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Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor cell composition, including phenotypic abnormalities and phenotype dominance. Relationship analyses between tumor and immune cells revealed characteristics of ecosystems related to immunosuppression and poor prognosis. High frequencies of PD-L1+ tumor-associated macrophages and exhausted T cells were found in high-grade ER+ and ER- tumors. This large-scale, single-cell atlas deepens our understanding of breast tumor ecosystems and suggests that ecosystem-based patient classification will facilitate identification of individuals for precision medicine approaches targeting the tumor and its immunoenvironment.
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Neoplasias da Mama , Tolerância Imunológica , Linfócitos do Interstício Tumoral , Macrófagos , Microambiente Tumoral/imunologia , Antígeno B7-H1/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/patologia , Proteínas de Neoplasias/imunologia , Taxa de SobrevidaRESUMO
Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity.
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Algoritmos , Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Antineoplásicos/química , Epistasia Genética , Estudo de Associação Genômica Ampla , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas PequenasRESUMO
The overall 5-year relative survival rate for all cancers combined is now 68%, and there are over 16.9 million survivors in the United States. Evidence from laboratory and observational studies suggests that factors such as diet, physical activity, and obesity may affect risk for recurrence and overall survival after a cancer diagnosis. The purpose of this American Cancer Society guideline is to provide evidence-based, cancer-specific recommendations for anthropometric parameters, physical activity, diet, and alcohol intake for reducing recurrence and cancer-specific and overall mortality. The audiences for this guideline are health care providers caring for cancer survivors as well as cancer survivors and their families. The guideline is intended to serve as a resource for informing American Cancer Society programs, health policy, and the media. Sources of evidence that form the basis of this guideline are systematic literature reviews, meta-analyses, pooled analyses of cohort studies, and large randomized clinical trials published since 2012. Recommendations for nutrition and physical activity during cancer treatment, informed by current practice, large cancer care organizations, and reviews of other expert bodies, are also presented. To provide additional context for the guidelines, the authors also include information on the relationship between health-related behaviors and comorbidities, long-term sequelae and patient-reported outcomes, and health disparities, with attention to enabling survivors' ability to adhere to recommendations. Approaches to meet survivors' needs are addressed as well as clinical care coordination and resources for nutrition and physical activity counseling after a cancer diagnosis.
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Sobreviventes de Câncer , Neoplasias , American Cancer Society , Dieta , Exercício Físico , Humanos , Neoplasias/terapia , Sobreviventes , Estados Unidos/epidemiologiaRESUMO
Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.
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Bancos de Espécimes Biológicos , Genética Médica , Genoma Humano , Genômica , Hispânico ou Latino , Humanos , Glicemia/genética , Glicemia/metabolismo , Estatura/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/classificação , Hispânico ou Latino/genética , Homozigoto , México , Fenótipo , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido , Genoma Humano/genéticaRESUMO
Like other insects, secretion by mosquito Malpighian tubules (MTs) is driven by the V-type H+-ATPase (VA) localized in the apical membrane of principal cells. In Aedes aegypti, the antidiuretic neurohormone CAPA inhibits secretion by MTs stimulated by select diuretic hormones; however, the cellular effectors of this inhibitory signaling cascade remain unclear. Herein, we demonstrate that the VA inhibitor bafilomycin selectively inhibits serotonin (5HT)- and calcitonin-related diuretic hormone (DH31)-stimulated secretion. VA activity increases in DH31-treated MTs, whereas CAPA abolishes this increase through a NOS/cGMP/PKG signaling pathway. A critical feature of VA activation involves the reversible association of the cytosolic (V1) and membrane (Vo) complexes. Indeed, higher V1 protein abundance was found in membrane fractions of DH31-treated MTs, whereas CAPA significantly decreased V1 abundance in membrane fractions while increasing it in cytosolic fractions. V1 immunolocalization was observed strictly in the apical membrane of DH31-treated MTs, whereas immunoreactivity was dispersed following CAPA treatment. VA complexes colocalized apically in female MTs shortly after a blood meal consistent with the peak and postpeak phases of diuresis. Comparatively, V1 immunoreactivity in MTs was more dispersed and did not colocalize with the Vo complex in the apical membrane at 3 h post blood meal, representing a time point after the late phase of diuresis has concluded. Therefore, CAPA inhibition of MTs involves reducing VA activity and promotes complex dissociation hindering secretion. Collectively, these findings reveal a key target in hormone-mediated inhibition of MTs countering diuresis that provides a deeper understanding of this critical physiological process necessary for hydromineral balance.
