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Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.
- MeSH
- depresivní porucha unipolární * MeSH
- dospělí MeSH
- konsensus MeSH
- kvalita života MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozeček patologie MeSH
- průřezové studie MeSH
- senioři MeSH
- stárnutí MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
f-statistics have emerged as a first line of analysis for making inferences about demographic history from genome-wide data. Not only are they guaranteed to allow robust tests of the fits of proposed models of population history to data when analyzing full genome sequencing data-that is, all single nucleotide polymorphisms (SNPs) in the individuals being analyzed-but they are also guaranteed to allow robust tests of models for SNPs ascertained as polymorphic in a population that is an outgroup in a phylogenetic sense to all groups being analyzed. True "outgroup ascertainment" is in practice impossible in humans because our species has arisen from a substructured ancestral population that does not descend from a homogeneous ancestral population going back many hundreds of thousands of years into the past. However, initial studies suggested that non-outgroup-ascertainment schemes might produce robust enough results using f-statistics, and that motivated widespread fitting of models to data using non-outgroup-ascertained SNP panels such as the "Affymetrix Human Origins array" which has been genotyped on thousands of modern individuals from hundreds of populations, or the "1240k" in-solution enrichment reagent which has been the source of about 70% of published genome-wide data for ancient humans. In this study, we show that while analyses of population history using such panels work well for studies of relationships among non-African populations and one African outgroup, when co-modeling more than one sub-Saharan African and/or archaic human groups (Neanderthals and Denisovans), fitting of f-statistics to such SNP sets is expected to frequently lead to false rejection of true demographic histories, and failure to reject incorrect models. Analyzing panels of SNPs polymorphic in archaic humans, which has been suggested as a solution for the ascertainment problem, has limited statistical power and retains important biases. However, by carrying out simulations of diverse demographic histories, we show that bias in inferences based on f-statistics can be minimized by ascertaining on variants common in a union of diverse African groups; such ascertainment retains high statistical power while allowing co-analysis of archaic and modern groups.
- MeSH
- Afričané * genetika MeSH
- biologická variabilita populace genetika MeSH
- černoši genetika MeSH
- demografie * dějiny MeSH
- fylogeneze * MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus * genetika MeSH
- lidé MeSH
- mapování chromozomů MeSH
- neandertálci genetika MeSH
- statistické modely MeSH
- zkreslení výsledků (epidemiologie) MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Apicomplexans and related lineages comprise many obligate symbionts of animals; some of which cause notorious diseases such as malaria. They evolved from photosynthetic ancestors and transitioned into a symbiotic lifestyle several times, giving rise to species with diverse non-photosynthetic plastids. Here, we sought to reconstruct the evolution of the cryptic plastids in the apicomplexans, chrompodellids, and squirmids (ACS clade) by generating five new single-cell transcriptomes from understudied gregarine lineages, constructing a robust phylogenomic tree incorporating all ACS clade sequencing datasets available, and using these to examine in detail, the evolutionary distribution of all 162 proteins recently shown to be in the apicoplast by spatial proteomics in Toxoplasma. This expanded homology-based reconstruction of plastid proteins found in the ACS clade confirms earlier work showing convergence in the overall metabolic pathways retained once photosynthesis is lost, but also reveals differences in the degrees of plastid reduction in specific lineages. We show that the loss of the plastid genome is common and unexpectedly find many lineage- and species-specific plastid proteins, suggesting the presence of evolutionary innovations and neofunctionalizations that may confer new functional and metabolic capabilities that are yet to be discovered in these enigmatic organelles.
- MeSH
- fotosyntéza genetika MeSH
- fylogeneze MeSH
- metabolické sítě a dráhy MeSH
- plastidy * genetika MeSH
- proteom * genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: The global health workforce suffers long-term understaffing in remote and underserved areas. To attract young doctors for rural work, it is necessary to identify the main motivating factors. MATERIALS AND METHODS: The pilot survey with 201 general practitioner trainees in the Czech Republic was conducted using a structured questionnaire. The response rate was 67%. RESULTS: Not only financial support motivates general practitioner trainees for rural work. A combination of incentives from sources other than medical would greatly increase the chance for general practitioner trainees to work in rural regions. CONCLUSIONS: To what extent can the survey outcomes relate with other European regions needs to be investigated further.
