A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage.

Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and γ-irradiation. DNA damage induces BATF in a G-CSF/STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to γ-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.

Phenotypic plasticity evolves at multiple biological levels in response to environmental predictability in a long-term experiment with a halotolerant microalga.

Phenotypic plasticity, the change in the phenotype of a given genotype in response to its environment of development, is a ubiquitous feature of life, enabling organisms to cope with variation in their environment. Theoretical studies predict that, under stationary environmental variation, the level of plasticity should evolve to match the predictability of selection at the timing of development. However, the extent to which patterns of evolution of plasticity for more integrated traits are mirrored by their underlying molecular mechanisms remains unclear, especially in response to well-characterized selective pressures exerted by environmental predictability. Here, we used experimental evolution with the microalgae Dunaliella salina under controlled environmental fluctuations, to test whether the evolution of phenotypic plasticity in responses to environmental predictability (as measured by the squared autocorrelation ρ2) occurred across biological levels, going from DNA methylation to gene expression to cell morphology. Transcriptomic analysis indicates clear effects of salinity and ρ2 × salinity interaction on gene expression, thus identifying sets of genes involved in plasticity and its evolution. These transcriptomic effects were independent of DNA methylation changes in cis. However, we did find ρ2-specific responses of DNA methylation to salinity change, albeit weaker than for gene expression. Overall, we found consistent evolution of reduced plasticity in less predictable environments for DNA methylation, gene expression, and cell morphology. Our results provide the first clear empirical signature of plasticity evolution at multiple levels in response to environmental predictability, and highlight the importance of experimental evolution to address predictions from evolutionary theory, as well as investigate the molecular basis of plasticity evolution.

An Early Treatment With BKI-1748 Exhibits Full Protection Against Abortion and Congenital Infection in Sheep Experimentally Infected With Toxoplasma gondii.

Congenital toxoplasmosis in humans and in other mammalian species, such as small ruminants, is a well-known cause of abortion and fetal malformations. The calcium-dependent protein kinase 1 (CDPK1) inhibitor BKI-1748 has shown a promising safety profile for its use in humans and a good efficacy against Toxoplasma gondii infection in vitro and in mouse models. Ten doses of BKI-1748 given every other day orally in sheep at 15 mg/kg did not show systemic or pregnancy-related toxicity. In sheep experimentally infected at 90 days of pregnancy with 1000 TgShSp1 oocysts, the BKI-1748 treatment administered from 48 hours after infection led to complete protection against abortion and congenital infection. In addition, compared to infected/untreated sheep, treated sheep showed a drastically lower rectal temperature increase and none showed IgG seroconversion throughout the study. In conclusion, BKI-1748 treatment in pregnant sheep starting at 48 hours after infection was fully effective against congenital toxoplasmosis.

The Role of Nicotinic Receptors on Ca2+ Signaling in Bovine Chromaffin Cells.

Chromaffin cells have been used as a physiological model to understand neurosecretion in mammals for many years. Nicotinic receptors located in the cells' membrane are stimulated by acetylcholine, and they participate in the exocytosis of chromaffin granules, releasing catecholamines in response to stress. In this work, we discuss how the participation of nicotinic receptors and the localization of active zones in the borders of the cytoskeleton can generate local calcium signals leading to secretion. We use a computational model of a cytoskeleton cage to simulate Ca2+ levels in response to voltage and acetylcholine pulses. We find that nicotinic receptors are able to enhance the differences between local and average calcium values, as well as the heterogeneous distributions around the active zones, producing a non-linear, highly localized Ca2+ entry that, although consisting of a few ions, is able to improve secretion responses in chromaffin cells. Our findings emphasize the intricate interplay among nicotinic receptors, the cytoskeleton, and active zones within chromaffin cells as an example of Ca2+-dependent neurosecretion in mammals.

Interaction of gonadal hormones, dopaminergic system, and epigenetic regulation in the generation of sex differences in substance use disorders: A systematic review.