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Neuropeptídeos , ATPases Vacuolares Próton-Translocadoras , Animais , Feminino , ATPases Vacuolares Próton-Translocadoras/metabolismo , Túbulos de Malpighi/metabolismo , Neuropeptídeos/metabolismo , Vasopressinas/metabolismo , Diuréticos/metabolismoRESUMO
Glyphosate (GLYP) is a widely used pesticide; it is considered to be a safe herbicide for animals and humans because it targets 5-enolpyruvylshikimate-3-phosphate synthase. However, there has been increasing evidence that GLYP causes varying degrees of toxicity. Moreover, oxidative stress and metabolism are highly correlated with toxicity. This review provides a comprehensive introduction to the toxicity of GLYP and, for the first time, systematically summarizes the toxicity mechanism of GLYP from the perspective of oxidative stress, including GLYP-mediated oxidative damage, changes in antioxidant status, altered signaling pathways, and the regulation of oxidative stress by exogenous substances. In addition, the metabolism of GLYP is discussed, including metabolites,metabolic pathways, metabolic enzymes, and the toxicity of metabolites. This review provides new ideas for the toxicity mechanism of GLYP and proposes effective strategies for reducing its toxicity.
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Glicina , Herbicidas , Animais , Antioxidantes , Glicina/análogos & derivados , Glicina/toxicidade , Herbicidas/toxicidade , Humanos , Estresse Oxidativo , GlifosatoRESUMO
MOTIVATION: Interpretability has become a necessary feature for machine learning models deployed in critical scenarios, e.g. legal system, healthcare. In these situations, algorithmic decisions may have (potentially negative) long-lasting effects on the end-user affected by the decision. While deep learning models achieve impressive results, they often function as a black-box. Inspired by linear models, we propose a novel class of structurally constrained deep neural networks, which we call FLAN (Feature-wise Latent Additive Networks). Crucially, FLANs process each input feature separately, computing for each of them a representation in a common latent space. These feature-wise latent representations are then simply summed, and the aggregated representation is used for the prediction. These feature-wise representations allow a user to estimate the effect of each individual feature independently from the others, similarly to the way linear models are interpreted. RESULTS: We demonstrate FLAN on a series of benchmark datasets in different biological domains. Our experiments show that FLAN achieves good performances even in complex datasets (e.g. TCR-epitope binding prediction), despite the structural constraint we imposed. On the other hand, this constraint enables us to interpret FLAN by deciphering its decision process, as well as obtaining biological insights (e.g. by identifying the marker genes of different cell populations). In supplementary experiments, we show similar performances also on non-biological datasets. CODE AND DATA AVAILABILITY: Code and example data are available at https://github.com/phineasng/flan_bio.
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Aprendizado de Máquina , Redes Neurais de Computação , Ligação ProteicaRESUMO
The flexibility of plant growth, development and stress responses is choreographed by an intricate network of signaling cascades and genetic programs. However, it is metabolism that ultimately executes these programs through the selective delivery of specific building blocks and energy. Photosynthetic carbon fixation is the central pillar of the plant metabolic network, the functioning of which is conditioned by environmental fluctuations. Hence, regulation of carbon assimilation metabolism must be particularly versatile and rapid to maintain efficiency and avoid dysfunction. While changes in gene expression can adjust the global inventory and abundance of relevant proteins, their specific characteristics are dynamically altered at the post-translational level. Here we highlight studies that show the extent of the regulatory impact by post-translational modification (PTM) on carbon assimilation metabolism. We focus on examples for which there has been empirical evidence of functional changes associated with a PTM, rather than just the occurrence of PTMs at specific sites in proteins, as regularly detected in proteomic studies. The examples indicate that we are only at the beginning of deciphering the PTM-based regulatory network that operates in plant cells. However, it is becoming increasingly clear that targeted exploitation of PTM engineering has the potential to control the metabolic flux landscape as a prerequisite for increasing crop yields, modifying metabolite composition, optimizing stress tolerance, and even executing novel growth and developmental programs.
