Chromosome Segregation Is Biased by Kinetochore Size

Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore—the critical chromosomal interface with spindle microtubules—impact chromosome segregation remains poorly understood. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to characterize and track individual chromosomes with distinct kinetochore size throughout mitosis. We show that centromere and kinetochore functional layers scale proportionally with centromere size. Measurement of intra-kinetochore distances, serial-section electron microscopy, and RNAi against key kinetochore proteins confirmed a standard structural and functional organization of the Indian muntjac kinetochores and revealed that microtubule binding capacity scales with kinetochore size. Surprisingly, we found that chromosome segregation in this species is not random. Chromosomes with larger kinetochores bi-oriented more efficiently and showed a 2-fold bias to congress to the equator in a motor-independent manner. Despite robust correction mechanisms during unperturbed mitosis, chromosomes with larger kinetochores were also strongly biased to establish erroneous merotelic attachments and missegregate during anaphase. This bias was impervious to the experimental attenuation of polar ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a. Thus, kinetochore size is an important determinant of chromosome segregation fidelity

Type-Inference Based Short Cut Deforestation (nearly) without Inlining

Deforestation optimises a functional program by transforming it into another one that does not create certain intermediate data structures. In [ICFP'99] we presented a type-inference based deforestation algorithm which performs extensive inlining. However, across module boundaries only limited inlining is practically feasible. Furthermore, inlining is a non-trivial transformation which is therefore best implemented as a separate optimisation pass. To perform short cut deforestation (nearly) without inlining, Gill suggested to split definitions into workers and wrappers and inline only the small wrappers, which transfer the information needed for deforestation. We show that Gill's use of a function build limits deforestation and note that his reasons for using build do not apply to our approach. Hence we develop a more general worker/wrapper scheme without build. We give a type-inference based algorithm which splits definitions into workers and wrappers. Finally, we show that we can deforest more expressions with the worker/wrapper scheme than the algorithm with inlining

Diagnóstico pouco usual de obstrução da traqueia

AbstractMale, 54 years old, with smoking habits. The patient complaints were cough, with bleeding secretions in the previous two months. Because of the persistence of the symptoms, a broncoscopy was proposed. This exam showed multiple lesions in the traquea, nearly 2cm above the vocal cords that compromised the airway and did not allow the progression of the bronchoscope. For this reason, it was decided to introduce a tracheal prosthesis. Because of instability, and the suspicion of malignancy we started thoracic irradiation. The histological specimen was compatible with anaplastic Lymphoma, CD 30+.Because of respiratory distress, with stridor, the prothesis was removed. The traquea was permeable after this.The patient was discharged and oriented to Clinical Haematology. He is clinically stable and under monitoring, having now completed a chemotherapy treatment with CHOP (Ciclophosphamide, Adriamycin or Hydroxydorubicin, Vincristine or Oncovin and Prednisone).The primary mediastinal Large Cells Lymphoma represents 11.5% of the Large Cells Lymphomas (2% of the non-Hodgkin’s Lymphomas). This neoplasm is in many studies considered incurable, but there are some positive results with the combination of radiotheraphy and chemotherapy. If there is any airway compromise, the tracheal prosthesis may be one option for the resolution of the respiratory insufficiency.Rev Port Pneumol 2006; XII (3): 303-30

Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency \u3c 0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care

Master curves for the stress tensor invariants in stationary states of static granular beds. Implications for the thermodynamic phase space

We prepare static granular beds under gravity in different stationary states by tapping the system with pulsed excitations of controlled amplitude and duration. The macroscopic state---defined by the ensemble of static configurations explored by the system tap after tap---for a given tap intensity and duration is studied in terms of volume, V, and force moment tensor, \Sigma. In a previous paper [Pugnaloni et al., Phys. Rev. E 82, 050301(R) (2010)], we reported evidence supporting that such macroscopic states cannot be fully described by using only V or \Sigma, apart from the number of particles N. In this work, we present an analysis of the fluctuations of these variables that indicates that V and \Sigma may be sufficient to define the macroscopic states. Moreover, we show that only one of the invariants of \Sigma is necessary, since each component of \Sigma falls onto a master curve when plotted as a function of Tr(\Sigma). This implies that these granular assemblies have a common shape for the stress tensor, even though it does not correspond to the hydrostatic type. Although most results are obtained by molecular dynamics simulations, we present supporting experimental results.Comment: 13 pages, 14 figure

Usulan Perancangan Tata Letak Penyimpanan Komponen Berdasarkan Kriteria Komoditi Komponen (Studi Kasus Di PT Triangle Motorindo Semarang)

