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1.
Int J Health Geogr ; 23(1): 12, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745292

RESUMO

BACKGROUND: Previous research indicates the start of primary school (4-5-year-old) as an essential period for the development of children's physical activity (PA) patterns, as from this point, the age-related decline of PA is most often observed. During this period, young children are exposed to a wider variety of environmental- and social contexts and therefore their PA is influenced by more diverse factors. However, in order to understand children's daily PA patterns and identify relevant opportunities for PA promotion, it is important to further unravel in which (social) contexts throughout the day, PA of young children takes place. METHODS: We included a cross-national sample of 21 primary schools from the Startvaardig study. In total, 248 children provided valid accelerometer and global positioning (GPS) data. Geospatial analyses were conducted to quantify PA in (social) environments based on their school and home. Transport-related PA was evaluated using GPS speed-algorithms. PA was analysed at different environments, time-periods and for week- and weekend days separately. RESULTS: Children accumulated an average of 60 min of moderate-to-vigorous PA (MVPA), both during week- and weekend days. Schools contributed to approximately half of daily MVPA during weekdays. During weekends, environments within 100 m from home were important, as well as locations outside the home-school neighbourhood. Pedestrian trips contributed to almost half of the daily MVPA. CONCLUSIONS: We identified several social contexts relevant for children's daily MVPA. Schools have the potential to significantly contribute to young children's PA patterns and are therefore encouraged to systematically evaluate and implement parts of the school-system that stimulate PA and potentially also learning processes. Pedestrian trips also have substantial contribution to daily MVPA of young children, which highlights the importance of daily active transport in school- and parental routines.


Assuntos
Exercício Físico , Instituições Acadêmicas , Humanos , Exercício Físico/fisiologia , Pré-Escolar , Masculino , Feminino , Acelerometria/métodos , Sistemas de Informação Geográfica , Fatores de Tempo , Itália/epidemiologia , Estudos Transversais
2.
Heliyon ; 10(9): e29947, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38707355

RESUMO

Whole brain radiotherapy (WBRT) is used to improve tumor control in patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor control. However, WBRT can lead to cognitive decline in patients. We assessed whether fractionated WBRT (fWBRT) affects spontaneous behavior of mice in automated home cages and cognition (spatial memory) using the Barnes maze. Male C57Bl/6j mice received bi-lateral fWBRT at a dosage of 4 Gy/day on 5 consecutive days. In line with previous reports, immunohistochemical analysis of doublecortin positive cells in the dentate gyrus showed a profound reduction in immature neurons 4 weeks after fWBRT. Surprisingly, spontaneous behavior as measured in automated home cages was not affected. Moreover, learning and memory measured with Barnes maze, was also not affected 4-6 weeks after fWBRT. At 10-11 weeks after fWBRT a significant difference in escape latency during the learning phase, but not in the probe test of the Barnes maze was observed. In conclusion, although we confirmed the serious adverse effect of fWBRT on neurogenesis 4 weeks after fWBRT, we did not find similar profound effects on spontaneous behavior in the automated home cage nor on learning abilities as measured by the Barnes maze. The relationship between the neurobiological effects of fWBRT and cognition seems more complex than often assumed and the choice of animal model, cognitive tasks, neurobiological parameters, and experimental set-up might be important factors in these types of experiments.

3.
Arthrosc Tech ; 13(4): 102912, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38690328

RESUMO

Haglund's deformity refers to the enlargement of the posterosuperior tuberosity of the calcaneus, which can cause debilitating posterior heel pain and swelling. Calcaneoplasty is indicated for the treatment of Haglund's deformity following a failure of conservative treatment. Endoscopic calcaneoplasty confers a few advantages over open surgery and has been growing in popularity as the preferred technique. This Technical Note presents an endoscopic calcaneoplasty technique with bone debridement followed by treatment with a Topaz radiofrequency device, with the patient in a supine position.

