AAA+ ATPases

Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon condit...

Kurallarına uygun olarak hazırladığım bu tez çalışmasında; • Tez içinde sunduğum verileri, bilgileri ve dokümanları akademik ve etik kurallar çerçevesinde elde ettiğimi, • Tüm bilgi, belge, değerlendirme ve sonuçları bilimsel etik ve ahlak kurallarına uygun olarak sunduğumu, • Tez çalışmasında yararlandığım eserlerin tümüne uygun atıfta bulunarak kaynak gösterdiğimi, • Kullanılan verilerde herhangi bir değişiklik yapmadığımı, • Bu tezde sunduğum çalışmanın özgün olduğunu, bildirir, aksi bir durumda aleyhime doğabilecek tüm hak kayıplarını kabullendiğimi beyan ederim. Engin ETİ 29/01/2025 v ELEKTRONİK İLETİŞİM VE BİLGİ İŞLEM SİSTEMLERİNDE TOPRAKLAMA VE KORUMA ( Lisans Tezi) Engin ETİ N24-182 UNIVERSITY OFNORTHWEST TÜRKİYE ELEKTRİK ELEKTRONİK MÜHENDİSLİĞİ Ocak 2025 ÖZET Elektrik sistemlerinde referans noktası olarak kabul edilen nötr topraklaması elektrik devrelerinde önemli bir kriterdir. Sistemlerde çeşitli sebeplerle oluşan tehlikeli ve zararlı akımları bertaraf etmeyi amaçlayan koruma topraklaması da diğer önemli bir işlemdir. Elektronik ve Haberleşme sistemleri ile Bilgi İşlem Tesisleri'nde oluşan arıza ve hataların sebepleri arasında yeterli etkinlikte yapılmamış topraklama işlemleri önemli bir yer tutmaktadır. Özellikle insanlar ve diğer canlılar için hayati tehlike ve yaralanma riskinin ortadan kaldırılmasına ilaveten elektrikle çalışan tüm sistemlerin düzgün ve kararlı çalışabilmesi ve uzun ömürlü olması için topraklama sistemleri büyük önem taşımaktadır. Mevcut tez çalışmasında, öncelikle topraklama ile ilgili genel tanımlar yapılarak, temel formül ve çalışmalar verilmiştir. Özgül direnç, topraklama elemanlarının yerleştirildiği toprağın cinsi, içindeki kimyasal bileşik ve elementler ile katkı maddelerinin oranlarına göre değişimler incelenmiştir. İlave olarak toprağın sıcaklık, donma durumları ve nem oranı gibi fiziksel şartlarına göre de özgül direncin değişimi topraklama işlemlerindeki önemli unsurlardır. Elektriksel sistem ve tesisatının topraklama dirençlerinin ölçülmesi için literatürde farklı yöntemler mevcuttur. Bunlar, Basit Gerilim Düşümü Metodu (BGDM) ve %62 Metodları yanı sıra, Eğim Metodu, Yıldız-Üçgen (Kesişen Doğru) Metodu ile Dört Nokta Metotları başlıcalarıdır. Topraklama sisteminin elektriksel devre modellemesi ve temel hesapları yapılırken, sistemin iki ana bileşeni olantoprak elektrodları ve kablolamalar, direnç ve bobin gibi techizatlar etkin değerlendirilmelidir. Toprağın yüksek potansiyel stres altında, dielektrik olarak farklı karakteristik özellik gösterdiği de dikkate alınmalıdır. Mevcut çalışmada bir yıldırım darbesi durumunda, topraklama sisteminin seri L-R akım devre modelinin geçici performansı etüt edilmiştir. Benzer şekilde geçiş darbeleri altındaki topraklama sistemlerinin davranışları, yayılma direnci, endüktans ve kapasitans elemanlarına sahip, sızdırmalı bir iletim hattı gibi modellenmiştir. İlave olarak, Elektronik Haberleşme Sistemlerinde topraklama sistemleri için kusur ve arıza örnekleri analiz edilmiştir. Son bölümde ise topraklama sistem ve devrelerinin matematiksel modeli çıkarılmıştır.

The Clp/Hsp100 family, part of the ATPase associated with various
cellular activities (AAA+) superfamily, includes caseinolytic
peptidase B (ClpB), a highly conserved protein found in bacteria,
fungi, protozoa, and plants. Notably, ClpB is present in all ESKAPE
pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa,
and Enterobacter spp. ClpB plays a crucial role in reactivating
and disaggregating proteins, enabling pathogens to survive under
host-induced stress and conferring thermotolerance to bacterial
cells. Infections caused by ESKAPE pathogens are particularly
challenging due to their resistance to broad-spectrum antibiotics and
biofilm formation, posing a significant global health threat as they
are often multidrug-resistant, extensively drug-resistant, and pandrug-resistant. Given its absence in human cells and its essential
role in bacterial survival under stress, ClpB is a promising target
for antimicrobial therapy. Targeting Hsp100 family proteins could
lead to the development of novel antifungal and antiprotozoal
treatments. This review explores the function of ClpB in the survival
of ESKAPE pathogens and the protozoan Plasmodium falciparum.
Relevant research findings were compiled using academic databases,
and data analysis was performed using Clustal Omega Multiple
Sequence Alignment and Boxshade tools

O presente Artigo Cientifico trata da grande importância e evolucao do pensamento da contabilidade, tendo em foco as escolas e os principais pensadores contabeis de cada epoca e se perceber o quantos pontos principais e fundamentais para se chegar a uma contabilidade com uma unica estrutura. Tendo muitos paises envolvidos com Leis e normas diferenciados, paises de origem anglo saxao como os Inglaterra e Estados Unidos, onde a lei que rege o pais e totalmente desenvolvida por um conjunto de interpretacoes mais o Juiz Tema palavra final (Commom Law) e de outro lado o Brasil, por exemplo, que tem uma norma que se chama Constituicao Federal que rege todo o pais e tudo se faz deve em virtude de lei, ou seja (Code Law), mais nao significa tambem que uma nao precise da outra. Embora a evolucao das escolas contabeis tenha contribuido de forma brilhante a tecnologia tambem foi muito precisa ao longo desses anos. Palavras-Chave: Pensadores contabeis, evolucao.

TIP49a and TIP49b, highly conserved proteins belonging to the AAA + superfamily of DNA dependent ATPases, participate in numerous cell processes, such as chromatin remodeling, regulation of gene transcription and mitotic cell division, maintenance of genome stability, and snoRNP biogenesis, as well as in the formation of active DNA-telomerase complexes. It has been shown that they are involved in com plex networks of protein-protein interactions and, in spite of their structural similarity, sometimes perform opposite functions. Although these proteins exhibit a wide range of activities, the mechanisms of their actions are still poorly understood. In this work, ring shaped heterohexameric TIP49a/b complexes containing in their central channel short fragments of double stranded DNA (dsDNA, 20 base pairs of different GC com position) were obtained for the first time using the molecular docking technique, while methods of molecular dynamics in a periodic water box were applied to investigate the conformational dynamics of these proteins and the mechanisms of their helicase activity. It was found that (1) interaction of a DNA helix with positively charged protein loops inside the central channel of the ring shaped hexameric complex caused unwinding of the helix; (2) the unwinding occurred only inside the hexameric ring, whereas the tails of the helix, which lie outside, retained the initial classical B form conformation throughout the 50 ns of molecular dynamics; and (3) the presence of ATP in TIP49a/b complexes affected the dynamics and the final structure of dsDNA, causing partial breaking of complementary bonds in GC poor DNA sequences.

