Delayed presentation of pacemaker Reel Syndrome and lead damage: Coincidence or consequence?

Reel syndrome is a pacemaker lead early dislodgment, characterized by reeling-in of the lead(s) without being damaged. We herein present a case of an 86-year-old woman, with medical history of single chamber pacemaker implantation two years ago, admitted in cardiology department with complete AV block. Chest-Xray revealed ventricular lead coiling around and behind the pacemaker device. Urgent extraction of the previous pacemaker was performed; however, the lead damage made its repositioning unfeasible. Successful implantation of single-chamber pacemaker has been made. This clinical case highlights the importance of adequate follow-up to timely identify lead dislodgement, avoid lethal complications and lead fracture.     

Role of Direct Repeat and Stem-Loop Motifs in mtDNA Deletions: Cause or Coincidence?

Deletion mutations within mitochondrial DNA (mtDNA) have been implicated in degenerative and aging related conditions, such as sarcopenia and neuro-degeneration. While the precise molecular mechanism of deletion formation in mtDNA is still not completely understood, genome motifs such as direct repeat (DR) and stem-loop (SL) have been observed in the neighborhood of deletion breakpoints and thus have been postulated to take part in mutagenesis. In this study, we have analyzed the mitochondrial genomes from four different mammals: human, rhesus monkey, mouse and rat, and compared them to randomly generated sequences to further elucidate the role of direct repeat and stem-loop motifs in aging associated mtDNA deletions. Our analysis revealed that in the four species, DR and SL structures are abundant and that their distributions in mtDNA are not statistically different from randomized sequences. However, the average distance between the reported age associated mtDNA breakpoints and their respective nearest DR motifs is significantly shorter than what is expected of random chance in human (p<10(-4)) and rhesus monkey (p = 0.0034), but not in mouse (p = 0.0719) and rat (p = 0.0437), indicating the existence of species specific difference in the relationship between DR motifs and deletion breakpoints. In addition, the frequencies of large DRs (>10 bp) tend to decrease with increasing lifespan among the four mammals studied here, further suggesting an evolutionary selection against stable mtDNA misalignments associated with long DRs in long-living animals. In contrast to the results on DR, the probability of finding SL motifs near a deletion breakpoint does not differ from random in any of the four mtDNA sequences considered. Taken together, the findings in this study give support for the importance of stable mtDNA misalignments, aided by long DRs, as a major mechanism of deletion formation in long-living, but not in short-living mammals.     

HLA-C and HIV-1: friends or foes?

The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins.     

RPA and POT1: Friends or foes at telomeres?

