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Abstract Background Long non-coding RNAs (lncRNAs) are pivotal players in cellular processes, and their unique cell-type specific expression patterns render them attractive biomarkers and therapeutic targets. Yet, the functional roles of most lncRNAs remain enigmatic. To address the need to identify new druggable lncRNAs, we developed a comprehensive approach integrating transcription factor binding data with other genetic features to generate a machine learning model, which we have called INFLAMeR (Identifying Novel Functional LncRNAs with Advanced Machine Learning Resources). Methods INFLAMeR was trained on high-throughput CRISPR interference (CRISPRi) screens across seven cell lines, and the algorithm was based on 71 genetic features. To validate the predictions, we selected candidate lncRNAs in the human K562 leukemia cell line and determined the impact of their knockdown (KD) on cell proliferation and chemotherapeutic drug response. We further performed transcriptomic analysis for candidate genes. Based on these findings, we assessed the lncRNA small nucleolar RNA host gene 6 (SNHG6) for its role in myeloid differentiation. Finally, we established a mouse K562 leukemia xenograft model to determine whether SNHG6 KD attenuates tumor growth in vivo. Results The INFLAMeR model successfully reconstituted CRISPRi screening data and predicted functional lncRNAs that were previously overlooked. Intensive cell-based and transcriptomic validation of nearly fifty genes in K562 revealed cell type-specific functionality for 85% of the predicted lncRNAs. In this respect, our cell-based and transcriptomic analyses predicted a role for SNHG6 in hematopoiesis and leukemia. Consistent with its predicted role in hematopoietic differentiation, SNHG6 transcription is regulated by hematopoiesis-associated transcription factors. SNHG6 KD reduced the proliferation of leukemia cells and sensitized them to differentiation. Treatment of K562 leukemic cells with hemin and PMA, respectively, demonstrated that SNHG6 inhibits red blood cell differentiation but strongly promotes megakaryocyte differentiation. Using a xenograft mouse model, we demonstrate that SNHG6 KD attenuated tumor growth in vivo. Conclusions Our approach not only improved the identification and characterization of functional lncRNAs through genomic approaches in a cell type-specific manner, but also identified new lncRNAs with roles in hematopoiesis and leukemia. Such approaches can be readily applied to identify novel targets for precision medicine.

Designing an exoskeleton that can improve user capabilities is a challenging task, and most designs rely on experiments to achieve this goal. A different approach is to use simulation-based designs to determine optimal device parameters. Most of these simulations use full trajectory tracking limb kinematics during a natural gait as a reference. However, exoskeletons typically change the natural gait kinematics of the user. Other types of simulations assume that human gait is optimized for a cost function that combines several objectives, such as the cost of transport, injury prevention, and stabilization. In this study, we use a 2D OpenSim model consisting of 10 degrees of freedom and considering 18 muscles, together with the Moco optimization tool, to investigate the differences between these two approaches with respect to running with a passive knee exoskeleton. Utilizing this model, we test the effect of a full trajectory tracking objective with different weights (representing the importance of the objective in the optimization cost function) and show that when using weights that are typically used in the literature, there is no deviation from the experimental data. Next, we develop a multi-objective cost function with foot clearance term based on peak knee angle during swing, that achieves trajectories similar (RMSE=7.4 deg) to experimental running data. Finally, we investigate the effect of different parameters in the design of a clutch-based passive knee exoskeleton (1.5 kg at each leg) and find that a design that utilizes a 2.5 Nm/deg spring achieves an improvement of up to 8% in net metabolic energy. Our results show that tracking objectives in the cost function, even with a low weight, hinders the simulation’s ability to change the gait trajectory. Thus, there is a need for other predictive simulation methods for exoskeletons.

El presente artículo tiene como objetivo analizar la crisis financiera de 2008 a partir del otorgamiento del Premio Nobel de Economía en 2022, concedido a los economistas Douglas W. Diamond, Philip H. Dybvig y Ben S. Bernanke. Se resalta la importancia del papel de la banca durante un periodo de recesión. La idea es comprender y abordar dicha crisis, a partir de los hallazgos de los galardonados, quienes demostraron lo crucial que es detener las quiebras bancarias generalizadas. Este análisis subraya que las lecciones extraídas de la crisis de las hipotecas subprime son fundamentales para garantizar la estabilidad económica global así como para orientar las regulaciones en un mundo cada vez más interconectado. Debido a que la crisis subprime y la quiebra de Lehman Brothers marcaron el colapso, que da como resulta una crisis bancaria global, el artículo inicia con un enfoque de dicha crisis, con el fin de exploran los antecedentes y causas que llevan a la creación de la burbuja inmobiliaria. Para contrarrestar el colapso y la quiebra bancaria global se implementaron regulaciones como la Ley Dodd-Frank y Basilea III, junto con un aumento del gasto gubernamental y tasas de interés cercanas a cero. La negligencia regulatoria y los riesgos no considerados por los bancos fueron factores fundamentales. Por último, se examina de forma breve la respuesta de la política monetaria a la recesión provocada por la pandemia durante 2020. A continuación como la Reserva Federal y otros bancos centrales recurrieron nuevamente a tasas de interés cercanas a cero y la relajación cuantitativa para impulsar la economía.