Reducing nematicide dose rates could be a useful strategy for mitigating their negative effects on health and the environment. In this study, enzymatic activities and the parasitic ability of Meloidogyne incognita after exposure to sub-lethal concentrations (0.25, 1, 2, and 5 ppm) of ethoprophos, fenamiphos, and oxamyl were investigated. Although the tested concentrations did not show nematicidal properties in vitro, they reduced root galls by at least 30% at 0.25 ppm and up to 67% at 5 ppm in pots, besides disrupting nematode fertility. For all three nematicides at 2 ppm, a chemotaxis assay showed that ≤ 11% of the nematode population was successfully oriented to the host roots, compared to 44% in the control. Ethoprophos and fenamiphos at 5 ppm showed poor inhibitory effects on acetylcholinesterase (AChE) activity (5.6% and 12.5%, respectively). In contrast, the same nematicides were shown to be strong ATPase inhibitors, causing 82.4% and 82.8% inhibition, respectively. At the same concentration, oxamyl moderately inhibited AChE and ATPase-specific activities, the inhibition being 22.5% and 35.2%, respectively. This study suggests that the use of very low nematicide concentrations could be a promising strategy for nematode management. Furthermore, it has also highlighted the role of ATPases as a possible target site for suppressing nematode activity in the development of future nematicides. Plant-parasitic nematodes are one of the most damaging plant pests 1. Worldwide annual yield losses due to nematode infection are estimated to be approximately US$157 billion 2. Among several plant parasitic nematodes, root-knot nematodes (Meloidogyne spp.) have an extremely wide host range 3,4 , and are responsible for massive crop losses in okra 5 , cotton 6 , tomato 7 , eggplant 8 , cucumber 9 , sweet potato 10 , and black pepper 11. This made this pest one of the most threatening polyphagous endoparasites found all over the world 12. To manage Meloidogyne spp, a variety of nematicides are used. However, the widespread use of these nematicides may have negative consequences for human health, beneficial organisms, and the environment 13. Thus, using nematicides to manage this pest with a minimal negative impact on the ecosystem may be a positive option. It is imperative to ask whether low levels of nematicides can similarly suppress nematodes as the higher doses do. Concerning this, some researchers have previously reported the potential effects of sublethal nematicide concentrations on the management of nematodes. For example, fluazaindolizine at 5 ppm was found to reduce the Meloidogyne incognita galls and eggs 14 , and fluazaindolizine at 5-10 ppm inhibited Heterodera schatii development inside the roots of Arabidopsis thaliana, without effects on mobility, host recognition, penetration, or the establishment of feeding sites 15. The ED50 (effective doses that caused inactivity for 50% of the population) values for oxamyl, fluensulfone, and fluazaindolizine (180, 131, and 89 ppm respectively) were found to suppress M. incognita reproduction in tomatoes 16. At LC 20 , emamectin benzoate, ivermectin, and milbemycin showed negative effects on the embryonic stages, reduced nematode larval size, development, body length and nematicidal effects on Bursaphelenchus xylophilus 17 .

The structural basis for induction of the mercury resistance operon with inorganic mercury and with the organomercurial compound phenylmercuric acetate was addressed by DNA sequencing analysis and by lac fusion transcription experiments regulated by merR in trans from broad-spectrum-resistance plasmid pDU1358 (Hg2+ and phenylmercury responding). The lac fusion results were compared with those from a narrow- spectrum-resistance (Hg2+ responding but not phenylmercuric responding) operon and the pDU1358 merR deleted at the 3' end. The nucleotide sequence of the beginning region of the broad-spectrum mer operon of plasmid pDU1358 was determined, including that of the merR gene, the operator-promoter region, the merT and merP genes, and the first 60% of the merA gene. Comparison of this sequence with DNA sequences of narrow-spectrum mer operons from transposon TnSOI and plasmid R100 showed that a major difference occurred in the 3' 29 base pairs of the merR gene, resulting in unrelated C-terminal 10 amino acids. A hybrid mer operon consisting of the merR gene from pDU1358, a hybrid merA gene (determining mercuric reductase enzyme), and lacking the merB gene (determining phenylmercury lyase activity) was inducible by both phenylmercury and inorganic Hg2+. This shows that organomercurial lyase is not needed for induction by organomercurial compounds. A mutant form of pDU1358 merR missing the C-terminal 17 amino acids responded to inorganic Hg2' but not to phenylmercury. Thus, the C-terminal region of the MerR protein of the pDU1358 mer operon is involved in the recognition of phenylmercury.

TIP49a and TIP49b, highly conserved proteins belonging to the AAA+ superfamily of DNA dependent ATPases, participate in numerous cell processes, such as chromatin remodeling, regulation of gene transcription and mitotic cell division, maintenance of genome stability, and snoRNP biogenesis, as well as in the formation of active DNA-telomerase complexes. It has been shown that they are involved in complex networks of protein-protein interactions and, in spite of their structural similarity, sometimes perform opposite functions. Although these proteins exhibit a wide range of activities, the mechanisms of their actions are still poorly understood. In this work, ring shaped heterohexameric TIP49a/b complexes containing in their central channel short fragments of double stranded DNA (dsDNA, 20 base pairs of different GC composition) were obtained for the first time using the molecular docking technique, while methods of molecular dynamics in a periodic water box were applied to investigate the conformational dynamics of these proteins and the mechanisms of their helicase activity. It was found that (1) interaction of a DNA helix with positively charged protein loops inside the central channel of the ring shaped hexameric complex caused unwinding of the helix; (2) the unwinding occurred only inside the hexameric ring, whereas the tails of the helix, which lie outside, retained the initial classical B form conformation throughout the 50 ns of molecular dynamics; and (3) the presence of ATP in TIP49a/b complexes affected the dynamics and the final structure of dsDNA, causing partial breaking of complementary bonds in GC poor DNA sequences.

The TIP49a and TIP49b proteins belong to the family of AAA+ ATPases and play essential roles in vital processes such as transcription, DNA repair, snoRNP biogenesis, and chromatin remodeling. We report the crystal structure of a TIP49b hexamer and the comparative analysis of large-scale conformational flexibility of TIP49a, TIP49b, and TIP49a/TIP49b complexes using molecular modeling and molecular dynamics simulations in a water environment. Our results establish key principles of domain mobility that affect protein conformation and biochemical properties, including a mechanistic basis for the downregulation of ATPase activity upon protein hexamerization. These approaches, applied to the lik-TIP49b mutant reported to possess enhanced DNA-independent ATPase activity, help explain how a three-amino acid insertion remotely affects the structure and conformational dynamics of the ATP binding and hydrolysis pocket while uncoupling ATP hydrolysis from DNA binding. This might be similar to the effects of conformations adopted by TIP49 heterohexamers.