Substance use disorder (SUD) is a chronic condition characterized by pathological drug-taking and seeking behaviors. Remarkably different between males and females, suggesting that drug addiction is a sexually differentiated disorder. The neurobiological bases of sex differences in SUD include sex-specific reward system activation, influenced by interactions between gonadal hormone level changes, dopaminergic reward circuits, and epigenetic modifications of key reward system genes. This systematic review, adhering to PICOS and PRISMA-P 2015 guidelines, highlights the sex-dependent roles of estrogens, progesterone, and testosterone in SUD. In particular, estradiol elevates and progesterone reduces dopaminergic activity in SUD females, whilst testosterone and progesterone augment SUD behavior in males. Finally, SUD is associated with a sex-specific increase in the rate of opioid and monoaminergic gene methylation. The study reveals the need for detailed research on gonadal hormone levels, dopaminergic or reward system activity, and epigenetic landscapes in both sexes for efficient SUD therapy development.

CCR5 deficiency impairs CD4+ T-cell memory responses and antigenic sensitivity through increased ceramide synthesis.

CCR5 is not only a coreceptor for HIV-1 infection in CD4+ T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR5 signaling reduces ceramide levels and thereby increases T-cell antigen receptor (TCR) nanoclustering in antigen-experienced mouse and human CD4+ T cells. This activity is CCR5-specific and independent of CCR5 co-stimulatory activity. CCR5-deficient mice showed reduced production of high-affinity class-switched antibodies, but only after antigen rechallenge, which implies an impaired memory CD4+ T-cell response. This study identifies a CCR5 function in the generation of CD4+ T-cell memory responses and establishes an antigen-independent mechanism that regulates TCR nanoclustering by altering specific lipid species.

Carbon Dots based Tissue Equivalent Dosimeter as an Ionizing Radiation Sensor.

This work explores the potential of carbon dots as a fluorescent probe in the determination of heavy ions and as an electrochemical biosensor. It also discusses how carbon dots can be introduced into the Fricke solution to potentially serve as an ionizing radiation sensor. The study presents a novel tissue equivalent dosimeter carbon dots-based as an ionizing radiation sensor. The methodology for the synthesis of Nitrogen-doped Carbon Dots N-CDs and the characterization of the material are described. The results show that the N-CDs have a high sensitivity to ionizing radiation and can be used as a dosimeter for radiation detection. The study also discusses the limitations and challenges of using carbon dots as a dosimeter for ionizing radiation. Overall, this study provides valuable insights into the potential applications of carbon dots in different fields and highlights the importance of further research in this area.

Retrospective multicenter study of elderly patients with platinum-sensitive relapsed ovarian cancer treated with trabectedin and pegylated liposomal doxorubicin (pld) in a real-world setting: a geico study.

BACKGROUND: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting. METHODS: This observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible. RESULTS: Forty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%). CONCLUSIONS: This analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients.

Revisiting niche divergence hypothesis in sexually dimorphic birds: Is diet overlap correlated with sexual size dimorphism?

The evolution of sexual size dimorphism (SSD) is a long-standing topic in evolutionary biology, but there is little agreement on the extent to which SSD is driven by the different selective forces. While sexual selection and fecundity selection have traditionally been proposed as the two leading hypotheses, SSD may also result from natural selection through mechanisms such as sexual niche divergence, which might have reduced resource competition between sexes. Here, we revisited the niche divergence hypothesis by testing the relationship between the sexual overlap in diet and SSD of 56 bird species using phylogenetic comparative analyses. We then assessed how SSD variation relates to the three main hypotheses: sexual selection, fecundity selection, and sexual niche divergence using phylogenetic generalized least squares (PGLS). Then, we compared sexual selection, fecundity selection and niche divergence selection as SSD drivers through phylogenetic confirmatory path analyses to disentangle the possible causal evolutionary relationships between SSD and the three hypotheses. Phylogenetic generalized least squares showed that SSD was negatively correlated with diet overlap, that is, the greater the difference in body size between males and females, the less diet overlap. As predicted by sexual selection theory, the difference in body size between sexes was higher in polygynous species. Confirmatory phylogenetic path analyses suggested that the most likely evolutionary path might include the mating system as a main driver in SSD and niche divergence as a result of SSD. We found no evidence of a role of fecundity selection in the evolution of female-biased SSD. Our study provides evidence that sexual selection has likely been the main cause of SSD and that dietary divergence is likely an indirect effect of SSD.

The synthesis of solid supports carrying base labile linkers to generate 3'-phosphate oligonucleotides.

Oligonucleotides carrying 3'-terminal phosphates and conjugates are important tools in molecular biology and diagnostic purposes. We described the preparation of solid supports carrying the base labile linker 4-((2-hydroxyethyl)sulfonyl)benzamide for the solid-phase synthesis of 3'-phosphorylated oligonucleotides. These supports are fully compatible with the phosphoramidite chemistry yielding the desired 3'-phosphate oligonucleotides in excellent yields. The use of mild deprotection conditions allows the generation of partially protected DNA fragments.

