and incorporate what they had learnt into the way they teach others in response to the MOOC. CONCLUSION: The MOOC provided an efficient way to increase physiotherapists' knowledge about the physiotherapy management of people with SCI. Participants enjoyed the MOOC, and indicated an intention to change clinical practice and the way they taught others.

pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle.

The chloroquine resistance transporter, PfCRT, of the human malaria parasite Plasmodium falciparum is sensitive to acidic pH. Consequently, PfCRT operates at 60% of its maximal drug transport activity at the pH of 5.2 of the digestive vacuole, a proteolytic organelle from which PfCRT expels drugs interfering with heme detoxification. Here we show by alanine-scanning mutagenesis that E207 is critical for pH sensing. The E207A mutation abrogates pH-sensitivity, while preserving drug substrate specificity. Substituting E207 with Asp or His, but not other amino acids, restores pH-sensitivity. Molecular dynamics simulations and kinetics analyses suggest an allosteric binding model in which PfCRT can accept both protons and chloroquine in a partial noncompetitive manner, with increased proton concentrations decreasing drug transport. Further simulations reveal that E207 relocates from a peripheral to an engaged location during the transport cycle, forming a salt bridge with residue K80. We propose that the ionized carboxyl group of E207 acts as a hydrogen acceptor, facilitating transport cycle progression, with pH sensing as a by-product.

DeeP4med: deep learning for P4 medicine to predict normal and cancer transcriptome in multiple human tissues.

BACKGROUND: P4 medicine (predict, prevent, personalize, and participate) is a new approach to diagnosing and predicting diseases on a patient-by-patient basis. For the prevention and treatment of diseases, prediction plays a fundamental role. One of the intelligent strategies is the design of deep learning models that can predict the state of the disease using gene expression data. RESULTS: We create an autoencoder deep learning model called DeeP4med, including a Classifier and a Transferor that predicts cancer's gene expression (mRNA) matrix from its matched normal sample and vice versa. The range of the F1 score of the model, depending on tissue type in the Classifier, is from 0.935 to 0.999 and in Transferor from 0.944 to 0.999. The accuracy of DeeP4med for tissue and disease classification was 0.986 and 0.992, respectively, which performed better compared to seven classic machine learning models (Support Vector Classifier, Logistic Regression, Linear Discriminant Analysis, Naive Bayes, Decision Tree, Random Forest, K Nearest Neighbors). CONCLUSIONS: Based on the idea of DeeP4med, by having the gene expression matrix of a normal tissue, we can predict its tumor gene expression matrix and, in this way, find effective genes in transforming a normal tissue into a tumor tissue. Results of Differentially Expressed Genes (DEGs) and enrichment analysis on the predicted matrices for 13 types of cancer showed a good correlation with the literature and biological databases. This led that by using the gene expression matrix, to train the model with features of each person in a normal and cancer state, this model could predict diagnosis based on gene expression data from healthy tissue and be used to identify possible therapeutic interventions for those patients.

PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport.

The chloroquine resistance transporter (PfCRT) confers resistance to a wide range of quinoline and quinoline-like antimalarial drugs in Plasmodium falciparum, with local drug histories driving its evolution and, hence, the drug transport specificities. For example, the change in prescription practice from chloroquine (CQ) to piperaquine (PPQ) in Southeast Asia has resulted in PfCRT variants that carry an additional mutation, leading to PPQ resistance and, concomitantly, to CQ re-sensitization. How this additional amino acid substitution guides such opposing changes in drug susceptibility is largely unclear. Here, we show by detailed kinetic analyses that both the CQ- and the PPQ-resistance conferring PfCRT variants can bind and transport both drugs. Surprisingly, the kinetic profiles revealed subtle yet significant differences, defining a threshold for in vivo CQ and PPQ resistance. Competition kinetics, together with docking and molecular dynamics simulations, show that the PfCRT variant from the Southeast Asian P. falciparum strain Dd2 can accept simultaneously both CQ and PPQ at distinct but allosterically interacting sites. Furthermore, combining existing mutations associated with PPQ resistance created a PfCRT isoform with unprecedented non-Michaelis-Menten kinetics and superior transport efficiency for both CQ and PPQ. Our study provides additional insights into the organization of the substrate binding cavity of PfCRT and, in addition, reveals perspectives for PfCRT variants with equal transport efficiencies for both PPQ and CQ.

Bevacizumab-Induced Hypertension in Glioblastoma Patients and Its Potential as a Modulator of Treatment Response.