Havai iletim hat arızalarının önemli bir kısmı, genellikle yıldırımın şiddetli olduğu bölgelerde gözlemlenmektedir. Yıldırım aşırı gerilimlerinin etkisinin azaltılması için uygulanacak koruma yöntemini belirlemeden önce her bir iletim hattının performansının ayrıntılı olarak değerlendirilmesi gerekmektedir. Bu çalışmada, Türkiye enerji iletim sisteminde kullanılan 154 kV'luk, çift devre, tek koruma hatlı, kafes direkli havai iletim hatlarına direkt yıldırım düşmesi durumu, ATP -EMTP yazılımı kullanılarak analiz edilmiştir. ATP -EMTP simülasyonları, bu tip direk üzerindeki izolatörlerde koruma hattı hatası nedeniyle iletim hattına direkt düşebilecek ve gerilim atlamasına sebep olabilecek minimum (kritik, Ic) ve maksimum yıldırım akımlarını (IMSF) tahmin etmek için kullanılmıştır. Bu minimum ve maksimum yıldırım akımları, iletim hatlarına direkt olarak düşen yıldırım akımları sonucu izolatörlerdeki gerilim atlaması oranının tahmininde ve iletim hatlarının izolasyon koordinasyonu çalışmalarında büyük bir öneme sahiptir. Ayrıca, izolatörlerdeki gerilim atlaması oranının tahmini, transformatörlerden önce yerleştirilen parafudrların arıza durumunda devrede olmamaları hali için de çalışılmıştır.

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Published topological models of the integral membrane a subunit of the vacuolar proton‐translocating ATPase complex have not been in agreement with respect to either the number of transmembrane helices within the integral membrane domain, or their limits and orientations within the lipid bilayer. In the present work we have constructed a predictive model of the membrane insertion of the yeast a subunit, Vph1p, from a consensus of seven topology prediction algorithms. The model was tested experimentally using epitope tagging, green fluorescent protein fusion, and protease accessibility analysis in purified yeast vacuoles. Results suggest that a consensus prediction of eight transmembrane helices with both the amino‐terminus and carboxyl‐terminus in the cytoplasm is correct. Characterization of two glycosylation sites within the homologous mouse a subunit membrane domain further corroborates this topology. Moreover, the model takes into account published data on cytoplasmic and lumina...

Currently, cell biology is based on glucose as the main source of energy. Cellular bioenergetic pathways have become unnecessarily complex in their eagerness to explain that how the cell is able to generate and use energy from the oxidation of glucose, where mitochondria play an important role through oxidative phosphorylation. During a descriptive study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together our findings with the widely accepted metabolic pathways already described in metabolic pathway databases, which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of scientific articles. However, firstly, the literature on metabolism is extensive but rarely conclusive evidence is available, and secondly, one would expect these databases to contain largely the same information, but the contrary is true. For the apparently well studied metabolic process Krebs cycle, which was described as early as 1937 and is found in nearly every biology and chemistry curriculum, there is a considerable disagreement between at least five databases. Of the nearly 7000 reactions contained jointly by these five databases, only 199 are described in the same way in all the five databases. Thus to try to integrate chemical energy from melanin with the supposedly well-known bioenergetic pathways is easier said than done; and the lack of consensus about metabolic network constitutes an insurmountable barrier. After years of unsuccessful results, we finally realized that the chemical energy released through the dissociation of water molecule by melanin represents over 90% of cell energy requirements. These findings reveal a new aspect of cell biology, as glucose and ATP have biological functions related mainly to biomass and not so much with energy. Our finding about the unexpected intrinsic property of melanin to transform photon energy into chemical energy through the dissociation of water molecule, a role performed supposedly only by chlorophyll in plants, seriously questions the sacrosanct role of glucose and thereby mitochondria as the primary source of energy and power for the cells.

This study examined the effects of direct transformer facilities on the network of medium voltage failures that can be caused by parafudr by using regional data and type project modeling. The plant, which is modeled first, has been checked to comply with the relevant regulations and regulations. Konya Eregli region was selected as the working zone in 2018 with 1952 pole type transformer plant and 2187 in 2019. The network worked was modeled with dpPower program and was intended to minimize accrual loss and plant repair costs due to parafudr failures. The total cost of failure, which was 1.370.444,54 ₺, in 2018, increased to 2.024.613,93 ₺ in 2019. Increasing failure costs each year are intended to be minimal after the proposed overhaul. Improvements made after modeling have prevented 88 subscribers from being energy-free from 89 subscribers fed on the line and increased customer satisfaction.

(1997) Efflux mechanisms of resistance to cadmium, arsenic and antimony in prokaryotes and eukaryotes. Zoological Studies 36(1): 1-16. Resistance to toxic metals is ubiquitously found in prokaryotes, both gram positive and gram negative, and in all types of eukaryotes, including fungi, plants, protozoans, and animals. In both prokaryotes and eukaryotes, toxic metals are extruded from cells through efflux transport systems to confer this resistance. Although the chemical substrates recognized by each transport system vary considerably, many heavy metal and metalloid translocating ATPases have been identified by evolutionarily unrelated pumps that have evolved the same function. Among these efflux mechanisms of resistance to heavy metals and metalloids, bacterial cadmium resistance is mediated by a primary transporter while the thiol-linked efflux systems have developed for cadmium resistance in eukaryotes. In contrast, bacterial resistance to arsenicals and antimonials is mediated by a primary ATP-coupled pump in association with a catalytic subunit, whereas an ATP-coupled As-thiol pump has evolved to confer the resistance in eukaryotic systems. The biochemical aspects of the efflux mechanisms related to cadmium, arsenic, and antimony resistance in prokaryotes and eukaryotes are discussed in detail in the present review.

This study describes the identification of the protein target of the first chemical inhibitor (RIP-1) of the 19S regulatory particle (RP) of the 26S proteasome. Periodate-triggered chemical cross-linking of DOPA-conjugated RIP-1 and the 26S proteasome identified Sug2/Rpt4, one of the six ATPases in the 19S RP as the molecular target of RIP-1. The specificity of RIP-1 for Sug2/Rpt4 was demonstrated by examining cross-linking reactions with each ATPase of the 19S RP. RIP-1 should provide a useful biological tool to probe the various biological roles of Rpt4. We recently reported the first 19S RP inhibitor, called RIP-1 (Regulatory Particle Inhibitor Peptoid-1) (Figure 1). 13 RIP-1 was isolated from a combinatorial library of approximately 33,000 peptoids, all of which were capped with a purine molecule in an attempt to bias the library towards binding one or more of the six ATPases in the 19S RP. It was demonstrated that RIP-1 inhibited the protein unfolding activity of the 19S RP in vitro and blocked proteasome-mediated turnover of the cell cycle protein p27 in HeLa cells. In this report, we describe experiments designed to identify the molecular target of RIP-1. RIP-1 was identified originally in a screen that registered binding of the peptoid to the intact 26S proteasome, which contains at least 34 different polypeptides. 13 To identify the RIP-1 receptor, we used a chemical cross-linking reaction that involves the oxidation of a