Kurang lancarnya suplai komponen ke bagian produksi dapat menyebabkan menurunnya produktivitas dari bagian produksi. Untuk itu perlu dilakukan perancangan tata letak penyimpanan komponen yang lebih baik sehingga dapat mengurangi waktu mencari komponen, mengurangi jarak perjalanan operator dalam pengambilan dan pengiriman komponen, dan meningkatkan pemanfaatan kapasitas gudang. PT. Triangle Motorindo merupakan Perusahaan yang bergerak dalam USAha perakitan sepeda motor. Secara garis besar, Perusahaan dapat dibagi menjadi dua bagian yaitu bagian gudang dan bagian produksi dimana bagian gudang menjadi pendukung dari bagian produksi. Bagian gudang terdiri dari gudang sortir, gudang rangka, dan gudang mesin. Dalam mengalokasikan komponen yang disimpan, Perusahaan menggunakan kebijakan penyimpanan random/acak yang berakibat tidak standarnya waktu yang dibutuhkan untuk mencari komponen dan bertambahnya waktu perjalanan operator dalam menyuplai komponen. Penelitian ini memberikan alternatif perancangan tata letak penyimpanan komponen yang dilakukan dengan memperhatikan komponen itu sendiri, dalam hal ini disebut faktor komoditi yang terdiri atas popularity, similarity, characteristic, dan size. Selain berdasarkan komponen yang disimpan, perancangan tata letak penyimpanan ini juga memperhatikan kondisi ruangan yang tersedia. Hasil pengolahan data dan analisis yang dilakukan menunjukkan bahwa tata letak penyimpanan komponen yang terbaik adalah berdasarkan kriteria process similarity. Tata letak penyimpanan komponen berdasarkan kriteria process similarity ini merupakan tata letak penyimpanan komponen terbaik

Gene expression parallels synaptic excitability and plasticity changes in Alzheimer's disease

Altres ajuts: CIBERNED CB06/05/0042 i BrightFocus Foundation (A2014417S)Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders

Analysis of instabilities in the Basque Coast Geopark coastal cliffs for its environmentally friendly management (Basque-Cantabrian basin, northern Spain)

Coastal cliffs provide a high landscape value to many natural sites around the world. This means that an ever-increasing number of people are attracted to them. At this point, there is a growing need to manage these spaces from the safety of visitors, but with a view to preserving the environment. With this aim, this paper presents an approach to analyze and manage instabilities in these environments, particularly those subjected to significant anthropic activity, which has been implemented in the cliffs of the Basque Coast Geopark. The starting point is a detailed topographic information, obtained from UAV flights, and the identification on site of unstable elements, including their typology, active source areas, dynamics and reach. From this information, the simulation of rockfall processes, which basically correspond to toppling and infinite slope instabilities favored by differential erosion along the coastline, is approached in two and three dimensions. Results allow the design of precise actions by sectors, according to the energy, height and reach of the detached blocks, including barriers, middle slope actions, ditches and information strategies, depending on the different uses of the sectors. Therefore, this approach leads to a more detailed and environmentally friendly management of these environments. © 2021This study has been carried out by the UPV/EHU Research GroupIT-1029/16 (Government of the Basque Country) in the framework of the strategic project ?Analysis of instabilities in coastal environments of the Basque Country? PES-18/97 (University of the Basque Country) and the collaboration of the Basque Coast Geopark (Geoparkea). Finally, the authors are grateful to the reviewers and the handling editor, for the valuable comments that highly improved the paper

Revealing cell vulnerability in Alzheimer's disease by single-cell transcriptomics

Acord transformatiu CRUE-CSICAlzheimer's disease (AD) is a neurodegenerative disorder that by affecting specific brain cell types and regions cause severe pathological and functional changes in memory neural circuits. A comprehensive knowledge of the pathogenic mechanisms underlying AD requires a deeper understanding of the cell-specific pathological responses through integrative molecular analyses. Recent application of high-throughput single-cell transcriptomics to postmortem tissue has proved powerful to unravel cell susceptibility and biological networks responding to amyloid and tau pathologies. Here, we review single-cell transcriptomic studies successfully applied to decipher cell-specific gene expression programs and pathways in the brain of AD patients. Transcriptional information reveals both specific and common gene signatures affecting the major cerebral cell types, including astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes. Cell type-specific transcriptomes associated with AD pathology and clinical symptoms are related to common biological networks affecting, among others pathways, synaptic function, inflammation, proteostasis, cell death, oxidative stress, and myelination. The general picture that emerges from systems-level single-cell transcriptomics is a spatiotemporal pattern of cell diversity and biological pathways, and novel cell subpopulations affected in AD brain. We argue that broader implementation of cell transcriptomics in larger AD human cohorts using standardized protocols is fundamental for reliable assessment of temporal and regional cell-type gene profiling. The possibility of applying this methodology for personalized medicine in clinics is still challenging but opens new roads for future diagnosis and treatment in dementia

First approach to automatic performance status evaluation and physical activity recognition in cancer patients

The evaluation of cancer patients’ recovery is still under the big subjectivity of physicians. Many different systems have been successfully implemented for physical activity evaluation, nonetheless there is still a big leap into Performance Status evaluation with ECOG and Karnofsky’s Performance Status scores. An automatic system for data recovering based on Android smartphone and wearables has been developed. A gamification implementation has been designed for increasing patients’ motivation in their recovery. Furthermore, novel and without-precedent algorithms for Performance Status (PS) and Physical Activity (PA) assessment have been developed to help oncologists in their diagnoses