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Carbono , Proteômica , Carbono/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Redes e Vias MetabólicasRESUMO
BACKGROUND: Colorectal cancer (CRC) screening is underused, particularly among low-income and minoritized populations, for whom the coronavirus disease 2019 (COVID-19) pandemic has challenged progress in achieving equity. METHODS: A hub-and-spoke model was used. The hub was a nonacademic organization and the spokes were three community health center (CHC) systems overseeing numerous clinic sites. Via a cluster-randomized trial design, nine clinic sites were randomized to intervention and 16 clinic sites were randomized to usual care. Patient-level interventions included invitation letters, mailed fecal immunochemical tests (FITs), and call/text-based reminders. Year 1 intervention impact, which took place during the COVID-19 pandemic, was assessed as the proportion completing screening among individuals not up to date at baseline, which compared intervention and nonintervention clinics accounting for intraclinic cluster variation; confidence intervals (CIs) around differences not including 0 were interpreted as statistically significant. RESULTS: Among 26,736 patients who met eligibility criteria, approximately 58% were female, 55% were Hispanic individuals, and 44% were Spanish speaking. The proportion completing screening was 11.5 percentage points (ppts) (95% CI, 6.1-16.9 ppts) higher in intervention versus usual care clinics. Variation in differences between intervention and usual care clinics was observed by sex (12.6 ppts [95% CI, 7.2-18.0 ppts] for females; 8.8 ppts [95% CI, 4.7-13.9 ppts] for males) and by racial and ethnic group (13.8 ppts [95% CI, 7.0-20.6 ppts] for Hispanic individuals; 13.0 ppts [95% CI, 3.6-22.4 ppts] for Asian individuals; 11.3 ppts [95% CI, 5.8-16.8 ppts] for non-Hispanic White individuals; 6.1 ppts [95% CI, 0.8-10.4 ppts] for Black individuals). CONCLUSIONS: A regional mailed FIT intervention was effective for increasing CRC screening rates across CHC systems serving diverse, low-income populations.
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BACKGROUND & AIMS: Transcription termination fine-tunes gene expression and contributes to the specification of RNA function in eukaryotic cells. Transcription termination of HBV is subject to the recognition of the canonical polyadenylation signal (cPAS) common to all viral transcripts. However, the regulation of this cPAS and its impact on viral gene expression and replication is currently unknown. METHODS: To unravel the regulation of HBV transcript termination, we implemented a 3' RACE (rapid amplification of cDNA ends)-PCR assay coupled to single molecule sequencing both in in vitro-infected hepatocytes and in chronically infected patients. RESULTS: The detection of a previously unidentified transcriptional readthrough indicated that the cPAS was not systematically recognized during HBV replication in vitro and in vivo. Gene expression downregulation experiments demonstrated a role for the RNA helicases DDX5 and DDX17 in promoting viral transcriptional readthrough, which was, in turn, associated with HBV RNA destabilization and decreased HBx protein expression. RNA and chromatin immunoprecipitation, together with mutation of the cPAS sequence, suggested a direct role of DDX5 and DDX17 in functionally linking cPAS recognition to transcriptional readthrough, HBV RNA stability and replication. CONCLUSIONS: Our findings identify DDX5 and DDX17 as crucial determinants of HBV transcriptional fidelity and as host restriction factors for HBV replication. IMPACT AND IMPLICATIONS: HBV covalently closed circular (ccc)DNA degradation or functional inactivation remains the holy grail for the achievement of HBV cure. Transcriptional fidelity is a cornerstone in the regulation of gene expression. Here, we demonstrate that two helicases, DDX5 and DDX17, inhibit recognition of the HBV polyadenylation signal and thereby transcriptional termination, thus decreasing HBV RNA stability and acting as restriction factors for efficient cccDNA transcription and viral replication. The observation that DDX5 and DDX17 are downregulated in patients chronically infected with HBV suggests a role for these helicases in HBV persistence in vivo. These results open new perspectives for researchers aiming at identifying new targets to neutralise cccDNA transcription.
