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1.
Braz J Psychiatry ; 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39298378

RESUMO

OBJECTIVE: To identify the effects of amygdala neuromodulation in the management disruptive behavior in patients, as well as changes in their quality of life and its relationship with epilepsy. METHODS: MEDLINE, OVID, WoS, Central Cochrane, and Scopus databases were systematically searched up to March 2023 for studies examining extremely aggressive patients who underwent ablative surgeries or deep brain stimulation (DBS) of the amygdala as the unique therapeutic target, with a six-month follow-up at least. RESULTS: The search yielded 1352 studies excluding duplicates, but only 11 case series, and 3 case reports met the inclusion criteria. They were published between 1963-2023 with a total of 1033 patients, mostly male, aged between 5 and 61 years. Most studies implemented amygdalotomy and only one DBS. More than 70% of the patients improved their behavior; approximately 30% had seizures, of which 40% presented improvement. Two studies reported worsening behavior. CONCLUSIONS: Although we found that amygdalotomy has a positive effect on the behavior of patients and the control of their seizures, it is necessary to carry out updated studies with greater epidemiological power. Future research should analyze the DBS use and the role of connectomics of the different neural networks involved with this brain structure.

2.
Eur J Cancer ; 211: 114310, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39270379

RESUMO

AIM: The aim of this study was to assess whether the use of sentinel lymph node (SLN) in addition to lymphadenectomy was associated with survival benefit in patients with early-stage cervical cancer. METHODS: International, multicenter, retrospective study. INCLUSION CRITERIA: cervical cancer treated between 01/2007 and 12/2016 by surgery only; squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, FIGO 2009 stage IB1-IIA2, negative surgical margins, and laparotomy approach. Patients undergoing neo-adjuvant and/or adjuvant treatment and/or with positive para-aortic lymph nodes, were excluded. Women with positive pelvic nodes who refused adjuvant treatment, were included. Lymph node assessment was performed by SLN (with ultrastaging protocol) plus pelvic lymphadenectomy ('SLN' group) or pelvic lymphadenectomy alone ('non-SLN' group). RESULTS: 1083 patients were included: 300 (27.7 %) in SLN and 783 (72.3 %) in non-SLN group. 77 (7.1 %) patients had recurrence (N = 11, 3.7 % SLN versus N = 66, 8.4 % non-SLN, p = 0.005) and 34 (3.1 %) (N = 4, 1.3 % SLN versus N = 30, 3.8 % non-SLN, p = 0.033) died. SLN group had better 5-year disease-free survival (DFS) (96.0 %,95 %CI:93.5-98.5 versus 92.0 %,95 %CI:90.0-94.0; p = 0.024). No 5-year overall survival (OS) difference was shown (98.4 %,95 %CI:96.8-99.9 versus 96.8 %,95 %CI:95.4-98.2; p = 0.160). SLN biopsy and lower stage were independent factors associated with improved DFS (HR:0.505,95 %CI:0.266-0.959, p = 0.037 and HR:2.703,95 %CI:1.389-5.261, p = 0.003, respectively). Incidence of pelvic central recurrences was higher in the non-SLN group (1.7 % versus 4.5 %, p = 0.039). CONCLUSION: Adding SLN biopsy to pelvic lymphadenectomy was associated with lower recurrence and death rate and improved 5-year DFS. This might be explained by the lower rate of missed nodal metastasis thanks to the use of SLN ultrastaging. SLN biopsy should be recommended in patients with early-stage cervical cancer.

3.
Arch Microbiol ; 206(9): 385, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39177836

RESUMO

Hydrophobins (HFBs) and cerato-platanins (CPs) are surface-active extracellular proteins produced by filamentous fungi. This study identified two HFB genes (pshyd1 and pshyd2) and one CP gene (pscp) in the marine fungus Paradendryphiella salina. The proteins PsCP, PsHYD2, and PsHYD1 had molecular weights of 12.70, 6.62, and 5.98 kDa, respectively, with isoelectric points below 7. PsHYD1 and PsHYD2 showed hydrophobicity (GRAVY score 0.462), while PsCP was hydrophilic (GRAVY score - 0.202). Stability indices indicated in-solution stability. Mass spectrometry identified 2,922 proteins, including CP but not HFB proteins. qPCR revealed differential gene expression influenced by developmental stage and substrate, with pshyd1 consistently expressed. These findings suggest P. salina's adaptation to marine ecosystems with fewer hydrophobin genes than other fungi but capable of producing surface-active proteins from seaweed carbohydrates. These proteins have potential applications in medical biocoatings, food industry foam stabilizers, and environmental bioremediation.