Abstract In this study, we examined a mathematical model of breast cancer (BC) treatment that combines an oral oestrogen receptor inhibitor, AZD9496 with Palbociclib, a selective inhibitor of cyclin- dependent kinases CDK4 and CDK6. Treatment is described by analytical functions that enable us to control the dosage and time interval of the treatment, thus personalising the treatment for each patient. Initially, we investigated the effect of each treatment separately, and finally, we investigated the combination of both treatments. By applying numerical simulations, we confirmed that the combination of AZD9496 with palbociclib was the optimal treatment for BC. The dosage of AZD9496 increased and decreased throughout the treatment period, while the intervals were constant between treatments. Palbociclib changed almost cyclically, whereas the time intervals remained constant. To investigate the mathematical model, we applied the singularly perturbed homotopy analysis method, which is a numerical algorithm. The significant advantage of this method is that the mathematical model does not have to contain a small parameter (as is standard in perturbation theory). However, it is possible to artificially introduce a small parameter into the system of equations, making it possible to study the model using asymptotic methods.

In classical evolutionary models, the force of natural selection diminishes with age toward zero by last reproduction. However, intergenerational resource transfers and other late-life contributions in social species may select for postreproductive longevity. We present a formal framework for estimating indirect fitness contributions via production transfers in a skills-intensive foraging niche, reflecting kinship and cooperation among group members. Among contemporary human hunter-gatherers and horticulturalists, indirect fitness contributions from transfers exceed direct reproductive contributions from before menopause until ages when surpluses end, around the modal age of adult death (∼70 y). Under reasonable assumptions, these benefits are the equivalent to having up to several more offspring after age 50. Despite early independence, minimal production surplus, and a shorter lifespan, chimpanzees could theoretically make indirect contributions if they adopted reliable food-sharing practices. Our results for chimpanzees hypothetically adopting hunter-gatherer subsistence suggest that a skills-intensive foraging ecology with late independence and late peak production could select for human-like life histories via positive feedback between longevity and late-life transfers. In contrast, life history changes preceding subsistence shifts would not favor further life extension or subsistence shifts. Our results formalize the theory that longevity can be favored under socioecological conditions characterized by parental and alloparental care funded through transfers of mid- to late-life production surpluses. We also extend our analysis beyond food transfers to illustrate the potential for indirect fitness contributions from pedagogy, or information transfers. While we focus mostly on humans, our approach is adaptable to any context or species where transfers can affect fitness.

Riboflavin, an essential vitamin for humans, is extensively used in various industries, with its global demand being met through fermentative processes. Hyphopichia wangnamkhiaoensis is a novel dimorphic yeast species capable of producing riboflavin. However, the nutritional factors affecting riboflavin production in this yeast species remain unknown. Therefore, we conducted a kinetic study on the effects of various nutritional factors—carbon and energy sources, nitrogen sources, vitamins, and amino acids—on batch riboflavin production by H. wangnamkhiaoensis. Batch experiments were performed in a bubble column bioreactor to evaluate cell growth, substrate consumption, and riboflavin production. The highest riboflavin production was obtained when the yeast growth medium was supplemented with glucose, ammonium sulfate, biotin, and glycine. Using these chemical components, along with the mineral salts from Castañeda-Agullo’s culture medium, we formulated a novel, low-cost, and effective culture medium (the RGE medium) for riboflavin production by H. wangnamkhiaoensis. This medium resulted in the highest levels of riboflavin production and volumetric productivity, reaching 16.68 mg/L and 0.713 mg/L·h, respectively, within 21 h of incubation. These findings suggest that H. wangnamkhiaoensis, with its shorter incubation time, could improve the efficiency and cost-effectiveness of industrial riboflavin production, paving the way for more sustainable production methods.