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Structural integrity and cellular homeostasis of the embryonic stem cell niche are critical for normal tissue development. In the telencephalic neuroepithelium, this is controlled in part by cell adhesion molecules and regulators of progenitor cell lineage, but the specific orchestration of these processes remains unknown. Here, we studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx-Cre mouse, we identify novel and critical roles of miRNAs in early brain development, demonstrating they are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx-Cre;DicerF/F mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptome analyses and functional experiments in vivo show that these defects result from upregulation of Irs2 upon loss of let-7 miRNAs in an apoptosis-independent manner. Our results reveal an unprecedented relevance of miRNAs in early forebrain development, with potential mechanistic implications in pediatric brain cancer.
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Homeostase , Proteínas Substratos do Receptor de Insulina/metabolismo , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Telencéfalo/embriologia , Telencéfalo/metabolismo , Junções Aderentes , Animais , Apoptose , Proliferação de Células , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Fator de Transcrição PAX6/metabolismo , Proteínas Repressoras/genética , Células-Tronco/metabolismo , Telencéfalo/citologia , Fatores de Transcrição/metabolismoRESUMO
PURPOSE OF REVIEW: We performed a narrative review of the recent findings in epidemiology, clinical presentation, mechanisms and treatment of vestibular migraine. RECENT FINDINGS: Vestibular migraine is an underdiagnosed condition that has a high prevalence among general, headache and neuro-otology clinics. Vestibular migraine has a bimodal presentation probably associated with a hormonal component in women. These patients could have a complex clinical phenotype including concomitant autonomic, inflammatory or connective tissue conditions that have a higher prevalence of psychological symptoms, which may mistakenly lead to a diagnosis of a functional neurological disorder. A high proportion of patients with postural perceptual persistent dizziness have a migraine phenotype. Independently of the clinical presentation and past medical history, patients with the vestibular migraine phenotype can respond to regular migraine preventive treatments, including those targeting the calcitonin gene-related peptide pathways. SUMMARY: Vestibular migraine is an underdiagnosed migraine phenotype that shares the pathophysiological mechanisms of migraine, with growing interest in recent years. A thorough anamnesis is essential to increase sensitivity in patients with unknown cause of dizziness and migraine treatment should be considered (see supplemental video-abstract).
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Tontura , Transtornos de Enxaqueca , Humanos , Tontura/diagnóstico , Tontura/fisiopatologia , Tontura/epidemiologia , Tontura/terapia , Tontura/etiologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/terapia , Vertigem/diagnóstico , Vertigem/fisiopatologia , Vertigem/terapia , Vertigem/epidemiologia , Vertigem/etiologia , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/epidemiologia , Doenças Vestibulares/terapia , Doenças Vestibulares/fisiopatologiaRESUMO
BACKGROUND & AIMS: Prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) is reported to be higher in Hispanic adults in the United States (U.S.), although rates vary substantially across studies and have increased given the evolving obesity epidemic. This systematic review and meta-analysis quantifies MASLD disease burden and severity in contemporary cohorts to characterize health disparities experienced by adult Hispanic individuals in the U.S. METHODS: We searched the MEDLINE, Embase, and Cochrane databases per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies from 2010 to December 2023 were included to capture data representative of current populations given the obesity epidemic. Studies from overlapping cohorts were excluded. Meta-analyses were conducted using random-effects models to estimate pooled prevalence and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: We identified 22 studies, comprising 756,088 subjects, of which 62,072 were Hispanic. The pooled prevalence in U.S. Hispanic adults was 41% (95% CI, 30%-52%) for MASLD, 61% (95% CI, 39%-82%) for metabolic dysfunction-associated steatohepatitis (MASH), 27% (95% CI, 15%-39%) for MASH-associated advanced fibrosis (AF), and 5% (95% CI, 1%-8%) for MASH cirrhosis. Compared with non-Hispanic adults, Hispanic adults had a RR of 1.50 (95% CI, 1.32-1.69) for MASLD, 1.42 (95% CI, 1.04-1.93) for MASH, 1.37 (95% CI, 0.96-1.96) for MASH-associated AF, and 0.93 (95% CI, 0.49-1.77) for MASH cirrhosis. CONCLUSION: Health disparities for U.S. Hispanic adults continue to worsen with significantly higher relative risk of MASLD and MASH compared with non-Hispanic adults. Public health efforts to optimize screening and care delivery for the adult Hispanic population are urgently needed.