Assuntos
Proteínas Fúngicas , Interações Hidrofóbicas e Hidrofílicas , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química , Ascomicetos/genética , Ascomicetos/metabolismo , Ascomicetos/química , Alga Marinha/microbiologia , Alga Marinha/química , Organismos Aquáticos/genética , Organismos Aquáticos/metabolismo , Regulação Fúngica da Expressão Gênica , Água do Mar/microbiologia
4.
NPJ Digit Med ; 7(1): 229, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39191937

RESUMO

Regulatory frameworks for artificial intelligence (AI) are needed to mitigate risks while ensuring the ethical, secure, and effective implementation of AI technology in healthcare and population health. In this article, we present a synthesis of 141 binding policies applicable to AI in healthcare and population health in the EU and 10 European countries. The EU AI Act sets the overall regulatory framework for AI, while other legislations set social, health, and human rights standards, address the safety of technologies and the implementation of innovation, and ensure the protection and safe use of data. Regulation specifically pertaining to AI is still nascent and scarce, though a combination of data, technology, innovation, and health and human rights policy has already formed a baseline regulatory framework for AI in health. Future work should explore specific regulatory challenges, especially with respect to AI medical devices, data protection, and data enablement.

5.
Int J Mol Sci ; 25(16)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39201537

RESUMO

Peptides are bioactive molecules whose functional versatility in living organisms has led to successful applications in diverse fields. In recent years, the amount of data describing peptide sequences and function collected in open repositories has substantially increased, allowing the application of more complex computational models to study the relations between the peptide composition and function. This work introduces AMP-Detector, a sequence-based classification model for the detection of peptides' functional biological activity, focusing on accelerating the discovery and de novo design of potential antimicrobial peptides (AMPs). AMP-Detector introduces a novel sequence-based pipeline to train binary classification models, integrating protein language models and machine learning algorithms. This pipeline produced 21 models targeting antimicrobial, antiviral, and antibacterial activity, achieving average precision exceeding 83%. Benchmark analyses revealed that our models outperformed existing methods for AMPs and delivered comparable results for other biological activity types. Utilizing the Peptide Atlas, we applied AMP-Detector to discover over 190,000 potential AMPs and demonstrated that it is an integrative approach with generative learning to aid in de novo design, resulting in over 500 novel AMPs. The combination of our methodology, robust models, and a generative design strategy offers a significant advancement in peptide-based drug discovery and represents a pivotal tool for therapeutic applications.


Assuntos
Peptídeos Antimicrobianos , Aprendizado de Máquina , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/farmacologia , Algoritmos , Descoberta de Drogas/métodos , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Biologia Computacional/métodos
6.
Mol Phylogenet Evol ; 199: 108167, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39103025

RESUMO

Disentangling the genomic intricacies underlying speciation and the causes of discordance between sources of evidence can offer remarkable insights into evolutionary dynamics. The ant-eating spider Zodarion nitidum, found across the Middle East and Egypt, displays yellowish and blackish morphs that co-occur sympatrically. These morphs additionally differ in behavioral and physiological features and show complete pre-mating reproductive isolation. In contrast, they possess similar sexual features and lack distinct differences in their mitochondrial DNA. We analyzed both Z. nitidum morphs and outgroups using genome-wide and additional mitochondrial DNA data. The genomic evidence indicated that Yellow and Black are reciprocally independent lineages without signs of recent admixture. Interestingly, the sister group of Yellow is not Black but Z. luctuosum, a morphologically distinct species. Genomic gene flow analyses pinpointed an asymmetric nuclear introgression event, with Yellow contributing nearly 5 % of its genome to Black roughly 320,000 years ago, intriguingly aligning with the independently estimated origin of the mitochondrial DNA of Black. We conclude that the blackish and yellowish morphs of Z. nitidum are long-diverged distinct species, and that the ancient and modest genomic introgression event registered resulted in a complete mitochondrial takeover of Black by Yellow. This investigation underscores the profound long-term effects that even modest hybridization events can have on the genome of organisms. It also exemplifies the utility of phylogenetic networks for estimating historical events and how integrating independent lines of evidence can increase the reliability of such estimations.


