Homologous Type Research Articles

Rational orthogonal calculus

We show that one can use model categories to construct rational orthogonal calculus. That is, given a continuous functor from vector spaces to based spaces one can construct a tower of approximations to this functor depending only on the rational homology type of the input functor, whose layers are given by rational spectra with an action of O(n). By work of Greenlees and Shipley, we see that these layers are classified by torsion {{mathrm{H}}}^*({{mathrm{B}}}SO(n))[O(n)/SO(n)]-modules.

Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity

TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC50s in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.

SATB2 Expression Is Sensitive but Not Specific for Osteosarcomatous Components of Gynecologic Tract Carcinosarcomas: A Clinicopathologic Study of 60 Cases.

The novel marker special AT-rich sequence binding protein (SATB2) is highly sensitive for mesenchymal tumors with osteoblastic differentiation. However, SATB2 expression in gynecologic tract carcinosarcoma has not been previously explored. Given the potential prognostic and therapeutic implications of heterologous carcinosarcoma in the gynecologic tract, this study investigates the utility of SATB2 in identifying osteosarcomatous elements. A multi-institution database review identified consecutive cases of gynecologic tract carcinosarcoma including both heterologous and homologous types. Clinicopathologic parameters were recorded. Nuclear SATB2 immunoreactivity was scored from 1 representative whole-slide section from each case. Sixty gynecologic tract carcinosarcoma were identified (uterine corpus=47, ovary=11, fallopian tube=1, cervix=1) including 32 heterologous type (7 osteosarcoma, 3 mixed osteosarcoma/chondrosarcoma, 6 chondrosarcoma, 12 rhabdomyosarcoma, 4 mixed chondrosarcoma/rhabdomyosarcoma) and 28 homologous type. Patient ages ranged from 41 to 90 yr (average 67.9 yr). Mostly diffuse strong SATB2 positivity was present in 10/10 (100%) cases containing osteosarcoma. In these cases, SATB2 positivity was seen in malignant cells intimately associated with osteoid or bone [3/10 (30%) of these cases additionally showed patchy weak/moderate SATB2 staining in areas of nonosteogenic sarcoma elsewhere in the same tumor]. SATB2 positivity was present in 30/50 (60%) cases lacking osteosarcoma, predominantly as patchy moderate staining within undifferentiated sarcoma. No cases showed SATB2 positivity in chondrosarcoma or rhabdomyosarcoma components. SATB2 is a highly sensitive marker for osteosarcomatous differentiation in gynecologic tract carcinosarcoma, and is also highly specific when used to differentiate osteosarcoma from chondrosarcoma and rhabdomyosarcoma elements in these tumors. However, a positive SATB2 result may lack specificity for differentiating osteosarcoma from an undifferentiated sarcoma component.

Interaction of Type IV Toxin/Antitoxin Systems in Cryptic Prophages of Escherichia coli K-12.

Toxin/antitoxin (TA) systems are widespread in prokaryotic chromosomes and in mobile genetic elements including plasmids and prophages. The first characterized Type IV TA system CbtA/CbeA was found in cryptic prophage CP4-44 in Escherichia coli K-12. Two homologous TA loci of CbtA/CbeA also reside in cryptic prophages of E. coli K-12, YkfI/YafW in CP4-6 and YpjF/YfjZ in CP4-57. In this study, we demonstrated that YkfI and YpjF inhibited cell growth and led to the formation of “lemon-shaped” cells. Prolonged overproduction of YkfI led to the formation of “gourd-shaped” cells and immediate cell lysis. YafW and YfjZ can neutralize the toxicity of YkfI or YpjF. Furthermore, we found that YkfI and YpjF interacted with cell division protein FtsZ in E. coli, but ectopic expression in Pseudomonas and Shewanella did not cause the formation of “lemon-shaped” cells. Moreover, deletion of all of the three toxin genes together decreased resistance to oxidative stress and deletion of the antitoxin genes increased early biofilm formation. Collectively, these results demonstrated that the homologous Type IV TA systems in E. coli may target cell division protein FtsZ in E. coli and may have different physiological functions in E. coli.

Convergent evolution of the adaptive immune response in jawed vertebrates and cyclostomes: An evolutionary biology approach based study

Two different adaptive immune systems (AIS) are present in the two phyla of vertebrates (jawed vertebrates and cyclostomes). The jawed vertebrate system is based on IG/TCR/RAG/MHC while the cyclostome system is based on VLRCs and AID-like enzymes both systems using homologous Cell types (B-cell and B-cell Like, T-cell and T-cell like).We will present our current view of the evolution of these two AISs and present alternative hypotheses that could explain the apparent convergent evolution of the two systems. We will also discuss why comparative immunology analyses should be based on evolutionary biology approaches and not on the scale of progress one.