Design, develop, and implement the strategic information system on health, dependence, and healthy aging: an analysis of the Mexican experience.

BACKGROUND: The Decade of Healthy Aging (2021-2030) emerges as a 10 years strategy to improve the lives of older adults, their families, and the communities in which they live. One of the actions defined in this framework is related to improving the measurement, monitoring, and understanding of characteristics, factors, and needs related to aging and health. The aim was to analyze and assess the process of construction and development of the Strategic Information System on Health, Funcional Dependence and Aging (SIESDE, for its acronym in Spanish). SIESDE will provide strategic information in Mexico at the municipal, state, and national levels that support the public policies on healthy aging. METHODS: The system processes and analyzes the data sources of the Health Information Systems and the National System of Statistical and Geographical Information. SIESDE comprises three components: (1) Design, construction, and evaluation of the indicators; (2) storage, management, and visualization, and (3) diffusion and translation of information. RESULTS: A total of 135 indicators were built on seven themes: (1) demographic, socioeconomic, and aging conditions, (2) health, (3) functional dependence, (4) healthy aging, (5) health services, (6) social and physical environments, and (7) complex indicators. CONCLUSIONS: SIESDE is an effective system for providing an overall view of health, aging, and functional dependence.

Size Matters: A Computational Study of Hydrogen Absorption in Ionic Liquids.

We combined both density functional theory and classical molecular dynamics simulations to investigate the molecular mechanisms governing hydrogen solvation in a total of 12 ionic liquids. Overall, the analysis of the structural properties under high temperature and pressure conditions revealed weak interactions between hydrogen and the ionic liquids, with a slight preference of this gas to be placed at the apolar domains. Interestingly, those ionic liquids comprising nitrate anions allow the accommodation of hydrogen molecules also in the polar areas. The study of the hydrogen velocity autocorrelation functions supports this observation. In addition, the structure of all of the tested ionic liquids was almost insensitive to the addition of hydrogen, so the available free volume and cavity formation are presumably the most important factors affecting solubility.

Early-life external exposome in children 2-5 years old in Colombia.

Exposome studies are advancing in high-income countries to understand how multiple environmental exposures impact health. However, there is a significant research gap in low- and middle-income and tropical countries. We aimed to describe the spatiotemporal variation of the external exposome, its correlation structure between and within exposure groups, and its dimensionality. A one-year follow-up cohort study of 506 children under 5 in two cities in Colombia was conducted to evaluate asthma, acute respiratory infections, and DNA damage. We examined 48 environmental exposures during pregnancy and 168 during childhood in eight exposure groups, including atmospheric pollutants, natural spaces, meteorology, built environment, traffic, indoor exposure, and socioeconomic capital. The exposome was estimated using geographic information systems, remote sensing, spatiotemporal modeling, and questionnaires. The median age of children at study entry was 3.7 years (interquartile range: 2.9-4.3). Air pollution and natural spaces exposure decreased from pregnancy to childhood, while socioeconomic capital increased. The highest median correlations within exposure groups were observed in meteorology (r = 0.85), traffic (r = 0.83), and atmospheric pollutants (r = 0.64). Important correlations between variables from different exposure groups were found, such as atmospheric pollutants and meteorology (r = 0.76), natural spaces (r = -0.34), and the built environment (r = 0.53). Twenty principal components explained 70%, and 57 explained 95% of the total variance in the childhood exposome. Our findings show that there is an important spatiotemporal variation in the exposome of children under 5. This is the first characterization of the external exposome in urban areas of Latin America and highlights its complexity, but also the need to better characterize and understand the exposome in order to optimize its analysis and applications in local interventions aimed at improving the health conditions and well-being of the child population and contributing to environmental health decision-making.

Neonatal kaempferol exposure attenuates impact of cerebral palsy model on neuromotor development, cell proliferation, microglia activation, and antioxidant enzyme expression in the hippocampus of rats.