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BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare peritoneal mucinous carcinomatosis with largely unknown underlying molecular mechanisms. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the only therapeutic option; however, despite its use, recurrence with a fatal outcome is common. The lack of molecular characterisation of PMP and other mucinous tumours is mainly due to the physicochemical properties of mucin. RESULTS: This manuscript describes the first protocol capable of breaking the mucin barrier and isolating proteins from mucinous tumours. Briefly, mucinous tumour samples were homogenised and subjected to liquid chromatography using two specific columns to reduce mainly glycoproteins, albumins and immunoglobulin G. The protein fractions were then subjected to mass spectrometry analysis and the proteomic profile obtained was analysed using various bioinformatic tools. Thus, we present here the first proteome analysed in PMP and identified a distinct mucin isoform profile in soft compared to hard mucin tumour tissues as well as key biological processes/pathways altered in mucinous tumours. Importantly, this protocol also allowed us to identify MUC13 as a potential tumour cell marker in PMP. CONCLUSIONS: In sum, our results demonstrate that this protein isolation protocol from mucin will have a high impact, allowing the oncology research community to more rapidly advance in the knowledge of PMP and other mucinous neoplasms, as well as develop new and effective therapeutic strategies.
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Radiolabeling and nuclear imaging techniques are used to investigate the biodistribution patterns of the soft and hard protein corona around poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) after administration to healthy mice. Soft and hard protein coronas of 131I-labeled BSA or 131I-labeled serum are formed on PLGA NPs functionalized with either polyehtylenimine (PEI) or bovine serum albumin (BSA). The exchangeability of hard and soft corona is assessed in vitro by gamma counting exposing PLGA NPs with corona to non-labeled BSA, serum, or simulated body fluid. PEI PLGA NPs form larger and more stable coronas than BSA PLGA NPs. Soft coronas are more exchangeable than hard ones. The in vivo fate of PEI PLGA NPs coated with preformed 18F-labeled BSA hard and soft coronas is assessed by positron emission tomography (PET) following intravenous administration. While the soft corona shows a biodistribution similar to free 18F BSA with high activity in blood and kidney, the hard corona follows patterns characteristic of nanoparticles, accumulating in the lungs, liver, and spleen. These results show that in vivo fates of soft and hard corona are different, and that soft corona is more easily exchanged with proteins from the body, while hard corona is largely retained on the nanoparticle surface.
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BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40â mg) were tested under fasted and fed (10â mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30â mg) were administered once daily for 7â days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53â h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87â h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.
