46 research outputs found
Redox Post-translational Modifications of Protein Thiols in Brain Aging and Neurodegenerative Conditions—Focus on S-Nitrosation
No full textReactive oxygen species and reactive nitrogen species (RONS) are by-products of aerobic metabolism. RONS trigger a signaling cascade that can be transduced through oxidation-reduction (redox)-based post-translational modifications (redox PTMs) of protein thiols. This redox signaling is essential for normal cellular physiology and coordinately regulates the function of redox-sensitive proteins. It plays a particularly important role in the brain, which is a major producer of RONS. Aberrant redox PTMs of protein thiols can impair protein function and are associated with several diseases. This mini review article aims to evaluate the role of redox PTMs of protein thiols, in particular S-nitrosation, in brain aging, and in neurodegenerative diseases. It also discusses the potential of using redox-based therapeutic approaches for neurodegenerative conditions
The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour
No full textMembers of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment
Epigenetic regulation of sensory axon regeneration after spinal cord injury
No full text Axon regeneration is hindered by a decline of intrinsic axon growth capability in mature neurons. Reversing this decline is associated with the induction of a large repertoire of regeneration-associated genes (RAGs), but the underlying regulatory mechanisms of the transcriptional changes are largely unknown. Here, we establish a correlation between diminished axon growth potential and histone 4 (H4) hypoacetylation. When neurons are triggered into a growth state, as in the conditioning lesion paradigm, H4 acetylation is restored, and RAG transcription is initiated. We have identified a set of target genes of Smad1, a proregenerative transcription factor, in conditioned DRG neurons. We also show that, during the epigenetic reprogramming process, histone-modifying enzymes work together with Smad1 to facilitate transcriptional regulation of RAGs. Importantly, targeted pharmacological modulation of the activity of histone-modifying enzymes, such as histone deacetylases, leads to induction of multiple RAGs and promotion of sensory axon regeneration in a mouse model of spinal cord injury. Our findings suggest epigenetic modulation as a potential therapeutic strategy to enhance axon regeneration. </p
Study of two mouse mutants to identify novel neurodegenerative pathways
No full textNeurodegenerative disorders (NDD) are an ever-increasing burden on healthcare; consequently, elucidating the mechanisms underlying neurodegeneration (ND) is critical for the development of effective treatments for these diseases. In order to unravel the molecular pathways underlying movement disorders and identify new genes involved in ND, two ataxic mouse mutants characterised by cell death in the cerebellum were studied in detail using a combination of in vitro and in vivo techniques. The robotic mouse demonstrated the key role of a transcription factor, Af4, in Purkinje cell (PC) survival and how only small changes in the levels of a single transcriptional cofactor could deleteriously affect normal cerebellum function. Expression array studies of the robotic PCs revealed the first confirmed targets of Af4-mediated transcription, including insulin-like growth factor 1 (Igf-1). It was demonstrated that Igf-1 is critical for PC survival, highlighting the role of the IGF-1 signalling pathway as a potential therapeutic target for the treatment of cerebellar ataxia in humans. Detailed analysis of the bella mutant demonstrated that ataxia and apoptotic cerebellar degeneration is caused by loss of the oxidative resistance 1 (Oxr1) gene. In vitro modelling experiments went on to show that the levels of this previously uncharacterised gene are critical for controlling the sensitivity of neuronal cells to oxidative stress (OS). Moreover, this study showed that Oxr1 was up-regulated both in human and pre-symptomatic mouse models of amyotrophic lateral sclerosis (ALS), demonstrating that Oxr1 was an early marker of ROS defence, prior to pathology, and potentially a novel neuroprotective factor in NDD. Preliminary interaction studies show that Oxr1 is likely to be a multi-functional protein that forms complexes with proteins known to be mutated in NDD. Thus, the study of both the robotic and the bella mouse has demonstrated the value of the phenotype-driven approach to investigate novel neurodegenerative pathways
Pogrzeb Mattea Ricciego SJ (1552–1610) w Historiae Sinarum Imperii Tomasza Szpota Dunina: Kulturowa interakcja