Given the health benefits of carotenoids, it is crucial to evaluate their levels in patients undergoing malabsorptive procedures like one anastomosis gastric bypass (OAGB). This study aimed to assess serum carotenoid levels before and 6 months following OAGB. Prospectively collected data from patients who underwent primary OAGB were analyzed. Data included anthropometrics, dietary intake assessments, and biochemical tests. Serum samples were analyzed for lipid profile and serum carotenoids, including lutein, zeaxanthin, α-carotene, β-carotene, phytofluene, ζ-carotene, and lycopene. Data from 27 patients (median age 47.0 years and 55.6% female) were available before and 6 months post-OAGB. The median pre-surgical BMI was 39.5 kg/m2, and the median excess weight loss at 6 months post-surgery was 63.9%. Significant decreases in all carotenoid levels were observed over time (p < 0.001 for all). A median relative decline of 65.1% in absolute total carotenoid levels and 12.7% in total cholesterol levels were found. No associations were observed between changes in clinical outcomes and carotenoid levels during the study period. This study reveals significant decreases in carotenoid levels within the first 6 months following OAGB. Nutritional intervention studies are needed to explore how incorporating carotenoid-rich foods affects post-surgery carotenoid levels and clinical outcomes.

Objectives To compare the discussions from two panels on the concept of palliative care quality for patients with advanced cancer, exploring the priorities reflected in each group’s perspectives.Design We convened two RAND-UCLA appropriateness panel discussions on palliative care quality in advanced cancer. Discussions were audio-recorded and transcribed verbatim. Panel transcripts were analysed thematically using a matrix approach to examine perceptions and experiences of quality.Setting Discussions were framed within the context of advanced cancer care and palliative care.Participants The patient–caregiver panel had 9 patients with current or a history of cancer and caregivers, and the practitioner panel had 10 expert practitioners representing fields of oncology, primary care, social work, palliative care, nursing, pain management and ethics.Results Our analysis identified three thematic categories for understanding quality common across both groups and nine subthemes within those categories. At the highest level, quality was conceived as: (1) the patient and caregiver experience of care, (2) technical competence and (3) the structure of health system. Among the subthemes, four were present in only one of the two group’s discussions: ‘purpose and action’ was specific to the patient–caregiver panel, whereas ‘adhering to best medical practice’, ‘mitigating unintended consequences and side effects’, and ‘health system resources and costs’ were specific to the practitioner panel.Conclusions While both panels aligned on the three key domains of quality, the particular dimensions through which they perceived quality varied in relation to their experience and role as a professional provider of care versus recipient of healthcare services. These differences suggest the importance of adopting a collaborative approach to quality measurement and improvement so that the values of all interested parties are represented in improvement efforts.

The structure-activity relationships data available in public databases of inhibitors of DNA methyltransferases (DNMTs), families of epigenetic targets, plus the structural information of DNMT1, enables the development of a robust structure-based drug design strategy to study, at the molecular level, the activity of DNMTs inhibitors. In this study, we discuss a consensus molecular docking strategy to aid in explaining the activity of small molecules tested as inhibitors of DNMT1. The consensus docking approach, which was based on three validated docking algorithms of different designs, had an overall good agreement with the experimental enzymatic inhibition assays reported in the literature. The docking protocol was used to explain, at the molecular level, the activity profile of a novel DNMT1 inhibitor with a distinct chemical scaffold whose identification was inspired by de novo design and complemented with similarity searching.

Objetivo: Describir las características del uso de una app preventiva en la población peruana durante su primer año de operaciones, en el periodo comprendido entre el 2019 y 2020. Materiales y métodos: Estudio de tipo descriptivo, transversal y retrospectivo, donde se revisó la base de datos de la app preventiva Salud Total respecto a las características demográficas y forma de uso en la población peruana durante su primer año de operaciones. Se analizaron las variables sociodemográficas (sexo y edad) y las formas de uso (los datos de salud ingresados, los hallazgos patológicos encontrados, la recurrencia de uso y el tipo y la cantidad de servicios solicitados). El análisis y procesamiento de los datos descriptivos se realizaron con el programa Microsoft Excel. Resultados: El número de usuarios que descargaron y se registraron en la app fue 9737 personas. Con respecto al sexo, la proporción fue similar, y el grupo etario predominante fue entre 21 y 50 años. Se obtuvieron 2304 datos de salud que los usuarios registraron voluntariamente, de los cuales los más reportados fueron el peso y la talla (45,3 %), seguidos de la presión arterial (20,4 %), la hemoglobina (17,1 %) y la circunferencia abdominal. Se encontraron hallazgos patológicos en los datos registrados tales como la presión arterial elevada (25,7 %) y el peso elevado (58,5 %), entre otros. Asimismo, los usuarios solicitaron por medio de la app un total de 1072 servicios de salud de diversos tipos, entre los cuales destacan la atención médica (58 %) y el laboratorio clínico (32 %). Conclusiones: Los usuarios pudieron registrarse e interactuar con una app preventiva con el fin de controlar su bienestar, y la usaron tanto para añadir sus datos de salud como para solicitar servicios médicos de forma remota, lo que puede significar una nueva herramienta de intervención para direccionar acciones preventivas, la atención oportuna de enfermedades y una nueva fuente de datos para la investigación en salud.