OBJECTIVES: This study aims to assess the effect of neonatal treatment with kaempferol on neuromotor development, proliferation of neural precursor cells, the microglia profile, and antioxidant enzyme gene expression in the hippocampus. METHODS: A rat model of cerebral palsy was established using perinatal anoxia and sensorimotor restriction of hindlimbs during infancy. Kaempferol (1 mg/ kg) was intraperitoneally administered during the neonatal period. RESULTS: Neonatal treatment with kaempferol reduces the impact of the cerebral palsy model on reflex ontogeny and on the maturation of physical features. Impairment of locomotor activity development and motor coordination was found to be attenuated by kaempferol treatment during the neonatal period in rats exposed to cerebral palsy. Neonatal treatment of kaempferol in cerebral palsy rats prevents a substantial reduction in the number of neural precursor cells in the dentate gyrus of the hippocampus, an activated microglia profile, and increased proliferation of microglia in the sub-granular zone and in the granular cell layer. Neonatal treatment with kaempferol increases gene expression of superoxide dismutase and catalase in the hippocampus of rats submitted to the cerebral palsy model. DISCUSSION: Kaempferol attenuates the impact of cerebral palsy on neuromotor behavior development, preventing altered hippocampal microglia activation and mitigating impaired cell proliferation in a neurogenic niche in these rats. Neonatal treatment with kaempferol also increases antioxidant defense gene expression in the hippocampus of rats submitted to the cerebral palsy model.

Long-Term Outcomes of the Altis® Single-Incision Sling: Up to 10 Years' Follow-up.

INTRODUCTION AND HYPOTHESIS: Single-incision slings (SIS) have emerged as a less invasive alternative to conventional slings for stress urinary incontinence (SUI) treatment. However, long-term efficacy and safety results remain uncertain owing to a lack of studies. MATERIAL AND METHODS: A retrospective review of 155 patients treated with Altis® for SUI between February 2012 and June 2017, held in 2022, as a continuation of a prospective study in which all patients (197) were reviewed for 2 years after surgery (1, 6, 12, and 24 months). Preoperative demographic data, comorbidities, and pressure-flow studies were also recorded. Continence status and satisfaction rates were assessed using the International Consultation on Incontinence Questionnaire-short form (ICIQ-SF) and the Patient Global Impression of Improvement (PGI-I) respectively. The assessment in the 2022 retrospective review was performed via a telephone survey. RESULTS: Mean follow-up time after surgery was 85.3 months (82.5-88.1). In 2022, complete continence was present in 75.4% of the patients. The presence of urinary urgency conditioned the ICIQ-SF score (10.9 vs 1.7 points, p < 0.01), with the ICIQ-SF = 0 in 84.5% of the patients with no associated urgency. Satisfaction assessed by the PGI-I was high, with 84.6% of the patients showing improvement. De novo urgency was present in 37,9% of the patients by 2022. Urinary tract infections were the most frequent complication (9.7%), with only 5 documented cases of mesh erosion. CONCLUSIONS: Altis® SIS is a safe and effective device for SUI treatment, with satisfaction rates comparable with those of the conventional slings. Persistence or development of urinary urgency influences the results.

3D-DXA Based Finite Element Modelling for Femur Strength Prediction: Evaluation Against QCT.

Osteoporosis is characterised by the loss of bone density resulting in an increased risk of fragility fractures. The clinical gold standard for diagnosing osteoporosis is based on the areal bone mineral density (aBMD) used as a surrogate for bone strength, in combination with clinical risk factors. Finite element (FE) analyses based on quantitative computed tomography (QCT) have been shown to estimate bone strength better than aBMD. However, their application in the osteoporosis clinics is limited due to exposure of patients to increased X-rays radiation dose. Statistical modelling methods (3D-DXA) enabling the estimation of 3D femur shape and volumetric bone density from dual energy X-ray absorptiometry (DXA) scan have been shown to improve osteoporosis management. The current study used 3D-DXA based FE analyses to estimate femur strength from the routine clinical DXA scans and compared its results against 151 QCT based FE analyses, in a clinical cohort of 157 subjects. The linear regression between the femur strength predicted by QCT-FE and 3D-DXA-FE models correlated highly (coefficient of determination R2 = 0.86) with a root mean square error (RMSE) of 397 N. In conclusion, the current study presented a 3D-DXA-FE modelling tool providing accurate femur strength estimates noninvasively, compared to QCT-FE models.

Assessing the relationship between multimorbidity, NCD configurations, frailty phenotypes, and mortality risk in older adults.