Telomere maintenance in cycling cells relies on both DNA replication and capping by the protein complex shelterin. Two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomere 1 (POT1) play critical roles in DNA replication and telomere capping, respectively. While RPA binds to ssDNA in a non-sequence-specific manner, POT1 specifically recognizes singlestranded TTAGGG telomeric repeats. Loss of POT1 leads to aberrant accumulation of RPA at telomeres and activation of the ataxia telangiectasia and Rad3-related kinase (ATR)-mediated checkpoint response, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. The requirement for both POT1 and RPA in telomere maintenance and the antagonism between the two proteins raises the important question of how they function in concert on telomeric ssDNA. Two interesting models were proposed by recent studies to explain the regulation of POT1 and RPA at telomeres. Here, we discuss how these models help unravel the coordination, and also the antagonism, between POT1 and RPA during the cell cycle.Key words: RPA, POT1, telomere, ATR, checkpointTelomeres, the natural ends of chromosomes, are composed of repetitive DNA sequences and “capped” by both specific proteins and non-coding RNAs.^1–3 One of the critical functions of telomeres is to prevent chromosomal ends from recognition by the DNA damage response machinery. Critically short or improperly capped telomeres lead to telomere dysfunction and are a major source of genomic instability.⁴ While telomeres need to be properly capped to remain stable, they also need to be duplicated during each cell division by the DNA replication machinery. The requirement of these two seemingly competing processes for telomere maintenance suggests that the cell must coordinate DNA replication and capping of telomeres to ensure faithful telomere duplication yet avoid an inappropriate DNA damage response.Telomeric DNA is unique in several ways. The bulk of each human telomere is comprised of double-stranded TTA GGG repeats. At the very end of each telomere, a stretch of single-stranded TTAGGG repeats exists as a 3′ overhang. The TTA GGG repeats in the telomeric single-stranded DNA (ssDNA) allow it to loop back and invade telomeric double-stranded DNA (dsDNA), forming a structure called the t-loop.⁵ At the base of the t-loop, the TTAGGG strand of the telomeric dsDNA is displaced by the invading single-stranded 3′ overhang to form a single-stranded D-loop. Thus, the unique DNA sequence and structures of telomeres confer the ability to bind proteins in both sequence- and structure-specific manners, providing the basis for additional regulations.In human cells, telomere capping is orchestrated by the protein complex shelterin, which contains TRF1, TRF2, RAP1, TIN2, TPP1 and POT1.³ Among these shelterin components, TRF1 and TRF2 interact with telomeric dsDNA in a sequence-specific manner, whereas POT1, in a complex with TPP1, binds to telomeric ssDNA in a sequence-specific manner.^6–8 While the human genome contains only one POT1 gene, the mouse genome contains two POT1-related genes, POT1a and POT1b.^9–11 TIN2 functions to stabilize TRF1 and TRF2 DNA binding and also tethers the POT1-TPP1 heterodimer to the rest of the shelterin complex on telomeric dsDNA.^12,13Unlike the properly capped telomeres, double-stranded DNA breaks (DSBs) with ssDNA overhangs are known to activate the ATR checkpoint kinase.^14,15 In a complex with its functional partner ATRIP, ATR is recruited to ssDNA by RPA, a non-sequence-specific ssDNA-binding protein complex.¹⁶ In addition to the ATR-ATRIP kinase complex, several other checkpoint proteins involved in ATR activation are also recruited in the presence of RPA-ssDNA.¹⁵ The structural resemblance between DSBs and telomeres and the presence of ssDNA at telomeres raise the important question as to how ATR activation is repressed at telomeres.     

Fibulins and cancer: friend or foe?

The fibulins are a family of secreted glycoproteins, which are characterised by repeated epidermal-growth-factor-like domains and a unique C-terminal structure. Six distinct fibulin genes, encoding at least nine protein products generated by alternative splicing, have been identified. Considerable evidence is available pointing towards a structural role for fibulins within the extracellular matrix. Fibulins have been shown to modulate cell morphology, growth, adhesion and motility. The dysregulation of certain fibulins occurs in a range of human disorders, including cancer. Indeed, both tumour suppressive and oncogenic activities have been proposed for members of the fibulin family. Herein, we discuss the possible roles of fibulins in cancer, in addition to their diagnostic and therapeutic potential.     

Case and configurationality: scrambling or mapping?

Kanum, a language of southern New Guinea, displays nonconfigurationality only for arguments marked with an overt structural case. After examining a variety of constraints on scrambling, in main and subordinate clauses, I argue that nonconfigurationality is a process of scrambling, rather than independent mapping from functional structure to constituency, and further is dependent on features associated with overt morphological case, and that alternative accounts in terms of grammatical function identity cannot be sustained.     

Endocytosis and Autophagy: Exploitation or Cooperation?

Autophagy is a lysosome-mediated degradative system that is a highly conserved pathway present in all eukaryotes. In all cells, double-membrane autophagosomes form and engulf cytoplasmic components, delivering them to the lysosome for degradation. Autophagy is essential for cell health and can be activated to function as a recycling pathway in the absence of nutrients or as a quality-control pathway to eliminate damaged organelles or even to eliminate invading pathogens. Autophagy was first identified as a pathway in mammalian cells using morphological techniques, but the Atg (autophagy-related) genes required for autophagy were identified in yeast genetic screens. Despite tremendous advances in elucidating the function of individual Atg proteins, our knowledge of how autophagosomes form and subsequently interact with the endosomal pathway has lagged behind. Recent progress toward understanding where and how both the endocytotic and autophagic pathways overlap is reviewed here.Autophagy is a lysosome-mediated pathway for the degradation of cytosolic proteins and organelles, which is essential for cell homeostasis, development, and for the prevention of several human diseases and infection (Choi et al. 2013). Importantly, autophagy cannot occur without an active lysosome. However, it is becoming increasingly recognized that the endosomal pathway plays a greater role than just providing the degradative enzymes found in the lysosome. Recent data suggest that in mammalian cells multiple contributions from several stages of the endocytic pathway are essential for efficient autophagy. Here we outline the autophagic pathway and then address the recent data on how different endosomal compartments contribute to autophagy, and the molecular machinery required for the interaction of the endosome and lysosome during the formation, and consumption of the autophagosome. Given the model emerging that the amino-acid-sensitive autophagic pathway originates from the endoplasmic reticulum (ER), several questions arise, including how do recognition and productive interaction occur between an ER-derived membrane and endosomes? How are these interactions mediated, and which are essential for efficient autophagy?     