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Antituberculosos , Voluntários Saudáveis , Humanos , Adulto , Masculino , Feminino , Método Duplo-Cego , Adulto Jovem , Pessoa de Meia-Idade , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Interações Alimento-Droga , Administração Oral , Adolescente , Placebos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a MedicamentosRESUMO
In molecular biology, it is a general assumption that the ensemble of expressed molecules, their activities and interactions determine biological function, cellular states and phenotypes. Stable protein complexes-or macromolecular machines-are, in turn, the key functional entities mediating and modulating most biological processes. Although identifying protein complexes and their subunit composition can now be done inexpensively and at scale, determining their function remains challenging and labor intensive. This study describes Protein Complex Function predictor (PCfun), the first computational framework for the systematic annotation of protein complex functions using Gene Ontology (GO) terms. PCfun is built upon a word embedding using natural language processing techniques based on 1 million open access PubMed Central articles. Specifically, PCfun leverages two approaches for accurately identifying protein complex function, including: (i) an unsupervised approach that obtains the nearest neighbor (NN) GO term word vectors for a protein complex query vector and (ii) a supervised approach using Random Forest (RF) models trained specifically for recovering the GO terms of protein complex queries described in the CORUM protein complex database. PCfun consolidates both approaches by performing a hypergeometric statistical test to enrich the top NN GO terms within the child terms of the GO terms predicted by the RF models. The documentation and implementation of the PCfun package are available at https://github.com/sharmavaruns/PCfun. We anticipate that PCfun will serve as a useful tool and novel paradigm for the large-scale characterization of protein complex function.
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Biologia Computacional , Proteínas , Biologia Computacional/métodos , Bases de Dados de Proteínas , Ontologia Genética , Humanos , Processamento de Linguagem NaturalRESUMO
Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that the weight, height or the head circumference are above the 97th centile or 2-3 standard deviations above the mean for age, gender, and ethnic group. Several copy-number variants (CNVs) have been associated with the development of OGS, such as the 5q35 microdeletion or the duplication of the 15q26.1-qter, among many others. In this study, we have applied 850K SNP-arrays to 112 patients and relatives with OGS from the Spanish OverGrowth Registry Initiative. We have identified CNVs associated with the disorder in nine individuals (8%). Subsequently, whole genome sequencing (WGS) analysis was performed in these nine samples in order to better understand these genomic imbalances. All the CNVs were detected by both techniques, settling that WGS is a useful tool for CNV detection. We have found six patients with genomic abnormalities associated with previously well-established disorders and three patients with CNVs of unknown significance, which may be related to OGS, based on scientific literature. In this report, we describe these findings and comment on genes associated with OGS that are located within the CNV regions.
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In brief: Social insect queens display both extraordinary longevity and fertility. In this point of view, we describe their distinctive traits that make them useful models for reproductive longevity, holding implications for human health discoveries. Abstract: Social insects present an extraordinary opportunity as models for reproductive longevity because they challenge the conventional patterns of aging and reproduction seen in other model organisms. Their queens are simultaneously long-lived and highly fecund, and understanding how these traits co-occur may lead to discoveries with important implications for human health.
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Envelhecimento , Fertilidade , Insetos , Longevidade , Reprodução , Animais , Longevidade/fisiologia , Reprodução/fisiologia , Insetos/fisiologia , Envelhecimento/fisiologia , Fertilidade/fisiologia , Humanos , Feminino , Comportamento SocialRESUMO
BACKGROUND: Haemophilia is a haematological disease, although most haemorrhages occur in the locomotor system. Patients are physically disabled from an early age and have a poorer perception of quality of life. In the day-to-day lives of patients and their families, psychosocial well-being, the disease's physical, personal, and social impact, as well as work-related problems are the most complicated aspects of the disease that need to be addressed. OBJECTIVE: To identify the role of occupational therapy in managing patients with haemophilia and to analyse the therapeutic potential of occupational therapy in treating these patients. METHODS: A scoping review was conducted to identify the role of occupational therapy in managing patients with haemophilia and to analyse the therapeutic potential of occupational therapy in treating these patients. The review was registered in the international registry PROSPERO (Id: CRD42022319637). The databases consulted were SCOPUS, PubMed, PsycINFO, Web of Science and Science Direct, including all studies published until 14 August 2023. RESULTS: No single study was found that specifically developed an occupational therapy intervention for patients with haemophilia. Measurement instruments have been identified, specific for patients with haemophilia and generic, that can be useful for the functional evaluation of these patients in the occupational therapy approach. Different studies showed the importance of multidisciplinary treatment, including occupational therapy. CONCLUSIONS: The use of occupational therapy could be effective in improving autonomy and quality of life in haemophilia patients. Therefore, it is of paramount importance to conduct research studies within the field of occupational therapy.