Assuntos
DNA Mitocondrial , Hibridização Genética , Filogenia , Aranhas , Simpatria , Animais , Aranhas/genética , Aranhas/classificação , DNA Mitocondrial/genética , Fluxo Gênico , Especiação Genética
7.
Genes (Basel) ; 15(8)2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39202366

RESUMO

This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression (BDI-II), acculturation/marginalization (ARSMA-II), and liver health as assessed by elastography. Heritability and genotype-by-environment (G×E) interactions were analyzed, focusing on the marginalization/separation measure of the ARSMA-II. Significant heritabilities were found for traits such as HbA1c (h2 = 0.52), marginalization (h2 = 0.30), AST (h2 = 0.25), ALT (h2 = 0.41), and BMI (h2 = 0.55). Genotype-by-environment interactions were significant for HbA1c, AST/ALT ratio, BDI-II, and CAP, indicating that genetic factors interact with marginalization to influence these traits. This study found that acculturation stress exacerbates the genetic response to chronic illness. These findings underscore the importance of considering G×E interactions in understanding disease susceptibility and may inform targeted interventions for at-risk populations. Further research is warranted to elucidate the underlying molecular pathways and replicate these findings in diverse populations.


Assuntos
Aculturação , Interação Gene-Ambiente , Americanos Mexicanos , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/etnologia , Masculino , Feminino , Americanos Mexicanos/genética , Adulto , Pessoa de Meia-Idade , Doença Crônica , Genótipo , Estresse Psicológico/genética , Predisposição Genética para Doença , Obesidade/genética , Texas/epidemiologia
8.
Front Oncol ; 14: 1385887, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38962267

RESUMO

Introduction: Cervical cancer is a public health problem in our country and worldwide. Less than 25% of cases are diagnosed in the early stages, where survival is more remarkable than 90% at five years. Here, we review surgical treatment in the early stages of cervical cancer. Methodology: A literature review was carried out in the MEDLINE database. The search was mainly limited to the English language, with priority given to systematic reviews with or without meta-analysis and randomized studies. However, only retrospective or observational evidence was found for some topics. Results: The standard treatment for early-stage cervical cancer is hysterectomy, and its radical nature will depend on the tumor size, lymphovascular permeation, and tumor-specific prognostic factors. Furthermore, the type of surgery (hysterectomy or trachelectomy) will rely on the patient's desire to preserve fertility. Nodal evaluation is indicated as part of the treatment from stage IAI with PLV. However, the sentinel lymph node is more relevant in the treatment. The incidental finding of cervical cancer after a hysterectomy requires a multidisciplinary evaluation to determine the therapeutic approach. Less radical surgery has been described as oncologically safe in low-risk groups. Conclusion: Surgical treatment in its early stages has evolved in recent decades, making it more individualized and seeking less morbidity in patients without compromising their survival.

9.
Sci Rep ; 14(1): 16000, 2024 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-38987406

RESUMO

Genomic surveillance (GS) programmes were crucial in identifying and quantifying the mutating patterns of SARS-CoV-2 during the COVID-19 pandemic. In this work, we develop a Bayesian framework to quantify the relative transmissibility of different variants tailored for regions with limited GS. We use it to study the relative transmissibility of SARS-CoV-2 variants in Chile. Among the 3443 SARS-CoV-2 genomes collected between January and June 2021, where sampling was designed to be representative, the Gamma (P.1), Lambda (C.37), Alpha (B.1.1.7), B.1.1.348, and B.1.1 lineages were predominant. We found that Lambda and Gamma variants' reproduction numbers were 5% (95% CI: [1%, 14%]) and 16% (95% CI: [11%, 21%]) larger than Alpha's, respectively. Besides, we observed a systematic mutation enrichment in the Spike gene for all circulating variants, which strongly correlated with variants' transmissibility during the studied period (r = 0.93, p-value = 0.025). We also characterised the mutational signatures of local samples and their evolution over time and with the progress of vaccination, comparing them with those of samples collected in other regions worldwide. Altogether, our work provides a reliable method for quantifying variant transmissibility under subsampling and emphasises the importance of continuous genomic surveillance.