Copper (Cu) is an essential, yet potentially toxic nutrient, as illustrated by inherited diseases of copper deficiency and excess. Elevated expression of the ATP7A Cu exporter is known to confer copper tolerance, however, the contribution of metal-binding metallothioneins is less clear. In this study, we investigated the relative contributions of ATP7A and the metallothioneins MT-I and MT-II to cell viability under conditions of Cu excess or deficiency. Although the loss of ATP7A increased sensitivity to low Cu concentrations, the absence of MTs did not significantly affect Cu tolerance. However, the absence of all three proteins caused a synthetic lethal phenotype due to extreme Cu sensitivity, indicating that MTs are critical for Cu tolerance only in the absence of ATP7A. A lack of MTs resulted in the trafficking of ATP7A from the trans-Golgi complex in a Cu-dependent manner, suggesting that MTs regulate the delivery of Cu to ATP7A. Under Cu deficiency conditions, the absence of M...

Elektrik tesislerinde kullanılan porselen izolatörler, sistemin sağlıklı bir şekilde çalışması ve malzeme izolasyonunun mükemmel bir şekilde sağlanması açısından oldukça önemli malzemelerdir. İzolatör yapımında hammadde olarak kullanılan materyallerin özellikleri, bununla birlikte çevresel faktörler, izolatör dayanımını ve faaliyetini etkileyen faktörlerdir. Bu çalışmada, çevresel etkiler ve porselen izolatör yapımında kullanılan malzemeler incelenmiş, bunların izolasyona ve sistemin sağlıklı bir şekilde çalışmasına olan tesirleri araştırılmıştır.

Pulsasyonlu yüksek frekanslı elektromagnetik akımların kırık iyi leşmesi üzerine etkileri 20 tavşan fibulasında araştırıldı. 5'i kontroL. 5'i deney grubundan olmak üzere 10 tavşanın sol fibulasına osteotomi yapıldı. Herhangi bir fiksasyan yöntemi uygulanmadı. Kontrol grubu kendi halinde iyileşmeye bırakılırken. deney grubundaki tavşanlara 28 gün süre ile her gün 15 dakika tedavi yapıldı. Pulsasyonlu yüksek

Pulsasyonlu yüksek frekanslı elektromagnetik akımların kırık iyi leşmesi üzerine etkileri 20 tavşan fibulasında araştırıldı. 5'i kontroL. 5'i deney grubundan olmak üzere 10 tavşanın sol fibulasına osteotomi yapıldı. Herhangi bir fiksasyan yöntemi uygulanmadı. Kontrol grubu kendi halinde iyileşmeye bırakılırken. deney grubundaki tavşanlara 28 gün süre ile her gün 15 dakika tedavi yapıldı. Pulsasyonlu yüksek

Mitochondrial antiviral signaling (MAVS) protein is required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling cascades, but the underlying structural mechanism is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N-terminal caspase activation and recruitment domain (CARD) of MAVS and a truncated MAVS lacking part of the proline-rich region and the C-terminal transmembrane domain. Both structures are left-handed three-stranded helical filaments, revealing specific interfaces between individual CARD subunits that are dictated by electrostatic interactions between neighboring strands and hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments.

The aim of this study was to investigate the association between metabolic syndrome (MetS) and the metabolic indicators of masticatory muscles in an animal model. A total of 16 male Wistar rats were used. To induce MetS, 10 rats were fed with standard rat chow and 32% sucrose solution ad libitum for 16 wk. Six rats fed with standard rat chow and water ad libitum formed the control group. All rats were killed at week 16, and the right superficial masseter muscles were harvested. Metabolic indicators of masticatory muscle metabolism, including antioxidant enzyme activities, ion transport ATPase activities, and the levels of macro and trace elements, were determined in the muscles. Superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities were significantly decreased by 32%, 26%, 33%, and 16%, respectively, in the MetS group. Na + /K +-ATPase activity was significantly decreased in the MetS group by 54% compared with the control group. The levels of chromium and selenium were significantly decreased, and the level of copper was increased, in the MetS group compared with the control group. These results show that significant alterations occurred in antioxidant defense mechanisms, ion transport mechanisms, and trace element levels of masseter muscles in MetS.

Widespread use of various antimicrobial agents resulted in the emergence of bacterial resistance. Mechanisms like direct efflux, formation, and sequestration of metals and drugs in complexes and antiporter pumps are some examples. This investigation aims to investigate the resistance pattern of penicillin-resistant bacterial strains to some physicochemical agents. Sensitivity/resistance pattern of common bacterial strains to antimicrobial agents were evaluated by disk diffusion assay. Broth and agar dilution method were used for determination of minimum inhibitory concentration and minimal bactericidal concentration. The impact of UV ray on the bacterial growth under laminar flow hood was measured using photonmeter. Our data demonstrates that the most prevalent metal resistance was against arsenate (95.92%), followed by cadmium (52.04%) and mercury (36.73%). There was significant difference between cetrimide resistances among studied microbial strains especially for P. aeruginosa ()...

This study examined the effects of direct transformer facilities on the network of medium voltage failures that can be caused by parafudr by using regional data and type project modeling. The plant, which is modeled first, has been checked to comply with the relevant regulations and regulations. Konya Eregli region was selected as the working zone in 2018 with 1952 pole type transformer plant and 2187 in 2019. The network worked was modeled with dpPower program and was intended to minimize accrual loss and plant repair costs due to parafudr failures. The total cost of failure, which was 1.370.444,54 ₺, in 2018, increased to 2.024.613,93 ₺ in 2019. Increasing failure costs each year are intended to be minimal after the proposed overhaul. Improvements made after modeling have prevented 88 subscribers from being energy-free from 89 subscribers fed on the line and increased customer satisfaction.