- MeSH
- lidé MeSH
- pracovní síly MeSH
- praktičtí lékaři * MeSH
- průzkumy a dotazníky MeSH
- venkovské obyvatelstvo MeSH
- zdravotnické služby pro venkov * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Prostorová mobilita seniorů patří k aktuálním zkoumaným tématům. Její aktuálnost je dána jednak stárnutím populace, jednak otázkami spojenými s kvalitou života seniorů. Je spojena s tím, jakým způsobem prostorová mobilita seniorů ovlivňuje jejich osobní nebo rodinný život, ale také život komunitní a veřejný. Předmětem soudobých zkoumání jsou faktory, které podporují prostorovou mobilitu, a naopak ty, které jí zabraňují. Ke zkoumaným tématům spojeným se stárnutím a stářím je také autonomie seniorů, která zahrnuje řadu aspektů. V průniku obou témat, tj. prostorové mobility a autonomie, vznikají otázky, jak spolu tyto jevy i procesy souvisejí, nakolik se podmiňují a ve výsledku, jaké takto pojatá mobilní autonomie plní funkce, či naopak za jakých okolností přestává být funkční. Byla provedena analýza 24 hloubkových rozhovorů se seniory staršími 70 let. Hlavním cílem bylo zjistit, jaký význam přisuzují senioři venkovní mobilitě pro svou autonomii. Cíl byl rozpracován do následujících výzkumných otázek: a) Jaký význam senioři přisuzují využívaným módům venkovní mobility? b) Jaké okolnosti senioři identifikují jako ovlivňující jejich mobilitu? c) Jak se senioři vyrovnávají s vnímanými omezeními venkovní mobility? Zvláště se ukázalo, jak významný je modus automobilu, význam je však diferencován podle různých kritérií, např. zda senior sám řídí, zda řídí jeho partner nebo zda je odkázán na pomoc druhých. Velkou otázkou je, jak se právě řidiči vyrovnávají se situací, kdy řídit přestanou či jsou nuceni přestat. Význam kola spjatý obvykle s širším rádiem každodenního žitého prostoru seniora závisí na zdravotní situací, kondici a životním způsobu. Z rozhovorů je patrné, že situaci seniorů a jejich strategie zvládání stárnutí zvláště v případě pokročilého stáří dobře charakterizuje to, jak jsou schopni pěšího pohybu a jak se mu věnují. Analýza rozhovorů vede k typologii přístupu seniorů k mobilitě a jejímu významu pro vlastní autonomii.
Spatial mobility of seniors is one of the current topics under investigation. Its relevance is due to both the ageing population and issues related to the quality of life of seniors. It is linked to how the spatial mobility of seniors affects their personal or family life, but also community and public life. The factors that promote spatial mobility and those that hinder it are the subject of contemporary research. Among the topics related to ageing and old age, the autonomy of seniors, which encompasses several aspects, is also under investigation. The intersection of these two topics, i.e., spatial mobility and autonomy, raises the questions of how these phenomena and processes are related, to what extent they condition each other and, as a result, what functions mobile autonomy, so conceived, fulfils or, conversely, under what circumstances it ceases to be functional. An analysis of 24 semi-structured interviews with seniors over 70 years of age was conducted. The main objective of the study was to discover what importance seniors attach to the outdoor mobility for their individual autonomy. We deconstructed this goal into the following research questions: (a) What importance do seniors attach to the outdoor mobility modes they use? (b) What circumstances do seniors identify as affecting their mobility? (c) How do seniors respond to the limitations in their outdoor mobility? In particular, the modus of the car has been shown to be important, but the importance is differentiated according to different criteria, e.g., whether the senior drives alone, whether his/her partner drives or whether s/he relies on the help of others. A big question is how drivers cope when they stop driving or are forced to stop. The importance of the bicycle, usually linked to the wider radius of the elderly person's daily living space, depends on health, fitness, and lifestyle. From the interviews, it is evident that the situation of seniors and their coping strategies, especially in the case of advanced old age, are well characterized by their ability and commitment to walking. The analysis of the interviews leads to a typology of seniors' attitudes towards mobility and its importance for their own autonomy.