Homological and homotopical finiteness properties of the group $${\mathcal {E}}(G)$$ E ( G )

For a group G and an isomorphism of groups \(\psi : G \rightarrow G^{\psi }\) we study homological and homotopical properties of the group $$\begin{aligned} {\mathcal {E}} (G) = \langle G, G^{\psi } \mid [{\mathcal {D}},{\mathcal {L}}] = 1 \rangle , \end{aligned}$$ where \({\mathcal {D}} = [G, G^{\psi }]\) and \({\mathcal {L}} = [G, \psi ]\). For \(k \ge 2\) we show that \({\mathcal {E}}(G)\) has homotopical type \(F_k\) (resp. homological type \(FP_k\)) if and only if \(G{/}G'\) is finite and G has homotopical type \(F_k\) (resp. homological type \(FP_k\)). In particular \({\mathcal {E}}(G)\) is finitely presented if and only if \(G{/}G'\) is finite and G is finitely presented.

Stability of tocopherol homologs in soybean, corn, canola, and olive oils under different moisture contents at 25°C

The stability of tocopherol homologs and oxidative stability were determined in edible oils including soybean, corn, canola, and olive oils under different relative humidities (RH), ranging from 0 to 93%, at 25°C for 8 months. The degree of oxidation was determined by conjugated dienoic acid (CDA) and p‐anisidine values (p‐AV), and any remaining tocopherols were also analyzed. The stability of tocopherols was significantly influenced by the presence of both moisture and other tocopherol homologs. Soybean and corn oils under low moisture conditions had significant remaining tocopherol levels, whereas canola and olive oils had different stabilities of tocopherols. The presence of δ‐tocopherol, which is found in soybean and corn oils, seems to play an important role in the stability of α‐ and γ‐tocopherols in vegetable oils stored at 25°C. The moisture content of the tested oils was different even when oils were stored at the same RH.Practical application: Many lipid‐rich foods contain tocopherol homologs to extend the shelf – life of the products. The stability of tocopherol homologs was significantly influenced by the presence of moisture, the types of oils, and the concentration of tocopherol homologs. Using the knowledge obtained in this study, shelf‐life of real foods containing oils can be enhanced by modifying the moisture content and concentration and types of tocol homologs.(i) Soybean and corn oils under low moisture conditions had significant remaining tocopherol levels, whereas canola and olive oils had different stabilities of tocopherols; (ii) the presence of δ‐tocopherol, which is found in soybean and corn oils, played an important role in the stability of α‐ and γ‐tocopherols in vegetable oils stored at 25°C; and (iii) the moisture content of the tested oils was different even when oils were stored at the same RH.

Transmission of a heterologous clade C Symbiodinium in a model anemone infection system via asexual reproduction.

Anemones of genus Exaiptasia are used as model organisms for the study of cnidarian-dinoflagellate (genus Symbiodinium) endosymbiosis. However, while most reef-building corals harbor Symbiodinium of clade C, Exaiptasia spp. anemones mainly harbor clade B Symbiodinium (ITS2 type B1) populations. In this study, we reveal for the first time that bleached Exaiptasia pallida anemones can establish a symbiotic relationship with a clade C Symbiodinium (ITS2 type C1). We further found that anemones can transmit the exogenously supplied clade C Symbiodinium cells to their offspring by asexual reproduction (pedal laceration). In order to corroborate the establishment of stable symbiosis, we used microscopic techniques and genetic analyses to examine several generations of anemones, and the results of these endeavors confirmed the sustainability of the system. These findings provide a framework for understanding the differences in infection dynamics between homologous and heterologous dinoflagellate types using a model anemone infection system.

Directed Homology Theories and Eilenberg-Steenrod Axioms

In this paper, we define and study a homology theory, that we call “natural homology”, which associates a natural system of abelian groups to every space in a large class of directed spaces and precubical sets. We show that this homology theory enjoys many important properties, as an invariant for directed homotopy. Among its properties, we show that subdivided precubical sets have the same homology type as the original ones ; similarly, the natural homology of a precubical set is of the same type as the natural homology of its geometric realization. By same type we mean equivalent up to some form of bisimulation, that we define using the notion of open map. Last but not least, natural homology, for the class of spaces we consider, exhibits very important properties such as Hurewicz theorems, and most of Eilenberg-Steenrod axioms, in particular the dimension, homotopy, additivity and exactness axioms. This last axiom is studied in a general framework of (generalized) exact sequences.

Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation.

The Linear Ubiquitin chain Assembly Complex (LUBAC) is a multimeric E3 ligase that catalyzes M1- or linear ubiquitination of activated immune receptor signaling complexes (RSCs). While mutations that disrupt linear ubiquitin assembly lead to complex disease pathologies including immunodeficiency and autoinflammation in both humans and mice, microbial toxins that target LUBAC function have not yet been discovered. Here, we report the identification of two homologous Shigella flexneri Type III Secretion System (T3SS) effector E3 ligases IpaH1.4 and IpaH2.5 that directly interact with LUBAC subunit HOIL-1L (RBCK1) and conjugate K48-linked ubiquitin chains to the catalytic RING-between-RING domain of HOIP (RNF31). Proteasomal degradation of HOIP leads to irreversible inactivation of linear ubiquitination and blunting of NF-κB nuclear translocation in response to TNF, IL-1β, and pathogen associated molecular patterns (PAMPs). Loss of function studies in mammalian cells in combination with bacterial genetics explains how Shigella evades a broad spectrum of immune surveillance systems by cooperative inhibition of receptor ubiquitination, and reveals the critical importance of LUBAC in host defense against pathogens.

Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing.

Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications. This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols. Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing. This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology.Genet Med 18 12, 1282-1289.

Collagens XV and XVIII show different expression and localisation in cutaneous squamous cell carcinoma: type XV appears in tumor stroma, while XVIII becomes upregulated in tumor cells and lost from microvessels.

As the second most common skin malignancy, cutaneous squamous cell carcinoma (cSCC) is an increasing health concern, while its pathogenesis at molecular level remains largely unknown. We studied the expression and localisation of two homologous basement membrane (BM) collagens, types XV and XVIII, at different stages of cSCC. These collagens are involved in angiogenesis and tumorigenesis, but their role in cancer development is incompletely understood. Quantitative RT-PCR analysis revealed upregulation of collagen XVIII, but not collagen XV, in primary cSCC cells in comparison with normal human epidermal keratinocytes. In addition, the Ha-ras-transformed invasive cell line II-4 expressed high levels of collagen XVIII mRNA, indicating upregulation in the course of malignant transformation. Immunohistochemical analyses of a large human tissue microarray material showed that collagen XVIII is expressed by tumor cells from grade 1 onwards, while keratinocytes in normal skin and in premalignant lesions showed negative staining for it. Collagen XV appeared instead as deposits in the tumor stroma. Our findings in human cSCCs and in mouse cSCCs from the DMBA-TPA skin carcinogenesis model showed that collagen XVIII, but not collagen XV or the BM markers collagen IV or laminin, was selectively reduced in the tumor vasculature, and this decrease associated significantly with cancer progression. Our results demonstrate that collagens XV and XVIII are expressed in different sites of cSCC and may contribute in a distinct manner to processes related to cSCC tumorigenesis, identifying these collagens as potential biomarkers in the disease.

Mathematical transformations of recurrent relations for different types of homologues

Most of discrete properties A of individual organic compounds belonging to single‐row homologous series (RX → RCH2X → … → R(CH2)nX) or multi‐row series (RkY → [RCH2]kY → … [R(CH2)n]kY, k > 1) can be approximated with first order linear recurrent relations A(n + 1) = aA(n) + b. The important chemical property of recurrences is the equality of coefficients a and b for various homologous series of similar topology (with the same homologous differences at the constancy of the number of rows). The values of coefficients a and b for single‐ and multi‐rows series even with the same structural fragments X = Y are different.The algorithm of the mutual recalculating of the coefficients of recurrent relations for single‐ and multi‐rows homologous series is proposed and considered. It allows evaluating different physicochemical properties of insufficiently characterized unsymmetrical organic compounds with different alkyl substituents, like C2H5NHC3H7, (CH3)2B(C2H5), (CF3)N(C2F5)2, etc., using the data for better characterized “symmetrical” homologues (illustrated by examples). Copyright © 2016 John Wiley & Sons, Ltd.

Crystal structures of the components of the Staphylococcus aureus leukotoxin ED.