O que é Contabilidade, para que serve, qual o ponto de partida para entendê-la e como aplicá-la na minha empresa ou na empresa em que irei trabalhar? Essas são algumas questões para as quais você certamente gostaria de obter respostas. Nossa proposta é oferecer um material didático que lhe possibilite assimilar com facilidade todo o mecanismo que envolve a Ciência Contábil, mesmo que você nunca a tenha estudado. Nos cursos regulares, você encontra várias matérias para estudar: Matemática, Língua Portuguesa, Geografia, História, Sociologia, Filosofia e outras. Dentre as matérias que você estuda, algumas não exigem concentração permanente, pois em certos casos, a compreensão de determinado capítulo independe de conhecimentos anteriores. Com a Contabilidade é diferente. Não que seja mais difícil, porém, a compreensão de cada aula é necessária para que você consiga acompanhar as aulas seguintes. A meta principal deste livro é ensinar todo o processo de contabilização, dando-lhe condições para conhecer e elaborar as Demonstrações Contábeis, dentre elas o Balanço Patrimonial. O que é Balanço Patrimonial? Se você nunca estudou Contabilidade, dificilmente saberá responder a essa pergunta. Entretanto, esse conceito não pode ser explicado agora. Veja por quê: Vamos comparar este curso com uma escada. No ápice está o Balanço Patrimonial. Cada degrau dessa escada representa um capítulo do livro. Vamos conduzi-lo até o ponto máximo, partindo do marco zero, conforme dissemos, considerando que você nunca tenha estudado Contabilidade. Assim, progressivamente, a cada linha, parágrafo, Seção ou Capítulo, acrescentaremos novas informações de modo que, ao passar para o capítulo seguinte, você tenha adquirido a base necessária para entendê-lo com facilidade. Porém, é preciso que você estude muito bem toda a parte teórica, lendo com atenção as notas, as observações e, inclusive, as notas de rodapé. Os assuntos foram organizados obedecendo à sequência lógica que a disciplina exige, permitindo que você, a todo instante, esteja em sintonia com a matéria. Acho que já deu para você perceber que há necessidade de manter um controle do seu Patrimônio, e é exatamente aí que a Contabilidade entra em cena. Mediante o conhecimento e a aplicação de técnicas contábeis, você poderá ter um controle permanente e eficiente da gestão do Patrimônio da sua empresa, obtendo informações econômicas, financeiras ou de outra natureza, no momento em que precisar. NOTAS: Para facilitar o entendimento da matéria, considere a empresa, objeto de estudo, como se fosse sua. Assim, quando a empresa compra, pense: eu compro; quando a empresa vende, pense: eu vendo, e assim por diante. Você aprendeu até aqui que Capital é uma importância em dinheiro com a qual uma pessoa constitui uma empresa. Porém, o Capital Inicial de qualquer empresa poderá ser formado também por outros elementos, como casa, carro, móveis, equipamentos etc. Portanto, o Capital de uma empresa poderá ser constituído somente por dinheiro, ou por dinheiro e outros Bens conjuntamente. Antes de entrarmos na contabilização propriamente dita, é necessário que você conheça alguns conceitos básicos, sem os quais ficará difícil o entendimento da matéria. Sendo assim, para se situar bem no assunto, você deve estudar com atenção os primeiros capítulos, que são importantíssimos. 1.2 O desafio da terminologia A terminologia é um dos desafios enfrentados pelos que iniciam o estudo da Contabilidade, pois pode, num primeiro momento, dificultar o entendimento da matéria. Na Língua Portuguesa, encontramos palavras que, dependendo do ponto de vista em que são consideradas, assumem significados diversos. A palavra ativo, por exemplo, poderá significar coisas diferentes, dependendo do setor de atuação de cada pessoa. Há casos em que dezenas de palavras podem ser utilizadas para significar a mesma coisa. Por exemplo, de acordo com o dicionário Novo Aurélio da Língua Portuguesa-Século XXI (São Paulo, Nova Fronteira, 1999), há mais de 20 maneiras diferentes de se dizer "ideia". Assim, é comum encontrarmos, em toda profissão, um conjunto de palavras cujo significado seja específico para aquela área de trabalho. A Contabilidade também possui linguagem própria e, em muitos casos, alguns termos, palavras ou expressões coincidem com termos, palavras ou expressões de nossa linguagem comum. Ocorre, porém, que nem sempre significam a mesma coisa. As palavras que mais perturbam o estudante, principalmente o principiante no estudo da Contabilidade, são débito e crédito. A palavra débito, na nossa linguagem comum, significa situação negativa, desfavorável; ou saldo negativo na conta-corrente bancária; ou estar em falta com alguém etc. Na terminologia contábil, essa palavra poderá ter esses mesmos significados ou até mesmo assumir uma situação positiva. A palavra crédito, na nossa linguagem cotidiana, poderá representar situação positiva, favorável; ou saldo positivo na conta-corrente bancária; ou ter crédito no mercado (possibilidade de poder comprar a prazo) etc. Na terminologia contábil, essa palavra poderá adquirir esses mesmos significados ou até mesmo corresponder à situação negativa. Não é fácil para o principiante no estudo da Contabilidade concordar que em determinado momento a palavra débito seja utilizada para significar algo positivo, favorável, uma vez que, em sua vida diária, essa palavra nunca assume esse significado. Portanto, para que você possa entender com facilidade não só o mecanismo do débito e do crédito, bem como todo o processo contábil, é preciso ter consciência de que algumas palavras, termos ou expressões utilizados no seu dia a dia, podem ter significados diferentes quando utilizados pela Ciência Contábil. Veja outros exemplos de termos, palavras e expressões que fazem parte da terminologia contábil, os quais mencionamos na Seção anterior, quando supostamente constituímos a sua empresa para comercializar calçados: empresa, Capital, estabelecimento, imóvel, ponto comercial, legalização da empresa, personalidade jurídica, pessoa física, pessoa jurídica, livros fiscais, talonários de Notas Fiscais, Móveis e Utensílios, Mercadorias, Compras à vista, Compras a prazo, Vendas à vista, Vendas a prazo, Obrigações, Direitos, saldos, estoque, lucro, prejuízo, gestão, Patrimônio, Fornecedores, Clientes, terceiros, Fatos Administrativos, Atos Administrativos etc. Se, no decorrer dos seus estudos, você encontrar alguma dificuldade para entender alguma explicação, procure verificar se o problema não está no significado de palavras, termos ou expressões técnicas que fazem parte da terminologia contábil. Procure analisar o significado de tais palavras a partir do contexto do tema em estudo. Para facilitar e orientar seus estudos, sempre que palavras ou expressões que integram a terminologia contábil forem apresentadas no texto, serão devidamente explicadas, e você não encontrará dificuldade para entender o significado de cada uma delas. 1.3 Conceito A Contabilidade é uma ciência que possibilita, por meio de suas técnicas, o controle permanente do Patrimônio das empresas. Sobre este conceito, poderão ocorrer indagações como: • O que é Patrimônio? • O que é empresa? Patrimônio: no exemplo que apresentamos no início deste capítulo (empresa para comercializar calçados), o Patrimônio era composto por dinheiro, balcões, vitrinas, prateleiras, máquina registradora, Mercadorias, enfim, pelo conjunto dos elementos necessários à sua existência. (No Capítulo 2, você encontrará maiores detalhes sobre Patrimônio.) Empresa: é uma unidade de produção, resultante da combinação dos três fatores da produção (natureza, trabalho e Capital) e constituída para o desenvolvimento de uma atividade econômica. A principal finalidade da Contabilidade é fornecer informações sobre o Patrimônio, informações essas de ordem econômica e financeira, que facilitam as tomadas de decisões, tanto por parte dos administradores ou proprietários como também por parte daqueles que pretendem investir na empresa. Instituições: são entidades econômico-administrativas com finalidades sociais e socioeconômicas. As com objetivos sociais são aquelas cuja administração tem por objetivo o bemestar social da coletividade, como as associações recreativas e esportivas, os hospitais beneficentes, os asilos etc.; as com finalidades socioeconômicas são aquelas cuja administração tem interesse no aspecto econômico da entidade, porém este reverte em benefício da coletividade a que pertencem. São exemplos os institutos de aposentadorias, pensões, previdência etc. Empresas: são entidades econômico-administrativas que têm finalidade econômica, isto é, visam ao lucro. Desenvolvem os mais variados ramos de atividades, como comércio, indústria, agricultura, pecuária, transporte, telecomunicações, turismo e uma infinidade de serviços. Quanto à natureza do Capital com que são constituídas, as empresas podem ser públicas, privadas e mistas. São públicas aquelas constituídas com Capital do Governo. São privadas (particulares) aquelas constituídas com Capital de particulares. São mistas aquelas constituídas com Capital do Governo e de particulares. Certamente você já ouviu falar em empresas, firmas, lojas, casas comerciais, clubes de futebol, indústrias, escolas, cinemas, teatros, lanchonetes etc. Há uma infinidade de entidades econômicoadministrativas que o ser humano constitui para atingir algum objetivo, seja de ordem econômica, seja social. Você pode imaginar vários tipos de organizações: instituições governamentais; empresas públicas, particulares e mistas; instituições com finalidades sociais ou socioeconômicas. Todas elas devem ser adequadamente organizadas e bem controladas para que possam atingir seus objetivos da melhor maneira possível. Esses controles são efetuados, como vimos, pela Contabi lidade, por meio de suas técnicas. Esse é o campo de aplicação da Contabilidade. Os usuários da Contabilidade, portanto, são todas as entidades econômico-administrativas que a utilizam...