4.
Front Pediatr ; 12: 1336154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38690521

RESUMO

Introduction: Recent evidence indicates that respiratory distress (RD) in near-term infants is caused by elevated airway liquid (EL) volume at the beginning of air-breathing after birth. While the adverse effects EL volumes on newborn lung function are known, the effects on respiratory control and breathing patterns shortly after birth (<4 h) are unknown. We investigated the effects of EL volumes on cardiorespiratory function and breathing patterns in spontaneously breathing near-term newborn lambs in the first hours after birth. Methods: At 137-8 days gestation (2-3 days prior to delivery; term ∼147 days), sterile surgery was performed on fetal sheep (n = 17) to implant catheters and blood flow probes. At 140 days, lambs were delivered via caesarean section under spinal anaesthesia. Airway liquid volumes were adjusted to mimic the level expected following vaginal delivery (∼10 ml/kg; Controls; n = 7), or elective caesarean section (∼30 ml/kg; elevated airway liquid group; EL; n = 10). Spontaneous breathing and cardiorespiratory parameters were recorded over four hours after birth. Non-invasive respiratory support with supplemental oxygen was provided if required. Results: EL lambs required higher inspired oxygen levels (p = 0.0002), were less active (p = 0.026), fed less (p = 0.008) and had higher respiratory morbidity scores than Controls (p < 0.0001). EL lambs also displayed higher rates of breathing patterns associated with RD, such as expiratory braking and tachypnoea. These patterns were particularly evident in male EL lambs who displayed higher levels of severe respiratory morbidity (e.g., expiratory braking) than female EL lambs. Conclusion: The study demonstrates that EL volumes at birth trigger respiratory behaviour and breathing patterns that resemble clinically recognised features of RD in term infants.

5.
An Acad Bras Cienc ; 96(2): e20230559, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38747788

RESUMO

Creatine is consumed by athletes to increase strength and gain muscle. The aim of this study was to evaluate the effects of creatine supplementation on maximal strength and strength endurance. Twelve strength-trained men (25.2 ± 3.4 years) supplemented with 20 g Creatina + 10g maltodextrin or placebo (20g starch + 10g maltodextrin) for five days in randomized order. Maximal strength and strength endurance (4 sets 70% 1RM until concentric failure) were determined in the bench press. In addition, blood lactate, rate of perceived effort, fatigue index, and mood state were evaluated. All measurements were performed before and after the supplementation period. There were no significant changing in maximal strength, blood lactate, RPE, fatigue index, and mood state in either treatment. However, the creatine group performed more repetitions after the supplementation (Cr: Δ = +3.4 reps, p = 0.036, g = 0.53; PLA: Δ = +0.3reps, p = 0.414, g = 0.06), and higher total work (Cr: Δ = +199.5au, p = 0.038, g = 0.52; PLA: Δ = +26.7au, p = 0.402, g = 0.07). Creatine loading for five days allowed the subjects to perform more repetitions, resulting in greater total work, but failed to change the maximum strength.


Assuntos
Creatina , Suplementos Nutricionais , Ácido Láctico , Força Muscular , Resistência Física , Humanos , Masculino , Adulto , Creatina/administração & dosagem , Creatina/farmacologia , Creatina/sangue , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Resistência Física/efeitos dos fármacos , Resistência Física/fisiologia , Ácido Láctico/sangue , Adulto Jovem , Treinamento Resistido/métodos , Fadiga Muscular/efeitos dos fármacos , Fadiga Muscular/fisiologia , Método Duplo-Cego
6.
An Acad Bras Cienc ; 96(2): e20230373, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38747835

RESUMO

Bioactive substances can be found in wine lees, a waste from the winemaking industry. This work developed two formulations, a nanoemulsion with coconut oil (NE-OC) and a nanoemulsion with coconut oil and 0.5% of wine lees extract (NE-OC-Ext), to investigate their effect on untreated, bleached, and bleached-colored hair. The oil-in-water (O/W) nanoemulsions were prepared with coconut oil, TweenTM 80, SpanTM 80, AristoflexTM AVC, Conserve NovaMit MFTM, wine lees extract, and deionized water. The hydration measurements were carried out using a Corneometer® CM 825 with the capacitance method. Scanning electron microscopy (SEM) was used to characterize the effect of formulations on hair fibers. Differential Thermal Analysis (DTA) was to assess the thermal stability and compatibility of wine lees and coconut oil in formulations. Compared to NE-OC, NE-OC-Ext showed a greater hydration effect on bleached-colored hair. DTA showed that NE-OC-Ext presented a smaller number of exothermic degradation events than those of NE-OC, suggesting good interaction and compatibility of the wine lees extract in this formulation. This study highlights the value of wine lees, a residue from the winemaking process, and its possibility of use as raw material for the cosmetic hair industry since it shows a greater moisturizing potential in colored hair.