Prions and chaperones: Friends or foes?

This review highlights the modern perception of anomalous folding of the prion protein and the role of chaperones therein. Special attention is paid to prion proteins from mammalian species, which are prone to amyloid-like prion diseases due to a unique aggregation pathway. Despite being a significantly popular current subject of investigations, the etiology, structure, and function of both normal and anomalous prion proteins still hold many mysteries. The most interesting of those are connected to the interaction with chaperone system, which is responsible for stabilizing protein structure and disrupting aggregates. In the case of prion proteins the following question is of the most importance — can chaperones influence different stages of the formation of pathological aggregates (these vary from intermediate oligomers to mature amyloid-like fibrils) and the whole transition from native prion protein to its amyloid-like fibril-enriched form? The existing inconsistencies and ambiguities in the observations made so far can be attributed to the fact that most of the investigations did not take into account the type and functional state of the chaperones. This review discusses in detail our previous works that have demonstrated fundamental differences between eukaryotic and prokaryotic chaperones in the action exerted on the amyloid-like transformation of the prion protein along with the dependence of the observed effects on the functional state of the chaperone.     

Homoplasy and homology: dichotomy or continuum?

Homology is the presence of the same feature in two organisms whose most recent common ancestor also possessed the feature. I discuss the bases on which we can tell that two features being compared share sufficient elements of sameness to allow them to be treated as homologous and therefore to be legitimately compared with one another in a way that informs comparative, evolutionary, and phylogenetic analysis. To do so, I discuss the relationship(s) between homology and homoplasy to conclude that we are dealing neither with a dichotomy between homoplasy as parallelism/convergence and homology as common descent nor with a dichotomy of homoplasy as the interrupted presence of the character in a lineage and homology as the continuous presence of the character. Rather, we are dealing with common descent with varying degrees of modification. Homoplasy and homology are not dichotomies but the extremes of a continuum, reflecting deep or more recent shared ancestry based on shared cellular mechanisms and processes and shared genes and gene pathways and networks. The same genes can be used to initiate the development of homoplastic and homologous structures. Consequently, structures may be lost but their developmental bases retained, providing the potential for homoplasy. It should not be surprising that similar features persist when a feature is present in the nearest common ancestor (homology). Neither should it be surprising to find that different environments or selective pressures can trigger the reappearance of similar features in organisms that do not share a recent common ancestor (homoplasy).     

Auxin and ethylene: collaborators or competitors?

The individual roles of auxin and ethylene in controlling the growth and development of young seedlings have been well studied. In recent years, these two hormones have been shown to act synergistically to control specific growth and developmental processes, such as root elongation and root hair formation, as well as antagonistically in other processes, such as lateral root formation and hypocotyl elongation. This review examines the growth and developmental processes that are regulated by crosstalk between these two hormones and explores the mechanistic basis for the regulation of these processes. The emerging trend from these experiments is that ethylene modulates auxin synthesis, transport, and signaling with unique targets and responses in a range of tissues to fine-tune seedling growth and development.     

Media and breastfeeding: Friend or foe?

This short essay examines infant formula marketing and information sources for their representation of "choice" in the infant feeding context, and finds that while providing information about breast and bottle feeding, infant formula manufacturers focus on mothers' feelings and intuition rather than knowledge in making decisions. In addition, the essay considers how "choice" operates in the history of reproductive rights, shifting the discourse from a rights-based set of arguments to one based on a consumerist mentality. Utilizing the work of historian Rickie Solinger and a 2007 paper for the National Bureau of Labor Statistics, I argue that the structure of market work, and not abstract maternal decision making, determine mothers' choices and practices concerning infant feeding. For true freedoms for mothers to be achieved, freedoms that would include greater social provisions for mothers, our culture will have to confront how structural constraints make breastfeeding difficult, as well as how the concept of choice divides mothers into those who make good choices and those who do not.