Staphylococcal leukotoxins are a family of β-barrel, bicomponent, pore-forming toxins with membrane-damaging functions. These bacterial exotoxins share sequence and structural homology and target several host-cell types. Leukotoxin ED (LukED) is one of these bicomponent pore-forming toxins that Staphylococcus aureus produces in order to suppress the ability of the host to contain the infection. The recent delineation of the important role that LukED plays in S. aureus pathogenesis and the identification of its protein receptors, combined with its presence in S. aureus methicillin-resistant epidemic strains, establish this leukocidin as a possible target for the development of novel therapeutics. Here, the crystal structures of the water-soluble LukE and LukD components of LukED have been determined. The two structures illustrate the tertiary-structural variability with respect to the other leukotoxins while retaining the conservation of the residues involved in the interaction of the protomers in the bipartite leukotoxin in the pore complex.

Structural basis for suppression of hypernegative DNA supercoiling by E. coli topoisomerase I.

Escherichia coli topoisomerase I has an essential function in preventing hypernegative supercoiling of DNA. A full length structure of E. coli topoisomerase I reported here shows how the C-terminal domains bind single-stranded DNA (ssDNA) to recognize the accumulation of negative supercoils in duplex DNA. These C-terminal domains of E. coli topoisomerase I are known to interact with RNA polymerase, and two flexible linkers within the C-terminal domains may assist in the movement of the ssDNA for the rapid removal of transcription driven negative supercoils. The structure has also unveiled for the first time how the 4-Cys zinc ribbon domain and zinc ribbon-like domain bind ssDNA with primarily π-stacking interactions. This novel structure, in combination with new biochemical data, provides important insights into the mechanism of genome regulation by type IA topoisomerases that is essential for life, as well as the structures of homologous type IA TOP3α and TOP3β from higher eukaryotes that also have multiple 4-Cys zinc ribbon domains required for their physiological functions.

Uterine and Ovary Carcinosarcomas

The aim of this study was to assess the outcome and the prognosis factors of uterine and ovarian carcinosarcomas. From January 1993 to January 2010, data from 68 consecutively treated patients with uterine (n=59) and ovarian (n=9) carcinosarcomas were retrospectively analyzed in a single French comprehensive cancer center. The median follow-up was 24.2 months (interquartile range [IQR]: 13.5 to 54.6). The median age was 69 years (IQR: 63 to 77). Patients were classified as FIGO stage I (n=28; 41%) and FIGO stage II to IV (n=40; 59%), respectively. There were 33 (49%) and 29 (43%) homologous and heterologous type, respectively. The median disease-free survival and overall survival were 21.9 months (IQR: 7.9 to 22.3) and 27.1 months (IQR: 14.5 to 72), respectively. No statistical differences of survival were reported concerning the initial location of the carcinosarcoma (uterine vs. ovarian). Radiation therapy (hazards ratio [HR]=0.3; 95% confidence interval [CI], 0.16-0.67) and FIGO stage I (HR=0.4; 95% CI, 0.17-0.9) were associated with an increased disease-free survival. Homologous type (HR=3; 95% CI, 1.4-6.3) and FIGO stage II to IV (HR=2.64; 95% CI, 1.3-5.4) were associated with a decreased overall survival. There was no survival improvement for the 12% of patients receiving a multimodal adjuvant therapy. Uterine and ovary carcinosarcomas present a worse prognosis. On the basis of the present study data, although it should be prospectively confirmed, a sequential or multimodal adjuvant therapy should be proposed to patients with early-stage uterine and ovary carcinosarcomas.

AMA1-deficient Toxoplasma gondii parasites transiently colonize mice and trigger an innate immune response that leads to long-lasting protective immunity.

The apical membrane antigen 1 (AMA1) protein was believed to be essential for the perpetuation of two Apicomplexa parasite genera, Plasmodium and Toxoplasma, until we genetically engineered viable parasites lacking AMA1. The reduction in invasiveness of the Toxoplasma gondii RH-AMA1 knockout (RH-AMA1(KO)) tachyzoite population, in vitro, raised key questions about the outcome associated with these tachyzoites once inoculated in the peritoneal cavity of mice. In this study, we used AMNIS technology to simultaneously quantify and image the parasitic process driven by AMA1(KO) tachyzoites. We report their ability to colonize and multiply in mesothelial cells and in both resident and recruited leukocytes. While the RH-AMA1(KO) population amplification is rapidly lethal in immunocompromised mice, it is controlled in immunocompetent hosts, where immune cells in combination sense parasites and secrete proinflammatory cytokines. This innate response further leads to a long-lasting status immunoprotective against a secondary challenge by high inocula of the homologous type I or a distinct type II T. gondii genotypes. While AMA1 is definitively not an essential protein for tachyzoite entry and multiplication in host cells, it clearly assists the expansion of parasite population in vivo.