Assuntos
Óleo de Coco , Emulsões , Vinho , Vinho/análise , Óleo de Coco/química , Microscopia Eletrônica de Varredura , Cabelo/química , Cabelo/efeitos dos fármacos , Humanos , Química Verde/métodos
8.
Diagn Microbiol Infect Dis ; 109(3): 116338, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38718661

RESUMO

The diagnosis if leprosy is difficult, as it requires clinical expertise and sensitive laboratory tests. In this study, we develop a serological test for leprosy by using bioinformatics tools to identify specific B-cell epitopes from Mycobacterium leprae hypothetical proteins, which were used to construct a recombinant chimeric protein, M1. The synthetic peptides were obtained and showed good reactivity to detect leprosy patients, although the M1 chimera have showed sensitivity (Se) and specificity (Sp) values higher than 90.0% to diagnose both paucibacillary (PB) and multibacillary (MB) leprosy patients, but not those developing tegumentary or visceral leishmaniasis, tuberculosis, Chagas disease, malaria, histoplasmosis and aspergillosis, in ELISA experiments. Using sera from household contacts, values for Se and Sp were 100% and 65.3%, respectively. In conclusion, our proof-of-concept study has generated data that suggest that a new recombinant protein could be developed into a diagnostic antigen for leprosy.

9.
Artigo em Inglês | MEDLINE | ID: mdl-38718773

RESUMO

Abstract The Z-scan technique is a nonlinear optical method that has found applications in characterizing various materials, particularly those exhibiting nonlinear optical response (NLOR). This study applies the continuous wave (CW) Z-scan technique to examine the NLOR in terms of the nonlinear optical phase shifts (ΔΦ_0) exhibited by the ccfDNA extracted from blood plasma samples collected from a group constituting 30 cancer-diagnosed patients and another group constituting 30 non-diagnosed individuals. The cancer group exhibited significantly higher ΔΦ_0vs. incident power slopes compared to the non-cancer group (0.34 vs 0.12) providing a clear distinction between the two groups. The receiver operating characteristic (ROC) curve analysis of the results indicates a clear separation between cancer and non-cancer groups, along with a 94% accuracy rate of the data. The Z-scan results are corroborated by spectrophotometric analysis, revealing a consistent trend in the concentration values of ccfDNA samples extracted from both cancerous and non-cancerous samples, measuring 3.24 and 1.41 respectively. Additionally, more sensitive fluorometric analyses of the respective samples demonstrate significantly higher concentrations of ccfDNA in the cancer group, further affirming the correlation with the Z-scan results. The study suggests that the Z-scan technique holds promise as an effective method for cancer detection, potentially contributing to improved oncology diagnosis and prognosis in the future. .

10.
J Vector Borne Dis ; 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38712708

RESUMO

BACKGROUND OBJECTIVES: Mosquito-borne diseases are increasing problems in various parts of the world, causing high mortality and morbidity for humans. This study was done to assess the vector protection measures taken by rural BPL (below-poverty-line) families, and to assess the awareness about vector-borne diseases along with Total Sanitation Campaign (TSC) in rural BPL families. METHODS: A cross-sectional study was conducted in rural areas, which won Nirmal Gram Puraskar Award, among 96 BPL families for a period of three months. These families (every 5th) were selected by systematic random sampling until we reached a sample size. Basic sociodemographic details, status of vector protection measures, solid waste management, vector- borne diseases and total sanitation campaign details were collected from the study participants. Pre-tested, semi-structured questionnaire was applied to the head of the families which included sanitation status at home by a house-to-house visit. The data collected was analysed using SPSS version 20. Data was presented as frequency, percentages, mean and SD. RESULTS: Among 96 families (454 adults and children) studied 84 (87.5%) were males and 12 (12.5%) were females. 291 (64.1%) were using one or the other mosquito protection measures, 52 (54.2%) were using bednets and 23 (23.9%) were using coils. 12 families (12.5%) were not using any mosquito protection measures. In our study, 66 (68.8%) families had individual household latrine (IHHL) and 50 (52.1%) had open drainage. Even though 314 participants had an access to individual household latrine, 20 (6.36%) had practice of open-air defecation compared to 127 (90.7%) who practiced open-air defecation without an access to individual household latrine. When asked about the awareness regarding vector-borne diseases, 56 (58.3%) were aware about chikungunya, 47 (48.9%) about dengue, 46 (47.9%) about malaria, 14 (14.6%) and only 5 (5.2%) families were aware about Japanese encephalitis. In this study, 37 (38.5%) were aware about the total sanitation campaign and 40 (41.6%) were aware about government support for sanitation. INTERPRETATION CONCLUSION: While there is a general awareness of vector-borne diseases, the implementation of vector protection measures is not uniform across the village. There is a need for targeted interventions to improve the effectiveness of vector protection measures and increase awareness among the community.