Glioblastoma invasion is the primary mechanism responsible for its dismal prognosis and is the direct result of interactions between glioblastoma cells and the tumor vasculature. The dysregulated microvasculature in glioblastoma tumors and vessels co-opted from surrounding brain tissue support rapid tumor growth and are utilized as pathways for invasive cancer cells. Attempts to target the glioblastoma vasculature with antiangiogenic agents (eg, bevacizumab) have nonetheless shown limited and inconsistent efficacy, and the underlying causes of such heterogeneous responses remain unknown. Several studies have identified that patients with glioblastoma who develop hypertension following treatment with bevacizumab show significant improvement in overall survival compared with normotensive nonresponders. Here we review these findings and discuss the potential of hypertension as a biomarker for glioblastoma treatment response in individual patients and the role of hypertension as a modulator of interactions between tumor cells and cells in the perivascular niche. We suggest that a better understanding of the actions of bevacizumab and hypertension at the cellular level will contribute to developing more effective personalized therapies that address glioblastoma tumor cell invasion.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/ßc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/ßc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/ßc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. SIGNIFICANCE: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749.

On the Fitness Functions Involved in Genetic Algorithms and the Cryptanalysis of Block Ciphers.

There are many algorithms used with different purposes in the area of cryptography. Amongst these, Genetic Algorithms have been used, particularly in the cryptanalysis of block ciphers. Interest in the use of and research on such algorithms has increased lately, with a special focus on the analysis and improvement of the properties and characteristics of these algorithms. In this way, the present work focuses on studying the fitness functions involved in Genetic Algorithms. First, a methodology was proposed to verify that the closeness to 1 of some fitness functions' values that use decimal distance implies decimal closeness to the key. On the other hand, the foundation of a theory is developed in order to characterize such fitness functions and determine, a priori, if one method is more effective than another in the attack to block ciphers using Genetic Algorithms.

Scaffold geometry modulation of mechanotransduction and its influence on epigenetics.

The dynamics of cell mechanics and epigenetic signatures direct cell behaviour and fate, thus influencing regenerative outcomes. In recent years, the utilisation of 2D geometric (i.e. square, circle, hexagon, triangle or round-shaped) substrates for investigating cell mechanics in response to the extracellular microenvironment have gained increasing interest in regenerative medicine due to their tunable physicochemical properties. In contrast, there is relatively limited knowledge of cell mechanobiology and epigenetics in the context of 3D biomaterial matrices, i.e., hydrogels and scaffolds. Scaffold geometry provides biophysical signals that trigger a nucleus response (regulation of gene expression) and modulates cell behaviour and function. In this review, we explore the potential of additive manufacturing to incorporate multi length-scale geometry features on a scaffold. Then, we discuss how scaffold geometry direct cell and nuclear mechanosensing. We further discuss how cell epigenetics, particularly DNA/histone methylation and histone acetylation, are modulated by scaffold features that lead to specific gene expression and ultimately influence the outcome of tissue regeneration. Overall, we highlight that geometry of different magnitude scales can facilitate the assembly of cells and multicellular tissues into desired functional architectures through the mechanotransduction pathway. Moving forward, the challenge confronting biomedical engineers is the distillation of the vast knowledge to incorporate multiscaled geometrical features that would collectively elicit a favourable tissue regeneration response by harnessing the design flexibility of additive manufacturing. STATEMENT OF SIGNIFICANCE: It is well-established that cells sense and respond to their 2D geometric microenvironment by transmitting extracellular physiochemical forces through the cytoskeleton and biochemical signalling to the nucleus, facilitating epigenetic changes such as DNA methylation, histone acetylation, and microRNA expression. In this context, the current review presents a unique perspective and highlights the importance of 3D architectures (dimensionality and geometries) on cell and nuclear mechanics and epigenetics. Insight into current challenges around the study of mechanobiology and epigenetics utilising additively manufactured 3D scaffold geometries will progress biomaterials research in this space.

Emerging biomaterials and technologies to control stem cell fate and patterning in engineered 3D tissues and organoids.

The ability to create complex three-dimensional cellular models that can effectively replicate the structure and function of human organs and tissues in vitro has the potential to revolutionize medicine. Such models could facilitate the interrogation of developmental and disease processes underpinning fundamental discovery science, vastly accelerate drug development and screening, or even be used to create tissues for implantation into the body. Realization of this potential, however, requires the recreation of complex biochemical, biophysical, and cellular patterns of 3D tissues and remains a key challenge in the field. Recent advances are being driven by improved knowledge of tissue morphogenesis and architecture and technological developments in bioengineering and materials science that can create the multidimensional and dynamic systems required to produce complex tissue microenvironments. In this article, we discuss challenges for in vitro models of tissues and organs and summarize the current state-of-the art in biomaterials and bioengineered systems that aim to address these challenges. This includes both top-down technologies, such as 3D photopatterning, magnetism, acoustic forces, and cell origami, as well as bottom-up patterning using 3D bioprinting, microfluidics, cell sheet technology, or composite scaffolds. We illustrate the varying ways that these can be applied to suit the needs of different tissues and applications by focussing on specific examples of patterning the bone-tendon interface, kidney organoids, and brain cancer models. Finally, we discuss the challenges and future prospects in applying materials science and bioengineering to develop high-quality 3D tissue structures for in vitro studies.

