Vesicle trafficking and pathways to neurodegeneration

Neurodegenerative diseases, encompassing a diverse range of inherited and sporadic disorders characterised by progressive loss of relatively discrete neuronal populations, are a significant and increasing challenge to human health and the global economy [1]. Despite significant advances in our understanding of the underlying ætiology of diseases such as Alzheimer’s, Parkinson’s and Huntington’s, and intense efforts targeting the development of disease-modifying therapies for these disorders, for the majority of people living with neurodegenerative conditions the prognosis remains poor [2,3,4]. Improving our knowledge of the underlying causes of neuronal loss in these disorders with the goal of developing novel disease-modifying therapies is thus a top priority for research, patient and care-giver communities

Актуальные задачи совершенствования государственного менеджмента в развитии Украины

У статті визначено недоліки використання в Україні доктрини дерегулювання. Обґрунтовано важливість державного регулювання крупного виробництва. Визначено головні завдання влади у розвитку економіки держави.In the article lacks of the use in Ukraine of doctrine of deregulation are considered. Importance of government control of large production is grounded. Main tasks of power in development of economy of the state are determined

Utilisation des ondes sismiques pour comprendre et contraindre la dynamique des effondrements gravitaires

Despite the great amount of studies, the understanding of landslides mechanics is still an open question, in particular due to the lack of field data relevant to their dynamics. We propose here to make use of the seismic signal generated by landslides to extract information on flow properties, by coupling landslide and wave propagation models and by comparing simulated and recorded seismic signal. We show that this methodology makes it possible to discriminate between possible alternative scenarios for flow dynamics and to provide first estimates of the rheological parameters

Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions

Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.

Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death

Sequenceserver: A Modern Graphical User Interface for Custom BLAST Databases

Comparing newly obtained and previously known nucleotide and amino-acid sequences underpins modern biological research. BLAST is a well-established tool for such comparisons but is challenging to use on new data sets. We combined a user-centric design philosophy with sustainable software development approaches to create Sequenceserver, a tool for running BLAST and visually inspecting BLAST results for biological interpretation. Sequenceserver uses simple algorithms to prevent potential analysis errors and provides flexible text-based and visual outputs to support researcher productivity. Our software can be rapidly installed for use by individuals or on shared servers

Microbotanical residues for the study of early hominin tools

More than 2 million years ago in East Africa, the earliest hominin stone tools evolved amidst changes in resource base, with pounding technology playing a key role in this adaptive process. Olduvai Gorge (now Oldupai) is a famed locality that remains paramount for the study of human evolution, also yielding some of the oldest battering tools in the world. However, direct evidence of the resources processed with these technologies is lacking entirely. One way to obtain this evidence is through the analysis of surviving residues. Yet, linking residues with past processing activities is not simple. In the case of plant exploitation, this link can only be established by assessing site-based reference collections inclusive of both anthropogenic and natural residues as a necessary first step and comparative starting point. In this paper, we assess microbotanical remains from rock clasts sourced at the same quarry utilized by Oldowan hominins at Oldupai Gorge. We mapped this signal and analysed it quantitatively to classify its spatial distribution objectively, extracting proxies for taxonomic identification and further comparison with freestanding soils. In addition, we used blanks to manufacture pounding tools for blind, controlled replication of plant processing. We discovered that stone blanks are in fact environmental reservoirs in which plant remains are trapped by lithobionts, preserved as hardened accretions. Tool use, on the other hand, creates residue clusters; however, their spatial distribution can be discriminated from purely natural assemblages by the georeferencing of residues and statistical analysis of resulting patterns. To conclude, we provide a protocol for best practice and a workflow that has the advantage of overcoming environmental noise, reducing the risk of false positive, delivering a firm understanding of residues as polygenic mixtures, a reliable use of controls, and most importantly, a stronger link between microbotanical remains and stone tool use. © 2022. The Author(s).Materials and methods Results - Blanks as environmental reservoirs - Utilization creates residue clusters - Anthropogenic residue distribution - Of lichen habitability, proxy palimpsests, and hardened accretions - A protocol to study plant residue from Oldowan pounding tool

Aggregated a-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons

α-Synuclein becomes misfolded and aggregated upon damage by various factors, for example, by reactive oxygen species. These aggregated forms have been proposed to have differential toxicities and their interaction with mitochondria may cause dysfunction within this organelle that contributes to the pathogenesis of Parkinson’s disease (PD). In particular, the association of α-synuclein with mitochondria occurs through interaction with mitochondrial complex I and importantly defects of this protein have been linked to the pathogenesis of PD. Therefore, we investigated the relationship between aggregated α-synuclein and mitochondrial dysfunction, and the consequences of this interaction on cell survival. To do this, we studied the effects of α-synuclein on cybrid cell lines harbouring mutations in either mitochondrial complex I or IV. We found that aggregated α-synuclein inhibited mitochondrial complex I in control and complex IV-deficient cells. However, when aggregated α-synuclein was applied to complex I-deficient cells, there was no additional inhibition of mitochondrial function or increase in cell death. This would suggest that as complex I-deficient cells have already adapted to their mitochondrial defect, the subsequent toxic effects of α-synuclein are reduced

Lamin A Rod Domain Mutants Target Heterochromatin Protein 1α and β for Proteasomal Degradation by Activation of F-Box Protein, FBXW10

Lamins are major structural proteins of the nucleus and contribute to the organization of various nuclear functions. Mutations in the human lamin A gene cause a number of highly degenerative diseases, collectively termed as laminopathies. Cells expressing lamin mutations exhibit abnormal nuclear morphology and altered heterochromatin organization; however, the mechanisms responsible for these defects are not well understood.The lamin A rod domain mutants G232E, Q294P and R386K are either diffusely distributed or form large aggregates in the nucleoplasm, resulting in aberrant nuclear morphology in various cell types. We examined the effects of these lamin mutants on the distribution of heterochromatin protein 1 (HP1) isoforms. HeLa cells expressing these mutants showed a heterogeneous pattern of HP1alpha and beta depletion but without altering HP1gamma levels. Changes in HP1alpha and beta were not observed in cells expressing wild-type lamin A or mutant R482L, which assembled normally at the nuclear rim. Treatment with proteasomal inhibitors led to restoration of levels of HP1 isoforms and also resulted in stable association of lamin mutants with the nuclear periphery, rim localization of the inner nuclear membrane lamin-binding protein emerin and partial improvement of nuclear morphology. A comparison of the stability of HP1 isoforms indicated that HP1alpha and beta displayed increased turnover and higher basal levels of ubiquitination than HP1gamma. Transcript analysis of components of the ubiquitination pathway showed that a specific F-box protein, FBXW10 was induced several-fold in cells expressing lamin mutants. Importantly, ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels.Mislocalized lamins can induce ubiquitin-mediated proteasomal degradation of certain HP1 isoforms by activation of FBXW10, a member of the F-box family of proteins that is involved in E3 ubiquitin ligase activity