Green function of correlated genes in a minimal mechanical model of protein evolution

Dutta, Sandipan,Eckmann, Jean-Pierre,Libchaber, Albert,Tlusty, Tsvi National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.20

<▼1><P><B>Significance</B></P><P>Many protein functions involve large-scale motion of their amino acids, while alignment of their sequences shows long-range correlations. This has motivated search for physical links between genetic and phenotypic collective behaviors. The major challenge is the complex nature of protein: nonrandom heteropolymers made of 20 species of amino acids that fold into a strongly coupled network. In light of this complexity, simplified models are useful. Our model describes protein in terms of the Green function, which directly links the gene to force propagation and collective dynamics in the protein. This allows for derivation of basic determinants of evolution, such as fitness landscape and epistasis, which are often hard to calculate.</P></▼1><▼2><P>The function of proteins arises from cooperative interactions and rearrangements of their amino acids, which exhibit large-scale dynamical modes. Long-range correlations have also been revealed in protein sequences, and this has motivated the search for physical links between the observed genetic and dynamic cooperativity. We outline here a simplified theory of protein, which relates sequence correlations to physical interactions and to the emergence of mechanical function. Our protein is modeled as a strongly coupled amino acid network with interactions and motions that are captured by the mechanical propagator, the Green function. The propagator describes how the gene determines the connectivity of the amino acids and thereby, the transmission of forces. Mutations introduce localized perturbations to the propagator that scatter the force field. The emergence of function is manifested by a topological transition when a band of such perturbations divides the protein into subdomains. We find that epistasis—the interaction among mutations in the gene—is related to the nonlinearity of the Green function, which can be interpreted as a sum over multiple scattering paths. We apply this mechanical framework to simulations of protein evolution and observe long-range epistasis, which facilitates collective functional modes.</P></▼2>

Cholera Toxin and Cholera Toxin B Subunit Induce IgA Switching Through the Action of TGF-β1¹

Pyeung-Hyeun Kim,Lars Eckmann,Wha Jung Lee,Wonkyo Han,Martin F,Kagnoff 강원대학교 기초과학연구소 1998 기초과학연구 Vol.9 No.-

Cholera toxin (CT) and its B subunit (CTB) are potent immonogens and adjuvants that, either alone or linked to protein Ags, can stimulate mucosal immune responses, modulate the induction of oral tolerance, and stimulate IgA isotype switching. The present studies addressed the mechanisms by which CT and CTB promote IgA switching. CT and rCTB, in the presence of IL-2, significantly increased IgA isotype switching at the clonal level in populations of purified and LPS-activated murine surface IgA￣spleen B cells, as determined by ELISA, enzyme linked immunospot assays, and limiting dilution analysis. The IgA stimulatory effects of CT and CTB were independent of the a subunit of CT.CTB and CT dld not increase the secretory rate of IgA-producing cells or the clonal burst size of IgA clones. and did inhibit B cell growth. Because TGF-β1 also Inhibits B cell growth and promotes IgA switching, further studies tested whether the activity of CTB and CT on IgA isotype switching was mediated through TGF-β1. Anti-TGFβ Ab and soluble TGF-β1 type ILR inhibited CTB-and CT-stimulated IgA isotype switching. Furthermore increased TGF-β1 mRNA levels and bioactive TGF-β1, within a range shown to induce IgA isotype switching, were detected in cultures of surface IgA￣B cells stimulated with CT or CTB and IL-2. These data indicate that CTB-and CT-stimulated IgA isotype switching are mediated through TGF-β1. The finding that CTB up-regulates TGF-β1 activity has important implications for understanding the mechanisms by which CTB promotes both IgA mucosal immunity and oral tolerance.

Strong Light-Matter Interactions in Heterostructures of Atomically Thin Films

Britnell, L.,Ribeiro, R. M.,Eckmann, A.,Jalil, R.,Belle, B. D.,Mishchenko, A.,Kim, Y.-J.,Gorbachev, R. V.,Georgiou, T.,Morozov, S. V.,Grigorenko, A. N.,Geim, A. K.,Casiraghi, C.,Neto, A. H. Castro,Nov American Association for the Advancement of Scienc 2013 Science Vol.340 No.6138

<P><B>Atomic Layer Heterostructures—More Is More</B></P><P>The isolation of stable layers of various materials, only an atom or several atoms thick, has provided the opportunity to fabricate devices with novel functionality and to probe fundamental physics. <B>Britnell <I>et al.</I></B> (p. 1311, published online 2 May; see the Perspective by <B>Hamm and Hess</B>) sandwiched a single layer of the transition metal dichalcogenide WS<SUB>2</SUB> between two sheets of graphene. The photocurrent response of the heterostructure device was enhanced, compared to that of the bare layer of WS<SUB>2</SUB>. The prospect of combining single or several-atom-thick layers into heterostructures should help to develop materials with a wide range of properties.</P>

Antimicrobial Management of Complicated Skin and Soft Tissue Infections in an Era of Emerging Multi-Drug Resistance: Perspectives from 5 Gulf Countries

Wadha Alfouzan,Zainab Al-Balushi,Muna Al-Maslamani,Asmaa Al-Rashed,Salman Al-Sabah,Jameela Al-Salman,Mohamed Baguneid,Faryal Khamis,Nervana Habashy,Ayman Kurdi,Christian Eckmann 대한외상중환자외과학회 2021 Journal of Acute Care Surgery Vol.11 No.3

The number of complicated skin and soft tissue infections (cSSTIs) in the Arabian Gulf region has risen in recent years, particularly those caused by multi-drug resistant (MDR) pathogens. The high prevalence of diabetes, obesity, and associated cardio-metabolic comorbidities in the region renders medical and surgical management of cSSTI patients with MDR infections challenging. An experienced panel of international and regional cSSTI experts (consensus group on cSSTIs) was convened to discuss clinical considerations for MDR infections from societal, antimicrobial stewardship, and cost perspectives, to develop best practice recommendations. This article discusses antibiotic therapies suitable for treating MDR cSSTIs in patients from the Gulf region and recommends that these should be tailored according to the local bacterial ecology by country and region. The article highlights the need for a comprehensive patient treatment pathway and defined roles of each of the multidisciplinary teams involved with managing patients with MDR cSSTIs. Aligned and inclusive definitions of cSSTIs for clinical and research purposes, thorough and updated epidemiological data on cSSTIs and methicillin-resistant Staphylococcus aureus in the region, clearcut indications of novel agents and comprehensive assessment of comparative data should be factored into decision-making are necessary. The number of complicated skin and soft tissue infections (cSSTIs) in the Arabian Gulf region has risen in recent years, particularly those caused by multi-drug resistant (MDR) pathogens. The high prevalence of diabetes, obesity, and associated cardio-metabolic comorbidities in the region renders medical and surgical management of cSSTI patients with MDR infections challenging. An experienced panel of international and regional cSSTI experts (consensus group on cSSTIs) was convened to discuss clinical considerations for MDR infections from societal, antimicrobial stewardship, and cost perspectives, to develop best practice recommendations. This article discusses antibiotic therapies suitable for treating MDR cSSTIs in patients from the Gulf region and recommends that these should be tailored according to the local bacterial ecology by country and region. The article highlights the need for a comprehensive patient treatment pathway and defined roles of each of the multidisciplinary teams involved with managing patients with MDR cSSTIs. Aligned and inclusive definitions of cSSTIs for clinical and research purposes, thorough and updated epidemiological data on cSSTIs and methicillin-resistant Staphylococcus aureus in the region, clear-cut indications of novel agents and comprehensive assessment of comparative data should be factored into decision-making are necessary.