BackgroundHumans life histories have been described as "slow", patterned by slow growth, delayed maturity, and long life span. While it is known that human life history diverged from that of a recent common chimpanzee-human ancestor some ~4-8 mya, it is unclear how selection pressures led to these distinct traits. To provide insight, we compare wild chimpanzees and human subsistence societies in order to identify the age-specific vital rates that best explain fitness variation, selection pressures and species divergence.MethodsWe employ Life Table Response Experiments to quantify vital rate contributions to population growth rate differences. Although widespread in ecology, these methods have not been applied to human populations or to inform differences between humans and chimpanzees. We also estimate correlations between vital rate elasticities and life history traits to investigate differences in selection pressures and test several predictions based on life history theory.ResultsChimpanzees' earlier maturity and higher adult mortality drive species differences in population growth, whereas infant mortality and fertility variation explain differences between human populations. Human fitness is decoupled from longevity by postreproductive survival, while chimpanzees forfeit higher potential lifetime fertility due to adult mortality attrition. Infant survival is often lower among humans, but lost fitness is recouped via short birth spacing and high peak fertility, thereby reducing selection on infant survival. Lastly, longevity and delayed maturity reduce selection on child survival, but among humans, recruitment selection is unexpectedly highest in longer-lived populations, which are also faster-growing due to high fertility.ConclusionHumans differ from chimpanzees more because of delayed maturity and lower adult mortality than from differences in juvenile mortality or fertility. In both species, high child mortality reflects bet-hedging costs of quality/quantity tradeoffs borne by offspring, with high and variable child mortality likely regulating human population growth over evolutionary history. Positive correlations between survival and fertility among human subsistence populations leads to selection pressures in human subsistence societies that differ from those in modern populations undergoing demographic transition.

The evolutionary biologist W. D. Hamilton (Hamilton 1966 J. Theor. Biol.12, 12-45. (doi:10.1016/0022-5193(66)90184-6)) famously showed that the force of natural selection declines with age, and reaches zero by the age of reproductive cessation. However, in social species, the transfer of fitness-enhancing resources by postreproductive adults increases the value of survival to late ages. While most research has focused on intergenerational food transfers in social animals, here we consider the potential fitness benefits of information transfer, and investigate the ecological contexts where pedagogy is likely to occur. Although the evolution of teaching is an important topic in behavioural biology and in studies of human cultural evolution, few formal models of teaching exist. Here, we present a modelling framework for predicting the timing of both information transfer and learning across the life course, and find that under a broad range of conditions, optimal patterns of information transfer in a skills-intensive ecology often involve postreproductive aged teachers. We explore several implications among human subsistence populations, evaluating the cost of hunting pedagogy and the relationship between activity skill complexity and the timing of pedagogy for several subsistence activities. Long lifespan and extended juvenility that characterize the human life history likely evolved in the context of a skills-intensive ecological niche with multi-stage pedagogy and multigenerational cooperation. This article is part of the theme issue 'Life history and learning: how childhood, caregiving and old age shape cognition and culture in humans and other animals'.

Abstract Background We aimed to assess the correlation between ovarian hyperstimulation syndrome (OHSS) in the early course of in vitro fertilization (IVF) pregnancies and obstetric outcomes. Methods We identified records of patients admitted due to OHSS following IVF treatment at our institution between 2008 and 2020. Cases were included if pregnancy resulted in a live singleton delivery (OHSS group). OHSS cases were matched at a 1:5:5 ratio with live singleton deliveries following IVF with fresh embryo transfer (fresh transfer group) and frozen embryo transfer (FET group), according to maternal age and parity. Computerized files were reviewed, and maternal, obstetric and neonatal outcomes compared. Results Overall, 44 OHSS cases were matched with 220 fresh transfer and 220 FET pregnancies. Patient demographics were similar between the groups, including body mass index, smoking and comorbidities. Gestational age at delivery, the rate of preterm births, preeclampsia and cesarean delivery were similar between the groups. Placental abruption occurred in 6.8% of OHSS pregnancies, 1.4% of fresh transfer pregnancies and 0.9% of FET pregnancies (p=0.02). On post-hoc analysis, the rate of placental abruption was significantly higher in OHSS pregnancies, compared with the two other groups, and this maintained significance after adjustment for confounders. Birthweights were 3017 ± 483, 3057 ± 545 and 3213 ± 542 grams in the OHSS, fresh transfer and FET groups, respectively (p=0.004), although the rate of small for gestational age neonates was similar between the groups. Conclusions OHSS in the early course of IVF pregnancies is associated with an increased risk of placental abruption.