11.
Dalton Trans ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38713065

RESUMO

Two new spin crossover (SCO) Fe(III) compounds were prepared, their structures were analysed and their magnetic properties were investigated. An exhaustive analysis of the effects of halogen substitution and aromatic ring functionalisation on the magnetic properties of non-solvated Fe(III) perchlorate complexes has been performed. Through comparative analysis, different magnetic profiles were found for the compounds studied, namely F (1), Cl (2), H (3), Br (4a, 4b), and I (5). Using tools like Hirshfeld analysis, the study revealed patterns in octahedral distortions and deviations from the ideal octahedral geometry. The SCO phenomenon as the conducting wire in this study, emphasises the influence of intermolecular interactions on the low spin (LS) to high spin (HS) transitions in these halogen-substituted complexes. The prevalence of H⋯H contributions has been demonstrated, albeit being the weakest and an inverse strength relationship in H⋯X interactions ranging from F to I. The findings not only interpret the intricate balance between halogen substitution, functionalisation, and intermolecular interactions in modulating magnetic properties but also direct future works in designing similar molecular systems.

12.
J Educ Health Promot ; 13: 84, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720684

RESUMO

BACKGROUND: There is tremendous variation in both the prevalence of suicide and the factors that contribute to its occurrence across geographic locations, cultures, and time. Therefore, the present study aims to identify the various socio-demographic risk factors and psychosocial stressors using population data. MATERIALS AND METHODS: The countries that were included in the study were based on data from the World Health Organization. We considered the top ten suicide countries and the ten lowest suicide nations. We searched five global databases for the most recent socio-demographic data and data on psychosocial stressors during the period of August and September 2022. We analyzed the correlation between suicide rates and various factors, and we considered a P value of less than 0.05 to be statistically significant. RESULTS: The correlation of suicide with sociodemographic factors like age (P 0.246), gender (male, P 0.357, and female, P 0.357), net enrolment rate (P 0.725), gender parity index (P 0.929), urban population percentage (P 0.571), marital status (male, P 0.345, and female, P 0.752), and literacy rate percentage (P 0.199) was not significant. The correlation of suicide with psychosocial stressors like unemployment percentage (P 0.552), alcoholism percentage (P 0.271), the prevalence of depression (P 0.523), the number of psychiatrists (P 0.605), the number of mental hospitals (r = -0.090, P 0.713), and the poverty rate percentage (P 0.538) were also not significant. CONCLUSION: Suicide is a major public health issue, yet global suicide data is scarce. Sociodemographic factors like age, urbanization, and literacy rate were negatively correlated, whereas psychosocial stressors like unemployment, alcohol misuse, and poverty were positively correlated, but none were significantly associated.

13.
Angew Chem Int Ed Engl ; : e202402052, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38705856

RESUMO

Carbene-metal-amides (CMAs) are emerging delayed fluorescence materials for organic light-emitting diode (OLED) applications. CMAs possess fast, efficient emission owing to rapid forward and reverse intersystem crossing (ISC) rates. The resulting dynamic equilibrium between singlet and triplet spin manifolds distinguishes CMAs from most purely organic thermally activated delayed fluorescence emitters. However, direct experimental triplet characterization in CMAs is underutilized, limiting our detailed understanding of the ISC mechanism. In this work, we combine time-resolved spectroscopy with tuning of state energies through environmental polarity and metal substitution, focusing on the interplay between charge-transfer (3CT) and local exciton (3LE) triplets. Unlike previous photophysical work, we investigate evaporated host:guest films of CMAs and small-molecule hosts for increased device relevance. Transient absorption reveals an evolution in the triplet excited-state absorption (ESA) consistent with a change in orbital character between hosts with differing dielectric constants. Using quantum chemical calculations, we simulate ESAs of the lowest triplet states, highlighting the contribution of only 3CT and donor-moiety 3LE states to spectral features, with no strong evidence for a low-lying acceptor-centered 3LE. Thus, our work provides a blueprint for understanding the role of triplet excited states in CMAs which will enable further intelligent optimization of this promising class of materials.

14.
J Prev Alzheimers Dis ; 11(3): 558-566, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38706272

RESUMO

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.


Assuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Satisfação do Paciente , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Método Duplo-Cego , Adulto , Inquéritos e Questionários , Ensaios Clínicos como Assunto
15.
J Biomech ; 168: 112122, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38703516

RESUMO

As the recovery from gait perturbations is coordinatively complex and error-prone, people often adopt anticipatory strategies when the perturbation is expected. These anticipatory strategies act as a first line of defence against potential balance loss. Since age-related changes in the sensory and neuromotor systems could make the recovery from external perturbations more difficult, it is important to understand how older adults implement anticipatory strategies. Therefore, we exposed healthy young (N = 10, 22 ± 1.05 yrs.) and older adults (N = 10, 64.2 ± 6.07 yrs.) to simulated slips on a treadmill with consistent properties and assessed if the reliance on anticipatory control differed between groups. Results showed that for the unperturbed steps in between perturbations, step length decreased and the backward (BW) margin of stability (MOS) increased (i.e., enhanced dynamic stability against backward loss of balance) in the leg that triggered the slip, while step lengths increased and BW MOS decreased in the contralateral leg. This induced step length and BW MOS asymmetry was significantly larger for older adults. When exposed to a series of predictable slips, healthy older adults thus rely more heavily on anticipatory control to proactively accommodate the expected backward loss of balance.

16.
Braz J Biol ; 84: e282386, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38695424

RESUMO

Due to the need to achieve the principles of sustainable development and to understand the processes of formation of phytocenoses in areas that were adversely affected by the industrial impact, this study assessed the condition of the Grachevsky uranium mine (Kazakhstan), which underwent conservation procedures about 25 years ago. The purpose is to determine the level of water quality and phytocenosis of the shores of the reservoir accumulating natural effluents from reclaimed dumps and anthropogenic sites of a uranium mine, as well as quality indicators and toxicology. The assessment included a qualitative research method (analysis of documents) to determine agro-climatic conditions and empirical methods of collecting information. The authors studied the intensity of ionizing radiation of the gamma background of the water surface of the reservoir (and sections of the shoreline and territories adjacent to the reservoir), and hydrochemical parameters of the waters of the reservoir, and performed a description of the botanical diversity. The vegetation cover of the sections of the reservoir shore is at different stages of syngenesis and is represented by pioneer groupings, group thicket communities, and diffuse communities. Favorable ecological conditions for the settlement and development of plants develop within the shores of the reservoir. The intensity levels of ionizing radiation do not exceed the maximum permissible levels and practically do not affect the formation of phytocenoses. An anthropogenically modified dry meadow with the participation of plants typical of the steppe zone has been formed on the floodplain terrace. Concerning the indicators of quality and toxicology of this reservoir, the water can be used for household and drinking purposes under the condition of prior water treatment. It can be concluded that a high level of natural purification of the reservoir waters occurred within twenty years after the reclamation of the uranium mine.


Assuntos
Mineração , Urânio , Qualidade da Água , Urânio/análise , Biodiversidade , Resíduos Industriais/análise , Cazaquistão , Monitoramento Ambiental/métodos , Plantas/química , Plantas/classificação , Poluentes Radioativos da Água/análise , Instalações de Eliminação de Resíduos
17.
Front Digit Health ; 6: 1359858, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38736708

RESUMO

Healthcare is a critical area where blockchain technology (BT) is being heralded as a potential game-changer for facilitating secure and efficient data sharing. The purpose of this review is to examine BT applications, performance challenges, and solutions in healthcare. To begin, This review paper explores popular blockchain networks for data exchange, encompassing both public and permissioned platforms, such as Ethereum and Hyperledger Fabric. This paper analyzes the potential applications of BT's decentralized, immutable, and smart contract capabilities in healthcare settings, including secure and interoperable health data exchange, patient consent management, drug supply chain oversight, and clinical trial management. The healthcare industry might greatly benefit from the increased privacy, transparency, and accessibility that these technologies provide. Despite BT's promising medical uses, the technology is not without its drawbacks. High energy consumption, throughput, and scalability are all concerns. We wrapped up by discussing the solutions that have been implemented, including consensus processes, scalability measures like sharding, and off-chain transactions that are designed to mitigate the drawbacks.

18.
Nature ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693261

RESUMO

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

20.
J Cell Mol Med ; 28(8): e18333, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38652192

RESUMO

Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti-AML activity of bortezomib (BTZ), emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem-like features of KG-1a cells, as observed by the reduction in CD34- and CD123-positive cells. A reduction in NF-κB p65 nuclear staining was observed in BTZ-treated KG-1a cells, in addition to upregulation of the NF-κB inhibitor gene NFΚBIB. BTZ-induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase-3 and cleaved PARP-(Asp 214) level in KG-1a cells. Furthermore, BTZ-induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z-VAD-(OMe)-FMK, indicating that BTZ induces caspase-mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.


Assuntos
Bortezomib , Leucemia Mieloide Aguda , NF-kappa B , Células-Tronco Neoplásicas , Estresse Oxidativo , Bortezomib/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Animais , NF-kappa B/metabolismo , Linhagem Celular Tumoral , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos SCID
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