Assuntos
Teorema de Bayes , COVID-19 , Mutação , SARS-CoV-2 , Chile , Humanos , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , COVID-19/transmissão , COVID-19/virologia , COVID-19/epidemiologia , Genoma Viral , Glicoproteína da Espícula de Coronavírus/genética
10.
Harmful Algae ; 137: 102679, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-39003024

RESUMO

Algal blooms can threaten human health if cyanotoxins such as microcystin are produced by cyanobacteria. Regularly monitoring microcystin concentrations in recreational waters to inform management action is a tool for protecting public health; however, monitoring cyanotoxins is resource- and time-intensive. Statistical models that identify waterbodies likely to produce microcystin can help guide monitoring efforts, but variability in bloom severity and cyanotoxin production among lakes and years makes prediction challenging. We evaluated the skill of a statistical classification model developed from water quality surveys in one season with low temporal replication but broad spatial coverage to predict if microcystin is likely to be detected in a lake in subsequent years. We used summertime monitoring data from 128 lakes in Iowa (USA) sampled between 2017 and 2021 to build and evaluate a predictive model of microcystin detection as a function of lake physical and chemical attributes, watershed characteristics, zooplankton abundance, and weather. The model built from 2017 data identified pH, total nutrient concentrations, and ecogeographic variables as the best predictors of microcystin detection in this population of lakes. We then applied the 2017 classification model to data collected in subsequent years and found that model skill declined but remained effective at predicting microcystin detection (area under the curve, AUC ≥ 0.7). We assessed if classification skill could be improved by assimilating the previous years' monitoring data into the model, but model skill was only minimally enhanced. Overall, the classification model remained reliable under varying climatic conditions. Finally, we tested if early season observations could be combined with a trained model to provide early warning for late summer microcystin detection, but model skill was low in all years and below the AUC threshold for two years. The results of these modeling exercises support the application of correlative analyses built on single-season sampling data to monitoring decision-making, but similar investigations are needed in other regions to build further evidence for this approach in management application.


Assuntos
Monitoramento Ambiental , Lagos , Microcistinas , Modelos Estatísticos , Microcistinas/análise , Lagos/química , Monitoramento Ambiental/métodos , Iowa , Cianobactérias , Clima , Estações do Ano , Proliferação Nociva de Algas , Qualidade da Água
11.
Brief Bioinform ; 25(4)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38856172

RESUMO

With their diverse biological activities, peptides are promising candidates for therapeutic applications, showing antimicrobial, antitumour and hormonal signalling capabilities. Despite their advantages, therapeutic peptides face challenges such as short half-life, limited oral bioavailability and susceptibility to plasma degradation. The rise of computational tools and artificial intelligence (AI) in peptide research has spurred the development of advanced methodologies and databases that are pivotal in the exploration of these complex macromolecules. This perspective delves into integrating AI in peptide development, encompassing classifier methods, predictive systems and the avant-garde design facilitated by deep-generative models like generative adversarial networks and variational autoencoders. There are still challenges, such as the need for processing optimization and careful validation of predictive models. This work outlines traditional strategies for machine learning model construction and training techniques and proposes a comprehensive AI-assisted peptide design and validation pipeline. The evolving landscape of peptide design using AI is emphasized, showcasing the practicality of these methods in expediting the development and discovery of novel peptides within the context of peptide-based drug discovery.


Assuntos
Inteligência Artificial , Descoberta de Drogas , Peptídeos , Peptídeos/química , Peptídeos/uso terapêutico , Peptídeos/farmacologia , Descoberta de Drogas/métodos , Humanos , Desenho de Fármacos , Aprendizado de Máquina , Biologia Computacional/métodos
12.
Int J Med Inform ; 189: 105510, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38901269

RESUMO

Optimal governance is among the key facilitators of the digital transformation of health systems intended to improve access to healthcare, quality, safety, and efficiency, and to attain universal health coverage. This paper highlights the findings of a survey assessing the status of governance of digital health in the WHO European Region. The 2022 survey is a continuation of the 2015 WHO Global Survey on eHealth. The survey focused on national digital health governance, monitoring and evaluation of digital health interventions, and funding and investment in digital health and was conducted through April to October 2022. All 53 Member States of the WHO European Region participated in the survey. The results showed that 83% of the Member States reported having a national digital health strategy in place, and 79% of the Member States reported having a health information system strategy. Most of the priorities of the national digital health strategies were devoted to increasing the accessibility, quality, safety, and efficiency of the health systems, strengthening health information systems, and improving information sharing and interoperability of data. Measures to ensure equity in access to digital healthcare services were directed towards improving broadband connectivity, information and communication technology, digital literacy, and digital health promotion. Oversight for the implementation and operation of the national digital health strategies are mostly delegated to government agencies. The prime source of funding for digital health programs was public funding, though a combination of funding sources was also noted. This analysis revealed increasing adoption of national digital health strategies for access to healthcare and creation of digital health agencies and funding programs for digital health.


