The multimodality cell segmentation challenge: toward universal solutions.

Cell segmentation is a critical step for quantitative single-cell analysis in microscopy images. Existing cell segmentation methods are often tailored to specific modalities or require manual interventions to specify hyper-parameters in different experimental settings. Here, we present a multimodality cell segmentation benchmark, comprising more than 1,500 labeled images derived from more than 50 diverse biological experiments. The top participants developed a Transformer-based deep-learning algorithm that not only exceeds existing methods but can also be applied to diverse microscopy images across imaging platforms and tissue types without manual parameter adjustments. This benchmark and the improved algorithm offer promising avenues for more accurate and versatile cell analysis in microscopy imaging.

Analysis of domain shift in whole prostate gland, zonal and lesions segmentation and detection, using multicentric retrospective data.

Despite being one of the most prevalent forms of cancer, prostate cancer (PCa) shows a significantly high survival rate, provided there is timely detection and treatment. Computational methods can help make this detection process considerably faster and more robust. However, some modern machine-learning approaches require accurate segmentation of the prostate gland and the index lesion. Since performing manual segmentations is a very time-consuming task, and highly prone to inter-observer variability, there is a need to develop robust semi-automatic segmentation models. In this work, we leverage the large and highly diverse ProstateNet dataset, which includes 638 whole gland and 461 lesion segmentation masks, from 3 different scanner manufacturers provided by 14 institutions, in addition to other 3 independent public datasets, to train accurate and robust segmentation models for the whole prostate gland, zones and lesions. We show that models trained on large amounts of diverse data are better at generalizing to data from other institutions and obtained with other manufacturers, outperforming models trained on single-institution single-manufacturer datasets in all segmentation tasks. Furthermore, we show that lesion segmentation models trained on ProstateNet can be reliably used as lesion detection models.

Computational analysis of peripheral blood smears detects disease-associated cytomorphologies.

Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a group of blood cancers characterised by cytopenias, dysplasia of hematopoietic cells and blast expansion. Examination of peripheral blood slides (PBS) in MDS often reveals changes such as abnormal granulocyte lobulation or granularity and altered red blood cell (RBC) morphology; however, some of these features are shared with conditions such as haematinic deficiency anemias. Definitive diagnosis of MDS requires expert cytomorphology analysis of bone marrow smears and complementary information such as blood counts, karyotype and molecular genetics testing. Here, we present Haemorasis, a computational method that detects and characterizes white blood cells (WBC) and RBC in PBS. Applied to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia, and iron deficiency anemia), Haemorasis detected over half a million WBC and millions of RBC and characterized their morphology. These large sets of cell morphologies can be used in diagnosis and disease subtyping, while identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS. Additionally, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. By integrating cytomorphological features using machine learning, Haemorasis was able to distinguish SF3B1-mutant MDS from other MDS using cytomorphology and blood counts alone, with high predictive performance. We validate our findings externally, showing that they generalize to other centers and scanners. Collectively, our work reveals the potential for the large-scale incorporation of automated cytomorphology into routine diagnostic workflows.

The longitudinal dynamics and natural history of clonal haematopoiesis.

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Understanding the Binding Specificity of G-Protein Coupled Receptors toward G-Proteins and Arrestins: Application to the Dopamine Receptor Family.

G-Protein coupled receptors (GPCRs) are involved in a myriad of pathways key for human physiology through the formation of complexes with intracellular partners such as G-proteins and arrestins (Arrs). However, the structural and dynamical determinants of these complexes are still largely unknown. Herein, we developed a computational big-data pipeline that enables the structural characterization of GPCR complexes with no available structure. This pipeline was used to study a well-known group of catecholamine receptors, the human dopamine receptor (DXR) family and its complexes, producing novel insights into the physiological properties of these important drug targets. A detailed description of the protein interfaces of all members of the DXR family (D1R, D2R, D3R, D4R, and D5R) and the corresponding protein interfaces of their binding partners (Arrs: Arr2 and Arr3; G-proteins: Gi1, Gi2, Gi3, Go, Gob, Gq, Gslo, Gssh, Gt2, and Gz) was generated. To produce reliable structures of the DXR family in complex with either G-proteins or Arrs, we performed homology modeling using as templates the structures of the ß2-adrenergic receptor (ß2AR) bound to Gs, the rhodopsin bound to Gi, and the recently acquired neurotensin receptor-1 (NTSR1) and muscarinic 2 receptor (M2R) bound to arrestin (Arr). Among others, the work demonstrated that the three partner groups, Arrs and Gs- and Gi-proteins, are all structurally and dynamically distinct. Additionally, it was revealed the involvement of different structural motifs in G-protein selective coupling between D1- and D2-like receptors. Having constructed and analyzed 50 models involving DXR, this work represents an unprecedented large-scale analysis of GPCR-intracellular partner interface determinants. All data is available at www.moreiralab.com/resources/dxr.