Copper is prevalent in coastal ecosystems due to its use as an algaecide and as an anti-fouling agent on ship hulls. Alteromonas spp. have previously been shown to be some of the early colonizers of copper-based anti-fouling paint but little is known about the mechanisms they use to overcome this initial copper challenge. The main models of copper resistance include the Escherichia coli chromosome-based Cue and Cus systems; the plasmid-based E. coli Pco system; and the plasmid-based Pseudomonas syringae Cop system. These were all elucidated from strains isolated from copper-rich environments of agricultural and/or enteric origin. In this work, copper resistance assays demonstrated the ability of Alteromonas macleodii strains CUKW and KCC02 to grow at levels lethal to other marine bacterial species. A custom database of Hidden Markov Models was designed based on proteins from the Cue, Cus, and Cop/Pco systems and used to identify potential copper resistance genes in CUKW and KCC02. C...

Hak dan Kewajiban merupakan sesuatu yang tidak dapat dipisahkan, akan tetapi terjadi pertentangan karena hak dan kewajiban tidak seimbang. Bahwa setiap warga negara memiliki hak dan kewajiban untuk mendapatkan penghidupan yang layak, tetapi pada kenyataannya banyak warga negara yang belum merasakan kesejahteraan dalam menjalani kehidupannya. Semua itu terjadi karena pemerintah dan para pejabat tinggi lebih banyak mendahulukan hak daripada kewajiban. Padahal menjadi seorang pejabat itu tidak cukup hanya memiliki pangkat akan tetapi mereka berkewajiban untuk memikirkan diri sendiri. Jika keadaannya seperti ini, maka tidak ada keseimbangan antara hak dan kewajiban. Jika keseimbangan itu tidak ada akan terjadi kesenjangan sosial yang berkepanjangan.

The first chemical inhibitor of the 19S Regulatory Particle (RP) of the proteasome is described. The molecule was identified by screening a library of nucleoside-capped peptoids for binding to the yeast 26S proteasome in a crude extract. The hit was resynthesized and shown to block 19S RP-mediated protein unfolding in vitro and proteasome-mediated turnover of p27 in HeLa cells. The 26S proteasome is an approximately 2.5 MDa multicatalytic protease complex that is responsible for most non-lysosomal protein degradation in eukaryotic cells. It is composed of a barrel-like catalytic 20S core particle (CP) that consists of four stacked hetero-heptameric rings capped on each side by a 19S regulatory particle (RP) (Fig. 1) 1 , which contains a putative heterohexameric ring of ATPases (Rpt1-6) as well as several other proteins. The RP binds polyubiquitylated proteins, unfolds them, and feeds the polypeptide chain into the interior of the barrel where the proteins are degraded into small peptides 2. Inhibition of the 20S CP proteolytic activity has emerged as an attractive pharmacological target for cancer and inflammatory diseases 3,4 as well as useful as mechanistic probes of proteasome function in a variety of biological processes 3. Recently, a number of pioneering studies have revealed that stimulating proteasome-mediated proteolysis is but one of several activities of the Rpt proteins. It is now clear that these ATPases play non-proteolytic roles in RNA polymerase II transcription, DNA repair, structural modification of chromatin and other nuclear processes 5-10. Therefore, pharmacological inhibitors of the proteasomal ATPases (Rpts) would be of great interest. Here we report the isolation of the first compound of this type from a library of nucleoside-capped peptoids. We show that this peptoid derivative inhibits the protein unfolding activity of the Rpt proteins in vitro and inhibits the proteasome activity in living cells. A "one bead one compound" peptoid library was constructed by split and pool synthesis (see Supp. Mat. Fig. S1) 11. Each peptoid molecule was capped with a purine analogue (Fig. 2A) in hope of biasing the library towards targeting one of the ATPases. The theoretical diversity of the library was 8 5

Currently, cell biology is based on glucose as the main source of energy. Cellular bioenergetic pathways have become unnecessarily complex in their eagerness to explain that how the cell is able to generate and use energy from the oxidation of glucose, where mitochondria play an important role through oxidative phosphorylation. During a descriptive study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together our findings with the widely accepted metabolic pathways already described in metabolic pathway databases, which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of scientific articles. However, firstly, the literature on metabolism is extensive but rarely conclusive evidence is available, and secondly, one would expect these databases to contain largely the same information, but the contrary is true. For the apparently well studied metabolic process Krebs cycle, which was described as early as 1937 and is found in nearly every biology and chemistry curriculum, there is a considerable disagreement between at least five databases. Of the nearly 7000 reactions contained jointly by these five databases, only 199 are described in the same way in all the five databases. Thus to try to integrate chemical energy from melanin with the supposedly well-known bioenergetic pathways is easier said than done; and the lack of consensus about metabolic network constitutes an insurmountable barrier. After years of unsuccessful results, we finally realized that the chemical energy released through the dissociation of water molecule by melanin represents over 90% of cell energy requirements. These findings reveal a new aspect of cell biology, as glucose and ATP have biological functions related mainly to biomass and not so much with energy. Our finding about the unexpected intrinsic property of melanin to transform photon energy into chemical energy through the dissociation of water molecule, a role performed supposedly only by chlorophyll in plants, seriously questions the sacrosanct role of glucose and thereby mitochondria as the primary source of energy and power for the cells.