- MeSH
- adaptace psychologická MeSH
- chůze psychologie MeSH
- lidé MeSH
- osobní autonomie MeSH
- pohybová aktivita * MeSH
- rozhovory jako téma MeSH
- samostatný způsob života * psychologie MeSH
- senioři nad 80 let psychologie MeSH
- senioři psychologie MeSH
- stárnutí MeSH
- životní styl MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let psychologie MeSH
- senioři psychologie MeSH
- Publikační typ
- práce podpořená grantem MeSH
Mitochondria are organelles essential for tumor cell proliferation and metastasis. Although their main cellular function, generation of energy in the form of ATP is dispensable for cancer cells, their capability to drive their adaptation to stress originating from tumor microenvironment makes them a plausible therapeutic target. Recent research has revealed that cancer cells with damaged oxidative phosphorylation import healthy (functional) mitochondria from surrounding stromal cells to drive pyrimidine synthesis and cell proliferation. Furthermore, it has been shown that energetically competent mitochondria are fundamental for tumor cell migration, invasion and metastasis. The spatial positioning and transport of mitochondria involves Miro proteins from a subfamily of small GTPases, localized in outer mitochondrial membrane. Miro proteins are involved in the structure of the MICOS complex, connecting outer and inner-mitochondrial membrane; in mitochondria-ER communication; Ca2+ metabolism; and in the recycling of damaged organelles via mitophagy. The most important role of Miro is regulation of mitochondrial movement and distribution within (and between) cells, acting as an adaptor linking organelles to cytoskeleton-associated motor proteins. In this review, we discuss the function of Miro proteins in various modes of intercellular mitochondrial transfer, emphasizing the structure and dynamics of tunneling nanotubes, the most common transfer modality. We summarize the evidence for and propose possible roles of Miro proteins in nanotube-mediated transfer as well as in cancer cell migration and metastasis, both processes being tightly connected to cytoskeleton-driven mitochondrial movement and positioning.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Nucleus, chromatin, and chromosome organization studies heavily rely on fluorescence microscopy imaging to elucidate the distribution and abundance of structural and regulatory components. Three-dimensional (3D) image stacks are a source of quantitative data on signal intensity level and distribution and on the type and shape of distribution patterns in space. Their analysis can lead to novel insights that are otherwise missed in qualitative-only analyses. Quantitative image analysis requires specific software and workflows for image rendering, processing, segmentation, setting measurement points and reference frames and exporting target data before further numerical processing and plotting. These tasks often call for the development of customized computational scripts and require an expertise that is not broadly available to the community of experimental biologists. Yet, the increasing accessibility of high- and super-resolution imaging methods fuels the demand for user-friendly image analysis workflows. Here, we provide a compendium of strategies developed by participants of a training school from the COST action INDEPTH to analyze the spatial distribution of nuclear and chromosomal signals from 3D image stacks, acquired by diffraction-limited confocal microscopy and super-resolution microscopy methods (SIM and STED). While the examples make use of one specific commercial software package, the workflows can easily be adapted to concurrent commercial and open-source software. The aim is to encourage biologists lacking custom-script-based expertise to venture into quantitative image analysis and to better exploit the discovery potential of their images.Abbreviations: 3D FISH: three-dimensional fluorescence in situ hybridization; 3D: three-dimensional; ASY1: ASYNAPTIC 1; CC: chromocenters; CO: Crossover; DAPI: 4',6-diamidino-2-phenylindole; DMC1: DNA MEIOTIC RECOMBINASE 1; DSB: Double-Strand Break; FISH: fluorescence in situ hybridization; GFP: GREEN FLUORESCENT PROTEIN; HEI10: HUMAN ENHANCER OF INVASION 10; NCO: Non-Crossover; NE: Nuclear Envelope; Oligo-FISH: oligonucleotide fluorescence in situ hybridization; RNPII: RNA Polymerase II; SC: Synaptonemal Complex; SIM: structured illumination microscopy; ZMM (ZIP: MSH4: MSH5 and MER3 proteins); ZYP1: ZIPPER-LIKE PROTEIN 1.