Assuntos
Organização Mundial da Saúde , Europa (Continente) , Humanos , Telemedicina , Atenção à Saúde , Inquéritos e Questionários , Sistemas de Informação em Saúde
13.
Genes (Basel) ; 15(5)2024 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-38790175

RESUMO

Statistical genetic models of genotype-by-environment (G×E) interaction can be divided into two general classes, one on G×E interaction in response to dichotomous environments (e.g., sex, disease-affection status, or presence/absence of an exposure) and the other in response to continuous environments (e.g., physical activity, nutritional measurements, or continuous socioeconomic measures). Here we develop a novel model to jointly account for dichotomous and continuous environments. We develop the model in terms of a joint genotype-by-sex (for the dichotomous environment) and genotype-by-social determinants of health (SDoH; for the continuous environment). Using this model, we show how a depression variable, as measured by the Beck Depression Inventory-II survey instrument, is not only underlain by genetic effects (as has been reported elsewhere) but is also significantly determined by joint G×Sex and G×SDoH interaction effects. This model has numerous applications leading to potentially transformative research on the genetic and environmental determinants underlying complex diseases.


Assuntos
Interação Gene-Ambiente , Genótipo , Modelos Genéticos , Humanos , Depressão/genética , Modelos Estatísticos , Masculino
14.
Digit Health ; 10: 20552076241251951, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38726219

RESUMO

Objectives: The call to scale up telemedicine services globally as part of the digital health transformation lacks an agreed-upon set of constructs to guide the implementation process. A lack of guidance hinders the development, consolidation, sustainability and optimisation of telemedicine services. The study aims to reach consensus among telemedicine experts on a set of implementation constructs to be developed into an evidence-based support tool. Methods: A modified Delphi study was conducted to evaluate a set of evidence-informed telemedicine implementation constructs comprising cores, domains and items. The study evaluated the constructs consisting of five cores: Assessment of the Current Situation, Development of a Telemedicine Strategy, Development of Organisational Changes, Development of a Telemedicine Service, and Monitoring, Evaluation and Optimisation of Telemedicine Implementation; seven domains: Individual Readiness, Organisational Readiness, Clinical, Economic, Technological and Infrastructure, Regulation, and Monitoring, Evaluation and Optimisation; divided into 53 items. Global telemedicine specialists (n = 247) were invited to participate and evaluate 58 questions. Consensus was set at ≥70%. Results: Forty-five experts completed the survey. Consensus was reached on 78% of the constructs evaluated. Regarding the core constructs, Monitoring, Evaluation and Optimisation of Telemedicine Implementation was determined to be the most important one, and Development of a Telemedicine Strategy the least. As for the domains, the Clinical one had the highest level of consensus, and the Economic one had the lowest. Conclusions: This research advances the field of telemedicine, providing expert consensus on a set of implementation constructs. The findings also highlight considerable divergence in expert opinion on the constructs of reimbursement and incentive mechanisms, resistance to change, and telemedicine champions. The lack of agreement on these constructs warrants attention and may partly explain the barriers that telemedicine services continue to face in the implementation process.

15.
Bone ; 184: 117090, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38579924

RESUMO

Mechanical properties are becoming fundamental for advancing the comprehension of cellular processes. This study addresses the relationship between viscoelastic properties and the cellular mineralization process. Osteoblast-like cells treated with an osteogenic medium were employed for this purpose. Additionally, the study explores the impact of hydroxyapatite (HA) and hydroxyapatite/silver (HA/Ag) composite on this process. AFM relaxation experiments were conducted to extract viscoelastic parameters using the Fractional Zener (FZ) and Fractional Kelvin (FK) models. Our findings revealed that the main phases of mineralization are associated with alterations in the viscoelastic properties of osteoblast-like cells. Furthermore, HA and HA/Ag treatments significantly influenced changes in the viscoelastic properties of these cells. In particular, the HA/Ag treatment demonstrated a marked enhancement in cell fluidity, suggesting a possible role of silver in accelerating the mineralization process. Moreover, the study underscores the independence observed between fluidity and stiffness, indicating that modifications in one parameter may not necessarily correspond to changes in the other. These findings shed light on the factors involved in the cellular mineralization process and emphasize the importance of using viscoelastic properties to discern the impact of treatments on cells.