BACKGROUND: Older adults are increasingly susceptible to prolonged illness, multiple chronic diseases, and disabilities, which can lead to the coexistence of multimorbidity and frailty. Multimorbidity may result in various noncommunicable disease (NCD) patterns or configurations that could be associated with frailty and death. Mortality risk may vary depending on the presence of specific chronic diseases configurations or frailty. METHODS: The aim was to examine the impact of NCD configurations on mortality risk among older adults with distinct frailty phenotypes. The population was analyzed from the Costa Rican Longevity and Healthy Aging Study Cohort (CRELES). A total of 2,662 adults aged 60 or older were included and followed for 5 years. Exploratory factor analysis and various clustering techniques were utilized to identify NCD configurations. The frequency of NCD accumulation was also assessed for a multimorbidity definition. Frailty phenotypes were set according to Fried et al. criteria. Kaplan‒Meier survival analyses, mortality rates, and Cox proportional hazards models were estimated. RESULTS: Four different types of patterns were identified: 'Neuro-psychiatric', 'Metabolic', 'Cardiovascular', and 'Mixt' configurations. These configurations showed a higher mortality risk than the mere accumulation of NCDs [Cardiovascular HR:1.65 (1.07-2.57); 'Mixt' HR:1.49 (1.00-2.22); ≥3 NCDs HR:1.31 (1.09-1.58)]. Frailty exhibited a high and constant mortality risk, irrespective of the presence of any NCD configuration or multimorbidity definition. However, HRs decreased and lost statistical significance when phenotypes were considered in the Cox models [frailty + 'Cardiovascular' HR:1.56 (1.00-2.42); frailty + 'Mixt':1.42 (0.95-2.11); and frailty + ≥ 3 NCDs HR:1.23 (1.02-1.49)]. CONCLUSIONS: Frailty accompanying multimorbidity emerges as a more crucial indicator of mortality risk than multimorbidity alone. Therefore, studying NCD configurations is worthwhile as they may offer improved risk profiles for mortality as alternatives to straightforward counts.

Clean-label products: Factors affecting liking and acceptability by Portuguese older adults.

Consumers are preferring more "natural" foods, made of "healthier" and "familiar" components - the "clean-label" trend. As the population ages, understanding the older adult consumer segment becomes increasingly important. This study aims to identify the factors influencing the acceptability and liking of clean-label products in older adults living in the community. A convenience sample of 100 older adults was used for this cross-sectional study. Socio-demographic data, health status, independence level, lifestyle characteristics, nutritional status, and food and nutrient intake data were collected. The acceptability and liking for clean-label products comprised two parts: Sensory analysis with overall liking evaluation of three pairs of products, using a 9-point hedonic scale and free comments; Willingness to eat and preference assessment of nine pairs of products using the Food Action scale and a simple preference test. The participants were 80% female with a mean age of 75 years old. The overall liking for clean-label versions of cookies and mayonnaise was lower than for traditional versions. However, participants were more willing to eat the clean-label versions of products, particularly ham and yogurt. Most of the participants would prefer buying the clean-label version of all nine pairs of products, especially for ham, loaf bread, sausages, and yogurt. In sum, older adults living in the community exhibit a lower liking but, a greater willingness to eat and a higher preference for buying clean-label products. Older adults who favor clean-label products have higher levels of education and are reported to have a more adequate diet.

Closed microbial communities self-organize to persistently cycle carbon.

Cycles of nutrients (N, P, etc.) and resources (C) are a defining emergent feature of ecosystems. Cycling plays a critical role in determining ecosystem structure at all scales, from microbial communities to the entire biosphere. Stable cycles are essential for ecosystem persistence because they allow resources and nutrients to be regenerated. Therefore, a central problem in ecology is understanding how ecosystems are organized to sustain robust cycles. Addressing this problem quantitatively has proved challenging because of the difficulties associated with manipulating ecosystem structure while measuring cycling. We address this problem using closed microbial ecosystems (CES), hermetically sealed microbial consortia provided with only light. We develop a technique for quantifying carbon cycling in hermetically sealed microbial communities and show that CES composed of an alga and diverse bacterial consortia self-organize to robustly cycle carbon for months. Comparing replicates of diverse CES, we find that carbon cycling does not depend strongly on the taxonomy of the bacteria present. Moreover, despite strong taxonomic differences, self-organized CES exhibit a conserved set of metabolic capabilities. Therefore, an emergent carbon cycle enforces metabolic but not taxonomic constraints on ecosystem organization. Our study helps establish closed microbial communities as model ecosystems to study emergent function and persistence in replicate systems while controlling community composition and the environment.