Adrenal Neuroblastoma Producing Catecholamines Diagnosed in Adults: Case Report.

Neuroblastoma is a solid tumor considered almost exclusively pediatric, with more than 95% of patients diagnosed before 10 years of age, with a mostly benign clinical course and with encouraging survival rates in these age ranges. It occurs rarely in adolescents, and the presentation in young adults or older people is even rarer; consequently, a more severe prognosis and higher mortality rates have been documented within this population. This is also due to a great limitation within the treatment since the chemotherapeutic regimens proposed so far are valid for pediatric patients, with low tolerance to it within the adult population. We present the case of a 24-year-old female patient with catecholamine-secreting neuroblastoma who obtained surgical management, with subsequent local tumor recurrence, with subsequent need for onco-specific and symptomatic management.

Spatiotemporal pattern of specialization of sunbird-plant networks on Mt. Cameroon.

Differences in interaction specializations between nectarivorous birds and plants across continents serve as common examples of evolutionary trajectory specificity. While New World hummingbird-plant networks have been extensively studied and are considered highly specialized, knowledge on the network specialization of their Old World counterparts, sunbirds (Nectariniidae), remains limited. A few studies from tropical Africa indicate that sunbird-plant networks are rather generalized. Unfortunately, these studies are limited to dry seasons and high elevations at the tree line, environments where niche-based hypotheses also often predict lower resource partitioning. In our study, we explored the specialization of sunbird-plant networks and their spatiotemporal variability on Mt. Cameroon (Cameroon). Using a combination of automatic video recordings and personal observations, we constructed eight comprehensive sunbird-plant networks in four forest types at different elevations in both the dry and wet seasons. As reported in previous studies, the montane forest plants, birds and whole networks were highly generalized. Nevertheless, we observed a much higher specialization in forests at lower elevations. Except at the lowest altitude, the wet season was also characterized by higher specialization. While less specialized flowering trees dominated in the dry season networks, more specialized herbs and shrubs were visited by birds during the wet season. As our findings do not support the generally accepted assumption that Old World bird-plant networks are rather generalized, we need further studies to understand the differences in bird-plant specializations on individual continents.

Conscious Exploration of Alpha-Cuts in the Parametric Solution of the School Bus Routing Problem with Fuzzy Walking Distance.

Combinatorial optimization problems allow for modeling multiple situations in which proper allocation of resources is needed. For some real-world problems, the use of fuzzy elements in the models allows for incorporating certain levels of uncertainty to better approximate such real-world situations. One way to solve combinatorial optimization problems with fuzzy elements is the parametric approach, where it is necessary to define how to explore different relaxation levels using alpha-cuts. Researchers tend to select such alpha-cuts uniformly. The current investigation proposes a novel strategy for selecting alpha-cuts in the School Bus Routing Problem with fuzzy students' maximum walking distance. This proposal bases its foundations on the number of student-bus stop pairs available according to the different levels of relaxations allowed. Results demonstrate how the proposed strategy gives attractive solutions with more diverse trade-offs, contrasted with other methods in the literature. Furthermore, it decreases the computational cost for those instances where the maximum relaxation does not provide new pairs of students-bus stops.

A partial evaluation approach for the School Bus Routing Problem.

Several real-life optimization problems, such as the case of several instances of the School Bus Routing Problem (SBRP), are very complex and expensive to solve with exact algorithms. Metaheuristics are a good alternative in these situations because they are capable of generating good quality solutions to these problems in a reasonable time. Metaheuristics iterate thousands of times by introducing changes concerning the previous solutions. Each new solution must be evaluated, and sometimes, the new solutions have elements unchanged that are unnecessarily re-evaluated. However, an approach avoids repeatedly evaluating parts of different solutions known as partial evaluation. This work applies this technique to the SBRP to reduce its execution time. To apply the partial evaluation approach in this problem, each solution contains the information of the change that was made concerning the solution from which it originates. With this information, when evaluating the objective function, it will be only necessary to analyze the routes that changed. In the literature reviewed, no previous work was found in which the partial evaluation approach has been applied in the context of SBRP. In this paper we apply it in order to reduce the computational cost of SBRP solutions based on metaheuristics. The results show that it is possible to decrease the execution time in 80% of the instances, reducing the execution time on average by 73.6%.

Con E de enfermera Consulta de manejo intestinal / With E for nurse Bowel management consultation

En el 2020, el Hospital Universitario La Fe, ubicado en Valencia, puso en marcha una consulta enfermera especializada en manejo intestinal. Eva García es su responsable, nos atiende para hablar del día a día de este servicio, de su labor y de la importancia de la Educación para la Salud para los pacientes con disfunción intestinal.(AU)