Broad thorny ganglion cells: a candidate for visual pursuit error signaling in the primate retina.

Functional analyses exist only for a few of the morphologically described primate ganglion cell types, and their correlates in other mammalian species remain elusive. Here, we recorded light responses of broad thorny cells in the whole-mounted macaque retina. They showed ON-OFF-center light responses that were strongly suppressed by stimulation of the receptive field surround. Spike responses were delayed compared with parasol ganglion cells and other ON-OFF cells, including recursive bistratified ganglion cells and A1 amacrine cells. The receptive field structure was shaped by direct excitatory synaptic input and strong presynaptic and postsynaptic inhibition in both ON and OFF pathways. The cells responded strongly to dark or bright stimuli moving either in or out of the receptive field, independent of the direction of motion. However, they did not show a maintained spike response either to a uniform background or to a drifting plaid pattern. These properties could be ideally suited for guiding movements involved in visual pursuit. The functional characteristics reported here permit the first direct cross-species comparison of putative homologous ganglion cell types. Based on morphological similarities, broad thorny ganglion cells have been proposed to be homologs of rabbit local edge detector ganglion cells, but we now show that the two cells have quite distinct physiological properties. Thus, our data argue against broad thorny cells as the homologs of local edge detector cells.

Interleukin-6-driven inflammatory response induces retinal pathology in a model of ocular toxoplasmosis reactivation.

Ocular inflammation is one of the consequences of infection with the protozoan parasite Toxoplasma gondii. Even if lesions are self-healing in immunocompetent persons, they pose a lifetime risk of reactivation and are a serious threat to vision. As there are virtually no immunological data on reactivating ocular toxoplasmosis, we established a model of direct intravitreal injection of parasites in previously infected mice with a homologous type II strain. Two different mouse strains with variable ability to control retinal infection were studied in order to describe protective and deleterious reaction patterns. In Swiss-Webster mice, which are already relatively resistant to primary infection, no peak of parasite load was observed upon reinfection. In contrast, the susceptible inbred strain C57BL/6 showed high parasite loads after 7 days, as well as marked deterioration of retinal architecture. Both parameters were back to normal on day 21. C57BL/6 mice also reacted with a strong local production of inflammatory and Th1-type cytokines, like interleukin-6 (IL-6), IL-17A, and gamma interferon (IFN-γ), while Swiss-Webster mice showed only moderate expression of the Th2 cytokine IL-31. Interestingly, rapid intraocular production of anti-Toxoplasma antibodies was observed in Swiss-Webster but not in C57BL/6 mice. We then localized the cellular source of different immune mediators within the retina by immunofluorescence. Finally, neutralization experiments of IFN-γ or IL-6 demonstrated the respective protective and deleterious roles of these cytokines for parasite control and retinal integrity during reinfection. In conclusion, we developed and immunologically characterized a promising mouse model of reactivating ocular toxoplasmosis.

Symbiodinium identity alters the temperature-dependent settlement behaviour of Acropora millepora coral larvae before the onset of symbiosis.

The global distribution of marine species, many of which disperse during the larval stages, is influenced by ocean temperature regimes. Here, we test how temperature and the coral symbionts (Symbiodinium) affect survival, symbiont uptake, settlement success and habitat choice of Acropora millepora larvae. Experiments were conducted at Heron Island (Australia), where larvae were exposed to 22.5, 24.5, 26.5 and 28.5°C. Within each temperature treatment, larvae were offered symbionts with distinct characteristics: (i) homologous Symbiodinium type C3, (ii) regionally homologous thermo-tolerant type D1, and (iii) heterologous thermo-tolerant type C15, as well as controls of (iv) un-filtered and (v) filtered seawater. Results show that lower instead of higher temperatures adversely affected recruitment by reducing larval survival and settlement. Low temperatures also reduced recruit habitat choice and initial symbiont densities, both of which impact on post-settlement survival. At lower temperatures, larvae increasingly settle away from preferred vertical surfaces and not on crustose coralline algae (CCA). Surprisingly, substrate preference to CCA was modified by the presence of specific symbiont genotypes that were present ex-hospite (outside the coral larvae). When different symbionts were mixed, the outcomes were non-additive, indicating that symbiont interactions modify the response. We propose that the observed influence of ex-hospite symbionts on settlement behaviour may have evolved through ecological facilitation and the study highlights the importance of biological processes during coral settlement.