No full textThe article analyzes the circumstances of the funeral of the Italian Jesuit Matteo Ricci, who died in Beijing in 1610. The author emphasizes the cultural complexity of this event and explores the broad cultural and religious context of China’s collision with Western civilization. Using historical and cultural analysis methods, mainly based on Historiae Sinarum Imperii by Tomasz Szpot Dunin, the author examines Confucian funeral ceremonies, their social and cultural significance, and their impact on cultural rapprochement between the East and West. The practices are compared with Western traditions, analyzing similarities and differences. Special attention is given to how Christianity and Confucianism contributed to Ricci’s unique funeral ceremony, combining elements of both cultures. The article highlights Ricci’s controversial figure and his significant impact on understanding and acceptance between cultures, with his funeral symbolizing harmony between Eastern and Western traditions, demonstrating how respect for local practices can transform intercultural relations.W artykule analizowane są okoliczności pogrzebu włoskiego jezuity Mattea Ricciego, zmarłego w Pekinie w 1610 r. Autor podkreśla złożoność kulturową tego wydarzenia i opierając się na najnowszych badaniach, eksploruje szeroki kontekst kulturowy oraz religijny zderzenia cywilizacji Chin z Zachodem. Wykorzystując metody analizy historycznej i kulturowej, głównie na podstawie Historiae Sinarum Imperii Tomasza Szpota Dunina, autor bada ceremonie pogrzebowe w tradycji konfucjańskiej, ich znaczenie społeczne i kulturowe, a także wpływ na zbliżenie kulturowe między Wschodem a Zachodem. Porównuje te praktyki z zachodnimi tradycjami, analizując różnice i podobieństwa. Szczególna uwaga poświęcona jest temu, jak chrześcijaństwo i konfucjanizm przyczyniły się do unikalnej formy ceremonii pogrzebowej Ricciego, łączącej elementy obu kultur. Artykuł podkreśla, że kontrowersyjna postać Ricciego miała istotny wpływ na zrozumienie i akceptację między kulturami, a jego pogrzeb stał się symbolem harmonii między tradycjami Wschodu i Zachodu, demonstrując, jak szacunek dla lokalnych praktyk może przekształcić relacje międzykulturowe
Differential Phosphorylation of Smad1 Integrates BMP and Neurotrophin Pathways through Erk/Dusp in Axon Development
No full textSummarySensory axon development requires concerted actions of growth factors for the precise control of axonal outgrowth and target innervation. How developing sensory neurons integrate different cues is poorly understood. We demonstrate here that Smad1 activation is required for neurotrophin-mediated sensory axon growth in vitro and in vivo. Through differential phosphorylation, Smad1 exerts transcriptional selectivity to regulate the expression and activity of Erk1 and Erk2—two key neurotrophin effectors. Specifically, bone morphogenetic proteins (BMPs) signal through carboxy-terminal phosphorylation of Smad1 (pSmad1C) to induce Erk1/2 transcription for enhanced neurotrophin responsiveness. Meanwhile, neurotrophin signaling results in linker phosphorylation of Smad1 (pSmad1L), which in turn upregulates an Erk-specific dual-specificity phosphatase, Dusp6, leading to reduced pErk1/2 and constituting a negative-feedback loop for the prevention of axon overgrowth. Together, the BMP and neurotrophin pathways form a tightly regulated signaling network with a balanced ratio of Erk1/2 and pErk1/2 to direct the precise connections between sensory neurons and peripheral targets
The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress
No full textOxidative stress is a pathological feature of many neurological disorders, therefore utilizing proteins that are protective against such cellular insults is a potentially valuable therapeutic approach. Oxidation resistance 1 (OXR1) has been shown previously to be critical for oxidative stress resistance in neuronal cells; deletion of this gene causes neurodegeneration in mice, yet conversely, over-expression of OXR1 is protective in cellular and mouse models of amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms involved are unclear. OXR1 contains the Tre2/Bub2/Cdc16 (TBC), Lysin motif (LysM), Domain catalytic (TLDC) domain, a motif present in a family of proteins including TBC1 domain family member 24 (TBC1D24), a protein mutated in a range of disorders characterized by seizures, hearing loss and neurodegeneration. The TLDc domain is highly conserved across species, although the structure-function relationship is unknown. To understand the role of this domain in the stress response, we carried out systematic analysis of all mammalian TLDc domain-containing proteins, investigating their expression and neuroprotective properties in parallel. In addition, we performed a detailed structural and functional study of this domain, in which we identified key residues required for its activity. Finally, we present a new mouse insertional mutant of Oxr1, confirming that specific disruption of the TLDc domain in vivo is sufficient to cause neurodegeneration. Our data demonstrate that the integrity of the TLDc domain is essential for conferring neuroprotection, an important step in understanding the functional significance of all TLDc domain-containing proteins in the cellular stress response and disease
Keeping It Real in the Hills: Representing Appalachia in Americana Music