Assuntos
Calcificação Fisiológica , Durapatita , Elasticidade , Osteoblastos , Prata , Durapatita/química , Osteoblastos/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/citologia , Prata/química , Calcificação Fisiológica/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Viscosidade , Linhagem Celular , Humanos , Microscopia de Força Atômica , Animais
16.
Microorganisms ; 12(3)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38543564

RESUMO

The process of soil genesis unfolds as pioneering microbial communities colonize mineral substrates, enriching them with biomolecules released from bedrock. The resultant intricate surface units emerge from a complex interplay among microbiota and plant communities. Under these conditions, host rocks undergo initial weathering through microbial activity, rendering them far from pristine and challenging the quest for biomarkers in ancient sedimentary rocks. In addressing this challenge, a comprehensive analysis utilizing Gas Chromatography Mass Spectrometry (GC-MS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) was conducted on a 520-Ma-old Cambrian rock. This investigation revealed a diverse molecular assemblage with comprising alkanols, sterols, fatty acids, glycerolipids, wax esters, and nitrogen-bearing compounds. Notably, elevated levels of bacterial C16, C18 and C14 fatty acids, iso and anteiso methyl-branched fatty acids, as well as fungal sterols, long-chained fatty acids, and alcohols, consistently align with a consortium of bacteria and fungi accessing complex organic matter within a soil-type ecosystem. The prominence of bacterial and fungal lipids alongside maturity indicators denotes derivation from heterotrophic activity rather than ancient preservation or marine sources. Moreover, the identification of long-chain (>C22) n-alkanols, even-carbon-numbered long chain (>C20) fatty acids, and campesterol, as well as stigmastanol, provides confirmation of plant residue inputs. Furthermore, findings highlight the ability of contemporary soil microbiota to inhabit rocky substrates actively, requiring strict contamination controls when evaluating ancient molecular biosignatures or extraterrestrial materials collected.

17.
Toxicol Appl Pharmacol ; 485: 116886, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452946

RESUMO

Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.


Assuntos
Imunoconjugados , Organoides , Organoides/efeitos dos fármacos , Organoides/patologia , Animais , Imunoconjugados/toxicidade , Humanos , Ratos , Avaliação Pré-Clínica de Medicamentos/métodos , Macaca fascicularis , Células Cultivadas , Testes de Toxicidade/métodos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia
18.
Sci Rep ; 14(1): 7392, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548781

RESUMO

The Tilt-depth is a popular approach for determining depths of magnetic sources. As this method is based on the distance between contour levels of the tilt angle, it can lead to inaccurate depth estimates when the contour lines are distorted by the presence of noise. In this paper, we stabilize the Tilt-depth method based on the computation of stable vertical derivative obtained by the ß-VDR method. The presented method is demonstrated on synthetic magnetic anomalies and real magnetic data from the Arabian Shield. The results obtained from the synthetic examples coincide well with the actual depths. These results proved the utility of the presented method in cases where the field is corrupted by noise. The real example shows that the presented method can provide valuable information on subsurface structures of the area where the Tilt-depth estimates are consistent with the result of the horizontal tilt angle. The findings show that the presented method is less sensitive to noise and can provide source edges and depths more clearly and with higher accuracy.

19.
Front Cardiovasc Med ; 11: 1285223, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38361580

RESUMO

Introduction: We conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF. Methods: We studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy. Results: We found a prevalence of 10% (CI 4.6%-15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p < 0.001 vs. CF controls). Selenium deficiency (Se < 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement. Conclusion: 10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients.

20.
Artigo em Inglês | MEDLINE | ID: mdl-38084649

RESUMO

Subacute or late-presenting unstable osseous mallet finger might be hard to reduce and, therefore, remain subluxed when using the traditional Ishiguro technique. In such cases, we suggest it is best to prioritize correction of joint subluxation over step-by-step adherence to the traditional Ishiguro technique. Specifically, we contend that carrying out the procedure in reverse order typically results in an easier and more stable reduction of both joint and fracture.

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