The incidence of syphilis has risen worldwide in the last decade in spite of being an easily treated infection. The causative agent of this sexually transmitted disease is the bacterium Treponema pallidum subspecies pallidum (TPA), very closely related to subsp. pertenue (TPE) and endemicum (TEN), responsible for the human treponematoses yaws and bejel, respectively. Although much focus has been placed on the question of the spatial and temporary origins of TPA, the processes driving the evolution and epidemiological spread of TPA since its divergence from TPE and TEN are not well understood. Here, we investigate the effects of recombination and selection as forces of genetic diversity and differentiation acting during the evolution of T. pallidum subspecies. Using a custom-tailored procedure, named phylogenetic incongruence method, with 75 complete genome sequences, we found strong evidence for recombination among the T. pallidum subspecies, involving 12 genes and 21 events. In most cases, only one recombination event per gene was detected and all but one event corresponded to intersubspecies transfers, from TPE/TEN to TPA. We found a clear signal of natural selection acting on the recombinant genes, which is more intense in their recombinant regions. The phylogenetic location of the recombination events detected and the functional role of the genes with signals of positive selection suggest that these evolutionary processes had a key role in the evolution and recent expansion of the syphilis bacteria and significant implications for the selection of vaccine candidates and the design of a broadly protective syphilis vaccine.
- MeSH
- frambézie * mikrobiologie MeSH
- fylogeneze MeSH
- infekce bakteriemi rodu Treponema * mikrobiologie MeSH
- lidé MeSH
- syfilis * epidemiologie mikrobiologie MeSH
- Treponema pallidum genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Single-celled yeasts form spatially structured populations - colonies and biofilms, either alone (single-species biofilms) or in cooperation with other microorganisms (mixed-species biofilms). Within populations, yeast cells develop in a coordinated manner, interact with each other and differentiate into specialized cell subpopulations that can better adapt to changing conditions (e.g. by reprogramming metabolism during nutrient deficiency) or protect the overall population from external influences (e.g. via extracellular matrix). Various omics tools together with specialized techniques for separating differentiated cells and in situ microscopy have revealed important processes and cell interactions in these structures, which are summarized here. Nevertheless, current knowledge is still only a small part of the mosaic of complexity and diversity of the multicellular structures that yeasts form in different environments. Future challenges include the use of integrated multi-omics approaches and a greater emphasis on the analysis of differentiated cell subpopulations with specific functions.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
It is well known that communication between the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC) is critical for various cognitive and behavioral functions. However, the exact role of these structures in spatial coordination remains to be clarified. Here we sought to determine the involvement of the mPFC and the vHPC in the spatial retrieval of a previously learned active place avoidance task in adult male Long-Evans rats, using a combination of unilateral and bilateral local muscimol inactivations. Moreover, we tested the role of the vHPC-mPFC pathway by performing combined ipsilateral and contralateral inactivations. Our results showed not only bilateral inactivations of either structure, but also the combined inactivations impaired the retrieval of spatial memory, whereas unilateral one-structure inactivations did not yield any effect. Remarkably, muscimol injections in combined groups exerted similar deficits, regardless of whether the inactivations were contralateral or ipsilateral. These findings confirm the importance of these structures in spatial cognition and emphasize the importance of the intact functioning of the vHPC-mPFC pathway.