In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease.

Parkinson's Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel antiparkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated with dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused on a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure- and ligand-based in silico approaches for the development of small molecules to target these receptors.

Sentidos da inclusão de alunos com deficiência na educação superior: olhares a partir da Universidade Federal de Juiz de Fora / Sense of inclusion of students with disabilities in higher education: looks from the Federal University of Juiz de Fora / Sentidos de la inclusión de alumnos con deficiencia en la educación superior: miradas a partir de la Universidad Federal de Juiz de Fora

Esta pesquisa tem como objetivo discutir o processo de inclusão de alunos com deficiência na educação superior brasileira, com especial foco nos sentidos mobilizados por esta inclusão nos discursos ali circulantes. Com caráter exploratório-descritivo, nos valemos da Análise de Discurso na ótica francesa para explorar o processo de produção de sentidos nas estatísticas oficias sobre esta inclusão no Brasil e em uma instituição federal de educação superior, realizando ainda, entrevistas com alunos autodeclarados com deficiência e demais sujeitos que com esses se relacionam no cotidiano universitário. Com as análises empreendidas, identificamos falhas nos dados oficiais sobre a presença de alunos com deficiência na educação superior brasileira, relacionadas tanto a ausência de mecanismos para levantamento desses dados na instituição base, quanto ao não reconhecimento da condição de deficiência por parte dos alunos que a possuem. Já em relação aos sentidos de sua inclusão, esta tem sido avaliada pelos sujeitos da educação superior enquanto presença ou enquanto provimento de condições de acessibilidade arquitetônica, indicando um despreparo e um desconhecimento para o provimento de condições de permanência para este aluno na educação superior, perpetuando barreiras à sua participação em igualdade de condições.

This research aims to discuss the process of inclusion of students with disabilities in Brazilian higher education, with a special focus on the senses mobilized by this inclusion in the circulating discourses. With an exploratory-descriptive character, we use the Discourse Analysis from the French perspective to explore the process of meaning production in the official statistics on this inclusion in Brazil and in a federal institution of higher education, also conducting interviews with self-declared students with disabilities and other subjects that with these are related in the daily life of the university. With the analyzes undertaken, we identified flaws in the official data on the presence of students with disabilities in Brazilian higher education, related both to the absence of mechanisms to collect these data in the base institution, and to the non-recognition of the deficiency condition by students that have. Regarding the meanings of their inclusion, this has been evaluated by the subjects of higher education as a presence or as a provision of architectural accessibility, indicating a lack of preparation and lack of knowledge for the provision of conditions of permanence for this student in higher education, perpetuating barriers to their participation on equal terms.

En esta investigación se tiene como objetivo, discutir el proceso de inclusión de alumnos con deficiencia en la educación superior brasileña, con especial enfoque a los sentidos movilizados por esta inclusión en los discursos allí circulantes. Con carácter exploratorio-descriptivo, nos valemos del Análisis de Discurso en la óptica francesa para explorar el proceso de producción de sentidos en las estadísticas oficias sobre esta inclusión en Brasil y en una institución federal de educación superior, realizando aun, entrevistas con alumnos auto declarados con deficiencia y demás sujetos que con estos se relacionan en el cotidiano universitario. Con los análisis emprendidos, identificamos fallas en los datos oficiales sobre la presencia de alumnos con deficiencia en la educación superior brasileña, relacionadas a ausencia de mecanismos para recopilación de estos datos en la institución base, y, también al no reconocimiento de la condición de deficiencia por parte de los alumnos que la poseen. Ya en relación a los sentidos de su inclusión, esta ha sido evaluada por los sujetos de la educación superior como presencia o como desestime de condiciones de accesibilidad arquitectónica, indicando falta de preparación y desconocimiento para el desestime de condiciones de permanencia para este alumno en la educación superior, perpetuando obstáculos a su participación en igualdad de condiciones.