No full textKEEPING IT REAL IN THE HILLS: REPRESENTING APPALACHIA IN AMERICANA was led by leading author, journalist and media personality Craig Havighurst and panelists radio producer Kris Truelsen, artist Kathy Mattea, artist Amythyst Kiah, and music educator Ted Olson. The topic of discussion was the state of old-time and Appalachian folk music and its sounds today, and the making of Kathy Mattea’s album Calling Me Home
Oxidation resistance 1 regulates post-translational modifications of peroxiredoxin 2 in the cerebellum
No full textProtein aggregation, oxidative and nitrosative stress are etiological factors common to all major neurodegenerative disorders. Therefore, identifying proteins that function at the crossroads of these essential pathways may provide novel targets for therapy. Oxidation resistance 1 (Oxr1) is a protein proven to be neuroprotective against oxidative stress, although the molecular mechanisms involved remain unclear. Here, we demonstrate that Oxr1 interacts with the multifunctional protein, peroxiredoxin 2 (Prdx2), a potent antioxidant enzyme highly expressed in the brain that can also act as a molecular chaperone. Using a combination of in vitro assays and two animal models, we discovered that expression levels of Oxr1 regulate the degree of oligomerization of Prdx2 and also its post-translational modifications (PTMs), specifically suggesting that Oxr1 acts as a functional switch between the antioxidant and chaperone functions of Prdx2. Furthermore, we showed in the Oxr1 knockout mouse that Prdx2 is aberrantly modified by overoxidation and S-nitrosylation in the cerebellum at the presymptomatic stage; this in-turn affected the oligomerization of Prdx2, potentially impeding its normal functions and contributing to the specific cerebellar neurodegeneration in this mouse model
Addiction to pornography : analysis of the clinical picture and treatment options
No full textPosljednja dva desetljeća mnogobrojni znanstvenici pišu o fenomenu bihevioralnih ovisnosti,
unutar kojih svrstavamo i ovisnost o pornografiji. Osim zbog razvoja saznanja o bihevioralnim
ovisnostima, tema ovisnosti o pornografiji značajna je i zbog činjenice da socijalno
distanciranje koje je trenutno prisutno u društvu te nagli napredak tehnologije i lakoća pristupa,
povećavaju vjerojatnost razvoja ovog tipa ovisničkog ponašanja. Cilj ovog diplomskog rada
jest, pregledom domaće i strane, stručne i znanstvene literature, sistematizirati informacije i
postojeće znanstvene spoznaje na temu ovisnosti o pornografiji, a u svrhu unaprjeđivanja
socijalnopedagoške znanosti i prakse. U radu se kroz pregled koji započinje definicijom i
terminologijom, preko kliničke slike i instrumenata, prevalencije i načina pristupa
pornografskom sadržaju, korelatima, rizičnim čimbenicima i posljedicama uporabe dolazi do
mehanizma razvoja ovisnosti te tretmanskih i preventivnih mogućnosti djelovanja stručnjaka
kao i zaključka autorice rada. Najbitniji zaključci rada odnose se na to da je ovisnost o
pornografiji, nova, nedovoljno jasno definirana, no sve češća problematika među odraslom i
adolescentskom populacijom. Naglašena je važnost posljedica ponašanja na pojedinca jer
upravo one čine razliku između normalnog i patološkog. Autorica ističe važnost bavljenja ovom
problematikom među stručnjacima pomažućih profesija, najviše u području prevencije razvoja
težih oblika problema.In the last two decades, numerous scientists have been writing about the phenomenon of
behavioral addictions, including addiction to pornography. In addition to the development of
knowledge about behavioral addictions, the topic of pornography addiction is also significant
since the social distancing that is currently present in society and the rapid progress of
technology and ease of access increases the likelihood of developing this type of addictive
behavior. The goal of this thesis is to systematize information and existing scientific knowledge
on the topic of addiction to pornography, to improve social-pedagogical science and practice,
by reviewing domestic and foreign professional and scientific literature. In the paper, through
an overview that begins with definitions and terminology, through the clinical picture and
instruments, prevalence and methods of access to pornographic content, correlates, risk factors
and consequences of use, the mechanism of addiction development and the treatment and
preventive actions of experts, as well as the author's conclusion, are reached. The most
important conclusions of the work refer to the fact that pornography addiction is a new, vaguely
defined, but increasingly common problem among the adult and adolescent population. The
importance of the consequences of behavior on the individual is emphasized, because it is
precisely these that make the difference between normal and pathological. The author points
out the importance of dealing with this issue among experts in the helping professions,
especially in the area of prevention of the development of more severe forms of the problem