TEİAŞ'a ait 400 kV transformatör merkezlerinde (TM) dağıtıma giden fiderlerde yaşanan kesintili toprak arızaları sırasında açığa çıkan aşırı gerilimler sonucunda parafudrlar termal strese dayanamayıp kalıcı hasarlar görmektedir. Bu kapsamda TEİAŞ'a ait bir 400 kV TM PSCAD üzerinde modellenmiş, kesintili toprak arızaları sırasında parafudrlar üzerinde biriken enerji seviyeleri incelenerek bu tür arızalara karşı parafudr seçimi yapılırken dikkat edilmesi gereken hususlar belirlenmiştir.

Metallothioneins (MTs) are low molecular weight, cysteine-rich, metal-binding proteins, which are proposed to have roles in essential trace metal homoeostasis and in the detoxification of metal ions. The genes encoding MTs have been isolated fi-om a wide range of eukaryotes, although MT genes have not previously been isolated fi-om prokaryotes. The polymerase chain reaction (PGR) was initially used to isolate a prokaryotic MT gene fi-agment from Synechococcus PCC 6301. PGR fragments were amplified using inosine-containing primers designed from the amino acid sequence of a prokaryotic MT. Subsequent cloning and nucleotide sequence analysis revealed that the deduced amino acid sequence of the PGR product corresponded to the amino acid sequence of the prokaryotic MT. The amplified product was thus part of the gene encoding the MT, and was designated smtA. The same primers used in the initial amplification were subsequently utilised for anchored PGR, to amplify the remainder of the coding region and the 3' and 5' flanking regions of the smtA gene. A genomic library was produced from Synechococcus PGG 7942 DNA and screened using the PGR products described above as probes. A genomic clone was isolated, nucleotide sequence analysis revealed the structure of the smt locus, two open reading frames, smtA and smtB, arranged in a divergent orientation about the smt operator/promoter region. The operator/promoter region contains the transcriptional and translational signals for the two genes and three regions that are candidate sites for interaction of regulatory proteins. The transcript start sites of the two genes were mapped within the operator/promoter region by primer extension analysis. An increase in the relative abundance of transcripts of both smt genes was studied in response to various metal ions in a series of northern blots. Inhibitor studies confirmed that the smtA gene is regulated at the transcriptional level. The 5' flanking region of the smtA gene conferred metal specific induction of the reporter gene lacZ. SmtB has sequence similarity to several prokaryotic regulatory proteins and contains a putative helix-turn-helix structural domain. Deletion analysis suggests that SmtB is a repressor of smtA expression. Subsequent work has confirmed that SmtB is a /ra«5-acting repressor of expression from the smt operator/promoter.

Günümüzde seri kapasitörler uzun iletim hatlarında, kayıpların azaltılması ve transfer kapasitesinin artırılmasında sıklıkla kullanılmaktadır. Kapasitörler aynı zamanda şebekenin gerilim kararlılığının iyileştirilmesinde de önemli rol oynamaktadır. Sağladığı bu olumlu katkıların yanında seri kapasitörlerin bulundukları hattaki mesafe koruma rölelerinin çalışmasını olumsuz yönde etkilediği bilinmektedir. Bu çalışmada seri kapasitör bulunan şebekelerde arıza yerinin tespiti için k-EYK sınıflandırma yöntemi kullanılarak geniş bölge izleme tabanlı bir koruma algoritması önerilmiştir. Algoritmanın testi Digsilent Power Factory programında oluşturulan radyal şebekede yapılmıştır. Test için oluşturulan kısa devre senaryolarında farklı arıza empedansları altında 3-faz dengeli ve tek-faz toprak arızaları analiz edilmiştir. Elde edilen sonuçlara göre önerilen algoritmanın hatların belirli noktalarında oluşturulan kısa devrelerde arızalı hattı doğru bir şekilde tespit edebildiği görülmüştür. Ç...

Bu çalışmada, IEEE 1584 standardı esas alınarak yüksek gerilim (YG) şebekeleri anahtarlama tesislerinde ortaya çıkabilecek ark patlaması enerji düzeyi hesaplamaları yapılmıştır. Neplan güç sistemi analiz yazılım programı ile oluşturulan örnek şebeke modeli üzerinde farklı arıza parametreleri kullanılarak ark patlaması analizleri gerçekleştirilmiştir. Bulunan sonuçlara göre personel güvenliğinin sağlanması amacıyla ark patlaması tehlike etiketleri, güvensiz çalışma bölgeleri ve NFPA 70E standardına bağlı olarak kullanılması gereken kişisel koruyucu donanımlar (KKD'ler) belirlenmiştir.

Nanosaniyelik darbeler, EMP (ElektroManyetik Darbe) yoluyla oluşabilir. EMP uzayda doğal yolla meydana gelebileceği gibi yapay yolla da oluşturulabilir. Yüksek irtifada meydana gelen bir EMP, çok geniş alanları etkisi altında bırakabilir. EMP'nin en önemli bozucu etkisi, elektronik sistemlerin ve cihazların iletkenlerine girişimde bulunarak bunların içine ulaşması ve sistem veya aygıtların bozulmasına ya da yanlış çalışmasına neden olmasıdır. EMP benzeri darbe gerilimleri genel olarak nanosaniye süreli darbelerdir. Cihazların böyle darbeler karşısındaki davranışlarını incelemek için yapay EMP üreteçleri kullanılır. Bu üreteçler EMP'nin oluşturduğu elektrik ve manyetik alanları üretirler. Bu çalışma kapsamında EMP benzeri nanosaniyelik darbelerin aygıtların iletkenlerine ve elektronik kartlarına ulaşmaları durumunda meydana gelebilecek olaylar değerlendirilmiştir. Bu amaçla, yaklaşık 50 nanosaniyede tepe değerine ulaşan ve toplamda yaklaşık 1000 nanosaniye süren 10 kV'a kadar darbe gerilimi üreten bir üreteç tasarlanmış ve gerçeklenmiştir. Üreteç tek katlı Marx devresi ilkesi ile çalışmaktadır. Elektronik aygıtların devre kartlarını benzetmek için elektronik devrelerde sıkça karşılaşılan yedi farklı geometride akım yolu FR-4 malzemeden yapılmış devre kartına hazırlanmıştır. Darbe gerilimi üretecinden elde edilen gerilimlerle akım yolları arasındaki boşalma olayları incelenmiştir. Numune akım yollarında geometriye bağlı olarak boşalma noktaları belirlenmiş, uygulanan gerilimler ile elektrotların yüzde elli atlama eğrileri çıkarılmıştır. Yapılan deneysel çalışma, teorik hesaplamalar ile desteklenmiştir. Bunun için sonlu elemanlar yöntemi ile bilgisayar analizi yapılmıştır. Bu çalışma ile nanosaniyelik darbe gerilimine maruz kalan elektronik kartlarda geometriye bağlı olarak etkilenme üzerine yorum yapılmıştır.

A 25.9-kb plasmid, pXU5, encoding high level cadmium resistance was isolated from Staphylococcus aureus strain ATCC25923. A labelled cadA probe from plasmid pI258 hybridised to a 2.3-kb EcoRI fragment of pXU5. pXU5 was incompatible with an S. aureus incompatibility group 1 plasmid.

Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance, a phenomenon not entirely understood, with contribution of drug detoxification, defective accumulation, and efflux from the cell. Downregulation of CTR1, responsible for Cu uptake by the cell, and up-regulation of the Cu-ATPases, ATP7A and ATP7B, which accept Cu from the cytosolic chaperone Atox1 and transfer the metal ion into the secretory pathway where it is incorporated into cuproenzymes, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, adsorbed on a solid supported ** We thank the Universities of Bari and Florence, the Ente Cassa di Risparmio di Firenze, the Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB),

Metalloregulators of the MerR family activate transcription upon metal binding by underwinding the operator-promoter DNA to permit open complex formation by pre-bound RNA polymerase. Historically, MerR's allostery has been monitored only indirectly via nuclease sensitivity or by fluorescent nucleotide probes and was very specific for Hg(II), although purified MerR binds several thiophilic metals. To observe directly MerR's ligand-induced behavior we made 2-fluorotyrosine-substituted MerR and found similar, minor changes in 19 F chemical shifts of tyrosine residues in the free protein exposed to Hg(II), Cd(II) or Zn(II). However, DNA binding elicits large chemical shift changes in MerR's tyrosine residues and in DNAbound MerR Hg(II) provokes changes very distinct from those of Cd(II) or Zn(II). These chemical shift changes and other biophysical and phenotypic properties of wild-type MerR and relevant mutants reveal elements of an allosteric network that enables the coordination state of the metal binding site to direct metal-specific movements in the distant DNA binding site and the DNA-bound state also to affect the metal binding domain.

Copper is prevalent in coastal ecosystems due to its use as an algaecide and as an anti-fouling agent on ship hulls. Alteromonas spp. have previously been shown to be some of the early colonizers of copper-based anti-fouling paint but little is known about the mechanisms they use to overcome this initial copper challenge. The main models of copper resistance include the Escherichia coli chromosome-based Cue and Cus systems; the plasmid-based E. coli Pco system; and the plasmid-based Pseudomonas syringae Cop system. These were all elucidated from strains isolated from copper-rich environments of agricultural and/or enteric origin. In this work, copper resistance assays demonstrated the ability of Alteromonas macleodii strains CUKW and KCC02 to grow at levels lethal to other marine bacterial species. A custom database of Hidden Markov Models was designed based on proteins from the Cue, Cus, and Cop/Pco systems and used to identify potential copper resistance genes in CUKW and KCC02. C...

Bacterial resistance to Ag(I) has been reported periodically with isolates from many environments where toxic levels of silver might be expected to occur, but initial reports were limited to the occurrence of resistant bacteria. The availability of silver-resistance conferring DNA sequences now allow genetic and mechanistic studies that had basically been missing. The genes determining Ag(I) resistance were sequenced from a plasmid found in a burn ward isolate. The 14.2 kb determinant contains seven recognized genes, arranged in three mRNA transcriptional units. The silE gene determines an extracellular (periplasmic space) metal-binding protein of 123 amino acids, including ten histidine residues implicated in Ag(I) binding. SilE is homologous to PcoE, of copper resistance. The next two genes, silR and silS, determine a two protein, histidine-kinase membrane sensor and aspartyl phosphate transcriptional responder, similar to other two component systems such as CzcR and CzcS (for cad...

Human ATP-dependent Lon protease (LONP1) forms homohexameric, ring-shaped complexes. Depletion of LONP1 causes aggregation of a broad range of proteins in the mitochondrial matrix and decreases the levels of their soluble forms. The ATP hydrolysis activity, but not protease activity, of LONP1 is critical for its chaperone-like anti-aggregation activity. LONP1 forms a complex with the import machinery and an incoming protein, and protein aggregation is linked with matrix protein import. LONP1 also contributes to the degradation of imported, aberrant, unprocessed proteins using its protease activity. Taken together, our results show that LONP1 functions as a gatekeeper for specific proteins imported into the mitochondrial matrix.

Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270þ4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPR mt) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome. More than 400 syndromic forms of deafness have been defined. 1 The specific genes causing some of these conditions have been identified, providing important insights into the molecular pathways and structures impaired in sensorineural hearing loss (SNHL). 2 Perrault syndrome (MIM 233400) is an autosomal-recessive disorder characterized by SNHL and premature ovarian failure (POF) secondary to ovarian dysgenesis. 3 It is clinically and genetically heterogeneous. 4,5 A spectrum of additional clinical features, including cerebellar ataxia, learning disability, and peripheral neuropathy, have been described in some affected individuals. 5-7 Mutations in two genes, HSD17B4 (MIM 601860), encoding D-bifunctional protein (DBP), and HARS2 (MIM 600783), encoding mitochondrial histidyl-tRNA synthetase, have been identified as underlying causes of Perrault syndrome, 8,9 but these genes do not account for all cases of this heterogeneous condition. 5,8,9 In our studies of hereditary deafness and Perrault syndrome, written informed consent was obtained from all participants after approval from the University of Manchester (reference 06138

The aim of this study was to investigate the association between metabolic syndrome (MetS) and the metabolic indicators of masticatory muscles in an animal model. A total of 16 male Wistar rats were used. To induce MetS, 10 rats were fed with standard rat chow and 32% sucrose solution ad libitum for 16 wk. Six rats fed with standard rat chow and water ad libitum formed the control group. All rats were killed at week 16, and the right superficial masseter muscles were harvested. Metabolic indicators of masticatory muscle metabolism, including antioxidant enzyme activities, ion transport ATPase activities, and the levels of macro and trace elements, were determined in the muscles. Superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities were significantly decreased by 32%, 26%, 33%, and 16%, respectively, in the MetS group. Na + /K +-ATPase activity was significantly decreased in the MetS group by 54% compared with the control group. The levels of chromium and selenium were significantly decreased, and the level of copper was increased, in the MetS group compared with the control group. These results show that significant alterations occurred in antioxidant defense mechanisms, ion transport mechanisms, and trace element levels of masseter muscles in MetS.

Se identificó y describió los principales determinantes genéticos implicados en la resistencia bacteriana a metales pesados reportados en la literatura, así como sus usos a nivel biotecnológico y ambiental. Se llevó a cabo una revisión bibliográfica de información de los últimos 10 años encontrados en revistas con indexación SJR disponibles en las diferentes bases de datos; bosquejando la situación actual del conocimiento sobre el tema y realizando comparaciones cualitativas entre las investigaciones seleccionadas. Las bacterias se encuentran en constante evolución y se vuelven más resistentes gracias a la adquisición de genes que les permite hacer frente a los efectos tóxicos de los metales. Por ello, se compiló desde varios autores los determinantes genéticos de resistencia bacteriana para los metales, como el arsénico, mercurio, cromato y cadmio siendo respectivamente: ars, mer, chr, cad y czc; estos sistemas pueden localizarse en el cromosoma o plásmidos de las bacterias. Se des...